https://orcid.org/0000-0001-7972-4252
Figures
Abstract
Objective
This study examined long-term outcomes of biological disease-modifying antirheumatic drugs (bDMARDs) and tofacitinib discontinuation in patients with rheumatoid arthritis (RA).
Methods
Ninety-seven RA patients who desired drug discontinuation after sustained remission or low disease activity for at least 48 weeks due to stable treatment with biological drugs or tofacitinib were enrolled into this study. All patients were prospectively followed until disease flare or the end of the study. Discontinued drugs (previous drugs) were reintroduced to treat flares.
Results
Following bDMARD/tofacitinib discontinuation (mean follow-up, 2.1 years; standard deviation, 2.0), disease flare occurred at a crude incidence rate of 0.36 per person-year. The median time to flare was 1.6 years (95% confidence interval [CI] 0.9–2.6), and the cumulative flare probability was estimated to be 45% at 1 year, 64% at 3 years, and 80% at 5 years. No or little radiological progression was shown in 87.1% of patients who maintained remission for 3 years. A Fine‒Gray competing risk regression analysis showed that predictive factors for a flare were longer RA duration at the start of bDMARD/tofacitinib treatment, previous failure of treatment with bDMARDs, and a shorter period of remission or low disease activity before drug discontinuation. Type of discontinued drug was not identified as a predictive factor after adjusting for other predictor variables. Restarting previous treatment regimens led to rapidly regaining disease control in 89% of flare patients within 1 month.
Conclusion
Discontinuation of bDMARD/tofacitinib may be a feasible strategy in RA patients, especially patients with early treated and longer-controlled RA. Flares are manageable in most RA patients and radiological progression is rare for at least 3 years in patients with sustained remission after bDMARD/tofacitinib discontinuation.
Citation: Mori S, Okada A, Koga T, Ueki Y (2022) Long-term outcomes after discontinuing biological drugs and tofacitinib in patients with rheumatoid arthritis: A prospective cohort study. PLoS ONE 17(6): e0270391. https://doi.org/10.1371/journal.pone.0270391
Editor: Chengappa Kavadichanda, Jawaharlal Institute of Postgraduate Medical Education and Research, INDIA
Received: February 15, 2022; Accepted: June 9, 2022; Published: June 23, 2022
Copyright: © 2022 Mori 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 data supporting the findings are available from the Human Research Ethics Committee of National Hospital Organization Kumamoto Saishun Medical Center for all interested researchers who meet the criteria for access to confidential data. Because these data include patients’ personal information, the Committee does not recommend that such data be made public unnecessarily. Please contact Mr. Hiroshi Tsumura, the Control Manager of the Committee, at 616-kikaku@mail.hosp.go.jp to request the data.
Funding: This study was supported by research funds from the National Hospital Organization, Japan. The funder had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.
Competing interests: S. Mori has received lecture fees from Pfizer Japan Inc., Eli Lilly Japan K.K., and Asahikasei Pharma. The other authors have declared that no conflicts of interest exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
Introduction
Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease that causes progressive damage to joint cartilage and bone, disability, and comorbidity [1]. RA has become a controllable disease. Long-term health-related patient quality of life has dramatically improved because of the availability of conventional, biological, and new non-biological targeted disease-modifying antirheumatic drugs (DMARDs) as well as application of early aggressive intervention and the treat-to-target approach with tight control of disease activity [2]. Today, clinical remission early in the disease course, with a low disease activity (LDA) as a best feasible alternative, is the therapeutic target for every RA patient. Maintaining a state of remission or LDA will relieve clinical signs and symptoms, inhibit the occurrence or progression of structural damage, and improve or normalize physical function and social and work-related activities [3–5]. However, adverse events and high healthcare costs associated with life-long immune-modulatory treatment are significant burdens on patients as well as rheumatologists. Patients frequently express a desire to decrease the dose and for drug holidays [6, 7].
Many studies have addressed the impact of tapering and/or discontinuation of biological DMARDs (bDMARDs) on clinical outcomes in RA patients who have achieved and maintained remission or LDA, including prospective observational studies, randomized controlled trials (RCTs), and open-label extension studies [8–12]. Outcomes of dose reduction and/or discontinuation of targeted synthetic DMARDs (tsDMARDs) have also been reported [13–15]. These studies suggested that a subset of patients may maintain remission or LDA after tapering and even discontinuation of bDMARDs and tsDMARDs. In most studies, however, follow-up periods after tapering and discontinuation of drugs were within 1 year.
In this observational study, we examined the long-term outcomes of bDMARD and tsDMARD discontinuation in RA patients who had maintained remission or LDA for ≥48 weeks. The cumulative probability of disease flare, predictive factors, radiological progression rate, and rescue therapy results were examined.
