Tumor necrosis factor α blockade as therapy for sarcoidosis: Comment on the article by Ulbricht et al


Tumor Necrosis Factor α Blockade as Therapy for Sarcoidosis: Comment on the Article by Ulbricht et al

To the Editor:

We read with great interest the report by Ulbricht and coworkers about successful treatment with infliximab of a patient with therapy-resistant systemic sarcoidosis (1). Even though a previous report by Yee and Pochapin (2) is referenced, the authors go on to state that, “To our knowledge, this is the first case of successful treatment of typical therapy-resistant multiorgan sarcoidosis.” We would like to point out to the readers of Arthritis & Rheumatism that the concept of anti–tumor necrosis factor α (anti-TNFα) therapy for sarcoidosis is not new, that depending on the agent used, anti–TNFα therapy has had mixed results, and that this treatment concept is currently undergoing active further investigation.

As pointed out by Ulbricht et al (1), there is a good scientific rationale for TNFα inhibition in sarcoidosis (3). Based on this rationale, 4 agents have been tried in sarcoidosis: pentoxifylline, thalidomide, etanercept, and infliximab. Pentoxifylline was the first anti-TNFα agent used in sarcoidosis (4). This drug inhibits the secretion of TNFα by activated monocytes and alveolar macrophages in vitro (5). To date, the reported clinical success of pentoxifylline has not been corroborated, but a formal prospective trial is currently ongoing at the National Institute of Health (http://clinicalstudies.info.nih.gov/detail/A_99-H-0057.html). Thalidomide, which selectively suppresses TNFα production by enhancing degradation of TNFα messenger RNA, has also been reported to be of benefit in patients with refractory sarcoidosis (6, 7). Recombinant protein TNFα inhibitors designed to neutralize circulating TNFα have recently become available, and etanercept and infliximab have been used in sarcoidosis. A recently performed open-label prospective trial of etanercept showed disappointing results in the treatment of stage II or III progressive pulmonary sarcoidosis, because the number of early treatment failures had triggered the early-stop rule of the trial (8).

In contrast, the reported experience with infliximab in sarcoidosis seems to be more encouraging. Nine cases, including the one described by Ulbricht et al, of successful infliximab use in sarcoidosis have been reported to date (1, 2, 9–13). The reported dramatic symptomatic and objective responses are indeed striking and include the most difficult situations such as neuro- or cardiac sarcoidosis. In addition, there have been several presentations at meetings, with published abstracts, that indicate similarly promising results. Although these reports on infliximab in sarcoidosis are encouraging, the number of patients with “therapy-resistant” sarcoidosis, who have failed to respond to infliximab, remains unknown. Therefore, the indiscriminate use of this agent in steroid-dependent sarcoidosis should be discouraged, and the results of an ongoing multicenter prospective randomized trial comparing infliximab with placebo in patients with chronic steroid-dependent sarcoidosis (http://www.clinicaltrials.gov/ct/show/NCT00073437) are eagerly awaited. We hope that results as promising as those reported by Ulbricht et al will be confirmed by the formal trial.

The failure of etanercept in pulmonary sarcoidosis should not lead to skepticism about the use of infliximab in sarcoidosis. Even though both agents effectively neutralize TNFα, different clinical effects of the 2 agents have been well documented in Crohn's disease (14–16). Documented properties of infliximab that are not shared with etanercept include its ability to bind to peripheral blood lymphocytes and lamina propria T cells, and to induce apoptosis of activated lymphocytes (17). These properties and possible differences in tissue bioavailability may explain the observed differences in efficacy between different anti-TNFα agents in granulomatous diseases such as sarcoidosis.

Augustine S. Lee MD*, James P. Utz MD*, Ulrich Specks MD*, * Mayo Clinic and Foundation, Rochester, MN.