Predictors of relapse after withdrawing biotherapies in children with inactive juvenile idiopathic arthritis: a retrospective cohort study of the JIR cohort

Predictors of relapse after withdrawing biotherapies in children with inactive juvenile idiopathic arthritis: a retrospective cohort study of the JIR cohort | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Predictors of relapse after withdrawing biotherapies in children with inactive juvenile idiopathic arthritis: a retrospective cohort study of the JIR cohort Vincent Jallot, Perrine Dusser, Sébastien Cavelot, Caroline Galeotti, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7334358/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Nov, 2025 Read the published version in Pediatric Rheumatology → Version 1 posted 14 You are reading this latest preprint version Abstract Objectives In patients with juvenile idiopathic arthritis (JIA), the approach to discontinuing biological treatments after a period of remission remains exploratory. We aimed to identify one or more predictors of relapse after the discontinuation of biologic/targeted synthetic disease-modifying anti-rheumatic drugs. Methods We reviewed JIA patients followed in two French tertiary centers and included in the JIR cohort who had discontinued their biologic treatments from 2000 to 2023. Remission was defined according to the Wallace criteria. The primary outcome was relapse within 1 year after treatment withdrawal. Multivariate regression was used to analyze predictors of relapse. Results A total of 697 JIA patients received treatment in the two centers during the study period. We analyzed 130 instances of treatment discontinuation in 115 patients (16.5%) (70.8% girls [92/130], median age 5.29 years at diagnosis [interquartile range 2.3–10.4]). Patients discontinued biological treatments after a median of 2.58 years, and 56.2% (73/130) of patients experienced relapse within 1 year after treatment withdrawal. The psoriasis subgroup had the highest relapse rate (89.5% [17/19]) and the systemic subgroup the lowest (33.3% [7/21]). The probably of relapse was increased with antinuclear antibody positivity at diagnosis (p < 0.05) and reduced with longer duration of clinically inactive disease before treatment withdrawal. Conclusion Relapses are common after discontinuing biologic therapies in JIA, particularly in patients with antinuclear antibody positivity and psoriatic arthritis and those who stop treatment shortly after reaching inactive disease status. JIA Treat to target Remission b/ts-DMARD withdrawal Predictors of relapse Figures Figure 1 Figure 2 key Message What is already known on this topic – Once remission on treatment has been achieved, criteria for withdrawing b/ts-DMARDs in JIA patients remain unclear. After cessation, more than half of patients will relapse, and few studies have succeeded in identifying factors predictive of relapse, which would be essential for patient follow-up. What this study adds –This study enabled us to identify risk factors for relapse, some of which were already suspected but others newly identified, such as anti-nuclear antibody levels and the duration of biotherapy treatment after remission. How this study might affect research, practice or policy –This is an important study which could be used to better target recommendations concerning the choice and discontinuation of biotherapies in juvenile arthritis. Introduction Juvenile idiopathic arthritis (JIA) represents the most common cause of chronic arthritis in children. It affects about 1 in 1000 children [ 1 ]. The current diagnosis criteria are based on the International League of Associations for Rheumatology (ILAR) classification criteria. Once the diagnosis is established, early treatment is one of the keys to a good response. The current therapeutic strategy is based on the “treat to target” approach [ 7 ]. This method is now used for many inflammatory diseases in both adults and children. As a first step, the treatment is most often based on anti-inflammatory drugs or intra-articular corticosteroids injections; oral corticosteroids are also a possibility but only in certain situations. In some cases (associated uveitis, persistent disease activity), a conventional synthetic disease-modifying anti-rheumatic drug (cs-DMARD) is introduced (most commonly methotrexate). For children without response or with severe disease, a biologic or targeted synthetic DMARD (b/ts-DMARD) can be prescribed instead of or in addition to a cs-DMARD [8;9]. With these biologic treatments, inactive disease is now achieved most of the time and the JIA remains inactive for a long period. Remission while on treatment is defined as 6 consecutive months of inactive disease according to Wallace criteria [10;11]. Once remission on treatment has been achieved, the DMARD is often tapered and then stopped because of a favorable benefit–risk ratio on discontinuation of treatment [ 12 – 19 ]. Studies have shown that stopping methotrexate before biologics is preferable because of the reduced relapse rate [15;20;21]. After treatment withdrawal, the disease may evolve in two different ways, depending on the child: no relapse after withdrawal or disease recurrence (treatment dependence and relapse as soon as the treatment is stopped). Approximately 10–40% of patients do not experience relapse after stopping treatment and have a transient form of JIA in childhood that does not persist into adulthood [ 22 – 24 ]. However, a major question for the physician is when and how to withdraw b/ts-DMARDs once remission on treatment is achieved. To date, there are only a few articles about the best way to stop the treatment. Therefore, criteria for withdrawing b/ts-DMARDs in JIA patients remain unclear and are mainly based on the clinical experience of the physician but also on the child’s drug tolerance. Here we aimed to identify one or more predictors of relapse after b/ts-DMARDs cessation that would encourage adaptation of the withdrawal strategy based on the risk of relapse. Methods Patients We designed a retrospective chart review of patients with JIA, classified according to the ILAR criteria [ 3 ], who were included in the Juvenile Inflammatory Rheumatism (JIR) cohort, an international multicenter database for patients with inflammatory or rheumatic diseases. We identified patients who received b/ts-DMARD treatment from 2000 to 2023 and were followed at two tertiary pediatric rheumatology centers: Bicêtre Hospital and Versailles Hospital, France. Any patient who received a b/ts-DMARD and achieved remission was eligible. Among these patients, we included those who received at least one b/ts-DMARD leading to inactive disease and then those who experienced a withdrawal of the b/ts-DMARD treatment because of disease remission (with age at b/ts-DMARD withdrawal ≤ 18 years). The definition of disease remission on treatment was based on Wallace criteria (no joint with active arthritis; no systemic symptoms such as fever, rash, lymphadenopathy or serositis; no active uveitis; normal C-reactive protein level; physician’s disease activity evaluation = 0). Patients had to meet all Wallace criteria for at least 6 months before withdrawal, as defined. Patients were excluded if they had less than 1 year of follow-up after stopping b/ts-DMARD treatment or if they had comorbidities that could be a confounding factor, such as inflammatory bowel disease, diabetes, chronic recurrent multifocal osteomyelitis, Mediterranean fever, or Verneuil's disease. Outcomes The primary outcome was relapse within 1 year after b/ts-DMARD treatment cessation due to remission of JIA. Relapse was defined as no longer fulfilling remission criteria within 1 year after b/ts-DMARD withdrawal. The same patient could stop the treatment several times because of an iterative remission and relapse history. In our study, the 115 patients we studied were responsible for 130 discontinuations. One secondary outcome was also defined: the occurrence of relapse within 3 years after discontinuation of b/ts-DMARD treatment due to JIA remission (late relapse). Data collected The following data were collected (according to previously identified risk factors for relapse in JIA): 1) At the point of registration (JIA diagnosis), demographics (age, sex), JIA subtype, laboratory findings (rheumatoid factor, anti-CCP and antinuclear antibody (ANA) status [-12; +12 months] [ANA positivity defined as ≥ 1/160 titers, with two blood measurements], ANA title, initial C-reactive protein level, HLA-B27 status); number of affected joints at diagnosis and joint involvement type at diagnosis. 2) During follow-up: disease activity assessment (Juvenile Arthritis Disease Activity Score [JADAS] or clinical JADAS). 3) At treatment withdrawal: type of b/ts-DMARD withdrawn and the withdrawal method (spacing or other), treatment decline duration before withdrawal, history of uveitis, previous b/ts-DMARD therapy before the one studied (first-line or second-line treatment), previous failure of b/ts-DMARD withdrawal, current methotrexate therapy, delay from diagnosis to b/ts-DMARD introduction, duration of the treatment stopped, time of b/ts-DMARD maintenance once inactive disease was achieved (cJADAS ≤ 2.5). Ethical considerations All patients (and/or their legal guardian) were informed about the JIRcohort cohort, and no objections to participation were recorded. This study was conducted in accordance with the principles of the Declaration of Helsinki. The JIR cohort was approved by the French ethics committee (CCTIRS) on April 21, 2015, and the electronic case report form was validated by the Commission Nationale de l'Informatique et des Libertés (CNIL). Statistical analysis In the descriptive analysis, treatment withdrawals were analysed by demographic and disease- and treatment-related factors. Results are described with median (interquartile range [IQR]) for continuous variables and frequencies (percentages) for categorical variables. Group comparability was assessed by comparing baseline demographic data and follow-up duration between groups. The normality of continuous variables was assessed with the Shapiro-Wilk test and heteroskedasticity with the Levene test, as appropriate. Continuous variables were standardized before statistical analysis to account for differences in measurement scales. Continuous outcomes were compared by unpaired Student t test, Welch t test, or Mann-Whitney U test depending on data distribution. Discrete outcomes were analyzed by chi-squared or Fisher’s exact test as appropriate. The alpha risk was set at 5%, and two-tailed tests were applied. Univariable and multivariable logistic regression was used to identify predictors of relapse within 1 year after b/ts-DMARD cessation. Variables included in the models were sex, age at diagnosis, ANA status at diagnosis, JIA subgroup (systemic/non-systemic), delay from diagnosis and b/ts-DMARD introduction, delay from first low c-JADAS and b/ts-DMARD cessation, b/ts-DMARD decrease type, line of b/ts-DMARD therapy, previous failure of b-DMARD withdrawal, methotrexate present at b/ts-DMARD cessation for remission, and number of affected joints at diagnosis. Variable selection for the multivariate analysis was pre-defined, focusing on factors known from the literature to be associated with increased risk of relapse. Variables related to each other could not be included together in the same multivariable analysis. Thus, type of treatment was related to the JIA subgroup, and durations were also often related to each other. Data were checked for multicollinearity with the Belsley-Kuh-Welsch technique. Heteroskedasticity and normality of residuals were assessed with the Breusch-Pagan and Shapiro-Wilk test, respectively. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. P < 0.05 was considered statistically significant. Patients with missing data were excluded from the analysis. All statistical analysis were performed with EasyMedStat 3.36 and supplemented by R 4.4.2. Results We screened 655 patients with JIA classified according to the ILAR criteria; 291 (44.4%) received b/ts-DMARD treatment. We finally included 115 patients (16.5%) responsible for 130 treatment discontinuations ( Figure 1 ). The baseline characteristics of the 130 instances of b/ts-DMARD withdrawal are in Table 1 . Most withdrawals occurred in female patients (70.8%; 92/130), and the median age at diagnosis was 5.29 years (IQR 2.3–10.4). JIA subtypes included enthesitis-related arthritis (ERA; 22.3%), oligoarticular-JIA (23.8%), polyarthritis-JIA (23.1%), psoriasis-JIA (14.6%), and systemic-JIA (16.2%). The median time from diagnosis to the first introduction of b/ts-DMARD was 197 days (67.5–478.8). The most stopped b/ts-DMARDs were etanercept (74/130), adalimumab (24/130), and tocilizumab (17/130), followed by anakinra (7/130), canakinumab (2/130), infliximab (5/130), and baricitinib (1/130). The median duration of b/ts-DMARD treatment before withdrawal was 2.58 years (1.72–3.42), and the median age was 11.2 (7.0–15.3) years at b/ts-DMARD cessation. The median time from achieving inactive disease to treatment withdrawal was 1.34 years (0.70–2.19). Overall, 78.3% of withdrawals followed a spacing strategy before definitive withdrawal, and 21.7% used other discontinuation methods (gradual tapering, abrupt stop, or mixed approaches). Additionally, 13.8% (18/130) of patients were still on methotrexate at the time of b/ts-DMARD discontinuation. Relapse analysis 1 year after treatment discontinuation At 1 year, the relapse rate after discontinuation of b/ts-DMARD was 56.2% (73/130). On univariate analysis, six variables were significantly associated with increased odds of relapse ( Table 2 ): younger age at diagnosis (p = 0.011) and at the time of treatment withdrawal (p = 0.027); ANA positivity at diagnosis (p < 0.001) and increased ANA titers (p = 0.028); JIA subtype (p < 0.001; higher with psoriatic- and oligoarticular-JIA (89.5% and 77.4%) and lower with systemic-JIA and ERA (33.3% and 37.9%). Relapse rate was reduced for patients following an injection spacing strategy before b/ts-DMARD cessation with long tapering (p = 0.016). On multivariable analysis (Figure 2), the odds of relapse was increased with ANA positivity at diagnosis (OR 13.0; 95% CI: 3.87–43.8) and reduced with longer duration of clinically inactive disease before treatment withdrawal (OR 0.57; 95% CI: 0.35–0.93) ( Table 3 ). These associations remained after excluding patients with systemic JIA from the analysis (supplementary Table 2 ). Relapse 3 years after treatment discontinuation The non-relapse group included patients who did not reach 3 years of follow-up but did not experience relapse within the first to third year ( Table 4 ) . For those with relapse, the relapse date marked the end of follow-up. Among cases of withdrawal that did not show relapse in the first year, the median follow-up after treatment cessation was 2.00 years (IQR 1.30–3.42). Five variables were linked to increased relapse rate: younger age at diagnosis (p = 0.010), ANA positivity at diagnosis (p < 0.001), increased ANA titers (p = 0.004), differences across JIA subtypes (p < 0.001), and shorter time from diagnosis to b/ts-DMARD initiation (p = 0.012). Table 1: Baseline characteristics of the 130 b/ts-DMARD withdrawals analyzed. CRP, C reactive protein; ANA, anti-nuclear antibodies; RF, rheumatoid factors; ACPA, anti-citrullinated protein antibodies. Characteristics Values No. (%)/ Median (IQR) Female 92 (70.8%) Male 38 (29.2%) Age at diagnosis (years) 5.29 (2.3-10.43) JIA subtype Enthesitis Oligoarthritis Polyarthritis Psoriatic Systemic 29 (22.3%) 31 (23.8%) 30 (23.1%) 19 (14.6%) 21 (16.2%) Number of impacted joints at diagnosis (n=128) 5 or more Less than 5 40 (31.2%) 88 (68.8%) Joint involvement type at diagnosis (n=128) Peripheral only Axial involvment 114 (89.1%) 14 (10.9%) Laboratory findings CRP at diagnosis (n=87) ANA+ (n=125) ANA in titer (n=102) RF+ (n=99) ACPA + (n=83) HLA-B27 + (n=74) 11.0 (5.0-58.0) 76 (60.8%) 320 (100.0-640.0) 7 (7.1%) 7 (8.4%) 18 (24.3%) Uveitis before b-DMARD withdrawal Yes No 24 (18.5%) 106 (81.5%) b-DMARD stopped for remission Adalimumab Anakinra Baricitinib Canakinumab Etanercept Infliximab Tocilizumab 24 (18.5%) 7 (5.4%) 1 (0.8%) 2 (1.5%) 74 (56.9%) 5 (3.8%) 17 (13.1%) Delay between diagnosis and b-DMARD introduction (days) 197 (67.5-478.75) Line of b-DMARD therapy First ≥1 110 (84.6%) 20 (15.4%) Mtx present at b-DMARD stop for remission Yes No 18 (13.8%) 112 (86,2%) b-DMARD withdrawal method Spacing Other 105 (80.8%) 25 (19.2%) Age at b-DMARD withdrawal 11.2 (7.04-15.34) Biologic total decline time (years), (n=114) 0.85 (0.46-1.58) b-DMARD duration before withdrawal (years) 2.58 (1.72-3.42) Delay between first low cJADAS and b-DMARD withdrawal (years) 1.34 (0.70-2.19) b-DMARD withdrawal failure in the past? Yes No 16 (12.3%) 114 (87.7) Flare within one year after b-DMARD withdrawal 73 (56.2%) Flare within three year after b-DMARD withdrawal 86 (66.2%) Patients who re-started biologic therapy, n (%) 63/86 (73.3%) Table 2: Factors associated with relapse (n=130); univariable analysis . M, men; W, women; cJADAS, clinical juvenile arthritis disease activity score; Mtx, methotrexate; Characteristics Relapse within one year after b-DMARD withdrawal N = 73 No. (%)/ Median (IQR) No relapse within one year after b-DMARD withdrawal N = 57 No. (%)/ Median (IQR) Univariable analysis p-Value Gender M W (REF) 18 (47.4%) 55 (59.8%) 20 (52.6%) 37 (40.2%) 0.270 Diagnosis age 3.97 (2.01-7.17) 6.71 (2.75-11.8) 0.011 JIA-all subgroup Enthesitis Oligoarthritis (REF) Polyarthritis Psoriatic Systemic 11 (37.9%) 24 (77.4%) 14 (46.7%) 17 (89.5%) 7 (33.3%) 18 (62.1%) 7 (22.6%) 16 (53.3%) 2 (10.5%) 14 (66.6%) <0.001 Uveitis before b-DMARD withdrawal Yes No 16 (66.6%) 57 (53.8%) 8 (33.3%) 49 (46.2%) 0.357 AAN at diagnosis Negative Positive (REF) 14 (28.6%) 56 (73.7%) n = 70 35 (71.4%) 20 (26.3%) n = 55 <0.001 AAN at diagnosis in titer 320 (160-640) n = 63 160 (80-320) n = 39 0.028 Biologic drug stopped for remission Adalimumab Anakinra Baricitinib Canakinumab Etanercept (REF) Infliximab Tocilizumab 10 (41.7%) 3 (42.9%) 0 (0.0%) 1 (50%) 49 (66.2%) 3 (60%) 7 (41.2%) 14 (58.3%) 4 (57.1%) 1 (100%) 1 (50%) 25 (33.8%) 2 (40%) 10 (58.8%) 0.139 Delay between diagnosis and b-DMARD introduction (days) 273.0 (96-486) 122 (43-326) 0.196 b-DMARD duration before withdrawal (years) 2.51 (1.58-3.17) 2.70 (2.04-3.64) 0.273 Delay between first low cJADAS and b-DMARD stop (years) 1.25 (0.69 -1.98) n = 71 1.43 (0.82-2.33) n = 56 0.168 b-DMARD decrease type Spacing (REF) Others 57 (54.3%) 16 (64%) 48 (45.7%) 9 (36%) 0.512 If spacing; b-DMARD total decline duration before withdrawal (years) 0.67 (0.432;1.09) 1.08 (0.496;2.19) 0.016 Line of b-DMARD therapy First ≥1 65 (59.1%) 8 (40%) 45 (40.9%) 12 (60%) 0.143 b-DMARD withdrawal failure in the past? Yes No 9 (56.3%) 64 (56.1%) 7 (43.7%) 50 (43.9%) >0.999 Number of impacted joints at diagnosis 5 or more less than 5 (REF) 22 (55%) 49 (55.7%) n = 71 18 (45%) 39 (44.3%) n = 57 >0.999 Age at biologic drug stopped for remission years 8.91 (6.32-14.7) 13.19 (8.57-15.7) 0.027 Mtx present at b-DMARD stop for remission Yes No 8 (44.4%) 65 (58.0%) 10 (55.6%) 47 (42.0%) 0.314 Table 3: Factors associated with relapse (n=113); multivariable analysis Variable Univariable analysis, odds ratio (95% CI) Univariable analysis p-Value Multivariable analysis, adjusted odds ratio (95% CI) Multivariable analysis p value Sex 1.65 [0.772-3.54] 0.270 1.98 [0.624-6.30] 0.246 Diagnosis age 0.902 [0.832-0.977] 0.011 0.698 [0.433-1.13] 0.140 JIA-subgroup systemic/non systemic 0.326 [0.122-0.873] 0.026 0.987 [0.248-3.92] 0.985 ANA at diagnosis 7.00 [3.14-15.6] <0.001 13.0 [3.87-43.8] <0.001 Delay between diagnosis and b-DMARD introduction (days) 1.30 [0.872-1.95] 0.196 0.940 [0.252-3.51] 0.927 Delay between first low cJADAS and b-DMARD stop (years) 0.776 [0.542-1.11] 0.168 0.576 [0.353-0.939] 0.027 b-DMARD decrease type 0.668 (0.271-1.65) 0.512 1.71 [0.504-5.78] 0.390 Line of b-DMARD therapy 0.462 (0.175-1.22) 0.143 0.530 [0.115-2.44] 0.416 b-DMARD withdrawal failure in the past? 1.00 (0.350-2.88) >0.999 0.743 [0.199-2.77] 0.659 Number of impacted joints at diagnosis 1.03 (0.485-2.18) >0.999 0.803 [0.263-2.45] 0.700 Mtx present at b-DMARD stop for remission 0.578 [0.212-1.58] 0.314 0.385 [0.0908-1.63] 0.195 Table 4: Factors associated with relapse within 3 years after b/ts-DMARD withdrawal (n=130); univariable analysis Characteristics Relapse within three years after b-DMARD withdrawal N = 86 No. (%)/ Median (IQR) No relapse within three years after b-DMARD withdrawal N = 44 No. (%)/ Median (IQR) Univariable analysis p-Value Sex M W (REF) 21 (55.3.%) 65 (70.7%) 17 (44.7%) 27 (29.3%) 0.138 Diagnosis age 4.0 (2.00-7.70) 6.76 (2.95-12.4) 0.010 JIA-all subgroup Enthesitis Oligoarthritis (REF) Polyarthritis Psoriatic Systemic 13 (44.8%) 27 (87.1%) 20 (66.7%) 17 (89.5%) 9 (42.9%) 16 (55.2%) 4 (12.9%) 10 (33.3%) 2 (10.5%) 12 (57.1%) <0.001 Uveitis before b-DMARD withdrawal Yes No 20 (83.3%) 66 (62.3%) 4 (16.7%) 40 (37.7%) 0.058 ANA at diagnosis Negative Positive (REF) 19 (38.8%) 63 (82.9%) n = 76 30 (61.2%) 13 (17.1%) n = 49 <0.001 ANA at diagnosis in titer 320 (160-640) n = 75 80 (80-320) n = 27 0.004 Biologic drug stopped for remission Adalimumab Anakinra Baricitinib Canakinumab Etanercept (REF) Infliximab Tocilizumab 14 (58.3%) 3 (42.9%) 0 (0.0%) 1 (50%) 54 (73.0%) 4 (80%) 10 (58.8%) 10 (41.7%) 4 (57.1%) 1 (100%) 1 (50%) 20 (27.0%) 1 (20%) 7 (41.2%) 0.264 Delay between diagnosis and b-DMARD introduction (days) 276.0 (97.0-522) 112.5 (32.3-303) 0.012 b-DMARD duration before withdrawal (years) 2.57 (1.68-3.50) 2.62 (2.01-3.37) 0.920 Delay between first low cJADAS and b-DMARD stop (years) 1.34 (0.775 -2.07) n = 84 1.40 (0.620-2.19) n = 43 0.957 b-DMARD decrease type Spacing (REF) Others 68 (64.8%) 18 (72%) 37 (35.2%) 7 (28%) 0.639 If spacing; b-DMARD total decline duration before withdrawal (years) 0.705 (0.443-1.29) 1.03 (0.498;1.82) 0.15 Line of b-DMARD therapy First ≥1 76 (69.1%) 10 (50%) 34 (30.9%) 10 (50%) 0.124 b-DMARD withdrawal failure in the past? Yes No 11 (68.8%) 75 (65.8%) 5 (31.2%) 39 (34.2%) >0.999 Number of impacted joints at diagnosis 5 or more less than 5 (REF) 28 (70%) 56 (63.6%) n = 84 12 (30%) 32 (36.4%) n = 44 >0.999 Age at biologic drug stopped for remission years 9.56 (6.36-15.2) 13.24 (8.56-16.03) 0.077 Mtx present at b-DMARD stop for remission Yes No 14 (77.8%) 72 (64.3%) 4 (22.2%) 40 (35.7%) 0.298 Discussion In this sample of 115 JIA patients in whom b/ts-DMARD was withdrawn 130 times after more than 1 year of remission, the probability of relapse within 1 year after the treatment cessation was 56.2%. This result is a little less than expected from previous studies (≥ 60%) [ 15 ]. Our data suggest that odds of relapse when b/ts-DMARDs are stopped is increased with ANA positivity at diagnosis. This result is accentuated by the association between the probability of relapse and ANA titers. Also, the association was confirmed regarding the relapse probability within 3 years after the withdrawal. This biological marker was already suspected in previous studies but remained conflicting [14; 16; 25; 26]. Furthermore, the timing and definition of ANA positivity used in previous studies were vague. The precision of the definition in our study simplifies this issue in clinical practice (ANA status at diagnosis [-12; +12 months]). In addition, relapse within 1 year was predicted by a longer interval between achieving a sustained low cJADAS (< 2.5) and stopping b/ts-DMARDs. There is currently insufficient evidence to suggest that prolonged maintenance of remission with biotherapy before withdrawal reduces the likelihood of relapse [14;15;27–29]. However, our findings seem to support this association, which was demonstrated in another study [ 14 ]. In addition, relapse rate was reduced with longer total duration of b/ts-DMARD therapy before discontinuation, regardless of the method of discontinuation. Other relapse risk factors such as younger age at diagnosis and psoriasis and oligoarticular-JIA subtypes were identified in the univariable analysis. Many studies had already identified early onset of JIA as a significant factor of persistence of the disease into adulthood [30;31]. Among different JIA categories, children with systemic JIA had the lowest probability of flares, and children with psoriasis- and oligoarticular-JIA the highest. These results are consistent with previously published articles, although slightly more pronounced in psoriatic forms. As in previous studies, we found no superior stopping method, particularly spacing, which is currently the most widely used [2;15;21;26;32–40]. As well, a history of uveitis before discontinuation has not been identified as a predictor of relapse, even though this factor was highly suspected in several studies [15;41]. Finally, the last analysis evaluating relapse within 3 years after b/ts-DMARD withdrawal is relevant. Indeed, the intrinsic characteristics of the patient and the patient’s disease form remained significant, whereas characteristics linked to the withdrawal method were less important (probably having a greater impact in the short term). Thus, a shorter delay from JIA diagnosis to biological treatment start seemed related to decreased relapse rate. This result confirms the recent research theory defending the concept of a “window of opportunity” for JIA [22;41], with early b-DMARD treatment associated with better disease control and outcome. Strengths and limitations The main strengths of our study are the large number of patients, the strict inclusion criteria and, above all, the clear definitions of the various parameters, thus improving the external validity. Furthermore, our study is one of the first to attempt to use cJADAS as a score of minimal disease activity (< 2.5), a criterion that could be useful in future years to more accurately assess the efficacy of therapeutic response and is more measurable than the strict Wallace criteria [ 42 ]. The most important limiting factor of our study is its retrospective design. Another important bias could be the multiple inclusions of certain patients for different withdrawals. An analysis was performed to ensure that the descriptive characteristics did not differ between all treatment cessations and the first cessation only (supplementary Table 1). Another weakness of our study may be absence of children classified as having undifferentiated JIA. In fact, we chose to leave children in the category chosen by the rheumatologist following the patient. The method used in current