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EULAR 2017 | Daily Highlights
META-ANALYSIS OF SERIOUS INFECTIONS WITH BARICITINIB, TOFACITINIB AND BIOLOGIC DMARDS IN RHEUMATOID ARTHRITISAbstract: THU0211
Authors: V. Strand1,*, S. Ahadieh2, R. DeMasi3, S. Krishnaswami2, J. Geier4, S. Menon2, J. J. Gomez-Reino5
1Division of Immunology/ Rheumatology, Standford University, Palo Alto, CA, 2Pfizer Inc, Groton, CT, 3Pfizer Inc, Collegeville, PA, 4Pfizer Inc, New York, NY, United States, 5Fundacion Ramon Dominguez, Hospital Clinico Universitario, Santiago de Compostela, Spain
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.
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.
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.
Two experienced nuclear medicine physicians blinded to clinical data reviewed the FDG PET/CT images. LV-GCA was suspected if increased FDG uptake in the wall of the aorta and/or supra-aortic branches was observed. A semi-quantitative approach was applied (a.m. Meller) in which FDG uptake was graded on a 5-point scale (0; no uptake, 1; ≤ blood pool, 2; > blood pool, ≤ liver, 3; ≥ liver, 4; ≥ 2xliver). A score ≥3 was considered consistent with vasculitis. Vascular composite scores (CS) was calculated summarizing grades from assessed vascular regions; Aortic: Aorta ascendens, aorta descendens and aortic arch; aortic branches: Vertebral, carotic and subclavian/axillary artery.
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.
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.
1. Strand V et al. Arthritis Res Ther 2015; 17: 362.
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
Swiss rheumatologist will soon have the unique privilege of having access to several JAK inhibitors (Jakinibs). Because of their novel mode of action and worries about their safety, health authorities have been cautious to allow these agents, both in Europe (EMA) and in the US (FDA). One of the main concerns has been serious infections with this new class of DMARD. In this abstract, the authors performed indirect comparison of the rate of serious infections events (SIE) between Tofacitinb, Baricitinib and biologic DMARDs (bDMARDs) in published randomized controlled trials (RCTs). The overall results suggest that the risk of serious infections with Jakinibs is comparable to biologics: The risk of SIE compared to placebo was increased by 50% with anti-TNF (RR: 1.50 (CI: 1 – 2.25) ), by 34% with Tofacitinib 5mg BID (RR: 1.34 (CI: 0.43 – 4.15) ) and by 13% with Baricitinib 2 mg/day (RR: 1.13 (CI: 0.24 – 5.35) ).While this is a valid methodology for comparative effectiveness research, it is important to realize that combining results from a variety of RCTs does not eliminate the possibility of selection bias. In particular, these RCTs were not all performed in the same geographic regions and did not include exactly the same patient population. We will have to wait for large unselected observational studies, with longer follow-up periods, before we can better compare the relative safety of these various medications. However, at this time, this meta-analysis of RCTs is useful and provides at least some sense of the relative safety of these medications in terms of infections.
Prof. Dr. Axel Finckh
Geneva University Hospital