Patients and methods
Patients
Participants in this study were patients with RA who desired drug discontinuation after maintaining remission or LDA for ≥48 weeks through stable drug treatment with bDMARDs or tsDMARDs from January 2007 to June 2020 in the Rheumatology department of the National Hospital Organization Kumamoto Saishun Medical Center. All participants were over 18 years of age at enrollment and fulfilled the 1987 American College of Rheumatology (ACR) criteria or the 2010 ACR/European League Against Rheumatism (EULAR) criteria for diagnosis of RA [16, 17]. Participants were also required to have had a high or moderate disease activity at the start of bDMARD/tsDMARD treatment despite previous methotrexate (MTX) monotherapy for ≥3 months. Additionally, the patients were required to have already tapered off prednisolone at the start of bDMARD/tsDMARD discontinuation.
Discontinuation of bDMARDs and tsDMARDs
All participants started the bDMARD and tsDMARD discontinuation after maintaining remission or LDA for ≥48 weeks, and they were prospectively followed-up to assess disease activity. A direct discontinuation strategy without stepwise tapering was implemented. All patients were recommended to return for a follow-up visit every 8 weeks after bDMARD/tsDMARD discontinuation. They were allowed to receive a stable dose of MTX (6 to 12 mg/week) during follow-up. They were not allowed to use other conventional synthetic DMARDs (csDMARDs) or prednisolone to control disease activity during follow-up. Follow-up started on the day of bDMARD/tsDMARD discontinuation and ended at the earliest date of the following: flare occurrence, lost to follow-up, death, adverse events, or the last follow-up visit before July 1, 2021. Loss to follow-up was defined as missing at least two scheduled visits without any contact. Adverse events were defined as those that caused MTX discontinuation. Decisions to discontinue MTX due to adverse events were made by the treating physicians on the basis of a comprehensive evaluation of physical findings, laboratory findings, and radiological examinations at each visit or at any time during follow-up if patients had clinical signs or symptoms.
Rescue therapy
Patients who experienced a disease flare started rescue therapy, which comprised restarting the discontinued drugs (previous drugs). Disease activity was examined every 2 weeks during rescue therapy. When disease activity was not controlled by the previous drugs within 4 weeks, patients were treated with another bDMARD or tsDMARD. The choice of the other bDMARD or tsDMARD therapy was at the discretion of each treating physician.
DMARDs
The bDMARDs used in this study included the following two classes: tumor necrosis factor (TNF) inhibitors (infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol) and an interleukin-6 inhibitor (tocilizumab). Tocilizumab was administered via an intravenous infusion at 8 mg/kg every 4 weeks or by a subcutaneous injection of 162 mg every other week. For patients who failed to achieve remission or LDA by the original subcutaneous tocilizumab regimen at 3 months, a 162-mg once-weekly regimen was used. In this study, tofacitinib was the only tsDMARD used to treat the participants. Tofacitinib was administered at a dose of 5 mg twice a day.
RA disease activity
The clinical disease activity index (CDAI) was used to quantify RA disease activity. Cut-off values for disease activity states were defined as follows: high disease activity, CDAI >22; moderate disease activity, CDAI >10 and ≤22; LDA, CDAI >2.8 and ≤10; and remission, CDAI ≤2.8 [18, 19]. After bDMARD/tsDMARD discontinuation, CDAI assessments were performed at each scheduled visit (usually every 8 weeks) or at any time if patients had clinical signs or symptoms. A disease flare was defined as a worsening of CDAI values (a return to moderate or high CDAI) at any time during follow-up.
Assessment of joint destruction
Radiographs of the hands and feet were taken at the start of treatment with bDMARD or tsDMARD, at the start of bDMARD/tsDMARD discontinuation, and every year during follow-up. These data were used to examine structural outcomes after bDMARD/tsDMARD discontinuation. Each radiograph was assessed independently by two readers (AO and TK) who were well trained and competent to score radiographs using the van der Heijde-modified total Sharp score (mTSS) [20]. The readers were also blinded to the patients’ clinical status and treatment and to the chronologic order of the films. To ensure objectivity of the scoring, the average of the mTSS scores determined by each of the two readers was used for each patient’s mTSS. A change in mTSS between the bDMARD/tsDMARD discontinuation and 3 years later (ΔmTSS) was determined for each patient who had maintained remission for 3 years or more. The proportion of patients with no (ΔmTSS ≤0 per 3 years) and little (ΔmTSS ≤1.0 per 3 years) radiological progression, which was defined as radiographic remission in this study, was determined [20].
Ethical approval
This study was conducted in accordance with the principles of the Declaration of Helsinki. The protocol of this study also met the requirements of the Ethical Guidelines for Medical and Health Research Involving Human Subjects, Japan and was approved by the Human Research Ethics Committees of National Hospital Organization Kumamoto Saishun Medical Center (Nos. 31–36 and 2–12). Informed written consent was obtained from all participants before enrollment into this study.
