Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by baseline body mass index: an analysis of pooled data from phase 3 studies.

OBJECTIVE: Tofacitinib is an oral Janus kinase for the treatment of rheumatoid arthritis (RA). This post hoc analysis assessed whether baseline body mass index (BMI) impacts tofacitinib efficacy in patients with RA. METHODS: Pooled data from six phase 3 studies in patients receiving tofacitinib 5 mg (N=1589) or 10 mg (N=1611) twice daily or placebo (advancing to active treatment at months 3 or 6; N=680), ±conventional synthetic disease-modifying antirheumatic drugs, were stratified by baseline BMI (<25, 25 to <30, ≥30 kg/m2). Endpoints (through to month 6) were assessed descriptively: American College of Rheumatology 20/50/70 response rates; changes from baseline (∆) in Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4(ESR)), DAS28-4(C-reactive protein), Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) and pain; and proportions of patients achieving DAS28-4(ESR) ≥1.2 and HAQ-DI ≥0.22 decreases from baseline, low disease activity (DAS28-4(ESR) ≤3.2 or CDAI ≤10) and radiographic non-progression (Δmodified Total Sharp Score ≤0.5; months 12 and 24). Estimates were adjusted using multivariable models for selected outcomes. Univariate/multivariable regression analyses determined predictors of month 6 outcomes. RESULTS: Of 3880 patients included, 1690 (43.6%), 1173 (30.2%) and 1017 (26.2%) had baseline BMI <25, 25 to <30 and ≥30 kg/m2, respectively. Tofacitinib showed greater efficacy improvements versus placebo in each BMI category. Differences in efficacy outcomes (adjusted and unadjusted) were generally not clinically meaningful across BMI categories within treatment groups. In regression analyses, BMI was not consistently associated with selected outcomes. CONCLUSIONS: Baseline BMI did not consistently affect tofacitinib response suggesting that tofacitinib is an effective oral treatment option for adults with moderate to severe RA regardless of baseline BMI, including patients with BMI ≥30 kg/m2. TRIAL REGISTRATION NUMBERS: NCT00814307, NCT01039688; NCT00960440; NCT00847613; NCT00856544; NCT00853385.

Switching From Immediate-Release to Delayed-Release Prednisone in Moderate to Severe Rheumatoid Arthritis: A Practice-Based Clinical Study.

INTRODUCTION: Rheumatoid arthritis (RA) produces debilitating morning stiffness. Exogenous glucocorticoids can help with these symptoms when timed appropriately. Bedtime dosing of delayed-release prednisone (DR-prednisone) matches the rise of inflammatory cytokines before awakening and can improve stiffness and other RA symptoms. A prospective open-label study was conducted in patients currently on stable doses of immediate-release prednisone (IR-prednisone) who were switched to DR-prednisone to analyze the incremental benefit of better timed and lower dose glucocorticoid therapy. METHODS: Twelve US sites enrolled patients with moderate-severe RA into a 12-week prospective study. Patients were switched from IR- to DR-prednisone while maintaining other existing background therapies. Change from baseline in morning stiffness severity, morning stiffness duration, swollen and tender joint counts (S-TJC), 28 joint disease activity score (DAS28), and patient/physician global assessment (PGA/PhGA), among others, were measured. Post-hoc analyses were performed on those completing 10 weeks of treatment and those with >60 min of morning stiffness at baseline. RESULTS: Fifty-six patients had at least one follow-up visit and were similar in demographics to previous controlled trials with DR-prednisone with regard to baseline age and DAS28-CRP but had lower morning stiffness and RA duration. DR-prednisone produced a trend toward lower morning stiffness severity and duration with a reduction in daily prednisone dose of almost 1 mg. Patients treated with DR-prednisone for ≥10 weeks demonstrated significant reductions in morning stiffness duration, SJC, TJC, DAS28-CRP, and PhGA (all p ≤ 0.04). Patients treated for ≥10 weeks with >60 min of baseline morning stiffness produced similar results in these measures as well as a 21% reduction in morning stiffness severity (p = 0.02). CONCLUSION: Patients switched to DR-prednisone from IR-prednisone in this practice-based study maintained or improved their outcomes across a variety of domains, and results were comparable to previous controlled trials in which patients completed at least 10 weeks of treatment. FUNDING: Horizon Pharma USA, Inc. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02287610.

Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial.

OBJECTIVE: Spleen tyrosine kinase (Syk) has been identified as an important modulator of immune signaling in B cells and cells bearing Fcgamma-activating receptors. R788, a prodrug of active metabolite R406, has been shown to be an inhibitor of Syk kinase, active in a variety of in vitro and in vivo models, suggesting potential activity in the treatment of rheumatoid arthritis (RA). METHODS: We enrolled 189 patients with active RA despite methotrexate therapy in a 3-month, multicenter, ascending-dose, double-blind, placebo-controlled trial. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. RESULTS: Twice-daily oral doses of 100 mg and 150 mg of R788 were significantly superior to placebo or twice-daily oral doses of 50 mg at week 12 (ACR20 achieved in 65% and 72% versus 38% and 32% of patients, respectively [P < 0.01]). ACR50 (achieved in 49% and 57% versus 19% and 17% of patients, respectively) and ACR70 (achieved in 33% and 40% versus 4% and 2% of patients, respectively) scores showed a similar pattern. Clinical effect was noted as early as 1 week after initiation of therapy. Reductions in serum interleukin-6 and matrix metalloproteinase 3 levels also occurred as early as week 1 in the groups receiving 100 mg and 150 mg R788. The major adverse effects were gastrointestinal side effects (predominantly diarrhea) and neutropenia (<1,500/mm3), both of which were dose related. CONCLUSION: These results indicate that an inhibitor of Syk kinase produces significant clinical benefits at 12 weeks in a population of patients with active RA receiving methotrexate therapy. Syk kinase may be an important new therapeutic target in RA and related autoimmune conditions.