NEW YORK — New revelations about the complex cellular processes underlying scleroderma suggest that manipulating the immune system with thalidomide may offer a new means of targeting the disease, Stephen J. Oliver, M.D., said at a rheumatology meeting sponsored by New York University.
Scleroderma begins with inflammation and the production of cytokines, including transforming growth factor (TGF)-β and interleukin (IL)-4, both of which are profibrogenic and activate the fibroblast.
Once the fibroblast becomes activated, it produces its own TGF-β and other cytokines, such as connective tissue growth factor. This leads to further proliferation of fibroblasts and the production of collagen, Dr. Oliver explained.
“At this point, immunosuppression could theoretically act to shut off the production of cytokines and other exogenous activators of the fibroblast. But immune suppression has not been as effective in scleroderma as we would have liked it to be and, in fact, in many cases it hasn't been effective at all.” Early studies targeted TGF-β. However, this cytokine has multiple functions aside from its profibrogenic actions, “so blocking TGF-β systemically might not be such a great idea,” said Dr. Oliver of New York University, New York.
An alternative approach now being studied involves immune manipulation with thalidomide. In scleroderma, the T helper (Th)2 type of immune response is predominant, and laboratory investigations have revealed that thalidomide stimulates a Th1-type cellular response, causing increased production of interferon (IFN)-γ, IL-2, and IL-12 and enhancing the T-cell expression of the CD40 ligand.
Its potential applicability in scleroderma was suggested by the observation that this autoimmune disease shares many clinical features with graft-versus-host disease—a condition that sometimes responds to thalidomide.
In the first open-label study of the drug in scleroderma, 8 of 11 patients completed 12 weeks of treatment. The initial dosage was 50 mg/day; this was gradually increased to 400 mg/day, which is the maximum dosage used for the treatment of erythema nodosum leprosum.
Pruritus and dry skin were reported by seven of the eight patients, but there were no serious adverse events, such as the induction of renal disease, Dr. Oliver said.
Among the changes seen in patients in this preliminary study were increases in CD8 cells within the skin; this could offset the increased levels of CD4 cells that are associated with fibrosis of the skin, he said. Increases also were seen in tumor necrosis factor-α and IL-12. Moreover, there was a “striking clinical effect” in the healing of digital ulcers in four of five patients (Clin. Immunol. 2000;97:109-20).
Recruitment for a double-blind, placebo-controlled trial is under way. Dr. Oliver noted that he had no potential conflicts of interest.
Clinicians with patients who may be candidates for the New York University Scleroderma Trial can contact Dr. Oliver at 212-263-3874.