NEWARK, New Jersey?Scleroderma-related interstitial lung disease (SSc-ILD) contributes to the high morbidity and mortality in SSc, and has responded poorly to treatment options such as stem cell transplantation, symptomatic treatment, and oral or intravenous (IV) cyclophosphamide (CYC).

“Imatinib mesylate and some TSK inhibitors used in oncology are current hot candidates for use in SSc.”?Frank Wollheim, MD, PhD, FRCP
Indu Sabnani, MD, and colleagues suspect that PDGF receptor amplification might be part of the problem. In a proof-of-principle pilot study, they report early online in Rheumatology that adding the tyrosine kinase (TSK) inhibitor imatinib (Gleevec®, Novartis AG) to CYC improved pulmonary function in one patient with mild restrictive lung disease, although the combination did not help patients with more advanced SSc-ILD.1

First study of imatinib plus CYC in SSc-related lung disease

“With these preliminary clinical data, along with experimental evidence of its ability to reduce fibrosis, imatinib, a well-tolerated, once daily oral medication, may emerge as a potential antifibrotic agent in the management of SSc-ILD. Large prospective trials are needed to address patient selection criteria, timing and duration of treatment, and the role of associated immunosuppressive treatment with imatinib.... We suggest that the combination of immunosuppressive and antifibrotic therapy might be an appropriate approach to treat SSc-ILD,” wrote Dr. Sabnani, who is in the division of hematology/oncology at Newark Beth Israel Medical Center in New Jersey.

The researchers report on five SSc patients with advanced SSc-ILD: four of whom had severe restrictive lung disease; one had mild restrictive lung disease. Disease duration was >10 years in all patients. SSc-ILD diagnosis was based on high-resolution computed tomography and all were treated with oral imatinib (200 mg/day) plus IV CYC (500 mg every 3 weeks) for up to 12 months. Safety was monitored via complete blood count, liver function tests, and cardiac function tests. The efficacy endpoint was pulmonary functions at 6 and 12 months.

“The primary objective was to evaluate the safety and efficacy of this combined therapy in patients with SSC-related pulmonary disease at the end of 1 y[ea]r of treatment,” the investigators wrote. In the patients with milder disease, both diffusion capacity for carbon monoxide (43%-50% of predicted) and forced vital capacity (80%-89% of predicted) improved during 12 months of treatment. The other patients tolerated treatment well but did not have improvements in lung function.

Translating research into more research

Prior to the report, there had been only one case report of using imatinib in SSc-ILD, according to Dr. Sabnani. Preclinical work with imatinib in an animal model was encouraging, but Frank Wollheim, MD, PhD, FRCP, of the department of rheumatology at Lund University Hospital in Sweden, had urged caution before moving to clinical trials. Now, Dr. Wollheim tells MSKreport.com that the time has come to move forward with the trials.

“There is enough animal evidence for efficacy. Several uncontrolled and at least one controlled trial are in progress,” Dr. Wollheim said. “Imatinib mesylate and some TSK inhibitors used in oncology are current hot candidates for use in SSc.”

Reference
1. Sabnani I, Zucker MJ, Rosenstein ED, et al. A novel therapeutic approach to the treatment of scleroderma-associated pulmonary complications: safety and efficacy of combination therapy with imatinib and cyclophosphamide [published online ahead of print 24 September, 2008]...Sabnani I, et al. Rheumatology. 2008. http://rheumatology.oxfordjournals.org/cgi/content/abstract/ken369v1.