Underlying Pathways: The Key to Progress in Rheumatology?

Alyssa Johnsen, MD PhD Immune-mediated rheumatic disorders are complex chronic diseases that arise from multiple genetic and environmental factors.1 Understanding of the immune system has progressed dramatically during the last two decades, resulting in significantly improved advanced therapeutic options for many rheumatic disorders, such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA).2 However, the complexity of immune-mediated diseases continues to limit physicians’ ability to successfully treat the entire spectrum of rheumatic conditions. Effective therapies remain limited for diseases like systemic lupus erythematosus (SLE), Sjögren’s syndrome (SjS), and systemic sclerosis (SSc). Disease Heterogeneity Complicates Diagnosis and Treatment Complexity in rheumatic disease diagnosis and treatment arises from the variability of disease etiologies and heterogeneity of presentation within each disease, confounding the ability to predict the degree of efficacy of a therapy for an individual patient.1,3 For example, immune-mediated rheumatic disease etiology has been attributed to genetic susceptibility, epigenetic modification, and environmental factors, leading to a dysregulated immune system and a break in immune tolerance.4 Uncovering the mechanistic basis for these diseases at the cellular level and examining the functions and patterns of the immune cells and pathways involved will help scientists develop more effective and precisely-targeted treatments. While there is heterogeneity within each disease, there are also shared symptoms and pathophysiologic drivers across different rheumatic diseases. Patients with certain immune-mediated rheumatic diseases are more likely to have family members with the same or different immune-mediated diseases, suggesting overlapping etiology, even when they show diverse clinical phenotypes.3 If we can better understand the seminal immune pathways driving multiple rheumatic diseases, it could lead to a future in which patients are treated based on the state of their immune system, and not the name of their disease. To tease out the contributions and interactions of multiple genetic and nongenetic risk factors in immune-mediated rheumatic diseases and to identify driving immune pathways, researchers often rely on genome-wide association studies (GWAS). GWAS have revealed shared genetic architectures among immune-mediated rheumatic diseases, elucidated common disease mechanisms, and implicated overlapping immune pathways in disease onset and outcome.3,5 Finding New Pathways to Treatment Recent innovations in single-cell technologies and integrative multi-omics analyses enabled researchers to understand common immune-mediated disease mechanisms and characterize similarities between diseases at the molecular level.3,6 Further, researchers used high-volume data analysis on molecular diagnostic data to investigate how disease-associated alleles contribute to the onset, probability, and severity of rheumatic diseases.5,7 These multi-level insights revealed markers, cells, and pathways that overlap between rheumatic disorders, offering the potential to develop therapeutics with efficacy against multiple rheumatic and other autoimmune diseases. One example of the power of modern analysis techniques is the development of new therapeutic options for PsA, a chronic, multifactorial, immune-mediated disease that can lead to a substantial decrease in quality of life. The severity of skin and joint symptoms in PsA patients varies and may involve painful skin plaques and inflammation of the joints and tendon and ligament attachment points. Numerous genetic risk loci, cell types, and pathways drive the pathogenesis of PsA. GWAS have identified multiple susceptibility loci related to the IL-17/IL-23 axis—a pro-inflammatory pathway driven by Th-17 T cells.8 IL-23 promotes the survival of Th-17 T cells, which produce pro-inflammatory cytokines including IL-17 that are crucial for Th-17-mediated PsA. Thanks to these findings, inhibitors of this pathway are now approved for use in adult patients with PsA. IL-23 is emerging as a seminal pathway for the treatment of this disease.8,9 Deep genotyping and cellular phenotyping of PsA highlighted pathways that became credible drug targets, revolutionizing how clinicians treat this complex disease. Researchers are employing similar methods to uncover the