literature review juvenile idiopathic arthritis

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Jones AP, Clayton D, Nkhoma G, et al. Different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis: the SIRJIA mixed-methods feasibility study. Southampton (UK): NIHR Journals Library; 2020 Jul. (Health Technology Assessment, No. 24.36.)

Different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis: the SIRJIA mixed-methods feasibility study.

Chapter 2 literature review on the use of corticosteroids in juvenile idiopathic arthritis.

• Introduction

The ultimate goals in managing JIA are to prevent or control joint damage, to prevent loss of function and to decrease pain. JIA is a chronic disease that is characterised by periods of remission and flare. Treatment is aimed at inducing rapid remission while minimising toxicity from medications, in the hope of inducing a permanent remission.

The standardised outcome measures used during the management of patients with JIA are of importance for both clinical care and research. To date, to our knowledge there have been no controlled trials on the use of intra-articular (IA) CSs versus systemic agents in children with JIA. To our knowledge, there are also no controlled trials on the dosage and route of systemic CSs (oral vs. IV). Outcome measures used in clinical trials in JIA to date have used the ACR Pedi responses, 4 but these are hard to calculate in clinical practice.

• Aim and objectives

Our aim was to undertake a literature review on the use of CSs in children with JIA. Our objectives were to identify whether or not there is a standardised use of CSs published in the literature and also to identify the outcome measures used in these JIA studies. This activity was a crucial part of the method to determine an agreed outcome measure(s) for the planned prospective feasibility study SIRJIA (Study of the Induction of Remission in Juvenile Idiopathic Arthritis).

For the purpose of this review, we included the articles published in English from 2000 to May 2016. We searched in the databases CINAHL, the Cochrane Library, EMBASE, MEDLINE, the Turning Research into Practice (TRIP) database, International Clinical Trials Registry, UK NIHR CRN study Portfolio and the Australian clinical trials register.

We carried out a literature search in the above databases for articles published from 2000 until May 2016 in English, using the following PICO format:

• patient, population – CYP with JIA
• intervention – treatment with CSs
• comparison – not applicable
• outcome – remission, reduction in disease activity, JIA core outcomes and JADAS.

We also gathered information from the referenced articles with the intention of obtaining as much evidence as possible from the literature regarding the use of CSs in JIA, and the outcome measures used.

A further literature search in MEDLINE and EMBASE was carried out by the clinical librarian to include on any additional studies published from 2016 to 2018. As the literature review was not systematic, Preferred Reporting Items for Systematic Reviews (PRISMA) or its extensions do not necessarily apply.

The combined electronic searches identified 272 records from eight databases, of which 25 records were removed after accounting for duplicates, leaving 247 records for further consideration. The titles and abstracts of the remaining records were screened for eligibility using the PICO screening tool, and 101 full-text papers were found to be potentially eligible for inclusion. The abstract and methodology sections of these articles were further analysed, and subsequently 54 articles contributed to the results outlined in this paper. In addition, references from the original articles, including expert opinions and review articles, were also included in the results despite being published prior to the study period (systematic reviews, n  = 17; evidence summaries, n  = 13; research articles, n  = 103; case reports, n  = 2; surveys, n  = 2; expert overviews, n  = 18).

The flow chart in Figure 1 illustrates the study selection process.

Flow diagram of the literature review.

• Synthesis of evidence

Intra-articular corticosteroids

The use of IACIs for the treatment of inflammatory arthritis in adults was initially reported by Hollander et al. in 1951. 37 The use of IACIs in children was first noted anecdotally in 1979, 38 and the first prospective evaluation of IACIs in the management of chronic arthritis in children was reported by Allen et al. in 1986. 39 In that prospective study, 53 knees were injected in 40 children with chronic arthritis and responses were evaluated at 6, 12 and 24 months for good clinical response, relapse and time to relapse. All knees responded well to treatment, with 36.7% relapse. IACIs appeared to be a safe and effective treatment option for the management of JIA, particularly the management of oligoarticular JIA. 40 , 41 IACIs are an effective way to control disease activity and to induce resolution of synovitis, decrease the presence of joint and limb deformities, improve function, provide pain relief and serve as an adjunct to the longer-term, first-line DMARD therapy, MTX. Various technical aspects, different formulations of CSs, duration of disease at treatment, concomitant use of other medications and disease severity might impact the efficacy of IACIs, although conclusive data that elucidate these factors are scarce. 42