practice at Kremlin-Bicêtre and Versailles consists of classifying children according to their predominant feature. After a thorough review of the files, the diagnoses corresponded well to the ILAR classification and there was no need to reclassify children as having undifferentiated disease. The low number of undifferentiated JIA cases could also be explained by the exclusion of any concomitant inflammatory or autoimmune disease and by patients with undifferentiated JIA often having more complex forms and therefore potentially less likely to stop their disease-modifying therapy because of remission. Two other types of prognostic factors for recurrence after b-DMARDs withdrawal are currently being studied and could provide a better framework for discontinuation: inflammatory parameters [ 43 – 49 ] and ultrasonography. These two points were not investigated in this study; they may require large prospective studies in the future. Our study showed that physicians use a variety of protocols to stop biotherapy. Clear protocols for b-DMARD withdrawal in JIA are needed to enable more rigorous analyses. In conclusion, factors for b/ts-DMARD withdrawal are not consensual and are the source of much discussion [19;32]. Our observations highlight already suspected relapse factors in JIA patients. ANA status at diagnosis may be a strong predictor to consider, with the same logic and risk factor as in JIA-liked uveitis. In addition, a prolonged (> 1 year) and gradual b/ts-DMARD decrease could be the best option before withdrawal. More investigations and more prospective studies are needed to confirm these findings. Declarations - Ethics approval and consent to participate : The JIR cohort was approved by the French ethics committee (CCTIRS) on April 21, 2015, and the electronic case report form was validated by the Commission Nationale de l'Informatique et des Libertés (CNIL). - Consent for publication : not applicable - Availability of data and materials : all data are available in the JIR cohort register - Competing interests : the authors declare that they have no competing interests - Funding : this study did not receive any financial support - Authors' contributions : IKP and VJ conceived and planned the study VJ wrote the main manuscript text supervised by IKP PD and VJ supervised the statistical analysis SC supervised the computing part of the JIR-cohort data VH, CG et LR participated in collecting data All authors participated in collecting data, drafting and revising the manuscript and approved the submitted version. - Acknowledgements : not applicable Author Contribution IKP and VJ conceived and planned the studyVJ wrote the main manuscript text supervised by IKPPD and VJ supervised the statistical analysisSC supervised the computing part of the JIR-cohort dataVH, CG et LR participated in collecting dataAll authors participated in collecting data, drafting and revising the manuscript and approved the submitted version. 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Rheumatol Int oct. 2013;33(10):2657–60. Baszis K, Garbutt J, Toib D, Mao J, King A, White A, et al. Clinical outcomes after withdrawal of anti-tumor necrosis factor α therapy in patients with juvenile idiopathic arthritis: A twelve-year experience: Withdrawal of Anti-TNFα Therapy in JIA. Arthritis Rheum oct. 2011;63(10):3163–8. Lovell DJ, Johnson AL, Huang B, Gottlieb BS, Morris PW, Kimura Y, et al. Risk, Timing, and Predictors of Disease Flare After Discontinuation of Anti–Tumor Necrosis Factor Therapy in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis With Clinically Inactive Disease. Arthritis Rheumatol sept. 2018;70(9):1508–18. Oliveira-Ramos F, Eusébio M, Martins M, Mourão F, Furtado AF, Campanilho-Marques C. Juvenile idiopathic arthritis in adulthood: fulfilment of classification criteria for adult rheumatic diseases, long-term outcomes and predictors of inactive disease, functional status and damage. RMD Open sept. 2016;2(2):e000304. Broughton T, Armon K. Defining Juvenile Idiopathic Arthritis Remission and Optimum Time for Disease-Modifying Anti-Rheumatic Drug Withdrawal: Why We Need a Consensus. Pediatr Drugs févr. 2012;14(1):7–12. Remesal A, Inocencio JD, Merino R. Discontinuation of Etanercept After Successful Treatment in Patients with Juvenile Idiopathic Arthritis. Pratsidou-Gertsi P, Trachana M, Pardalos G, Kanakoudi-Tsakalidou F. A follow-up study of patients with juvenile idiopathic arthritis who discontinued etanercept due to disease remission. Clin Exp Rheumatol. 2010;28(6):919–22. For the Childhood Arthritis and Rheumatology Research Alliance Systemic Juvenile Idiopathic Arthritis Workgroup, Shenoi S, Nanda K, Schulert GS, Bohnsack JF, Cooper AM, et al. Physician practices for withdrawal of medications in inactive systemic juvenile arthritis, Childhood Arthritis and Rheumatology Research Alliance (CARRA) survey. Pediatr Rheumatol déc. 2019;17(1):48. Klotsche J, Minden K, Niewerth M, Horneff G. Time spent in inactive disease before MTX withdrawal is relevant with regard to the flare risk in patients with JIA. Ann Rheum Dis juill. 2018;77(7):996–1002. Gottlieb BS, Keenan GF, Lu T, Ilowite NT. Discontinuation of Methotrexate Treatment in Juvenile Rheumatoid Arthritis. Pediatr 1 déc. 1997;100(6):994–7. Foell D, Wulffraat N, Wedderburn LR, Wittkowski H, Frosch M, Gerß J et al. Methotrexate Withdrawal at 6 vs 12 Months in Juvenile Idiopathic Arthritis in Remission. Cai Y, Liu X, Zhang W, Xu J, Cao L. Clinical trial of etanercept tapering in juvenile idiopathic arthritis during remission. Rheumatol Int sept. 2013;33(9):2277–82. Lerman MA, Lewen MD, Kempen JH, Mills MD. Uveitis Reactivation in Children Treated With Tumor Necrosis Factor Alpha Inhibitors. Am J Ophthalmol juill. 2015;160(1):193–e2001. Kearsley-Fleet L, Baildam E, Beresford MW, Douglas S, Foster HE, Southwood TR, et al. Successful stopping of biologic therapy for remission in children and young people with juvenile idiopathic arthritis. Rheumatol 2 mai. 2023;62(5):1926–35. Trincianti C, Van Dijkhuizen EHP, Alongi A, Mazzoni M, Swart JF, Nikishina I, et al. Definition and Validation of the American College of Rheumatology 2021 Juvenile Arthritis Disease Activity Score Cutoffs for Disease Activity States in Juvenile Idiopathic Arthritis. Arthritis Rheumatol nov. 2021;73(11):1966–75. Yamasaki Y, Takei S, Imanaka H, Nerome Y, Kubota T, Nonaka Y, et al. Prediction of long-term remission of oligo/polyarticular juvenile idiopathic arthritis with S100A12 and vascular endothelial growth factor. Mod Rheumatol 3 juill. 2016;26(4):551–6. Gerss J, Roth J, Holzinger D, Ruperto N, Wittkowski H, Frosch M, et al. Phagocyte-specific S100 proteins and high-sensitivity C reactive protein as biomarkers for a risk-adapted treatment to maintain remission in juvenile idiopathic arthritis: a comparative study. Ann Rheum Dis déc. 2012;71(12):1991–7. Gerss J, Tedy M, Klein A, Horneff G, Miranda-Garcia M, Kessel C, et al. Prevention of disease flares by risk-adapted stratification of therapy withdrawal in juvenile idiopathic arthritis: results from the PREVENT-JIA trial. Ann Rheum Dis juill. 2022;81(7):990–7. Mor-Vaknin N, Rivas M, Legendre M, Mohan S, Yuanfan Y, Mau T, et al. High Levels of DEK Autoantibodies in Sera of Patients With Polyarticular Juvenile Idiopathic Arthritis and With Early Disease Flares Following Cessation of Anti–Tumor Necrosis Factor Therapy. Arthritis Rheumatol avr. 2018;70(4):594–605. Anink J, Van Suijlekom-Smit LWA, Otten MH, Prince FHM, Van Rossum MAJ, Dolman KM, et al. MRP8/14 serum levels as a predictor of response to starting and stopping anti-TNF treatment in juvenile idiopathic arthritis. Arthritis Res Ther déc. 2015;17(1):200. Rothmund F, Gerss J, Ruperto N, Däbritz J, Wittkowski H, Frosch M, et al. Validation of Relapse Risk Biomarkers for Routine Use in Patients With Juvenile Idiopathic Arthritis. Arthritis Care Res juin. 2014;66(6):949–55. Rech J, Hueber AJ, Finzel S, Englbrecht M, Haschka J, Manger B, et al. Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment. Ann Rheum Dis sept. 2016;75(9):1637–44. Additional Declarations No competing interests reported. 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b/ts-DMARD, biologic/targeted synthetic disease-modifying anti-rheumatic drug; ILAR, International League of Associations for Rheumatology; IBD, inflammatory bowel disease; CRMO, chronic recurrent multifocal osteomyelitis; FMF, familial Mediterranean fever\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7334358/v1/3ab5d13b3f9ea43e7510866f.jpeg"},{"id":91073778,"identity":"a133beca-19b6-4fe6-b0d8-31c437af8839","added_by":"auto","created_at":"2025-09-11 11:00:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":75125,"visible":true,"origin":"","legend":"\u003cp\u003eMultivariable analysis of predictors of relapse after discontinuation of b/ts-DMARDs\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7334358/v1/b397514aa86fcd87990e4553.png"},{"id":96650107,"identity":"f766e27b-7121-4e27-8d98-136b72f43823","added_by":"auto","created_at":"2025-11-24 16:07:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2364101,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7334358/v1/3a1f6839-dc1c-4cc7-9a7c-fbe285aab350.pdf"},{"id":91073780,"identity":"9a88ccc7-8116-4285-9ca2-d4f7ac988f47","added_by":"auto","created_at":"2025-09-11 11:00:42","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":94968,"visible":true,"origin":"","legend":"","description":"","filename":"Table1SA.docx","url":"https://assets-eu.researchsquare.com/files/rs-7334358/v1/1baa03300b98d4eeae77e7cb.docx"},{"id":91075935,"identity":"5758f779-49c2-411e-9a87-568f4934eca3","added_by":"auto","created_at":"2025-09-11 11:08:42","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":100398,"visible":true,"origin":"","legend":"","description":"","filename":"Table2SA.docx","url":"https://assets-eu.researchsquare.com/files/rs-7334358/v1/c80848e0c620790f85c0d4e7.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Predictors of relapse after withdrawing biotherapies in children with inactive juvenile idiopathic arthritis: a retrospective cohort study of the JIR cohort","fulltext":[{"header":"key Message","content":"\u003cp\u003e\u003cstrong\u003e\u003cu\u003eWhat is already known on this topic\u003c/u\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u0026ndash;\u0026nbsp;\u003c/strong\u003eOnce remission on treatment has been achieved,\u0026nbsp;criteria for withdrawing b/ts-DMARDs in JIA patients remain unclear. After cessation, more than half of patients will relapse, and few studies have succeeded in identifying factors predictive of relapse, which would be essential for patient follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eWhat this study adds\u003c/u\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u0026ndash;This study enabled us to identify risk factors for relapse, some of which were already suspected but others newly identified, such as anti-nuclear antibody levels and the duration of biotherapy treatment after remission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eHow this study might affect research, practice or policy\u003c/u\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u0026ndash;This is an important study which could be used to better target recommendations concerning the choice and discontinuation of biotherapies in juvenile arthritis.\u0026nbsp;\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eJuvenile idiopathic arthritis (JIA) represents the most common cause of chronic arthritis in children. It affects about 1 in 1000 children [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The current diagnosis criteria are based on the International League of Associations for Rheumatology (ILAR) classification criteria.\u003c/p\u003e\u003cp\u003eOnce the diagnosis is established, early treatment is one of the keys to a good response. The current therapeutic strategy is based on the \u0026ldquo;treat to target\u0026rdquo; approach [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This method is now used for many inflammatory diseases in both adults and children. As a first step, the treatment is most often based on anti-inflammatory drugs or intra-articular corticosteroids injections; oral corticosteroids are also a possibility but only in certain situations. In some cases (associated uveitis, persistent disease activity), a conventional synthetic disease-modifying anti-rheumatic drug (cs-DMARD) is introduced (most commonly methotrexate). For children without response or with severe disease, a biologic or targeted synthetic DMARD (b/ts-DMARD) can be prescribed instead of or in addition to a cs-DMARD [8;9]. With these biologic treatments, inactive disease is now achieved most of the time and the JIA remains inactive for a long period. Remission while on treatment is defined as 6 consecutive months of inactive disease according to Wallace criteria [10;11].