Clinical State-of-the-ArtThe RATIO observatory: French registry of opportunistic infections, severe bacterial infections, and lymphomas complicating anti-TnFα therapy◊
Introduction
Tumor necrosis factor alpha (TNFα) is involved in the pathogenesis of chronic inflammatory diseases [1], [2], [3], [4], [5], [6]. TNFα antagonists, which are either antibodies against TNFα or soluble receptors for TNFα, are effective in rheumatoid arthritis [7], Crohn's disease [8], ankylosing spondylitis [9], and psoriasis [10] and have radically improved the prognosis of these conditions in patients who are unresponsive to conventional treatments. TNFα is crucial to defense mechanisms against infections, most notably those caused by intracellular organisms [11]. It induces the differentiation of monocytes to macrophages and plays a key role both in initiating granuloma formation and in maintaining granuloma integrity [12], [13]. Because TNFα antagonists are potent inhibitors of macrophage functions [14], they increase the risk of infection, particularly due to intracellular organisms [15].
Because the risk of infection was predictable, infection rates were monitored carefully during the clinical development of TNFα antagonists. As early as the late 1990s, an increase in cases of tuberculosis was detected in patients taking infliximab. A study of 70 cases reported in the US before June 2000 was published in 2001 [16]. Median time from treatment initiation to the diagnosis of tuberculosis was only 12 weeks, and 40% of patients had extrapulmonary disease (miliary or involvement of the lymph nodes, pleural cavity, or peritoneal cavity). Over 98% of the patients were from areas of low tuberculosis endemicity. These characteristics are consistent with reactivation of quiescent mycobacteria within macrophages. Inhibition of the macrophage response by TNFα antagonist therapy may allow mycobacteria to resume proliferation. The high rate of extrapulmonary disease may reflect an inability to generate a granuloma that walls in the initial focus of pulmonary reactivation.
Recommendations for patients who are starting TNFα antagonist therapy have been developed in several countries. In France, specific tuberculosis prophylaxis guidelines were issued by the RATIO study group [17] and the AFSSAPS. The immune deficiency induced by TNFα antagonists may explain occurrences of other opportunistic infections, and more specifically those caused by intracellular bacteria (e.g. listeriosis) [18], fungi (e.g. histoplasmosis [19], aspergillosis [20], and pneumocystosis [21]), and viruses (e.g. CMV [22]). These infections are often severe and in some cases require intensive care unit admission. Fatal cases have been reported. Finally, TNFα is involved in cytotoxic T-cell responses against lymphomatous B cells [23], [24]. This indicates a theoretical risk of lymphoma in patients taking TNFα antagonists [25], [26], [27]. Studies have shown a small increase in the risk of lymphoma but have failed to determine whether this result is due to the medication or to greater disease activity in patients selected to TNFα antagonist therapy [28].
In this fast-flowing situation, creating a specific system to capture cases of infection and lymphoma in patients on TNFα antagonists was essential. A multidisciplinary task force was set up in France in 2001. Members were representatives of learned societies concerned with TNFα antagonists (rheumatology, gastroenterology, dermatology, infectiology, internal medicine, methodology, and pulmonology). The task force, called research on TNFα antagonists and opportunistic infections (RATIO) has produced most of the studies conducted in France on the safety of TNFα antagonists. The RATIO observatory is a nationwide prospective registry of infections and lymphomas in patients with a past or present history of TNFα antagonist therapy. It pursues a dual objective: to describe infections and lymphomas in patients treated with TNFα antagonists via active surveillance designed to achieve a high case-ascertainment rate and to identify risk factors by conducting a nested case–control study. The RATIO observatory is a clinical research network created by the French societies for rheumatology, gastroenterology, internal medicine, infectious diseases, pulmonology, and dermatology; as well as by pharmacovigilance centers. The observatory efforts are coordinated by two methodologists (Ph. Ravaud and F. Tubach), supported by two publicly funded institutions (the INSERM and the AFSSAPS), and funded in large part by the three pharmaceutical companies that market TNFα antagonists (Abbott, Schering Plough, and Wyeth (Table 1)).
Section snippets
The RATIO observatory
To obtain information on the incidence, natural history, and outcomes of opportunistic infections, severe bacterial infections, and lymphomas in patients with a past or present history of TNFα antagonist therapy, cases are recorded prospectively and monitored for 3 years. Case-ascertainment is the main challenge. Ideally, all cases in France should be identified. To achieve this goal, considerable efforts must be made to motivate clinicians. A letter signed by the AFSSAPS and the RATIO task
The nested case–control study
A nested case–control study is under way to identify risk factors for opportunistic infection, severe bacterial infection, and lymphoma in patients treated with TNFα antagonists. Opportunistic infection, severe bacterial infection, and lymphoma will be analyzed separately.
Conclusion
The objective of the RATIO observatory is to describe infections and lymphomas in patients with a past or present history of TNFα antagonist therapy and to identify risk factors for these events. Available safety data on TNFα antagonists come mainly from three sources: follow-up of patients included in clinical studies (randomized trials and cohort studies), follow-up of patients in everyday practice (most notably via registries such as those maintained in Sweden and in the United Kingdom), and
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Lecture held on the occasion of the 18th French Congress for Rheumatology.