case study about rheumatoid arthritis

• Case report
• Open access
• Published: 19 November 2020

Case report: a man with untreated rheumatoid arthritis, cryoglobulinemic vasculitis, membranous nephropathy and pulmonary sarcoidosis

• Qiyu Wang   ORCID: orcid.org/0000-0003-4959-7437 1 ,
• Juan P. Ruiz 2 &
• Peter D. Hart 2  

BMC Nephrology volume  21 , Article number:  496 ( 2020 ) Cite this article

3233 Accesses

3 Citations

Metrics details

Glomerular involvement in rheumatoid arthritis has been known to be associated with treatment side effects from medications and secondary amyloidosis. However, limited basic science and clinical studies have been performed to address the potential disease specific immune-mediated mechanisms causing secondary glomerular pathology, its various types of presentation, and the potential treatments.

Case presentation

A 41-year-old man with chronic active rheumatoid arthritis presented with nephrotic syndrome and was found to have membranous nephropathy with eosinophilic intracapillary thrombi on renal biopsy. Proteinuria persisted despite complete withdrawal from non-steroidal anti-inflammatory drugs (NSAIDs) and disease-modifying anti-rheumatic drugs (DMARDs). Throughout the disease course, he developed cryoglobulinemic vasculitis and pulmonary sarcoidosis, both of which achieved clinical resolution with glucocorticoids. However, only partial improvement was observed in proteinuria with treatment of steroids and Rituximab.

Our case presented a unique and complicated clinical phenotype of active rheumatoid arthritis, with clinical features of cryoglobulinemic vasculitis, histopathologic features of membranous and cryoglobulinemic nephropathy in the absence of DMARDs use, as well as pulmonary sarcoidosis. We speculate that there is a wider spectrum of glomerular disease in patients with untreated rheumatoid arthritis. In addition, the potential association between rheumatoid arthritis and cryoglobulinemic vasculitis should probably be revisited and requires further studies to elucidate the underlying mechanisms and treatment options.

Peer Review reports

Rheumatoid arthritis (RA) is a chronic inflammatory condition that primarily affects the joints, with multi-system involvement including skin, heart and lungs. Renal manifestations, however, appear to be much less prevalent in the pre-existing literature. In the pre-methotrexate era, secondary amyloidosis was reported to be a major cause of chronic kidney disease (CKD) in patients with RA who had a prolonged disease course and high inflammatory markers. Long-term use of the nonsteroidal anti-inflammatory drug (NSAIDs) and traditional disease-modifying anti-rheumatic drugs (DMARDs) including penicillamine and gold are known to be responsible for most types of glomerular disease in patients with RA [ 1 ]. Other than glomerulonephritis secondary to chronic medication use, glomerular pathology has rarely been reported to be from a direct immune-mediated mechanism in patients with RA.

A 41-year-old Hispanic man with history of rheumatoid arthritis (RA) and type2 diabetes mellitus was referred to the emergency room (ER) of a large urban city hospital from the rheumatology clinic for newly developed bilateral lower extremity rashes and edema after 1 year of being lost to follow-up. He was diagnosed with RA 2 years prior to admission after presenting with polyarthritis and strongly positive serum immunologic markers (rheumatoid factor titer 1220 IU/ml [normal range, < 20 IU/ml], anti-cyclic citrullinated peptide titer 240.05 U/ml [normal range, < 20 U/ml; strongly positive, > 60 U/ml]). Methotrexate, low dose prednisone and sulfasalazine had resulted in better control of disease activity. Unfortunately, the patient was lost to follow-up. He had been off of disease-modifying antirheumatic drugs (DMARDs) for RA and was only taking ibuprofen 800 mg every 8 h as needed for about a month for joint pain.

When the patient was seen in the ER (day 0), the physical exam showed pinpoint, non-tender, non-blanchable purpuric macules coalescing into large patches on the left leg, with smaller areas of involvement on the right leg. The skin lesions were in a dependent distribution involving more of the flexor surface than extensor surface. Joint exam revealed polyarticular arthritis with pain and swelling in the right 2nd and 3rd metacarpophalangeal (MCP) joints and left 3rd (MCP). Boutonniere deformities were observed in both hands (left more than right), as well as subcutaneous nodules under the elbow. Significant pitting edema was found in the lower extremities. The rest of the physical exam was unremarkable.

His urinalysis showed red blood cell of 21/high power field (hpf) and white blood cell 7/hpf. His creatinine was 0.9 mg/dl, with estimated GFR of 93 ml/min using MDRD equation. The diagnosis of nephrotic syndrome was established given large proteinuria (11 g/gm) on the spot urine sample, hypoalbuminemia (2.2 g/dL), and peripheral edema.

Further serology work-up showed low C3 of 86 (normal range 88–201), C4 of 24 (normal range 16–47), positive cryoglobulin qualitative with < 1% Cryocrit, as well as negative c-ANCA, p-ANCA, and ANA (including Anti-dsDNA, Anti-Smith, Anti-SSA and Anti-SSB). He had a polyclonal elevation in IgG (1790 mg/dl, normal range 694-1618 mg/dl) and IgA (661 mg/dl, normal range 68-378 mg/dl), with a normal IgM (181 mg/dl, normal range 77-220 mg/dl). There was absence of M-spike on serum protein electrophoresis. HIV, Hepatitis C and hepatitis B serologies were negative. Unfortunately, rheumatoid factor (RF) titer was not checked at that point of time. Prednisone was started at 10 mg daily empirically for treatment of nephrotic syndrome and active RA, and patient was referred to renal clinic for further diagnosis and monitoring of therapy.

Three days after being discharged (Day 5) and prior to being seen in the renal clinic, the patient developed painful purplish discoloration of the distal right thumb, which prompted another ER visit (Day 12). On exam, the distal phalanx was cool to touch and exquisitely tender on palpation with signs of onycholysis. There was no sign of cutaneous necrosis or surrounding cellulitis. Doppler ultrasound showed good radial and ulnar pulses with good blood flow to the distal phalanx of the right thumb. He was discharged from the ER since no macrovascular signs were found, and he was given follow up with rheumatology. On Day 16, rheumatology noticed new lower lip purpuric lesions, which, in conjunction to the positive cryoglobulin qualitative test along with the thumb and lower leg lesions, prompted an increase in Prednisone dose to 80 mg daily for treatment of systemic cryoglobulinemic vasculitis. Unfortunately, his skin lesions were not biopsied.

Renal biopsy was performed on day 28. A total of 23 glomeruli were obtained, of which 1 was sclerosed. Light microscopy showed diffuse capillary wall thickening (Fig.  1 ) with rare eosinophilic intracapillary thrombi (Figs.  2 , 3 ). Silver stain showed spikes and holes in the glomerular basement membrane. Immunofluorescence (IF) staining showed diffuse, finely granular deposits of IgG (Fig.  4 ), IgA, IgM, κ and γ light chains, C1q and C3. Anti-phospholipase A2 receptor (PLA2R) stain was negative. Electron microscopy (EM) showed widespread subepithelial and intramembranous electron-dense deposits, with diffuse foot process effacement (Fig.  5 ). Subendothelial or mesangial tubuloreticular inclusions suggestive of lupus nephritis were not found. The final pathologic diagnosis was compatible with membranous nephropathy with features of cryoglobulinemic glomerulonephritis. There were no signs of diabetic nephropathy on light microscopy.

H&E, diffuse capillary wall thickening

H&E, intracapillary thrombi (arrows)

Trichrome stain, intracapillary thrombi, bright red (arrow)

Immunofluorescence, diffuse granular staining for IgG

Electron microscopy, subepithelial deposits

Given the multisystem involvement (purpuric, non-blanching lesions in multiple skin and mucosal surfaces), characteristic pathological features (intracapillary thrombi) on renal biopsy and positive cryoglobulin qualitative test, a decision was made to start treatment empirically as systemic cryoglobulinemic vasculitis with Rituximab, considering that this is the first line treatment for hepatitis C-related cryoglobulinemic disease and evidence is limited for treatment of renal involvement in non-infectious mixed cryoglobulinemia. Unfortunately, treatment was delayed due to indeterminate Quantiferon and PPD tests.

One and a half months after starting high dose steroids (day 62), his right thumb and lower lip lesions had resolved, and his urine protein/creatinine ratio had decreased to 3.4 g/g.

Patient was started on Rituximab 1 g every 2 weeks and received 2 doses on day 67 and day 88, resulting in improvement of his proteinuria to 1.3 g/g (day 88). By this time, patient was on Prednisone 40 mg daily. Due to the persistently elevated blood sugar and Cushingoid features, a taper of the steroids occurred over the following 2 months.

Two months after he completed rituximab, the patient was admitted for presumed pneumonia (day 158) secondary to immunosuppression after presenting with 2-week history of dyspnea and cough. He underwent a CT scan of the chest with contrast, which showed hilar and mediastinal adenopathy without parenchymal consolidations. He underwent bronchoscopy with endobronchial ultrasound (EBUS), and the transbronchial lymph node biopsy of the mediastinal lymph node showed non-caseating granulomas. Acid fast stain and mycobacterium culture were negative. To rule out a lymphoproliferative disorder as a differential of non-caseating granulomas, PET scan, bone marrow biopsy and flow cytometry were performed, and they were negative for clonal lymphocytic proliferation. A clinical diagnosis of sarcoidosis was made, and his Prednisone dose was increased to 40 mg daily (patient was on a steroid taper and taking Prednisone 20 mg daily prior to this admission), resulting in rapid pulmonary symptoms improvement. No extrapulmonary signs of sarcoidosis developed in the course of his illness (e.g. erythema nodosum).

Six months after his first course of Rituximab, his proteinuria had increased back to 7 g/gm (day 291), so a decision to repeat Rituximab course was made. Unfortunately, this was again delayed due to patient’s personal issues, and he started it 2 months later. This time he received weekly Rituximab 750 mg for a total of 4 doses. Patient again manifested a dramatic initial response to the treatment with reduction of proteinuria to 1.1 g/g (day 371), but with a slow increase in his urine protein to creatinine ratio over the following 3 months, to an average of 3.8 g/g, compatible with an overall partial response if compared with his initial proteinuria of 11 g/g on presentation (Fig. 6 ). His Creatinine level has remained stable between 0.8 ~ 1.1 mg/dl during the period of one and half year follow-up. His skin lesions and articular manifestations have completely resolved since the initiation of high dose steroids on day 62. Repeat Cryoprecipitate levels has been persistently positive. A timeline of the disease course is summarized in Fig. 7 .

Horizontal line—days from the time of diagnosis; Vertical axis (left)—spot urine protein to creatinine ratio; Vertical axis (right)—prednisone dose; black arrows: first course of Rituximab treatment (day67 1000 mg, day 88 1000 mg) and second course of Rituximab treatment (day308 750 mg, day318 750 mg, day 325 750 mg, day 332 750 mg), respectively

Timeline of clinical manifestation and diagnosis

Discussion and conclusions

We present a complicated case of membranous nephropathy, systemic cryoglobulinemic vasculitis with renal involvement, and pulmonary sarcoidosis in a patient with underlying chronic active rheumatoid arthritis. The patient experienced complete resolution of the cutaneous findings and pulmonary symptoms with high dose steroids, with partial improvement of the proteinuria after 2 courses of Rituximab therapy. We will discuss the diagnostic challenge of this case and the association of RA with this patient’s renal, cutaneous and pulmonary findings.

Renal involvement in rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory condition that primarily affects the joints, with multi-system involvement including skin, heart and lung. Renal manifestations, however, appear to be much less prevalent. In the pre-methotrexate era, secondary amyloidosis was reported to be a major cause of chronic kidney disease (CKD) in patients with RA who had a prolonged disease course (mean duration from the time of diagnosis 17.2 ± 7.3 years) and high inflammatory markers [ 2 ]. However, in recent years when DMARDs have been widely used, studies have suggested a weaker than previously thought association of RA disease duration and severity with the development of CKD. For example, one cross-sectional study performed in Japanese population showed that the strongest risk factors for CKD (defined by eGFR< 60 ml/hr) in patients with rheumatoid arthritis were hypertension and advanced age (> = 65-year-old), whereas the duration and disease activity of rheumatoid arthritis had a weaker association with the presence of CKD [ 3 ].

Long-term use of nonsteroidal anti-inflammatory drug (NSAIDs) and traditional disease-modifying anti-rheumatic drugs (DMARDs) including Penicillamine and gold are known to be the cause of most types of glomerular disease in patient with RA, with mesangial proliferative glomerulonephritis and membranous nephropathy being the most common pathological findings [ 1 ]. Other than secondary to chronic medication use, glomerular pathology has rarely been reported to be from a direct immune-mediated mechanism in patients with RA. In our patient, NSAIDs-induced secondary membranous nephropathy was deemed to be unlikely given the persistence of nephrotic-range proteinuria after complete withdrawal of ibuprofen for more than 5 months [ 4 ].

The diagnosis of cryoglobulinemic vasculitis

According to the Brouet classification, type1 cryoglobulinemia involves monoclonal IgM and is typically associated with B cell lymphoproliferative diseases including Waldenstroms macroglobulinemia and multiple myeloma. Type 2 cryoglobulinemia involves monoclonal IgM against the Fc portion of polyclonal IgG, and is most commonly seen in chronic viral infections and systemic autoimmune diseases [ 5 ]. Chronic hepatitis C infection constituted 60 ~ 90% of the cases in type 2 mixed cryoglobulinemia in a large retrospective study in France [ 6 ], with Sjogren syndrome being the most common associated autoimmune condition. Type 3 cryoglobulinemia, however, is the least well described entity. It is suggested as a transient state between polyclonal gammopathy and type 2 cryoglobulinemia [ 5 ].

Similar to most other autoimmune conditions, “cryoglobulinemic vasculitis” lacks straightforward diagnostic criteria. In 2012, the Italian Study Group on Cryoglobulinemia (GISC) proposed a preliminary classification criterion for the cryoglobulinemic vasculitis, which includes fulfilling two out of the three set of items (clinical questionnaire, clinic presentation, and laboratory tests). This classification criteria provided a specificity of 95.4% with a reasonably good sensitivity 88.5% [ 7 ]. In our patient, his clinical manifestation fulfills the clinical questionnaire (episodes of red rashes on the skin and mucosal surface) and clinical presentation items (fatigue, purpura) with positive serum cryoglobulin tests 6 month apart, and should be considered as a likely diagnosis of cryoglobulinemic vasculitis. Our patient did not have any complaint of sensory or motor deficits during the clinical encounters, however, comprehensive neurological exam was not performed due to limited time of clinical encounter.

Renal involvement in cryoglobulinemic vasculitis

Renal pathology was not included during the development of the aforementioned GISC criteria. Membranoproliferative glomerulonephritis (MPGN) was known to be the predominant histologic pattern in cryoglobulinemic vasculitis. In a retrospective analysis of the 62 cases of non-infectious mixed cryoglobulinemic glomerulonephritis (GN) identified in the French CryoVas Survey, 92.5% of the 62 cases had a pathological feature of MPGN, with mesangial proliferative GN constituting the rest of the pathology and none of the cases showing a membranous pattern on biopsy [ 6 ]. On detailed review of the renal pathology of our patient, there were rare eosinophilic intracapillary thrombi (Figs. 2 , 3 ), which have been traditionally viewed as a characteristic feature of cryoglobulinemic GN, correlating with rapid immunoglobulin (often IgM) deposition into the glomerular basement membrane [ 8 ]. However, the specificity of this feature is less clear in the background of membranous GN, instead of MPGN.

Diagnostic dilemma

The constellation of cutaneous vasculitis, positive serum qualitative cryoprecipitate and eosinophilic intracapillary thrombi representing immune globulin plugs in the glomerular tufts suggests an immune complex-mediated disease process—systemic cryoglobulinemic vasculitis. However, the glomerular pathology was incongruent with the pre-existing literature, which suggests that cryoglobulinemic glomerulonephritis rarely presents with membranous nephropathy. The immunofluorescent stain of our patient’s renal biopsy showed diffuse finely granular deposits of IgG (3+), IgA (3+), IgM (3+) with positive C3 and C1Q (or a “full house” pattern) typically seen in cryoglobulinemic glomerulonephritis. No macrophages were found in the intracapillary hyaline thrombi in the sampled glomeruli. It is also worth noticing that our patient does not have significant impairment of his GFR during the one and half year follow-up, with an overall Cr level ranging from 0.8 ~ 1.1 mg/dl (GFR 73 ~ 106 ml/min per MDRD equation). Reduced GFR is typically expected in patients with cryoglobulinemic vasculitis due to endocapillary proliferative lesions. Based on the aforementioned French CryoVas Survey, a mean GFR of 39.5 ml/min was observed in the cases of biopsy-proven cryoglobulinemic glomerulonephritis [ 6 ]. In addition, despite the “full-house” staining on immunofluorescence, lupus nephritis was deemed to be unlikely given a repeatedly negative serological profile, the lack of typical extra-renal lupus manifestations (e.g. malar rash, photosensitivity, oral ulcers), and lack of typical pathological features on renal biopsy (no signs of extra-glomerular immune deposits on IF, no signs of subendothelial or mesangial tubulo-reticular inclusions on electron microscopy).

An alternative explanation of this complicated presentation is to split the cutaneous and renal findings: patient developed cryoglobulinemic vasculitis, while his membranous nephropathy being a separate co-existing disease process not directly related to the pathophysiology of cryoglobulinemic vasculitis. Primary membranous nephropathy appears to be unlikely given the negative serum level and staining for anti-phospholipase A2 receptor (PLA2R) in the renal biopsy. After excluding all known secondary causes of membranous GN, we propose that the glomerular pathology in our patient might be directly related to his underlying active RA probably through an immune-mediated mechanism, and it could potentially be part of the wider spectrum of glomerular disease in RA (Fig. 8 ). Cases of membranous nephropathy without other identifiable secondary causes as well as negative work-up for primary membranous GN have been reported in patients with long-standing rheumatoid arthritis [ 9 ].

Diagnostic path

The association between rheumatoid arthritis and cryoglobulinemic vasculitis

The presence of serum cryoglobulin and vasculitis was described in early literature by Weisman et al. in 1975 as an associated condition in patients with RA. When comparing the 8 patients who had clinical evidence of vasculitis with those who did not, those who had vasculitis had a significantly higher RF titer and lower C3 level [ 10 ]. The term rheumatoid vasculitis was used to describe a type of necrotizing vasculitis that occurs in long-standing active rheumatoid arthritis. Interestingly, however, renal involvement was not present in any of the patients in the above study. The incidence of “rheumatoid vasculitis” and the use of this term has declined dramatically since the 1980s, which was attributed to better control of the inflammation with the introduction of multiple disease modifying agents and biologics [ 11 ].

Very few studies have described the association between rheumatoid arthritis and cryoglobulinemic vasculitis. In a retrospective analysis in patient with non-infectious type2 mixed cryoglobulinemia in Northern France, underlying RA was found in only 2 out of 33 patients studied, with Sjogren syndrome being the most common associated autoimmune condition [ 12 ]. In contrast to the relatively well-studied HCV-related mixed cryoglobulinemic vasculitis, the evidence of RA as the etiology of systemic cryoglobulinemic vasculitis has not been well established, and the potential mechanism has also not been elucidated. Given the biochemical plausibility that rheumatoid factor, an IgM that has affinity towards the Fc portion of IgG, forms large immune complexes which could potentially activate complement, an immune-complex mediated mechanism of the vasculitis was proposed.

Treatment challenge

Despite the diagnostic difficulty, the decision was made to treat the patient with Rituximab, considering that it is increasingly considered as an effective treatment for primary membranous nephropathy, and is now preferred for the treatment of hepatitis C-associated cryoglobulinemic vasculitis over cyclophosphamide, in both instances. Unfortunately, limited evidence exists for the effectiveness of Rituximab and corticosteroid in patients with non-infectious mixed cryoglobulinemia. The patient showed significant treatment response immediately after treatment, however, his proteinuria quickly rebounded over a 2-month period (Fig. 6 ). A repeat renal biopsy was considered to evaluate for potential changes of pathology type (e.g. new signs of diabetic nephropathy), or persistent or worsening features of cryoglobulinemia which might raise a consideration of therapy switch to cyclophosphamide. However, due to the current COVID-19 pandemic and patient’s personal issues, the procedure has not been able to be arranged.

The association between rheumatoid arthritis and sarcoidosis

Another interesting clinical manifestation during our patient’s disease course is the development of pulmonary symptoms which led to the diagnosis of pulmonary sarcoidosis. The patient developed cough and dyspnea after his first course of Rituximab treatment and while being quickly tapered off of Prednisone (patient was on Prednisone 20 mg daily when he developed clinical symptoms). The diagnosis of pulmonary sarcoidosis was established by consistent clinical, radiographical (bilateral hilar and mediastinal lymphadenopathy) as well as pathological evidence of non-caseating granuloma on mediastinal lymph node biopsy. The timing of this presentation is certainly intriguing in his complicated clinical course. On retrospective review of his prior chest radiographs obtained serially since his diagnosis, the hilar lymphadenopathy had been overall stable and didn’t show any significant changes at the time when the patient became symptomatic. His respiratory symptoms quickly resolved after up titrating his Prednisone dose to 40 mg daily. One possible explanation is that the patient had a symptomatic flare of pulmonary sarcoidosis during the rapid steroid taper, and his disease had remained asymptomatic clinically much longer prior the diagnosis of pulmonary sarcoidosis was made. Supportive evidence includes one of the observational studies performed in patients with pulmonary sarcoidosis who were treated with Prednisone, and who were observed clinically without initiation of therapy. Significant higher relapse rate was observed after clinical remission was achieved in patients who have received induction therapy with corticosteroids (74% vs. 8%, p  < 0.01) [ 13 ].

Sarcoidosis has long been reported to co-exist with or mimic other autoimmune conditions including rheumatoid arthritis, suggesting overlapping immune dysregulation among these conditions. The clinical presentation of sarcoidosis has been reported to precede or lag behind the diagnosis of RA, and in some cases, the two conditions can manifest themselves at the same time [ 14 ]. Rituximab was also reported to be an effective treatment in some cases of extrapulmonary sarcoidosis, and is being studied as treatment for refractory pulmonary sarcoidosis [ 15 ]. More interestingly, with the introduction of biologics, cases of sarcoidosis being induced by the use of tumor necrosis factor alpha (TNF-α,) inhibitors (mostly etanercept) as treatment for RA have been reported over the past 20 years [ 16 ]. The exact pathophysiology of worsening of the granulomatous disease after introduction of biologics remains unexplained as TNF-α inhibitors would be expected to block the effect of TNF-α: an important cytokine responsible for macrophage activation and granuloma formation.

In summary, our case presented a unique and complicated clinical phenotype of active rheumatoid arthritis, with clinical features of cryoglobulinemic vasculitis, histopathologic features of membranous nephropathy in the absence of DMARDs use, and pulmonary sarcoidosis. All the clinical features showed an excellent response to corticosteroids, except for his renal manifestation, which only showed partial response to steroids and B-cell depletion therapy. We speculate that there is a wider spectrum of glomerular disease in patients with untreated RA. In addition, the association between rheumatoid arthritis and cryoglobulinemic vasculitis should be revisited and requires further studies to elucidate the underlying mechanisms and treatment options.

Availability of data and materials

Most of the clinical data used and analyzed in this case report is presented in this manuscript. More detailed information is available from the corresponding author on reasonable request.

Abbreviations

• Rheumatoid arthritis

Chronic kidney disease

Nonsteroidal anti-inflammatory drugs

Disease-modifying anti-rheumatic drugs

Emergency room

Metacarpophalangeal

Proximal interphalangeal

Rheumatoid factor

Angiotensin converting enzyme inhibitor

Anti-phospholipase A2 receptor

Endobronchial ultrasound

Membranoproliferative glomerulonephritis

Glomerulonephritis

Kapoor T, Bathon J. Renal manifestations of rheumatoid arthritis. Rheum Dis Clin N Am. 2018;44(4):571–84.

Article   Google Scholar  

Helin HJ, Korpela MM, Mustonen JT, et al. Renal biopsy findings and clinicopathologic correlations in rheumatoid arthritis. Arthritis Rheum. 1995;38(2):242–7.

Article   CAS   Google Scholar  

Mori S, Yoshitama T, Hirakata N, et al. Prevalence of and factors associated with renal dysfunction in rheumatoid arthritis patients: a cross-sectional study in community hospitals. Clin Rheumatol. 2017;36(12):2673–82.

Radford MG Jr, Holley KE, Grande JP, et al. Reversible membranous nephropathy associated with the use of nonsteroidal anti-inflammatory drugs. Jama. 1996;276(6):466–9.

Ramos-Casals M, Stone JH, Cid MC, et al. The cryoglobulinaemias. Lancet. 2012;379(9813):348–60.

Zaidan M, Terrier B, Pozdzik A, et al. Spectrum and prognosis of noninfectious renal mixed Cryoglobulinemic GN. J Am Soc Nephrol. 2016;27(4):1213–24.

De Vita S, Soldano F, Isola M, et al. Preliminary classification criteria for the cryoglobulinaemic vasculitis. Ann Rheum Dis. 2011;70(7):1183–90.

Fogo AB, Lusco MA, Najafian B, et al. AJKD atlas of renal pathology: cryoglobulinemic glomerulonephritis. Am J Kidney Dis. 2016;67(2):e5–7.

Iida A, Wada Y, Hayashi J, et al. Membranous nephropathy caused by rheumatoid arthritis. CEN Case Rep. 2019;8(4):233–8.

Weisman M, Zvaifler N. Cryoimmunoglobulinemia in rheumatoid arthritis. Significance in serum of patients with rheumatoid vasculitis. J Clin Invest. 1975;56(3):725–39.

Watts RA, Mooney J, Lane SE, et al. Rheumatoid vasculitis: becoming extinct? Rheumatology (Oxford). 2004;43(7):920–3.

Foessel L, Besancenot JF, Blaison G, et al. Clinical spectrum, treatment, and outcome of patients with type II mixed cryoglobulinemia without evidence of hepatitis C infection. J Rheumatol. 2011;38(4):716–22.

Gottlieb JE, Israel HL, Steiner RM, et al. Outcome in sarcoidosis. The relationship of relapse to corticosteroid therapy. Chest. 1997;111(3):623–31.

Papanikolaou IC, Sharma OP. A 47-year-old woman with rheumatoid arthritis and dyspnea on exertion. Chest. 2009;136(6):1694–7.

Sweiss NJ, Lower EE, Mirsaeidi M, et al. Rituximab in the treatment of refractory pulmonary sarcoidosis. Eur Respir J. 2014;43(5):1525–8.

