expert roundtables

Predicting Treatment Response in Patients With Inadequate Responses to Methotrexate

by Leonard H. Calabrese, DO; Jeffrey R. Curtis, MD, MS, MPH; and Jonathan Kay, MD

Overview

Risk factors for patients with rheumatoid arthritis (RA) who have an inadequate response (IR) to initial methotrexate (MTX) therapy have been identified, but these factors are also indicative of more active disease. Such patients should generally be treated more aggressively.

Q:

Which baseline factors most strongly predict an IR to MTX, and what does the MTX-IR status portend for selection of the next/additional therapy?

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

“We would love to predict whether a patient is more likely to do better on one drug vs another. Currently, however, the factors that predict MTX-IR merely predict the need for more aggressive treatment, and, likely, the need for combination therapy.” 

Jeffrey R. Curtis, MD, MS, MPH

Some of the risk factors or independent predictors of nonresponse to MTX include higher disease activity, elevated inflammatory markers (eg, C-reactive protein), and seropositivity for rheumatoid factor. These are all basically predictors for not doing well or for having more active disease. It is important to note that they are also predictors for doing poorly on almost any drug, if response is defined as getting into low disease activity or remission. 

There are new biomarkers that are being evaluated (eg, baseline global leukocyte DNA methylation, interleukin 6), but any new biomarker must be validated and confirmed in separate cohorts to ensure that it holds up as a viable method for predicting response. The predictive value of a new risk factor is also important in that it must add incremental power to that of other risk factors or provide additional independent information beyond what is already seen with the other risk factors. Ultimately, we would love to predict whether a patient is more likely to do better on one drug vs another. Currently, however, the factors that predict MTX-IR merely predict the need for more aggressive treatment, and, likely, the need for combination therapy. 

The take-home message is that, although predictors of an incomplete response or an IR to MTX as monotherapy are known, this should not lead us to stop using MTX completely; rather, it means that we should not use MTX by itself and that, if possible, MTX should be used in combination with a biologic or targeted therapy, or perhaps even in triple therapy if the former alternatives are not an option. It also means that combination therapy should be started as quickly as possible because these patients are not likely to do well on MTX alone without something else given in conjunction. And so, rather than waiting the 3 to 6 months to add the second agent like we normally might, one would be inclined to start the patient on MTX and then add the biologic or another agent in a more timely manner.

Leonard H. Calabrese, DO

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

“I think that most of our decisions regarding treatment subsequent to MTX are based on comorbidities and patient preferences.”

Leonard H. Calabrese, DO

MTX is still the initial treatment of choice for patients with RA, and here we are considering the group of patients who have or will have an IR to MTX despite adequate dosing, absorption, etc. While there has been some discussion with regard to the time frame for using MTX alone as initial therapy and whether the use of MTX monotherapy affects response to treatment, I do not believe that there is any evidence that you lose ground in the long-term control of the RA when MTX is used alone initially.

I agree with the statements of Dr Curtis with respect to the limitations of biomarker predictors to help select subsequent therapy. We just do not have a satisfying answer to that question. We have hints of what we should do in patients who have continued disease activity after initiating MTX, but we are still just searching and using our clinical judgment when we approach these treatment decisions. I think that most of our decisions regarding treatment subsequent to MTX are based on comorbidities and patient preferences. Regarding cardiovascular comorbidity, we know that cardiovascular risk in patients with RA is higher than in the general population. Predicting cardiovascular risk in RA is a complex and fascinating area, and some of the recent work by Dr Curtis and others using the multi-biomarker disease activity (MBDA) test could be a real game changer in terms of how we follow these patients.

Jonathan Kay, MD

Professor of Medicine and Population and Quantitative Health Sciences
Timothy S. and Elaine L. Peterson Chair in Rheumatology
Director of Clinical Research, Rheumatology
University of Massachusetts Medical School
Worcester, MA

“I agree that there are not many baseline factors that specifically predict an IR to MTX. MTX remains the anchor drug for the treatment of RA; most rheumatologists first initiate patients with RA on treatment with MTX and observe the clinical response.”

Jonathan Kay, MD

Several studies evaluating predictors of response to MTX have focused on the opposite question: Which patients might respond adequately to MTX without structural progression and who might successfully taper off a biologic agent? For example, high disease activity, as measured by the MBDA index score, can predict the risk of structural progression. If a patient with RA treated with MTX has an MBDA score greater than 44, they are at risk for structural progression, while those with lower scores may successfully continue MTX monotherapy without an increased risk of structural progression. Similarly, patients with RA with higher MBDA scores are less likely to successfully taper off a biologic agent without experiencing increased disease activity. I agree with what has been said by my colleagues (ie, that there are not many baseline factors that specifically predict an IR to MTX). MTX remains the anchor drug for the treatment of RA; most rheumatologists first initiate patients with RA on treatment with MTX and observe the clinical response.

References

Curtis JR, Flake DD, Weinblatt ME, et al. Adjustment of the multi-biomarker disease activity score to account for age, sex and adiposity in patients with rheumatoid arthritis. Rheumatology (Oxford). 2019;58(5):874-883.

de Rotte MCFJ, Pluijm SMF, de Jong PHP, et al. Development and validation of a prognostic multivariable model to predict insufficient clinical response to methotrexate in rheumatoid arthritis. PLoS One. 2018;13(12):e0208534.

Gosselt HR, van Zelst BD, de Rotte MCFJ, Hazes JMW, de Jonge R, Heil SG. Higher baseline global leukocyte DNA methylation is associated with MTX non-response in early RA patients. Arthritis Res Ther. 2019;21(1):157.

Teitsma XM, Jacobs JWG, Welsing PMJ, et al. Inadequate response to treat-to-target methotrexate therapy in patients with new-onset rheumatoid arthritis: development and validation of clinical predictors. Ann Rheum Dis. 2018;77(9):1261-1267.

Vanier A, Smolen JS, Allaart CF, et al. An updated matrix to predict rapid radiographic progression of early rheumatoid arthritis patients: pooled analyses from several databases. Rheumatology (Oxford). 2019 Nov 13. pii: kez542. doi: 10.1093/rheumatology/kez542. [Epub ahead of print]

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