seminal pathways driving even more heterogeneous immune-mediated rheumatic diseases, such as SLE, SjS and SSc. These disorders have few, if any, therapeutic options. Identifying immune pathways that have pivotal roles in these diseases could lead to breakthroughs in how they are treated and may accelerate development of therapies that help patients living with difficult-to-treat immune-mediated rheumatic diseases. By studying an immune pathway that is driving a rheumatic disease, we can generate distinct pathway insights that enable us to unlock the pathway's potential to treat patients. How do we find the seminal pathway for diseases that continue to be difficult to treat, like SLE, SjS and SSc? We will need to marry genetic and molecular techniques with state-of-the-art data science approaches. The Role of Data Science in Discovery and Development Data science aids drug discovery and development by improving target validation, patient selection, and predictive molecular, imaging, and digital endpoints. To advance knowledge of molecular drivers of pathogenesis and identify predictive biomarkers, scientists apply innovative data science approaches to large genetic data sets from multiple single-cell technologies.6 Mass-cytometry also enables researchers to simultaneously detect multiple phenotypic markers at single-cell resolution.6 Next-generation sequencing (NGS) technologies facilitate studying the interaction between environmental factors and genetics in rheumatic disease pathogenesis, opening new avenues for precision medicine in rheumatology.10 NGS and related -omics technologies have helped classify different clinical cohorts based on a patients’ epigenomic signatures, transcriptomic profiles, and gene expression patterns. This combination of detailed immunophenotyping and sophisticated data analyses could maximize outcomes for patients by linking therapies to molecular contributors to rheumatic diseases.10,11 Pioneering New Pathways in Rheumatology With a better understanding of immune pathways and the application of new technologies, researchers can shift to a new paradigm focused on the mechanisms driving immune-mediated diseases instead of the organs and anatomical regions involved. This shift from a “one drug, one disease” mentality to “one drug, many diseases” is a hallmark of Janssen’s approach to developing medicines with the goal of transforming patient lives. Today, too many people living with immune-mediated rheumatic diseases continue to wait for science to deliver a disease- and symptom-free life. My team and I at Janssen are committed to understanding the key pathways driving immune-mediated diseases. With this data-centric, holistic pathway-based approach, we are poised to develop more powerful and targeted therapies that can help more patients achieve remission. Alyssa Johnsen, M.D., Ph.D., is Vice President, Rheumatology Disease Area Leader at The Janssen Pharmaceutical Companies of Johnson and Johnson References R. Burmester et al., “Managing rheumatic and musculoskeletal diseases — past, present, and future,” Nat Rev Rheumatol, 13:443-448, 2017. D. Aggarwal, S. Abraham, “Rheumatoid arthritis treatments: a historical perspective,” JSM Arthritis, 1:1011-1014, 2016. F. Conti et al., “Biological therapies in rheumatic diseases,” Clin Ter, 164:413-428, 2013. J. Cho, M. Feldman, “Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies,” Nat Med, 21:730-738, 2015. S. Eyre et al., “The genetics revolution in rheumatology: large scale genomic arrays and genetic mapping,” Nat Rev Rheumatol, 13:421- 432, 2017. P. Cheung et al., “Single-cell technologies — studying rheumatic diseases one cell at a time,” Nat Rev Rheumatol, 15:340-354, 2019. M. Luan et al., “The shared and specific mechanism of four autoimmune diseases,” Oncotarget, 8:108355-108374, 2017. M. Vecellio et al., “The IL-17/IL-23 axis and its genetic contribution to psoriatic arthritis,” Front Immunol, 11:596086, 2020. M. Arnone et al., “Guselkumab: widened action in psoriatic disease,” Clinics (Sao Paulo), 76, 2021. L. Donlin et al., “Insights into rheumatic diseases from next-generation sequencing,” Nat Rev Rheumatol, 15:327-339, 2019. H. Al-Mossawi et al., “Precision medicine in psoriatic arthritis: how should we select targeted therapies?” The Lancet Rheumatology, 1:66-73, 2019.

Underlying Pathways: The Key to Progress in Rheumatology?

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