Advancing the Research on Selective TNF Inhibition in Psoriatic Disease

By M. Elaine Husni, MD, MPH

Collaborators: Unni Chandrasekaran, PhD, Raminderjit Kaur, PhD, and Anthony Fernandez, MD, PhD

The latest clinical practice guidelines issued jointly by the American College of Rheumatology and the National Psoriasis Foundation recommend TNF-α inhibitors or soluble TNF-α receptors as first-line therapy for active psoriatic disease. Five anti-TNF medications approved by the FDA to treat psoriatic disease — etanercept, adalimumab, golimumab, infliximab and certolizumab pegol — act by binding to circulating TNF-α and blocking the association between TNF-α and its two immune cell surface receptors, TNFR1 and TNFR2. However, various studies to date have raised questions about whether long-term global TNF-α inhibition may be associated with the development of potential serious adverse effects, including serious infections and malignancies, in which the action of TNFR1 has a protective role.

The Husni lab

Our lab at Cleveland Clinic has recognized this unmet need for safer therapies and is currently focused on studying the mechanisms of selective inhibition of TNF-α in psoriatic disease. Our team postulates that global TNF-α inhibition may not be necessary to effectively treat psoriasis, and that selective inhibition of one of the receptors — TNFR2 — could potentially reduce the signs and symptoms of psoriatic disease. while preserving the protective effects of TNF-α and its interaction with TNFR1. In one of our recent studies, we identified arginine methyltransferase 5 (PRMT5), an enzyme downstream of TNF-α signaling, as critical for TNF-α-mediated signaling pathways, which makes it a suitable target for treating TNF-α-dependent inflammatory diseases.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health awarded our lab a $1.8 million R01 grant for five years to investigate the mechanisms of TNFR2 activation and its impact on psoriatic pathogenesis. We plan to continue our translational work in both murine models and our patient biorepository. Selective targeting of TNFR2 is a novel approach and can be applied to improving the safety and precision of treating a broad range of immune-mediated diseases.

PRMT5 inhibition, TNFR1 and TNFR2 signaling

In continuation of this research, our team recently presented data at the GRAPPA 2021 annual meeting and symposium. We examined how inhibition of PRMT5 activity will influence the expression of psoriasis-related genes and aimed to further clarify the role of PRMT5 in TNFR1 and TNFR2 signaling. Gene expression studies conducted in human endothelial cells found that PRMT5 indeed has a critical role in TNF-α induction of gene expression at varying levels. Namely, PRMT5 depletion causes a significant percent reduction in the expression of IL-8 (67.3%), IL-6 (73.7%), CXCL11 (88.23%), E-selectin (66.3%) and VCAM-1 (75.2%), all of which are implicated in psoriatic disease.

Further testing revealed that PRMT5 depletion significantly inhibited TNFR2-mediated, but not TNFR1-mediated NFκB activation. This finding is particularly interesting as we recently found that targeting TNFR2, but not TNFR1, alleviates psoriasis-like disease in a mouse model. In future studies, we will use this information to help personalize therapy with PRMT5 inhibition and compare the effectiveness and side effect profile of this strategy to current therapies

Taken together, these findings support the potential role of TNFR2/PRMT5 axis in the pathogenesis of psoriatic disease and point to the possibility of developing new targeted therapies with safer side effect profiles. Our team is committed to advancing this research further with the hopes of providing safer therapies for patients suffering from psoriatic diseases.

Dr. Husni is Vice Chair of the Department of Rheumatic and Immunologic Disease and Director of the Arthritis and Musculoskeletal Center.