A systematic review to evaluate the advantages of administering CSs during arthrocentesis for temporomandibular disorders, including JIA, found no significant differences in the clinical outcomes observed between the CS injection group and the control groups (which were injected with normal saline, physiological salt water or Ringer’s lactate). 43

Ravelli et al. 44 conducted a multicentre, prospective, randomised, open-label trial that compared the effects of IACIs with IACIs plus oral MTX (15 mg/m 2 , maximum 20 mg). The CS used was TH (for shoulder, elbow, wrist, knee and tibiotalar joints) or methylprednisolone acetate (for subtalar and tarsal joints). The trial reported that concomitant administration of oral MTX did not augment the effect of IACI therapy.

Comparative effects of different corticosteroids in intra-articular injections

A double-blinded study of adults with rheumatoid arthritis of the knee found that intra-articular injection of TH resulted in significantly greater initial and more lasting improvement in joint inflammation than prednisolone t -butyl acetate or methylprednisolone acetate. 45 In the first double-blinded comparison of CS preparations reported in children, TH was found to be superior to betamethasone in reducing knee swelling and stiffness in children with oligoarticular JIA. 46 Honkanen et al. 47 compared the effect of IACIs in the knee in 45 children with JIA who were administered 1.5 mg/kg methylprednisolone acetate and 34 children injected with 0.7 mg/kg TH, and found a significantly higher remission rate ( p  < 0.005) in the TH group. Zulian et al. 48 found TH to be superior to TA, even when the TA dose was doubled from 2 mg/kg to a maximum of 80 mg. The joints in patients injected with TA relapsed first in 53.8% of the joints injected, compared with only six (15.4%) of the joints injected with TH. Eberhard et al. , 49 who carried out a retrospective study of 227 joints, reported a longer time to relapse with TH than with TA, with the mean time to relapse being 10.14 ± 0.49 months and 7.75 ± 0.49 months in the TH group and the TA group, respectively. The updated literature search identified a report of TA use in recent practice in India owing to the easier availability of the drug. 50

The duration of response to IACI is dependent on the actual CS used, with less soluble preparations providing a longer duration of response. The greater efficacy of TH in IACI can probably be explained by its PD properties: it is less soluble and absorbed more slowly than TA; thus synovial levels are maintained for longer and systemic corticoid levels are reduced. 51 As a result of this study, TH has been recognised among paediatric rheumatologists as the medication of choice for IA administration of CYP with JIA.

Dosage regimen for intra-articular corticosteroids

The dosage regimen for TH currently used by the majority of UK paediatric rheumatologists is 1 mg/kg for large joints (i.e. knees, hips and shoulders) and 0.5 mg/kg for medium-sized joints (i.e. ankles, wrists and elbows). 52 There is more variability in the smaller joints in the hands, where methylprednisolone acetate is recommended. 52 In addition, TH is recommended for the hands and feet at 1–2 mg per joint for metacarpophalangeals/metatarsophalangeals and 0.6–1 mg per joint for proximal interphalangeals. 52

Paediatric rheumatologists frequently administer multiple IACIs in a single episode of treatment of JIA, while simultaneously initiating therapy with a DMARD and/or biologic/biosimilar agents. This strategy, the so-called ‘bridge’ effect, is regarded as an alternative to systemic CSs. The aim is to induce prompt remission of synovitis, that is to achieve a quick control of inflammatory symptoms, while awaiting the full therapeutic effect of a DMARD or biologic/biosimilar medication. 53

