Elsevier

The Lancet

Volume 389, Issue 10072, 4–10 March 2017, Pages 909-916
The Lancet

Articles
Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial

https://doi.org/10.1016/S0140-6736(17)30065-XGet rights and content

Summary

Background

Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy.

Methods

We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m2; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70.

Findings

Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event.

Interpretation

Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis.

Funding

Italian Agency of Drug Evaluation.

Introduction

Juvenile idiopathic arthritis comprises a heterogeneous group of disorders of unknown cause. Disorders are currently classified into seven categories on the basis of the clinical and laboratory features present in the first 6 months of illness.1 With a prevalence of approximately one patient per 1000 population, it is one of the more common chronic diseases of childhood and a major cause of acquired disability.2 Many children with juvenile idiopathic arthritis do not achieve long-term remission, thus the burden of disease to the patient, family, and ultimate society, is substantial.3, 4

Oligoarticular juvenile idiopathic arthritis is defined as an arthritis that affects four or fewer joints during the first 6 months of illness. It is a distinctly, if not uniquely, paediatric disease, and accounts for the vast majority (50–80%) of all white children with chronic arthritis in North America and Europe.5 Although structural joint changes and functional disability in oligoarthritis are often less frequent and severe than those seen in other forms of juvenile idiopathic arthritis, children with this disease might develop significant musculoskeletal abnormalities, such as fixed flexion contractures, valgus deformities, and localised growth abnormalities of bones (which can, in turn, produce complications, such as leg-length inequality or micrognathia).2 Furthermore, 25–50% of patients have a progressive increase in the number of affected joints over time (so-called extended oligoarthritis), so that by 1–2 years after onset, they have polyarthritis (affecting five or more joints). In this subgroup, structural joint damage is frequent and the probability of remission is low.6, 7

Research in context

Evidence before this study

Oligoarthritis is the most common subtype of juvenile idiopathic arthritis in white children. We searched PubMed for papers published between Jan 1, 1980, to Dec 31, 2008, using the keywords: “juvenile rheumatoid arthritis”, “juvenile chronic arthritis”, “juvenile idiopathic arthritis”, “oligoarthritis”, “oligoarticular”, “treatment”, “therapy”, and “trial”. Our search results highlighted a paucity of randomised clinical trials assessing the efficacy and safety of therapeutic interventions in oligoarthritis.

Added value of this study

Concomitant administration of methotrexate might prolong and, to a lesser extent, augment the effectiveness of intra-articular corticosteroid therapy in children with oligoarthritis, without an appreciable increase in toxicity. The addition of methotrexate did not reduce the prevalence of new onset of synovitis in previously unaffected joints.

Implication of all the available evidence

The combination of intra-articular corticosteroids and methotrexate could be considered as reference treatment in everyday clinical practice for paediatricians. Evaluating the capacity of therapeutic interventions to prevent arthritis extension in oligoarthritis should be the objective of future clinical trials.

By contrast with the numerous randomised controlled trials that have been done in polyarticular and systemic juvenile idiopathic arthritis,8 little evidence-based information is available to guide the treatment of oligoarthritis.9, 10, 11, 12 Additionally, most studies have included non-steroidal anti-inflammatory drugs (NSAIDs), which might alleviate inflammatory symptoms, but are rarely able to control arthritis. As a result, the management of this condition is largely empirical and is likely variable among practitioners.13 The 2011 recommendations from the American College of Rheumatology provide some guidance for the initial treatment of oligoarthritis.14 However, it remains unclear when in the course of disease and in what combinations these treatments should be started to produce optimal outcomes.

Intra-articular corticosteroid injections are widely used in the management of children with oligoarthritis to induce short-term relief of inflammation symptoms and functional recovery and to obviate the need for regular systemic therapy.15, 16 This intervention could enable correction of joint contractures, prevention of leg-length discrepancy, regression of Baker's cysts, and improvement of tenosynovitis.17 Many paediatric rheumatologists use intra-articular corticosteroid therapy as first-line therapy in oligoarthritis.15, 16 However, although intra-articular corticosteroid injections are highly efficacious, most children have recurrence of arthritis in injected joints (flare) after a variable period of time.18 Arthritis flare might require a repeat injection of corticosteroids, which can cause considerable emotional distress to children and their parents. In addition, the need of general anaesthesia in younger children can increase organisational and financial costs.

Methotrexate is the cornerstone disease-modifying antirheumatic drug for the treatment of juvenile idiopathic arthritis on the basis of results from two randomised controlled trials.19, 20 However, these trials have enrolled only patients with polyarthritis.19, 20 Although this medication is widely used also in children with oligoarthritis, typically after failure of NSAIDs or intra-articular corticosteroids, its exact place in the management of this subset is still unclear. In the American College of Rheumatology recommendations,14 all advice about methotrexate initiation in children with history of arthritis of four joints or fewer was assigned a level of evidence C. The recent observation that early methotrexate therapy might prevent the onset of uveitis in juvenile idiopathic arthritis21 could support its first-line use in children with oligoarthritis, who are at high risk for this potentially serious complication.

There is therefore a need for evidence-based data to help practitioners increase rationality in the therapeutic approach to oligoarticular juvenile idiopathic arthritis. Additionally, considering that current clinical practice mandates the achievement of complete and sustained disease control, it would be desirable to explore the role of early aggressive protocols. In this respect, a key and still unanswered question is whether the combination with methotrexate increases and prolongs the effectiveness of intra-articular corticosteroid therapy. Additionally, non-controlled studies suggest that concurrent methotrexate therapy reduces the risk of arthritis flare after intra-articular corticosteroid injection.22, 23 We designed this trial aiming to assess whether the concomitant administration of methotrexate to children with oligoarticular juvenile idiopathic arthritis who undergo intra-articular corticosteroid therapy augments the rate and duration of arthritis remission, without exposing children to an increased frequency of untoward side-effects.

Section snippets

Study design and participants

We did a prospective, randomised, open-label trial at ten hospital units that are part of the Italian Paediatric Rheumatology Study Group. We enrolled children younger than 18 years with oligoarticular juvenile idiopathic arthritis (as per the International League of Associations for Rheumatology [ILAR] criteria),1 who were candidates to receive an intra-articular corticosteroid injection in at least two or more joints. However, after an amendment of the protocol (approved by both ethics

Results

Between July 7, 2009 and March 31, 2013, we screened 226 participants and randomly assigned 207 (figure 1). The last patient completed the study on March 31, 2014. Participants had the typical features of children with oligoarthritis: young age at disease onset, marked female prevalence, and high frequency of antinuclear antibody positivity (table 1). The study population had early disease (table 1). There were no imbalances between treatment groups, apart from higher erythrocyte sedimentation

Discussion

This is the first randomised controlled trial designed to test the superiority of intra-articular corticosteroids combined with systemically administered therapy with methotrexate compared with intra-articular corticosteroids alone in oligoarticular juvenile idiopathic arthritis. Patients in this study had, on average, a short disease duration, which suggests that our analysis provides insights into the effectiveness of the two interventions used as early treatment strategies. We chose a 12

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