Statistical analysis
Mean and standard deviation (SD) were used as descriptive statistics for data with a continuous distribution, which included non-normally distributed data [21, 22], and as the number (percentage) for categorical data. Crude incidence rates (IRs) of flare and the 95% confidence intervals (CIs) were also calculated by dividing the number of incidence cases by the number of corresponding follow-up person-years (PYs).
The probability of a disease flare event occurring over time after drug discontinuation was estimated using the cumulative incidence function (CIF) because we considered the presence of competing risks in the present study (i.e., lost to follow-up). The occurrence of a competing risk event precludes the occurrence of the primary event of interest. In the presence of competing risks, the simple use of the Kaplan–Meier survival function can overestimate the cumulative incidence probability of a flare event. To avoid this possibility, we used the CIF instead of the Kaplan–Meier survival function. The median time to disease flare (95% CI) and the cumulative flare probability (95% CI) were estimated using the CIF. Gray’s test with the post hoc Holm’s procedure was used to test the equality of CIF plots among the previous drugs. Gray’s test is the analogue to the log-rank test that is used for testing the equality of Kaplan–Meier survival curves between groups [23, 24].
Considering the presence of competing risks, Fine‒Gray competing risk regression analysis was used to evaluate the effect of clinical characteristics on the occurrence of disease flare during follow-up after bDMARD/tsDMARD discontinuation. Clinical characteristics at the start of bDMARD/tsDMARD treatment and those at the start of drug discontinuation that were considered to be clinically relevant based on previous knowledge were used as predictor variables. Univariable Fine‒Gray regression analyses were performed first for each predictor variable. Thereafter, all predictor variables with p values <0.10 in the univariable analyses were introduced into a multivariable analysis. A backward selection procedure with a cut-off significance level of 0.05 was used in the multivariable model. Risk differences are presented as adjusted hazard ratios (HRs) with 95% CIs.
For all tests, a probability value (p value) of <0.05 was considered to indicate statistical significance. All calculations were performed using Easy R (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [25].
Results
Patient characteristics
As shown in Fig 1, 97 patients with RA who desired drug discontinuation after maintenance of remission or LDA for ≥48 weeks due to stable treatment with bDMARDs (46 patients with TNF inhibitors and 19 with tocilizumab) or tofacitinib (32 patients) were enrolled into this study. The participants’ clinical characteristics are shown in Table 1. When treatment with these DMARDs was introduced, 44 patients (45.4%) had high CDAI values and 54 (55.7%) had early RA (≤2 years of disease duration). The mean mTSS was 16.9. The mean time from RA onset to the first use of MTX was 2.4 years, and 63 patients (64.9%) were bDMARD-naïve patients. During treatment with bDMARDs or tofacitinib, MTX was concomitantly used in 90 patients (92.8%), and 11 patients (11.3%) used prednisolone for priming when introducing bDMARDs or tofacitinib (within 3 months). Immediately before starting the bDMARD/tsDMARD discontinuation, 81 patients (83.5%) were in remission. The mean length of remission or LDA was 4.2 years. All patients received a stable dose of MTX after starting DMARD/tofacitinib discontinuation.
*Patients who experienced a disease flare after discontinuation of TNF inhibitors (n = 32) achieved remission or LDA with the same TNF inhibitors (n = 24), abatacept (n = 1), or tofacitinib (n = 7). The other patients regained a good outcome with previous DMARDs. RA, rheumatoid arthritis; LDA, low disease activity; bDMARDs, biological disease-modifying antirheumatic drugs; TNFI, tumor necrosis factor inhibitor; TCZ, tocilizumab; ABT, abatacept; TOF, tofacitinib.
Disease flare following discontinuation of bDMARDs and tofacitinib
As shown in Table 2, the mean follow-up period after discontinuation was 2.1 years (SD 2.0), and disease flare occurred in 74 patients (76.3%). Crude IRs of disease flare during follow-up were 0.36 per PY (95% CI 0.29–0.45). CIF plots for the probability of disease flare from the discontinuation of bDMARDs and tofacitinib are shown in Fig 2A. The estimated median time to disease flare was 1.6 years (95% CI 0.9–2.6). The mean of the cumulative flare probability was estimated to be 0.45 (95% CI 0.35‒0.55) at 1 year, 0.56 (0.46‒0.66) at 2 years, 0.64 (95% CI 0.54‒0.73) at 3 years, and 0.80 (95% CI 0.68‒0.87) at 5 years (Table 2). Fig 2B shows the cumulative incidence of disease flare after grouping according to the discontinued drugs (TNF inhibitors, tocilizumab, and tofacitinib). There were significant differences in flare estimates over time among these patient groups (p = 0.038 for the comparison of all groups using Gray’s test and p = 0.023 for tofacitinib versus TNF inhibitors with the post hoc Holm’s test). The median time to disease flare was shorter in patients who had discontinued tofacitinib compared with TNF inhibitors (0.6 years vs. 2.2 years), and the flare rate at 1 year was greater in the tofacitinib group compared with the TNF inhibitor group (66% vs. 35%) (Table 2). Kaplan–Meier plots for the flare-free survival probability after the discontinuation of bDMARDs and tofacitinib are also shown in S1 Fig.
