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Comparative Study
. 2019 Jan 24:364:l67.
doi: 10.1136/bmj.l67.

Comparative effectiveness of rituximab, abatacept, and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors: prospective cohort study

Jacques-Eric Gottenberg  1   2 , Jacques Morel  3 , Elodie Perrodeau  4 , Thomas Bardin  5 , Bernard Combe  3 , Maxime Dougados  6 , Rene-Marc Flipo  7 , Alain Saraux  8 , Thierry Schaeverbeke  9 , Jean Sibilia  10 , Martin Soubrier  11 , Olivier Vittecoq  12 , Gabriel Baron  4 , Arnaud Constantin  13 , Philippe Ravaud  4 , Xavier Mariette  14 ; French Society of Rheumatology and the investigators participating in AIR, ORA, and REGATE registries
Affiliations
Comparative Study

Comparative effectiveness of rituximab, abatacept, and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors: prospective cohort study

Jacques-Eric Gottenberg et al. BMJ. .

Abstract

Objective: To compare the effectiveness and safety of three non-tumour necrosis factor (TNF) α inhibitors (rituximab, abatacept, and tocilizumab) in the treatment of rheumatoid arthritis.

Design: Population based prospective study.

Setting: 53 university and 54 non-university clinical centres in France.

Participants: 3162 adults (>18 years) with rheumatoid arthritis according to 1987 American College of Rheumatology criteria, enrolled in one of the three French Society of Rheumatology registries; who had no severe cardiovascular disease, active or severe infections, or severe immunodeficiency, with follow-up of at least 24 months.

Intervention: Initiation of intravenous rituximab, abatacept, or tocilizumab for rheumatoid arthritis.

Main outcome measure: The primary outcome was drug retention without failure at 24 months. Failure was defined as all cause death; discontinuation of rituximab, abatacept, or tocilizumab; initiation of a new biologic or a combination of conventional disease modifying antirheumatic drugs; or increase in corticosteroid dose >10 mg/d compared with baseline at two successive visits. Because of non-proportional hazards, treatment effects are presented as life expectancy difference without failure (LEDwf), which measures the difference between average duration of survival without failure.

Results: Average durations of survival without failure were 19.8 months for rituximab, 15.6 months for abatacept, and 19.1 months for tocilizumab. Average durations were greater with rituximab (LEDwf 4.1, 95% confidence interval 3.1 to 5.2) and tocilizumab (3.5, 2.1 to 5.0) than with abatacept, and uncertainty about tocilizumab compared with rituximab was substantial (-0.7, -1.9 to 0.5). No evidence was found of difference between treatments for mean duration of survival without death, presence of cancer or serious infections, or major adverse cardiovascular events.

Conclusion: Among adults with refractory rheumatoid arthritis followed-up in routine practice, rituximab and tocilizumab were associated with greater improvements in outcomes at two years compared with abatacept.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: JEG reports personal fees from AbbVie, MSD, Janssen, Pfizer, UCB, and Lilly; grants and personal fees from Bristol-Meyers Squibb and Roche during the conduct of the study; and grants from Pfizer and Bristol-Meyers Squibb outside the submitted work. BC reports personal fees from Abbvie, Bristol-Meyers Squibb, Lilly, MSD, Janssen, Pfizer, Roche, Chigai, and Sanofi, during the conduct of the study, and grants from Abbvie, Bristol-Meyers Squibb, Lilly, MSD, Janssen, Pfizer, Roche, Chugai, and Sanofi outside the submitted work. MD reports grants and personal fees from Bristol-Meyers Squibb, AbbVie, Pfizer, Novartis, Lilly, UCB, Merck, and Janssen outside the submitted work. R-MF reports grants and personal fees from Roche, Chugai, Abbvie, and Pfizer, and personal fees from Bristol-Meyers Squibb outside the submitted work. AS reports grants, personal fees, and non-financial support from Roche, Chugai, and Bristol-Meyers Squibb outside the submitted work. TS reports and has been implicated in clinical trials for all the disease modifying antirheumatic drugs that are considered in the paper. JS reports personal fees from Roche, Chugai, and Bristol-Meyers Squibb during the conduct of the study, and personal fees from Roche, Chugai, Bristol-Meyers Squibb, UCB, GSK, LFB, Actelion, Pfizer, MSD, Novartis, Amgen, Hospira, AbbVie, Sandoz, Gilead, Lilly, Sanofi, Janssen, and Mylan outside the submitted work. OV reports personal fees from Bristol Myers Squibb, Roche, Chugai, MSD, Novartis, Pfizer, Abbvie, and Lilly outside the submitted work. AC reports personal fees from Bristol-Meyers Squibb, Chugai, Roche, Abbvie, MSD, Pfizer, and UCB outside the submitted work. XM received an honorarium for participation in boards without any relation to this study from Bristol-Meyers Squibb, GSK, Janssen, Pfizer, and UCB.

Figures

Fig 1
Fig 1
Flow of participants through study. *Not meeting one of the inclusion criteria (n=781) or missing value for at least one inclusion criterion (n=170). †Severe cardiovascular disease, active or severe infections, severe immune deficiency. ‡Inclusion period: patients who initiated treatment before March 2013 (ie, two years before database was locked, in March 2015, to have at least two years of theoretical follow-up). §Patients with treatment failure before two years of follow-up or with at least two years of follow-up. ACR=American College of Rheumatology
Fig 2
Fig 2
Kaplan-Meier curves of drug retention without failure at 24 months (after inverse probability weighting). Vertical bars represent censored patients
Fig 3
Fig 3
Sensitivity analyses of drug retention without failure at month 24 for abatacept and rituximab. RMST=restricted mean survival time; LED=life expectancy difference (difference between RMST); RTX=rituximab; ABA=abatacept. *Truncated weights used in weighted cohort. †1=death or discontinuation of study drug; 2=death or initiation of a combination of conventional disease modifying antirheumatic drugs (DMARDs) or a biologic DMARD; 3=death or discontinuation of study drug or initiation of a combination of conventional DMARDs or biologic DMARD
Fig 4
Fig 4
Sensitivity analyses of drug retention without failure at month 24 for abatacept and tocilizumab. RMST=restricted mean survival time; LED=life expectancy difference (difference between RMST); TOC=tocilizumab; ABA=abatacept. *Truncated weights used in weighted cohort. †1=death or discontinuation of study drug; 2=death or initiation of a combination of conventional disease modifying antirheumatic drugs (DMARDs) or a biologic DMARD; 3=death or discontinuation of study drug or initiation of a combination of conventional DMARDs or biologic DMARD.
Fig 5
Fig 5
Sensitivity analyses of drug retention without failure at month 24 for rituximab and tocilizumab. RMST=restricted mean survival time; LED=life expectancy difference (difference between RMST); TOC=tocilizumab; RTX=rituximab. *Truncated weights used in weighted cohort. †1=death or discontinuation of study drug; 2=death or initiation of a combination of conventional disease modifying antirheumatic drugs (DMARDs) or a biologic DMARD; 3=death or discontinuation of study drug or initiation of a combination of conventional DMARDs or biologic DMARD
Fig 6
Fig 6
Kaplan-Meier curves of survival without serious adverse events (among serious infection, major adverse cardiovascular events, cancer, and death) at 24 months (after inverse probability weighting). Vertical bars represent censored patients
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