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INFLIXIMAB SHOWS SOME PROMISE IN THE TREATMENT OF ASTHMA AND SARCOIDOSIS
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Key Point
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| The anti–TNF-a antibody infliximab prevented exacerbations in patients with moderate asthma and increased the FVC of patients with chronic severe pulmonary sarcoidosis. |
LONDON AND CINCINNATI—In two separate studies, the anti–tumor necrosis factor-a (anti–TNF-a) antibody infliximab appeared to be a potentially effective adjunctive treatment for asthma and sarcoidosis with pulmonary involvement. In the first study, Trevor T. Hansel, FRCPath, PhD, and associates found that infliximab reduced the risk of exacerbations in patients with symptomatic moderate asthma.1
"We focused on moderate rather than severe asthma in this preliminary study because it provided a greater margin of safety," related Dr. Hansel, Medical Director of the National Heart and Lung Institute Clinical Studies Unit at the Imperial College in London. "TNF-a antibodies have been associated with some risk of reactivating latent tuberculosis and with the ability to exacerbate stable asthma," Dr. Hansel explained. "But our findings were promising, so larger trials involving patients with more severe asthma are warranted," he told Pulmonary Reviews.
In the second study, Robert P. Baughman, MD, Professor of Medicine at the University of Cincinnati, and colleagues reported that infliximab produced a statistically significant improvement after 24 weeks in the FVC of patients with chronic severe pulmonary sarcoidosis.2 However, the drug did not improve any of the major secondary end points studied, such as the six-minute walk distance or the St. George’s Respiratory Questionnaire score, raising doubt about the clinical relevance of the observed FVC improvement.
Further analysis suggested that the greatest benefit from infliximab occurred in the subgroup with the most severe disease, although the authors warned that these results must be viewed with caution, due to their post hoc nature. Despite the weaknesses in their findings, the authors recommended further evaluation of anti–TNF-a therapy for chronic severe pulmonary sarcoidosis./font>
INFLIXIMAB FOR MODERATE ASTHMA
Dr. Hansel’s group randomized 38 patients with moderate asthma (as defined by the Global Initiative on Asthma) to infliximab or placebo in double-blind fashion. After a two- to four-week run-in period, the patients received IV infusions of placebo or 5 mg/kg of the study drug at baseline, two weeks, and six weeks.
All of the patients continued their usual inhaled corticosteroid therapy, which averaged 753 µg/d in the infliximab group and 606 µg/d in the placebo group. Other than short-acting b2-agonists taken as needed, no other asthma medications were permitted.
Infliximab therapy produced no improvement in the primary efficacy end point of mean morning PEF at 50 to 56 days compared with the last seven days of run-in. However, the asthma exacerbation rate was significantly lower with infliximab than placebo during follow-up (29% vs 72%); the probability of freedom from exacerbations rose over time in the infliximaß-treated patients.
Also, those patients demonstrated a much larger decrease in the mean diurnal variation in PEF at week 8 than did the placebo group. They showed significantly lower levels of sputum cytokines as well, including TNF-a, interleukin-1a (IL-1a), IL-6, IL-8, and human interferon-inducible protein 10. "No safety issues were raised in this study, with infliximab exhibiting a safety profile similar to placebo," the authors pointed out.
PHASE II TRIAL IN PATIENTS WITH SARCOIDOSIS
The Baughman study was a multicenter phase II trial in which 138 patients with chronic severe pulmonary sarcoidosis were randomized to IV infusions of placebo or 3 or 5 mg/kg of infliximab at baseline and at weeks 2, 6, 12, 18, and 24. As in the Hansel study, the patients continued taking their other medications, including at least 10 mg/d of prednisone or the equivalent or one or more immunosuppressants. Of the patients, 133 completed the study.
The primary efficacy end point, the change in the percent predicted FVC from baseline to week 24, rose by a mean of 2.5% in the infliximaß-treated patients, versus no change for placebo recipients. The improvement was similar in the 3- and 5-mg/kg infliximab groups (2.8% and 2.2%, respectively). Although infliximab did not improve the secondary outcome measures (these also included the Borg’s CR10 dyspnea score and an adaptation of the Lupus Pernio Physician’s Global Assessment), the drug did reduce the incidence of reticulonodular opacities on chest radiographs by about 26%.
Furthermore, post hoc analysis revealed that infliximab was associated with a larger improvement in the percent predicted FVC at week 24 in the patients with a longer disease duration, lower FVC, higher St. George’s Respiratory Questionnaire score, and more symptoms. "Infliximab therapy seemed to be more beneficial in patients receiving immunosuppressants or higher doses of corticosteroids or in those with multiorgan extrapulmonary involvement," added the authors.
The adverse event rates in the infliximab and placebo groups were similar through week 24 (81.3% and 79.5%, respectively) and week 52 (87.9% and 93.2%, respectively). Upper respiratory tract infection, dyspnea, pain, and coughing were reported most often.
"On first approximation, this study merely corroborates the lack of efficacy of TNF-a antagonists in sarcoidosis. Or does it?" commented Eric S. White, MD, in an editorial.3 On closer scrutiny, the findings of Baughman and colleagues "allow us to maintain some degree of optimism regarding the potential use of infliximab for sarcoidosis," said Dr. White, Assistant Professor of Internal Medicine at the University of Michigan in Ann Arbor.
The authors used a multicenter, randomized, double-blind, placebo-controlled trial design, something that has been severely lacking in the sarcoidosis literature, Dr. White explained, and there were large numbers of sarcoidosis patients with both pulmonary and extrapulmonary disease. He concluded that although the study findings did not provide better answers about infliximab or justify its use in sarcoidosis, they have enabled researchers and clinicians to ask better questions.
—Timothy Begany
References
1. Erin EM, Leaker BR, Nicholson GC, et al. The effects of a monoclonal antibody directed against tumor necrosis factor-a in asthma. Am J Respir Crit Care Med. 2006;174:753-762.
2. Baughman RP, Drent M, Kavuru M, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med. 2006;174:795-802.
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