CIF plots for the probability of patients who experienced disease flare following drug discontinuation are shown for all patients (A) and patients grouped according to the previous drugs (B). The cumulative flare probability over time among the patient groups were compared using Gray’s test with the post hoc Holm’s procedure. The p values are as follows: p = 0.038 for a comparison among the three groups; p = 0.023 for tofacitinib versus TNF inhibitors; p = 0.14 for tocilizumab versus tofacitinib; and p = 0.53 for TNF inhibitors versus tocilizumab. Numbers below this figure represent the number of patients remaining in the analysis. CIF, cumulative incidence function; bDMARDs, biological disease-modifying antirheumatic drugs; TNF, tumor necrosis factor.
Rescue therapy for flares occurring after the discontinuation of bDMARDs and tofacitinib
As shown in Fig 1, all patients who experienced disease flare, except one who was lost to follow-up, started rescue therapy with the previous drugs. Among these patients, 89% recaptured remission or LDA as follows: all patients in the tocilizumab-discontinuation group (15 patients) and the tofacitinib-discontinuation group (26 patients) regained disease control within 1 month by restarting the previous drugs; among 32 patients who discontinued TNF inhibitors, 24 (75%) successfully achieved remission within 1 month of restarting the same drug. The other eight failed to achieve LDA, but remission was reached by switching to abatacept (one patient) or tofacitinib (seven patients).
Influence of bDMARD/tofacitinib discontinuation on structural outcome
Thirty-one patients maintained remission for 3 years or more after drug discontinuation (previous drugs: 16 TNF inhibitors, nine tocilizumab, and six tofacitinib). Mean values of mTSS, erosion score, and joint space narrowing score (JNS) were determined at the time of starting and discontinuing bDMARD/tofacitinib treatment and 3 years after drug discontinuation. A cumulative probability plot of 3-year changes in mTSS (ΔmTSS) from drug discontinuation is shown in Fig 3. No or little radiological progression was shown in 87.1% of the patients who maintained remission for 3 years or more after drug discontinuation; the rates of patients with ΔmTSS ≤0 per 3 years and those with ΔmTSS >0 and ≤1 per 3 years were 71.0% and 16.1%, respectively.
mTSS, van der Heijde-modified total Sharp score.
Predictive factors for the risk of disease flare following discontinuation of bDMARD and tofacitinib
Results of univariable and multivariable Fine‒Gray competing risk regression analyses are shown in Table 3. The univariable analyses showed that RA duration, mTSS score (erosion score), and time from RA onset to first MTX use at the start of bDMARD or tofacitinib treatment, previous failure of treatment with bDMARDs, the type of treatment drugs that led to remission or LDA, and disease activity and duration of maintaining the remission or LDA status at the start of bDMARD/tofacitinib discontinuation were predictor variables with p<0.10. These variables were placed into the multivariable regression analysis. In the multivariable regression model, longer RA duration, previous failure of treatment with bDMARDs, and a longer duration of remission or LDA status were identified as the predictive factors for disease flare; the adjusted HR (95% CI) was 1.06 (1.02‒1.10) for RA duration per additional year (p = 0.0041), 0.58 (0.35–0.94) for bDMARD-naïve compared with previous bDMARD failure (p = 0.028), and 0.89 (0.35–0.94) for duration of remission or LDA per additional year (p = 0.0083). After adjusting for other predictor variables, the treatment drug type did not remain a predictive factor for disease flare.
Discussion
Following bDMARD and tofacitinib discontinuation after the sustained remission or LDA status for ≥48 weeks in RA patients, disease flare occurred at an IR of 0.36 per PY, and the median time to flare was 1.6 years. No or little radiological progression was observed in 87.1% of patients who maintained remission for 3 years. In patients with a flare, 89% regained remission or LDA within 1 month by restarting the previous treatment regimens. The Fine‒Gray competing risk regression analysis showed that a longer RA duration at the start of bDMARD/tofacitinib, previous failure of treatment with bDMARDs, and shorter sustained duration of remission or LDA were predictive factors for the occurrence of a disease flare after bDMARD/tofacitinib discontinuation.