Clementine RR, Lyman J, Zakem J, et al. Tumor necrosis factor-alpha antagonist-induced sarcoidosis. J Clin Rheumatol. 2010;16(6):274–9.

Download references

Acknowledgements

Dr. David J. Cimbaluk at the department of pathology at Rush University Medical Center provided the pathology slides. All members at the nephrology department at Cook County Health contributed to this case.

The authors received no financial support for this case report .

Author information

Authors and affiliations.

Internal Medicine Residency Program, Department of Medicine, Cook County Health, Chicago, IL, USA

Department of Nephrology, Cook County Health, Chicago, IL, USA

Juan P. Ruiz & Peter D. Hart

You can also search for this author in PubMed   Google Scholar

Contributions

QW contributed in gathering patient data from review of electronic medical records and drafting the manuscript. JPR is involved in clinical care of the patient, conceptualized and modified the case report. PDH critically reviewed the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Qiyu Wang .

Ethics declarations

Ethics approval and consent to participate.

Institutional Board Review does not require review and approval for case reports.

Consent for publication

The patient provided written consent for the publication of data.

Competing interests

The authors declare that they have no competing interest.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Wang, Q., Ruiz, J.P. & Hart, P.D. Case report: a man with untreated rheumatoid arthritis, cryoglobulinemic vasculitis, membranous nephropathy and pulmonary sarcoidosis. BMC Nephrol 21 , 496 (2020). https://doi.org/10.1186/s12882-020-02161-5

Download citation

Received : 28 June 2020

Accepted : 10 November 2020

Published : 19 November 2020

DOI : https://doi.org/10.1186/s12882-020-02161-5

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Nephrotic syndrome
• Membranous nephropathy
• Cryoglobulinemic vasculitis
• Pulmonary sarcoidosis

BMC Nephrology

ISSN: 1471-2369

• Submission enquiries: [email protected]
• General enquiries: [email protected]

Case Study: Treatment-Resistant RA With Surprising Progression

— mri and therapeutic advances offered older man relief after more than a decade of pain.

by Kate Kneisel , Contributing Writer, MedPage Today

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

This month: A noteworthy case study.

What to do for this 70-year-old man with a 13-year history of poorly controlled rheumatoid arthritis (RA) when he develops severe arthritis pain in his shoulder?

That's what clinicians in Brazil needed to determine, as Camille Pinto Figueiredo, MD, PhD, of Universidade Católica de São Paulo in Sorocaba, Brazil, and colleagues reported in BMC Musculoskeletal Disorders .

As they related in their case report, when the patient was diagnosed in 2010 tests had revealed elevated titers of rheumatoid factor and antibodies against cyclic citrullinated peptides. In the time since, his disease proved to be resistant to a range of previous treatments, including "corticosteroids and approved doses of hydroxychloroquine for 2 years, methotrexate for 3 years, leflunomide for 7 years, and adalimumab for 6 years."

Treatment with corticosteroids resulted in osteonecrosis of the hip, for which he underwent total arthroplasty.

In 2018, the team noted, the patient was admitted to hospital when he developed acute interstitial lung disease (ILD), which was diagnosed as organizing pneumonia. To address the possibility that his disease-modifying antirheumatic drugs and biologic therapies might be linked with the ILD and concomitant infection, these therapies were discontinued for 2 months.

At that point, the patient received only high glucocorticoid doses (methylprednisolone 80 mg/day with progressive dose reduction) to manage his RA and the lung disease.

A few months later, he presented with "a persistent flare with symmetric polyarthritis in peripheral joints and a severe painful bilateral shoulder arthritis," Pinto Figueiredo and co-authors said.

An assessment indicated a high level of disease activity, with a disease activity score in 28 joints (DAS28) of 6.42. An x-ray of the left shoulder showed significant bone destruction: "Anteroposterior radiograph expansive intramedullary osteolytic lesion, at the metaepiphysis region of the humerus, with well-defined contours and sclerotic border, presenting internal septations. The image also shows an erosive lesion on the superolateral region of the humeral head, with slightly cortical thinning alongside," the team wrote.

A subsequent MRI confirmed the findings and provided a more detailed description of the lesion, which included erosions related to a giant humeral head geode, along with synovitis, a large bursitis, and tendinopathy.

Clinicians prescribed a regimen of sulfasalazine up to 3 gm/day and intravenous abatacept (750 mg/dose), which was continued for 10 months. Nevertheless, the severe pain in the patient's shoulder and hands persisted, with a DAS28 of 5.45.

This was "associated with high levels of inflammatory markers (C-reactive protein [CRP] up to 3.76 mg/dL and erythrocyte sedimentation rate [ESR] up to 106 mm/1 hour), and functional impairment," Pinto Figueiredo and co-authors noted.

They switched the patient from abatacept to intravenous tocilizumab 8 mg/kg and administered "intra and periarticular corticosteroid injection in the left shoulder and intra-articular injection in both wrists." Treatment with leflunomide 20 mg/day was also resumed. In the following months, the patient achieved pain control, normal levels of inflammatory markers (CRP<0.03 mg/dL and ESR=3), and disease remission (DAS28=1.75).

Rheumatoid arthritis involving the shoulder is seen much less commonly than involvement of the hands, feet, or wrists, which makes this case of "radiological progression with erosive damage and a giant geode, in an aggressive uncontrolled disease, even more unique," the authors said. MRI findings that revealed both bone and soft tissue damage confirmed the diagnosis.

One study found that with or without involvement of other joints, shoulder arthritis affected 12.6% of RA patients, with associated symptoms more commonly observed in patients over age 60.

In a 2003 analysis of shoulder involvement in 43 patients with RA, x-rays revealed that erosions affected the humeral head in 26 patients and the glenoid fossa in 12 patients. "On the other hand, MRI was able to detect erosions in glenohumeral joint in 39 patients and cystic lesions in 15," Pinto Figueiredo and co-authors said.

They explained that differential diagnoses for cystic lesions of the glenohumeral joint vary and include a range of conditions, including hallmarks of osteoarthritis such as joint space narrowing, subchondral bone sclerosis, marginal osteophytes, and subchondral radiolucencies. Solitary or large cysts only occur rarely.

"Gout manifests radiographic alterations as a late-stage effect of the disease, with deposits of urate crystals or tophi causing erosions of the underlying bone that resemble geodes or cysts," the case authors wrote.

They noted that although intraosseous ganglia tend to manifest on their own, as "unilocular or multilocular cystic lesions in the epiphysis of long bones," joint degeneration may lead to formation of cystic bone lesions in patients with septic arthritis, synovial chondromatosis, pigmented villonodular synovitis, and amyloidosis.

"Thus, MRI was of considerable assistance in the reported case," the team said.

The recent development of several biologic drugs used in to treat RA have made a significant impact due to their ability to control disease activity and decrease joint damage, Pinto Figueiredo and co-authors explained. These biological DMARDs (bDMARDs) have demonstrated the capacity to "inhibit damage installation and progression in peripheral small joints, as well as in large joints of lower extremities such as hip and knees."

This patient achieved disease control after "the association of conventional and an anti-interleukin-6 receptor biological DMARD, the team pointed out. "There are no data of bDMARD -specific effects in shoulder joints of RA patients."

In this "rare clinical presentation of a giant geode in the humeral head ... MRI proved to be a valuable imaging method for identifying damage in both bone and soft tissue, supporting clinical data when other hypotheses may be implicated," the case authors concluded.

Read previous installments of this series:

Part 1: RA Beginnings: Before the Painful Joints

Part 2: RA: Still a Clinical Diagnosis

Part 3: RA: Choosing Initial Treatment

Kate Kneisel is a freelance medical journalist based in Belleville, Ontario.

Disclosures

Pinto Figueiredo and co-authors reported no competing interests.

Primary Source

BMC Musculoskeletal Disorders

Source Reference: Pirola FJC, et al "A rare giant geode of humeral head in an uncontrolled rheumatoid arthritis: a case report" BMC Musculoskelet Disord 2023; 24: 572-576.

• Search Menu
• Advance Articles
• Editor's Choice
• Collections
• Supplements
• InSight Papers
• BSR Registers Papers
• Virtual Roundtables
• Author Guidelines
• Submission Site
• Open Access Options
• Self-Archiving Policy
• About Rheumatology
• About the British Society for Rheumatology
• Editorial Board
• Advertising and Corporate Services
• Journals Career Network
• Dispatch Dates
• Terms and Conditions
• Journals on Oxford Academic
• Books on Oxford Academic

Article Contents

Introduction, acknowledgements.

• < Previous

Role of stress in the development of rheumatoid arthritis: a case–control study

• Article contents
• Figures & tables
• Supplementary Data

Vincent Germain, Marc Scherlinger, Thomas Barnetche, Clémence Pichon, Alexandre Balageas, Laurence Lequen, Emilie Shipley, Jennifer Foret, Stéphanie Dublanc, Lucile Capuron, Thierry Schaeverbeke, the Fédération Hospitalo-Universitaire ACRONIM, Role of stress in the development of rheumatoid arthritis: a case–control study, Rheumatology , Volume 60, Issue 2, February 2021, Pages 629–637, https://doi.org/10.1093/rheumatology/keaa216

• Permissions Icon Permissions

The primary objective of this study was to assess the stressful life events preceding the onset of symptoms in RA. The secondary objectives were to assess how early RA patients perceive stress and cope with stressors.

A case–control study was performed, comparing patients recently diagnosed with RA to age- and gender-matched control subjects recently hospitalized for an unplanned surgical procedure not known to be influenced by stress. The Social Readjustment Rating Scale assessed the cumulative stress induced by stressful life events in the year preceding the onset of symptoms. Coping strategies, stress and anxiety symptoms were evaluated using validated psychological scales.

Seventy-six subjects were included in each group. The mean Social Readjustment Rating Scale score was twice as high in cases compared with controls [respectively, 167.0 (172.5) vs 83.3 (124.4), P  < 0.001]. The association between cumulative stress and RA was statistically significant only in women, with a dose-dependent association between stress and RA. While female patients with RA attributed more often the onset of symptoms to a life event than female controls (70.2 vs 24.5%, P  < 0.001), no significant difference was found when comparing male RA patients with male controls (26.9 vs 18.5%, respectively, P  = 0.46). Increased perceived stress score ( P  = 0.04) and coping based on emotions ( P  = 0.001) were found in cases compared with controls.

Patients with early RA reported more life events in the year preceding the onset of symptoms than controls. Gender specificities were found with a significant association between cumulative stress and RA only in women.

RA patients reported an increased cumulative stress in the year before the onset of symptoms.

More than half of RA patients attributed the onset of symptoms to a life event.

The association between cumulative stress and RA was significant only in women.

The question ‘what is the cause of my disease?’ is often asked by RA patients in clinical practice. This questioning holds particular relevance for the understanding of RA pathophysiology. Most RA patients carry ACPA and/or RF, defining an immunological disease called seropositive RA. During the development of seropositive RA, it has been demonstrated that the ‘first hit’ leading to the immunological disorders: (i) precedes the clinical manifestations by several years [ 1 ], and (ii) does not mandatorily lead to clinical symptoms, since the percentage of RF- and/or ACPA-positive healthy blood donors is higher than RA prevalence [ 2 ].

The ‘second hit’ hypothesis suggests that other factors are necessary to trigger a clinical RA in a healthy subject carrying ACPA. This hypothesis is supported by clinical observations such as RA emerging upon hormonal changes [ 3 ], after checkpoint inhibitor therapy [ 4 ] or after an infection [ 5 ]. Another trigger discussed in the literature and frequently by patients is the role of stressors in RA onset [ 6 ]. Several studies have demonstrated an increased psychological distress at the time of diagnosis and in very early RA [ 7 , 8 ]. Gender specificities may exist, since life events were more often reported by women before the occurrence of RA in some studies [ 6 , 9 ].

Stressors may be addressed in different ways. They may correspond to old life events such as childhood traumas and/or previous events that could precipitate and aggravate a post-traumatic stress disorder (PTSD) in adulthood [ 10 ]. These events may participate in the structuration of an individual identity and therefore influence response to stressors (also called coping) and predispose to psychiatric disorders [ 11 ]. However, these old events do not explain a sudden changeover. To investigate the role of stress in RA onset, recent life events should be analysed in light of how each individual specifically perceives and copes with them [ 12 ].

The primary objective of this case–control study was to assess the recent stressful life events preceding the onset of symptoms in patients with early RA. The secondary objectives were to assess how early RA patients perceive stress and cope with stressors. The influence of gender was assessed in these primary and secondary objectives.

Study design

A multicentre case–control study was conducted in one tertiary and three secondary hospitals in the south-west of France, upon approval by a national independent ethic committee affiliated to the Ministry of Health (ethics board reference: Comité de Protection des Personnes, Ile-de-France 3).

Identification of cases and controls

Cases were ambulatory patients recently diagnosed with RA according to the 2010 ACR/EULAR criteria [ 13 ], whose symptoms began <2 years before the study (between July 2016 and July 2018). Controls were subjects treated with an unplanned surgery during the same time interval. Surgical interventions included acute digestive and orthopaedic conditions not known to be influenced by stress: appendectomy, cholecystectomy, intestinal obstruction due to adhesions, incisional, umbilical or inguinal hernia for digestive surgery, and wrist fracture for orthopaedic surgery. Cases and controls were asked to participate by postal service with an information note specifying the purpose of the study. It was explained that the aim of the project was to improve the knowledge of the factors leading to RA. The word ‘stress’ was not specified, in order to not influence the responses to questionnaires. Cases and controls were individually matched on gender and age (more or less 5 years), at a 1:1 ratio. All subjects were older than 18 years, and French-speaking without language difficulties. Matching cases and controls on clinical centre was not possible because of organizational issues for surgery controls. Most of the RA patients and all controls were recruited in the tertiary hospital. The four participating hospitals were located in nearby cities, in the same geographic region.

Recorded variables and questionnaires

Questionnaires with scales were sent to eligible subjects. Classical demographic data and traditional risk factors for RA were recorded from health records. For RA patients, sudden onset of clinical symptoms, RF/ACPA status and treatments were gathered. If they agreed to participate in the study, subjects completed questionnaires at home before sending them back by mail. All scales were validated self-administered questionnaires widely used in health psychology, with available French translation.

The primary outcomes were the evaluation of:

Social readjustment using the Social Readjustment Rating Scale (SRRS) by Holmes and Rahe [ 14 ], a standardized measure of the impact of a wide range of the most common life stressors, which is composed of 43 hierarchical life events including medical, familial, professional, financial and social stressors. A higher score corresponds to a high cumulative stress induced by these events. Participants were asked to report the stressors that occurred during the year preceding the onset of RA symptoms for cases, or the surgery for controls. If an event recurred, it was counted several times. The score ranges from 0 to no upper limit. The life events and their corresponding scores included in SRRS are detailed in Supplementary Data S1, available at Rheumatology online. According to the authors, 50% of subjects with a score >150 will develop a stress-induced illness within 1 year.

The proportion of subjects attributing the onset of RA symptoms/the surgery to a life event responsible for a psychological stress. The question asked was: ‘Do you think that the onset of RA/the surgery may have been triggered by a particular event, resulting in a psychological shock or psychological stress?’ The type and the date of the reported event were recorded.

The secondary outcomes were the evaluation of:

Perceived stress using the Perceived Stress Scale by Cohen et al . [ 15 ], built to assess the degree to which people perceive their lives as stressful. This 14-item questionnaire reflects the perceived stress in the past 4 weeks and ranges from 0 to 56. Higher values correspond to an increased perceived stress.

Perceived control using the Multidimensional Health Locus of Control Scale by Wallston et al . [ 16 ], an 18-item scale assessing the subject’s perception of control over his own health. This scale defines the feeling of the patient between two opposite behaviours: on one hand individuals with an internal locus of control who establish a link between their own behaviour and the external obtained reinforcement/outcome (positive or negative), and on the other hand individuals with an external locus of control who do not establish any link between their behaviour and the outcome. The scale includes three subscales ranging from 6 to 24 and corresponding, respectively, to internality (health control depends on the behaviour of the subject himself), chance externality (health control depends on fate and luck) and powerful others externality (health control depends on external persons such as health professionals).

Perceived social support using the Social Support Questionnaire by Sarason et al . [ 17 ], a 6-item short questionnaire composed of two subscales: availability of social support (number of dependable persons in case of need) ranging from 0 to 54, and satisfaction regarding social support ranging from 6 to 36.

Anxiety symptoms using the state version of the State-Trait Anxiety Inventory by Spielberger et al . [ 18 ], a 20-item scale measuring the anxiety related to a particular situation at a specific time, ranging from 20 to 80. Higher values correspond to an increased level of state anxiety.

Coping strategies using the Ways of Coping Checklist by Folkman and Lazarus [ 19 ], in its French 27-item validated version [ 20 ]. The checklist was built to analyse the strategies used by a patient to deal successfully with a difficult situation. This scale investigates three types of coping strategies: based on the problem (score from 10 to 40), based on emotions (from 9 to 36) and based on the seeking of social support (from 8 to 32).

Statistical analysis

Quantitative variables were expressed as means ( s . d .) or as medians with interquartile ranges, and were compared using a Student’s test, or a non-parametric Mann–Whitney test in case of small sample size or non-normal distribution. Qualitative variables were expressed as percentages, and were compared using a Chi-squared test, or Fisher’s exact test in case of small sample size. Odds ratios (OR) measuring the association between different SRRS thresholds and RA were calculated using logistic regression and expressed with their 95% CI. Subgroup analyses on gender were prespecified. Calculations were made with the STATA 13.1 SE software (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP). A P -value <0.05 was considered as statistically significant.

Population and disease characteristics

Among 101 newly diagnosed RA patients, 76 (75.2%) accepted to participate (59 patients recruited in the tertiary hospital and 17 patients recruited in the three secondary hospitals). Seventy-six surgery controls were subsequently individually matched on gender and age, corresponding to a participation rate of 43.2% in the control group (76/176). As detailed in supplementary Table S2 , available at Rheumatology online, RA patients who refused to participate were more likely to be seropositive for RF and/or ACPA than patients who accepted; no statistical difference was found in terms of age and gender.

Mean duration between onset of RA symptoms and study inclusion was 14.9 (7.2) months for cases, vs 13.7 (7.0) months between surgery and study inclusion for controls ( P  = 0.30).

Population characteristics are described in Table 1 . Cases and controls were comparable for age and gender, with a mean age of 57.7 (13.9) years for RA and of 57.6 (14.0) for controls, and with 64.5% (49/76) of females in each group.

Population and disease characteristics including RA cases and surgery controls

Except for means, results are expressed as number (%). Statistically significant differences ( P -value <0.05) are highlighted in bold. csDMARD: conventional synthetic disease-modifying antirheumatic drug; bDMARD: biological synthetic disease-modifying antirheumatic drug.

There was no significant difference in terms of main clinical risk factors for RA between cases and controls regardless of gender. Male RA patients reported more often a history of smoking stopped before the onset of symptoms than male controls (40.7 vs 14.8%, P  = 0.03), whereas there was no significant difference regarding current smoking. Female RA patients did not report more often a history of smoking than female controls.

RA patients were seropositive for RF and/or ACPA in 73.7% of cases; 82.9% were treated with a conventional synthetic DMARD, 27.6% with a biological DMARD and 46.1% received CS. A sudden onset of RA symptoms was reported by 82.9% of patients.

Stressful life events preceding the onset of symptoms

The mean SRRS score, measuring the cumulative stress induced by stressors during the year preceding the onset of RA symptoms for cases or the surgery for controls, was significantly higher in RA patients compared with surgery controls [167.0 (172.5) vs 83.3 (124.4), P  < 0.001]. The mean number of reported stressful life events preceding the onset of symptoms was significantly higher in RA patients than in controls [5.4 (4.7) vs 2.7 (4.0), P  < 0.001]. When evaluating the influence of gender, the SRRS score was significantly higher in female cases compared with female controls [180.6 (168.1) vs 75.7 (132.3), P  < 0.001], and no significant difference was found between male cases and male controls [142.6 (180.6) vs 97.0 (109.6), P  = 0.27]. Table 2 summarizes the results in the overall population, as well as according to gender.

Life events, perception of stress and coping strategies in cases and controls

Statistically significant differences ( P -value <0.05) are highlighted in bold. SRRS: Social Readjustment Rating Scale; PSS-14: Perceived Stress Scale; MHLCS: Multidimensional Health Locus of Control Scale; SSQ-6: Social Support Questionnaire; STAI-Y-A: State-Trait Anxiety Inventory; WCC: Ways of Coping Checklist scale.

Using different SRRS thresholds, we found a dose-dependent association between cumulative stress and RA, with an OR of 3.68 (95% CI: 1.57, 8.62) for the highest scores of SRRS, higher than 150 (see Table 3 ). This dose-dependent association was significant in females with an OR of 5.40 (95% CI: 1.82, 16.03) in case of SRRS >150, and was not found in males [OR 1.87 (95% CI: 0.47, 7.53)].

Association between RA and different thresholds of cumulative stress

Statistically significant associations are highlighted in bold. OR: odds ratio; SRRS: Social Readjustment Rating Scale.

Among RA patients, 54.8% attributed the onset of symptoms to a life event responsible for a psychological stress, compared with 22.4% of controls ( P  < 0.001) (see Table 2 ). Life events reported by RA patients were mainly the death of a close relative or friend (30%), professional difficulties (15%), family or marital conflict (12.5%), illness of a relative (7.5%), financial difficulties (5%) or conjugal separation (5%). When evaluating the influence of gender, female cases attributed more often the onset of symptoms to a life event than female controls (70.2 vs 24.5%, P  < 0.001), and no significant difference was found when comparing male cases with male controls (26.9 vs 18.5%, respectively, P  = 0.46). Among RA patients, women attributed more often than males the onset of symptoms to a psychological stressor (70.2 vs 26.9%, P  < 0.001). Gender specificities in RA patients regarding all evaluated criteria are shown in supplementary Table S3 , available at Rheumatology online.

Regarding the influence of RF and/or ACPA seropositivity among RA patients, no significant difference was found between seropositive and seronegative patients when comparing the mean SRRS score and the number of reported life events (data not shown).

Perception of stress and coping strategies in early RA

Perceived stress as assessed by the Perceived Stress Scale was significantly higher in RA patients compared with controls [respective mean of 22.8 (8.2) vs 19.9 (9.0), P  = 0.04]. No other significant difference was found regarding scores of perceived control (Multidimensional Health Locus of Control Scale), perceived social support (Social Support Questionnaire) and state anxiety (State-Trait Anxiety Inventory). In the Ways of Coping Checklist, coping strategies based on emotions were greater in RA patients compared with controls [mean of 21.8 (4.7) in cases vs 19.0 (5.4) in controls, P  = 0.001]. No statistical difference was found for coping styles based on the problem or the seeking of social support between the overall case and control groups. Regarding gender specificities, coping strategy based on the seeking of social support was greater in male RA patients than in male controls [respective mean of 24.3 (4.0) and 21.0 (4.0), P  < 0.01], a difference that was not found in women. The results of scales assessing the perception of stress and coping strategies in case and control groups are summarized in Table 2 . Among RA patients, females had a higher state anxiety score than males [48.9 (13.4) vs 42.1 (10.1), P  = 0.03] (see supplementary Table S3 , available at Rheumatology online).

In our study, early RA patients had a SRRS score twice as high as controls, indicating an increased cumulative stress induced by stressful life events in the year preceding the onset of symptoms. Gender specificities were found with a significant association between cumulative stress and RA in all patients and in women (but not in men), and with a dose-dependent association between stress and RA. The onset of symptoms was attributed to a life event responsible for a psychological stress in more than half of RA patients, with an association significant only in women.

While previous studies have suggested possible causal events reported by RA patients to explain the onset of their disease [ 6 , 9 ] and patients being mentally less healthy at the time of RA diagnosis [ 7 , 8 ], few data are available concerning the cumulative stress preceding the onset of symptoms. Two case–control studies comparing the SRRS score between RA patients and OA controls have previously shown an increased number of stressful life events before RA onset [ 21 , 22 ]. A first limitation of these two studies is that subjects were diagnosed >10 years before their inclusion, leading to important recall biases. Furthermore, the control subjects consisted of patients suffering from OA, a disorder for which the onset is much more progressive and insidious than RA and surgery, and therefore impossible to date accurately. Finally, patients and controls included in those studies were not matched on age and gender.

One important limitation in such case–control studies is the risk of recall biases. RA patients could seek to explain their chronic disease and overestimate or misinterpret previous events compared with healthy subjects. The use of predefined stressors listed in the SRRS questionnaire, the inclusion of cases with recent RA (mean duration of symptoms of 14.9 months) and controls with recent surgical procedures (mean duration of 13.7 months before study inclusion), and the strict limitation to events that occurred within a single year before the onset of symptoms, allowed us to reduce this risk. While controls may have been more likely to omit some minor stressful events than cases, they certainly did not forget recent events resulting in a strong emotional charge. Another reason for assessing only recent stressors is that the risk of autoimmune disease is highest in the months following their occurrence [ 23 ].

In clinical practice, most RA patients are able to date accurately their first symptoms to a certain day or week [ 24 ]. A rapid onset of symptoms is often reported [ 25 ], and this fact was confirmed in >80% of cases in the present study. This sudden start of symptoms warranted our choice of controls, who were subjects undergoing an unplanned surgery, which is an event that is easy to date. The selected digestive and orthopaedic surgery procedures were not known to be triggered by stress, and only patients with recent surgical intervention were included in order to limit the recall bias.

We have chosen to match cases and controls on age and gender. Taking age into account seemed important as the chance of being exposed to life events depends on age, and because perception of stress and coping strategies have been shown to change over a person’s lifespan [ 26 , 27 ]. Interestingly, we demonstrated a great influence of gender, with an association between stress and RA only in females. Since our study included only one-third men, we cannot exclude that it was underpowered to show such an association in men. However, our results are in accordance with the literature, as Söderlin et al. previously showed that women reported more life events than men to explain the beginning of RA, and in particular more psychological and physical traumas [ 6 ]. A Swedish population-based case–control study finding a weak association between any traumatic life event in the preceding 5 years and RA occurrence also reported gender specificities, with results more consistent in females than in males [ 9 ]. Women are known to develop anxiety symptoms more often than men [ 28 ]. This was confirmed in our study, with a higher anxiety score in RA females than in RA males, a result previously shown in patients with early inflammatory arthritis [ 29 ].

Depression is more prevalent in women than in men [ 30 , 31 ], and life events are known to increase the risk of this mental disorder [ 32 ], especially in women [ 33 ]. The stress system mainly involves the endocrine and nervous systems, both closely linked to the immune system. An inadequate stress response in RA may contribute to a pro-inflammatory state, involving the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system [ 34 ]. Decreased autonomic and hypothalamic–pituitary–adrenal axis responsiveness to acute psychosocial stress has been demonstrated in women compared with men, related to the action of female sex hormones and oestrogen exposure [ 35 ]. Higher anxiety levels, differences in personality and emotion regulation, and decreased stress response in women are hypotheses to explain gender specificities in the association between stress and RA occurrence.