\u003c/p\u003e\u003cp\u003eOnce remission on treatment has been achieved, the DMARD is often tapered and then stopped because of a favorable benefit\u0026ndash;risk ratio on discontinuation of treatment [\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17 CR18\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Studies have shown that stopping methotrexate before biologics is preferable because of the reduced relapse rate [15;20;21]. After treatment withdrawal, the disease may evolve in two different ways, depending on the child: no relapse after withdrawal or disease recurrence (treatment dependence and relapse as soon as the treatment is stopped). Approximately 10\u0026ndash;40% of patients do not experience relapse after stopping treatment and have a transient form of JIA in childhood that does not persist into adulthood [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHowever, a major question for the physician is when and how to withdraw b/ts-DMARDs once remission on treatment is achieved. To date, there are only a few articles about the best way to stop the treatment. Therefore, criteria for withdrawing b/ts-DMARDs in JIA patients remain unclear and are mainly based on the clinical experience of the physician but also on the child\u0026rsquo;s drug tolerance. Here we aimed to identify one or more predictors of relapse after b/ts-DMARDs cessation that would encourage adaptation of the withdrawal strategy based on the risk of relapse.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatients\u003c/h2\u003e\u003cp\u003eWe designed a retrospective chart review of patients with JIA, classified according to the ILAR criteria [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], who were included in the Juvenile Inflammatory Rheumatism (JIR) cohort, an international multicenter database for patients with inflammatory or rheumatic diseases. We identified patients who received b/ts-DMARD treatment from 2000 to 2023 and were followed at two tertiary pediatric rheumatology centers: Bic\u0026ecirc;tre Hospital and Versailles Hospital, France. Any patient who received a b/ts-DMARD and achieved remission was eligible.\u003c/p\u003e\u003cp\u003eAmong these patients, we included those who received at least one b/ts-DMARD leading to inactive disease and then those who experienced a withdrawal of the b/ts-DMARD treatment because of disease remission (with age at b/ts-DMARD withdrawal\u0026thinsp;\u0026le;\u0026thinsp;18 years). The definition of disease remission on treatment was based on Wallace criteria (no joint with active arthritis; no systemic symptoms such as fever, rash, lymphadenopathy or serositis; no active uveitis; normal C-reactive protein level; physician\u0026rsquo;s disease activity evaluation\u0026thinsp;=\u0026thinsp;0). Patients had to meet all Wallace criteria for at least 6 months before withdrawal, as defined.\u003c/p\u003e\u003cp\u003ePatients were excluded if they had less than 1 year of follow-up after stopping b/ts-DMARD treatment or if they had comorbidities that could be a confounding factor, such as inflammatory bowel disease, diabetes, chronic recurrent multifocal osteomyelitis, Mediterranean fever, or Verneuil's disease.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary outcome was relapse within 1 year after b/ts-DMARD treatment cessation due to remission of JIA. Relapse was defined as no longer fulfilling remission criteria within 1 year after b/ts-DMARD withdrawal. The same patient could stop the treatment several times because of an iterative remission and relapse history. In our study, the 115 patients we studied were responsible for 130 discontinuations.\u003c/p\u003e\u003cp\u003eOne secondary outcome was also defined: the occurrence of relapse within 3 years after discontinuation of b/ts-DMARD treatment due to JIA remission (late relapse).\u003c/p\u003e\n\u003ch3\u003eData collected\u003c/h3\u003e\n\u003cp\u003eThe following data were collected (according to previously identified risk factors for relapse in JIA): 1) At the point of registration (JIA diagnosis), demographics (age, sex), JIA subtype, laboratory findings (rheumatoid factor, anti-CCP and antinuclear antibody (ANA) status [-12; +12 months] [ANA positivity defined as \u0026ge;\u0026thinsp;1/160 titers, with two blood measurements], ANA title, initial C-reactive protein level, HLA-B27 status); number of affected joints at diagnosis and joint involvement type at diagnosis. 2) During follow-up: disease activity assessment (Juvenile Arthritis Disease Activity Score [JADAS] or clinical JADAS). 3) At treatment withdrawal: type of b/ts-DMARD withdrawn and the withdrawal method (spacing or other), treatment decline duration before withdrawal, history of uveitis, previous b/ts-DMARD therapy before the one studied (first-line or second-line treatment), previous failure of b/ts-DMARD withdrawal, current methotrexate therapy, delay from diagnosis to b/ts-DMARD introduction, duration of the treatment stopped, time of b/ts-DMARD maintenance once inactive disease was achieved (cJADAS\u0026thinsp;\u0026le;\u0026thinsp;2.5).\u003c/p\u003e\n\u003ch3\u003eEthical considerations\u003c/h3\u003e\n\u003cp\u003eAll patients (and/or their legal guardian) were informed about the JIRcohort cohort, and no objections to participation were recorded. This study was conducted in accordance with the principles of the Declaration of Helsinki. The JIR cohort was approved by the French ethics committee (CCTIRS) on April 21, 2015, and the electronic case report form was validated by the Commission Nationale de l'Informatique et des Libert\u0026eacute;s (CNIL).\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eIn the descriptive analysis, treatment withdrawals were analysed by demographic and disease- and treatment-related factors. Results are described with median (interquartile range [IQR]) for continuous variables and frequencies (percentages) for categorical variables. Group comparability was assessed by comparing baseline demographic data and follow-up duration between groups. The normality of continuous variables was assessed with the Shapiro-Wilk test and heteroskedasticity with the Levene test, as appropriate. Continuous variables were standardized before statistical analysis to account for differences in measurement scales. Continuous outcomes were compared by unpaired Student \u003cem\u003et\u003c/em\u003e test, Welch \u003cem\u003et\u003c/em\u003e test, or Mann-Whitney U test depending on data distribution. Discrete outcomes were analyzed by chi-squared or Fisher\u0026rsquo;s exact test as appropriate. The alpha risk was set at 5%, and two-tailed tests were applied.\u003c/p\u003e\u003cp\u003eUnivariable and multivariable logistic regression was used to identify predictors of relapse within 1 year after b/ts-DMARD cessation. Variables included in the models were sex, age at diagnosis, ANA status at diagnosis, JIA subgroup (systemic/non-systemic), delay from diagnosis and b/ts-DMARD introduction, delay from first low c-JADAS and b/ts-DMARD cessation, b/ts-DMARD decrease type, line of b/ts-DMARD therapy, previous failure of b-DMARD withdrawal, methotrexate present at b/ts-DMARD cessation for remission, and number of affected joints at diagnosis.\u003c/p\u003e\u003cp\u003eVariable selection for the multivariate analysis was pre-defined, focusing on factors known from the literature to be associated with increased risk of relapse. Variables related to each other could not be included together in the same multivariable analysis. Thus, type of treatment was related to the JIA subgroup, and durations were also often related to each other.\u003c/p\u003e\u003cp\u003eData were checked for multicollinearity with the Belsley-Kuh-Welsch technique. Heteroskedasticity and normality of residuals were assessed with the Breusch-Pagan and Shapiro-Wilk test, respectively. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Patients with missing data were excluded from the analysis.\u003c/p\u003e\u003cp\u003eAll statistical analysis were performed with EasyMedStat 3.36 and supplemented by R 4.4.2.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eWe screened 655 patients with JIA classified according to the ILAR criteria; 291 (44.4%) received b/ts-DMARD treatment. We finally included 115 patients (16.5%) responsible for 130 treatment discontinuations (\u003cu\u003eFigure 1\u003c/u\u003e). The baseline characteristics of the 130 instances of b/ts-DMARD withdrawal are in \u003cu\u003eTable 1\u003c/u\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMost withdrawals occurred in female patients (70.8%; 92/130), and the median age at diagnosis was 5.29 years (IQR 2.3\u0026ndash;10.4). JIA subtypes included enthesitis-related arthritis (ERA; 22.3%), oligoarticular-JIA (23.8%), polyarthritis-JIA (23.1%), psoriasis-JIA (14.6%), and systemic-JIA (16.2%). The median time from diagnosis to the first introduction of b/ts-DMARD was 197 days (67.5\u0026ndash;478.8). The most stopped b/ts-DMARDs were etanercept (74/130), adalimumab (24/130), and tocilizumab (17/130), followed by anakinra (7/130), canakinumab (2/130), infliximab (5/130), and baricitinib (1/130). The median duration of b/ts-DMARD treatment before withdrawal was 2.58 years (1.72\u0026ndash;3.42), and the median age was 11.2 (7.0\u0026ndash;15.3) years at b/ts-DMARD cessation. The median time from achieving inactive disease to treatment withdrawal was 1.34 years (0.70\u0026ndash;2.19). Overall, 78.3% of withdrawals followed a spacing strategy before definitive withdrawal, and 21.7% used other discontinuation methods (gradual tapering, abrupt stop, or mixed approaches). Additionally, 13.8% (18/130) of patients were still on methotrexate at the time of b/ts-DMARD discontinuation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelapse analysis 1 year after treatment discontinuation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt 1 year, the relapse rate after discontinuation of b/ts-DMARD was 56.2% (73/130). On univariate analysis, six variables were significantly associated with increased odds of relapse (\u003cu\u003eTable 2\u003c/u\u003e): younger age at diagnosis (p = 0.011) and at the time of treatment withdrawal (p = 0.027); ANA positivity at diagnosis (p \u0026lt; 0.001) and increased ANA titers (p = 0.028); JIA subtype (p \u0026lt; 0.001; higher with psoriatic- and oligoarticular-JIA (89.5% and 77.4%) and lower with systemic-JIA and ERA (33.3% and 37.9%). Relapse rate was reduced for patients following an injection spacing strategy before b/ts-DMARD cessation with long tapering (p = 0.016).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn multivariable analysis (Figure 2), the odds of relapse was increased with ANA positivity at diagnosis (OR 13.0; 95% CI: 3.87\u0026ndash;43.8) and reduced with longer duration of clinically inactive disease before treatment withdrawal (OR 0.57; 95% CI: 0.35\u0026ndash;0.93) (\u003cu\u003eTable 3\u003c/u\u003e). These associations remained after excluding patients with systemic JIA from the analysis (supplementary \u003cu\u003eTable 2\u003c/u\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelapse 3 years after treatment discontinuation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe non-relapse group included patients who did not reach 3 years of follow-up but did not experience relapse within the first to third year (\u003cu\u003eTable 4\u003c/u\u003e\u003cu\u003e)\u003c/u\u003e. For those with relapse, the relapse date marked the end of follow-up. Among cases of withdrawal that did not show relapse in the first year, the median follow-up after treatment cessation was 2.00 years (IQR 1.30\u0026ndash;3.42). Five variables were linked to increased relapse rate: younger age at diagnosis (p = 0.010), ANA positivity at diagnosis (p \u0026lt; 0.001), increased ANA titers (p = 0.004), differences across JIA subtypes (p \u0026lt; 0.001), and shorter time from diagnosis to b/ts-DMARD initiation (p = 0.012).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eTable 1:\u003c/u\u003e \u003cu\u003eBaseline characteristics of the 130 b/ts-DMARD withdrawals analyzed.\u0026nbsp;\u003c/u\u003eCRP, C reactive protein; ANA, anti-nuclear antibodies; RF, rheumatoid factors; ACPA, anti-citrullinated protein antibodies.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eValues\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNo. (%)/ Median (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e92 (70.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e38 (29.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at diagnosis (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e5.29 (2.3-10.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJIA subtype\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eEnthesitis\u003c/p\u003e\n \u003cp\u003eOligoarthritis\u003c/p\u003e\n \u003cp\u003ePolyarthritis\u003c/p\u003e\n \u003cp\u003ePsoriatic\u003c/p\u003e\n \u003cp\u003eSystemic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e29 (22.3%)\u003c/p\u003e\n \u003cp\u003e31 (23.8%)\u003c/p\u003e\n \u003cp\u003e30 (23.1%)\u003c/p\u003e\n \u003cp\u003e19 (14.6%)\u003c/p\u003e\n \u003cp\u003e21 (16.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of impacted joints at diagnosis (n=128)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e5 or more\u003c/p\u003e\n \u003cp\u003eLess than 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e40 (31.2%)\u003c/p\u003e\n \u003cp\u003e88 (68.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJoint involvement type at diagnosis (n=128)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003ePeripheral only\u003c/p\u003e\n \u003cp\u003eAxial involvment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e114 (89.1%)\u003c/p\u003e\n \u003cp\u003e14 (10.