In daily clinical practice, patients frequently desire drug discontinuation after reaching remission or LDA status due to the treatment with bDMARDs or tsDMARDs because of the fear of adverse events associated with these drugs. When considering drug discontinuation, one of the most critical concerns is whether patients can rapidly recover their baseline condition by reintroducing the previous DMARDs if a disease flare occurs. In the present study, 89% of patients who experienced disease flare regained disease control using rescue therapy with the previous DMARDs. Successful recapture of remission or LDA by restarting the previous regimen has been reported in recent RCTs and observational studies involving bDMARDs and tsDMARDs [13–15, 26–37]. Rapid recovery of disease control with rescue therapy may encourage rheumatologists and RA patients to make a therapeutic decision in favor of bDMARD/tsDMARD discontinuation. Patients need to be informed about the risk of disease flares and their management strategies [38]. Additionally, patient eligibility for discontinuation should be considered. In this study, patients were scheduled to start bDMARD and tsDMARD discontinuation if they maintained a CDAI-based remission or LDA for at least 48 weeks with stable bDMARD or tsDMARD treatment and had already tapered off prednisolone.
Henaux et al. performed a systematic review and meta-analysis on structural damage, and they showed that bDMARD discontinuation was more likely to increase the risk of losing remission or LDA as well as the risk of radiological progression compared with continuing the initial bDMARD regimen [12]. In the PRESERVE study, patients who started discontinuation of etanercept had disease flares and showed radiological progression at 52 weeks more frequently compared with those receiving full- or reduced-dose etanercept [39]. In the DRESS study, radiological progression was associated with a time-weighted average of disease activity for 18 months after tapering of TNF inhibitors, although there was no association between the occurrence or number of flares and radiological progression. The findings suggested that radiological progression is caused by the long-term increase in disease activity over time after tapering [40]. These studies indicated the importance of maintaining a state of remission or LDA in patients as well as the need to regularly monitor radiological progression. It is not clear whether small increases in joint damage may become significant over time. In the present study, we showed that radiological damage did not continue to progress in approximately 90% of RA patients who maintained remission over 3 years after bDMARD/tofacitinib discontinuation.
There are few long-term outcome data regarding the bDMARD/tsDMARD-free strategy. In the HONOR study, which was conducted in Japan, 52 patients who maintained remission with adalimumab plus MTX for at least 6 months started adalimumab discontinuation. During a 5-year follow-up, adalimumab-free remission, which was determined by the 28-joint disease activity score based on erythrocyte sedimentation rate, was persistent in 48% of patients at 1 year, 31% at 3 years, and 21% at 5 years. No significant radiological changes were observed in patients who sustained LDA for 5 years, and among them, eight of nine patients (88.9%) maintained structural remission defined as ΔmTSS ≤0.5 per year [37]. In the present study, the rates of flare patients were estimated to be 45% at 1 year, 64% at 3 years, and 80% at 5 years after the discontinuation of bDMARDs and tofacitinib in RA patients. Among patients achieving bDMARD/tofacitinib-free 3-year remission, 27 of 31 (87.1%) had an mTSS ≤1 over the 3 years. Similar findings were obtained between the HONOR study and the present study.
In the present study, the predictive factors for disease flare following bDMARD/tofacitinib discontinuation were longer RA duration at the start of bDMARD/tofacitinib treatment, previous failure of biological treatment, and a shorter sustained period of the remission or LDA status before the start of drug discontinuation. Previous studies also identified several patient clinical and imaging characteristics as determinant factors for failure or success to sustain remission or LDA after the start of bDMARD tapering and discontinuation. The identified characteristics included disease activity at baseline, RA duration, timing of treatment (initial or delayed), previous use of bDMARDs, residual synovial inflammation under ultrasound examinations, and deep/long-standing remission [26, 37, 41–48]. These patient characteristics may help predict the sustained clinical benefit after bDMARD/tofacitinib tapering and discontinuation.
There are several limitations to this study. First, the sample size was relatively small, which may have made it difficult to draw a definitive conclusion about predictors for disease flare after bDMARD/tofacitinib discontinuation. To estimate the sample size, we needed to input an expected probability of flare-free survival at a time point of interest. However, we were unable to determine the expected long-term survival probability due to a lack of previous data. Second, the present study was an observational study in a real-world clinical setting, and therefore, allowing bDMARD/tofacitinib discontinuation was left to the discretion of the treating physician and the patient’s preference, which may have produced some bias. However, we used clear inclusion criteria for this study. We included only patients with MTX-resistant RA who had sustained remission or LDA with stable DMARD treatment (which included the type and dose) for ≥48 weeks and had already tapered off prednisolone. Additionally, we defined a disease flare based on CDAI values that were regularly monitored at each scheduled visit. We continued stable doses of MTX for all patients, but an additional use of prednisolone or other csDMARDs was not allowed to control disease activity during follow-ups. Considering such consistency in the definition of a flare and the eligibility of participants, the present study provides useful information regarding long-term outcomes in RA patients after bDMARD/tofacitinib discontinuation.
