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Reply

To the Editors:

We are pleased that Dr. Huppertz has thought critically about the 2011 ACR recommendations for the treatment of JIA and we thank him for his kind comments regarding the potential utility of our proposed treatment groups, features of poor prognosis, and measures of disease activity. However, we wish to clarify and rebut a number of misperceptions raised.

First, these recommendations remained silent on the appropriateness of the use of systemic glucocorticoids for the treatment of synovitis. This is not equivalent to a recommendation to withhold the use of systemic glucocorticoids from children with polyarticular JIA, as the author suggests. Put simply, this therapeutic approach cannot be recommended as appropriate or inappropriate given the absence of any published studies of the effectiveness or safety of this practice. We personally do not dispute the observation that synovitis frequently responds to treatment with systemic glucocorticoids. Contrary to the author's statement, the published algorithms in the recommendations for the treatment of polyarticular JIA do not include the administration of systemic glucocorticoids.

We too are surprised that there are no published studies on the treatment of synovitis with systemic glucocorticoids in children. Nevertheless, this is not strictly a pediatric problem. A similar paucity of data exists in the published literature on RA and this led to the decision to omit systemic glucocorticoids from the ACR recommendations for the treatment of RA (1–3). However, the decision to omit systemic glucocorticoids for the treatment of synovitis was not influenced by the diverse methods of their delivery, as suggested by the author.

Ample knowledge of the “intelligent” use of systemic glucocorticoids cannot be derived from published studies. The textbook chapter referenced by the author contains only a single sentence on the topic, and this does not appear to endorse chronic systemic glucocorticoids as conventional treatment: “Glucocorticoids have a limited role as systemic therapy in polyarthritis, although judicious use of systemic steroids as a bridging agent can be considered” (4).

What can be consistently gleaned from a review of the published literature are the extensive expected adverse effects associated with long-term systemic glucocorticoid use, including Cushing's syndrome, growth suppression, osteoporosis, infection, hypertension, dyslipoproteinemia, impaired glucose tolerance, cataracts, and glaucoma (5). These known and common adverse effects of glucocorticoid use must be taken into account when making treatment decisions, just as the author correctly asserts that we must consider that biologic therapeutic agents may possibly cause rare adverse effects with long latency periods.

The lack of rapid joint destruction in every child with JIA does not appear to be a valid reason to withhold biologic therapy. The initiation of TNFα inhibitors is frequently accompanied by immediate relief of active arthritis and the associated pain and disability (6, 7). Moreover, there may exist a window of opportunity during which the attainment of complete control of the inflammatory process may permanently alter the natural history of the disease course (8).

In the absence of adequate studies of the comparative effectiveness and safety of biologic therapeutic agents versus chronic daily systemic glucocorticoids, one cannot assume that the preferential use of biologics will necessarily “lead to our patients' disadvantage.” It is possible that the converse may be true; namely, the relatively early use of biologics could result in more effective control of arthritis, fewer adverse medication effects, and improved patient quality of life compared to systemic glucocorticoids.

Despite all of these differences, we completely agree that the use of systemic glucocorticoids as either a bridge to or long-term therapy for synovitis should be further studied so that future updates to the ACR recommendations can comment on the appropriateness of these therapeutic approaches.

With respect to the appropriateness of hydroxychloroquine for the treatment of synovitis, the evidence appears clearer. Hydroxychloroquine combined with nonsteroidal antiinflammatory drugs was shown to be inefficacious for the treatment of active polyarthritis in a randomized placebo-controlled clinical trial (9). This trial result is consistent with the recommendation that the use of hydroxychloroquine is inappropriate for the treatment of children with active arthritis.

With respect to methotrexate administration and dosing, the recommendation was based on the results of a randomized clinical trial that demonstrated the efficacy of 15 mg/m2 via the parenteral route among children who failed to respond to 8–12.5 mg/m2 via the oral route (10).

Clearly, we are in desperate need of definitive studies of the comparative effectiveness and safety of therapeutics in the treatment of JIA. We appreciate this critical evaluation of the recently published ACR recommendations for the treatment of JIA, as this represents an appropriate starting point for future investigations.

Timothy Beukelman MD, MSCE*, Randy Q. Cron MD, PhD*, Nivedita M. Patkar MD, MSPH*, Kenneth G. Saag MD, MSc*, Esi Morgan DeWitt MD, MSCE†, Daniel J. Lovell MD, MPH†, Norman T. Ilowite MD‡, Yukiko Kimura MD§, Ronald M. Laxer MDCM, FRCPC¶, Alberto Martini MD**, Nicolino Ruperto MD, MPH**, C. Egla Rabinovich MD, MPH††, * University of Alabama at Birmingham, Birmingham, AL, † Cincinnati Children's Hospital Medical Center, Cincinnati, OH, ‡ Children's Hospital at Montefiore, Bronx, NY, § Hackensack University, Hackensack, NJ, ¶ Hospital for Sick Children, Toronto, Ontario, Canada, ** IRCCS Istituto G. Gaslini, Genoa, Italy, †† Duke University, Durham, NC.

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