By Eric B. Suhler, MD, MPH
The place of newer biologic therapies versus more established immunosuppressives is a common clinical dilemma in the management of children with uveitis. This article's authors attempt an answer by performing a structured review of all clinical trials on pediatric uveitis treatment published from 1992 through June 2008 identified through a MEDLINE search. Studies covering treatments other than methotrexate, sulfasalazine, mycophenolate mofetil, cyclosporin A, azathioprine and tumor necrosis factor alpha (TNFα) blockers etanercept, infliximab and adalimumab were excluded.
The included studies covered heterogeneous patient populations mostly with juvenile idiopathic arthritis (JIA) associated uveitis but also idiopathic and sarcoid uveitis. The structured review suggested that methotrexate and the monoclonal antibodies against TNFα are the most effective treatments for childhood uveitis. Given the high cost of the biologics investigated, relative paucity of long-term safety data and positive evidence presented for methotrexate, the authors recommend starting therapy with methotrexate before adding TNFα blockers for refractory disease. However, they rightly caution against overgeneralization of their findings based on the lack of randomized studies and the heterogeneity of endpoint ascertainment from a review of nonrandomized and descriptive studies.
Six studies were found on treatment with methotrexate, none for sulfasalazine, nine for cyclosporin A, four for azathioprine, three for mycophenolate mofetil and two for TNFα-blocking agents. Evidence for each immunosuppressive was ranked as Class I (more than one randomized controlled study), II (more than one nonrandomized study or significant effects within noncontrolled studies) or III (descriptive studies or opinion). Grades A and B evidence indicated high or moderate evidence of benefit, grade C little evidence of benefit and grades D and E moderate or high evidence against benefit.
Methotrexate was found consistently to be effective for treating uveitis in children and adolescents. But the evidence was rated IIIA, due to the absence of controlled studies. The authors noted that patients with persistent inflammation who were taking methotrexate often required additional steroid or immunosuppressive treatment.
Published studies were found on the use of sulfasalazine only in adults with uveitis. Mixed results were reported in a small number of articles on cyclosporin A and azathioprine. The authors rated all three treatments IIIC. Mycophenolate mofetil was found to have better evidence of benefit and fewer side effects than azathioprine, earning a IIIB rating.
The authors thoroughly discussed evidence for the three commercially available TNFα blockers. Evidence for the effectiveness of injectable TNFα-receptor fusion protein etanercept was mixed and rated IIC; one small randomized and possibly underpowered study failed to show benefit. Infliximab, an intravenously infused chimeric monoclonal antibody against TNFα given a IIA rating, showed more promising results in controlled studies, with fairly universal evidence of benefit. Multiple nonrandomized retrospective comparative studies showed a consistent advantage of infliximab over etanercept in either physician-graded response to therapy or flare rate reduction. The injectable recombinant human monoclonal antibody adalimumab, though less well studied, also yielded promising results in uncontrolled studies and was rated IIIA.
Strikingly, there was no Class I evidence of benefit for childhood uveitis of any of the commercially available immunosuppressives, a deficiency the authors said should be remediated by the scientific community.
Financial Disclosures
Dr. Suhler has received grant support from the National Eye Institute, Genentech, Inc., Allergan, Inc., Bausch and Lomb, Inc., Lux Biosciences, Inc., Centocor, Inc., Abbott Pharmaceuticals, EyeGate Pharma and Cerimon Pharmaceuticals, Inc.