Conclusion
In this longitudinal observational study, it was estimated that half of RA patients had disease flare within 1.6 years after discontinuing bDMARDs and tofacitinib. The timing of bDMARD/tofacitinib start (RA duration before the treatment), previous failure of treatment with bDMARDs, and the length of remission or LDA before the discontinuation were significant predictive factors for successful discontinuation. Approximately 90% of patients who maintained bDMARD/tofacitinib-free remission for 3 years had no or little radiological progression. Restarting the original treatment regimen allowed rapid recapture of disease control within 1 month in almost all flare cases. Thus, attempting bDMARD/tofacitinib-free management may be a viable option that could be pursued after achieving stable control of disease activity in RA patients, especially those who had started the treatment at early RA stages and maintained remission or LDA for a longer time. Regular monitoring of disease activity and patient education about early signs of disease flare are crucial to prevent persistent disease flares and radiological damages during bDMARD/tofacitinib-free treatment for RA.
Supporting information
S1 Fig. Kaplan–Meier plots: The probability of flare-free survival after the discontinuation of bDMARDs and tofacitinib.
Kaplan–Meier plots for the proportion of patients who experienced no disease flare during follow-up are shown for patients who discontinued TNF inhibitors, tocilizumab, or tofacitinib. The flare-free probability among the patient groups was compared using the log-rank test with the post hoc Holm’s procedure. The p values were as follows: p = 0.069 for a comparison among the three groups; p = 0.030 for tofacitinib versus TNF inhibitors; p = 0.14 for tocilizumab versus tofacitinib; and p = 0.52 for TNF inhibitors versus tocilizumab. Median time to disease flare (95% CI) was 2.2 years (1.0–3.4 years) for TNF inhibitors, 3.1 years (0.0–6.3 years) for tocilizumab, and 0.6 years (0.2–1.0 years) for tofacitinib. Numbers below this figure represent the number of patients remaining in the analysis. bDMARDs, biological disease-modifying antirheumatic drugs; TNF, tumor necrosis factor; CI, confidence interval.
https://doi.org/10.1371/journal.pone.0270391.s001
(TIF)
References
- 1. McInnes IB, Schett G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet 2017;389(10086):2328–2337. pmid:28612747
- 2. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet 2016;388(10055):2023–2038. pmid:27156434
- 3. Singh JA, Saag KG, Bridges SL Jr., Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 2016;68(1):1–26. pmid:26545940
- 4. Lau CS, Chia F, Dans L, Harrison A, Hsieh TY, Jain R, et al. 2018 update of the APLAR recommendations for treatment of rheumatoid arthritis. Int J Rheum Dis 2019;22(3):357–375. pmid:30809944
- 5. Smolen JS, Landewe RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 2020;79(6):685–699. pmid:31969328
- 6. Lenert A, Lenert P. Tapering biologics in rheumatoid arthritis: a pragmatic approach for clinical practice. Clin Rheumatol 2017;36(1):1–8. pmid:27896522
- 7. Cavalli G, Favalli EG. Biologic discontinuation strategies and outcomes in patients with rheumatoid arthritis. Expert Rev Clin Immunol 2019;15(12):1313–1322. pmid:31663390
- 8. Kuijper TM, Lamers-Karnebeek FB, Jacobs JW, Hazes JM, Luime JJ. Flare rate in patients with rheumatoid arthritis in low disease activity or remission when tapering or stopping synthetic or biologic DMARD: a systematic review. J Rheumatol 2015;42(11):2012–2022. pmid:26428204
- 9. Schett G, Emery P, Tanaka Y, Burmester G, Pisetsky DS, Naredo E, et al. Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions. Ann Rheum Dis 2016;75(8):1428–1437. pmid:27261493
- 10. Lau CS, Gibofsky A, Damjanov N, Lula S, Marshall L, Jones H, et al. Down-titration of biologics for the treatment of rheumatoid arthritis: a systematic literature review. Rheumatol Int 2017;37(11):1789–1798. pmid:28852832
- 11. Ruscitti P, Sinigaglia L, Cazzato M, Grembiale RD, Triolo G, Lubrano E, et al. Dose adjustments and discontinuation in TNF inhibitors treated patients: when and how. A systematic review of literature. Rheumatology (Oxford) 2018;57(57 Suppl 7):vii23–vii31.
