Oral methotrexate prolonged and slightly boosted the efficacy of intra-articular corticosteroid injections in children with oligoarticular juvenile idiopathic arthritis without causing serious adverse effects, based on the results of a first-in-kind multicenter, randomized, open-label trial.
“This combination could be considered as reference treatment in everyday clinical practice for pediatricians, particularly in children with higher erythrocyte sedimentation rate,” Angelo Ravelli, MD, of Istituto Giannini Gaslini, Genoa, Italy, and his associates wrote in The Lancet. The regimen also could take center stage in treat-to-target strategies for children with chronic arthritis, they said (Lancet. 2017 Feb 2. doi: 10.1016/S0140-673630065-X ).
Oligoarticular juvenile arthritis affects up to four joints during the first 6 months of illness. This “distinctly, if not uniquely, pediatric” disease accounts for 50%-80% of cases of chronic arthritis among white children in North America and Europe, the investigators noted. Intra-articular steroids are initially effective, but not in the long run. Although methotrexate is often prescribed for children who flare despite steroid injections, the optimal role and timing of methotrexate therapy remain unclear, the researchers said.
For the study, they randomly assigned 207 children and adolescents with oligoarticular juvenile idiopathic arthritis to receive intra-articular injections with triamcinolone hexacetonide or methylprednisolone acetate, either alone or with 15 mg/m2 oral methotrexate at a maximum dose of 20 mg. The primary endpoint was the proportion of patients with remission of all injected joints at 12 months.
Methotrexate missed this endpoint – 12-month remission rates were 34% in the injection-only group and 39% in the dual therapy group (P = .48). However, methotrexate seemed to prolong the time to arthritis flare. The median time to flare was 10.1 months (95% confidence interval, 7.6 to more than 16 months) when patients received injections plus methotrexate, and only 6 months (95% CI, 4.6-8.2 months) when they received injections only (hazard ratio, 0.67; 95% CI, 0.46-0.97; P = .03).
Consequently, the dual therapy group had a higher rate of remission at 6 months (67%; 95% CI, 56%-75%) than did the injection-only group (49%; 95% CI, 39%-58%). Cumulative remission rates at 12 months also were higher for dual therapy (46%), compared with injections only (35%).
Erythrocyte sedimentation rate predicted arthritis flare, but did not seem to affect the chances of methotrexate being effective, the researchers said. After controlling for erythrocyte sedimentation rate, methotrexate decreased the 12-month risk of flare by 47%, “although the statistical effect was marginal,” they noted (adjusted odds ratio, 0.53; 95% CI, 0.27-1.01; P = .05).
These findings support those of noncontrolled studies and can inform strategies for initial treatment of oligoarticular juvenile idiopathic arthritis because study participants had short disease durations, the researchers said. But they emphasized that the cohort excluded patients with monoarthritis of the knee, for whom they use only local injections, adding methotrexate if patients relapse soon after the knee is injected or if arthritis spreads to other joints within 6-12 months.
Rates of new-onset uveitis were less than 10% and did not significantly differ between arms. Methotrexate most frequently caused nausea, vomiting, or constipation, but eight patients developed elevated liver enzymes. One patient stopped methotrexate as a result, and five interrupted treatment or had dose reductions. Another patient stopped treatment because of gastrointestinal discomfort, but no there were no serious adverse effects of any type, the researchers said. They will follow the cohort for up to 2 years to evaluate longer-term safety, they added.
The Italian Agency of Drug Evaluation funded the study. Dr. Ravelli disclosed personal fees from AbbVie, Bristol-Myers Squibb, Novartis, Pfizer, Roche, and Johnson & Johnson. Several coinvestigators also disclosed ties to a number of pharmaceutical companies.