Efficacy of Long-Term Treatment with Once-Daily Baricitinib 2 mg in Patients with Active Rheumatoid Arthritis: Post Hoc Analysis of Two 24-Week, Phase III, Randomized, Controlled Studies and One Long-Term Extension Study.

INTRODUCTION: To evaluate long-term efficacy of once-daily baricitinib 2 mg in patients with active rheumatoid arthritis who had an inadequate response (IR) to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) or biologic DMARDs (bDMARD). METHODS: Data from patients treated with baricitinib 2 mg daily in two 24-week, phase III studies, RA-BUILD (csDMARD-IR; NCT01721057) and RA-BEACON (bDMARD-IR; NCT01721044), and one long-term extension study (RA-BEYOND; NCT01885078), were analyzed (120 weeks). The main outcomes were achievement of low-disease activity (LDA; Simple Disease Activity Index [SDAI] ≤ 11), clinical remission (SDAI ≤ 3.3), Health Assessment Questionnaire Disability Index (HAQ-DI) ≤ 0.5 and improvement from baseline of ≥ 0.22, and safety. Analysis populations included (1) all patients and (2) never-rescued patients. Completer and non-responder imputation (NRI) analyses were conducted on each population. RESULTS: In RA-BUILD, 684 were randomized (229 to baricitinib 2 mg, 180 of whom completed RA-BUILD and entered RA-BEYOND). In RA-BEACON, 527 were randomized (174 to baricitinib 2 mg, 117 of whom completed RA-BEACON and entered RA-BEYOND). In RA-BUILD-BEYOND, 85.1% (63/74, completer) and 27.5% (63/229, NRI) of csDMARD-IR patients treated with baricitinib 2 mg achieved SDAI LDA; 40.5% (30/74, completer) and 13.1% (30/229, NRI) were in SDAI remission; 62.2% (46/74, completer) and 20.1% (46/229, NRI) had HAQ-DI ≤ 0.5 and 81.1% (60/74, completer); and 26.2% (60/229, NRI) achieved ≥ 0.22 change from baseline at week 120. In RA-BEACON-BEYOND, 86.5% (32/37, completer) and 18.4% (32/174, NRI) of bDMARD-IR patients treated with baricitinib 2 mg achieved SDAI LDA; 24.3% (9/37, completer) and 5.2% (9/174, NRI) were in SDAI remission; 50.0% (19/38, completer) and 10.9% (19/174, NRI) had HAQ-DI ≤ 0.5; and 73.7% (28/38, completer) and 16.1% (28/174, NRI) achieved ≥ 0.22 change from baseline at week 120. Rates of adverse events of special interest were consistent with previous reports. CONCLUSIONS: Long-term treatment with baricitinib 2 mg demonstrated efficacy for up to 120 weeks and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01721057, NCT01721044, and NCT01885078.

Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease control: results of a prospective study.

OBJECTIVES: This study investigated the effects of dose step-down in patients with rheumatoid arthritis (RA) who achieved sustained disease control with baricitinib 4 mg once a day. METHODS: Patients who completed a baricitinib phase 3 study could enter a long-term extension (LTE). In the LTE, patients who received baricitinib 4 mg for ≥15 months and maintained CDAI low disease activity (LDA) or remission (REM) were blindly randomised to continue 4 mg or taper to 2 mg. Patients could rescue (to 4 mg) if needed. Efficacy and safety were assessed through 48 weeks. RESULTS: Patients in both groups maintained LDA (80% 4 mg; 67% 2 mg) or REM (40% 4 mg; 33% 2 mg) over 48 weeks. However, dose reduction resulted in small, statistically significant increases in disease activity at 12, 24 and 48 weeks. Dose reduction also produced earlier and more frequent relapse (loss of step-down criteria) over 48 weeks compared with 4 mg maintenance (23% 4 mg vs 37% 2 mg, p=0.001). Rescue rates were 10% for baricitinib 4 mg and 18% for baricitinib 2 mg. Dose reduction was associated with a numerically lower rate of non-serious infections (30.6 for baricitinib 4 mg vs 24.9 for 2 mg). Rates of serious adverse events and adverse events leading to discontinuation were similar across groups. CONCLUSIONS: In a large randomised, blinded phase 3 study, maintenance of RA control following induction of sustained LDA/REM with baricitinib 4 mg was greater with continued 4 mg than after taper to 2 mg. Nonetheless, most patients tapered to 2 mg could maintain LDA/REM or recapture with return to 4 mg if needed.

Biologic Treatment Registry Across Canada (BioTRAC): a multicentre, prospective, observational study of patients treated with infliximab for ankylosing spondylitis.