The most traumatic life events may result in PTSD. The association between PTSD and an increased risk of most autoimmune diseases including RA is well described in the literature [ 23 , 36 , 37 ], with data showing a higher risk in women compared with men, confirming once again gender differences [ 36 ]. PTSD is susceptible to referring to ancient traumatic events that may affect the way a person will face new occurrences. In our study, we chose to focus on recent life events, and we did not investigate symptoms possibly reflecting PTSD, although it could be a vulnerability factor for coping strategies. However, coping could be an indirect marker of PTSD.

In that way, one original feature of our study lies in the assessment of stressors considering stress not only as a simple reaction to an event, but as a multifactorial reaction. The influence of stress on the disease is the combination of the nature of the stressful life events themselves, and the perception of these events by the patients and the way they cope with them [ 12 ]. Conversely to the SRRS questionnaire, which allowed study of life events before the onset of RA, scales assessing perception of stress and coping strategies focussed on the time of the study, that is, after the onset of symptoms. Thus, it is difficult to know if the differences highlighted are consequences rather than causes of the disease. However, assessing how early RA patients perceive stress and cope with stressors seemed interesting, because very few data exist on this subject; our study is indeed the first one comparing perceived stress and coping strategies between RA patients and a control population. We showed slight increased perceived stress score and coping based on emotions in RA patients. A similar finding was also reported in a recent study showing an association between perceived stress and incident inflammatory arthritis in an at-risk RA population [ 38 ]. Overall, in RA, a higher perceived social support, and lower perceived stress and levels of anxiety are correlated with better quality of life and well-being [ 39–42 ]. Coping strategies based on the problem, i.e. developing an active plan to face the challenge, is more favourable than emotion-focussed coping [ 42–44 ]. As demonstrated by Stanton et al ., emotion-focussed coping reflects rather negative emotional reactions and failures to adequately cope [ 45 ].

This study did not investigate the relationship between stress and disease activity. It would be interesting to know whether more stressed-out RA patients have more treatment-resistant disease. An exploratory study has shown that mental health status was independently associated with flare following TNF inhibitor tapering [ 46 ]. There appears to be a correlation between a better RA control and a greater emotional reactivity, for instance evaluated by the occurrence of tears while reading a sentimental story to RA patients [ 47 ].

Quite a few patients considered as being in remission still complain of multiple symptoms, particularly widespread pain or chronic fatigue [ 48 ]. Management of psychological distress, anxiety symptoms and coping strategies may be particularly beneficial for such RA patients, since psychological interventions have proved to be effective against residual symptoms in RA [ 49 ]. Building on this work, we will subsequently follow this cohort of early RA patients in order to study disease activity, evolution of coping strategies and of stress management, and production of proinflammatory cytokines according to the stress level in these patients.

Conclusions

While results from this study do not allow a causal relationship to be established, they strongly support the idea that stressful life events could contribute to the onset of RA symptoms. Gender specificities were found, with a significant association between cumulative stress and RA only in women. Assessing stress and related adjustment strategies in RA patients could help physicians to better manage the disease.

We acknowledge Professor Bruno Aouizerate for the final proofreading.

Funding : No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

Disclosure statement : The authors declare no conflicts of interest related to this work.

Supplementary data

Supplementary data are available at Rheumatology online.

Nielen MMJ , van Schaardenburg D , Reesink HW et al. . Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors . Arthritis Rheum 2004 ; 50 : 380 – 6 .

Google Scholar

Kokkonen H , Mullazehi M , Berglin E et al. . Antibodies of IgG, IgA and IgM isotypes against cyclic citrullinated peptide precede the development of rheumatoid arthritis . Arthritis Res Ther 2011 ; 13 : R13 .

Peschken CA , Robinson DB , Hitchon CA et al. . Pregnancy and the risk of rheumatoid arthritis in a highly predisposed North American Native population . J Rheumatol 2012 ; 39 : 2253 – 60 .

Kwok TSH , Bell MJ. Immune checkpoint inhibitor-induced rheumatoid arthritis: insights into an increasingly common aetiology of polyarthritis . BMJ Case Rep 2019 ; 12 : e227995 .

Li S , Yu Y , Yue Y , Zhang Z , Su K. Microbial infection and rheumatoid arthritis . J Clin Cell Immunol 2013 ; 4 : 174 .

Söderlin MK , Bergsten U , Svensson B , for the BARFOT study group. Patient-reported events preceding the onset of rheumatoid arthritis: possible clues to aetiology . Musculoskelet Care 2011 ; 9 : 25 – 31 .

Boer AC , Ten Brinck RM , Evers AWM , van der Helm-van Mil A. Does psychological stress in patients with clinically suspect arthralgia associate with subclinical inflammation and progression to inflammatory arthritis? Arthritis Res Ther 2018 ; 20 : 93 .

Bacconnier L , Rincheval N , Flipo R-M et al. . Psychological distress over time in early rheumatoid arthritis: results from a longitudinal study in an early arthritis cohort . Rheumatology (Oxford) 2015 ; 54 : 520 – 7 .

Wesley A , Bengtsson C , Skillgate E et al. . Association between life events and rheumatoid arthritis: results from a population-based case-control study: life events and rheumatoid arthritis . Arthritis Care Res (Hoboken) 2014 ; 66 : 844 – 51 .

Gekker M , Coutinho ESF , Berger W et al. . Early scars are forever: childhood abuse in patients with adult-onset PTSD is associated with increased prevalence and severity of psychiatric comorbidity . Psychiatry Res 2018 ; 267 : 1 – 6 .

McLaughlin KA , Conron KJ , Koenen KC , Gilman SE. Childhood adversity, adult stressful life events, and risk of past-year psychiatric disorder: a test of the stress sensitization hypothesis in a population-based sample of adults . Psychol Med 2010 ; 40 : 1647 – 58 .

Bruchon-Schweitzer M , Dantzer R. Introduction à la psychologie de la santé . Paris : Presses Universitaires de France , 2000 .

Google Preview

Aletaha D , Neogi T , Silman AJ et al. . 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative . Arthritis Rheum 2010 ; 62 : 2569 – 81 .

Holmes TH , Rahe RH. The social readjustment rating scale . J Psychosom Res 1967 ; 11 : 213 – 8 .

Cohen S , Kamarck T , Mermelstein R. A global measure of perceived stress . J Health Soc Behav 1983 ; 24 : 385 .

Wallston KA , Wallston BS , DeVellis R. Development of the Multidimensional Health Locus of Control (MHLC) scales . Health Educ Monogr 1978 ; 6 : 160 – 70 .

Sarason IG , Sarason BR , Shearin EN , Pierce GR. A brief measure of social support: practical and theoretical implications . J Soc Person Relat 1987 ; 4 : 497 – 510 .

Spielberger CD , Gorsuch RL , Lushene R , Vagg PR , Jacobs GA. Manual for the State-Trait Anxiety Inventory (Form Y1 – Y2). Palo Alto, CA: Consulting Psychologists Press, Vol. IV. 1983 .

Folkman S , Lazarus RS. An analysis of coping in a middle-aged community sample . J Health Soc Behav 1980 ; 21 : 219 .

Cousson F , Bruchon-Schweitzer M , Quintard B , Nuissier J , Rascle N. Analyse multidimensionnelle d’une échelle de ‘coping’: validation française de la W.C.C. (ways of coping checklist) . Psychol Française 1996 ; 41 : 155 – 64 .

Latman NS , Walls R. Personality and stress: an exploratory comparison of rheumatoid arthritis and osteoarthritis . Arch Phys Med Rehabil 1996 ; 77 : 796 – 800 .

Gross J , Oubaya N , Eymard F et al. . Stressful life events as a trigger for rheumatoid arthritis onset within a year: a case–control study . Scand J Rheumatol 2017 ; 46 : 507 – 8 .

Song H , Fang F , Tomasson G et al. . Association of stress-related disorders with subsequent autoimmune disease . JAMA 2018 ; 319 : 2388 .

Luukkainen R , Isomäki H , Kajander A. Prognostic value of the type of onset of rheumatoid arthritis . Ann Rheum Dis 1983 ; 42 : 274 – 5 .

Stack RJ , Sahni M , Mallen CD , Raza K. Symptom complexes at the earliest phases of rheumatoid arthritis: a synthesis of the qualitative literature . Arthritis Care Res (Hoboken) 2013 ; 65 : 1916 – 26 .

Trouillet R , Gana K , Lourel M , Fort I. Predictive value of age for coping: the role of self-efficacy, social support satisfaction and perceived stress . Aging Ment Health 2009 ; 13 : 357 – 66 .

Osmanovic-Thunström A , Mossello E , Åkerstedt T , Fratiglioni L , Wang H-X. Do levels of perceived stress increase with increasing age after age 65? A population-based study . Age Ageing 2015 ; 44 : 828 – 34 .

Asher M , Asnaani A , Aderka IM. Gender differences in social anxiety disorder: a review . Clin Psychol Rev 2017 ; 56 : 1 – 12 .

Ramjeet J , Koutantji M , Barrett EM , Scott D. Coping and psychological adjustment in recent-onset inflammatory polyarthritis: the role of gender and age . Rheumatology (Oxford) 2005 ; 44 : 1166 – 8 .

Seedat S , Scott KM , Angermeyer MC et al. . Cross-national associations between gender and mental disorders in the World Health Organization World Mental Health Surveys . Arch Gen Psychiatry 2009 ; 66 : 785 – 95 .

Riecher-Rössler A. Sex and gender differences in mental disorders . Lancet Psychiatry 2017 ; 4 : 8 – 9 .

Kendler KS , Karkowski LM , Prescott CA. Causal relationship between stressful life events and the onset of major depression . Am J Psychiatry 1999 ; 156 : 837 – 41 .

Maciejewski PK , Prigerson HG , Mazure CM. Sex differences in event-related risk for major depression . Psychol Med 2001 ; 31 : 593 – 604 .

Straub RH , Kalden JR. Stress of different types increases the proinflammatory load in rheumatoid arthritis . Arthritis Res Ther 2009 ; 11 : 114 .

Kajantie E , Phillips D. The effects of sex and hormonal status on the physiological response to acute psychosocial stress . Psychoneuroendocrinology 2006 ; 31 : 151 – 78 .

O’Donovan A , Cohen BE , Seal KH et al. . Elevated risk for autoimmune disorders in Iraq and Afghanistan veterans with posttraumatic stress disorder . Biol Psychiatry 2015 ; 77 : 365 – 74 .

Lee YC , Agnew-Blais J , Malspeis S et al. . Post-traumatic stress disorder and risk for incident rheumatoid arthritis . Arthritis Care Res (Hoboken) 2016 ; 68 : 292 – 8 .

Polinski KJ , Bemis EA , Feser M et al. . Perceived stress and inflammatory arthritis: a prospective investigation in the Studies of the Etiologies of Rheumatoid Arthritis (SERA) cohort . Arthritis Care Res (Hoboken) 2019 ; doi:10.1002/acr.24085.

Minnock P , Fitzgerald O , Bresnihan B. Quality of life, social support, and knowledge of disease in women with rheumatoid arthritis . Arthritis Rheum 2003 ; 49 : 221 – 7 .

Kojima M , Kojima T , Ishiguro N et al. . Psychosocial factors, disease status, and quality of life in patients with rheumatoid arthritis . J Psychosom Res 2009 ; 67 : 425 – 31 .

Coty M-B , Wallston KA. Problematic social support, family functioning, and subjective well-being in women with rheumatoid arthritis . Women Health 2010 ; 50 : 53 – 70 .

Nicassio PM , Kay MA , Custodio MK , Irwin MR et al. . An evaluation of a biopsychosocial framework for health-related quality of life and disability in rheumatoid arthritis . J Psychosom Res 2011 ; 71 : 79 – 85 .

Vriezekolk JE , van Lankveld WG , Geenen R , van den Ende CH. Longitudinal association between coping and psychological distress in rheumatoid arthritis: a systematic review . Ann Rheum Dis 2011 ; 70 : 1243 – 50 .

Englbrecht M , Gossec L , DeLongis A et al. . The impact of coping strategies on mental and physical well-being in patients with rheumatoid arthritis . Semin Arthritis Rheum 2012 ; 41 : 545 – 55 .

Stanton AL , Danoff-Burg S , Cameron CL , Ellis AP. Coping through emotional approach: problems of conceptualization and confounding . J Pers Soc Psychol 1994 ; 66 : 350 – 62 .

Bechman K , Sin FE , Ibrahim F et al. . Mental health, fatigue and function are associated with increased risk of disease flare following TNF inhibitor tapering in patients with rheumatoid arthritis: an exploratory analysis of data from the Optimizing TNF Tapering in RA (OPTTIRA) trial . RMD Open 2018 ; 4 : e000676 .

Ishii H , Nagashima M , Tanno M , Nakajima A , Yoshino S. Does being easily moved to tears as a response to psychological stress reflect response to treatment and the general prognosis in patients with rheumatoid arthritis? Clin Exp Rheumatol 2003 ; 21 : 611 – 6 .

McWilliams DF , Ferguson E , Young A , Kiely PDW , Walsh DA. Discordant inflammation and pain in early and established rheumatoid arthritis: latent Class Analysis of Early Rheumatoid Arthritis Network and British Society for Rheumatology Biologics Register data . Arthritis Res Ther 2016 ; 18 : 295 .

Prothero L , Barley E , Galloway J , Georgopoulou S , Sturt J. The evidence base for psychological interventions for rheumatoid arthritis: a systematic review of reviews . Int J Nurs Stud 2018 ; 82 : 20 – 9 . Jun

• rheumatoid arthritis
• surgical procedures, operative
• coping behavior
• stressful events
• symptom onset

Email alerts

Citing articles via.

• Rheumatology Twitter
• BSR Twitter
• BSR Facebook
• Recommend to Your Librarian

Affiliations

• Online ISSN 1462-0332
• Print ISSN 1462-0324
• Copyright © 2024 British Society for Rheumatology
• About Oxford Academic
• Publish journals with us
• University press partners
• What we publish
• New features  
• Open access
• Institutional account management
• Rights and permissions
• Get help with access
• Accessibility
• Advertising
• Media enquiries
• Oxford University Press
• Oxford Languages
• University of Oxford

Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide

• Copyright © 2024 Oxford University Press
• Cookie settings
• Cookie policy
• Privacy policy
• Legal notice

This Feature Is Available To Subscribers Only

Sign In or Create an Account

This PDF is available to Subscribers Only

For full access to this pdf, sign in to an existing account, or purchase an annual subscription.

Case study: management and counselling of a patient with rheumatoid arthritis

Exploring questions to be considered when managing a patient with rheumatoid arthritis.

Shutterstock.com

Case scenario

Mrs PJ is a 67-year-old woman with rheumatoid arthritis. Her current prescription includes:

• Salazopyrin EN 500mg twice a day;
• Diclofenac 50mg three times a day;
• Paracetamol 1g up to four times a day when required.

She collected her first prescription for sulfasalazine two weeks ago. She has returned to the pharmacy and asks to speak to you. She has several problems with her medication which she wishes to discuss. First, she complains that her medication is not working properly and she tells you that she has not noticed any benefit from it. She asks you whether you think she should make an appointment with her GP to discuss this.

Case discussion

Pharmacy Case Studies by Soraya Dhillon and Rebekah Raymond. Pp 471 £29.99. London: Pharmaceutical Press; 2009. ISBN 978 0 85369 724 4

This discussion, adapted from Pharmacy Case Studies [1]   published by Pharmaceutical Press, highlights the main questions to be considered in managing Mrs PJ’s case. 

How is the dose of sulfasalazine normally initiated and titrated?

The patient should start with one tablet daily, increasing their dosage by a tablet a day each week until one tablet four times a day, or two tablets three times a day are reached, according to tolerance and response.

Why is the dose increased gradually?

Nausea may be a problem for some patients, hence the dose is titrated up gradually to avoid this.

What advice would you give Mrs PJ in answer to her question? 

Mrs PJ should be informed that the onset of effect of sulfasalazine is slow and an initial benefit may not be seen for 4–16 weeks. It would be useful to check what instructions Mrs PJ has been given regarding the titration of her medication. She is currently on a dose at the lower end of the titration scale.

You could ask Mrs PJ when her follow-up appointment with the prescribing doctor is due. If she has an appointment in the very near future, her dose may be increased at that consultation. 

If Mrs PJ has not been given a titrating dose, it may be worth suggesting that she contacts her prescribing doctor to confirm the instructions given to her at the initial appointment. It is important to reiterate that the onset of action of the sulfasalazine is slow.

Mrs PJ also mentions that she has to go to her practice nurse for some blood tests but she’s not sure why. The British National Formulary recommends that liver function tests, full blood counts and renal function tests are carried out regularly.

How often should the above tests be performed?

Close monitoring of the full blood count and liver function tests is necessary initially and then at monthly intervals for at least the first three months of treatment. Renal function tests may be performed periodic­ally, as recommended by the manufacturers.

Why should these tests be performed?

Side effects of sulfasalazine include blood dyscrasias which usually occur in the first 3–6 months of treatment. The full blood count should be checked regularly so that any haematological abnormalities can be ­identified at an early stage. 

There have been reports of hepatitis and renal dysfunction in patients taking sulfasalazine, therefore liver function tests and renal function tests should be performed at regular intervals.

In the course of the conversation, Mrs PJ tells you that since she has started taking her new medication, she has been experiencing stomach discomfort about half an hour after she has taken her tablets. 

What do you think could be the cause of this problem?

As the symptoms initially appear to be related to her medication she may be experiencing gastric irritation as a result of her diclofenac or she may be suffering from nausea due to the sulfasalazine. Ask Mrs PJ whether she is suffering from any alarm symptoms like gastrointestinal bleeding, unintentional weight loss, difficulty swallowing, abdominal swelling or persistent vomiting. If Mrs PJ is experiencing any of these symptoms, she should be referred to her GP urgently.

What suggestions could you offer Mrs PJ to help resolve this problem?

With further questioning, it may be possible to clarify the symptoms and to ascertain whether one of the drugs is likely to be causing the problem. You should check that Mrs PJ is taking her diclofenac with food so as to reduce the risk of gastric irritation. If you decide that the problem is likely to be dyspepsia, in most cases an antacid may help. In this case, however, an antacid could not be taken at the same time as either sulfasalazine or diclofenac. This is because both are enteric-coated tablets and the presence of an antacid may lead to the premature dissolution of the coating due to the presence of an alkaline pH. Therefore, the use of an antacid would not be a suitable suggestion.

As this is a suspected adverse drug reaction, it would be prudent to suggest to Mrs PJ that she returns to her GP to discuss this issue with them.

What alternative medication might a doctor prescribe to help Mrs PJ with her upset stomach?  

If the doctor decided that the cause of Mrs PJ’s upset stomach may be non-steroidal anti-inflammatory drug (NSAID)-induced dyspepsia, it would be usual to stop NSAID treatment. However in the case of Mrs PJ, this might not be possible due to her concurrent medical history of rheumatoid arthritis. 

The doctor may decide to stop the NSAID and see how Mrs PJ ­manages without the diclofenac or may consider adding in a proton pump inhibitor, in line with Clinical Knowledge Summaries guidance [2] , to manage the incid­ence of NSAID-induced dyspepsia. If it is felt that the problem is related to the sulfasalazine and the nausea does not abate, the doctor may try an alternative treatment. As Mrs PJ is currently only on a low dose of sulfasalazine it would not really be possible to reduce the dose and still maintain efficacy.

Four months later, Mrs PJ returns to your pharmacy. She says that she still has not had much benefit from her sulfasalazine despite the fact that her dose has been titrated to an appropriate level.

What are the goals of therapy when treating rheumatoid arthritis?

When treating rheumatoid arthritis, the goals of therapy are to reduce the symptoms of the disease, slow progression of the disease and limit the amount of joint deformation, while improving the patient’s quality of life.

Please list the alternative treatments that may be used in the management of rheumatoid arthritis and briefly discuss when an alternative treatment would be tried.

When a drug has been titrated to the maximum dose that can be tolerated and the level of disease control is still unacceptable, therapy may be switched to an alternative agent or another drug may be added in. Other treatments available for managing rheumatoid arthritis include:

• methotrexate
• gold injections
• antimalarials
• leflunomide
• penicillamine
• ciclosporin
• azathioprine
• cyclophosphamide
• cytokine modulators
• corticosteroids

Nicola Parr , BPharm (Hons), MSc, MRPharmS is senior pharmacist, Addenbrooke’s Hospital, Cambridge and Tracy Garnier , BSc (Hons), PhD, PgCert, MRPharmS is principal lecturer in pharmaceutics, School of Pharmacy, University of Hertfordshire.

[1]   Pharmacy Case Studies by Soraya Dhillon and Rebekah Raymond. Pp 471 £29.99. London: Pharmaceutical Press; 2009. ISBN 978 0 85369 724 4

[2]  Clinical Knowledge Summaries (2015) Dyspepsia. Available at:  http://cks.nice.org.uk/dyspepsia-unidentified-cause#!scenario:2

General reference

Bryant DM & Alldred A. Rheumatoid arthritis and osteoarthritis (2007). In: Walker R and Whittlesea C (Eds)  Clinical Pharmacy and Therapeutics , 4th edn. Edinburgh: Churchill Livingstone.

You might also be interested in…

TNFα-inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis

Biosimilar medicines in rheumatology

Osteoarthritis: management

Rheumatoid arthritis: Differentiating between forms of crippling arthritis

Emma, a 32-year-old with existing foot and hand pain, visits her healthcare provider after hand pain, neck stiffness, and worsening fatigue over the last three months.

Emma’s healthcare provider conducts a full clinical history and physical examination and decides to test for rheumatoid arthritis.  

Emma is experiencing joint pain and fatigue. See how serological testing can help confirm a diagnosis of rheumatoid arthritis.

Patient History

Family history.

• Mother has unknown form of crippling arthritis.

Emma's Personal History

• Localized pain in knuckles of hand and pads of feet.
• Ibuprofen helps some, and acetaminophen does not.
• Imaging: Marginal erosions were detected on radiographs.
• Physical examination: Normal with the exception of the hands, which were tender when palpated over the second and third proximal interphalangeal joints.

Emma’s  Test Results

These results together with this patient's case history and symptoms, help confirm the diagnosis.  

Differential Diagnosis

REFINED DIAGNOSIS

• Inflammatory arthritis, rheumatoid.

HEALTHCARE PROVIDER MANAGEMENT PLAN

• Steroids and methotrexate initially.
• Biologics or triple therapy if inadequate response.
• Follow up every eight to 12 weeks in the beginning to assess therapies and monitor lab work.
• Healthcare provider visits may extend to every three to six months if well controlled.

The people, places, and events depicted in these case studies and photographs do not represent actual patients, nor are they affiliated in any way with Thermo Fisher Scientific.

Select your language/region

Before you proceed ...

We noticed you may be visiting a version of our website that doesn’t match your current location. Would you like to view content based on your region?

Nursing Case Study for Rheumatoid Arthritis

Watch More! Unlock the full videos with a FREE trial

Included In This Lesson

Study tools.

Access More! View the full outline and transcript with a FREE trial

A new graduate nurse, Tim, is shadowing at a local primary care clinic as part of his residency program. The first appointment of the day is a 38-year-old female patient, Doris, complaining of arm and leg joint pain and morning joint stiffness.  She reports the symptoms have been going on a while and worsening to the point she seeks medical treatment.  The nurse supervising Tim says, “I wonder if it is rheumatoid arthritis?” 

Why does Tim understand this suspicion of the supervising nurse?

• Medical history, with particular attention to joint pain, reported swelling, and the presence, location (peripheral joints rather than low back), and duration (at least 30 minutes) of morning stiffness. The absence of other conditions or symptoms suggesting an alternative diagnosis, such as psoriasis, inflammatory bowel disease (IBD), or a systemic rheumatic disease such as systemic lupus erythematosus (SLE), helps to exclude other disorders.
• Symptoms of arthritis that have been present for a short time (for example, less than six weeks) may well be due to an acute viral polyarthritis rather than RA. The longer symptoms persist, the more likely the diagnosis of RA becomes.

Should he be cautious of this suspicion at this time? Why?

• Joint pain involving the hands is a common clinical presentation for a variety of conditions, thus a number of other diagnoses must be considered in the differential diagnosis of rheumatoid arthritis (RA).
• It could be viral polyarthritis (a variety of viral illnesses can cause this). Also, “Early RA may be difficult to distinguish from the arthritis of systemic lupus erythematosus (SLE), Sjögren’s syndrome, dermatomyositis (DM), or overlap syndromes such as mixed connective tissue disease.”

What tests does Tim anticipate will be performed in the primary care clinic to confirm or rule out this condition?

• The provider should carefully assess the patient but that alone cannot confirm or rule out the condition. That will take a more in-depth examination, testing, and consultation. But to start, a thorough medical history including travel and/or outdoor activities (to determine if there are infectious causes).
• Next, a complete physical exam with attention to looking at the joints, in particular those in the hands. “The key features of early rheumatoid inflammation are pain and swelling of the affected joints. Painful inflammation is demonstrated either by local tenderness from pressure applied on the joint or by pain on moving the joint.”

During history taking, the patient states she has a relative with “joint problems” but thought her issues were just from stress. She has a full-time job with many deadlines and has two children. She denies alcohol or substance use but says, “I still smoke about a half a pack a day.” Her primary concern is that her hands “don’t seem to work right.” She denies rashes or skin problems and also says, “I am never sick, especially lately I’ve been healthy as a horse. This is such a hassle.”

Are there further clues as to what may be causing Doris’ pain?

• There are some risk factors she mentions: family history (possibly), stress and smoking can exacerbate RA. She denies rash so that may help rule out other possibilities (psoriatic arthritis, Lyme disease). And the fact her hands are involved may be an indication of RA

The provider completes an exam and takes a detailed history. He advises nursing staff to prepare to take labs and schedule a follow-up appointment for her to get the results. Tim asks about radiologic exams, like x rays, and the provider states, “Those are not needed right now.”

Why might Tim ask about radiology tests? Why does Tim think the provider does not want them now?

• He knows they may help with diagnosis or rule out. Plus, “Radiographs of the hands, wrists, and feet – during the initial evaluation primarily as a baseline for monitoring disease progression.”
• The provider may want to obtain labs before looking at other diagnostics. Also, the primary care clinic may not have the equipment on site (remember, this is not an acute care facility).

What labs does Tim anticipate drawing?

• Rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) Erythrocyte sedimentation rate (ESR or “sed rate”) and serum C-reactive protein (CRP) – Both the ESR and CRP are typically elevated in RA.
• Antinuclear antibody (ANA) testing
• Complete blood count (CBC) with differential and platelet count, tests of liver and kidney function, serum uric acid, and a urinalysis – The CBC is often abnormal in RA, with anemia and thrombocytosis consistent with chronic inflammation. Liver and kidney testing abnormalities indicate a disorder other than RA; if caused by comorbid conditions.

Two weeks later, Doris returns for her lab results.

ESR 69 mm/h CRP 15 mg/L ANA positive Rheumatoid factor positive

HBG 10 g/dL HCT 30% WBC WNL Platelets 500,000 cells/mcl

What does Tim understand about these results?

• Elevated ESR and CRP are not disease-specific but indicate inflammation. They are commonly elevated in RA. She has a positive Rh factor and ANA, also common in RA. She is mildly anemic and has thrombocytosis, both conditions not diagnostic of RA but common in those with the condition.

The provider refers Doris to a rheumatologist. He educates the patient about how it is vital that she follow up as soon as possible. After the provider leaves, she asks, “What’s the rush? Am I going to die or something?”

How should Tim address Doris’ questions?

• It is important she is diagnosed early and sees a specialist to begin a medication regimen to reduce damage.
• The aim of rheumatoid arthritis (RA) treatment is to control symptoms, prevent joint damage, and maximize your quality of life and ability to function. Joint damage caused by RA generally occurs within the first two years of diagnosis, and it is difficult to predict which individuals will develop long-term complications. Therefore, the initial treatment of RA aims to eliminate or minimize inflammation.

Doris verbalizes understanding of the need to see a specialist. She says she has read a little on the internet about RA and wonders about medications she may be prescribed.

What type of education should Tim provide about RA medications?

• Often, more than one medication is used. NSAIDs (ibuprofen, diclofenac for example) DMARDS – methotrexate, biologics (i.e. adalimumab, etanercept, infliximab), steroids, DMARDs are some types of meds used. Side effects should be taught about each type.

Doris makes an appointment with the rheumatologist and thanks the staff for their help.

What are some barriers that some RA patients may face regarding their treatment?

• Some patients may not have access to care from specialists. They may not be able to take new or newer medications due to cost. Also, the follow-up with the prescriber may be harder for low-income patients or those without health care insurance.

View the FULL Outline

When you start a FREE trial you gain access to the full outline as well as:

• SIMCLEX (NCLEX Simulator)
• 6,500+ Practice NCLEX Questions
• 2,000+ HD Videos
• 300+ Nursing Cheatsheets

“Would suggest to all nursing students . . . Guaranteed to ease the stress!”

References:

View the full transcript, nursing case studies.

This nursing case study course is designed to help nursing students build critical thinking.  Each case study was written by experienced nurses with first hand knowledge of the “real-world” disease process.  To help you increase your nursing clinical judgement (critical thinking), each unfolding nursing case study includes answers laid out by Blooms Taxonomy  to help you see that you are progressing to clinical analysis.We encourage you to read the case study and really through the “critical thinking checks” as this is where the real learning occurs.  If you get tripped up by a specific question, no worries, just dig into an associated lesson on the topic and reinforce your understanding.  In the end, that is what nursing case studies are all about – growing in your clinical judgement.

Nursing Case Studies Introduction

Cardiac nursing case studies.

• 6 Questions
• 7 Questions
• 5 Questions
• 4 Questions

GI/GU Nursing Case Studies

• 2 Questions
• 8 Questions

Obstetrics Nursing Case Studies

Respiratory nursing case studies.

• 10 Questions

Pediatrics Nursing Case Studies

• 3 Questions
• 12 Questions

Neuro Nursing Case Studies

Mental health nursing case studies.

• 9 Questions

Metabolic/Endocrine Nursing Case Studies

Other nursing case studies.

Rheumatoid arthritis - hands

Citation, doi, disclosures and case data.

At the time the case was submitted for publication Samir Benoudina had no recorded disclosures.

Presentation

Bilateral hand pain.

Patient Data

• bilateral and symmetrical involvement
• proximal interphalangeal joint space narrowing  
• metacarpal heads erosions 
• metacarpophalangeal joint space narrowing 
• metacarpophalangeal joint osteopenia 
• pancarpal and radiocarpal involvement with erosions 
• carpometacarpal erosion 
• distal radioulnar joint loss of space  
• distal interphalangeal joints spared
• soft tissue swelling
• proximal interphalangeal joint space narrowing (yellow arrows)
• metacarpal heads erosions (red arrows)
• metacarpophalangeal joint space narrowing (blue arrows)
• metacarpophalangeal joint osteopenia (green circles)
• pancarpal and radiocarpal involvement with erosions (yellow circles)
• carpometacarpal erosion (purple arrows)
• distal radioulnar joint loss of space (black arrows)

Case Discussion

This is a known case of rheumatoid arthritis . Rheumatoid arthritis is a relatively common arthritis with a prevalence of 0.5-1% and female preponderance. There are a number of classical imaging features in the hands, as illustrated in this case.

• 1. Sommer OJ, Kladosek A, Weiler V et-al. Rheumatoid Arthritis: A Practical Guide to State-of-the-Art Imaging, Image Interpretation, and Clinical Implications1. (2005) RadioGraphics. 25 (2): 381-98. doi:10.1148/rg.252045111 - Pubmed

2 articles feature images from this case

• Rheumatoid arthritis
• Rheumatoid arthritis (musculoskeletal manifestations)

74 public playlists include this case

• msk nov 2018 by Karina Dorfman
• Erosive Arthropathies - Classic 2B Findings by Pauline Gammack
• BOARDS by Rachel Martin
• MSK by Sourabh Malhotra
• Liðbólgur by Jón Bjarnason
• GOUT by Nguyễn Thị Thu
• Polyarthrite rhumatoïde by Hesham Algaami
• Arthropathies of hands & feet by John Fitzpatrick
• Part 2 Board Cases Prep by Ali Smith
• 07 MSK (CPSP) by Afaaq Rasool
• MSK Viva 3 by Minh Xuan Truong ◉
• MSK by Naseera Khanum
• Arthritides by Whitney Graff
• Imágenes del SME by Silvana F Ciardullo
• Gout by Thuy Thuy Duong
• Teaching Rounds by Thomas M. Anderson ◉
• Arthropathy by Sukhdev Singh Saini
• MSK 2 by Jyothish
• N2 by Nuha homeida
• MSK ARTHRITIS by Bilal Vanlioglu
• RadioP 2020 by anthony trimboli
• MSK by Kenneth Kwok
• BJ exam 2 by Chelsea S
• 0001 Rheumatoid arthritis by Tom Molyneux
• MSK - arthritides by Georgia Yeo
• Arthritis by Kayla Beck
• MSK ZAK by Z Khan
• FRCR 2b MSK - D part 1 by Dilina Rajapakse
• Boards Part 4 radiology review by Juliet Murray
• MSK teaching 25/2/21 by Geoffrey Chow
• Hand arthopathies by Seb Belfrage
• 3) MSK by Dominik Franz-Josef
• Shuyi MSK by Shuyi Guo
• MANA INTERESANT by Marius Oprea
• Taller de repaso by Silvana F Ciardullo
• ARTHRITIS by Daoud akhtar
• Rad DX Exam 1 Practice by Jacob Freeman
• arthritis hands - LM by Lorie Markowsky
• AK test cases 10 by Amandeep Kahlon
• MSK by Anthony Adeleke Adewumi ◉
• ARTHRITIS by Maha Elaassar
• Panel 2.2 by Isanka Udayangani
• Promet MSK by Turay Cesur
• Röntgen by Priya Jenny Singh
• BP II by Mai-Linh Le
• MSK viva PF 2B prep list 1 by Dai Roberts ◉
• MSK by R A A
• Rhumato by Vincent no Vorburger
• castle by Shalitha Bandara Samarakoon
• Viva 13 march by Nazahat Pasha
• Canada Med students by Chris Newman
• MSK VIVA Set 1 by Cameron Grant
• MSK by Ian Graham
• Canterbury - metabolic by Ben Roberson
• Msk by Damian Brauchli
• Artropatias by Daniel Díaz Espinosa
• FRCR 2B 22/08/23 by Thomas Tattersfield
• 2b by Michael Courtney
• Imaging 3 - Rheumatoid Arthritis/ Scleroderma/ Lupus by John Bassano
• MSK 1 by Khalida Khurshid
• MSK by saima hafeez khokhar
• Arthritides by Robyn Blain
• FRCR 2b viva and long by Amr Ahmed Awad Mahmoud
• MSK by Khalida Khurshid
• MSK cases 2 by Rahim Akram
• MSK 10 - Arthritis Patterns by Praveen Samarawickrama
• MSK by MANIMEKALA THAMBITHURAI
• MSK EDIR by Hugo Glez
• 1Galune_virsutine by Tomas Jurevicius
• 2024 MSK Upper limb by Richard Hodgson ◉

Related Radiopaedia articles

Promoted articles (advertising), how to use cases.

You can use Radiopaedia cases in a variety of ways to help you learn and teach.

• Add cases to playlists
• Share cases with the diagnosis hidden
• Use images in presentations
• Use them in multiple choice question

Creating your own cases is easy.

• Case creation learning pathway

ADVERTISEMENT: Supporters see fewer/no ads

By Section:

• Artificial Intelligence
• Classifications
• Imaging Technology
• Interventional Radiology
• Radiography
• Central Nervous System
• Gastrointestinal
• Gynaecology
• Haematology
• Head & Neck
• Hepatobiliary
• Interventional
• Musculoskeletal
• Paediatrics
• Not Applicable

Radiopaedia.org

• Feature Sponsor
• Expert advisers

A case of methotrexate-related lymphoproliferative disease showing multiple liver lesions in a patient with rheumatoid arthritis

• Case Report
• Open access
• Published: 20 April 2024

Cite this article

You have full access to this open access article

• Yamato Nagata   ORCID: orcid.org/0009-0001-4384-0670 1 ,
• Shotaro Akiba 1 ,
• Hidekazu Horiuchi 1 ,
• Kazuo Okumoto 1 ,
• Shigemi Hachinohe 1 &
• Rintaro Ohe 2  

86 Accesses

Explore all metrics

A 66-year-old woman with rheumatoid arthritis (RA) who had been receiving methotrexate (MTX) for 2 years presented with tarry stools. Contrast-enhanced computed tomography (CT) of the abdomen revealed irregular wall thickening in the ileocecal region and multiple low-contrast masses in both lobes of the liver. Lower gastrointestinal endoscopy revealed a type 2 tumor in the ileocecal region with a semi-peripheral ulcer. Histological examination of liver and colon biopsies showed other iatrogenic immunodeficiency-associated lymphoproliferative disorder (Oi-LPD), diffuse large B-cell lymphoma type, with positivity for Epstein-Barr virus DNA. After withdrawal of MTX, the LPD lesions disappeared and the patient achieved remission. We considered this to be a sporadic case of Oi-LPD, diffuse large B-cell lymphoma type, in the liver and colon due to treatment with MTX. There has been no previous report of this condition with simultaneous hepatic and colonic lesions, and the present case is thought to be highly informative in relation to the pathogenesis.

Avoid common mistakes on your manuscript.

Introduction

Lymphoproliferative disorders (LPDs) arise in patients who have been treated with immunosuppressants, and diffuse large B-cell lymphoma (DLBCL) is the most common type. One such immunosuppressant, methotrexate (MTX), is the first choice for patients with rheumatoid arthritis (RA) [ 1 , 2 ]. EBV reactivation associated with reduced immunocompetence is known to be responsible for the development of MTX-LPD. As MTX administration for RA tends to be prolonged, development of MTX-LPD is known to be a severe complication [ 3 ]. Here we report our experience with a RA patient who developed MTX-LPD, DLBCL type, in the liver and colon.

Case presentation

A 66 year-old woman was admitted to our hospital with a 3 day history of tarry stools. She had RA and had been treated with salazosulfapyridine, iguratimod and MTX for 2 years. Her RA symptoms were well controlled. Her abdomen was flat, soft, and not tender. Severe anemia (hemoglobin 7.6 g/dL) was evident, and the serum levels of C-reactive protein and soluble interleukin-2 receptor were 9.19 mg/dL and 2,630 U/mL, respectively. Epstein–Barr virus (EBV) DNA was detected in the peripheral blood at 3.60 log IU/ml (Table  1 ). Contrast-enhanced CT revealed a mass with enhancement in the ileocecal region (Fig.  1 A), and multiple nodular masses without enhancement in the liver and para-aortic region (Fig.  1 B and C). Contrast-enhanced magnetic resonance imaging (MRI) with gadolinium-ethoxybenzyl diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA) showed multiple tumors in the liver with central necrosis (Fig.  1 D-G). Lower gastrointestinal endoscopy revealed a mass in the ileocecal region which was suspected malignant tumor (Fig.  2 ). Liver metastasis of ileocecal cancer or malignant lymphoma was suspected, and ultrasound-guided biopsy of the liver tumors was performed. Histological examination of the liver and colon specimens revealed proliferation of CD20-positive large lymphoid cells with necrosis and in situ hybridization (ISH) demonstrated Epstein-Barr encoding region (EBER)-1 positivity. Histological examination showed diffuse proliferation of mostly large lymphoid cells with necrosis in the liver (Fig.  3 A and B ) and colon, although there was no atypia in the epithelium of the surface mucosa of colon. Immunohistochemically, these large lymphoid cells were CD20 ( +) (Fig.  3 C), CD30 ( +) (Fig.  3 D), CD10 ( +) (Fig.  3 E), CD 23 (−) (Fig.  3 F), BCL2 (−) (Fig.  3 G), BCL6 (−) (Fig.  3 H), and MUM1 (−) (F i g.  3 I). The Ki-67 labeling index was 80% (Fig.  3 J). EBER positivity was detected by ISH (Fig.  3 K). Immunostaining of biopsies from the colon yielded similar findings (Fig.  3 L and M). The final diagnosis was Oi-DLBCL based on the WHO classification revised fourth edition, as the multiple tumors began to shrink after MTX withdrawal.

Abdominal imaging modalities. Contrast-enhanced computed tomography (CT) showed a mass with enhancement in the ileocecal region ( A , arrow ), and multiple nodular masses without enhancement in the liver ( B ) and para-aortic region ( C , arrow ). Penetrating vessels running through the tumor were detected in the liver ( B , arrow). Contrast-enhanced magnetic resonance imaging (MRI) with gadolinium-ethoxybenzyl diethylenetriamine-penta-acetic acid (Gd-EOB-DTPA) showed that multiple tumors in the liver were lower contrast than the liver parenchyma in portal phase ( D ). T1-weighted images showed low signal in all lesions ( E ). The coarse lesion was centrally high signal on T2-weighted images ( F ) and low signal on DWI images ( G )

Lower gastrointestinal endoscopy. Lower gastrointestinal endoscopy revealed a mass in the ileocecal region which was suspected malignant tumor

Histological findings in the liver and colon specimens. Histological examination showed diffuse proliferation of mostly large lymphoid cells with necrosis ( A , B ). Immunohistochemically, the liver specimens revealed CD20 ( +) ( C ), CD30 ( +) ( D ), CD10 ( +) ( E ), CD 23 (−) (F), BCL2 (−) (G), BCL6 (−) (H), MUM1 (−) ( I ), and Ki-67 labeling index 80% ( J ). EBV encoding RNA (EBER) positivity was detected by in situ hybridization (ISH) ( K ). Similarly, histology of the colon specimens also revealed CD20 ( +) ( L ) and EBER-ISH positivity ( M )

Observation was continued, and CT of the abdomen four months later revealed spontaneous shrinkage of most of the tumors (Fig.  4 A). The serum level of sIL-2R improved spontaneously (312 IU/ml), and EBV DNA in the peripheral blood decreased to less than the standard value. After the withdrawal of MTX, the patient experienced no deterioration in her joints. There has been no sign of recurrence for 8 months (Fig.  4 B and 5 ).

Imaging of the abdomen after methotrexate withdrawal. CT of the abdomen four months later revealed spontaneous shrinkage of most of the tumors ( A ). There has been no sign of recurrence for eight months ( B )

Lower gastrointestinal endoscopy after methotrexate withdrawal. The tumor in the ileocecal region disappeared 8 months later

RA patients are known to have a 2- to 4-fold higher incidence of malignant lymphoma as a complication than the general population [ 4 ]. Although MTX is used as a first-line treatment for patients with RA, it carries a risk of LPD [ 2 ]. When LPD occurs, biologics are often used in the RA patients as an alternative to MTX [ 5 ]. LPD, including malignant lymphoma, has been found to occur in RA patients receiving MTX, and this is termed MTX-LPD. The WHO classifies it as immunodeficiency-associated LPD. EBV infection is said to be a complication in about half of MTX-LPD cases, and EBV reactivation has been implicated [ 6 , 7 , 8 ]. It is thought that the EBV gene releases factors similar to growth factors, transcription factors, and apoptosis inhibitors, causing B lymphocytes to transform into lymphoblasts, exhibiting tumor-like growth [ 9 ]. The most common sites of MTX-LPD are lymph nodes [ 10 ] and tonsils [ 11 ], but thyroid [ 12 ], lung [ 13 ], liver [ 14 ], and colon lesions [ 15 ] have also been reported.

Imaging modalities, such as US and CT, can aid the diagnosis of hepatic lymphoma/MTX-LPD. A previous report has indicated that penetrating vessels running through the tumor visualized by US was helpful for diagnosis of hepatic lymphoma [ 16 ]. In the present case, penetrating vessels running through the tumor were detected by CT scan. The evidence suggests that MTX-LPD should be considered in RA patients who are receiving MTX medications when CT or US shows a hepatic mass with signs of penetrating vessels.

A search of PubMed using the terms “MTX-LPD” and “hepatic”, or “MTX-LPD” and “liver”, yielded 12 available studies published in English between 2000 and 2022 [ 10 , 14 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. In all cases the patients had been treated with immunosuppressants such as MTX, steroids, infliximab, and tacrolimus. All had taken MTX for more than 24 months, and the median total dose of MTX was 1932 mg (960–6000 mg). Ten patients showed reactivation of EBV. The present patient had taken MTX for 24 months (total dose, 960 mg) and also showed reactivation of EBV. MTX-LPD involving the liver along with other parenchymal organs must be differentiated from cancer metastasis. As shown in Table  2 , five patients with hepatic MTX-LPD accompanied by other parenchymal organ lesions involvement of the adrenal gland ( n  = 2), multiple lymph nodes ( n  = 1), spleen ( n  = 1), and colon ( n  = 1, this case).

In the listed MTX-LPD, DLBCL type cases ( n  = 8), MTX was discontinued and three of the patients achieved complete remission. Three additional patients achieved complete remission with chemotherapy. Two patients were treated by partial hepatectomy and had no recurrence. Two patients with MTX-LPD, Hodgkin lymphoma type, also stopped using MTX. One of them suffered relapse even after withdrawal of MTX, and the other underwent partial hepatectomy and had no recurrence. Our present patient achieved complete remission after MTX had been withdrawn. These findings suggest that immediate withdrawal of MTX is recommended for patients with hepatic MTX-LPD, DLBCL type. Our patient had two lesions; these may have been concurrent, or one may have been due to metastasis from the colon to the liver. Because of the multiple lymph node metastases and the histological similarities of the lesions, the possibility that the colon lesion had metastasized to the liver could not be ruled out. To our knowledge, this is the first case of MTX-LPD involving both the liver and colon to have been reported in English.

We have experienced a case of MTX-LPD, DLBCL type, in which multiple liver masses and colon lesions were concurrent. Multiple systemic masses in RA patients receiving MTX are suggestive of MTX-LPD, and early discontinuation of MTX should be considered.

Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68:1–26.

Article   PubMed   Google Scholar  

Ohe R, Yang S, Yamashita D, et al. Pathogenesis of follicular thymic hyperplasia associated with rheumatoid arthritis. Pathol Int. 2022;72:252–60.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Saito S, Takeuchi T. Immune response in LPD during methotrexate administration (MTX-LPD) in rheumatoid arthritis patients. J Clin Exp Hematop. 2019;59:145–55.

Article   PubMed   PubMed Central   Google Scholar  

Anderson LA, Gadalla S, Morton LM, et al. Population-based study of autoimmune conditions and the risk of specific lymphoid malignancies. Int J Cancer. 2009;125:398–405.

Katsuyama T, Sada KE, Yan M, et al. Prognostic factors of methotrexate-associated lymphoproliferative disorders associated with rheumatoid arthritis and plausible application of biological agents. Mod Rheumatol. 2017;27:773–7.

Article   CAS   PubMed   Google Scholar  

Kikuchi K, Miyazaki Y, Tanaka A, et al. Methotrexate-related epstein-barr virus (EBV)-associated lymphoproliferative disorder–so-called “Hodgkin-like lesion”–of the oral cavity in a patient with rheumatoid arthritis. Head Neck Pathol. 2010;4:305–11.

Kitamura N, Sugiyama K, Nagasawa Y, et al. Involvement of Epstein-Barr virus in the development and spontaneous regression of methotrexate-associated lymphoproliferative disorder in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2022;40:1330–5.

PubMed   Google Scholar  

Afonso C, Roque A, Almeida C, et al. Methotrexate-associated lymphoproliferative disorder in a patient with psoriasis: a case report and review of the literature. Case Rep Hematol. 2022;2022:7178065.

PubMed   PubMed Central   Google Scholar  

Grywalska E, Markowicz J, Grabarczyk P, et al. Epstein-Barr virus-associated lymphoproliferative disorders. Postepy Hig Med Dosw (Online). 2013;67:481–90.

Tsukazaki Y, Shinohara T, Tanaka K, et al. Hepatosplenic Hodgkin lymphoma without lymphadenopathy following reversible methotrexate-associated lymphoproliferative disorder. Mod Rheumatol. 2017;27:372–5.

Watanabe T, Teratani Y. Unusual manifestation of methotrexate-associated lymphoproliferative disorder as a palatal mass. BMJ Case Rep. 2022. https://doi.org/10.1136/bcr-2022-250616 .

Hiruma M, Tsuboi K, Hirose T. Methotrexate-associated lymphoproliferative disorder in the thyroid gland of a patient with chronic thyroiditis. J Med Ultrason. 2001;2023(50):575–6.

Google Scholar  

Suemori K, Hasegawa H, Ishizaki J, et al. Methotrexate-associated lymphoproliferative disease with multiple pulmonary nodules in a patient with rheumatoid arthritis. Intern Med. 2015;54:1421–5.

Omameuda T, Miyato H, Sata N, et al. Primary hepatic methotrexate-associated lymphoproliferative disorder associated with Epstein-Barr virus reactivation and accompanied by spontaneous necrosis: a case report. Medicine (Baltimore). 2022;101: e31993.

Shirakabe K, Mizokami K. Methotrexate-associated lymphoproliferative disease detected as a colorectal mass lesions: a case report. J Surg Case Rep. 2023. https://doi.org/10.1093/jscr/rjad098 .

Takasumi M, Okai K, Asano T, et al. A case of methotrexate-associated lymphoproliferative disorder diagnosed by liver biopsy. Nihon Shokakibyo Gakkai Zasshi. 2015;112(1):115–22.

Soubrier M, Arrestier S, Bouloudian S, et al. Epstein-Barr virus infection associated hepatic lymphoma in a patient treated with methotrexate for rheumatoid arthritis. Joint Bone Spine. 2006;73:218–9.

Fujita T, Tanabe M, Iida E, et al. Multi-modality imaging findings of methotrexate-related Epstein-Barr virus-associated hepatic tumor. Clin Imaging. 2013;37:962–4.

Tatsumi G, Ukyo N, Hirata H, et al. Primary hepatic lymphoma in a patient with rheumatoid arthritis treated with methotrexate. Case Rep Hematol. 2014;2014: 460574.

Kawahara A, Tsukada J, Yamaguchi T, et al. Reversible methotrexate-associated lymphoma of the liver in rheumatoid arthritis: a unique case of primary hepatic lymphoma. Biomark Res. 2015;3:10.

Miyagawa K, Shibata M, Noguchi H, et al. Methotrexate-related primary hepatic lymphoma in a patient with rheumatoid arthritis. Intern Med. 2015;54:401–5.

Ohkura Y, Shindoh J, Haruta S, et al. Primary adrenal lymphoma possibly associated with Epstein-Barr virus reactivation due to immunosuppression under methotrexate therapy. Medicine (Baltimore). 2015;94: e1270.

Matsumoto R, Numata K, Doba N, et al. A case of multiple hepatic lesions associated with methotrexate-associated lymphoproliferative disorder. J Med Ultrason. 2001;2016(43):545–51.

Takei D, Abe T, Amano H, et al. Methotrexate-associated primary hepatic malignant lymphoma following hepatectomy: a case report. Int J Surg Case Rep. 2017;31:5–9.

Ono R, Kumagae T, Uojima H, et al. Hepatic methotrexate-associated lymphoproliferative disorders identified by multiple liver tumors: a case report and review of the literature. J Med Case Rep. 2019;13:196.

Ito N, Masuda T, Yamaguchi K, et al. Pneumonia and meningoencephalitis due to varicella-zoster virus reinfection and Epstein-Barr virus reactivation in a patient with rheumatoid arthritis. Intern Med. 2022;61:2961–5.

Download references

Acknowledgements

This work was supported by JSPS KAKENHI Grant number JP21K06901.

This work was supported by JSPS KAKENHI under JP21K06901 for Rintaro Ohe

Author information

Authors and affiliations.

Department of Gastroenterology, Yamagata Prefectural Shinjo Hospital, 720-1 Kanazawa, Shinjo, Yamagata, 996-8585, Japan

Yamato Nagata, Shotaro Akiba, Hidekazu Horiuchi, Kazuo Okumoto & Shigemi Hachinohe

Department of Pathology, Faculty of Medicine, Yamagata University, Yamagata, Japan

Rintaro Ohe

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Yamato Nagata .

Ethics declarations

Conflict of interest, ethical approval and consent to participate.

Not applicable.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and permissions

About this article

Nagata, Y., Akiba, S., Horiuchi, H. et al. A case of methotrexate-related lymphoproliferative disease showing multiple liver lesions in a patient with rheumatoid arthritis. Clin J Gastroenterol (2024). https://doi.org/10.1007/s12328-024-01963-6

Download citation

Received : 29 January 2024

Accepted : 19 March 2024

Published : 20 April 2024

DOI : https://doi.org/10.1007/s12328-024-01963-6

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Methotrexate-related lymphoproliferative disease
• Diffuse large B-cell lymphoma
• Rheumatoid arthritis
• Find a journal
• Publish with us
• Track your research

• Open access
• Published: 14 November 2023

Employment of patients with rheumatoid arthritis - a systematic review and meta-analysis

• Lilli Kirkeskov 1 , 2 &
• Katerina Bray 1 , 3  

BMC Rheumatology volume  7 , Article number:  41 ( 2023 ) Cite this article

1791 Accesses

1 Citations

7 Altmetric

Metrics details

Patients with rheumatoid arthritis (RA) have difficulties maintaining employment due to the impact of the disease on their work ability. This review aims to investigate the employment rates at different stages of disease and to identify predictors of employment among individuals with RA.