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLaboratory findings\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eCRP at diagnosis (n=87)\u003c/p\u003e\n \u003cp\u003eANA+ (n=125)\u003c/p\u003e\n \u003cp\u003eANA in titer (n=102)\u003c/p\u003e\n \u003cp\u003eRF+ (n=99)\u003c/p\u003e\n \u003cp\u003eACPA + (n=83)\u003c/p\u003e\n \u003cp\u003eHLA-B27 + (n=74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11.0 (5.0-58.0)\u003c/p\u003e\n \u003cp\u003e76 (60.8%)\u003c/p\u003e\n \u003cp\u003e320 (100.0-640.0)\u003c/p\u003e\n \u003cp\u003e7 (7.1%)\u003c/p\u003e\n \u003cp\u003e7 (8.4%)\u003c/p\u003e\n \u003cp\u003e18 (24.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUveitis before b-DMARD withdrawal\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e24 (18.5%)\u003c/p\u003e\n \u003cp\u003e106 (81.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eb-DMARD stopped for remission\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAdalimumab\u003c/p\u003e\n \u003cp\u003eAnakinra\u003c/p\u003e\n \u003cp\u003eBaricitinib\u003c/p\u003e\n \u003cp\u003eCanakinumab\u003c/p\u003e\n \u003cp\u003eEtanercept\u003c/p\u003e\n \u003cp\u003eInfliximab\u003c/p\u003e\n \u003cp\u003eTocilizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e24 (18.5%)\u003c/p\u003e\n \u003cp\u003e7 (5.4%)\u003c/p\u003e\n \u003cp\u003e1 (0.8%)\u003c/p\u003e\n \u003cp\u003e2 (1.5%)\u003c/p\u003e\n \u003cp\u003e74 (56.9%)\u003c/p\u003e\n \u003cp\u003e5 (3.8%)\u003c/p\u003e\n \u003cp\u003e17 (13.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDelay between diagnosis and b-DMARD introduction (days)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e197 (67.5-478.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLine of b-DMARD therapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eFirst\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026ge;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e110 (84.6%)\u003c/p\u003e\n \u003cp\u003e20 (15.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMtx present at b-DMARD stop for remission\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18 (13.8%)\u003c/p\u003e\n \u003cp\u003e112 (86,2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eb-DMARD withdrawal method\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eSpacing\u003c/p\u003e\n \u003cp\u003eOther\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e105 (80.8%)\u003c/p\u003e\n \u003cp\u003e25 (19.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at b-DMARD withdrawal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e11.2 (7.04-15.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBiologic total decline time (years), (n=114)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e0.85 (0.46-1.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eb-DMARD duration before withdrawal (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e2.58 (1.72-3.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDelay between first low cJADAS and b-DMARD withdrawal (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e1.34 (0.70-2.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eb-DMARD withdrawal failure in the past?\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16 (12.3%)\u003c/p\u003e\n \u003cp\u003e114 (87.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFlare within one year after b-DMARD withdrawal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e73 (56.2%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFlare within three year after b-DMARD withdrawal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e86 (66.2%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 348px;\"\u003e\n \u003cp\u003ePatients who re-started biologic therapy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 219px;\"\u003e\n \u003cp\u003e63/86 (73.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eTable 2:\u003c/u\u003e \u003cu\u003eFactors associated with relapse (n=130); univariable analysis\u003c/u\u003e. M, men; W, women; cJADAS, clinical juvenile arthritis disease activity score; Mtx, methotrexate;\u003cu\u003e\u0026nbsp;\u003c/u\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"756\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRelapse within one year after b-DMARD withdrawal\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eN = 73 \u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo. (%)/ Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo relapse within one year after b-DMARD withdrawal\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eN = 57 \u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo. (%)/ Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariable analysis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ep-Value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003cp\u003eW (REF)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18 (47.4%)\u003c/p\u003e\n \u003cp\u003e55 (59.8%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e20 (52.6%)\u003c/p\u003e\n \u003cp\u003e37 (40.2%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.270\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnosis age\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e3.97 (2.01-7.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e6.71 (2.75-11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.011\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJIA-all subgroup\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eEnthesitis\u003c/p\u003e\n \u003cp\u003eOligoarthritis (REF)\u003c/p\u003e\n \u003cp\u003ePolyarthritis\u003c/p\u003e\n \u003cp\u003ePsoriatic\u003c/p\u003e\n \u003cp\u003eSystemic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (37.9%)\u003c/p\u003e\n \u003cp\u003e24 (77.4%)\u003c/p\u003e\n \u003cp\u003e14 (46.7%)\u003c/p\u003e\n \u003cp\u003e17 (89.5%)\u003c/p\u003e\n \u003cp\u003e7 (33.3%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18 (62.1%)\u003c/p\u003e\n \u003cp\u003e7 (22.6%)\u003c/p\u003e\n \u003cp\u003e16 (53.3%)\u003c/p\u003e\n \u003cp\u003e2 (10.5%)\u003c/p\u003e\n \u003cp\u003e14 (66.6%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUveitis before b-DMARD withdrawal\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16 (66.6%)\u003c/p\u003e\n \u003cp\u003e57 (53.8%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (33.3%)\u003c/p\u003e\n \u003cp\u003e49 (46.2%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.357\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAAN at diagnosis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003cp\u003ePositive\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(REF)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (28.6%)\u003c/p\u003e\n \u003cp\u003e56 (73.7%)\u003c/p\u003e\n \u003cp\u003en = 70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e35 (71.4%)\u003c/p\u003e\n \u003cp\u003e20 (26.3%)\u003c/p\u003e\n \u003cp\u003en = 55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAAN at diagnosis in titer\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e320 (160-640)\u003c/p\u003e\n \u003cp\u003en = 63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e160 (80-320)\u003c/p\u003e\n \u003cp\u003en = 39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.028\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Biologic drug stopped for remission\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAdalimumab\u003c/p\u003e\n \u003cp\u003eAnakinra\u003c/p\u003e\n \u003cp\u003eBaricitinib\u003c/p\u003e\n \u003cp\u003eCanakinumab\u003c/p\u003e\n \u003cp\u003eEtanercept (REF)\u003c/p\u003e\n \u003cp\u003eInfliximab\u003c/p\u003e\n \u003cp\u003eTocilizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10 (41.7%)\u003c/p\u003e\n \u003cp\u003e3 (42.9%)\u003c/p\u003e\n \u003cp\u003e0 (0.0%)\u003c/p\u003e\n \u003cp\u003e1 (50%)\u003c/p\u003e\n \u003cp\u003e49 (66.2%)\u003c/p\u003e\n \u003cp\u003e3 (60%)\u003c/p\u003e\n \u003cp\u003e7 (41.2%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (58.3%)\u003c/p\u003e\n \u003cp\u003e4 (57.1%)\u003c/p\u003e\n \u003cp\u003e1 (100%)\u003c/p\u003e\n \u003cp\u003e1 (50%)\u003c/p\u003e\n \u003cp\u003e25 (33.8%)\u003c/p\u003e\n \u003cp\u003e2 (40%)\u003c/p\u003e\n \u003cp\u003e10 (58.8%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.139\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDelay between diagnosis and b-DMARD introduction\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(days)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e273.0 (96-486)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e122 (43-326)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.196\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eb-DMARD duration before withdrawal (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e2.51 (1.58-3.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2.70 (2.04-3.64)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.273\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDelay between first low cJADAS and b-DMARD stop (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e1.25 (0.69 -1.98)\u003c/p\u003e\n \u003cp\u003en = 71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e1.43 (0.82-2.33)\u003c/p\u003e\n \u003cp\u003en = 56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.168\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eb-DMARD decrease type\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eSpacing (REF)\u003c/p\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e57 (54.3%)\u003c/p\u003e\n \u003cp\u003e16 (64%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e48 (45.7%)\u003c/p\u003e\n \u003cp\u003e9 (36%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.512\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIf spacing; b-DMARD total decline duration before withdrawal (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e0.67 (0.432;1.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e1.08 (0.496;2.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.016\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLine of b-DMARD therapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eFirst\u003c/p\u003e\n \u003cp\u003e\u0026ge;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e65 (59.1%)\u003c/p\u003e\n \u003cp\u003e8 (40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e45 (40.9%)\u003c/p\u003e\n \u003cp\u003e12 (60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.143\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eb-DMARD withdrawal failure in the past?\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 (56.3%)\u003c/p\u003e\n \u003cp\u003e64 (56.1%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7 (43.7%)\u003c/p\u003e\n \u003cp\u003e50 (43.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026gt;0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of impacted joints at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e5 or more\u003c/p\u003e\n \u003cp\u003eless than 5 (REF)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e22 (55%)\u003c/p\u003e\n \u003cp\u003e49 (55.7%)\u003c/p\u003e\n \u003cp\u003en = 71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18 (45%)\u003c/p\u003e\n \u003cp\u003e39 (44.3%)\u003c/p\u003e\n \u003cp\u003en = 57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026gt;0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at biologic drug stopped for remission years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8.91 (6.32-14.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13.19 (8.57-15.