Scleroderma Research: The Chronic Management Challenges of a Once-Fatal Disease

By Soumya Chatterjee, MD, MS, FRCP

Cleveland Clinic’s Scleroderma Program integrates evidence-based care with clinical and translational research exploring the complex pathogenesis and management of scleroderma. The program is participating in several clinical trials involving diverse aspects of scleroderma management. This article profiles three of those trials, focusing on the medical need and scientific rationale behind each.

Ischemic Digital Ulcers

Medical need. Digital ulcers (Figure 1) are a major complication of scleroderma, occurring in about 30 percent of patients annually. They are associated with vasculopathy of the fingers and toes, in which the intima of vessels is thickened and the lumen occluded. As digital ulcers cause significant pain and functional impairment, they have a major impact on quality of life. They can become infected, resulting in osteomyelitis. Digital gangrene may require amputation. Management of digital ulcers in scleroderma involves nonpharmacologic and pharmacologic interventions for treatment and prevention. The aim is to reduce ulcer burden and impact on quality of life.

Figure 1. Ischemic digital ulcer in a patient with scleroderma.

Several medications are available for the treatment and prevention of digital ulcers. However, most regimens are empiric and not based on randomized controlled trials. To date, no drug has been approved outside Europe to treat digital ulcers in scleroderma patients, although one agent ‒ the dual endothelin receptor antagonist bosentan ‒ has been approved in Europe for reducing the number of new digital ulcers in scleroderma patients.

The need is clear for pharmacotherapy that would affect the natural course of digital ulcers in scleroderma, improve tissue integrity and viability, and prevent or reduce new ulcer development. To address this need, our Scleroderma Program is participating in the DUAL-1 study (Macitentan for the Treatment of Digital Ulcers in Systemic Sclerosis Patients).

Scientific rationale. In scleroderma, endothelial injury is thought to precede loss of normal vasodilator response to nitric oxide and prostacyclin, leading to abnormal responses to vasoconstrictive mediators that include endothelin-1 and catecholamines. Endothelin-1, the most potent naturally occurring vasoconstrictor, is released as a result of endothelial damage. It also stimulates fibroblast matrix biosynthesis and fibroblast and smooth muscle cell proliferation. Because serum endothelin-1 levels are increased in scleroderma patients, the use of endothelin receptor antagonists may be justified in digital ischemia refractory to conventional vasodilators since these agents also favorably affect fibroproliferative vascular remodeling.

Macitentan is a novel dual endothelin receptor antagonist that emerged from a tailored drug discovery process. It has a number of potentially key beneficial characteristics, including increased in vivo efficacy compared with existing endothelin receptor antagonists, due to sustained receptor binding and tissue penetration properties. In addition, macitentan has a low propensity for drug-drug interactions.

Skin Tightness

Medical need. Management of skin tightness in scleroderma (Figure 2) has been disappointing. Various immunomodulatory agents have been tried empirically, based on anecdotal reports and small clinical trials. Currently available agents used off label to treat skin tightening include traditional disease-modifying antirheumatic drugs (DMARDs) such as hydroxychloroquine, methotrexate, azathioprine, mycophenolate mofetil, thalidomide, cyclosporine, prednisone and cyclophosphamide. Yet these agents have marginal effects at best and often need to be discontinued due to adverse events or inherent toxicity. No specific agent has been consistently effective or has been approved by regulatory agencies for ameliorating skin tightness in scleroderma patients.

Figure 2. Diffuse swelling and induration of skin in a patient with early diffuse scleroderma.

To help meet this need for effective disease-modifying therapies for skin tightness, our Scleroderma Program is enrolling systemic sclerosis patients in a two-year multicenter study of tocilizumab, a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Study details are outlined in the table.

Scientific rationale. IL-6 has been postulated to play a potentially crucial role in the pathogenesis of scleroderma based on murine models and data from patients with scleroderma. Elevated levels of circulating IL-6 have been reported in patients with scleroderma, particularly those with early disease. IL-6 is overexpressed in endothelial cells and fibroblasts of involved skin in patients with scleroderma, and elevated IL-6 levels are detected in the bronchoalveolar lavage fluid. Dermal fibroblasts from patients with scleroderma constitutively express higher levels of IL-6 compared with those from healthy controls. In addition, serum IL-6 levels correlate positively with skin sclerosis and acute-phase proteins.

The multicenter trial in which we are participating is the first randomized, controlled assessment of the benefit and safety of IL-6R inhibition with tocilizumab in patients with scleroderma.

Interstitial Lung Disease

Medical need. Lung disease is the leading cause of death in patients with systemic sclerosis. Nonspecific interstitial pneumonitis is the predominant form of interstitial lung disease (ILD). Cleveland Clinic’s combined Rheumatology/Pulmonary Clinic evaluates and manages scleroderma patients with ILD and/or pulmonary hypertension. Patients are evaluated by both a rheumatologist and one of two pulmonologists with expertise in scleroderma lung disease. This ensures optimal investigation of complications and development of the most effective management plan.

Management of ILD in scleroderma has been a challenge. A multitude of DMARDs have been tried unsuccessfully. Initial optimism about cyclophosphamide’s success in stabilizing ILD in scleroderma met with disappointment. The marginal beneficial effects on lung function and quality of life in the NIH-sponsored Scleroderma Lung Study were no longer apparent at the end of the second year of follow-up after discontinuation of a one-year trial of daily oral cyclophosphamide.

To help search for newer therapies to tackle this potentially fatal complication, our Scleroderma Program is participating in a phase 2 proof-of-concept study of pomalidomide in patients with diffuse scleroderma with ILD (see table).

Scientific rationale. Pomalidomide is a new immunomodulatory agent and a chemical analog of thalidomide. Experience with thalidomide has demonstrated beneficial effects in treating patients with scleroderma. The rationale for using pomalidomide in scleroderma arises from evidence of its immunomodulatory and anti-fibrotic effects in both in vitro models and in vivo settings that share immunopathologic mechanisms with scleroderma. Prior studies suggest that pomalidomide has the potential to achieve an anti-fibrotic effect in scleroderma patients through an immunomodulatory mechanism involving inhibition of Th2 cytokines and enhanced production of anti-fibrotic Th1 cytokines such as IFN-α, GM-CSF and IL-2. In addition to the Th2-to-Th1 phenotype shift, pomalidomide enhances endothelial progenitor cell differentiation and has direct effects on the cytoskeletal structure of fibroblasts.

The Quest Continues

Modern treatments have transformed scleroderma from a once fatal condition to a chronic illness. While that is immensely rewarding, many challenges remain. We must find safer and more effective therapies for this debilitating disease and its many complications. This is best accomplished by research efforts to identify the disease’s precise pathogenetic pathways ‒ efforts that will maximize our collective chance to manage this illness more effectively.

Dr. Chatterjee directs the Scleroderma Program in the Department of Rheumatic and Immunologic Diseases. He welcomes comments and physician referrals of scleroderma patients for participation in the ongoing clinical trials.