The study was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines focusing on studies reporting employment rate in adults with diagnosed RA. The literature review included cross-sectional and cohort studies published in the English language between January 1966 and January 2023 in the PubMed, Embase and Cochrane Library databases. Data encompassing employment rates, study demographics (age, gender, educational level), disease-related parameters (disease activity, disease duration, treatment), occupational factors, and comorbidities were extracted. Quality assessment was performed employing Newcastle–Ottawa Scale. Meta-analysis was conducted to ascertain predictors for employment with odds ratios and confidence intervals, and test for heterogeneity, using chi-square and I 2 -statistics were calculated. This review was registered with PROSPERO (CRD42020189057).

Ninety-one studies, comprising of a total of 101,831 participants, were included in the analyses. The mean age of participants was 51 years and 75.9% were women. Disease duration varied between less than one year to more than 18 years on average. Employment rates were 78.8% (weighted mean, range 45.4–100) at disease onset; 47.0% (range 18.5–100) at study entry, and 40.0% (range 4–88.2) at follow-up. Employment rates showed limited variations across continents and over time. Predictors for sustained employment included younger age, male gender, higher education, low disease activity, shorter disease duration, absence of medical treatment, and the absence of comorbidities.

Notably, only some of the studies in this review met the requirements for high quality studies. Both older and newer studies had methodological deficiencies in the study design, analysis, and results reporting.

Conclusions

The findings in this review highlight the prevalence of low employment rates among patients with RA, which increases with prolonged disease duration and higher disease activity. A comprehensive approach combining clinical and social interventions is imperative, particularly in early stages of the disease, to facilitate sustained employment among this patient cohort.

Peer Review reports

Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease that can lead to joint destruction. RA particularly attacks peripheral joints and joint tissue, gradually resulting in bone erosion, destruction of cartilage, and, ultimately, loss of joint integrity. The prevalence of RA varies globally, ranging from 0.1- 2.0% of the population worldwide [ 1 , 2 ]. RA significantly reduces functional capacity, quality of life, and results in an increase in sick leave, unemployment, and early retirement [ 3 , 4 , 5 ]. The loss of productivity due to RA is substantial [ 2 , 5 , 6 , 7 ]. A 2015 American study estimated the cost of over $250 million annually from RA-related absenteeism in United States alone [ 8 ].

Research has highlighted the importance of maintaining a connection to the labour market [ 3 , 9 ], Even a short cessation from work entails a pronounced risk of enduring work exclusion [ 10 ]. In Denmark merely 55% on sick leave for 13 weeks succeeded in re-joining the workforce within one year. Among those on sick leave for 26 weeks, only 40% returned to work within the same timeframe [ 11 ]. Sustained employment is associated with an improved health-related quality of life [ 12 , 13 ]. Early and aggressive treatment of RA is crucial for importance in achieving remission and a favourable prognosis reducing the impact of the disease [ 2 , 14 , 15 , 16 ]. Therefore, initiating treatment in a timely manner and supporting patients with RA in maintaining their jobs with inclusive and flexible workplaces if needed is critical [ 3 , 17 ].

International studies have indicated, that many patients with RA are not employed [ 18 ]. In 2020, the average employment rate across Organization for Economic Co-operation and Development (OECD) countries was 69% in the general population (15 to 64 years of age), exhibiting variations among countries, ranging from 46–47% in South Africa and India to 85% in Iceland [ 19 ]. Employment rates were lower for individuals with educational levels below upper secondary level compared to those with upper secondary level or higher education [ 19 ]. For individuals suffering with chronic diseases, the employment rates tend to be lower. Prognostic determinants for employment in the context of other chronic diseases encompasses the disease’s severity, employment status prior to getting a chronic disease, and baseline educational level [ 20 , 21 , 22 ]. These somatic and social factors may similarly influence employment status of patients with RA. Several factors, including the type of job (especially physically demanding occupations), support from employers and co-workers, social safety net, and disease factors such as duration and severity, could have an impact on whether patients with RA are employed [ 17 , 23 , 24 ]. Over the years, politicians and social welfare systems have tried to improve the employment rates for patients with chronic diseases. In some countries, rehabilitation clinics have been instrumental in supporting patients to remain in paid work. Healthcare professionals who care for patients with RA occupy a pivotal role in preventing work-related disability and support the patients to remain in work. Consequently, knowledge of the factors that contribute to retention of patients with RA at work is imperative [ 17 , 25 ].

The aim of this study is therefore to conduct a systematic review, with a primary focus on examining employment rates among patients with RA at the onset of the disease, at study entry, and throughout follow-up. Additionally, this study intends to identify predictors of employment. The predefined predictors, informed by the author’s comprehensive understanding of the field and specific to RA, encompass socioeconomic factors such as age, gender, level of education, employment status prior to the disease, disease stage and duration, treatment modalities, and comorbidities, including depression, which are relevant both to RA and other chronic conditions [ 26 ].

This systematic review was carried out according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) for studies that included employment rate in patients with rheumatoid arthritis [ 27 ]. PROSPERO registration number: CRD42020189057.

Selection criteria and search strategies

A comprehensive literature search was conducted, covering the period from January 1966 to January 2023 across the PubMed, Embase, and Cochrane Library databases using the following search terms: (Rheumatoid arthritis OR RA) AND (employment OR return to work). Only studies featuring a minimum cohort size of thirty patients and articles in the English language were deemed eligible for inclusion.

The initial screening of articles was based on the titles and abstracts. Studies comprising a working-age population, with current or former employment status, and with no limitations to gender, demographics, or ethnicity were included in this review. Articles addressing topics of employment, work ability or disability, return to work or disability pension were encompassed within the scope of this review. Full-time and part-time employment, but not ‘working as housewives’ was included in this review’s definition of employment. Studies involving other inflammatory diseases than RA were excluded. Reference lists in the selected articles were reviewed, and more articles were included if relevant. A review of the reference lists in the initially selected articles was conducted, with additional articles incorporated if they proved relevant to the research objectives. The eligible study designs encompassed cohort studies, case–control studies, and cross-sectional studies. All other study designs, including reviews, case series/case reports, in vitro studies, qualitative studies, and studies based on health economics were systematically excluded from the review.

Data extraction, quality assessment and risk-of-bias

The data extraction from the selected articles included author names, year of publication, study design, date for data collection, employment rate, study population, age, gender, educational level, ethnicity, disease duration, and pharmacological treatment. To ensure comprehensive evaluation of study quality and potential bias, quality assessment was independently assessed by two reviewers (LK and KB) using the Newcastle–Ottawa Scale (NOS) for cross-sectional and cohort studies [ 28 ]. Any disparities in the assessment were resolved by discussion until consensus was reached. For cross-sectional studies the quality assessment included: 1) Selection (maximum 5 points): representativeness of the sample, sample size, non-respondents, ascertainment of the risk factor; 2) Comparability (maximum 2 points); study controls for the most important, and any additional factor; 3) Outcome (maximum 3 points): assessment of outcome, and statistical testing. For cohort studies the assessment included: 1) Selection (maximum 4 points): representativeness of the exposed cohort, selection of the non-exposed cohort, ascertainment of exposure, demonstration that the outcome of interest was not present at start of study; 2) Comparability (maximum 2 points): comparability of cohorts on the basis of the design or analysis; 3) Outcome (maximum 3 points): assessment of outcome, was the follow-up long enough for outcomes to occur, and adequacy of follow up of cohorts. The rating scale was based on 9–10 items dividing the studies into high (7–9/10), moderate (4–6) or low (0–3) quality. A low NOS score (range 0–3) indicated a high risk of bias, and a high NOS score (range 7–9/10) indicated a lower risk of bias.

Analytical approach

For outcomes reported in numerical values or percentages, the odds ratio along with their 95% confidence intervals (CI) were calculated, whenever feasible. Weighted means were calculated, and comparisons between these were conducted using t-test for unpaired data. Furthermore, meta-analysis concerning the pre-determined and potentially pivotal predictors for employment status, both at disease onset, study entry, and follow-up was undertaken. The predictors included age, gender, ethnicity, level of education, duration of disease, treatment, and the presence of comorbities, contingent upon the availability of the adequate data. Additionally, attempts have been made to find information regarding on job categorizations, disease activity (quantified through DAS28; disease activity score for number of swollen joints), and quality of life (SF-36 scores ranging from 0 (worst) to 100 (best)). Age was defined as (< = 50/ > 50 years), gender (male/female), educational level college education or more/no college education), race (Caucasian/not Caucasian), job type (non-manual/manual), comorbidities (not present/present), MTX ever (no/yes), biological treatment ever (no/yes), prednisolone ever (no/yes), disease duration, HAQ score (from 0–3)), joint pain (VAS from 1–10), and DAS28 score. Age, disease duration, HAQ score, VAS score, SF36 and DAS28 were in the studies reported by mean values and standard deviations (SD). Challenges were encountered during attempts to find data which could be used for analysing predictors of employment status before disease onset, and at follow-up, as well as factors related to treatments beyond MTX, prednisolone, and biological as predictors for being employed after disease onset. Test for heterogeneity was done using Chi-squared statistics and I 2 , where I 2 below 40% might not be important; 30–60% may represent moderate heterogeneity; 50–90% substantial heterogeneity; and 75–100% considerable heterogeneity. Meta-analysis for predictors for employment and odds ratio; confidence intervals; and test for heterogeneity were calculated using the software Review Manager (RevMan, version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).

General description of included studies

The search yielded a total of 2277 references addressing RA its association with employment. Following the initial title screen, 199 studies were considered relevant for further evaluation. Of those, 91 studies ultimately met the inclusion criteria. Figure  1 shows the results of the systematic search strategy.

Flow chart illustrating the systematic search for studies examining employment outcome in patients with rheumatoid arthritis

Table 1 summarizes the general characteristics of the included studies. The publication year of the included studies ranged from 1971 to 2022. Among the studies, 60 (66%) adopted a cross-sectional research design [ 13 , 18 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 129 ] with a total of 41,857 participants analysing data at a specific point in time. Concurrently, 31 studies (34%) adopted a cohort design [ 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 130 ] with a total of 59,974 participants. Most of these studies exhibited a small to moderate sample size, with a median of 652 participants. Additionally, single centre studies and studies from high-income countries were predominant. Study details are shown in Table 1 .

General description of study participants

On average, patients with RA were 51 years old, with an age range spanning from 42 to 64 years. Furthermore, the female population accounted for 75.9% of the patient cohort, with a range from 41 to 92%. The duration of the disease at study entry exhibited significant variability, ranging from less than one year up to more than 18 years on average.

• Employment rate

At disease onset, the employment rate was 78.8% (weighted mean, range 45.4–100), at study entry 47.0% (range 18.5–100), and during the follow-up period 40.0% (range 4–88.2), as shown in Table 2 . Notably, a comparative analysis of the employment rates between Europe and North America indicated no substantial difference ( p  = 0.93). However, the comparison between Europe, North America and ‘other continents’ did yield significant differences (or nearly differences) with p -values of 0.003 and 0.08, respectively.

The employment rate exhibited no change, when comparing studies from the 1980s through to 2022. Specifically, the weighted mean for the years 1981–2000 was 49.2%, aligning closely with the corresponding figures for the years 2001–2010 (49.2%) and 2011–2022 43.6%. These findings were statistically non-significant, with p -values of 0.80 for comparison between year 1981–2000 and 2001–2010; 0.66 for 2001–2010 and 2011–2022, and 0.94 for 1981–2000 and 2011–2022, shown in Figure S 1 , see Additional file.

Among the studies included in the analysis, nineteen studies included data of employment at follow-up, with durations ranging from 1 to 20 years, Table 2 . For instance, Jäntti, 1999 [ 97 ] reported an employment rate 69% one year after disease onset, which gradually declined to 50% after 15 years and further to 20% after 20 years. Similarly, Mäkisara, 1982 [ 63 ] demonstrated that 60% of the patients were employed 5 years after disease onset, 50% after 10 years, and 33% after 15 years. Nikiphorou, 2012 [ 101 ] reported an employment rate of 67% at study entry, which decreased to 43% after 10 years.

In addition, seven studies included data of employment rate among patients comparing different medical treatments [ 18 , 44 , 56 , 91 , 105 , 110 , 119 ]. These studies indicated that, on average, 55.0% (weighted mean) of the patients were employed after receiving treatment with MTX, while 42.8% after undergoing treatment with a combination of MTX + Adalimumab (all patients were employed at disease onset in these specific studies).

Predictors for employment

Information of normative comparison data to use for meta-analysis of predictors for employment at study entry was available for age, gender, educational level, race, job type, comorbidities, MTX at any time, biological treatment at any time, prednisolone at any time, disease duration, HAQ score, joint pain (VAS-score), and disease activity (DAS28 score). Predictors for employment at study entry was being younger /age below 50 years, being a male, higher educational level (college or more), non-manual work, having no comorbidities, no medical treatment, short disease duration, and low HAQ score, VAS-score, or DAS28 score. Heterogeneity was small for age, gender, medical treatment, and moderate for educational level, and job type as indicted by the I 2 values, Table  3 , and shown in detail in Figures S 2 , S 3 , S 4 , S 5 , S 6 , S 7 , S 8 , S 9 , S 10 , S 11 , S 12 , S 13 , S 14 , S 15 and S 16 , see Additional file.

Assessment of quality of included studies

All studies were subject to rigorous quality assessment. These assessments resulted in categorisation of either medium quality ( n  = 64; 70%) or high-quality studies ( n  = 27; 30%), with no studies falling into the low-quality category. The quality assessment is shown in Tables  4 and 5 .

Notably, many studies were characterised by several common attributes, including cross-sectional study design, single-centre-settings, relatively small sample sizes, and the reliance on self-reported patient data. When including only the high-quality studies in the analyses, the employment rates at study entry changed from 47% (weighted mean, all studies) to 50% (weighted mean, high quality studies).

Key findings

This systematic review has identified a decline in the employment rate among patients with RA, with a notable decrease from disease onset during the study entry to follow-up, where only half of the patients were employed. These findings corroborate earlier research that indicated a substantial decline in employment rates among patients with RA over time. Notably, previous studies have reported that approximately one third of patients with RA stopped working within 2 to 3 years after disease onset, and more than half was unable to work after 10 to 15 years [ 23 , 63 , 93 , 97 , 101 ]. Only few studies have included data from the general population, comparing the employment rates with the rates for patients with RA [ 89 , 90 ]. Comparisons with the general population further underscored the challenges faced by RA patients, as their employment rates were consistently lower.

Despite changes in medical treatment, social security systems, and societal norms over the past decades, there was no significant improvement in the employment for patients with RA. This pattern aligns with data from the Global Burden of Disease studies, highlighting the persistent need for novel approaches and dedicated efforts to support patients with RA in sustaining employment [ 2 , 123 ]. Recent recommendations from EULAR (European Alliance of Associations for Rheumatology) and ACR (American College of Rheumatology) have emphasized the importance of enabling individuals with rheumatic and musculoskeletal diseases to engage in healthy and sustainable work [ 17 , 124 , 125 ].

While different countries possess different social laws and health care systems for supporting patients with chronic diseases, the variations in the weighted mean of employment rates across countries were relatively minor.

In the meta-analysis, one of the strongest predictors for maintaining employment was younger age at disease onset [ 43 , 51 , 101 , 116 ]. Verstappen, 2004 found that older patients with RA had an increased risk of becoming work disabled, potentially caused by the cumulative effects of long-standing RA, joint damage, and diminished coping mechanisms, compared to younger patients [ 23 ].

More women than men develop RA, however this study showed that a higher proportion of men managed to remain employed compared to women [ 18 , 36 , 42 , 43 , 46 , 62 , 71 , 89 , 101 , 116 ]. Previous studies have shown inconsistent results in this regard. Eberhart, 2007 found that a significantly higher number of men with RA worked even though there was no difference in any disease state between the sexes [ 93 ]. De Roos,1999 showed that work-disabled women were less likely to be well-educated and more likely to be in a nonprofessional occupation than working women. Interestingly, there was no association of these variables among men. Type of work and disease activity may influence work capacity more in women than in men [ 46 ]. Sokka, 2010 demonstrated a lower DAS28 and HAQ-score in men compared to women among the still working patients with RA, which indicated that women continued working at higher disability and disease activity levels compared with men [ 18 ].

Disease duration also played a significant role as a predictor of employment outcomes [ 33 , 36 , 45 , 71 , 77 , 86 , 102 , 111 ]. Longer disease duration correlate with decreased employment likelihood, which could be attributed to older age and increased joint damage and disability in patients with longer-standing RA.

Higher educational levels were associated with a greater possibility of employment [ 30 , 43 , 45 , 46 , 51 , 62 , 86 ]. This is probably due to enhanced job opportunities, flexibility, lower physical workload, better insurance coverage, and improved health care for well-educated individuals. This is further supported by the fact that having a manual work was a predictor for not being employed [ 30 , 39 , 43 , 44 , 45 ].

Furthermore, health-related quality of life, as measured by SF 36, lower disease activity (DAS28 scores), reduced joint pain (VAS-score), and lower disability (HAQ score) were additionally predictors for being employed [ 33 , 35 , 36 , 45 , 71 , 86 ]. This support the statement that the fewer symptoms from RA, the greater the possibility of being able to work.

The results showed that the presence of comorbidity was a predictor for not being employed, aligning with findings from previous studies that chronic diseases such as cardiovascular disease, lung disease, diabetes, cancer, and depression reduced the chances of being employed [ 126 ]. Moreover, the risk of exiting paid work increased with multimorbidity [ 127 ].

While limited data were available for assessing the impact of treatment on employment, indications suggested that patients with RA were receiving medical treatments, such as MTX or biological medicine, were more likely to be unemployed. One possible explanation for this phenomenon could be that patients with RA, who were receiving medical treatment, had a more severe and a longer duration of RA compared to those, who had never been on medical treatment. However, the scarcity of relevant studies necessitates caution when drawing definitive conclusions in this regard.

Therefore, the predictors for employment found in this review were being younger, being a male, having higher education, low disease activity, low disease duration, and being without comorbidities. This is supported by previous studies [ 93 , 116 ]

In summary, this review underscores the importance of managing disease activity, offering early support to patients upon diagnosis, and reducing physically demanding work to maintain employment among patients with RA. Achieving success in this endeavour requires close cooperation among healthcare professionals, rehabilitation institutions, companies, and employers. Furthermore, it is important that these efforts are underpinned by robust social policies that ensure favourable working conditions and provide financial support for individuals with physical disabilities, enabling them to remain active in the labour market.

Strengths and limitations

The strength of this review and meta-analysis lies in the inclusion of a large number of articles originating from various countries. Furthermore, the data showed a consistent employment rate in high quality studies compared to all studies. However, there are some limitations to this review. No librarian was used to define search terms and only three databases were searched. Furthermore, the initial search, selection of articles, data extraction, and analysis was undertaken only by one author, potentially leading to the omission of relevant literature and data. The review also extended back to 1966, with some articles from the 1970s and 1980s included. Given the significant changes in medical treatment, social security systems, and society over the past decades, the generalizability of the findings may be limited.

Moreover, the majority of studies did not include a control group from the general population, which limited the ability to compare employment rates with the general population in the respective countries. Many studies were cross-sectional in design, which limits the evidence of causality between employment rate and having RA. However, the employment rate was approximately the same in high quality studies compared to all studies, which supports an association. A substantial number of studies relied on self-reported employment rates, introducing the potential for recall bias. Additionally, many studies did not account for all relevant risk factors for unemployment failing to control for all relevant confounders.

EULAR have made recommendation for point to consider when designing, analysing, and reporting of studies with work participation as an outcome domain in patients with inflammatory arthritis. These recommendations include study design, study duration, and the choice of work participation outcome domains (e.g., job type, social security system) and measurement instruments, the power to detect meaningful effects, interdependence among different work participation outcome domains (e.g., between absenteeism and presentism), the populations included in the analysis of each work participation outcome domain and relevant characteristics should be described. In longitudinal studies work-status should be regularly assessed and changes reported, and both aggregated results and proportions of predefined meaningful categories should be considered [ 128 ]. Only some of the studies in this review met the requirements for high quality studies. In both older and newer studies methodological deficiencies persisted in study design, analysis, and reporting of results, as recommended by EULAR.

Perspectives for future studies

Future research in this area should focus on developing and evaluating new strategies to address the ongoing challenges faced by patients with RA in maintaining employment. Despite many initiatives over the years, there has been no success in increasing employment rates for patients with RA in many countries. Therefore, there is a pressing need for controlled studies that investigated the effectiveness of interventions such as education, social support, and workplace adaptations in improving employment outcomes for these individuals.

This systematic review underscores the low employment rate among patients with RA. Key predictors of sustained employment include being younger, having higher educational level, short disease duration, and lower disease activity, along with fewer comorbidities. Importantly, the review reveals that the employment rate has not changed significantly across different time periods. To support patients with RA in maintaining their employment, a comprehensive approach that combines early clinical treatment with social support is crucial. This approach can play a pivotal role in helping patients with RA stay connected to the labour market.

Availability of data and materials

The datasets used and/or analyzed during the current study are available in the supplementary file.

Abbreviations

• Rheumatoid arthritis

Methotrexate

Newcastle Ottawa Quality Assessment Scale

Standard deviation

Not analyzed

Not relevant

Disease activity

Health Assessment Questionnaire

Visual analog scale for pain

European Alliance of Associations for Rheumatology

American College of Rheumatology

Almutairi K, Nossent J, Preen D, Keen H, Inderjeeth C. The global prevalence of rheumatoid arthritis: a meta-analysis based on a systematic review. Rheumatol Int. 2021;41:863–77.

Article   PubMed   Google Scholar  

Safiri S, Kolahi AA, Hoy D, Smith E, Bettampadi D, Mansournia MA, et al. Global, regional and national burden of rheumatoid arthritis 1990–2017: a systematic analysis of the Global Burden of Disease study 2017. Ann Rheum Dis. 2019;78:1463–71.

Verstappen SMM. Rheumatoid arthritis and work: The impact of rheumatoid arthritis on absenteeism and presenteeism. Best Pract Res Clin Rheumatol. 2015;29:495–511.

Madsen CMT, Bisgaard SK, Primdahl J, Christensen JR, von Bülow C. A systematic review of job loss prevention interventions for persons with inflammatory arthritis. J Occup Rehabil. 2021;4:866–85.

Kessler RC, Maclean JR, Petukhova M, Sarawate CA, Short L, Li TT, et al. The effects of rheumatoid arthritis on labor force participation, work performance, and healthcare costs in two workplace samples. J Occup Environ Med. 2008;50:88–98.

Filipovic I, Walker D, Forster F, Curry AS. Quantifying the economic burden of productivity loss in rheumatoid arthritis. Rheumatology. 2011;50:1083–90.

Burton W, Morrison A, Maclean R, Ruderman E. Systematic review of studies of productivity loss due to rheumatoid arthritis. Occup Med. 2006;56:18–27.

Article   Google Scholar  

Gunnarsson C, Chen J, Rizzo JA, Ladapo JA, Naim A, Lofland JH. The employee absenteeism costs of reumatoid arthritis. Evidence from US National Survey Data. J Occup Environ Med. 2015;57:635–42.

van der Noordt M, Ijzelenberg H, Droomers M, Proper KI. Health effects of employment: a systematic review of prospective studies. Occup Environ Health. 2014;71:730–6.

Google Scholar  

Virtanen M, Kivimäki M, Vahtera J, Elovainio M, Sund R, Virtanen P, et al. Sickness absence as a risk factor for job termination, unemployment, and disability pension among temporary and permanent employees. Occup Environ Med. 2006;63:212–7.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Vilhelmsen J. Længerevarende sygefravær øger risikoen for udstødning [long-term sick-leave increase the risk of job termination]. 2007.  https://www.ae.dk/analyse/2007-10-laengerevarende-sygefravaer-oeger-risikoen-for-udstoedning .

Grønning K, Rødevand E, Steinsbekk A. Paid work is associated with improved health-related quality of life in patients with rheumatoid arthritis. Clin Rheumatol. 2010;29:1317–22.

Article   PubMed   PubMed Central   Google Scholar  

Chorus AMJ, Miedema HS, Boonen A, van der Linden S. Quality of life and work in patients with rheumatoid arthritis and ankylosing spondylitis of working age. Ann Rheum Dis. 2003;62:7.

Ma MHY, Kingsley GH, Scott DL. A systematic comparison of combination DMARD therapy and tumour necrosis inhibitor therapy with methotrexate in patients with early rheumatoid arthritis. Rheumatology (Oxford). 2010;49:91–8.

Article   CAS   PubMed   Google Scholar  

Vermeer M, Kuper HH, Hoekstra M, Haagsma CJ, Posthumus MD, Brus HL, et al. Implementation of a treat-to-target strategy in very early rheumatoid arthritis. Results of the Dutch arthritis monitoring remission induction cohort study. Arthritis Rheum. 2011;63:2865–72.

Vermeer M, Kuper HH, Bernelot Moens HJ, Drossaers-Bakker KW, van der Bijl AE, van Riel PL, et al. Sustained beneficial effects of a protocolized treat-to-target strategy in very early rheumatoid arthritis: three-year results of the Dutch rheumatoid arthritis monitoring remission induction cohort. Arthritis Care Res. 2013;65:1219–26.

Article   CAS   Google Scholar  

Boonen A, Webers C, Butink M, Barten B, Betteridge N, Black DC, et al. 2021 EULAR points to consider to support people with rheumatic and musculoskeletal diseases to participate in healthy and sustainable paid work. Ann Rheum Dis. 2023;82:57–64.

Sokka T, Kautianen H, Pincus T, Verstappen SMM, Aggarwai A, Alten R, et al. Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA study. Arthritis Res Ther. 2010;1(R42):1–10.

OECD. Employment rate (indicator). 2020. https://dataoecd.org/emp/employment-rate.htm . Assessed on 11 May.

Hannerz H, Pedersen BH, Poulsen OM, Humle F, Andersen LL. A nationwide prospective cohort study on return to gainful occupation after stroke in Denmark 1996–2006. BMJ Open. 2011;1:1–5.