Use of systemic corticosteroids

Systemic CSs, that is CSs administered orally or by IV infusion or IM injection, are used in the treatment of children with acute severe arthritis, both around the time of presentation and during disease flare. Systemic CSs have been used mainly for the treatment of children with polyarticular or systemic JIA. However, to date, there are no standardised protocols or guidelines and no RCTs comparing the effect of various forms and dosages of systemic CSs to treat children with systemic JIA. It is important to note that the choice of CS in systemic JIA is likely to be influenced by the tendency for this type of JIA to be complicated by potentially life-threatening macrophage activation syndrome.

Michels 54 published the results of a survey conducted among paediatric rheumatologists from North America, Israel, Australia and Europe. The survey, utilising a standardised questionnaire, elicited rheumatologists’ personal definitions of low-dose, long-term CS treatment of JIA. The results obtained from 99 respondents revealed that paediatric rheumatologists’ definitions of low-dose, long-term CS therapy varies within a wide range. The dosage that was still considered low was 0.26 ± 0.14 mg/kg/day prednisolone (minimum–maximum, 0.04–0.5 mg/kg/day). Reported dosages were higher in northern Europe (0.29 ± 0.12 mg/kg/day; n  = 9), western Europe (0.42 ± 0.14 mg/kg/day; n  = 7), southern Europe (0.30 ± 0.14 mg/kg/day; n  = 9), eastern Europe (0.25 ± 0.14 mg/kg/day; n  = 6) and North America (0.33 ± 0.17 mg/kg/day; n  = 16) than in central Europe (0.19 ± 0.09 mg/kg/day; n  = 43).

The ReACCh-Out study 55 was a multicentre, prospective, inception cohort study of CYP with JIA who were diagnosed within 12 months before enrolment. Prospective data were collected at enrolment, 6-monthly for 2 years and then annually. Initial data published in 2010 showed that oral prednisolone was used most often in CYP with systemic JIA and rheumatoid factor (RF)-positive polyarticular JIA. 23 The probability of instituting systemic CSs within 6 months of diagnosis was 79% and 61% in systemic JIA and RF-positive polyarticular JIA, respectively. 55 The literature includes a case report of an adolescent with systemic JIA that responded to oral CSs 56 and a report of CS-dependent refractory systemic JIA. 57 The reports do not include the details of all the dosing regimens used.

The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed standardised consensus treatment plans (CTPs) for systemic JIA with the goal of comparing their effectiveness (in achieving clinically inactive disease) using data collected for the CARRA registry. 58 The physicians chose the actual CTPs for each of their patients with systemic JIA and an electronic survey was sent to voting members of CARRA regarding CTP choice for CYP with new-onset systemic JIA in whom treatment with non-steroidal anti-inflammatory drug (NSAID) monotherapy had failed. Respondents were asked to select one or more of the following CTPs for each clinical case scenario: (a) systemic CSs only, (b) MTX (with or without CSs), (c) anti-interleukin 1 (IL-1) therapy (with or without CSs) or (d) anti-IL-6 therapy (with or without CSs). Respondents could choose more than one CTP if factors such as insurance limitations or family preference might affect treatment. The results showed significant variability in systemic JIA treatment approaches, no clear standard of care among CARRA members 58 and widespread use of MTX and CSs. MTX use increased with more arthritis features. However, MTX and CSs are frequently used, regardless of presenting disease features. Overall, concurrent CS use was indicated by the majority of respondents across all CTPs.

In a prospective cohort study (TREAT) of 85 children with polyarticular JIA, patients were randomised blindly to MTX, etanercept or rapidly tapered prednisolone and assessed for clinically inactive disease (CID) over 1 year of treatment. 59 Patients starting on methylprednisolone acetate achieved CID earlier, and had more study days in CID, than those starting MTX, but the differences were not significantly different.

