Eiji Sakashita, Katsuya Nagatani, Hitoshi Endo, Seiji Minota
Abstract
Objectives
Compared to conventional disease-modifying antirheumatic drugs (DMARDs), biological DMARDs demonstrate superior efficacy but come with higher costs and increased infection risks. The ability to stop and resume biological DMARD treatment while maintaining remission would significantly alleviate these barriers and anxieties. The objective of this study was to identify biomarkers that can predict an imminent relapse, hopefully enabling the timely resumption of biological DMARDs before relapse occurs.
Introduction
Patients with rheumatoid arthritis (RA) had suffered persistent pain from joint inflammation for a long period, culminating in joint deformity and miserable life until the advent of methotrexate. Methotrexate showed very good effects in reducing rheumatoid inflammation and pain and became an anchor drug in RA treatment [1–3]. However, a large number of patients did not enjoy its beneficial effect due to inadequate efficacy or an unacceptable level of side effects [4,5]. Biological disease-modifying antirheumatic drugs (bDMARDs) are made of monoclonal antibodies against inflammation-promoting cytokines. By blocking the actions of these cytokines physicochemically, bDMARDs mitigate joint inflammation in many patients with RA who are resistant to methotrexate. The number of patients who respond to and the degree of remission achieved by bDMARD are much greater than those of conventional DMARDs. If bDMARDs are introduced into treatment in the early stage of RA, many patients do not realise that they have RA. The sooner patients receive treatment, the better functional outcome ensues, as is true for any diseases [6]. However, there are several obstacles to starting bDMARDs in the early stage: cost and infection risk [7] from the patient’s point of view.
Materials and methods
Study design and study population
This article used the same cohort of 40 RA patients previously reported who were recruited from February 4, 2010 through March 31, 2021 [8,9]. Briefly, forty patients with RA in long-term remission, i.e., for at least one year, had been followed monthly after bDMARD withdrawal until exacerbation occurred or for 2 years if exacerbation did not occur. Serum samples were collected monthly, aliquoted, and stored at ‒80°C until use from all 40 patients. Each patient’s serum aliquot was thawed only once, and all samples were measured simultaneously to mitigate inter-measurement variation. Fourteen patients remained in remission, while twenty-six patients exacerbated at some time points. Among 26 patients who relapsed, 13 patients relapsed very early, i.e., within 6 months, after the bDMARD withdrawal, and another 13 relapsed late, i.e., after 6 months [9]. To find cytokines, if any, that could predict imminent relapse, cytokine levels were measured in sera collected monthly from 13 patients who relapsed late in the follow-up. In this paper, the term ’deep remission’ is employed to characterize a level of remission that is akin to Boolean remission.
Results
Patient demographics
We previously reported a cohort of 40 RA patients who were treated with bDMARD and had been in remission for at least one year [8,9]. bDMARDs were withdrawn from the patients and they were followed monthly for 2 years. The patient demographics are shown in Table 1. Fourteen patients remained in remission for 2 years (non-relapse), 13 patients relapsed within 6 months (early relapse), and another 13 relapsed after 6 months (late relapse). There were no differences in baseline characteristics between the three groups, as shown in Table 1. Thirty-four and six patients were treated with TNF inhibitors and IL-6 inhibitor, respectively (Table 1). Only one patient was treated with the IL-6 inhibitor in the late relapse group, which was the target group analyzed in this report.
Discussion
The great efficacy of bDMARDs in the field of rheumatology has provided RA patients with a much better quality of life and a brighter future, which invigorated not only patients but also rheumatologists [14,15]. Before the advent of bDMARDs, the rheumatology clinic was gloomy; It was seldom possible, if ever, to find effective drugs except methotrexate [1]. Today, rheumatologists recommend, actively and confidently, RA patients to take one of bDMARDs. However, there are several obstacles to overcome before reluctant patients willingly accept bDMARDs; the cost and infection risk are much higher than those of conventional DMARDs.
Acknowledgments
The authors would like to thank all the patients who participated in this study. The authors also thank Dr. Takamasa Murosaki, Dr. Natsuki Shima, and Dr. Hiroi Kusaka for patient care, and Ms. Chiyomi Hayashi, Ms. Sachiko Mamada, and Ms. Chisato Udagawa for excellent technical assistance. They are all the staff of Jichi Medical University.
Citation: Sakashita E, Nagatani K, Endo H, Minota S (2024) Biomarker combination predicting imminent relapse after discontinuation of biological drugs in patients with rheumatoid arthritis in remission. PLoS ONE 19(3): e0299450. https://doi.org/10.1371/journal.pone.0299450
Publisher: Masataka Kuwana, Nippon Medical School, JAPAN
Received: July 28, 2023; Accepted: February 10, 2024; Published: March 21, 2024
Copyright: © 2024 Sakashita et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Competing interests: None
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0299450#abstract0
