Background Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Baricitinib is a JAK inhibitor being investigated for RA. Serious infection events (SIEs) have been reported in RA randomised controlled trials (RCTs) but limited head-to-head data are available to directly compare rates of these events for tofacitinib vs biologic (b)DMARDs and baricitinib.
Objectives We present an updated meta-analysis of published RCTs and corresponding long-term extension (LTE) studies to contextualise the risk of SIEs1 with tofacitinib and extend this work to include the JAK inhibitor baricitinib.
Methods An initial systematic literature search (Medline, Embase, PubMed and regulatory submission documents) was conducted for SIEs with tofacitinib and bDMARDs (abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab and tocilizumab).1 A subsequent systematic literature review of RCTs was conducted using Medline, BIOSIS, Embase and conference abstracts to evaluate SIEs with baricitinib. Incidence rates (IRs; patients with events per 100 patient-years) were calculated for each agent, utilising a random effects meta-analytic model using R (version 2.15.2 for tofacitinib and bDMARDs; version 3.2.2 for baricitinib) with a Restricted Maximum Likelihood Estimator for between-study variances. Risk ratios and risk differences were calculated for each agent vs control across RCTs up to rescue of patients randomised to receive placebo using the random effects Mantel-Haenszel method.
Results Six RCTs with baricitinib were included in this updated analysis. In the original analysis, 70 RCTs and 18 LTE studies met inclusion criteria for tofacitinib and bDMARDs. The table provides a summary of the meta-analyses conducted for SIE IRs (with and without LTE), risk ratios and risk differences relative to control. The IRs (95% confidence interval [CI]; heterogeneity [I2]) for baricitinib were 4.75 (2.32, 9.74; I2=19%) for 2 mg and 3.67 (2.33, 5.78; I2=36%) for 4 mg. The analysis of risk ratios (p values 0.22 for 2 mg; 0.95 for 4 mg) and risk differences (p values 0.41 for 2 mg; 1.00 for 4 mg) did not reveal a significant difference from control for both doses of baricitinib, which is consistent with analyses of tofacitinib and bDMARDs. There were limited data to assess SIE incidence for baricitinib (4 mg) monotherapy vs in combination with methotrexate (MTX); the RA-BEGIN study showed IRs of 3.77 (1.7, 8.4) and 2.33 (0.97, 5.59), respectively. Pooled IR estimates for tofacitinib from the development programme were 1.70 (0.91, 2.92) and 1.79 (1.00, 2.95) for 5 and 10 mg BID monotherapy, respectively; when administered in combination with MTX, the IRs were 3.44 (2.41, 4.76) and 3.42 (2.42, 4.70) for 5 and 10 mg BID, respectively.
Conclusions The results from these meta-analyses suggest that the risk of SIEs (IRs, risk ratios and risk differences) with tofacitinib is comparable with published rates for bDMARDs and baricitinib in patients with moderate to severe RA.
Strand V et al. Arthritis Res Ther 2015; 17: 362.
Acknowledgements This study was sponsored by Pfizer Inc. Editorial support was provided by K Nicholson and C Viegelmann of CMC and funded by Pfizer Inc.
Disclosure of Interest V. Strand Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, CORRONA, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, S. Ahadieh Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Krishnaswami Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Geier Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Gomez-Reino Grant/research support from: AbbVie, MSD, Novartis, Pfizer Inc, Roche, UCB, Speakers bureau: AbbVie, Biogen, Bristol-Myers Squibb, Janssen, MSD, Pfizer Inc, Roche, UCB