Uveitis is the one of the most severe complications of JIA. There are studies 60 , 61 reporting the use of systemic CSs for severe uveitis associated with JIA, and these were included in this literature review, as uveitis may be an indication for CSs in JIA in the absence of any specific joint indication. It was felt that evidence for the use of systemic CSs to treat uveitis could usefully supplement the evidence regarding response to different modalities of treatment as either arthritis or uveitis could be the indication for CS treatment at different times and convergence of treatment plans could be helpful. However, the evidence base of use of systemic CSs in uveitis is also limited. Marvillet et al. 60 conducted a retrospective analysis of records of 70 children with JIA. Severe ocular involvement necessitated systemic CS therapy in 29 (42.0%) patients. 60 Among immunomodulating agents, MTX and cyclosporine were used in 41 patients and tumour necrosis factor α antagonists were used in 15 patients. Twelve patients (17.4%) achieved complete resolution of uveitis, whereas 14 (20.3%) experienced a relapsing course and in 23 (33.3%) uveitis became chronic, with relapses as soon as the treatment was decreased and 21 (30.4%) had a severe course. Nouair et al. 61 reported use of CSs in 41% of patients in a retrospective analysis of children with non-infectious uveitis who were followed between 2004 and 2013.

With regard to IV infusion of CSs in JIA, the literature search revealed little of note apart from a single case report of a patient with systemic JIA 57 in whom a methylprednisolone succinate pulse of 1 g for 2 days was followed by a maintenance dose of prednisolone of 1.3 mg/kg/day.

The literature review revealed a lack of standardised dosing regimens for either induction or maintenance therapy and no evidence of tapering doses of CSs.

In the STIVEA trial, 62 adult patients with very early inflammatory polyarthritis (4–10 weeks’ duration) were randomised to receive three IM injections of 80 mg of either methylprednisolone acetate or placebo, administered at weekly intervals. 62 Assessments were carried out monthly for the first 6 months after the first injection, with a final 6-month review at 12 months after the first injection. Patients in the placebo group (76%) were more likely to need DMARDs during the first 6 months of the trial than patients in the CS group (61%) [adjusted odds ratio (OR) = 2.11, 95% confidence interval (CI) 1.16 to 3.85; p  = 0.015). Disease activity did not differ between the two groups at 12 months. After 12 months, arthritis had resolved without the need for DMARDs in 9.9% (11/111) of patients in the placebo group and in 19.8% (22/111) of patients in the CS-treated group (adjusted OR = 0.42, 95% CI 0.18 to 0.99; p  = 0.048). We found no RCTs of the use of IM CSs in children with JIA.

• Corticosteroid side effects

There is a paucity of studies in the literature to guide practitioners in counselling CYP about the anticipated weight changes and side effects following CS initiation in JIA.

In a prospective study 63 that examined CS-related changes in body mass index among CYP with rheumatic diseases, the median starting CS dosage was 1.3 mg/kg/day prednisone equivalents. However, the study participants included those with other rheumatological diagnoses and only 38% of the study participants had a diagnosis of JIA.

Cleary et al. 40 reported that it is likely that multiple IACIs (10 or more joints, including large joints) result in sufficient systemic absorption of CS to produce a Cushingoid appearance. The clinical features of Cushing’s syndrome can include a moon-shaped face, centripetal adiposity, supraclavicular fat pad accumulation, bruising, striae and proximal myopathy, but adverse effects can also be subclinical or overlap with those of other medical conditions. There is an increased risk of developing diabetes or hypertension and a predisposition to opportunistic infections. 57 Huppertz and Pfüller 64 reported transient suppression of cortisol release detected by a low morning peak value of salivary cortisol. No adverse events were recorded secondary to this transient adrenal suppression.