OBJECTIVES: To describe the profile of patients with ankylosing spondylitis (AS) treated with infliximab in Canadian routine care and to assess the effectiveness and safety of infliximab in real world. SETTING: 46 primary care rheumatology practices across Canada. PARTICIPANTS: 303 biological-naïve patients with AS or patients previously treated with a biological for <6 months and who were eligible for infliximab treatment as per routine care within the Biologic Treatment Registry Across Canada (BioTRAC). INTERVENTION: Not applicable (non-interventional study). PRIMARY AND SECONDARY OUTCOMES: Effectiveness was assessed with changes in disease parameters (AS Disease Activity Score (ASDAS), Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), Health Assessment Questionnaire Disease Index (HAQ-DI), physician global assessment of disease activity (MDGA), patient global disease activity (PtGA), back pain, C-reactive protein, erythrocyte sedimentation rate (ESR), morning stiffness). Safety was assessed with the incidence of adverse events (AEs). RESULTS: Of the 303 patients included, 44.6% were enrolled in 2005-2007 and 55.4% in 2008-2013. Patients enrolled in 2005-2007 had significantly higher MDGA and ESR at baseline while all other disease parameters examined were numerically higher with the exception of PtGA. Treatment with infliximab significantly (p<0.001) improved all disease parameters over time in both groups. At 6 months, 56% and 31% of patients achieved clinically important (change≥1.1) and major (change≥2.0) improvement in ASDAS, respectively; at 48 months, these proportions increased to 75% and 50%, respectively. Among patients unemployed due to disability at baseline, 12.1% returned to work (mean Kaplan-Meier (KM)-based time=38.8 months). The estimated retention rate at 12 and 24 months was 78.3% and 60.1%, respectively. The profile and incidence of AEs were comparable to data previously reported for tumour necrosis factor-α inhibitors. CONCLUSIONS: Characteristics of patients with AS at infliximab initiation changed over time towards lower disease activity and shorter disease duration. Infliximab treatment significantly reduced disease activity independent of treatment initiation year, although patients enrolled in recent years achieved lower disease activity over 48 months. TRIAL REGISTRATION NUMBER: NCT00741793.

Use of corticosteroids in patients with rheumatoid arthritis treated with infliximab: treatment implications based on a real-world Canadian population.

OBJECTIVE: To describe the rate of concomitant oral corticosteroid use at antitumour necrosis factor (TNF) initiation and at disease remission, and to assess its effect on incidence of infection and sustainability of remission among patients with rheumatoid arthritis (RA) treated with infliximab in Canadian routine care. METHODS: Biological naïve patients with RA followed in the Biologic Treatment Registry Across Canada (BioTRAC) were included. The time-dependent association between corticosteroid dose (no use, ≤5 mg/day, >5 mg/day) and the incidence of first infection, while considering possible confounders, remission sustainability and the incidence of subsequent infections were assessed with Cox regression. RESULTS: 838 patients were included; mean (SD) baseline age and disease duration were 55.6 (13.5) and 10.5 (9.8) years, respectively. After a mean (SD) of 51.3 (43.6) months, the total incidence of adverse events (AEs) and infections were 110.2 and 19.6 per 100 person-years (PY), respectively. In multivariate analysis, the HR (95% CI) for acquiring an infection was 2.48 (1.24 to 4.98) with >5 mg/day of corticosteroids versus no corticosteroids. Similarly, ≤5 mg/day of corticosteroids was associated with increased hazard for infection (2.12 (0.97 to 4.66)). Despite DAS28 (disease activity score 28) or Clinical Disease Activity Index (CDAI) remission, corticosteroids were continued in 16.4% and 16.7% of cases, respectively. Continued corticosteroid treatment was not associated with sustainability of remission (HRDAS28 (95% CI) 1.40 (0.95 to 2.06); HRCDAI 1.19 (0.75 to 1.88)), however, it had a significant impact on development of infection (HRDAS28 (95% CI) 1.78 (1.00 to 3.19); HRCDAI 2.38 (1.14 to 4.99)). CONCLUSIONS: Oral corticosteroid treatment was associated with increased risk of development of infection without impacting sustainability of remission. These results support the notion that corticosteroids should be used concomitantly with anti-TNF for the shortest period possible to achieve remission, and then tapered. TRIAL REGISTRATION NUMBER: NCT00741793.

Effectiveness and safety of infliximab in rheumatoid arthritis: analysis from a Canadian multicenter prospective observational registry.

OBJECTIVE: To describe the profile of rheumatoid arthritis (RA) patients treated with infliximab in Canadian routine care and to assess the real-world effectiveness and safety of infliximab. METHODS: Biologics-naive RA patients from the Biologic Treatment Registry Across Canada were stratified based on their enrollment year. Effectiveness was assessed with the changes in clinical/laboratory parameters and patient-reported outcomes and the achievement of minimal disease activity and remission. Safety was assessed with the incidence of treatment-emergent adverse events (AEs). RESULTS: Among 628 patients, 45.9%, 34.6%, and 19.6% were enrolled between 2002-2005, 2005-2008, and 2008-2011, respectively. Patients recruited in more recent years had significantly lower Disease Activity Score with a 28-joint count using the C-reactive protein level (DAS28-CRP), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), swollen joint count in 28 joints, tender joint count in 28 joints, physician's global assessment of disease activity, patient's global assessment of disease activity, Health Assessment Questionnaire disability index, pain, erythrocyte sedimentation rate, and CRP level (P < 0.01 for all). Patient management also changed with a trend to initiate infliximab after failure of fewer disease-modifying antirheumatic drugs (DMARDs). Six-month treatment with infliximab resulted in statistically significant and clinically important improvements in all disease parameters examined, which were sustained over 36 months. The cumulative probability of achieving remission by 36 months, as defined by the DAS28, SDAI, and CDAI, was 56.2 (95% confidence interval [95% CI] 47.8-64.8), 31.0 (95% CI 23.8-39.8), and 36.2 (95% CI 28.5-45.3), respectively, which was significantly greater in patients with lower baseline disease activity. The profile and incidence of AEs were comparable to data previously reported for tumor necrosis factor α inhibitors. CONCLUSION: RA patient characteristics at infliximab initiation changed over time toward lower disease activity. Furthermore, a trend to treat patients with fewer DMARDs before initiation of infliximab was observed. However, treatment with infliximab was effective in significantly reducing disease activity independent of the treatment initiation year.