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.027\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 289px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMtx present at b-DMARD stop for remission\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 186px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (44.4%)\u003c/p\u003e\n \u003cp\u003e65 (58.0%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 187px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10 (55.6%)\u003c/p\u003e\n \u003cp\u003e47 (42.0%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.314\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eTable 3:\u003c/u\u003e \u003cu\u003eFactors associated with relapse (n=113); multivariable analysis\u003c/u\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"752\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 174px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariable \u0026nbsp;analysis, odds ratio (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariable analysis\u003cbr\u003e\u0026nbsp;p-Value\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultivariable analysis, adjusted odds ratio (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultivariable analysis p value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 174px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e1.65 [0.772-3.54]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0.270\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp\u003e1.98 [0.624-6.30]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0.246\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 174px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnosis age\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e0.902 [0.832-0.977]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.011\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp\u003e0.698 [0.433-1.13]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0.140\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 174px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJIA-subgroup systemic/non systemic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e0.326 [0.122-0.873]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.026\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp\u003e0.987 [0.248-3.92]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0.985\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 174px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eANA at diagnosis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e7.00 [3.14-15.6]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e13.0 [3.87-43.8]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 174px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDelay between diagnosis and b-DMARD introduction\u0026nbsp;\u003cbr\u003e\u0026nbsp;(days)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e1.30 [0.872-1.95]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0.196\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp\u003e0.940 [0.252-3.51]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0.927\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 174px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDelay between first low cJADAS and b-DMARD stop (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e0.776 [0.542-1.11]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0.168\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.576 [0.353-0.939]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.027\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 174px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eb-DMARD decrease type\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e0.668 (0.271-1.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0.512\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp\u003e1.71 [0.504-5.78]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0.390\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 174px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLine of b-DMARD therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e0.462 (0.175-1.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0.143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp\u003e0.530 [0.115-2.44]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0.416\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 174px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eb-DMARD withdrawal failure in the past?\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e1.00 (0.350-2.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026gt;0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp\u003e0.743 [0.199-2.77]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0.659\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 174px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of impacted joints at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e1.03 (0.485-2.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026gt;0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp\u003e0.803 [0.263-2.45]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0.700\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 174px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMtx present at b-DMARD stop for remission\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e0.578 [0.212-1.58]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0.314\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 177px;\"\u003e\n \u003cp\u003e0.385 [0.0908-1.63]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 144px;\"\u003e\n \u003cp\u003e0.195\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eTable 4:\u003c/u\u003e \u003cu\u003eFactors associated with relapse within 3 years after b/ts-DMARD withdrawal (n=130); univariable analysis\u003c/u\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"756\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRelapse within three years after b-DMARD withdrawal\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eN = 86 \u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo. (%)/ Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo relapse within three years after b-DMARD withdrawal\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eN = 44\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo. (%)/ Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnivariable analysis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ep-Value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003cp\u003eW (REF)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e21 (55.3.%)\u003c/p\u003e\n \u003cp\u003e65 (70.7%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17 (44.7%)\u003c/p\u003e\n \u003cp\u003e27 (29.3%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.138\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDiagnosis age\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e4.0 (2.00-7.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e6.76 (2.95-12.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.010\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eJIA-all subgroup\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eEnthesitis\u003c/p\u003e\n \u003cp\u003eOligoarthritis (REF)\u003c/p\u003e\n \u003cp\u003ePolyarthritis\u003c/p\u003e\n \u003cp\u003ePsoriatic\u003c/p\u003e\n \u003cp\u003eSystemic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13 (44.8%)\u003c/p\u003e\n \u003cp\u003e27 (87.1%)\u003c/p\u003e\n \u003cp\u003e20 (66.7%)\u003c/p\u003e\n \u003cp\u003e17 (89.5%)\u003c/p\u003e\n \u003cp\u003e9 (42.9%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16 (55.2%)\u003c/p\u003e\n \u003cp\u003e4 (12.9%)\u003c/p\u003e\n \u003cp\u003e10 (33.3%)\u003c/p\u003e\n \u003cp\u003e2 (10.5%)\u003c/p\u003e\n \u003cp\u003e12 (57.1%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUveitis before b-DMARD withdrawal\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e20 (83.3%)\u003c/p\u003e\n \u003cp\u003e66 (62.3%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (16.7%)\u003c/p\u003e\n \u003cp\u003e40 (37.7%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.058\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eANA at diagnosis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003cp\u003ePositive\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(REF)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e19 (38.8%)\u003c/p\u003e\n \u003cp\u003e63 (82.9%)\u003c/p\u003e\n \u003cp\u003en = 76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30 (61.2%)\u003c/p\u003e\n \u003cp\u003e13 (17.1%)\u003c/p\u003e\n \u003cp\u003en = 49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eANA at diagnosis in titer\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e320 (160-640)\u003c/p\u003e\n \u003cp\u003en = 75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e80 (80-320)\u003c/p\u003e\n \u003cp\u003en = 27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Biologic drug stopped for remission\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eAdalimumab\u003c/p\u003e\n \u003cp\u003eAnakinra\u003c/p\u003e\n \u003cp\u003eBaricitinib\u003c/p\u003e\n \u003cp\u003eCanakinumab\u003c/p\u003e\n \u003cp\u003eEtanercept (REF)\u003c/p\u003e\n \u003cp\u003eInfliximab\u003c/p\u003e\n \u003cp\u003eTocilizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (58.3%)\u003c/p\u003e\n \u003cp\u003e3 (42.9%)\u003c/p\u003e\n \u003cp\u003e0 (0.0%)\u003c/p\u003e\n \u003cp\u003e1 (50%)\u003c/p\u003e\n \u003cp\u003e54 (73.0%)\u003c/p\u003e\n \u003cp\u003e4 (80%)\u003c/p\u003e\n \u003cp\u003e10 (58.8%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10 (41.7%)\u003c/p\u003e\n \u003cp\u003e4 (57.1%)\u003c/p\u003e\n \u003cp\u003e1 (100%)\u003c/p\u003e\n \u003cp\u003e1 (50%)\u003c/p\u003e\n \u003cp\u003e20 (27.0%)\u003c/p\u003e\n \u003cp\u003e1 (20%)\u003c/p\u003e\n \u003cp\u003e7 (41.2%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.264\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDelay between diagnosis and b-DMARD introduction\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(days)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e276.0 (97.0-522)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e112.5 (32.3-303)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.012\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eb-DMARD duration before withdrawal (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2.57 (1.68-3.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2.62 (2.01-3.37)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.920\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDelay between first low cJADAS and b-DMARD stop (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e1.34 (0.775 -2.07)\u003c/p\u003e\n \u003cp\u003en = 84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e1.40 (0.620-2.19)\u003c/p\u003e\n \u003cp\u003en = 43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.957\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eb-DMARD decrease type\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eSpacing (REF)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Others\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e68 (64.8%)\u003c/p\u003e\n \u003cp\u003e18 (72%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e37 (35.2%)\u003c/p\u003e\n \u003cp\u003e7 (28%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.639\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIf spacing; b-DMARD total decline duration before withdrawal (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e0.705 (0.443-1.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e1.03 (0.498;1.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLine of b-DMARD therapy\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eFirst\u003c/p\u003e\n \u003cp\u003e\u0026ge;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e76 (69.1%)\u003c/p\u003e\n \u003cp\u003e10 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e34 (30.9%)\u003c/p\u003e\n \u003cp\u003e10 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.124\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eb-DMARD withdrawal failure in the past?\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (68.8%)\u003c/p\u003e\n \u003cp\u003e75 (65.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5 (31.2%)\u003c/p\u003e\n \u003cp\u003e39 (34.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e\u0026gt;0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNumber of impacted joints at diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e5 or more\u003c/p\u003e\n \u003cp\u003eless than 5 (REF)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e28 (70%)\u003c/p\u003e\n \u003cp\u003e56 (63.6%)\u003c/p\u003e\n \u003cp\u003en = 84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12 (30%)\u003c/p\u003e\n \u003cp\u003e32 (36.4%)\u003c/p\u003e\n \u003cp\u003en = 44\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e\u0026gt;0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at biologic drug stopped for remission years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9.56 (6.36-15.2)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13.24 (8.56-16.03)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.077\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 267px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMtx present at b-DMARD stop for remission\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Yes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (77.8%)\u003c/p\u003e\n \u003cp\u003e72 (64.3%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 214px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (22.2%)\u003c/p\u003e\n \u003cp\u003e40 (35.7%)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.298\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this sample of 115 JIA patients in whom b/ts-DMARD was withdrawn 130 times after more than 1 year of remission, the probability of relapse within 1 year after the treatment cessation was 56.2%. This result is a little less than expected from previous studies (\u0026ge;\u0026thinsp;60%) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOur data suggest that odds of relapse when b/ts-DMARDs are stopped is increased with ANA positivity at diagnosis. This result is accentuated by the association between the probability of relapse and ANA titers. Also, the association was confirmed regarding the relapse probability within 3 years after the withdrawal. This biological marker was already suspected in previous studies but remained conflicting [14; 16; 25; 26]. Furthermore, the timing and definition of ANA positivity used in previous studies were vague. The precision of the definition in our study simplifies this issue in clinical practice (ANA status at diagnosis [-12; +12 months]).