Exploring Novel Treatment for Scleroderma-Associated Interstitial Lung Disease

By Kristin Highland, MD, MS

Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are leading causes of morbidity and mortality in rheumatic disease. Both PAH and ILD may occur in patients with well-defined rheumatologic disorders, but they may also precede the extrapulmonary manifestations for years, or may have a forme fruste presentation limited to the lungs as seen in systemic sclerosis sine scleroderma.

There is also a heterogeneous group of patients with PAH and/or ILD that have a clinical flavor of an underlying autoimmune disease. Recently the terminology “interstitial pneumonia with autoimmune features” (IPAF) has been proposed for patients with ILD and autoimmune features who do not meet American College of Rheumatology criteria for a defined connective tissue disease (CTD).

Early identification and treatment of these pulmonary complications is essential in order to improve outcomes in rheumatic diseases.

Cleveland Clinic’s Rheumatic Lung Disease Program offers a comprehensive multidisciplinary approach to the care of these complex patients that includes close collaboration with physicians from our rheumatology department as well as from the ILD, pulmonary hypertension and transplantation programs within the Respiratory Institute.

The pathogenesis of rheumatic disease is complex and is characterized by systemic, immunological, vascular and fibrotic abnormalities. At Cleveland Clinic, we are involved in multiple research studies that are shifting treatment paradigms towards the targeting of these multiple pathways through repurposing drugs approved for other indications and the exploration of novel therapies. One example is our work on scleroderma-associated ILD.

Systemic sclerosis (SSc) is a debilitating disease of unknown etiology. Patients suffer from fibrosis of multiple organs, leading to chronic morbidity and premature death. Second only to skin involvement, lung involvement is common and portends a poor prognosis, with a median survival of five to eight years in SSc-ILD.

Historically, cyclophosphamide was considered the treatment of choice for SSc-ILD, based on a modest effect on forced vital capacity (FVC), but its use is limited in regard to treatment duration due to its toxicity. Mycophenolate mofetil (MMF) is widely used for SSc-ILD based on results of the Scleroderma Lung Study II, which showed that MMF had a similarly modest effect on FVC, but better tolerability than cyclophosphamide.

Nintedanib is an antifibrotic agent that is approved for the treatment of idiopathic pulmonary fibrosis based on its ability to slow the rate of decline in FVC. In animal models of SSc, nintedanib effectively attenuated skin and lung fibrosis by reducing extracellular matrix deposition and myofibroblast accumulation. Nintedanib also attenuated pulmonary vascular remodeling by reducing the number of vascular smooth muscle cells and occluded pulmonary vessels. Lastly, nintedanib has been demonstrated to inhibit T-cell and B-cell activity. These pleiotropic effects of nintedanib on the fibrotic, vascular and inflammatory pathways support its further investigation in rheumatic lung disease.

The SENSCIS® study, which I colead with Dr. Oliver Distler of the University Hospital in Zurich, Switzerland, is a multinational, randomized, placebo-controlled trial of nintedanib versus placebo in 580 subjects with SSc-ILD, making it the largest trial in scleroderma to date. Patients may be on baseline MMF or methotrexate. The primary outcome measure of the trial is the annual rate of decline in FVC over 52 weeks, while secondary measures are skin fibrosis score and quality of life as measured by the Saint George’s Respiratory Questionnaire.

This study is one of three major multicenter trials in which Cleveland Clinic’s Rheumatic Lung Disease Program is participating. It is hoped that this trial will ultimately expand the therapeutic approach to treating the devastating pulmonary complications of rheumatic disease.

To refer a patient, call 855.REFER.123.

Dr. Highland directs the Rheumatic Lung Disease Program in the Respiratory Institute at Cleveland Clinic.