JIA Uveitis Control Improved With Adalimumab + MTX

Janis C. Kelly

May 02, 2017

Adalimumab added to methotrexate (MTX) significantly delayed treatment failure in patients with uveitis associated with juvenile idiopathic arthritis (JIA) and reduced the treatment failure rate at 18 months by more than half, a new study has found.

"[A]dalimumab in combination with [MTX] was an effective therapy in children and adolescents with JIA-associated uveitis," researchers from the SYCAMORE Study Group report in an article published in the April 27 issue of the New England Journal of Medicine. "However, the drug was associated with a higher incidence of adverse and serious adverse events than was placebo plus methotrexate."

Athimalaipet V. Ramanan, MD, FRCPCH, FRCP, from the Department of Paediatric Rheumatology, University of Bristol, United Kingdom, and colleagues also found that significantly more patients in the adalimumab group were able to reduce or discontinue topical glucocorticoid treatment.

"This nicely performed randomized placebo-controlled study confirms what has been widely observed in clinical practice for more than a decade: monoclonal [tumor necrosis factor] inhibitors are highly effective for the treatment of JIA-associated chronic anterior uveitis," Timothy G. Beukelman, MD, associate professor, Division of Pediatric Rheumatology, Department of Pediatrics, University of Alabama, Birmingham, told Medscape Medical News.

"Compared to the risks of permanent eye damage from uncontrolled uveitis and the toxicity of chronic topical glucocorticoid eye drops, the small increase in adverse events associated with adalimumab is inconsequential," he said. Dr Beukelman was not involved in the study.

The authors note that JIA is the most common rheumatic disease in children and that 12% to 38% of patients with JIA develop uveitis within 7 years after arthritis onset. Moreover, despite best currently used treatment, up to 15% of those who develop uveitis become legally blind. The fully humanized anti-tumor necrosis factor-α monoclonal antibody adalimumab was tested for JIA uveitis because it had proven effective in children with active rheumatoid arthritis.

The multicenter, double-blind, randomized, placebo-controlled trial tested the efficacy and safety of adding adalimumab to a stable dose of MTX in children and adolescents who had active JIA-associated uveitis despite having received at least 12 weeks of MTX. The trial was originally designed with 90% power to detect a 50% difference in the rate of treatment failure, estimated to be 60% with placebo and 30% with adalimumab. As a result of recruitment problems, the researchers reduced the power of the study to 80%, which reduced the required number of patients to 114.

All patients continued background MTX, and the researchers randomly assigned them to also receive either adalimumab (n = 76) or placebo (n = 38) subcutaneously every 2 weeks. Adalimumab was dosed at either 20 or 40 mg, according to body weight. Treatment continued until 18 months or treatment failure, and patients were followed for up to 2 years.

The primary study endpoint was time to treatment failure, which the researchers defined according to an intraocular inflammation score based on the Standardization of Uveitis Nomenclature criteria.

The study ended early at the recommendation of the safety and data monitoring committee because a significant difference in favor of the adalimumab group became apparent at the interim analysis after enrollment of 90 of the planned 114 subjects. This met the prespecified early stopping criteria. At that time, the authors observed treatment failures in 27% of the adalimumab group (16/60) compared with 60% of the placebo group (18/30; hazard ratio, 0.25; 95% confidence interval, 0.12 - 0.49; P < .0001).

Rates of adverse events were 10.07 events per patient-year in the adalimumab group vs 6.51 events per patient-year in the placebo group. Rates of serious adverse events were 0.29 events per patient-year in the adalimumab group vs 0.19 events per patient-year in the placebo group.

Adverse events reported in at least 5% of the adalimumab group included oropharyngeal pain (27% vs 7% placebo), cough (37% vs 10%), arthralgia (20% vs 7%), viral infections (22% vs 3%), varicella infection (5% vs 0%), urinary traction infection (15% vs 10%), tonsillitis (20% vs 0%), pharyngitis (7% vs 0%), lower respiratory traction infection (13% vs 7%), pyrexia (20% vs 7%), injection-site reaction (12% vs 0%), vomiting (30% vs 17%), diarrhea (13% vs 3%), and eye pain ( 7% vs 0%).

Serious adverse events included 10 infections or infestations among 8/60 patients in the adalimumab group compared with no infections or infestations among the 30 patients in the placebo group. Total serious adverse events included 17 in 13/60 adalimumab patients and 3 in 2/30 placebo patients. Treatment-related severe adverse events included one injection site reaction and one instance of arthritis in the adalimumab group, and one patient with anterior chamber flare and one with uveitis in the placebo group.

"The follow-up period during the course of the trial was not long enough for us to detect events such as cancers and demyelinating diseases. The sample size precludes commentary regarding rarer events," the authors caution.

The study is "a welcome addition" to the sparse literature on treatment of childhood uveitis, Jennifer E. Thorne, MD, PhD, from the Wilmer Eye Institute, Johns Hopkins University School of Medicine, and the Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, both in Baltimore, Maryland, writes in an accompanying editorial.

However, the patients in the study probably had more severe disease, as they had active disease despite MTX treatment, she notes. Thus, the results are likely not generalizable to all patients being treated for JIA-associated uveitis. Similarly, because adalimumab was given only with MTX, the study provides no information about the efficacy or safety of adalimumab used alone in JIA-associated uveitis.

"Monoclonal [tumor necrosis factor] inhibitors, such as adalimumab, are the first-line treatment for chronic anterior uveitis that requires more than methotrexate," Dr Beukelman advised.

The study was supported by grants from the National Institute for Health Research Health Technology Assessment Programme and Arthritis Research UK. University Hospitals Bristol NHS Foundation Trust, as the sponsor of this trial, has a data-sharing agreement with AbbVie in support of regulatory purposes. Dr Ramanan reports grant support from the National Institute for Health Research Health Technology Assessment and Arthritis Research UK during the conduct of the study; personal fees and nonfinancial support from AbbVie; and other support from University Hospitals Bristol NHS Foundation Trust outside the submitted work. Other coauthors report grant, nonfinancial, and other support from AbbVie, Inc. Dr Thorne reports grants from Allergan Inc, personal fees from Gilead, institutional fees for consulting from NightstaRx, personal fees from Santen, grants and personal fees from XOMA, and grants and personal fees from AbbVie, Inc, all outside the submitted work. Dr Beukelman reports consulting fees from UCB, Novartis, and Genentech/Roche.

N Engl J Med. 2017;376:1637-1646, 1682-1683. Article abstract, Editorial extract

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