Castillo-Vilella et al. Pediatric Rheumatology (2021) 19:130 https://doi.org/10.1186/s12969-021-00607-0 RESEARCH ARTICLE Open Access Clinical remission and subsequent relapse in patients with juvenile idiopathic arthritis: predictive factors according to therapeutic approach Mireia Castillo-Vilella1,2,3,4* , Nuria Giménez4,5,6 , Jose Luis Tandaipan2,7,8, Salvador Quintana9 and Consuelo Modesto3,10 Abstract Background: Juvenile idiopathic arthritis constitutes a significant cause of disability and quality of life impairment in pediatric and adult patients. The aim of this study was to ascertain clinical remission (CR) and subsequent relapse in juvenile idiopathic arthritis (JIA) patients, according to therapeutic approach and JIA subtype. Evidence in literature regarding its predictors is scarce. Methods: We conducted an observational, ambispective study. Patients diagnosed of JIA, treated with synthetic and/or biologic disease modifying antirheumatic drugs (DMARD) were included and followed-up to December 31st, 2015. Primary outcome was clinical remission defined by Wallace criteria, both on and off medication. In order to ascertain CR according to therapeutic approach, DMARD treatments were divided in four groups: 1) synthetic DMARD (sDMARD) alone, 2) sDMARD combined with another sDMARD, 3) sDMARD combined with biologic DMAR D (bDMARD), and 4) bDMARD alone. Results: A total of 206 patients who received DMARD treatment were included. At the time the follow-up was completed, 70% of the patients in the cohort had attained CR at least once (144 out of 206), and 29% were in clinical remission off medication (59 out of 206). According to treatment group, CR was more frequently observed in patients treated with synthetic DMARD alone (53%). Within this group, CR was associated with female sex, oligoarticular persistent subtypes, ANA positivity, Methotrexate treatment and absence of HLA B27, comorbidities and DMARD toxicity. 124 DMARD treatments (62%) were withdrawn, 64% of which relapsed. Lower relapse rates were observed in those patients with persistent oligoarticular JIA (93%) when DMARD dose was tapered before withdrawal (77%). * Correspondence: mireiacastillo.vi@gmail.com Salvador Quintana is retired. 1 Department of Rheumatology, Hospital UniversitariSagrat Cor, C/ Londres, 28-38 3rd floor, 08029 Barcelona, Spain 2 Department of Rheumatology, Hospital UniversitariMútua Terrassa, Terrassa, Spain Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Castillo-Vilella et al. Pediatric Rheumatology (2021) 19:130 Page 2 of 10 Conclusions: More than two thirds of JIA patients attained CR along the 9 years of follow-up, and nearly one third achieved CR off medication. Females with early JIA onset, lower active joint count and ANA positivity were the ones achieving and sustaining remission more frequently, especially when receiving synthetic DMARD alone and in the absence of HLA B27, comorbidities or previous DMARD toxicity. Keywords: Juvenile arthritis, Remission, DMARD, Withdrawal, Relapse, Predictor Background biologic DMARD alone or combined is of significant Juvenile idiopathic arthritis is the most common chronic relevance due to its influence on its tolerability, adher- rheumatic disease in childhood. This term comprises an ence, safety, efficacy and on subsequent disease out- heterogenous group of arthritis of unknown aetiology, comes [9, 19, 20]. each of which has differential genetics, etiopathogenesis, onset age and disease outcomes [1, 2]. It constitutes a significant cause of disability and quality of life impair- Methods ment in JIA pediatric and adult patients [3–5]. We conducted a single-center, observational, retrospect- Recent advances in JIA treatment addressing more spe- ive-prospective study of JIA patients who were attended cific targets have led to better short and long-term disease at Vall d’Hebrón University Hospital’s Pediatric outcomes. Evidence throughout the last decade has shown Rheumatology Unit. This tertiary care hospital is a refer- that an early and tight treatment to target approach of the ence centre for JIA patients in Catalonia (Spain), where disease increases the likelihood of achieving and sustain- the mean JIA incidence was estimated to be of 6.9 per ing clinical remission over time [6–9]. Nevertheless, a not- 100,000 children by 2010 [21]. able proportion of patients relapse, either while still on A retrospective cohort was created on January 1st, medication or after its withdrawal [10–12]. 