Link between Metabolic Stress and Fatigue in Rheumatoid Arthritis. Role of Janus Kinase (JAK) Inhibitors

Overview

Project Summary

Rheumatoid Arthritis (RA) is a chronic autoimmune disease affecting approximately 0.46% of adults worldwide, characterized by joint inflammation and systemic involvement. It causes pain, stiffness, and progressive disability, significantly reducing quality of life and imposing a high economic burden, with annual costs per patient estimated between US$2,408 and US$83,845. Despite treatment advances, fatigue remains a highly prevalent and debilitating symptom of RA, affecting up to 75% of patients. It impacts physical, cognitive, and emotional well-being and appears to have a multifactorial origin, involving disease-related factors, personal characteristics, and cognitive-behavioral influences. Even with immunosuppressive therapies, fatigue remains poorly managed, with many RA patients in clinical remission continuing to experience it, which suggests the involvement of non-inflammatory mechanisms. Fatigue is also a key symptom of Fibromyalgia (FM), a condition characterized by nociplastic pain. FM serves as an archetypal model for non-inflammatory pain conditions, further supporting that fatigue in RA may involve mechanisms beyond inflammation. However, its underlying pathophysiology remains poorly understood.

Emerging research identifies mitochondrial dysfunction as a contributor to rheumatic diseases like RA. Mitochondria regulate energy production, oxidative stress, immune signaling, and apoptosis- processes implicated in chronic inflammation and fatigue. Studies in FM show morpho-functional mitochondrial alterations, leading to energy deficits, muscle fatigue, and increased pain sensitivity, supporting the role of mitochondrial dysfunction in fatigue. However, the specific metabolic and mitochondrial changes underlying RA-related fatigue remain largely unexplored.

Janus Kinase inhibitors (JAKi) modulate immune responses via the JAK-STAT pathway and may also influence metabolic and mitochondrial pathways. These targeted synthetic drugs approved for RA treatment, significantly reduce fatigue, outperforming conventional therapies. However, the precise mechanisms behind the fatigue-reducing effects of JAKi remain unclear, but their understanding could open new therapeutic avenues for managing fatigue in RA.

This project aims to bridge this knowledge gap by investigating the metabolic and mitochondrial signatures of RA-related fatigue and exploring JAKi’s role in modulating these pathways. Specifically, we will conduct a cross-sectional study involving a well-characterized cohort of RA patients stratified by different disease activity and fatigue levels, FM patients, and healthy controls and will: 1) Identify metabolic and mitochondrial fingerprints in circulating immune cells; 2) Characterize metabolic profiles of immune cell subpopulations, linking mitochondrial dysfunction to pro-inflammatory reprogramming and distinguishing systemic vs. synovial immune cell metabolism; 3) Correlate metabolic and mitochondrial impairments with disease activity, remission status, and fatigue severity; 4) Assess the impact of JAKi on metabolic stress in RA immune cells and their relationship with fatigue improvement; 5) Investigate how JAKi modulate immune metabolism and mitochondrial-dependent inflammatory pathways, particularly NLRP3 inflammasome and cGAS-STING signaling. By addressing these objectives, this project will enhance understanding of RA-related fatigue and inform new therapeutic strategies targeting metabolic and mitochondrial dysfunction in autoimmune diseases. Unlike previous studies that examined inflammation, metabolism, or fatigue separately, this research integrates all three for a more comprehensive analysis. It is also among the first to explore JAKi’s effects on immune metabolism and mitochondrial function, offering insights into their therapeutic potential beyond inflammation control. Cutting-edge methodologies will include metabolic and mitochondrial profiling via Mitoplate microarrays, Seahorse technology, and SCENITH assays, as well as immune cell phenotyping using flow cytometry to assess mitochondrial function and metabolic dependencies. Molecular analysis of NLRP3 inflammasome and cGAS-STING inflammatory signaling pathways will explore their role in RA fatigue. Finally, computational modeling and machine learning will identify metabolic signatures linked to fatigue and treatment responses.

Led by a multidisciplinary team of rheumatologists, immunologists, and experts in metabolic dysfunction, this study builds on extensive experience in mitochondrial research, immune metabolism, and inflammatory signaling. It will be conducted by a renowned Research Unit specializing in Biomedicine and Biotechnology and a leading tertiary care center with access to a well-characterized cohort of over 1,400 RA patients. By addressing a critical unmet need in RA treatment, this project has the potential to transform the understanding and management of fatigue, ultimately improving patient outcomes and quality of life.

Main Goals

1. Identify metabolic and mitochondrial fingerprints in circulating immune cells of RA patients, comparing them with FM subjects (positive
control) and healthy donors (negative control).
2. Characterize metabolic profiles of immune cell subpopulations, linking mitochondrial dysfunction to pro-inflammatory reprogramming and
comparing systemic vs. synovial immune cell metabolism.
3. Correlate metabolic profiles with disease activity, remission, and fatigue severity.
4. Evaluate the effects of JAKi on metabolic stress in circulating immune cells and their link with fatigue and disease activity.
5. Investigate the mechanisms by which JAKi modulate immune metabolism and mitochondrial-dependent inflammatory signaling.

Project Details