expert roundtables

Pathobiology-Guided Therapy in Rheumatoid Arthritis

by Leonard H. Calabrese, DO, Jeffrey R. Curtis, MD, MS, MPH, Eric M. Ruderman, MD

Overview

Pathobiology-guided therapy has long been a goal in the treatment of patients with rheumatoid arthritis (RA). Despite limited success in the past, there is optimism today stemming from research on the cellular constituents of the synovium and related molecular and genetic profiles.

Q: What are the recent developments in the pursuit of a more personalized, pathophysiologically targeted approach to RA treatment?

Jeffrey R. Curtis, MD, MS, MPH

Marguerite Jones Harbert-Gene V. Ball, MD Professor of Medicine
Co-Director, UAB Pharmacoepidemiology and Pharmacoeconomics Research (PEER) Unit
Division of Clinical Immunology and Rheumatology
University of Alabama at Birmingham
Birmingham, AL

“As a first step, it may be more important to identify those patients who will not respond to a therapy. Since anti-TNF agents are usually the default biologics that are used first, it would be especially helpful to know whether a patient is unlikely to respond to these drugs."

Jeffrey R. Curtis, MD, MS, MPH

A lot of time and money have been spent on using biomarkers or genetics to guide targeted therapy, but, so far, it has been a dark hole. However, we know what does not work. Genetic genotyping is not going to be the salvation in terms of predicting treatment response to a specific drug in RA. While there are some treatment-response associations with genetic markers, I do not think that genetics will be able to identify a specific targeted therapy for a given patient with RA. Some companies are trying to use gene expression profiling to identify patients who will respond to treatment. As a first step, however, it may be more important to identify those who will not  respond to a therapy. For example, since anti–tumor necrosis factor (anti-TNF) agents are usually the default biologics that are used first, it would be especially helpful to know whether a patient is unlikely to respond to these drugs. The next step would be to identify those who will respond to an agent with a different mechanism of action (MOA). You want to make sure that you are not simply picking out refractory patients who will not respond to anything. You need empiric, if not causal, evidence that they are going to do better on something with a different MOA. Some of the early work that I have seen suggests that you will likely need 90% or greater accuracy for a test to be acceptable to rheumatologists. We have seen many potential single predictors of response, but we need validation in a separate cohort. We must show not only that a patient will not respond to a particular agent, but also that they will respond better to a different type of agent.

Eric M. Ruderman, MD

Professor of Medicine
Associate Chief for Clinical Affairs
Division of Rheumatology
Northwestern University Feinberg School of Medicine
Chicago, IL

“Using synovial biopsies to identify the pathobiology that is occurring locally is a promising approach. This is analogous to using tumor biopsies to identify characteristics of malignancies that drive precision treatment in oncology.”

Eric M. Ruderman, MD

We have been looking at serum biomarkers ever since we began using anti-TNF agents, but nothing has really panned out. We still have not identified the population of patients that is not going to have the type of response we are looking for. Using synovial biopsies to identify the pathobiology that is occurring locally is a promising approach. This is analogous to using tumor biopsies to identify characteristics of malignancies that drive precision treatment in oncology. Perhaps we can learn more from the synovial tissue than we can from the blood, and perhaps this will tell us more about the response to treatment, since the synovial cells are so central in that respect. Such analyses would go beyond simply examining the histology that identifies the inflammatory aspect of the disease. The next step would be to further analyze the macrophages, T cells, fibroblasts, and subtypes of cells present in the synovium to see distinct cellular profiles that can give us clues to guide our treatment approaches. This may also allow us to predict who will respond to a particular treatment paradigm. Although this technology is in the early stages, it holds a lot of promise. Centers in the United States are performing ultrasound-guided synovial biopsies more and more. This is a relatively noninvasive procedure that ensures that you get true synovial tissue. We then have laboratory techniques of single-cell sequencing and metabolomics that can help us to learn more from that tissue. I think that this is the hope for truly targeted therapy at some point in the future.

Leonard H. Calabrese, DO

Professor of Medicine
RJ Fasenmyer Chair, Center for Clinical Immunology
Vice Chair, Department of Rheumatic and Immunologic Diseases
Cleveland Clinic Foundation
Cleveland, OH

“The role of pivotal cytokines such as IL-6 in domains such as fatigue, pain, mood, and sleep is provocative, and whether this can be used to predict outcomes is still a work in progress.”

Leonard H. Calabrese, DO

This is an interesting area, but how close we are to achieving the goal of pathophysiologically targeted therapy in RA is a matter of debate. I am increasingly interested in using molecular markers to assess disease control so that I can identify the patients who have had an excellent response to therapy. I would investigate further by using quality-of-life measures to determine where social behavioral interventions are needed. The role of pivotal cytokines such as interleukin 6 (IL-6) in domains such as fatigue, pain, mood, and sleep is provocative, and whether this can be used to predict outcomes is still a work in progress. There are some preliminary data suggesting that targeting IL-6 could be superior to anti-TNF therapy in some of these domains, but we need larger collaborative studies to confirm this. There are also preliminary data indicating that baseline IL-6 levels may predict response to anti–IL-6 agents, but that also needs validation. Although there are advances in the use of biomarkers, we need high throughput, noninvasive tools to make this work in clinical practice.

References

Choy EHS, Calabrese LH. Neuroendocrine and neurophysiological effects of interleukin 6 in rheumatoid arthritis. Rheumatology (Oxford). 2018;57(11):1885-1895.

Humby F, Mahto A, Ahmed M, et al. The relationship between synovial pathobiology and magnetic resonance imaging abnormalities in rheumatoid arthritis: a systematic review. J Rheumatol. 2017;44(9):1311-1324.

Kondo Y, Suzuki K, Inoue Y, et al. Significant association between joint ultrasonographic parameters and synovial inflammatory factors in rheumatoid arthritis. Arthritis Res Ther. 2019;21(1):14.

Mandelin AM II, Homan PJ, Shaffer AM, et al. Transcriptional profiling of synovial macrophages using minimally invasive ultrasound-guided synovial biopsies in rheumatoid arthritis. Arthritis Rheumatol. 2018;70(6):841-854.

Nielsen MA, Deleuran B, Kragstrup TW. In vitro proof-of-concept of pathobiology-guided therapy in immune mediated inflammatory arthritis. Abstract presented at: 2018 American College of Rheumatology/Association of Rheumatology Health Professionals Annual Meeting; October 19-24, 2018; Chicago, IL. Abstract 2048.

Ramírez J, Celis R, Usategui A, et al. Immunopathologic characterization of ultrasound-defined synovitis in rheumatoid arthritis patients in clinical remission. Arthritis Res Ther. 2016;18:74.

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