Exploring Novel Treatment for CTD-Associated Pulmonary Hypertension

By Kristin Highland, MD, MS

Pulmonary hypertension (PH) and interstitial lung disease (ILD) are leading causes of morbidity and mortality in rheumatic disease. Both PH 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 PH 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 CTD-associated pulmonary arterial hypertension (CTD-PAH).

Despite available therapies, the prognosis for pulmonary arterial hypertension (PAH) remains poor, especially for patients with CTD. Approved vasodilation therapies generally do not yield significant functional improvements in CTD-PAH patients.

Bardoxolone methyl and its analogs are potent inhibitors of the NF-κB inflammatory pathway. The established pharmacologic effects of bardoxolone, including suppression of inflammation, mitochondrial dysfunction and autoimmune processes, are directly applicable to the treatment of WHO Group I CTD-PAH. Preliminary efficacy data from a phase 2 study in PAH patients showed that bardoxolone methyl improves six-minute walk distance (6MWD) on top of optimal vasodilation background therapies in CTD-PAH patients.

The Catalyst study is a phase 3, multinational, placebo-controlled study of bardoxolone versus placebo for CTD-PAH. The primary endpoint is change from baseline in 6MWD relative to placebo at week 24. The secondary endpoint is time to first clinical improvement consisting of a persistent change in functional class, increase from baseline in 6MWD by at least 10 percent and decrease from baseline in creatinine kinase, as a surrogate biomarker for muscle injury and inflammation, by at least 10 percent.

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.