\u003c/p\u003e\u003cp\u003eIn addition, relapse within 1 year was predicted by a longer interval between achieving a sustained low cJADAS (\u0026lt;\u0026thinsp;2.5) and stopping b/ts-DMARDs. There is currently insufficient evidence to suggest that prolonged maintenance of remission with biotherapy before withdrawal reduces the likelihood of relapse [14;15;27\u0026ndash;29]. However, our findings seem to support this association, which was demonstrated in another study [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In addition, relapse rate was reduced with longer total duration of b/ts-DMARD therapy before discontinuation, regardless of the method of discontinuation. Other relapse risk factors such as younger age at diagnosis and psoriasis and oligoarticular-JIA subtypes were identified in the univariable analysis.\u003c/p\u003e\u003cp\u003eMany studies had already identified early onset of JIA as a significant factor of persistence of the disease into adulthood [30;31]. Among different JIA categories, children with systemic JIA had the lowest probability of flares, and children with psoriasis- and oligoarticular-JIA the highest. These results are consistent with previously published articles, although slightly more pronounced in psoriatic forms.\u003c/p\u003e\u003cp\u003eAs in previous studies, we found no superior stopping method, particularly spacing, which is currently the most widely used [2;15;21;26;32\u0026ndash;40]. As well, a history of uveitis before discontinuation has not been identified as a predictor of relapse, even though this factor was highly suspected in several studies [15;41].\u003c/p\u003e\u003cp\u003eFinally, the last analysis evaluating relapse within 3 years after b/ts-DMARD withdrawal is relevant. Indeed, the intrinsic characteristics of the patient and the patient\u0026rsquo;s disease form remained significant, whereas characteristics linked to the withdrawal method were less important (probably having a greater impact in the short term).\u003c/p\u003e\u003cp\u003eThus, a shorter delay from JIA diagnosis to biological treatment start seemed related to decreased relapse rate. This result confirms the recent research theory defending the concept of a \u0026ldquo;window of opportunity\u0026rdquo; for JIA [22;41], with early b-DMARD treatment associated with better disease control and outcome.\u003c/p\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eStrengths and limitations\u003c/h2\u003e\u003cp\u003eThe main strengths of our study are the large number of patients, the strict inclusion criteria and, above all, the clear definitions of the various parameters, thus improving the external validity. Furthermore, our study is one of the first to attempt to use cJADAS as a score of minimal disease activity (\u0026lt;\u0026thinsp;2.5), a criterion that could be useful in future years to more accurately assess the efficacy of therapeutic response and is more measurable than the strict Wallace criteria [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe most important limiting factor of our study is its retrospective design. Another important bias could be the multiple inclusions of certain patients for different withdrawals. An analysis was performed to ensure that the descriptive characteristics did not differ between all treatment cessations and the first cessation only (supplementary Table\u0026nbsp;1). Another weakness of our study may be absence of children classified as having undifferentiated JIA. In fact, we chose to leave children in the category chosen by the rheumatologist following the patient. The method used in current practice at Kremlin-Bic\u0026ecirc;tre and Versailles consists of classifying children according to their predominant feature. After a thorough review of the files, the diagnoses corresponded well to the ILAR classification and there was no need to reclassify children as having undifferentiated disease. The low number of undifferentiated JIA cases could also be explained by the exclusion of any concomitant inflammatory or autoimmune disease and by patients with undifferentiated JIA often having more complex forms and therefore potentially less likely to stop their disease-modifying therapy because of remission.\u003c/p\u003e\u003cp\u003eTwo other types of prognostic factors for recurrence after b-DMARDs withdrawal are currently being studied and could provide a better framework for discontinuation: inflammatory parameters [\u003cspan additionalcitationids=\"CR44 CR45 CR46 CR47 CR48\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e] and ultrasonography. These two points were not investigated in this study; they may require large prospective studies in the future.\u003c/p\u003e\u003cp\u003eOur study showed that physicians use a variety of protocols to stop biotherapy. Clear protocols for b-DMARD withdrawal in JIA are needed to enable more rigorous analyses.\u003c/p\u003e\u003cp\u003eIn conclusion, factors for b/ts-DMARD withdrawal are not consensual and are the source of much discussion [19;32]. Our observations highlight already suspected relapse factors in JIA patients. ANA status at diagnosis may be a strong predictor to consider, with the same logic and risk factor as in JIA-liked uveitis. In addition, a prolonged (\u0026gt;\u0026thinsp;1 year) and gradual b/ts-DMARD decrease could be the best option before withdrawal. More investigations and more prospective studies are needed to confirm these findings.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e- \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eEthics approval and consent to participate\u003c/span\u003e: The JIR cohort was approved by the French ethics committee (CCTIRS) on April 21, 2015, and the electronic case report form was validated by the Commission Nationale de l'Informatique et des Libert\u0026eacute;s (CNIL).\u003c/p\u003e\u003cp\u003e- \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eConsent for publication\u003c/span\u003e: not applicable\u003c/p\u003e\u003cp\u003e- \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAvailability of data and materials\u003c/span\u003e: all data are available in the JIR cohort register\u003c/p\u003e\u003cp\u003e- \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eCompeting interests\u003c/span\u003e: the authors declare that they have no competing interests\u003c/p\u003e\u003cp\u003e- \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eFunding\u003c/span\u003e: this study did not receive any financial support\u003c/p\u003e\u003cp\u003e- \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAuthors' contributions\u003c/span\u003e:\u003c/p\u003e\u003cp\u003eIKP and VJ conceived and planned the study\u003c/p\u003e\u003cp\u003eVJ wrote the main manuscript text supervised by IKP\u003c/p\u003e\u003cp\u003ePD and VJ supervised the statistical analysis\u003c/p\u003e\u003cp\u003eSC supervised the computing part of the JIR-cohort data\u003c/p\u003e\u003cp\u003eVH, CG et LR participated in collecting data\u003c/p\u003e\u003cp\u003eAll authors participated in collecting data, drafting and revising the manuscript and approved the submitted version.\u003c/p\u003e\u003cp\u003e- \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eAcknowledgements\u003c/span\u003e: not applicable\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eIKP and VJ conceived and planned the studyVJ wrote the main manuscript text supervised by IKPPD and VJ supervised the statistical analysisSC supervised the computing part of the JIR-cohort dataVH, CG et LR participated in collecting dataAll authors participated in collecting data, drafting and revising the manuscript and approved the submitted version.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eManners PJ, Bower C. Worldwide Prevalence of Juvenile Arthritis \u0026mdash; Why Does It Vary So Much? The Journal of Rheumatology.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eProtocole National de Diagnostic et de Soins. (PNDS) AJI; 2017.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMerino R, Inocencio JD, Garc\u0026iacute;a-Consuegra J. Edmonton. Evaluation of Revised International League of Associations for Rheumatology Classification Criteria for Juvenile Idiopathic Arthritis in Spanish Children (2001).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMartini A, Ravelli A, Avcin T, Beresford MW, Burgos-Vargas R, Cuttica R, et al. Toward New Classification Criteria for Juvenile Idiopathic Arthritis: First Steps, Pediatric Rheumatology International Trials Organization International Consensus. J Rheumatol f\u0026eacute;vr. 2019;46(2):190\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen K, Zeng H, Togizbayev G, Martini A, Zeng H. New classification criteria for juvenile idiopathic arthritis. Int J Rheum Dis oct. 2023;26(10):1889\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePediatrics Department P, Catarino S, Nunes J, Pediatrics Department S et al. Pediatric and Young Adult Rheumatology Unit, Pediatrics Department, Centro Hospitalar Universit\u0026aacute;rio S\u0026atilde;o Jo\u0026atilde;o, Porto, Portugt alApplication of the new PRINTO classification criteria for juvenile idiopathic arthritis in a sample of Portuguese patients. ARP Rheumatol. mars. 2024;3(1):11\u0026thinsp;\u0026ndash;\u0026thinsp;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTer Haar NM, Van Dijkhuizen EHP, Swart JF, Van Royen-Kerkhof A, El Idrissi A, Leek AP, et al. Treatment to Target Using Recombinant Interleukin‐1 Receptor Antagonist as First‐Line Monotherapy in New‐Onset Systemic Juvenile Idiopathic Arthritis: Results From a Five‐Year Follow‐Up Study. Arthritis Rheumatol juill. 2019;71(7):1163\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRingold S, Angeles-Han ST, Beukelman T, Lovell D, Cuello CA, Becker ML, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non‐Systemic Polyarthritis, Sacroiliitis, and Enthesitis. Arthritis Care Res juin. 2019;71(6):717\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOnel KB, Horton DB, Lovell DJ, Shenoi S, Cuello CA, Angeles-Han ST, et al. 2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Oligoarthritis, Temporomandibular Joint Arthritis, and Systemic Juvenile Idiopathic Arthritis. Arthritis Rheumatol avr. 2022;74(4):553\u0026ndash;69.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWallace CA, Giannini EH, Huang B, Itert L, Ruperto N, Childhood Arthritis Rheumatology Research Alliance (CARRA). American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res juill. 2011;63(7):929\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWallace CA, Ruperto N. Preliminary Criteria for Clinical Remission for Select Categories of Juvenile Idiopathic Arthritis. The Journal of Rheumatology.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBeukelman T, Xie F, Chen L, Horton DB, Lewis JD, Mamtani R, et al. Risk of malignancy associated with paediatric use of tumour necrosis factor inhibitors. Ann Rheum Dis juill. 2018;77(7):1012\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTarkiainen M, Tynj\u0026auml;l\u0026auml; P, V\u0026auml;h\u0026auml;salo P, Lahdenne P. Occurrence of adverse events in patients with JIA receiving biologic agents: long-term follow-up in a real-life setting. Rheumatol juill. 2015;54(7):1170\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSimonini G, Ferrara G, Pontikaki I, Scoccimarro E, Giani T, Taddio A, et al. Flares After Withdrawal of Biologic Therapies in Juvenile Idiopathic Arthritis: Clinical and Laboratory Correlates of Remission Duration. Arthritis Care Res juill. 2018;70(7):1046\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHalyabar O, Mehta J, Ringold S, Rumsey DG, Horton DB. Treatment Withdrawal Following Remission in Juvenile Idiopathic Arthritis: A Systematic Review of the Literature. Pediatr Drugs d\u0026eacute;c. 2019;21(6):469\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGuzman J, Oen K, Huber AM, Watanabe Duffy K, Boire G, Shiff N, et al. The risk and nature of flares in juvenile idiopathic arthritis: results from the ReACCh-Out cohort. Ann Rheum Dis juin. 2016;75(6):1092\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGidman W, Meacock R, Symmons D. The Humanistic and Economic Burden of Juvenile Idiopathic Arthritis in the era of Biologic Medication. Curr Rheumatol Rep mai. 2015;17(5):31.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFor the Paediatric Rheumatology International Trials Organisation (PRINTO), BiKeR and the board of the Swedish Registry, Swart J, Giancane G, Horneff G, Magnusson B, Hofer M et al. Pharmacovigilance in juvenile idiopathic arthritis patients treated with biologic or synthetic drugs: combined data of more than 15,000 patients from Pharmachild and national registries. Arthritis Res Ther. d\u0026eacute;c. 2018;20(1):285.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVan Til JA, Kip MMA, Schatorj\u0026eacute; EJH, Currie G, Twilt M, Benseler SM et al. Withdrawing biologics in non-systemic JIA: what matters to pediatric rheumatologists? Pediatr Rheumatol. 11 juill. 2023;21(1):69.