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Targeted Therapy in Systemic Sclerosis
1Chief Division of Rheumatology, Jewish General Hospital, Montreal, Quebec, Canada; and Professor of Medicine, McGill University, Montreal, Quebec, Canada.
Abstract:
Targeted therapies use an understanding of the pathophysiology of a disease in an individual patient. Although targeted therapy for systemic sclerosis (SSc, scleroderma) has not yet reached the level of patient-specific treatments, recent developments in the understanding of the global pathophysiology of the disease have led to new treatments based on the cells and pathways that have been shown to be involved in the disease pathogenesis. The presence of a B cell signature in skin biopsies has led to the trial of rituximab, an anti-CD20 antibody, in SSc. The well-known properties of transforming growth factor (TGF)-β in promoting collagen synthesis and secretion has led to a small trial of fresolimumab, a human IgG4 monoclonal antibody capable of neutralizing TGF-β. Evidence supporting important roles for interleukin-6 in the pathogenesis of SSc have led to a large trial of tocilizumab in SSc. Soluble guanylate cyclase (sGC) is an enzyme that catalyzes the production of cyclic guanosine monophosphate (cGMP) upon binding of nitric oxide (NO) to the sGC molecule. Processes such as cell growth and proliferation are regulated by cGMP. Evidence that sGC may play a role in SSc has led to a trial of riociguat, a molecule that sensitizes sGC to endogenous NO. Tyrosine kinases (TKs) are involved in a wide variety of physiologic and pathological processes including vascular remodeling and fibrogenesis such as occurs in SSc. This has led to a trial of nintedanib, a next-generation tyrosine-kinase (TK) inhibitor which targets multiple TKs, in SSc.
Insights
New targeted therapies for systemic sclerosis (SSc) are emerging, focusing on key cells and pathways like B cells and transforming growth factor-beta. Clinical trials are investigating drugs such as rituximab and fresolimumab for SSc treatment.
Area of Science:
- Rheumatology and Immunology
- Translational Medicine
Background:
- Systemic sclerosis (SSc), or scleroderma, is a complex autoimmune disease characterized by fibrosis and vascular abnormalities.
- Understanding the underlying pathophysiology of SSc has paved the way for developing targeted therapeutic strategies.
- While patient-specific treatments are still developing, recent insights into disease pathogenesis have guided the selection of novel drug candidates.
Approach:
- Investigating the role of B cells in SSc pathogenesis, leading to trials of rituximab (anti-CD20 antibody).
- Targeting transforming growth factor-beta (TGF-β), a key mediator of collagen synthesis, with fresolimumab.
- Exploring the impact of interleukin-6 (IL-6) in SSc pathogenesis, prompting trials of tocilizumab.
- Examining the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) pathway, with trials of riociguat.
- Assessing the role of tyrosine kinases (TKs) in fibrogenesis and vascular remodeling, leading to trials of nintedanib.
Key Points:
- Rituximab targets B cells implicated in SSc.
- Fresolimumab neutralizes TGF-β to inhibit collagen production.
- Tocilizumab targets IL-6, a cytokine involved in SSc pathogenesis.
- Riociguat modulates the sGC pathway.
- Nintedanib inhibits multiple tyrosine kinases involved in SSc processes.
Conclusions:
- Several targeted therapies are under investigation for systemic sclerosis, addressing distinct cellular and molecular pathways.
- These trials represent a shift towards mechanism-based treatments for SSc, moving beyond generalized immunosuppression.
- Further research and clinical trials are crucial to establish the efficacy and safety of these novel SSc therapies.
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