Tumin D, Chou H, Hayes D Jr, Tobias JD, Galantowicz M, McConnell PI. Employment after hearth transplantation among adults with congenital heart disease. Congenit Heart Dis. 2017;12:794–9.

Islam T, Dahlui M, Majid HA, Nahar AM, MohdTaib NA, Su TT, MyBCC study group. Factors associated with return to work of breast cancer survivors: a systematic review. BMC Public Health. 2014;14:1–13.

Verstappen SMM, Bijlsma JWJ, Verkleij H, Buskens E, Blaauw AAM, Borg EJ, Jacobs JWG. Overview of work disability in rheumatoid arthritis patients as observed in cross-sectional and longitudinal surveys. Arthritis Rheum. 2004;51:488–97.

Wilkie R, Bjork M, Costa-Black KM, Parker M, Pransky G. Managing work participation for people with rheumatic and musculoskeletal diseases. Best Pract Res. 2020;34:1–16.

Varekamp I, Haafkens JA, Detaille SI, Tak PP, van Dijk FJH. Preventing work disability among employees with rheumatoid arthritis: what medical preofessionals can learn form patients’ perspective. Arthritis Rheum. 2005;53:965–72.

Kirkeskov L, Carlsen RK, Lund T, Buus NH. Emloyment of patients with kidney failure treated with dialysis or kidney transplantation - a systematic review and metaanalysis. BMC Nephrol. 2021;22–348:1–17.

Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2020;2021:372. https://doi.org/10.1136/bmj.n71 .

Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. 2009. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp .

Al-Jabi SW, Seleit DI, Badran A, Koni A, Zyoud SH. Impact of socio-demographic and clinical characteristics on functional disability and health-related quality of life in patients with rheumatoid arthritis: a cross-sectional study from Palestine. Health Qual Life Outcomes. 2021;19:241.

Allaire SH, Anderson JJ, Meenan RF. Reducing work disability associated with rheumatoid arthritis: Identifiction of additional risk factors and persons likely to benefit from intervention. Arthritis Care Res. 1996;9(5):9.

Allaire S, Wolfe F, Niu J, Lavalley MP. Comtemporary prevalence and incidence of work disability associated with rheumatoid arthritis in the US. Arthritis Rheum. 2008;59(4):7.

Anno S, Sugioka Y, Inui K, Tada M, Okano T, Mamoto K. Evaluation of work disability in Japanese patients with rheumatoid arthritis: from the TOMORROW study. Clin Rheumatol. 2018;37:9.

Azevedo ABC, Ferraz MB, Ciconelli RM. Indirect costs of rheumatoid arthritis in Brazil. Value Health. 2008;11:869–77.

Backman CL, Kennedy SM, Chalmers A, Singer J. Participation in paid and unpaid work by adults with rheumatoid arthritis. J Rheumatol. 2004;31:47–57.

PubMed   Google Scholar  

Berner C, Haider S, Grabovac I, Lamprecht T, Fenzl KH, Erlacher L, et al. Work ability and employment in rheumatoid arthritis: a cross-sectional study on the role of muscle strength and lower extremity function. Int J Rheumatol. 2018;2018:11.

Bertin P, Fagnani F, Duburcq A, Woronoff AS, Chauvin P, Cukierman G, et al. Impact of rheumatoid arthritis on career progression, productivity, and employability: the PRET Study. Joint Bone Spine. 2016;83:6.

Bodur H, Borman P, Alper B, Keskin D. Work status and related variables in patients with rheumatoid arthitis and ankylosing spondylitis. Turk J Rheumatol. 2011;26(2):19.

Cadena J, Vinaccia S, Perez A, Rico MI, Hinojosa R, Anaya JM. The impact of disease activity on the quality of life, mental health status, and family dysfunction in Colombian patients with rheumatoid arthritis. Clin Rheumatol. 2003;9:142–50.

Callahan LF, Bloch DA, Pincus T. Identification of work disability in rheumatoid arthritis : physical, radiographic and laboratory variables do not add explanatory power to demographic and functional variables. J Clin Epidemiol. 1992;45(2):12.

Camilleri JP, Jessop AM, Davis S, Jessop JD, Hall M. A survey of factors affecting the capacity to work in patients with rheumatoid arthritis in South Wales. Clin Rehabil. 1995;9:4.

Chen MH, Lee MH, Liao HT, Chen WS, Lai CC, Tsai CY. Health-related quality of life outcomes in patients with rehumatoid arthritis and ankylosing spondylitis after tapering biologic treatment. Clin Rheumatol. 2018;37:429–38.

Chorus AMJ, Miedema HS, Wevers CJ, van der Linden S. Labour force participation among patients with rheumtoid arthritis. Ann Rheum Dis. 2000;59:6.

Chorus AMJ, Miedema HS, Wevers CJ, van der Linden S. Work factors and behavioural coping in relation to withdrawal from the labour force in patients with rheumatoid arthritis. Ann Rheum Dis. 2001;60:8.

Chung CP, Sokka T, Arbogast PG, Pincus T. Work disability in early rheumatoid arthritis: higher rates but better clinical status in Finland compared with the US. Ann Rheum Dis. 2006;65:5.

Dadoniene J, Stropuviene S, Venalis A, Boonen A. High work disability rate among rheumatoid arthritis patients in Lithuania. Arthritis Rheum. 2004;51:433–9.

De Roos AJ, Callahan LF. Differences by sex in correlates of work status in rheumatoid arthritis patients. Arthritis Care Res. 1999;12:381–91.

Dejaco C, Mueller T, Zamani O, Kurtz U, Egger S, Resch-Passini J, et al. A prospective study to evaluate the impact of Golimumab therapy on work productivity and activity, and quality of life in patients with rheumatoid arthritis, psoriatic arthritis and axil spondylarthritis in a real life setting in AUSTRIA. The Go-ACTIVE Study. Front Med. 2022;9:1–9.

Doeglas D, Suurmeijer T, Krol B, Sanderman R, van Leeuwen M, van Rijswijk M. Work disability in early rheumatoid arthritis. Ann Rheum Dis. 1995;54:6.

Fara N, Recchia O, Sequeira G, Sanchez K. Disability due to rheumatic diseases in the city of Junín, Argentina. Rheumatol Int. 2019;39:729–33.

Fifield J, Reisine S, Sheehan TJ, McQuillan J. Gender, paid work, and symptoms of emotional distress in rheumatoid arthritis patients. Arthritis Rheum. 1996;39:427–35.

Gomes RKS, Schreiner LC, Vieira MO, Machado PH, Nobre MRC. Staying in the labor force among patients with rheumatoid arthritis and associated factors in Southern Brazil. Adv Rheumatol. 2018;58(14):1–9.

Hamdeh HA, Al-Jabi SW, Koni A, Zyoud SH. Health-related quality of life and treatment satisfaction in Palestinians with rheumatoid arthritis: a cross-sectional study. BMC Rheumatol. 2022;6(19):1–12.

Hazes JM, Taylor P, Strand V, Purcaru O, Coteur G, Mease P. Physical function improvements and relief from fatigue and pain are associated with incresed productivity at work and at home in rheumatoid arthritis patients treated with certolizumab pegol. Rheumatology. 2010;49:1900–10.

Hulander E, Lindqvist HM, Wadell AT, Gjertsson I, Winkvist A, Bärebring L. Improvements in body composition after a proposed anti-inflammatory diet are modified by employment status in weight-stable patients with rheumatoid arthritis, a randomized controlled crossover trial. Nutrients. 2022;14:1058.

Intriago M, Maldonado G, Guerrero R, Moreno M, Moreno L, Rios C. Functional disability and its determinants in Ecudorian patients with rheumatoid arthritis. Open Access Rheumatol. 2020;12:97–104.

Kavanaugh A, Smolen JS, Emery P, Purcaru O, Keystone E, Richard L, et al. Effect of certolizumab pegol with ethotrexate on home and work place productivity and social activities in patients with active rheumatoid arthritis. Arthritis Rheum. 2009;61:1592–600.

Kwon JM, Rhee J, Ku H, Lee EK. Socioeconomic and employment status of patients with rheumatoid arthritis in Korea. Epidemiol Health. 2003;34:1–7.

Lacaille D, Sheps S, Spinelli JJ, Chalmers A, Esdaile JM. Identification of modifiable work-related factors that influence the risk of work disability in rheumatoid arthritis. Arthritis Rheum. 2004;51:843–52.

Lahiri M, Cheung PPM, Dhanasekaran P, Wong SR, Yap A, Tan DSH, et al. Evaluation of a multidisciplinary care model to improve quality of life in rheumatoid arthritis: a randomised controlled trial. Qual Life Res. 2022;31:1749–59.

Lapcevic M, Vukovic M, Gvozdenovic BS, Mioljevic V, Marjanovic S. Socioeconomic and therapy factor influence on self-reported fatigue, anxiety and depression in rheumatoid arthritis patients. Rev Bras Reumatol. 2017;57(6):12.

Mattila K, Buttgereit F, Tuominen R. Impact of morning stiffness on working behaviour and performance in people with rhematoid arthritis. Rheumatol Int. 2014;34:1751–8.

McQuillan J, Andersen JA, Berdahl TA, Willett J. Associations of rheumatoid arthritis and depressive symptoms over time: Are there differences by education, race/ethnicity, and gender? Arthritis Care Res. 2022;0:1–9.

Mäkisara GL, Mäkisara P. Prognosis of funcrional capacity and work capacity in rheumatoid arthritis. Clin Rheumatol. 1982;1(2):9.

Meenan RF, Yelin EH, Nevitt M, Epstein WV. The impact of chronic disease. A sociomedical profile of rheumatoid arthritis. Arthritis Rheum. 1981;24:544–9.

Morf H, Castelar-Pinheiro GR, Vargas-Santos AB, Baerwald C, Seifert O. Impact of clinical and psychological factors associated with depression in patients with rheumatoid arthritis: comparative study between Germany and Brazil. Clin Rheumatol. 2021;40:1779–87.

Newhall-Perry K, Law NJ, Ramos B, Sterz M, Wong WK, Bulpitt KJ, et al. Direct and indirect costs associated with the onset of seropositive rheumatoid arthritis. J Rheumatol. 2000;27:1156–63.

CAS   PubMed   Google Scholar  

Osterhaus JT, Purcaru O, Richard L. Discriminant validity, responsiveness and reliability of the rheumatoid arthritis-specific Work Productivity Survey (WPS-RA). Arthritis Res Ther. 2009;11(R73):1–12.

Pieringer H, Puchner R, Pohanka E, Danninger K. Power of national economy, disease control and employment status in patients with RA - an analytical multi-site ecological study. Clin Rheumatol. 2016;35:5.

Rosa-Gocalves D, Bernardes M, Costa L. Quality of life and functional capacity in patients with rheumatoid arthritis - Cross-sectional study. Reumatol Clin. 2018;14:360–6.

Sacilotto NC, Giorgi RDN, Vargas-Santos AB, Albuquerque CP, Radominski SC, Pereira IA, et al. Real - rheumatoid arthritis in real life - study cohort: a sociodemographic profile of rheumatoid arthritis in Brazil. Adv Rheumatol. 2020;60:20.

Shanahan EM, Smith M, Roberts-Thomson L, Esterman A, Ahern M. Influence of rheumatoid arthritis on work participation in Australia. Intern Med J. 2008;38:166–73.

Smolen JS, van der Heijde DM, Keystone EC, van Vollenhoven RF, Golding MB, Guérette B, et al. Association of joint space narrowing with impairment of physical function and work ability in patients with early rheumatoid arthritis: protection beyond disease control by adalimumab plus methotrexate. Ann Rheum Dis. 2012;72:1156–62.

Syngle D, Singh A, Verma A. Impact of rheumatoid arthritis on work capacity impairment and its predictors. Clin Rheumatol. 2020;39:1101–9.

Tamborenea MN, Pisoni C, Toloza S, Mysler E, Tate G. Pereira D et al Work instability in rheumatoid arthritis patients from Argentina: prevalence and associated factors. Rheumatol Int. 2015;35:107–14.

Tanaka Y, Kameda H, Saito K, Kanedo Y, Tanaka E, Yasuda S, et al. Response to tocilizumab and work productivity in patients with rheumatoid arthritis: 2-year follow-up of FIRST ACT-SC study. Mod Rheumatol. 2021;21:42–52.

van der Zee-Neuen A, Putrik P, Ramiro S, Keszei AP, Hmamouchi I, Dougados M, Boonen A. Large country differences in work outcomes in patients with RA - an analysis in the multinational study COMORA. Arthritis Res Ther. 2017;19:216.

van Jaarsveld CHM, Jacobs JWG, Schrijvers AJP, van Albada-Kuipers GA, Hofman DM, Bijlsma JWJ. Effects of rheumatoid arthritis on employment and social participation during the first years of disease in the Netherlands. Br J Rheumatol. 1998;37:848–53.

Verstappen SMM, Boonen A, Bijlsma JWJ, Buskens E, Verkleij H, Schenk Y, et al. Working status among Dutch patients with rheumatoid arthritis: work disability and working conditions. Rheumatology. 2005;44:202–6.

Vliet Vlieland TPM, Buitenhuis NA, van Zeben D, Vandenbroucke JP, Breedveld FC, Hazes JMW. Sociodemographic factors and the outcome of rheumatoid arthritis in young women. Ann Rheum Dis. 1994;53:803–6.

Li F, Ai W, Ye J, Wang C, Yuan S, Xie Y, et al. Inflammatory markers and risk factors of RA patients with depression and application of different scales in judging depression. Clin Rheumatol. 2022;41:2309–17.

Wan SW, He HG, Mak A, Lahiri M, Luo N, Cheung PP, et al. Health-related quality of life and its predictors among patients with rheumatoid arthritis. Appl Nurs Res. 2016;30:176–83.

Xavier RM, Zerbini CAF, Pollak DF, Morales-Torres JLA, Chalem P, Restrepo JFM, et al. Burden of rheumatoid arthritis on patients’ work productivity and quality of life. Adv Rheumatol. 2019;59:47.

Yajima N, Kawaguchi T, Takahashi R, Nishiwaki H, Toyoshima Y, Oh K, et al. Adherence to methotrexate and associated factors considering social desirability in patients with rheumatoid arthritis: a multicenter cross-sectional study. BMC Rheumatol. 2022;6(75):1–8.

Yates M, Ledingham JM, Hatcher PA, Adas M, Hewitt S, Bartlett-Pestell S, et al. Disease activity and its predictors in early inflammatory arthritis: findings from a national cohort. Rheumatology. 2021;60:4811–20.

Yelin E, Henke C, Epstein W. The work dynamics of the person with rheumatoid arthritis. Arthritis Rheum. 1987;30:507–12.

Zhang W, Bansback N, Guh D, Li X, Nosyk B, Marra CA, et al. Short-term influence of adalimumab on work productivity outcomes in patients with rheumatoid arthritis. J Rheumatol. 2008;35:1729–36.

Żołnierczyk-Zreda D, Jędryka-Góral A, Bugajska J, Bedyńska S, Brzosko M, Pazdur J. The relationship between work, mental health, physical health, and fatigue in patients with rheumatoid arthritis: a cross-sectional study. J Health Psychol. 2020;25:665–73.

da Rocha Castellar Pinheiro G, Khandker RK, Sato R, Rose A, Piercy J. Impact of rheumatoid arthritis on quality of life, work productivity and resource utilisation: an observational, cross-sectional study in Brazil. Clin Exp Rheumatol. 2013;31:334–40.

Albers JMC, Kuper HH, van Riel PLCM, Prevoo MLL, Van’t Hof MA, van Gestel AM, et al. Socio-economic consequences of rheumatoid arthritis in the first year of the disease. Rheumatology. 1999;38:423–30.

Barrett EM, Scott DGI, Wiles NJ. The impact of rheumatoid arthritis on employment status in the early years of disease: a UK community-based study. Rheumatology. 2000;39:7.

Bejano V, Quinn M, Conaghan PG, Reece R, Keenan AM, Walker D, et al. Effect of the early use of the anti–tumor necrosis factor Adalimumab on the prevention of job loss in patients with early rheumatoid arthritis. Arthritis Care Res. 2008;59:1467–74.

Eberhardt K, Larsson BM, Nived K. Early rheumatoid arthritis – some social, economical, and psychological aspects. Scand J Rheum. 1993;22:119–23.

Eberhardt K, Larsson BM, Nived K, Lindqvist E. Work disability in rheumatoid arthritis- development over 15 years and evaluation of predictive factors over time. J Rheumatol. 2007;34:481–7.

Halpern MT, Cifaldi MA, Kvien TK. Impact of adalimumab on work participation in rheumatoid arthritis: comparison of an open-label extension study and a registry-based control group. Ann Rheum Dis. 2009;68:930–7.

Herenius MMJ, Hoving JI, Sluiter JK, Raterman HG, Lems WF, Dijkmans BAC, et al. Improvement of work ability, quality of life, and fatique in patients with rheumatoid arthritis treated with adalimumab. J Occup Environ Health. 2010;52:618–21.

Hoving JL, Bartelds GM, Sluiter JK, Sadiraj K, Groot I, Lems WF, et al. Perceived work ability, quality of life, and fatigue in patients with rheumatoid arthritis after a 6-month course of TNF inhibitors: prospective intervention study and partial economic evaluation. Scand J Rheumatol. 2009;38:246–50.

Jäntti J, Aho K, Kaarela K, Kautiainen H. Work disability in an inception cohort of patients with seropositive rheumatoid arthritis: a 20 year study. Rheumatology. 1999;38:4.

Kaarela K, Lehtinen K, Luukkainen R. Work capacity of patients with inflammatory joint diseases: an eight-year follow-up study. Scand J Rheumatol. 1987;16:403–6.

McWilliams DF, Varughese S, Young A, Kiely PD, Walsh DA. Work disability and state benefit claims in early rheumatoid arthritis: the ERAN cohort. Rheumatology. 2014;53:9.

Mau W, Bornmann M, Weber H, Weidemann HF, Hecker H, Raspe HH. Prediction of permanent work disability in a follow-up study of early rheumatoid arthritis: results of a tree structured analysis using RECPAM. Br J Rheumatol. 1996;35:652–9.

Nikiphorou E, Guh D, Bansback N, Zhang W, Dixey J, Williams P, et al. Work disability rates in RA. Results from an inception cohort with 24 years follow-up. Rheumatology. 2012;51:8.

Nordmark B, Blomqvist P, Andersson B, Hägerström M, Nordh-Grate K, Rönnqvist R, et al. A two-year follow-up of work capacity in early rheumatoid arthritis: a study of multidisciplinary team care with emphasis on vocational support. Scand J Rheumatol. 2006;35:7–14.

Pincus T, Callahan LF, Sale WG, Brooks AL, Payne LE, Vaughn WK. Severe functional declines, work disability, and increased mortality in seventy-five rheumatoid arthritis patients studied over mine years. Arthritis Rheum. 1984;27:864–72.

Puolakka K, Kautiainen H, Möttönen T, Hannonen P, Hakala M, Korpela M, et al. Predictors of productivity loss in early rheumatoid arthritis: a 5 year follow up study. Ann Rheum Dis. 2005;64:130–3.

Puolakka K, Kautiainen H, Möttönen T, Hannonen P, Korpela M, Julkunen H, et al. Impact of initial aggressive drug treatment with a combination of disease-modifying antirheumatic drugs on the development of work disability in early rheumatoid arthritis. Arthritis Rheum. 2004;50:55–62.

Reisine S, Fifield J, Walsh S, Feinn R. Factors associated with continued employment among patients with rheumatoid arthritis: a survival model. J Rheumatol. 2001;28:2400–8.

Reisine S, Fifield J, Walsh S, Dauser D. Work disability among two cohorts of women with recent onset rheumatoid arthritis: a survival analysis. Arthritis Rheum. 2007;57:372–80.

Robinson HS, Walters K. Return to work after treatment of rheumatoid arthritis. Can Med Assoc J. 1971;105:166–9.

CAS   PubMed   PubMed Central   Google Scholar  

Smolen JS, Han C, van der Heijde D, Emery P, Bathon JM, Keystone E, et al. Infliximab treatment maintains employability in patients with early rheumatoid arthritis. Arthritis Rheum. 2006;54:716–22.

van Vollenhoven RF, Cifaldi MA, Ray S, Chen N, Weisman MH. Improvement in work place and household productivity for patients with early rheumatoid arthritis treated with adalimumab plus methotrexate: work outcomes and their correlations with clinical and radiographic measures from a randomized controlled trial companion study. Arthritis Care Res. 2010;62:226–34.

Vazquez-Villegas ML, Gamez-Nava JI, Celis A, Sanchez-Mosco D, de la Cerda-Trujillo LF, Murillo-Vazquez JD, et al. Prognostic factors for permanent work disability in patients with rheumatoid arthritis who received combination therapy of conventional synthetic disease-modifying antirheumatic drugs. A retrospective cohort study. J Clin Rheumatol. 2017;23:376–82.

Verstappen SMM, Jacobs JWG, Kruize AA, Erlich JC, van Albada-Kuipers GA, Verkleij H, et al. Trends in economic consequences of rheumatoid arthritis over two subsequent years. Rheumatology. 2007;46:968–74.

Vlak T, Eldar R. Disability in rheumatoid arthritis after monotherapy with DMARDs. Int J Rehabil Res. 2003;26:207–12.

Yelin E, Trupin L, Katz P, Lubeck D, Rush S, Wanke L. Association between etanercept use and employment outcomes among patients with rheumatoid arthritis. Arthritis & Rheum. 2003;48:3046–54.

Young A, Dixey J, Cox N, Davies P, Devlin J, Emery P, et al. How does functional disability in early rheumatoid arthritis (RA) affect patients and their lifes? Results of 5 years of follow-up in 732 patients from the Early RA Study (ERAS). Rheumatology. 2000;39:603–11.

Young A, Dixey J, Kulinskaya E, Cox N, Davies P, Devlin J, et al. Which patients stop working because of rheumatoid arthritis? Results of five years’ follow up in 732 patients from the Early RA Study (ERAS). Ann Rheum Dis. 2002;61:335–40.

Zirkzee EJM, Sneep AC, de Buck PDM, Allaart CF, Peeters AJ, Ronday HK, et al. Sick leave and work disability in patients with early arthritis. Clin Rheumatol. 2008;27:9.

Reisine S, McQuillan J, Fifield J. Predictors of work disability in rheumatoid arthritis patients. Arthritis Rheum. 2005;38:1630–7.

Verstappen SMM, Watson KD, Lunt M, McGrother K, Symmons PM, Hyrich KL. Working status in patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis: results from the British Society for Rheumatology Biogics Register. Rheumatology. 2010;49:1570–7.

Nissilä M, Isomäki H, Kaarela K, Kiviniemi P, Martio J, Sarna S. Prognosis of inflammatory joint diseases. A three-year follow-up study. Scand J Rheumatol. 1983;12:33–8.

Han C, Smolen J, Kavanaugh A, St.Clair EW, Baker D, Bala M. Comparison of employability outcomes among patients with early or long-standing rheumatoid arthritis. Arthritis Rheum. 2008;59:510–4.

Gwinnutt JM, Leggett S, Lunt M, Barton A, Hyrich KL, Walker-Bone K, et al. Predictors of presenteeism, absenteeism and job loss in patients commencing methotrexate or biologic therapy for rheumatoid arthritis. Rheumatology. 2020;59:2908–19.

Cieza A, Causey K, Kamenov K, Hanson SW, Chatterji S, Vos T. Global estimates of the need for rehabilitation based on the Global Burden of Disease study 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020. https://doi.org/10.1016/S0140-6736(20)32340-0:1-12 .

Gwinnutt JM, Wieczorek M, Balanescu A, Bischoff-Ferrari HA, Boonen A, Cavalli G, et al. 2021 EULAR recommendations regarding lifestyle behaviours and work participation to prevent progression of rheumatic and musculoskeletal diseases. Ann Rheum Dis. 2023;82:48–56.

England BR, Smith BJ, Baker NA, Barton JL, Oatis CA, Guyatt G, et al. 2022 American College of Rheumatology Guideline for exercise, rehabilitation, diet, and additional integrative interventions for rheumatoid arthritis. Arthritis Care Res. 2023;75:1603–15.

Vu M, Carvalho N, Clarke PM, Buchbinder R, Tran-Duy A. Impact of comorbid conditions on healtcare expenditure and work-related outcomes in patients with rheumatoid arthritis. J Rheumatol. 2021;48:1221–9.

Amaral GSG, Ots P, Brouwer S, van Zon SKR. Multimorbidity and exit from paid employment: the effect of specific combinations of chronic health conditions. Eur J Public Health. 2022;32:392–7.

Boonen A, Putrik P, Marques ML, Alunno A, Abasolo L, Beaton D, et al. EULAR Points to Consider (PtC) for designing, analysing and reporting of studies with work participation as an outcome domain in patients with inflammatory arthritis. Ann Rheum Dis. 2021;80:1116–23.

Lajas C, Abasolo L, Bellajdel B, Hernandez-Garcia C, Carmona L, Vargas E, et al. Costs and predictors of costs in rheumatoid arthritis: A prevalence-based study. Arthritis Care Res. 2003;49:64–70.

Reisine S, McQuillan J, Fifield J. Predictors of work disability in rheumatoid arthritis patients. Arthritis Rheum. 1995;38:1630–7.

Download references

Acknowledgements

Open access funding provided by Royal Library, Copenhagen University Library

Author information

Authors and affiliations.

Department of Social Medicine, University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark

Lilli Kirkeskov & Katerina Bray

Department of Social Medicine, University Hospital Bispebjerg-Frederiksberg, Nordre Fasanvej 57, Vej 8, Opgang 2.2., 2000, Frederiksberg, Denmark

Lilli Kirkeskov

Department of Occupational and Social Medicine, Holbaek Hospital, Holbaek, Denmark

Katerina Bray

You can also search for this author in PubMed   Google Scholar

Contributions

LK performed the systematic research, including reading articles, performed the blinded quality assessment and the meta-analysis, and drafted and revised the article. KM performed the blinded quality assessment and the discussion afterwards of articles to be included in the research and the scores, and drafted and revised the article.

Corresponding author

Correspondence to Lilli Kirkeskov .

Ethics declarations

Ethics approval and consent to participate.

Not applicable as this is a systematic review. All the studies that are included have obtained ethical approval and consent as appreciated by the journal in which they have been published.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1: figure s1..

Employment; year of investigation.

Additional file 2: Figure S2.

Forest Plot of Comparison: Predictors for employment. Outcome: Younger or older age.

Additional file 3: Figure S3.

Forest Plot of Comparison: Predictors for employment. Outcome: >50 yr or <50 yr of age.

Additional file 4: Figure S4.

Forest Plot of Comparison: Predictors for employment. Outcome: Gender: Male or Female.