There is a case report of severe acneiform rashes in two adolescents with JIA following bilateral knee IACI of TH. 65

Valta et al. 66 reported a prospective study evaluating bone health and growth in 62 CYP with JIA. No correlation was found between the bone mineral density and the disease characteristics or cumulative CS dose. 66 This study showed low prevalence of osteoporosis and normal growth in CYP with JIA. However, the study population was small and this question warrants larger controlled trials.

• Outcome measures used in juvenile idiopathic arthritis studies

We analysed outcome measures used in studies that were identified by our literature review. The most widely used primary outcome measures that were identified were the number of active and restricted joints, the number of flares, medications, ESR, JIA core outcome variables, CHAQ, visual analogue scale (VAS), Pa/PtGA and PGA and clinical remission (based on clinical examination, ACR Pedi 30 or ACR Pedi 70).

Esbjörnsson and colleagues measured gait dynamics using three-dimensional gait analysis and foot-related disability using the Juvenile Arthritis Foot disability Index in their study of the effect of IACIs on foot and walking function. 67 In the BSPAR etanercept study, 68 JADAS, ACR, Juvenile Arthritis Disease Activity Score, 71-joint count (JADAS-71), ACR Pedi 90 and minimal disease activity at 1 year were measured.

There is limited literature regarding the use of outcome measures in systemic JIA specifically. The main outcomes used are clinical inactivity with no arthritis, no fever, rash, serositis and generalised lymphadenopathy. In studies specifically of temporomandibular joint arthritis, jaw pain or dysfunction, maximal incisal opening distance and magnetic resonance imaging-detected inflammation have been used as outcome measures. The Disease Activity Score-28 was used in one study. Other measures identified include duration of morning stiffness, knee joint circumference and knee joint flexion in degrees.

There was no evidence of any PPI involvement in the choice of outcome measures used in any of these studies.

• Limitations

Our review was a scoping review of literature on the use of CSs rather than a systematic analysis. Articles in languages other than English were not included in the study.

There is good evidence for the use of IACIs in CYP with JIA, leading to grade A recommendations for use. There is reasonable evidence supporting the efficacy of systemic CSs in CYP with systemic JIA, polyarticular JIA and JIA-associated uveitis; however, the optimal mode of administration remains unclear. In children with polyarticular JIA, IACIs are more often used as a bridging therapy while waiting for the disease to show a complete response to DMARD agents and biologic therapy.

No standardised dosing regimen for either induction or maintenance therapy, or any defined tapering dose of CS, is available in the literature. It appears that there is widespread variation in the use of CSs among different clinical settings and centres. There is very little evidence regarding CS treatment regimens and, in particular, there is no good evidence of the relative efficacy and tolerability of oral and IV modes of CS administration.

It is of note that this review is limited to published clinical trials, as would be expected when attempting to establish evidence-based practice. However, one cannot ignore the fact that, historically, in the field of clinical medicine, reasons for favouring certain methods of treatment over others may be educated by individual experiences. These experiences contribute to herd opinions among HCPs. Patient preferences may change with time, and knowledge of the pathogenesis and evolution of a chronic disease may lead to a different treatment focus at different times. A good example of this is macrophage activation syndrome, which is now diagnosed much more frequently in the systemic JIA subset because awareness has increased. CS treatments are now more intensive in an attempt to prevent the high mortality rate associated with this disorder.

There is a clear and pressing need for future studies comparing the efficacy, toxicity and tolerability of different CS treatment regimens (multiple IACIs, oral and systemic routes of administration). The length of follow-up of a future RCT needs to consider both short-term efficacy and longer-term outcomes, such as future flare rate, as demonstrated by several of the reviewed studies.

• Cite this Page Jones AP, Clayton D, Nkhoma G, et al. Different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis: the SIRJIA mixed-methods feasibility study. Southampton (UK): NIHR Journals Library; 2020 Jul. (Health Technology Assessment, No. 24.36.) Chapter 2, Literature review on the use of corticosteroids in juvenile idiopathic arthritis.
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