Rationale for phosphodiesterase-4 inhibition as a treatment strategy for interstitial lung diseases associated with rheumatic diseases.

Interstitial lung disease (ILD) associated with rheumatoid arthritis or with connective tissue diseases such as systemic sclerosis can be collectively named systemic autoimmune rheumatic disease-associated ILDs (SARD-ILDs) or rheumatic musculoskeletal disorder-associated ILDs. SARD-ILDs result in substantial morbidity and mortality, and there is a high medical need for effective therapies that target both fibrotic and inflammatory pathways in SARD-ILD. Phosphodiesterase 4 (PDE4) hydrolyses cyclic AMP, which regulates multiple pathways involved in inflammatory processes.

Treatment Response Biomarkers for Systemic Sclerosis-Associated Interstitial Lung Disease.

Objective: This studied investigated whether changes in circulating biomarkers predict progressive pulmonary fibrosis (PFF) in patients with systemic sclerosis-associated interstitial lung disease (ILD) receiving treatment.

Method: Participants of Scleroderma Lung Study (SLS) II, which compared mycophenolate (MMF) versus cyclophosphamide (CYC) for SSc-ILD, who had blood samples at baseline and 12-months were included. Levels for C-reactive protein (CRP), interleukin (IL)-6, chemokine ligand 4 (CXCL4), chemokine ligand 18 (CCL18) and Krebs von den Lungen 6 (KL-6) were measured, and a logistic regression model evaluated relationships between changes in these biomarkers and the development of PPF by 24 months.

A Phase II study of avenciguat, a novel soluble guanylate cyclase activator, in patients with systemic sclerosis: Study design and rationale of the VITALISScE™ study.

Introduction: Systemic sclerosis is a rare autoimmune connective tissue disease characterised by (1) microvasculopathy; (2) immune dysregulation; and (3) progressive fibrosis of the skin and internal organs. Soluble guanylate cyclase plays an important role in maintaining vascular and immunological homeostasis and preventing organ fibrosis. Pharmacological modulation of soluble guanylate cyclase with soluble guanylate cyclase stimulators has shown anti-inflammatory and antifibrotic effects in animal models of systemic sclerosis, with a trend towards clinical efficacy in a Phase II study (RISE-SSc).