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNieto-Gonz\u0026aacute;lez JC, Garulo DC, Boteanu A, Trives-Folguera L, Garc\u0026iacute;a-Fern\u0026aacute;ndez A, Navarro PG, et al. What to Expect When Systemic Treatment in Juvenile Idiopathic Arthritis Is Withdrawn? J Rheumatol oct. 2023;50(10):1326\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChang CY, Meyer RML, Reiff AO. Impact of Medication Withdrawal Method on Flare-Free Survival in Patients with Juvenile Idiopathic Arthritis on Combination Therapy. Arthritis Care Res mai. 2015;67(5):658\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMinden K, Horneff G, Niewerth M, Seipelt E, Aringer M, Aries P, et al. Time of Disease-Modifying Antirheumatic Drug Start in Juvenile Idiopathic Arthritis and the Likelihood of a Drug‐Free Remission i7 Young Adulthood. Arthritis Care Res avr. 2019;71(4):471\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGlerup M, Rypdal V, Arnstad ED, Ekelund M, Peltoniemi S, Aalto K, et al. Long-Term Outcomes in Juvenile Idiopathic Arthritis: Eighteen Years of Follow‐Up in the Population‐Based Nordic Juvenile Idiopathic Arthritis Cohort. Arthritis Care Res avr. 2020;72(4):507\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBertilsson L, Andersson-G\u0026auml;re B, Fasth A, Petersson IF, Forsblad-D\u0026rsquo;elia H. Disease Course, Outcome, and Predictors of Outcome in a Population-based Juvenile Chronic Arthritis Cohort Followed for 17 Years. J Rheumatol mai. 2013;40(5):715\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIglesias E, Torrente-Segarra V, Bou R, Ricart S, Gonz\u0026aacute;lez MI, S\u0026aacute;nchez J, et al. Non-systemic juvenile idiopathic arthritis outcome after reaching clinical remission with anti-TNF-α therapy: a clinical practice observational study of patients who discontinued treatment. Rheumatol Int ao\u0026ucirc;t. 2014;34(8):1053\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAquilani A, Marafon DP, Marasco E, Nicolai R, Messia V, Perfetti F, et al. Predictors of Flare Following Etanercept Withdrawal in Patients with Rheumatoid Factor\u0026ndash;negative Juvenile Idiopathic Arthritis Who Reached Remission while Taking Medication. J Rheumatol juill. 2018;45(7):956\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePrince FHM, Twilt M, Simon SCM, Van Rossum MAJ, Armbrust W, Hoppenreijs EPAH, et al. When and how to stop etanercept after successful treatment of patients with juvenile idiopathic arthritis. Annals Rheumatic Dis 1 juill. 2009;68(7):1228\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePostępski J, Kobusińska K, Olesińska E, Osińska V, Opoka-Winiarska V. Clinical remission in juvenile idiopathic arthritis after termination of etanercept. Rheumatol Int oct. 2013;33(10):2657\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBaszis K, Garbutt J, Toib D, Mao J, King A, White A, et al. Clinical outcomes after withdrawal of anti-tumor necrosis factor α therapy in patients with juvenile idiopathic arthritis: A twelve-year experience: Withdrawal of Anti-TNFα Therapy in JIA. Arthritis Rheum oct. 2011;63(10):3163\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLovell DJ, Johnson AL, Huang B, Gottlieb BS, Morris PW, Kimura Y, et al. Risk, Timing, and Predictors of Disease Flare After Discontinuation of Anti\u0026ndash;Tumor Necrosis Factor Therapy in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis With Clinically Inactive Disease. Arthritis Rheumatol sept. 2018;70(9):1508\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOliveira-Ramos F, Eus\u0026eacute;bio M, Martins M, Mour\u0026atilde;o F, Furtado AF, Campanilho-Marques C. Juvenile idiopathic arthritis in adulthood: fulfilment of classification criteria for adult rheumatic diseases, long-term outcomes and predictors of inactive disease, functional status and damage. RMD Open sept. 2016;2(2):e000304.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBroughton T, Armon K. Defining Juvenile Idiopathic Arthritis Remission and Optimum Time for Disease-Modifying Anti-Rheumatic Drug Withdrawal: Why We Need a Consensus. Pediatr Drugs f\u0026eacute;vr. 2012;14(1):7\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRemesal A, Inocencio JD, Merino R. Discontinuation of Etanercept After Successful Treatment in Patients with Juvenile Idiopathic Arthritis.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePratsidou-Gertsi P, Trachana M, Pardalos G, Kanakoudi-Tsakalidou F. A follow-up study of patients with juvenile idiopathic arthritis who discontinued etanercept due to disease remission. Clin Exp Rheumatol. 2010;28(6):919\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFor the Childhood Arthritis and Rheumatology Research Alliance Systemic Juvenile Idiopathic Arthritis Workgroup, Shenoi S, Nanda K, Schulert GS, Bohnsack JF, Cooper AM, et al. Physician practices for withdrawal of medications in inactive systemic juvenile arthritis, Childhood Arthritis and Rheumatology Research Alliance (CARRA) survey. Pediatr Rheumatol d\u0026eacute;c. 2019;17(1):48.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKlotsche J, Minden K, Niewerth M, Horneff G. Time spent in inactive disease before MTX withdrawal is relevant with regard to the flare risk in patients with JIA. Ann Rheum Dis juill. 2018;77(7):996\u0026ndash;1002.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGottlieb BS, Keenan GF, Lu T, Ilowite NT. Discontinuation of Methotrexate Treatment in Juvenile Rheumatoid Arthritis. Pediatr 1 d\u0026eacute;c. 1997;100(6):994\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFoell D, Wulffraat N, Wedderburn LR, Wittkowski H, Frosch M, Ger\u0026szlig; J et al. Methotrexate Withdrawal at 6 vs 12 Months in Juvenile Idiopathic Arthritis in Remission.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCai Y, Liu X, Zhang W, Xu J, Cao L. Clinical trial of etanercept tapering in juvenile idiopathic arthritis during remission. Rheumatol Int sept. 2013;33(9):2277\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLerman MA, Lewen MD, Kempen JH, Mills MD. Uveitis Reactivation in Children Treated With Tumor Necrosis Factor Alpha Inhibitors. Am J Ophthalmol juill. 2015;160(1):193\u0026ndash;e2001.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKearsley-Fleet L, Baildam E, Beresford MW, Douglas S, Foster HE, Southwood TR, et al. Successful stopping of biologic therapy for remission in children and young people with juvenile idiopathic arthritis. Rheumatol 2 mai. 2023;62(5):1926\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTrincianti C, Van Dijkhuizen EHP, Alongi A, Mazzoni M, Swart JF, Nikishina I, et al. Definition and Validation of the American College of Rheumatology 2021 Juvenile Arthritis Disease Activity Score Cutoffs for Disease Activity States in Juvenile Idiopathic Arthritis. Arthritis Rheumatol nov. 2021;73(11):1966\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYamasaki Y, Takei S, Imanaka H, Nerome Y, Kubota T, Nonaka Y, et al. Prediction of long-term remission of oligo/polyarticular juvenile idiopathic arthritis with S100A12 and vascular endothelial growth factor. Mod Rheumatol 3 juill. 2016;26(4):551\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGerss J, Roth J, Holzinger D, Ruperto N, Wittkowski H, Frosch M, et al. Phagocyte-specific S100 proteins and high-sensitivity C reactive protein as biomarkers for a risk-adapted treatment to maintain remission in juvenile idiopathic arthritis: a comparative study. Ann Rheum Dis d\u0026eacute;c. 2012;71(12):1991\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGerss J, Tedy M, Klein A, Horneff G, Miranda-Garcia M, Kessel C, et al. Prevention of disease flares by risk-adapted stratification of therapy withdrawal in juvenile idiopathic arthritis: results from the PREVENT-JIA trial. Ann Rheum Dis juill. 2022;81(7):990\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMor-Vaknin N, Rivas M, Legendre M, Mohan S, Yuanfan Y, Mau T, et al. High Levels of DEK Autoantibodies in Sera of Patients With Polyarticular Juvenile Idiopathic Arthritis and With Early Disease Flares Following Cessation of Anti\u0026ndash;Tumor Necrosis Factor Therapy. Arthritis Rheumatol avr. 2018;70(4):594\u0026ndash;605.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAnink J, Van Suijlekom-Smit LWA, Otten MH, Prince FHM, Van Rossum MAJ, Dolman KM, et al. MRP8/14 serum levels as a predictor of response to starting and stopping anti-TNF treatment in juvenile idiopathic arthritis. Arthritis Res Ther d\u0026eacute;c. 2015;17(1):200.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRothmund F, Gerss J, Ruperto N, D\u0026auml;britz J, Wittkowski H, Frosch M, et al. Validation of Relapse Risk Biomarkers for Routine Use in Patients With Juvenile Idiopathic Arthritis. Arthritis Care Res juin. 2014;66(6):949\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRech J, Hueber AJ, Finzel S, Englbrecht M, Haschka J, Manger B, et al. Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment. Ann Rheum Dis sept. 2016;75(9):1637\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"proj","sideBox":"Learn more about [Pediatric Rheumatology](http://ped-rheum.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/proj/default.aspx","title":"Pediatric Rheumatology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"JIA, Treat to target, Remission, b/ts-DMARD withdrawal, Predictors of relapse","lastPublishedDoi":"10.21203/rs.3.rs-7334358/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7334358/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e\u003cp\u003eIn patients with juvenile idiopathic arthritis (JIA), the approach to discontinuing biological treatments after a period of remission remains exploratory. We aimed to identify one or more predictors of relapse after the discontinuation of biologic/targeted synthetic disease-modifying anti-rheumatic drugs.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe reviewed JIA patients followed in two French tertiary centers and included in the JIR cohort who had discontinued their biologic treatments from 2000 to 2023. Remission was defined according to the Wallace criteria. The primary outcome was relapse within 1 year after treatment withdrawal. Multivariate regression was used to analyze predictors of relapse.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 697 JIA patients received treatment in the two centers during the study period. We analyzed 130 instances of treatment discontinuation in 115 patients (16.5%) (70.8% girls [92/130], median age 5.29 years at diagnosis [interquartile range 2.3\u0026ndash;10.4]). Patients discontinued biological treatments after a median of 2.58 years, and 56.2% (73/130) of patients experienced relapse within 1 year after treatment withdrawal. The psoriasis subgroup had the highest relapse rate (89.5% [17/19]) and the systemic subgroup the lowest (33.3% [7/21]). The probably of relapse was increased with antinuclear antibody positivity at diagnosis (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and reduced with longer duration of clinically inactive disease before treatment withdrawal.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eRelapses are common after discontinuing biologic therapies in JIA, particularly in patients with antinuclear antibody positivity and psoriatic arthritis and those who stop treatment shortly after reaching inactive disease status.\u003c/p\u003e","manuscriptTitle":"Predictors of relapse after withdrawing biotherapies in children with inactive juvenile idiopathic arthritis: a retrospective cohort study of the JIR cohort","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-11 11:00:37","doi":"10.21203/rs.3.rs-7334358/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-29T15:18:29+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-29T13:30:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-28T16:56:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"128344225559481417599082231590281919513","date":"2025-09-23T07:32:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"330588921381384866130681612453338980754","date":"2025-09-23T06:33:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"63397325979581322762505410880746815269","date":"2025-09-22T06:03:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"209697882568521290390051543935835523805","date":"2025-09-21T10:04:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"76282951974769645078838711847536326795","date":"2025-09-21T09:59:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-09T11:27:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"327695006461776226915294521300996725634","date":"2025-09-04T08:50:48+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-04T05:07:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-26T01:53:30+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-26T01:52:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Rheumatology","date":"2025-08-09T13:54:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"proj","sideBox":"Learn more about [Pediatric Rheumatology](http://ped-rheum.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/proj/default.aspx","title":"Pediatric Rheumatology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"746cc5dd-de35-450f-a823-7bc85191506f","owner":[],"postedDate":"September 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-24T16:01:12+00:00","versionOfRecord":{"articleIdentity":"rs-7334358","link":"https://doi.org/10.1186/s12969-025-01171-7","journal":{"identity":"pediatric-rheumatology","isVorOnly":false,"title":"Pediatric Rheumatology"},"publishedOn":"2025-11-20 15:57:35","publishedOnDateReadable":"November 20th, 2025"},"versionCreatedAt":"2025-09-11 11:00:37","video":"","vorDoi":"10.1186/s12969-025-01171-7","vorDoiUrl":"https://doi.org/10.1186/s12969-025-01171-7","workflowStages":[]},"version":"v1","identity":"rs-7334358","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7334358","identity":"rs-7334358","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}