- 12. Henaux S, Ruyssen-Witrand A, Cantagrel A, Barnetche T, Fautrel B, Filippi N, et al. Risk of losing remission, low disease activity or radiographic progression in case of bDMARD discontinuation or tapering in rheumatoid arthritis: systematic analysis of the literature and meta-analysis. Ann Rheum Dis 2018;77(4):515–522. pmid:29187350
- 13. Kubo S, Yamaoka K, Amano K, Nagano S, Tohma S, Suematsu E, et al. Discontinuation of tofacitinib after achieving low disease activity in patients with rheumatoid arthritis: a multicentre, observational study. Rheumatology (Oxford) 2017;56(8):1293–1301. pmid:28407099
- 14. Takeuchi T, Genovese MC, Haraoui B, Li Z, Xie L, Klar R, et al. Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease control: results of a prospective study. Ann Rheum Dis 2019;78(2):171–178. pmid:30194275
- 15. Mori S, Ueki Y. Outcomes of dose reduction, withdrawal, and restart of tofacitinib in patients with rheumatoid arthritis: a prospective observational study. Clin Rheumatol 2019;38(12):3391–3400. pmid:31399850
- 16. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31(3):315–324. pmid:3358796
- 17. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62(9):2569–2581. pmid:20872595
- 18. Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 2005;23(5 Suppl 39):S100–108.
- 19. Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi T, Michaud K, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken) 2012;64(5):640–647. pmid:22473918
- 20. van der Heijde D. How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol 2000;27(1):261–263. pmid:10648051
- 21. Lydersen S. Statistical review: frequently given comments. Ann Rheum Dis 2015;74(2):323–325. pmid:25261576
- 22. Lydersen S. Mean and standard deviation or median and quartiles? Tidsskr Nor Laegeforen 2020;140(9):pii 20–0032. pmid:32549024
- 23. Austin PC, Lee DS, Fine JP. Introduction to the Analysis of Survival Data in the Presence of Competing Risks. Circulation 2016;133(6):601–609. pmid:26858290
- 24. Austin PC, Fine JP. Accounting for competing risks in randomized controlled trials: a review and recommendations for improvement. Stat Med 2017;36(8):1203–1209. pmid:28102550
- 25. Kanda Y. Investigation of the freely available easy-to-use software ’EZR’ for medical statistics. Bone Marrow Transplant 2013;48(3):452–458. pmid:23208313
- 26. van den Broek M, Klarenbeek NB, Dirven L, van Schaardenburg D, Hulsmans HM, Kerstens PJ, et al. Discontinuation of infliximab and potential predictors of persistent low disease activity in patients with early rheumatoid arthritis and disease activity score-steered therapy: subanalysis of the BeSt study. Ann Rheum Dis 2011;70(8):1389–1394. pmid:21515916
- 27. Nishimoto N, Amano K, Hirabayashi Y, Horiuchi T, Ishii T, Iwahashi M, et al. Retreatment efficacy and safety of tocilizumab in patients with rheumatoid arthritis in recurrence (RESTORE) study. Mod Rheumatol 2014;24(1):26–32. pmid:24261755
- 28. van Herwaarden N, Herfkens-Hol S, van der Maas A, van den Bemt BJ, van Vollenhoven RF, Bijlsma JW, et al. Dose reduction of tocilizumab in rheumatoid arthritis patients with low disease activity. Clin Exp Rheumatol 2014;32(3):390–394. pmid:24773727
- 29. Huizinga TW, Conaghan PG, Martin-Mola E, Schett G, Amital H, Xavier RM, et al. Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study. Ann Rheum Dis 2015;74(1):35–43. pmid:25169728
- 30. Tanaka Y, Hirata S, Kubo S, Fukuyo S, Hanami K, Sawamukai N, et al. Discontinuation of adalimumab after achieving remission in patients with established rheumatoid arthritis: 1-year outcome of the HONOR study. Ann Rheum Dis 2015;74(2):389–395. pmid:24288014
- 31. van Vollenhoven RF, Ostergaard M, Leirisalo-Repo M, Uhlig T, Jansson M, Larsson E, et al. Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis. Ann Rheum Dis 2016;75(1):52–58. pmid:25873634
- 32. Alivernini S, Peluso G, Fedele AL, Tolusso B, Gremese E, Ferraccioli G. Tapering and discontinuation of TNF-alpha blockers without disease relapse using ultrasonography as a tool to identify patients with rheumatoid arthritis in clinical and histological remission. Arthritis Res Ther 2016;18:39. pmid:26842890
- 33. Fautrel B, Pham T, Alfaiate T, Gandjbakhch F, Foltz V, Morel J, et al. Step-down strategy of spacing TNF-blocker injections for established rheumatoid arthritis in remission: results of the multicentre non-inferiority randomised open-label controlled trial (STRASS: Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study). Ann Rheum Dis 2016;75(1):59–67. pmid:26103979
