Understanding the Side Effects of TNFa Inhibitors

The inhibition of a central molecule, such as TNFa, has been associated with side effects, allowing a better understanding of the physiological role of TNFa. In addition, the heterogeneity of the response, and the risk of disease reactivation when stopping the inhibition, indicates that these inflammatory diseases cannot be simplified as diseases of the TNFa pathway.

TNFa is a critical molecule in the control of acute and chronic infections. Not surprisingly, a greater mortality was observed during the treatment of toxic shock with TNFa inhibitors. For long-term treatment, the major complication has been the appearance of opportunistic infections. If all types of opportunistic infections were observed, tuberculosis has been by far the most frequent cause (Keane et al., 2001). Its severity associated to an unusual mortality rate quickly drew attention. Epidemiological studies showed that it was essentially a reactivation of known or undiagnosed tuberculosis, suggesting an acquired defect of cell-mediated immunity. Primary immune defects have been described in association with mutations of genes coding for interferon y and IL-12 receptor (Casanova and Abel, 2002). These defects are responsible for severe mycobacterial infections usually secondary to BCG vaccination.

In the context of chronic inflammation, such as occurs in RA, there is already a systemic response defect to IL-12 and IL-18, key cytokines for the production of interferon y (Kawashima and Miossec, 2004). The synergy between these two cytokines is related to the effect of IL-12 on the induction of a functional IL-18 receptor (Kawashima and Miossec, 2003). Such defect in RA results in a lower production of interferon y by blood cells in response to IL-12 and IL-18. This defect is proportional to the level of systemic inflammation, as measured by C-reactive protein levels. This could explain the increased frequency of tuberculosis in RA, even in the absence of anti-TNFa treatment (Carmona et al., 2003). At initiation of a treatment with a TNFa inhibitor, the disease is usually still very active. The additive effect of the inhibitor explains the rapid appearance and the severity of these reactivations. Later, the risk is reduced because the improvement of the clinical situation has been able to correct the systemic immune defect related to inflammation, reducing the risk of reactivation. The specific anti-TNFa effect results from an inhibition of cell-cell interactions and has a positive impact on local inflammation, resulting in the beneficial clinical effect. Conversely, inhibition of these interactions also results in granuloma disintegration, leading to the diffusion of mycobacteria that were kept under control in these granulomas.

The induction of antinuclear antibodies is common, but rarely associated with clinical manifestations of lupus (Shakoor et al., 2002). A positive connection between TNFa and lupus has been established in lupus mice where the inhibition of TNFa increases incidence and mortality from renal disease (Kontoyiannis and Kollias, 2000). Conversely, administration of TNFa has a protective effect on mouse lupus. The anti-inflammatory cytokine IL-10 is directly involved in the production of autoantibodies and IgG (Llorente et al., 1995). These properties indicate a mutual inhibition between TNFa and IL-10 actions. Furthermore, the inhibition of TNFa favors the production of IL-10, leading to the production of autoantibodies and the orientation of the Th1-Th2 cytokine balance toward Th2 (Miossec and van den Berg, 1997).

These notions also must be taken into account to estimate the possible effect of TNFa inhibitors on the incidence of lymphomas (Brown et al., 2002), but their interpretation is extremely difficult because of a greater frequency of lymphomas in the general population, a frequency further increased in association with RA and even more, with Sjogren's syndrome. The contribution of TNFa to apoptosis and the amplified immunosuppressive effect of IL-10 must be considered. Conversely, TNFa is involved in lymph node hypertrophy, a common sign of activity of inflammatory diseases (McLachlan et al., 2003).

The beneficial effect obtained in the treatment of RA and CD would suggest that all inflammatory diseases, and in particular those associated with a Th1 profile, could be controlled with the same TNFa inhibitors. However, TNFa inhibition in multiple sclerosis was associated to an increase in clinical and radiological signs (Mohan et al., 2001). The mechanism has not been clarified, but could be related to the anatomical site and to the contribution of the blood brain barrier (Robinson et al., 2001). The importance of TNFa inhibition also could be demonstrated with the reintroduction of infliximab in a case of aseptic meningitis (Marotte et al., 2001).

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