Large Vessel Vasculitis: Recent Advances in Pathophysiology and Targeted Therapies

Area of Science:

• Rheumatology and Immunology
• Vascular Biology
• Genetics and Omics

Background:

• Large vessel vasculitides (LVV), encompassing giant cell arteritis (GCA) and Takayasu arteritis (TAK), involve inflammation of major arteries but differ in onset and pathogenesis.
• Understanding these differences is crucial for developing effective, targeted therapies.

Purpose of the Study:

• To review recent advancements in the understanding of GCA and TAK pathogenesis.
• To discuss emerging targeted therapies informed by these insights.
• To highlight key biomarkers and genetic factors influencing treatment response.

Main Methods:

• Narrative review of recent literature on GCA and TAK.
• Analysis of omics-based signatures, genetic and somatic risk factors.
• Evaluation of current and emerging therapeutic strategies, including biologic agents and small molecules.

Main Results:

• Identified specific molecular signatures (e.g., ULK3, SLAMF7 in GCA; EGR1 in TAK) and risk factors (e.g., clonal hematopoiesis, IL6R variants).
• Common pathways involve T-cells, macrophages, B-cells, IL-6, JAK/STAT, and IL-17.
• GCA characterized by GM-CSF macrophages and PD-1/PD-L1 dysregulation; TAK by CD8+ T-cells and TNF-α signaling.
• Interleukin-6 receptor inhibitors and JAK inhibitors show efficacy in GCA and TAK, with varying results for IL-17 blockade.

Conclusions:

• Biomarker research, including IL-6 receptor and IL-17A gene polymorphisms, is advancing personalized therapeutic strategies for LVV.
• Combination therapy with short-term glucocorticoids and biologics is a growing focus.
• Targeted therapies like IL-6 receptor inhibitors, JAK inhibitors, and GM-CSF blockade offer promising alternatives for GCA and TAK management.