- 34. Kaneko Y, Kato M, Tanaka Y, Inoo M, Kobayashi-Haraoka H, Amano K, et al. Tocilizumab discontinuation after attaining remission in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate: results from a prospective randomised controlled study (the second year of the SURPRISE study). Ann Rheum Dis 2018;77(9):1268–1275. pmid:29853455
- 35. Emery P, Burmester GR, Bykerk VP, Combe BG, Furst DE, Maldonado MA, et al. Re-treatment with abatacept plus methotrexate for disease flare after complete treatment withdrawal in patients with early rheumatoid arthritis: 2-year results from the AVERT study. RMD Open 2019;5(1):e000840. pmid:30997151
- 36. Emery P, Burmester GR, Naredo E, Sinigaglia L, Lagunes I, Koenigsbauer F, et al. Adalimumab dose tapering in patients with rheumatoid arthritis who are in long-standing clinical remission: results of the phase IV PREDICTRA study. Ann Rheum Dis 2020;79(8):1023–1030. pmid:32404343
- 37. Yamaguchi A, Hirata S, Kubo S, Fukuyo S, Hanami K, Nakano K, et al. 5-year remission rate after the discontinuation of adalimumab in patients with rheumatoid arthritis: long-term follow-up results of the HONOR study. Mod Rheumatol 2020;30(5):799–806. pmid:31814496
- 38. Verhoef LM, Selten EMH, Vriezekolk JE, de Jong AJL, van den Hoogen FHJ, den Broeder AA, et al. The patient perspective on biologic DMARD dose reduction in rheumatoid arthritis: a mixed methods study. Rheumatology (Oxford) 2018;57(11):1947–1955. pmid:30010899
- 39. Smolen JS, Pedersen R, Jones H, Mahgoub E, Marshall L. Impact of flare on radiographic progression after etanercept continuation, tapering or withdrawal in patients with rheumatoid arthritis. Rheumatology (Oxford) 2020;59(1):153–164. pmid:31257453
- 40. Bouman CA, den Broeder AA, van der Maas A, van den Hoogen FH, Landewe RB, van Herwaarden N. What causes a small increase in radiographic progression in rheumatoid arthritis patients tapering TNF inhibitors? RMD Open 2017;3(1):e000327. pmid:28405469
- 41. Saleem B, Keen H, Goeb V, Parmar R, Nizam S, Hensor EM, et al. Patients with RA in remission on TNF blockers: when and in whom can TNF blocker therapy be stopped? Ann Rheum Dis 2010;69(9):1636–1642. pmid:20421345
- 42. Iwamoto T, Ikeda K, Hosokawa J, Yamagata M, Tanaka S, Norimoto A, et al. Prediction of relapse after discontinuation of biologic agents by ultrasonographic assessment in patients with rheumatoid arthritis in clinical remission: high predictive values of total gray-scale and power Doppler scores that represent residual synovial inflammation before discontinuation. Arthritis Care Res (Hoboken) 2014;66(10):1576–1581. pmid:24515410
- 43. Kavanaugh A, Lee SJ, Curtis JR, Greenberg JD, Kremer JM, Soto L, et al. Discontinuation of tumour necrosis factor inhibitors in patients with rheumatoid arthritis in low-disease activity: persistent benefits. Data from the Corrona registry. Ann Rheum Dis 2015;74(6):1150–1155. pmid:25471471
- 44. Naredo E, Valor L, De la Torre I, Montoro M, Bello N, Martinez-Barrio J, et al. Predictive value of Doppler ultrasound-detected synovitis in relation to failed tapering of biologic therapy in patients with rheumatoid arthritis. Rheumatology (Oxford) 2015;54(8):1408–1414. pmid:25731769
- 45. Yoshida K, Kishimoto M, Radner H, Matsui K, Okada M, Saeki Y, et al. Low rates of biologic-free clinical disease activity index remission maintenance after biologic disease-modifying anti-rheumatic drug discontinuation while in remission in a Japanese multicentre rheumatoid arthritis registry. Rheumatology (Oxford) 2016;55(2):286–290.
- 46. Hashimoto M, Furu M, Yamamoto W, Fujimura T, Hara R, Katayama M, et al. Factors associated with the achievement of biological disease-modifying antirheumatic drug-free remission in rheumatoid arthritis: the ANSWER cohort study. Arthritis Res Ther 2018;20(1):165. pmid:30075810
- 47. Brahe CH, Krabbe S, Ostergaard M, Ornbjerg L, Glinatsi D, Rogind H, et al. Dose tapering and discontinuation of biological therapy in rheumatoid arthritis patients in routine care—2-year outcomes and predictors. Rheumatology (Oxford) 2019;58(1):110–119. pmid:30169706
- 48. Tanaka Y, Oba K, Koike T, Miyasaka N, Mimori T, Takeuchi T, et al. Sustained discontinuation of infliximab with a raising-dose strategy after obtaining remission in patients with rheumatoid arthritis: the RRRR study, a randomised controlled trial. Ann Rheum Dis 2020;79(1):94–102. pmid:31630117