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Infliximab in Sarcoidosis

More Answers or More Questions?

University of Michigan Medical School, Ann Arbor, Michigan

Ever since the first description of sarcoidosis by Sir Jonathan Hutchinson in 1877 (1), clinicians and investigators have attempted to identify effective therapeutic options for symptomatic patients. Corticosteroids remain the mainstay of therapy, although meta-analyses conclude that they offer little improvement in lung function and may have no effect on modifying long-term outcomes (2). Conversely, the adverse effects caused by long-term corticosteroid use are common and undisputed (3). In the spirit of primum non nocere, identification of alternative agents that specifically target disease pathogenesis while avoiding steroid side effects is of great importance. In this issue of the Journal (pp. 795–802), Baughman and colleagues address the role of two different doses of the tumor necrosis factor (TNF)- antagonist infliximab in patients with chronic sarcoidosis and pulmonary involvement (4).

In sarcoidosis, it is likely that an antigenic challenge in a genetically susceptible host triggers an exaggerated granulomatous inflammatory response characterized by the production of T-helper type 1 cytokines, including TNF-. TNF- appears to be important in development of granulomatous inflammation in sarcoidosis, based on numerous lines of evidence. First, excessive TNF- expression localizes to the site of granulomas in sarcoidosis lymph nodes (5). Second, elevated levels of TNF- can be found in the bronchoalveolar lavage fluid of patients with sarcoidosis (6). Third, alveolar macrophages isolated from patients with sarcoid produce exaggerated amounts of TNF- spontaneously and after lipopolysaccharide stimulation (7). Finally, mice genetically deficient in TNF- are unable to form granulomata after experimental mycobacterial challenge (8). It would seem, then, that TNF- could be a suitable target in the treatment of sarcoidosis. Indeed, numerous case reports documenting the efficacy of TNF- antagonists in treatment-refractory sarcoidosis can be found throughout the literature.

Despite promising anecdotal evidence, a recent open-label trial by Utz and colleagues of the anti–TNF- antibody etanercept in patients with stage II and III pulmonary sarcoidosis failed to demonstrate any clinical benefit, with disease progressing in 11 of 17 patients receiving etanercept therapy (9). In the present study, Baughman's group demonstrates a statistically (but not biologically) significant increase in forced vital capacity of 2.5% at 24 weeks in the combined infliximab-treated groups (3 and 5 mg/kg) compared with placebo-treated patients, but this modest improvement in pulmonary function was not accompanied by differences among groups in either of the subjective symptom scores examined (St. George's Respiratory Questionnaire or Borg's C10 dyspnea score) (4). Further, the significant difference in 6-min walk distance test among groups at 52 weeks largely resulted from average decreases in distance walked in the placebo group (4). On first approximation, this study (4) merely corroborates the lack of efficacy of TNF- antagonists in sarcoidosis. Or does it?

On closer scrutiny, differences between the studies by Utz and colleagues (9) and Baughman and colleagues (4) allow us to maintain some degree of optimism regarding the potential use of infliximab for sarcoidosis. In addition to the obvious difference in agents, Baughman's group used a multicenter, randomized, double-blind, placebo-controlled strategy (something severely lacking in the sarcoidosis literature), including large numbers of patients with both pulmonary and extrapulmonary sarcoidosis (4). In so doing, they were able to perform post hoc exploratory subgroup analyses, identifying two groups that might potentially benefit from infliximab: those with multiorgan, extrapulmonary disease, and those receiving immunosuppressants or higher doses of corticosteroids (i.e., patients with more "active" disease). Notably, the vast majority of case reports demonstrating successful use of infliximab in sarcoidosis also deal with patients with severe extrapulmonary sarcoidosis. It is possible, then, that infliximab might be most beneficial in patients without pulmonary disease. Indeed, TNF- levels in bronchoalveolar lavage fluid did not demonstrably change after etanercept treatment in the Utz and colleagues' study (9), suggesting that perhaps etanercept (and possibly infliximab) does not penetrate into the lung epithelial lining fluid to a significant degree. While this is purely speculative, it would certainly account for the lack of significant improvement in pulmonary function observed by Baughman and colleagues (4) and Utz and colleagues (9) and would be worth testing prior to further study of TNF- inhibitors for lung diseases. Similarly, the exploratory analyses reported (4) suggest that it is worth prospectively testing the effects of TNF- inhibition in patients with severe extrapulmonary sarcoidosis.

Some might argue that the lack of biologically significant improvement in lung function in the Baughman and colleagues' study (4) was predictable. After all, etanercept failed to control progression of sarcoid lung disease; why should infliximab be any different? True, both etanercept and infliximab antagonize the activity of TNF-. However, their efficacy varies widely among different diseases. For example, in rheumatoid arthritis, both etanercept and infliximab appear efficacious (10, 11). Conversely, etanercept appears to be ineffective in Crohn's disease (12), whereas infliximab is beneficial (13). Based on these conflicting data, it is unfair to extrapolate the results of clinical trials using a specific TNF- antagonist to all TNF- antagonists. These discrepant results also highlight the importance (and wisdom) of undertaking the current study. Unfortunately, it now appears that both etanercept and infliximab are ineffective for the treatment of pulmonary sarcoidosis.

An important consideration when interpreting the results of this study is the risk–benefit analysis. As with all therapeutic agents, clinicians must decide whether the benefit gained from use of a drug outweighs the potential risks to the patient. Although the overall risk of adverse events in the infliximab-treated groups was similar to the placebo-treated group, the risk of pneumonia was greater in the infliximab-treated groups (4). Moreover, two patients randomized to receive infliximab developed malignancies during the 52-week follow-up (although it is not clear if there is a true cause-and-effect relationship) (4), whereas none of the placebo-treated patients did. Bearing these adverse events in mind, the potential benefit of a 2.5% increase in forced vital capacity does not appear to justify use of infliximab for this indication. Hence, infliximab cannot be endorsed for routine use in patients with pulmonary sarcoidosis.

This study of infliximab therapy in patients with sarcoidosis illustrates the importance of well-designed clinical treatment trials: although we do not yet have better answers, we are able to ask better questions.

FOOTNOTES

Conflict of Interest Statement: E.S.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

REFERENCES

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Infliximab Therapy in Patients with Chronic Sarcoidosis and Pulmonary Involvement

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