CHICAGO — A new era is emerging in the management of systemic sclerosis, and within 5 years the number of available drugs should resemble the sort of variety seen with other rheumatic disease treatment options, Dr. John Varga said at a symposium sponsored by the American College of Rheumatology.
Dr. Carol Black and her fellow investigators “looked at a systemic sclerosis population with associated pulmonary artery hypertension [PAH] before and after 2002 to determine the effect of introducing the endothelin-1 receptor antagonist,” in a retrospective study, said Dr. Varga, who is the Gallagher Research Professor in Rheumatology at Northwestern University, Chicago.
The investigators, of University College Medical School, London, divided patients into a “historical” control group of 47 patients studied before 2002 and a “current treatment era” group of 45 patients studied after 2002.
The historical cohort received basic treatment, including diuretics, digoxin, oxygen, and warfarin, and 27 patients in the group also received prostanoids. The “current treatment era” group got bosentan.
Survival rate in the historical control group was 68% at 1 year and 47% at 2 years, whereas in the current era treatment group survival was 81% and 71%, respectively, according to Kaplan-Meier analysis. In addition, vascular resistance was stabilized in the bosentan cohort (Heart 2006, Jan. 31;doi 10.1136/hrt.2005.069484 [Epub ahead of print]).
“These data are very helpful but are preliminary, and I think it will be very important to follow these patients to see how much of an improvement they [make],” said Dr. Varga. Blocking endothelin-1 may do more than just block vasoconstriction. Bosentan, through vascular proliferation or the production of new blood vessels, may promote vascular repair, according to the study.
Another promising drug in the same class as bosentan is sitaxsentan, which has received approval under the FDA's orphan drug program, but is not yet clinically available in the United States. Bosentan is currently being evaluated in patients with systemic sclerosis-associated interstitial lung disease, noted Dr. Varga.
In a recently completed multicenter, placebo-controlled study of patients with early disease and alveolitis, treatment with oral cyclophosphamide yielded significant benefit at 12 months.
Data from the Scleroderma Lung Study also show that bronchoalveolar lavage (BAL) did not influence outcome, which Dr. Varga said contradicts earlier findings from retrospective studies and calls into question the role of BAL.
Another promising avenue in treating sclerosis-associated PAH is to enhance nitric oxide by using phosphodiesterase inhibitors. “In a published British study, investigators compared sildenafil to endothelial receptor antagonists and the data are similar in terms of short-term symptomatic improvement and better exercise tolerance,” said Dr. Varga. Sildenafil has received FDA approval for the treatment of PAH (Am. J. Respir. Crit. Care Med. 2005;171:1292–7).
Prostacyclines also are available for treating PAH. “Inhaled iloprost, a stable analog of prostacycline, leads to clinical benefits. So there are a number of drugs and it's currently difficult to know where they fit in clinically.” Autologous hematopoietic stem cell transplantation (HSCT) induced marked improvement or complete remission in animal models of autoimmunity, as well as in some patients with lupus and rheumatoid arthritis, said Dr. Varga. A large multicenter trial comparing HSCT with monthly cyclophosphamide in patients with severe sclerosis is underway.
Another approach, explained Dr. Varga, may be to target autoimmunity and prevent the initial activation of fibroblasts using anticytokine antibodies to connective tissue growth factor or transforming growth factor β. This is similar to the approach in rheumatoid arthritis treatment using tumor necrosis factor-α inhibitors, said Dr. Varga. “A clinical trial with an antichemokine antibody looking at early lung diseases in scleroderma is planned for later this year,” he said.