Serious infections during anti-TNFα treatment in rheumatoid arthritis patients☆
Introduction
More than 1,500,000 patients throughout the world have received anti-TNFα agents for all therapeutic indications since their introduction in 1999, including many who have experienced a dramatic improvement in severe rheumatoid arthritis (RA). Randomised clinical trials (RCTs) of the three currently licensed agents (the monoclonal antibodies infliximab and adalimumab, and the soluble TNFα receptor etanercept) have shown that they are effective in reducing inflammatory activity and limiting joint destruction in patients with active early and long-standing RA [1], [2], [3], [4], [5], [6].
However, they have also raised a number of safety concerns of which, given the major role of TNFα in host defence mechanisms, one of the most important is an increased risk of infection. Infectious adverse events are common in patients with rheumatic diseases [7] and it has been reported that the rate of infections in the RA population is nearly twice as high as that observed in matched non-RA controls [8], which may be related to the underlying disease itself (alterations in immunological functions, disability) or the drugs used to treat it (especially immunosuppressants drugs and corticosteroids). The question that needs to be answered is whether anti-TNFα treatment further increases that risk.
The greatest concern is tuberculosis because the use of TNFα antagonists is accompanied by an increased susceptibility to active tuberculosis (ATB) or the reactivation of latent tuberculosis infection (LTBI) [9], which should be considered characteristic of the drug class [10]. However, health authorities published recommendations for screening patients with LTBI who were candidates for TNFα antagonist treatment in 2002, and the subsequent decrease in the number of reports of new ATB cases suggests that the problem of LTBI is now under control [11].
Nevertheless, there are still concerns relating to other infective conditions as well as a lack of information concerning the long-term safety of the daily use of biological agents. There have been a number of post-marketing surveillance and other reports indicating the occurrence of serious infections during the use of TNFα blockers (including opportunistic infections such as candidosis, listeriosis, nocardiosis, histoplasmosis, aspergillosis and pneumocystosis) [12], [13], [14], [15], but the results of RCTs do not consistently demonstrate any significant increase in the incidence of opportunistic or serious infections in patients treated with anti-TNFα agents in comparison with those observed in patients receiving methotrexate plus placebo [1], [2], [3], [4], [5], [6]. However, these RCTs may have had insufficient power to detect such an increase because their designs and stringent inclusion/exclusion criteria may limit enrolment to patients at low risk of infection. Moreover, questions concerning the long-term safety of therapy with biological agents cannot be addressed by short-term RCTs not only because of their short duration, but also because they recruit too few patients to detect rare events.
For these reasons, large population-based registries that allow long-term follow-up are increasingly being used to investigate the incidence of adverse events in RA patients exposed to anti-TNFα drugs [16], [17], [18], [19], [20]. However, as no national pharmacovigilance registry has yet been planned in Italy, we conducted a prospective population-based cohort study of RA patients enrolled in four major Lombardy Rheumatology Units (the LOHREN Registry) [21].
Section snippets
The LORHEN registry
LORHEN is a regional population-based registry that was established with the aim of examining the efficacy and safety of TNFα blockers in the everyday treatment of RA. LORHEN contains a cohort of all of the RA patients treated with anti-TNFα agents in four major Rheumatology Units in Lombardy (Italy) since 1999, when they first became available for compassionate use [21].
This analysis covers the first 36 months from the date of the first administered dose (median follow-up: 23.22 months for
Study population
Since October 1999, a total of 1114 RA patients have received at least one anti-TNFα dose, of whom 833 (79.9%) have received only a first-line (22.4% etanercept, 29.8% adalimumab, and 47.8% infliximab), 237 (17%) a second-line (65.8% etanercept, 28.7% adalimumab, and 5.5% infliximab), and 44 a third-line (22.7% etanercept, 68.2% adalimumab, and 9.1% infliximab), for a total of 1395 treatment courses.
Fifty patients were lost to follow-up during the first six months of treatment, and so only 1064
Discussion
The aim of this study, conducted under conditions of everyday practice, was to record the incidence of serious infections in RA patients treated with anti-TNFα agents, as well as all information concerning infection patterns, characteristics and risk factors, concentrating on the potential role of the individual agents.
The overall rate of serious infections in our cohort (35.9 [95% CI: 27.66–44.13] per 1000 patient-years) was significantly lower than those reported in other post-marketing
Conclusions
In a setting of clinical practice, we found that the overall rate of serious infections (35.9 per 1000 patient-years) was significantly lower than those reported in other post-marketing observational studies, but substantially similar to those reported in phase III RCTs. The most frequent infection site was the lower respiratory tract, with 14 cases of pneumonia (19.2%) and one case of TB. Another four cases of extra-pulmonary TB were also reported, two of which occurred during the
Take-home messages
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The registries are increasingly being used to investigate the incidence of adverse events in RA patients.
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The overall rate of serious infections in our study was significantly lower than those reported in other post-marketing observational studies.
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The most frequent infection site was the lower respiratory tract.
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No differences among the individual anti-TNF agents were detected.
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An increased risk of serious infections was associated with age, ESR and corticosteroid use, but not with anti-TNF
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All of the authors have received consultancy fees or Congress invitations from Schering-Plough, Wyeth, and Abbott.