SAN FRANCISCO—Drugs that target tumor necrosis factor alpha (TNF-alpha) may prove to be more effective in the treatment of sarcoidosis than are the corticosteroids and other anti-inflammatories often prescribed, reported Robert P. Baughman, MD, at the American Thoracic Society 97th International Conference, held in San Francisco.[1] In clinical trials, most of the sarcoidosis patients who were administered anti–TNF-alpha agents saw resolution of their refractory skin lesions.

“Tumor necrosis factor is the central cytokine in sarcoidosis,” emphasized Dr. Baughman, a Professor of Medicine in the Pulmonary and Critical Care Division at the University of Cincinnati Medical Center in Ohio. Elevated levels of TNF-alpha are found in bronchoalveolar lavage fluid of patients with untreated sarcoidosis; the levels abate when these patients are treated with systemic corticosteroids for three to six months.

Pentoxifylline and thalidomide suppress the release of TNF-alpha from phagocytes. Infliximab, a monoclonal antibody to TNF-alpha, blocks the protein’s activity. Although each of these drugs has only been studied in small numbers of sarcoidosis patients, results are encouraging, Dr. Baughman said.

Pentoxifylline’s anti–TNF-alpha activity, particularly in the lung, has been demonstrated in a six-month, open-label trial. The trial was limited, though, by its small size; only 23 patients had been enrolled. More important, the subjects all had relatively mild acute sarcoidosis that may have gone into spontaneous remission in a fair number of cases, Dr. Baughman said. Up to 40% of patients with sarcoidosis go into remission after six months, he noted.

The patients received 25 mg/kg/d of pentoxifylline, about twice the dosage amount given for the drug’s primary indication, claudication. “This is a fairly difficult dose,” Dr. Baughman remarked. As a result, three patients dropped out because of gastrointestinal toxicity. Another two patients were lost to follow-up. But, of the 18 patients available for evaluation, 11 experienced remission of their sarcoidosis; seven remained stable.

A MULTICENTER THALIDOMIDE TRIAL

One of the more useful agents for chronic sarcoidosis may turn out to be thalidomide. Obviously, the drug does have a number of drawbacks, “not the least of which is its teratogenicity,” which eliminates its use in women who might become pregnant, acknowledged Dr. Baughman. The drug can also cause peripheral neuropathy and somnolence. Its toxicity appears to be dose-dependent.

The researchers enrolled 15 patients with lupus pernio, an uncommon chronic form of sarcoidosis. These patients had high rates of pulmonary and sinus involvement. Most were on multiple sarcoidosis medications, such as methotrexate and azathioprine. Three were taking corticosteroids.

Their daily thalidomide regimen included one month at 50 mg, followed by another month at 100 mg and then two months at 200 mg. One patient was excluded from the trial after a myocardial infarction.

Twelve of the 14 patients who completed the trial had improvement in their skin lesions with doses of 100 mg or less, and all of the patients improved by week 16. Thalidomide produced little or no improvement in lung or sinus disease, however. Somnolence was the most common complication.

ANTIBODY THERAPY SHOWS PROMISE

Dr. Baughman reported on three patients with refractory multi-organ sarcoidosis who had been treated with infliximab. The lesions of two patients were primarily cutaneous; the other patient had pulmonary lesions. After three months, cutaneous involvement completely resolved and the patient with pulmonary disease showed nearly a 25% improvement in vital capacity. “We also saw a marked reduction in the corticosteroid dosage,” Dr. Baughman said.

He reported similar findings with infliximab in 11 patients with refractory sarcoidosis and multi-organ involvement. After six months to a year of therapy, the index lesions had completely resolved in three patients, improved in seven, and remained unchanged in one; the need for corticosteroids decreased in many of the patients. Previous combination therapy with most other sarcoidosis drugs had produced inadequate results in both groups, Dr. Baughman said.

Further trials of anti–TNF-alpha drugs are warranted, Dr. Baughman concluded. Randomized double-blind trials of several of these agents are under way.

—Timothy Begany

Reference
1. Baughman RP. Use of thalidomide and other anti–TNF agents. Presented at: American Thoracic Society 97th International Conference; May 22, 2001; San Francisco.

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