In a recent issue of Arthritis Care & Research, a group of investigators mainly from North America published recommendations endorsed by the American College of Rheumatology (ACR) for the treatment of juvenile idiopathic arthritis (JIA) (1).
The authors admit that they did not consider indications for systemic glucocorticoids for the treatment of synovitis since they could not find any published evidence. This is remarkable since generations of pediatric rheumatologists have relied on the administration of systemic glucocorticoids. In fact, there are several reasons to question the appropriateness of excluding systemic glucocorticoids from the treatment of arthritis in children with JIA.
It is textbook knowledge that synovitis is amenable to treatment with systemic glucocorticoids, including a long record of efficacy and adverse effects (2). Pediatric rheumatologists have learned how to, at best, avoid adverse events and keep the desirable effects by “intelligent” use of glucocorticoids. However, the ample knowledge on the treatment of arthritis with systemic steroids predates the introduction of controlled trials.
There is good evidence showing the appropriateness of using several biologic disease-modifying antirheumatic drugs (DMARDs) because these new substances were required to demonstrate effectiveness in controlled trials prior to approved for use in children. Such randomized placebo-controlled trials are costly and there is no financial incentive to test glucocorticoids. Consequently, the authors' path favors new costly therapies over old inexpensive treatments that have been available for decades such as glucocorticoids.
Glucocorticoids can be administered in various ways (i.e., oral, intravenously, local), dosages, durations, and repetitions as in pulse therapies. These extreme variations rendered handling of this drug in the authors' article very difficult if not impossible. This difficulty is no excuse for the exclusion of the drug.
The authors do not discuss the concept of glucocorticoids as a bridging agent.
The actual algorithms for the treatment of polyarticular JIA include the administration of systemic glucocorticoids.
The concept proposed by the authors argues for the early introduction of biologic DMARDs, including tumor necrosis factor α (TNFα) blockers. The therapeutic efficacy and the safety record of these drugs are impressive. However, the unresolved debate on the rare, but possible induction of malignant lymphoma due to administration of TNFα blockers should remind us of the necessity of continuing vigilance. So in the absence of long-term safety data, biologic DMARDs should be started when conventional treatment with methotrexate and glucocorticoids has failed.
The strongest argument for the early introduction of TNFα blockers rests on the assumption that early and aggressive treatment of rheumatoid arthritis (RA) may prevent definitive damage due to suppression of inflammation and pannus formation. However, in contrast to RA, the pathogenesis of JIA does not progress rapidly to joint destruction, with the exception of the few cases of rheumatoid factor–positive polyarticular JIA.
In my opinion, it is wrong to withhold systemic glucocorticoids from children with polyarticular JIA. It is correct that the efficacy of the drug should be tested in controlled trials. The lack of the appropriate evidence is the pediatric rheumatology community's fault and this negligence should not lead to our patients' disadvantage.
When the authors update their recommendations, they should include available older knowledge on effective treatment of patients with JIA and transform it into new evidence by controlled studies.
Further minor criticisms include the following. Tocilizumab is not mentioned, although it is licensed for JIA in Japan and for RA in Europe and will be approved soon for systemic JIA in Europe.
Hydroxychloroquine is labeled inappropriate for active synovitis. The drug is known to act very slowly and if there are other means to control acute arthritis, including intraarticular steroids, it may well prevent flare with a very good safety record.
The recommendation of rituximab is based solely on references concerning RA. There is no pediatric evidence beyond case reports. Rituximab should be reserved for very rare cases or given in controlled trials in JIA only.
Methotrexate dose is recommended at 15 mg/m2 administered by parenteral route. The drug usually is given at 10–12 mg/m2 and there is no convincing evidence in children that the parenteral route is superior to the oral route, which might be more appropriate for children.
For abatacept, there is a single controlled trial in patients with polyarticular JIA that showed efficacy; however, there are no other data confirming the initial publication and there are no data on long-term safety. The drug has to show consistent efficacy over a period of years and a good safety record, which can be determined by registries as has been shown for etanercept.
This criticism is not meant to belittle the tremendous progress for the treatment of JIA that has been achieved by creating these recommendations. The authors have altered the approach to the patient with JIA by creating JIA treatment groups, by establishing features of poor prognosis, and by formulating different levels of disease activity. Use of these features all over the world will show if these new tools will stand up against the necessities of daily care and how they might be modified.