Additional file 5: Figure S5.

Forest Plot of Comparison: Predictors for employment. Outcome: Educational level: no college education or college education or higher.

Additional file 6: Figure S6.

Forest Plot of Comparison: Predictors for employment. Outcome: no comorbidities present or one or more comorbidities present.

Additional file 7: Figure S7.

Forest Plot of Comparison: Predictors for employment. Outcome: Ethnicity: Caucasian or other than Caucasian.

Additional file 8: Figure S8.

Forest Plot of Comparison: Predictors for employment. Outcome: Short or long disease duration.

Additional file 9: Figure S9.

Forest Plot of Comparison: Predictors for employment. Outcome: Low or high Health Assessment Questionnaire, HAQ-score.

Additional file 10: Figure S10.

Forest Plot of Comparison: Predictors for employment. Outcome: Low or high VAS-score.

Additional file 11: Figure S11.

Forest Plot of Comparison: Predictors for employment. Outcome: Job type: blue collar workers or other job types.

Additional file 12: Figure S12.

Forest Plot of Comparison: Predictors for employment. Outcome: No MTX or MTX.

Additional file 13: Figure S13.

Forest Plot of Comparison: Predictors for employment. Outcome: No biological or biological.

Additional file 14: Figure S14.

Forest Plot of Comparison: Predictors for employment. Outcome: No prednisolone or prednisolone.

Additional file 15: Figure S15.

Forest Plot of Comparison: Predictors for employment. Outcome: Low or high DAS score.

Additional file 16: Figure S16.

Forest Plot of Comparison: Predictors for employment. Outcome: Low or high SF 36-score.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Kirkeskov, L., Bray, K. Employment of patients with rheumatoid arthritis - a systematic review and meta-analysis. BMC Rheumatol 7 , 41 (2023). https://doi.org/10.1186/s41927-023-00365-4

Download citation

Received : 07 June 2023

Accepted : 20 October 2023

Published : 14 November 2023

DOI : https://doi.org/10.1186/s41927-023-00365-4

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Return to work
• Unemployment

BMC Rheumatology

ISSN: 2520-1026

• Submission enquiries: [email protected]
• General enquiries: [email protected]

• Qazi Corner
• Biosimilars Spotlight
• DME & nAMD On-Demand Presentation

• Multimedia Series
• Conferences
• Advisory Board

Case Study 2: Rheumatoid Arthritis Patient Case Overview and Therapeutic Goals

EP: 1 . Case Study 1: Psoriatic Arthritis Patient Case Overview and Therapeutic Goals

EP: 2 . Case Study 2: Rheumatoid Arthritis Patient Case Overview and Therapeutic Goals

EP: 3 . Case Study 3: Non-Radiographic Axial Spondylia Patient Case Overview and Therapeutic Goals

EP: 4 . Summary

Transcript:

Wright, MD : Case 2; let’s switch. You see his Crohn's Disease Activity Index [CDAI], so you know where we’re going with this one. This is a 48-year-old man initially presented to his primary care provider with noticeable stiffness in both hands, wrists, and ankles in the morning for the last 9 months. Why he waited 9 months is my first question. He has been treating himself with 800 mg 3 times daily of ibuprofen which initially worked but then stopped working. On exam when he comes to us, he’s got bilateral synovitis in his hands wrists and ankles, and he has a nodule of uncertain duration or type on his left elbow; we see he’s tender and swollen. He has a CDAI of 38 which is very active disease, whatever this disease is.

His labs are a little bit different. He’s got a CRP of 5.7 of 42, modest rheumatoid factor of 44, and a respectable cyclic citrullinated peptide antibody of 90. This is certainly not a super high number, and on his x-ray imaging those joint space narrowing with periarticular osteopenia, but no evidence of erosions based on x-ray. The recommendation for him at his first visit was to start methotrexate 10 mg per week oral and increase that to 15 mg after 4 weeks if he tolerates that, which is what he did, but 3 months later he is only minimally better; he has continuous stiffness, pain, and swelling in the wrists. His sedimentation rate is still up, and he complains of now being even more unproductive at work because of his joint pain.

The big problem I think that we have is, number 1, we’ve got all of these therapies, but we’re still being forced to step to methotrexate. If I put on my advocacy hat we need to be able to make the decisions that are right for the patient based on signs and not based on this sort of step board process where we lose time; he’s going to show up with erosions before we get to his first biologics.

Again, I just sort of put all the classes together here, and I remember when that first bag of Remicade was hung in New York City because it was in my office. That was just the other day, so patients no longer want them. We had patients come in with large rheumatoid nodules on the mitral valve. Plural nodules that were all rheumatoid. We don’t see that as much anymore because we’re not waiting around for 20 years to treat them, so here’s our plethora.

I won’t bore you with this, you are familiar with all of the names. We would’ve thought we were going to have forgot about it to the Janus kinase inhibitors, but they’ve had a delay in their approval process, so we will see where that ends up. This was the non-tumor necrosis factor [TNF] versus TNF treatment efficacy after the first treatment failure, so what happens when I switch? And whether we use a European League Against Rheumatism [EULAR] good or moderate response disease activity score 28 [DAS 28] response less than 3.2 for disease activity response or DAS 28 remission as a score.

You’ll see that the light blue and a dark blue keep the same Relative proportions. If I switch to a non-TNF within the class, and this was going from TNF to another TNF, we see that whether we’re looking at week 24 a week 52, no matter what the metric was whether it was a EULAR response, low disease activity response, or DAS 28 remission response, it was independent of that. These patients had a better response when they left class. However, the functional scores did not differ much, which is very interesting.

Transcript Edited for Clarity

ORIGINAL RESEARCH article

Association between serum antinuclear antibody and rheumatoid arthritis.

• 1 Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
• 2 Department of Rheumatology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China

Background: The relationship between serum antinuclear antibody (ANA) and rheumatoid arthritis (RA) remains unknown. Therefore, we aimed to evaluate whether serum ANA was associated with an increased risk of RA in a case–control study.

Methods: Patients with rheumatoid arthritis hospitalized at Shandong Provincial Hospital from January 2018 to December 2022 were recruited as the case group, and patients with other types of arthritis and healthy people at the same time were taken as the control group. Antinuclear antibody (ANA) was detected by indirect immunofluorescence assays. Propensity score matching was employed to construct a cohort of patients exhibiting comparable baseline characteristics. The relationship between serum ANA and the risk of rheumatoid arthritis was analyzed by logistic regression analysis.

Results: A total of 1,175 patients with RA and 1,662 control subjects were included in this study. After adjusting for potential confounding factors in the propensity-score matched cohort, the risk of RA gradually increased with rising of ANA titers. When ANA titers were divided into three groups (1:100, 1:320, and 1:1,000), the OR (95% CI) for ANA titers from low to high was 3.95 (3.01, 5.18), 16.63 (9.44, 29.30), and 17.34 (9.53, 31.54), respectively, compared to those when ANA was negative. The ANA patterns closely related to the occurrence of RA include nuclear homogeneous, nuclear speckled, and cytoplasmic speckled. Among them, the positive rate of nuclear homogeneous was the highest, which accounted for 42.64%. The OR (95% CI) of ANA patterns including nuclear homogeneous, nuclear speckled, and cytoplasmic speckled was 16.81 (11.46, 24.65), 3.40 (2.49, 4.63), and 3.09 (1.77, 5.40), respectively.

Conclusion: There was a curve relation between ANA titer and RA, and the higher the ANA titer, the higher the probability of RA. However, there was no statistical difference in probability of RA for 1:320 versus 1:1,000 ANA titers. The most important kind of ANA pattern in the blood of RA patients was nuclear homogeneous. These findings suggest that ANA may be a novel risk marker for RA.

Introduction

Rheumatoid arthritis (RA) is recognized as an autoimmune disorder characterized by chronic inflammation that primarily impacts the joints while also being linked to various systemic aberrations of the immune system ( 1 ). If inadequately treated, RA can lead to progressive joint deterioration and irreversible impairment ( 2 ). Many circulating autoantibodies have been found in the serum of most patients with RA, including rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) ( 3 , 4 ).

Antinuclear antibodies (ANAs) comprise a diverse array of autoantibodies that specifically target various nuclear and cytoplasmic components within cells. The detection of ANA is facilitated through the implementation of various immunochemical methods, including indirect immunofluorescence assay (IIFA), enzyme-linked immunosorbent assay (ELISA), multiplex assay, and line immunoassay formats. Notably, the IIFA utilizing HEp-2 cells has long been regarded as the gold standard for ANA detection, providing reliable and accurate results ( 5 , 6 ).

ANA test results are typically presented in two parts: besides the titer or fluorescence intensity of the antibodies, it also provides the fluorescence pattern produced by these antibodies. The observed fluorescence patterns encompass various cellular components such as the nucleus, cytoplasm, and patterns associated with mitotic cells. In order to establish a standardized nomenclature and definition for ANA, the International Consensus on ANA Patterns (ICAP) initiative has achieved consensus and aims to gradually transition to a more appropriate term: anti-cellular antibodies (ACs). These AC categories consist of 29 distinct staining patterns denoted as AC1-AC29 ( 7 ). Each individual staining pattern arises from the presence of one or multiple autoantibodies ( 8 ).

As is well known, ANA are important biomarkers for multiple systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), scleroderma (SSc), polymyositis (PM), and mixed connective tissue disease (MCTD) ( 5 , 9 ). However, the precise clinical implications of ANA in RA and the relationship with other serological markers have remained ambiguous. The current study was conducted with the aim of elucidating the correlation between serum ANA and RA. Meanwhile, several autoantibodies (including CCP and MCV) and acute phase reactants (such as C-reactive protein and erythrocyte sedimentation rate) of the disease were also investigated.

Materials and methods

We recruited patients with rheumatoid arthritis, which were newly diagnosed according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA in the Department of Rheumatology of Shandong Provincial Hospital Affiliated to Shandong First Medical University from January 2018 to December 2022 as case group. The control group was composed of patients with other types of arthritis (such as ankylosing spondylitis, gout arthritis, and osteoarthritis) hospitalized in the Department of Rheumatology and healthy people during the same period. Just as shown in Figure 1 , participants were all over 18 years old. Participants were excluded if they suffered from two or more types of arthritis. Patients with other autoimmune diseases, such as SLE, SS, SSc, PM, and vasculitis, were also excluded from the analyses. All procedures involving human participants were approved by the Shandong Provincial Hospital Affiliated to Shandong First Medical University Research Ethics Committee, and informed consents were obtained from all participants.

Figure 1 Flowchart showing selection criteria and analysis process of study participants.

Data collection and blood indicators detection

Demographic variables including age, gender, history of common autoimmune diseases (AID, such as SLE, SS, SSc, PM, and vasculitis) were obtained. Blood examination included antinuclear antibody (ANA), cyclic citrullinated peptide (CCP), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and mutant citrulline vimentin (MCV). Elbow venous blood was extracted from all participants after fasting for 6–8 h. ANA levels were determined by an indirect immunofluorescence assay using HEp-2 cells as the substrate by a commercial kit (Euroimmun, Germany). All sections were examined independently by two experienced laboratory staff, and positive and negative control serum samples were included in each run. The analysis was performed for the most prevalent ANA patterns (nuclear homogeneous, nuclear speckled, cytoplasmic speckled, nucleolar, and centromere), and other less common ANA patterns were classified as other patterns. Only monospecific nuclear patterns were included; the primary pattern was selected for two or more patterns. Serum ANA level exceeding 1:100 was seen as positive.

Statistical analysis

In light of the variances in the baseline characteristics among participants in the two groups ( Table 1 ), propensity-score matching (with propensity score in the range of 0.02) was applied to construct a cohort of patients with similar baseline characteristics. Age and sex were matched with the use of a 1:1 matching between RA and non-RA groups. In our research, numerical variables were presented in the form of mean ± standard deviation (SD) or median with interquartile range (IQR). Student’s t-test was employed for assessing normal distributions, while the Mann–Whitney test was utilized for non-normal distributions. Categorical variables, on the other hand, were expressed as frequencies and evaluated using Pearson’s χ 2 test or Fisher exact test. We evaluated the possible linear and nonlinear relationships between ANA and RA by multivariate linear regression models adjusted for age and gender in the propensity-score matched cohort. Smooth curve fitting was also employed to analyze the independent relationship between them after adjusting the confounding factors. All analyses were performed using Empower Stats software (version 4.1, USA) and R software ( http://www.R-project.org ). p < 0.01 was considered statistically significant.

Table 1 Baseline characteristics of the participants before and after propensity-score matching.

Patient selection for subsequent analyses

A total of 2,837 patients met the criteria for this study; 1,175 patients with rheumatoid arthritis were selected as the case group, while 787 patients with other types of arthritis (including 554 ankylosing spondylitis, 184 gout arthritis, and 49 cases of osteoarthritis) and 875 healthy subjects during the same period as the control group. The patient characteristics before and after propensity-score matching are listed in Table 1 . Before propensity-score matching, there were significant differences between the two groups with regard to age, gender, ANA titers and patterns, CCP, MCV, RF, CRP, and ESR on the basis of available data. There was no difference between RA and non-RA group in terms of age, gender, and CRP after matching, and 38.13% patients were ANA positive in the non-RA group while the positive rate of ANA in patients with RA was 77.76%. Furthermore, the highest percentage of ANA pattern of RA patients was nuclear homogeneous (42.64%).

Characteristics of ANA-positive patients

To further study the influence of ANA in RA, the characteristics of age, gender, and blood indicators between the ANA-positive and ANA-negative group are described in Table 2 . CCP, MCV, and RF of patients testing positive for ANA were significantly higher than those of patients testing negative for ANA (all p < 0.001). The relationships between ANA and CCP or RF among rheumatoid arthritis patients with or without CCP + or RF + were analyzed by logistic regression analysis. Just as shown in Supplementary Tables S3 , S4 , the results suggested that ANA titer was positively correlated with CCP or RF among patients with RA. Similarly, the results also suggested that nuclear homogeneous was significantly associated with CCP or RF among rheumatoid arthritis patients.

Table 2 Characteristics of ANA-negative and ANA-positive patients with RA.

The nonlinear relation between the ANA and rheumatoid arthritis

Smooth curve fitting ( Figure 2 ) was performed after the adjustment of sex and age in the matched cohort. It was seen from the smooth curves that there existed nonlinear relations between ANA (its titer and pattern) and the probability of rheumatoid arthritis. ANA titer was positively associated with RA, and the higher the ANA titer, the higher the probability of RA. ANA patterns related to the probability of RA included nuclear homogeneous, nuclear speckled, and cytoplasmic speckled, especially nuclear homogeneous.

Figure 2 The smooth curve fitting showed the association between ANA titers (A) , ANA patterns (B) and rheumatoid arthritis after the adjustment of sex and age in the matched cohort. The red lines represented the upper and lower 95% confidence intervals (CIs).

Relationship of ANA patterns and titers to rheumatoid arthritis

Logistic regression analysis was performed further in patients with and without RA after matching. In both unadjusted and adjusted (age and sex) logistic regression models, ANA titers were related to rheumatoid arthritis. Compared with those in the ANA-negative patients, the multi-adjusted ORs (95% CIs) of rheumatoid arthritis related to ANA titers (1:100, 1:320, and 1:1,000) were 3.95 (3.01, 5.18), 16.63 (9.44, 29.30), and 17.34 (9.53, 31.54), respectively ( Table 3 ). However, there was no statistical difference in probability of RA for 1:320 versus 1:1,000 ANA titers as shown in Table 4 ( p = 0.9163). Similarly, the results also suggested that ANA patterns (including nuclear homogeneous, nuclear speckled, and cytoplasmic speckled) were significantly associated with RA in the unadjusted analysis (all p < 0.0001). This difference remained statistically significant even after controlling for age and gender. Compared with those in the ANA-negative patients, the multi-adjusted ORs (95% CIs) of rheumatoid arthritis related to ANA patterns mentioned above were 16.81 (11.46, 24.65), 3.40 (2.49, 4.63), and 3.09 (1.77, 5.40), respectively ( Table 3 ). We also found that nuclear homogeneous was more significantly associated with rheumatoid arthritis than other ANA patterns except centromere ( Table 4 ). According to the reference values of CCP and RF, the participants were categorized as four groups, including CCP−, CCP+, RF−, and RF+ groups. The association between ANA and RA among the four groups with and without matching was analyzed by logistic regression analysis. There was no association between ANA and the risk of RA in the CCP− group, while ANA titer was positively correlated with RA, and the ANA patterns (including nuclear homogeneous and nuclear speckled) were associated with incidence of RA in CCP + group and RF− group, which were basically consistent with above conclusions ( Supplementary Tables S10 , S11 ). The relationships between ANAs and the risk of ankylosing spondylitis, gouty arthritis, or osteoarthritis were analyzed by logistic regression analysis. After adjusting for sex and age, we found that there was no connection between them just as shown in Supplementary Tables S5 - S7 .

Table 3 Association between ANA positivity and the incidence risk of RA in the propensity-score matched cohort*.

Table 4 Odds ratio (OR) and 95% confidence interval (CI) for the association between ANA and RA in the propensity-score matched cohort*, took 1:320 and nuclear homogeneous as reference, respectively.

In the present study, our results supported the notion that there was a significant association between ANA and the risk of RA. There were nonlinear relationships between ANA (its titer and pattern) and the incidence of RA. ANA titer was positively correlated with RA. Three ANA patterns (including nuclear homogeneous, nuclear speckled, and cytoplasmic speckled), especially nuclear homogeneous, were associated with increased risk of developing RA.

Less study was focus on the relationship between serum ANA and RA, and the relation between them was still unclear. In those subjects with active RA, ANA positivity was associated with being RF+, especially high titer ( 10 ), which was similar to our conclusion. Because we showed that RF of patients testing positive for ANA were significantly higher than that of patients testing negative for ANA. Ishikawa et al. ( 11 ) found that ANA was associated with poor treatment response to biological disease-modifying anti-rheumatic drugs (DMARDs) in patients with RA, and they believed ANA as a potential predictor for poor treatment response. Paknikar et al. ( 12 ) found that there were significant dissimilarities in patients with rheumatoid arthritis who tested positive and negative for ANA concerning the duration to satisfy the RA criteria and choice of initial pharmacotherapy. Moreover, ANA-positive individuals experienced prolonged duration to fulfill RA criteria. Another study showed that anti-Golgi antibody pattern (one type of ANA patterns) with high titer was closely related to RA ( 13 ). These findings could indicate a difference in clinical presentation of patients with RA between ANA positive and ANA negative. Further research was needed to study the association between ANA and RA. To our knowledge, the present study is the first report to clarify the correlation of ANA titer and pattern together with RA.

Thus far, the universally accepted standard for defining the positivity of ANA remains elusive. Previous studies have shown that HEp-2 cell lines derived from cultured human laryngeal epithelial carcinoma exhibit greater sensitivity to the presence of ANA in both patients and controls, when compared to animal tissue sections such as mouse or rat kidney ( 14 ). In August 2009, the American College of Rheumatology (ACR) released a recommendation advocating for the utilization of HEp-2 indirect fluorescent antibody in all ANA screenings. Currently, there are two types of screening dilution systems used to determine ANA levels: one utilizes twofold screening dilution systems, including dilutions such as 1:40, 1:80, 1:160, and 1:320. The other employs 3.2-fold screening dilution systems, encompassing dilutions like 1:100, 1:320, 1:1,000, and 1:3,200 ( 15 , 16 ). Notably, the 1:100 screening dilution has been frequently adopted as the cutoff value in certain clinical assessments ( 14 , 17 ). In our investigation, patients were subjected to ANA testing using the aforementioned screening dilution systems with HEp-2 cells and monkey liver as substrates, facilitated by a commercial kit. The manufacturers specified reference screening dilutions at four dilutions, namely, 1:100, 1:320, 1:1,000, and 1:3,200. Consequently, the titer exceeding 1:100 was employed as the criterion for defining ANA positivity in our institution. The analyses revealed that the positive rate of ANA in the patients with RA was 45.45%, 16.77%, and 13.19% for a titer of 1:100, 1:320, and 1:1,000, respectively, and no ANA was found with titer higher than 1:1,000. The higher the ANA titer (within the scope from negative to 1:1,000), the higher the probability of RA.

Initially, a consensus encompassing 28 distinct HEp-2 patterns was established, each assigned an alphanumeric code ranging from AC-1 to AC-28 in accordance with the International Consensus on ANA Patterns (ICAP) ( 18 ). Subsequent to this initial classification, two additional patterns, AC-29 ( 19 ) and AC-0 (negative) ( 20 ) were introduced in 2018. Notably, each unique staining pattern observed was attributed to the presence of one or more specific autoantibodies. The most common autoantibodies of nuclear homogeneous pattern included anti-dsDNA antibody (dsDNA), anti-histones antibody (AHA), and anti-nucleosomes antibody (AnuA). Moreover, anti-SS-A antibody (SSA), anti-SS-B antibody (SSB), anti-U1 ribonucleoprotein antibodies (U1RNP), and anti-smith antibody (Sm) were specific autoantibodies of nuclear speckled pattern. Anti-Jo-1 antibody (Jo-1) and anti-ribosomal P protein antibody (Rib-P) were specific autoantibodies of cytoplasmic-speckled pattern ( 21 ). In this study, the analysis was performed for the most prevalent ANA patterns including nuclear homogeneous, nuclear speckled, cytoplasmic speckled, nucleolar, and centromere. Other less common ANA patterns were classified as other patterns. We found that ANA patterns related to the risk of RA included nuclear homogeneous, nuclear speckled, and cytoplasmic speckled, especially nuclear homogeneous. The proportion of nuclear homogeneous of RA patients was the highest among all ANA patterns. However, the most common autoantibodies of three kinds of ANA pattern related to RA as described above were negative. This indicated that the antibodies corresponding to ANAs in RA patients were not their common autoantibodies, and the corresponding antibodies were still unclear.

The strengths of our study are the large sample size and well-adjudicated analysis. Our study also has some limitations. First, it tested association, not causation. Furthermore, using a convenience sample from one single institution rather than a population-based study created potential selection bias and limits generalizability. In addition, we lacked data on clinical characteristics of RA, such as disease duration, arthritis distribution, extra-articular symptoms, treatment, and outcomes, which might affect ANA titer ( 11 , 12 , 22 , 23 ). Finally, the conclusions are not suitable for CCP-negative patients by our subgroup analysis. More prospective studies are required to assess the importance of this research.

Conclusions

In conclusion, our results show that high ANA titer may be associated with increased risk of developing RA, so do three ANA patterns (including nuclear homogeneous, nuclear speckled, and cytoplasmic speckled), especially nuclear homogeneous. These findings suggest that ANA may be a novel risk marker for RA; however, future studies investigating the role of ANA in the treatment and outcomes of patients with RA are needed.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving humans were approved by Ethics Committee of the Shandong Provincial Hospital Affiliated to Shandong First Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

Author contributions

YS: Conceptualization, Writing – review & editing. XW: Data curation, Formal analysis, Writing – original draft, Writing – review & editing. FL: Data curation, Formal analysis, Writing – original draft. CP: Software, Writing – original draft. JZ: Data curation, Formal analysis, Writing – original draft. ML: Methodology, Writing – original draft.

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Acknowledgments

We appreciated the contributions of Department of Rheumatology, Shandong Provincial Hospital Affiliated to Shandong First Medical.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2024.1358114/full#supplementary-material

1. Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, et al. Rheumatoid arthritis. Nat Rev Dis Primers . (2018) 4:18001. doi: 10.1038/nrdp.2018.1

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Finckh A, Gilbert B, Hodkinson B, Bae SC, Thomas R, Deane KD, et al. Global epidemiology of rheumatoid arthritis. Nat Rev Rheumatol . (2022) 18:591–602. doi: 10.1038/s41584-022-00827-y

3. Petrovská N, Prajzlerová K, Vencovský J, Šenolt LFilková M. The pre-clinical phase of rheumatoid arthritis: From risk factors to prevention of arthritis. Autoimmun Rev . (2021) 20:102797. doi: 10.1016/j.autrev.2021.102797

4. Sokolova MV, Schett GSteffen U. Autoantibodies in rheumatoid arthritis: historical background and novel findings. Clin Rev Allergy Immunol . (2022) 63:138–51. doi: 10.1007/s12016-021-08890-1

5. Bossuyt X, De Langhe E, Borghi MOMeroni PL. Understanding and interpreting antinuclear antibody tests in systemic rheumatic diseases. Nat Rev Rheumatol . (2020) 16:715–26. doi: 10.1038/s41584-020-00522-w

6. Stochmal A, Czuwara J, Trojanowska MRudnicka L. Antinuclear antibodies in systemic sclerosis: an update. Clin Rev Allergy Immunol . (2020) 58:40–51. doi: 10.1007/s12016-018-8718-8

7. Damoiseaux J, Andrade LEC, Carballo OG, Conrad K, Francescantonio PLC, Fritzler MJ, et al. Clinical relevance of HEp-2 indirect immunofluorescent patterns: the International Consensus on ANA patterns (ICAP) perspective. Ann Rheum Dis . (2019) 78:879–89. doi: 10.1136/annrheumdis-2018-214436

8. von Mühlen CA, Garcia-De La Torre I, Infantino M, Damoiseaux J, Andrade LEC, Carballo OG, et al. How to report the antinuclear antibodies (anti-cell antibodies) test on HEp-2 cells: guidelines from the ICAP initiative. Immunol Res . (2021) 69:594–608. doi: 10.1007/s12026-021-09233-0

9. Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis . (2019) 78:1151–9. doi: 10.1002/art.40930

10. Matsos MP, Pope JESpencer-Green G. ANA+ (anti-nuclear antibody) is correlated with RF+ (rheumatoid factor) in rheumatoid arthritis. Inflammopharmacology . (2004) 12:229–31. doi: 10.1163/1568560042342301

11. Ishikawa Y, Hashimoto M, Ito H, Tanaka M, Yukawa N, Fujii T, et al. Anti-nuclear antibody development is associated with poor treatment response to biological disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis. Semin Arthritis Rheum . (2019) 49:204–10. doi: 10.1016/j.semarthrit.2019.02.003

12. Paknikar SS, Crowson CS, Davis JMThanarajasingam U. Exploring the role of antinuclear antibody positivity in the diagnosis, treatment, and health outcomes of patients with rheumatoid arthritis. ACR Open Rheumatol . (2021) 3:422–6. doi: 10.1002/acr2.11271

13. Zhai J, Liao J, Wang M, Huang Z, Hu J, Xu H, et al. Anti-golgi antibody as a potential indicator for rheumatoid arthritis. Lab Med . (2022) 53:156–60. doi: 10.1093/labmed/lmab046

14. Ma X, Xin L, Sun JLiu Z. Antinuclear antibody-positive cohort constitutes homogeneous entity in juvenile idiopathic arthritis. Mod Rheumatol . (2016) 26:75–9. doi: 10.3109/14397595.2015.1056993

15. Ma L, Zeng A, Chen Y, Chen BZhou R. Anti-golgi antibodies: Prevalence and disease association in Chinese population. Clin Chim Acta . (2019) 496:121–4. doi: 10.1016/j.cca.2019.06.027

16. Leuchten N, Hoyer A, Brinks R, Schoels M, Schneider M, Smolen J, et al. Performance of antinuclear antibodies for classifying systemic lupus erythematosus: A systematic literature review and meta-regression of diagnostic data. Arthritis Care Res (Hoboken) . (2018) 70:428–38. doi: 10.1002/acr.23292

17. Hong M, Ma B, Lin Z, Zhou X, Geng X, Shen L, et al. Hep-2 cell based indirect immunofluorescence assay for antinuclear antibodies as a potential diagnosis of drug-induced autoimmunity in nonclinical toxicity testing. Regul Toxicol Pharmacol . (2015) 71:141–7. doi: 10.1016/j.yrtph.2014.10.005

18. Chan EK, Damoiseaux J, Carballo OG, Conrad K, de Melo Cruvinel W, Francescantonio PL, et al. Report of the first international consensus on standardized nomenclature of antinuclear antibody HEp-2 cell patterns 2014-2015. Front Immunol . (2015) 6:412. doi: 10.3389/fimmu.2015.00412

19. Andrade LEC, Klotz W, Herold M, Conrad K, Rönnelid J, Fritzler MJ, et al. International consensus on antinuclear antibody patterns: definition of the AC-29 pattern associated with antibodies to DNA topoisomerase I. Clin Chem Lab Med . (2018) 56:1783–8. doi: 10.1515/cclm-2018-0188

20. Herold M, Klotz W, Andrade LEC, Conrad K, de Melo Cruvinel W, Damoiseaux J, et al. International Consensus on Antinuclear Antibody Patterns: defining negative results and reporting unidentified patterns. Clin Chem Lab Med . (2018) 56:1799–802. doi: 10.1515/cclm-2018-0052

21. Vulsteke JB, Van Hoovels L, Willems P, Vander Cruyssen B, Vanderschueren S, Westhovens R, et al. Titre-specific positive predictive value of antinuclear antibody patterns[J]. Ann Rheum Dis . (2021) 80:e128. doi: 10.1136/annrheumdis-2019-216245

22. Buch MH, Johnsen ASchiff M. Can switching to abatacept therapy in patients with rheumatoid arthritis on background methotrexate reverse TNF-inhibitor-induced antinuclear autoantibody/double-stranded DNA autoantibody conversion? An analysis of the AMPLE and ATTEST trials. Clin Exp Rheumatol . (2019) 37:127–32.

