If Remission Is Our Goal, Rheumatology Must Embrace the Importance of Studying New Mechanisms

Alyssa Johnsen, MD, PhD, shares her insight on the importance of understanding key pathways that drive immune-mediated diseases, which can help rheumatologists develop more potent and specific therapies for patients with rheumatic disease.

Scientific breakthroughs in immunology have fueled a renaissance in the treatment of diseases like rheumatoid arthritis (RA) and psoriatic arthritis (PsA). The practice of rheumatology has been transformed from providing symptomatic therapy as patients’ disease progressed unabated, to modifying the underlying pathophysiology to provide not only symptom relief but also the potential to prevent disability for patients.

Over the course of my career in rheumatology, I have witnessed and been privileged to contribute to the growing understanding of immune system dysfunction in rheumatic diseases, and more broadly in immune-mediated diseases. For example, development of therapies that inhibit the pro-inflammatory cytokine tumor necrosis factor (TNF) alpha revolutionized the way we treat rheumatic diseases like RA and PsA. Despite these advances, however, most patients do not achieve lasting remission. Additionally, unmet needs and limited treatment options in other rheumatic diseases, such as systemic lupus erythematosus (SLE), lupus, Sjogren’s syndrome, and scleroderma, also persist.

PsA has been a particular challenge because it is a heterogeneous disease characterized by inflammation not just in the joints, but also in the skin (psoriasis), as well as soft tissues (enthesitis and dactylitis).1 An ideal treatment for PsA should provide lasting efficacy for multiple disease domains with a tolerable safety profile. Because PsA is particularly variable from patient to patient, and as of yet we cannot predict the efficacy of a given therapy for a specific patient, it is beneficial for the physician to have therapies targeting multiple different mechanisms. If a patient is not in remission on his or her current therapy, the physician needs alternative therapies to treat the patient.

Treating Rheumatic Disease in New Ways: The Pathway Approach

Recent advances in technology have provided new insights into how the immune system works in health and disease.For example, we can examine the behavior of a single cell and now have the computational power to combine the information from thousands of cells to enhance our understanding of biology. In addition, advances in genetics have permitted identification of more disease-associated genes, tantalizing clues to disease pathogenesis. We are harnessing these new methods to identify additional pathways that are central to driving disease. Every new pathway discovered unlocks novel targets for the development of future therapies for patients with immune-mediated diseases.

As we start to focus on key pathways in disease, it becomes clear that many pathways are shared across different diseases. In the past, this was determined empirically. For example, we learned that certain immune-mediated diseases, such as RA, PsA, ankylosing spondylitis and inflammatory bowel disease could be treated by inhibiting TNF alpha, but others, such as systemic lupus erythematosus (SLE), could not.2 Our advances in studying the immune system should allow us to predict with greater certainty the relevance of particular pathways in immune-mediated diseases.

Focusing on key pathways allows us to move away from defining diseases by organ and anatomical region. Just as the paradigm shifted from targeting specific tumors based on their tissue of origin to targeting biological hallmarks of cancer growth and persistence, we are zeroing in on the underlying mechanisms driving immune-mediated diseases, targeting the pathways implicated in diseases like psoriasis and PsA. By marrying unmet need to the mechanisms, we can expand the reach of drugs targeting relevant pathways to all patients who may benefit. In essence, this is a shift from the “one drug, one disease” mindset of the past to a “one drug, many diseases” approach.

As we continue to build upon our understanding of the molecular mechanisms of immune-mediated diseases, we expand our ability to develop smarter, more targeted therapeutic strategies addressing chronic inflammation across multiple disorders.

Looking to the Future

We are at another pivotal moment in immunology. By understanding key pathways that drive immune-mediated diseases, we can develop more potent and specific therapies. This will help us not only increase the number of patients achieving remission in diseases like RA and PsA but will also help develop better therapies for patients who currently have limited therapeutic options, including patients with SLE, Sjögren's syndrome, and scleroderma.

Today, patients living with immune-mediated disease show great fortitude as they see improvements in treatment options but still wait patiently for science to progress even further. Their expectation should be a future in which these patients can live disease- and symptom-free and enjoy a normal quality of life, without pain and disability. It is this aspiration and resilience that motivates and inspires all of us in our relentless pursuit of new and better medicines. We are a large community of people thinking about the same problems from different perspectives, mobilizing multiple facets of expertise in medicine, biology, genetics, and technology and driven by a mission to restore the balance of the immune system to create a lifetime of vibrant health for the millions of people living with immune disease. These are indeed exciting times.

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About Alyssa Johnsen

Alyssa Johnsen, MD, PhD, is Vice President and Rheumatology Disease Area Leader for the Immunology Therapeutic Area at Janssen Research & Development, LLC. In this role, Alyssa is responsible for driving scientific leadership in rheumatology and related immune-mediated conditions, overseeing innovative compounds across multiple phases of development.

Alyssa received her bachelor’s degree in chemistry at Duke University and her PhD in immunology and MD at Case Western Reserve University. She completed residency training in internal medicine at the Massachusetts General Hospital and a fellowship in Rheumatology at the Brigham and Women’s Hospital.

Connect with Alyssa on LinkedIn here.

References:

1. McInnes IB. Psoriatic arthritis: embracing pathogenetic and clinical heterogeneity?. Clin Exp Rheumatol. 2016;34(4 Suppl 98):9-11.

2. Li P, Zheng Y, Chen X. Drugs for Autoimmune Inflammatory Diseases: From Small Molecule Compounds to Anti-TNF Biologics. Front Pharmacol. 2017;8:460. Published 2017 Jul 12. doi:10.3389/fphar.2017.00460