Background/Purpose:

TNF-a inhibitors have changed the prognosis of rheumatoid arthritis (RA). The number of molecules and the time of exposure have increased. However, few studies have compared  the safety of the five TNF-alpha inhibitors between them, and their medium term safety. The aim of our study was to compare medium term safety (particularly death and severe infection) obtained from randomized controlled trials for the five TNF alpha inhibitors used in the treatment of RA.

Methods:

A systematic review of articles published from January 2000 to January 2013 was performed using MEDLINE, EMBASE and COCHRANE databases. We included randomized, controlled, double-blind trials, with a follow-up period of at least 6 months, comparing TNF-a inhibitors to placebo, with or without concomitant Methotrexate. The primary outcome measure was the occurrence of a serious adverse event, defined by the occurrence of death or of a severe infection (with the requirement of hospitalization). The MedCalc software was used for the statistical analysis.

Results:

Among the 396 articles initially identified, 22 were finally selected. These articles included 6682 patients in the anti-TNF-a group (Adalimumab: 2507, Golimumab: 575, Certolizumab: 1512, Infliximab: 1087 and Etanercept: 1001) and 3607 in the placebo group. The duration of patient follow-up ranged from 24 to 78 weeks. 
There was no excess of risk of serious adverse event (death or severe infection) in the TNF-a inhibitors compared to placebo (Odds Ratio OR: 1.14, 95% Confidence Interval CI: 0.91-1.44). Nevertheless, we noticed an increased risk of serious event  under Certolizumab (OR: 2.06, CI: 1,35-3,15).

There was no increases risk of death in the TNF-a inhibitor group compared to the placebo group (OR: 1.27). We referenced 36 deaths among 6208 patients under TNF alpha inhibitors (0,58%) and 10/3282 deaths under placebo (0,30%). However, increased risk of severe infections in the TNF alpha inhibitor group was observed compared to the placebo group (OR: 1.66) with 192 serious infections among 5889 patients under TNF alpha inhibitors (3,26%) versus 63 serious infections among 3398 patients under placebo (1,85%). Sensibility analysis revealed that adalimumab had an increased risk of severe infection (OR: 2.10)

	Total	Adalimumab	Golimumab	Certolizumab	Infliximab	Etanercept
Death (CI 95%)	1.27 0.71-2.25	2.27 0.84- 6.16	2.02 0.22-18.19	1.19 0.27-5.18	0.47 0.16-1.40	1.28 0.22-7.24
Serious infections (CI 95%)	1.66 1.24-2.23	2.10 1.28-3.46	2.47 0.93-6.54	3.47 0.94-12.78	1.59 0.87-2.90	0.75 0.40-1.41
SAE (CI 95%)	1.14 0.91-1.44	0.91 0.68-1.23	1.82 0.45-7.29	2.06 1.35-3.15	1.13 0.80-1.59	0.80 0.57-1.12

Conclusion

This meta-analysis has been performed on a large number of patients and included the five TNF-a inhibitors currently available. It allowed an indirect comparison between the different molecules according to their medium-term safety. We did not find an increased risk of serious adverse events or deaths in patients treated with TNF-a inhibitors. However, we observed an increased risk of severe infections. Further studies aiming at the evaluation of the long-term safety are now needed to confirm these results.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/medium-term-safety-of-tnf-alpha-inhibitors-in-rheumatoid-arthritis-a-meta-analysis-of-randomized-controlled-trials/