PubMed Abstract | Google Scholar

23. Mori A, Saito T, Takahashi M, Shibata M, Tsuji G, Hatachi S, et al. Presence of anti-nuclear antibodies is a risk factor for the appearance of anti-drug antibodies during infliximab or adalimumab therapy in patients with rheumatoid arthritis[J]. PloS One . (2020) 15:e0243729. doi: 10.1371/journal.pone.0243729

Keywords: rheumatoid arthritis, antinuclear antibody, correlation analysis, curve relation, smooth curve

Citation: Liu F, Wang X-Q, Zou J-W, Li M, Pan C-C and Si Y-Q (2024) Association between serum antinuclear antibody and rheumatoid arthritis. Front. Immunol. 15:1358114. doi: 10.3389/fimmu.2024.1358114

Received: 19 December 2023; Accepted: 29 March 2024; Published: 22 April 2024.

Reviewed by:

Copyright © 2024 Liu, Wang, Zou, Li, Pan and Si. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Yuan-Quan Si, [email protected] ; Cui-Cui Pan, [email protected]

† These authors have contributed equally to this work

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• PMC11031444

An investigation of the differential therapeutic effects of romosozumab on postmenopausal osteoporosis patients with or without rheumatoid arthritis complications: a case–control study

Kosuke ebina.

1 Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka 565-0871 Japan

2 Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka 565-0871 Japan

Yoshio Nagayama

3 Nagayama Rheumatology and Orthopaedic Clinic, 4-3-25 Hiokisounishi-Machi, Higashi-Ku, Sakai, 599-8114 Japan

Masafumi Kashii

4 Department of Orthopaedic Surgery, National Hospital Organization Osaka Minami Medical Center, 2-1 Kidohigashimachi, Kawachinagano, Osaka 586-8521 Japan

Hideki Tsuboi

5 Department of Orthopaedic Surgery, Osaka Rosai Hospital, 1179-3 Nagasone-Cho, Kita-Ku, Sakai, 591-8025 Japan

Gensuke Okamura

Akira miyama.

6 Department of Orthopaedic Surgery, Osaka Toneyama Medical Center, 5-1-1 Toneyama, Toyonaka, Osaka 560-8552 Japan

Takaaki Noguchi

Makoto hirao, taihei miura, yuji fukuda, takuya kurihara.

7 Department of Health and Sport Sciences, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka 565-0871 Japan

Seiji Okada

Associated data.

The data reported in this paper is available from the corresponding author upon a reasonable request.

The impact of ROMO on the width of anabolic windows and the increase in BMD was reduced in the RA group compared to the non-RA group, and this reduction was associated with correlations to RA-related factors.

To investigate the effects of romosozumab (ROMO) in postmenopausal osteoporosis, with and without comorbid rheumatoid arthritis (RA).

In this retrospective, case-controlled, multicenter study, 171 postmenopausal patients who did not receive oral glucocorticoid, comprising 59 in the RA group and 121 in the non-RA group, received uninterrupted ROMO treatment for 12 months. Propensity score matching was employed to ensure comparability in clinical backgrounds, resulting in 41 patients in each group. Baseline characteristics were as follows: overall (mean age, 76.3 years; T-score of lumbar spine (LS), − 3.0; 45.1% were treatment-naive for osteoporosis); RA group (anti-cyclic citrullinated peptide antibody (ACPA) positivity, 80.5%; titer, 206.2 U/ml; clinical disease activity index (CDAI), 13.6; health assessment questionnaire disability index (HAQ-DI), 0.9). Bone mineral density (BMD) and serum bone turnover markers were monitored over a 12-month period.

The rate of increase in the bone formation marker, PINP, and the rates of decrease in the bone resorption marker, TRACP-5b, exhibited a trend toward smaller changes in the RA group compared to the non-RA group, implying a smaller anabolic window. After 12 months, the RA group displayed lower BMD increases in the LS (9.1% vs. 12.6%; P  = 0.013) and total hip (2.4% vs. 4.8%; P  = 0.025) compared to the non-RA group. Multiple regression analysis in the all RA group ( n  = 59) for the association between RA-specific factors and 12-month BMD changes revealed negative correlations between ACPA titer and LS BMD and between HAQ-DI and femoral neck BMD.

Conclusions

The efficacy of ROMO may be attenuated by RA-related factors.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00198-024-07019-2.

Introduction

Rheumatoid arthritis (RA) represents one of the principal etiologies of secondary osteoporosis [ 1 ], with decreased systemic bone mineral density (BMD) observed early in its course [ 2 ]. Various contributing factors to progressive bone loss in RA have been documented. Pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and IL-6, which are closely linked to disease activity, stimulate the expression of receptor activation of nuclear factor κB ligand (RANKL) by osteocytes, thereby promoting osteoclastogenesis [ 3 ]. Furthermore, TNF-α, glucocorticoid, and mechanical unloading also stimulate sclerostin production by osteocytes. Sclerostin, in turn, directly inhibits Wnt signaling, thus dampening osteoblast-mediated bone formation [ 4 ]. Additionally, sclerostin hinders the production of osteoprotegerin, an in vivo decoy receptor for RANKL produced by both osteocytes and osteoblasts, further exacerbating osteoclastogenesis [ 4 ]. Notably, individuals with RA exhibit higher levels of serum sclerostin and bone resorption markers compared to healthy controls [ 5 ], indicative of an augmented bone resorption and impaired bone formation in RA patients.

Romosozumab (ROMO), a monoclonal anti-sclerostin antibody, represents a novel therapeutic agent for osteoporosis. ROMO enhances Wnt signaling by neutralizing sclerostin [ 6 ]. By directly stimulating bone formation by osteoblasts and indirectly inhibiting bone resorption by osteoclasts [ 4 ], ROMO exerts a “dual effect,” resulting in a broader anabolic window when compared to other anti-osteoporosis agents [ 7 ]. Indeed, in patients with postmenopausal osteoporosis, ROMO has demonstrated superior improvements in BMD compared to alendronate, teriparatide [ 6 ], and denosumab (DMAb) [ 8 ].

However, it remains uncertain whether the altered bone metabolism seen in RA might potentiate or diminish the effects of ROMO. In this case-controlled study, our objective was to elucidate the impact of ROMO in RA patients compared to non-RA postmenopausal osteoporosis patients. Our primary endpoint was to assess differences in changes in bone turnover markers and BMD between the two groups, while our secondary endpoint aimed to elucidate the influence of RA-related factors on ROMO’s effects as determined by changes in BMD.

Study design and patients

This retrospective, case-controlled study was conducted across five centers. Treatment with ROMO (administered subcutaneously at 210 mg every month) was initiated between March 2019 and November 2021 for patients deemed to have a high fracture risk as defined by either the World Health Organization’s 1998 criteria or the Japanese Guidelines for Prevention and Treatment of Osteoporosis from 2011 [ 9 ]. Inclusion criteria encompassed patients with one or more of the following: (1) BMD T-score <  − 2.5 with at least one fragility fracture, (2) lumbar spine (LS) BMD T-score <  − 3.3, (3) two or more vertebral fractures, or (4) semiquantitative (SQ) grade 3 vertebral fracture [ 10 ].

Exclusion criteria for ROMO initiation were as follows: patients with contraindications to ROMO (i.e., those with major cardiovascular events within the past year), patients with conditions affecting bone metabolisms such as thyroid or parathyroid disorders, individuals receiving hormone replacement therapy, individuals with cancer undergoing radiation therapy involving the skeletal system, patients with osteomalacia (characterized by low serum levels of 25(OH)D, calcium, and phosphorus; elevated alkaline phosphatase; and intact parathyroid hormone), or patients with severe renal impairment (estimated glomerular filtration rate (eGFR) < 30 (ml/min/1.73 m 2 )). Additionally, patients lacking BMD data, male patients, and those with concurrent oral glucocorticoid use, other autoimmune diseases, or those who discontinued ROMO treatment before completing 12 months of therapy were also excluded from this study.

BMD assessment

BMD values of the LS (L2–L4), total hip (TH), and femoral neck (FN) were assessed using dual-energy X-ray absorptiometry (DXA) equipment (Horizon W; Hologic, Inc., Marlborough, MA, USA/PRODIGY; GE Healthcare, Tokyo, Japan) at baseline and subsequently at 6-month intervals following ROMO initiation. The percent coefficient of variation for L2-L4 was 0.63% for the Horizon system and 0.41% for the PRODIGY system. BMD data were standardized using the reference values obtained from the Japanese population for each respective DXA device, following the correction method proposed by the Japan Osteoporosis Society and the International Society for Clinical Densitometry Guidance [ 11 ]. As previously mentioned, regions of severe sclerosis, degenerative spine conditions, vertebral fractures, and surgical sites were excluded from the BMD measurements [ 12 ].

Biochemical markers of bone turnover

Blood samples were collected in the morning following an overnight fast. Bone turnover markers were measured at baseline and subsequently at 1, 6, and 12 months during the ROMO treatment. Total N-terminal type I procollagen propeptide (PINP; interassay coefficient of variation ≤ 5.0%; Roche Diagnostics, Basel, Switzerland) served as a bone formation marker, and Isoform 5b of tartrate-resistant acid phosphatase (TRACP-5b; interassay coefficient of variation ≤ 9.0%; Nittobo Medical Co. Ltd., Tokyo, Japan) was measured as a bone resorption marker (TRACP-5b demonstrates superior sensitivity and signal-to-noise ratio compared to serum cross-linked C-telopeptide of type I collagen (CTX) [ 13 ]). Serum 25-hydroxycholecalciferol (25(OH)D) levels were assessed via electrochemiluminescence using the Elecsys system (Roche Diagnostics, Basel, Switzerland).

Radiographs

Spinal radiographs were routinely obtained at baseline and subsequently at 6-month intervals following ROMO initiation [ 14 ]. Vertebral fractures with grades ≥ 1 were defined using the SQ method [ 10 ]. For patients exhibiting symptoms of incidental clinical, vertebral, or nonvertebral fractures, each attending investigator evaluated unscheduled radiographs.

Statistical analysis

Changes in BMD and bone turnover marker levels were evaluated based on the percentage change from baseline. The Mann–Whitney U test, chi-square test, and Fisher exact test were employed for statistical comparisons between the two groups. Changes in BMD and bone turnover marker levels from baseline to specified time points within each study group were assessed using the Wilcoxon signed-rank test. Multiple regression analysis, examining associations with RA-specific factors and increase in BMD at 12 months (incorporating the LS as a region abundant in trabecular bone and the FN as a region abundant in cortical bone), was conducted by incorporating variables known to affect BMD in RA patients based on previous reports (anti-citrullinated peptide antibody (ACPA) titer [ 15 ], clinical disease activity index (CDAI) [ 16 ], health assessment questionnaire disability index (HAQ-DI) [ 2 ], and biological disease-modifying antirheumatic drugs (bDMARDs) [ 17 ] or Janus kinase inhibitors (JAKi) [ 18 ] usage). The number of variables utilized in the multiple regression analysis was determined in accordance with a previously reported methodology, which defined the number of variables by dividing the number of cases by 15 [ 19 ].

All statistical analyses were performed using EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which provides a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [ 20 ]. P values < 0.05 were considered indicative of statistical significance.

Propensity score matching

To align the clinical backgrounds that could potentially influence bone metabolism, we implemented 1:1 optimal propensity score matching without replacement. This matching process included variables such as age, body mass index, BMD (T-score) of LS, TH, and FN, as well as differences in prior osteoporosis treatment (naïve, switched from bisphosphonates, denosumab, or teriparatide) as previously described [ 21 ].

Ethical statement

This study was conducted following the ethical standards of the Declaration of Helsinki. It received approval from the institutional ethical review board of Osaka University Graduate School of Medicine (approval No. 18258) and each participating institute. Informed consent was obtained from the patients, and opt-out information was made available on the hospital’s homepage.

Patient disposition and characteristics

The detailed patient flow is presented in the CONSORT flow diagram (Fig.  1 ). Among 209 patients who initiated treatment with ROMO, 171 patients met the inclusion criteria. Patients were divided into two groups: the RA group ( n  = 59) and the non-RA group ( n  = 121). After propensity score matching, 41 patients from each group were selected.

Study design and patient flow. BMD, bone mineral density

Table ​ Table1 1 presents the clinical characteristics of the propensity score-matched patients at the time of ROMO induction. No significant differences were observed among the groups, except for corrected serum calcium levels. In the RA group, 80.5% of the patients were ACPA positive (mean titer; 206.2 U/ml), 53.7% of the patients were remission or low disease activity evaluated by CDAI (≤ 10), and 39.0% of the patients were HAQ remission (≤ 0.5). Additionally, 31.7% of patients were treated with bDMARDs or JAKi. The clinical characteristics of the non-matched patients at the time of ROMO induction are shown in Supplementary Table  1 .

Table 1

Initial clinical characteristics of patients following propensity score matching

Mean ± standard deviation. %—number of patients with measurements/total number of patients

Differences between the groups were determined by the Mann–Whitney U test, chi-square test, or Fisher exact test

N.A. , not applicable; BMD , bone mineral density; eGFR , estimated glomerular filtration rate; PINP , type I collagen N-terminal propeptide; TRAP-5b , isoform 5b of tartrate-resistant acid phosphatase; 25(OH)D , 25-hydroxycholecalciferol; RF , rheumatoid factor; ACPA , anti-cyclic citrullinated peptide antibody; CRP , C-reactive protein; MMP-3 , matrix metalloproteinase-3; DAS28-CRP , disease activity score assessing 28 joints with CRP; CDAI , Clinical Disease Activity Index; HAQ , Health Assessment Questionnaire; MTX , methotrexate; csDMARDs , conventional synthetic disease-modifying antirheumatic drugs; bDMARDs , biological disease-modifying antirheumatic drugs; JAKi , Janus kinase inhibitors

Bone turnover markers

Figure  2 a and b show the percentage change in serum PINP and TRACP-5b levels, respectively. The non-RA group tended to exhibit a higher rate of increase in PINP compared to the RA group from 6 to 12 months. Conversely, the non-RA group tended to show a greater rate of decrease in TRACP-5b compared to the RA group from 6 to 12 months, indicating a larger anabolic window in the non-RA group. The percentage change in serum PINP and TRACP-5b levels for the non-matched patients is provided in Supplementary Table  2 .

Percentage change of serum PINP level ( a ) and TRACP-5b level ( b ). PINP, N-terminal type I procollagen propeptide; TRACP-5b, isoform 5b of tartrate-resistant acid phosphatase; RA, rheumatoid arthritis. Bars indicate mean ± standard error. * P  < 0.05, ** P  < 0.01, *** P  < 0.001; change within each treatment group compared with baseline

Changes in BMD

Regarding the percent change of BMD in the LS (Fig.  3 a), the increase (mean ± standard error; P value compared with baseline) observed at 12 months was significantly higher in the non-RA group compared to the RA group (12.6 ± 1.0% vs. 9.1 ± 0.3%; P  = 0.013), as well as in the TH (Fig.  3 b) (4.8 ± 0.8% vs. 2.4 ± 0.6%; P  = 0.025). In the FN, the non-RA group tended to show a higher BMD increase compared to the RA group at 12 months (Fig.  3 c) (3.9 ± 1.0% vs. 2.3 ± 0.7%; P  = 0.22). The percentage change in BMD for the non-matched patients is presented in Supplementary Table  3 . In non-matched RA patients, treatment-naïve cases ( n  = 19) tended to show higher BMD increase compared to switched cases ( n  = 40) in the LS (10.5 ± 1.4% vs. 7.4 ± 0.8%; P  = 0.078) and in the TH (3.7 ± 0.8% vs. 2.1 ± 0.8%; P  = 0.21) at 12 months, although no significant difference was observed between the groups (Supplementary Table  4 ).

Percentage change of BMD in the lumbar spine ( a ), total hip ( b ), and femoral neck ( c ). BMD, bone mineral density; RA, rheumatoid arthritis. Bars indicate mean ± standard errors. # P  < 0.05; difference between the two indicated groups. * P  < 0.05, ** P  < 0.01, *** P  < 0.001; change from baseline within each treatment group

Finally, we conducted a multiple regression analysis to investigate the association between RA-specific factors and an increase in LS or FN BMD at 12 months of non-matched RA patients ( n  = 59; Table  2 ). As a result, BMD increase in the LS was negatively associated with ACPA titer (OR =  − 0.0052, 95% CI =  − 0.0097– − 0.00071, P  = 0.024) and positively associated with CDAI (OR = 0.162, 95% CI = 0.0281–0.297, P  = 0.019). Conversely, BMD increase in the FN was negatively associated with HAQ-DI (OR =  − 3.101, 95% CI =  − 4.798– − 1.403, P  = 0.00061).

Table 2

Results of multiple regression analysis assessing the association between RA-specific factors and the change in lumbar spine or femoral neck BMD over 12 months in non-matched RA patients ( n  = 59)

BMD , bone mineral density; RA , rheumatoid arthritis; OR , odds ratio; CI , confidence interval; ACPA , anti-cyclic citrullinated peptide antibody; CDAI , clinical disease activity index; HAQ-DI , health assessment questionnaire disability index; bDMARDs , biological disease-modifying antirheumatic drugs; JAKi , Janus kinase inhibitors

Incidence of fragility fractures

In the RA group, one patient experienced a proximal humerus fracture due to a fall. In the non-RA group, one patient suffered a vertebral fracture from a fall, and one patient experienced a stress fracture of the rib.

To the best of our knowledge, this study represents the first comparison of the effects of ROMO between RA and non-RA patients with postmenopausal osteoporosis. In RA patients, the anabolic window tended to be narrower, resulting in a smaller increase in BMD compared to non-RA patients.

Previous studies investigating the effects of ROMO in RA patients have primarily focused on comparisons between ROMO and DMAb. Mochizuki et al. demonstrated that ROMO was more effective in increasing LS BMD than DMAb in RA patients with severe osteoporosis [ 22 ]. Conversely, Kobayakawa et al. reported that in RA patients receiving oral glucocorticoids (GC), the effects of ROMO on LS BMD increase were comparable to those of DMAb [ 8 ]. Taken together, ROMO may be no less effective than DMAb in RA patients, although differences in the effects of ROMO between RA and non-RA patients remain unclear.

Concerning the effects of ROMO in RA patients, factors influencing sclerostin production from osteocytes warrant consideration. TNF-α, glucocorticoids, and mechanical unloading promote sclerostin production from osteocytes, while sex hormones inhibit it [ 4 ]. These factors are closely associated with postmenopausal RA, and indeed, serum sclerostin levels are elevated in patients with RA compared to healthy controls [ 5 ].

Additionally, TNF-α induces the production of another Wnt inhibiting factor, Dickkopf-related protein 1 (Dkk-1), from synoviocytes [ 23 ], and serum Dkk-1 levels are also up-regulated in RA patients compared to healthy controls [ 5 ]. Moreover, we have previously reported that IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2/ERK and SHP2/PI3K/Akt2 pathways, apart from Wnt pathway [ 24 ].

Consequently, it is conceivable that Wnt-related bone formation is down-regulated not only by sclerostin but also by Dkk-1. Furthermore, IL-6 may inhibit an alternative bone formation pathway apart from Wnt, potentially leading to decreased bone formation in response to ROMO.

Regarding bone resorption, ACPA binds to citrullinated vimentin expressed on the surface of osteoclasts, inducing the expression of IL-8, which leads to their differentiation in an autocrine manner [ 25 ]. Indeed, a high ACPA titer is associated with increased bone resorption and decreased BMD in RA patients [ 15 ]. Therefore, patients with a high ACPA titer may exhibit reduced inhibition of bone resorption and a smaller increase in BMD in response to ROMO, particularly in the LS where osteoclasts are abundant.

A previous study demonstrated that greater physical disability, as evaluated by the HAQ, was negatively associated with femoral BMD in female patients with RA [ 2 ]. In ovariectomized monkeys, an increase of FN BMD results from remodeling inhibition (due to RANKL inhibition), modeling-based bone formation (due to Wnt signaling modulation via sclerostin inhibition), and secondary mineralization [ 26 ]. Reduced mechanical loading induces the production of both RANKL and sclerostin by osteocytes, leading to the promotion of osteoclast differentiation and inhibition of bone formation [ 27 ]. Therefore, patients with high HAQ scores may experience reduced mechanical loading in the femur, potentially impairing the effects of ROMO due to increased RANKL and sclerostin production.

Conversely, high disease activity, as evaluated by CDAI, was positively associated with BMD increases by ROMO treatment in the LS, and a similar trend was observed in the FN. A previous study demonstrated that higher disease activity is associated with increased bone turnover in RA patients [ 5 ], and we have recently reported that baseline serum PINP levels were significantly associated with BMD increases by ROMO treatment in patients with postmenopausal osteoporosis [ 28 ]. Indeed, baseline PINP levels and CDAI tended to be correlated (odds ratio = 1.37, 95% CI =  − 0.35–3.10, P  = 0.12), and baseline PINP levels and the percent increase in BMD in the LS at 12 months showed a significant correlation (odds ratio = 5.77, 95% CI = 1.20–10.33, P  = 0.014) in the non-matched RA group ( n  = 59) of this study.

This study has several limitations. Firstly, due to its retrospective, case-controlled design, there may be some selection bias in the baseline patient characteristics, which could have influenced the results. The RA patients included in this study had relatively long disease durations, with approximately half of them experiencing moderate to high disease activity and not taking oral glucocorticoids. Secondly, the statistical power of the results might be compromised due to the small number of patients included. Thirdly, we assessed serum TRACP-5b as a bone resorption marker, but serum CTX data were not available.

However, a notable strength of this study is that propensity score matching and multiple regression analysis were employed to mitigate variations in confounding factors related to postmenopausal osteoporosis between the RA and non-RA groups.

In conclusion, the efficacy of ROMO treatment may be attenuated in the RA group compared to the non-RA group, primarily due to a smaller anabolic window and subsequent BMD increases in the LS and TH. The effects of ROMO treatment may be influenced by RA-related factors, including ACPA titers and HAQ-DI.

Below is the link to the electronic supplementary material.

Acknowledgements

The authors thank Yasunori Tsukamoto, Yasuji Kato, and Hideki Yoshikawa as well as all the medical staff for their excellent cooperation in the conduct of this study.

Author contribution

Study design: KE and YN. Study conduct: KE, YN, MK, YE, and TN. Data collection: KE, YN, MK, HT, GO, AM, YE, TN, TM, YF, and TK. Data analysis: KE, YN, and MK. Data interpretation: KE, YN, MK, HT, YE, and TN. Drafting the manuscript: KE and YN. Supervise: MH, KN, and SO. Approving the final version of the manuscript: KE, YN, MK, HT, GO, AM, YE, TN, MH, TM, YF, TK, KN, and SO. KE takes responsibility for the integrity of the data analysis.

Open Access funding provided by Osaka University.

Data Availability

Declarations.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

KE is affiliated with the Department of Musculoskeletal Regenerative Medicine, Osaka University, Graduate School of Medicine, which is supported by Taisho. KE has received research grants from Asahi-Kasei, Astellas, Eisai, Ono, and Teijin Pharma. KE has received payments for lectures from Abbive, Amgen, Asahi-Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Ono, Pfizer, Taisho, Tanabe-Mitsubishi, and Teijin Pharma. YN has received payments for lectures from Abbvie, Amgen, Asahi-Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, and Tanabe-Mitsubishi. MK has received payments for lectures from Amgen, Asahi-Kasei, Astellas, and Daiichi Sankyo. HT has received a research grant from Chugai and has received payments for lectures from Abbive, Amgen, Asahi-Kasei, Astellas, Ayumi, Chugai, Eisai, Mochida, Pfizer, and Tanabe-Mitsubishi. GO has received payments for lectures from Eisai. YE and MH have received a research grant from Eli Lilly. KN has received a research grant from Astellas and supervises the Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, which is supported by Taisho. AM, TN, TM, YF, TK, and SO declare that they have no conflicts of interest.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.