2012, in which patients diagnosed of JIA, treated with On the other hand, it seems reasonable to withdraw DMARD, and followed-up to December 31st, 2013, were all medications in those patients that already have included. Thereafter, a two-year prospective follow-up achieved CR to avoid the costs and possible adverse was performed from January 1st, 2014 to December events derived of maintaining it over time. In this 31st, 2015.Patients were included if: (a) the symptoms scenario, the main concern to most physicians is the started before age 16 and lasted for at least 6 weeks, (b) occurrence of a relapse, which has shown to be fre- fulfilled the ILAR Edmonton 2001 criteria [22], and (c) quent in most studies [13–15]. In those patients who were receiving synthetic and/or biologic DMARD. attain CR despite having a more aggressive course of Patients were evaluated every 3 months according to the disease, maintaining tapered DMARD doses could study protocol and local clinical practice. Demographic, increase the likelihood of sustaining a quiescent status clinical, immunologic and treatment data were collected of the disease over time, and avoid relapse after treat- from paper charts and electronic medical records. Uve- ment withdrawal [9, 13, 15, 16]. itis and other non-uveitis comorbidities were considered No consistent evidence or guidelines are available re- as separate variables taking into account the clinical rele- garding how or when to withdraw DMARD, or whether to vance of JIA-associated uveitis. Non-uveitis comorbidi- do it abruptly or after the dose has been gradually tapered. ties were defined as coexisting disorders or diseases, Some studies have analysed the possible predictors of flare other than uveitis, and not causally related to drug tox- in patients in CR on and off medication, obtaining hetero- icity. DMARDs were initiated in therapeutic doses ac- geneous and conflicting results. Moreover, those predictors cording to patient’s body surface when an optimal have not been validated to address therapeutic strategies in control of disease activity could not be attained or when a real practice setting. This fact is partly explained by the corticosteroids could not be withdrawn along the first 3 heterogeneity within JIA categories, which consequently months from disease or follow-up onset. Treatment ad- generates great variability in the definition and compos- justments were performed at scheduled appointments or ition of study populations. In addition, evidence in litera- earlier, if needed, in flare occurrence. DMARD tapering ture has shown heterogeneity in clinical remission and was defined as performing either a dose reduction inactive disease definitions, as well as significant variability (below therapeutic dose) or an increase in the interval in therapeutic strategies carried out by pediatric rheuma- between doses. When dose tapering was not performed, tologists in JIA treatment [13, 15, 17, 18]. the DMARD was abruptly withdrawn. Few studies have analysed the prevalence and likeli- This study was done in accordance with Ethics hood of CR regarding the therapeutic approach, which Research Committees of Vall d’Hebrón University Hos- stands the aim of our study. Administering synthetic and pital and Mútua Terrassa University Hospital, in the Castillo-Vilella et al. Pediatric Rheumatology (2021) 19:130 Page 3 of 10 corresponding phases of the study. Written consent was DMARD treatments. After 47 subsequent exclusions, obtained from patients and/or parents. 159 patients were included in the prospective study, which received 267 DMARD. At the end of follow-up, Clinical remission 136 patients remained on treatment, with 202 DMARD Primary outcome was Clinical Remission (CR) of the dis- (Fig. 1). ease, defined by Wallace criteria [23, 24] as: (a) no joints The cohort was 71% female and 93% Caucasian, with active arthritis, (b) no fever, rash, serositis, spleno- 52% had an oligoarticular JIA, 79% of which were megaly or lymphadenopathy attributable to JIA, (c) no persistent. Patients included had a median age at dis- active uveitis, (d) Normal erythrocyte sedimentation rate ease onset of 3 years [Inter quartile range (IQR) 4 or C-reactive protein level, (e) lowest possible physician’s years], at diagnosis of 4 years (IQR 5 years) and me- global assessment of disease activity score, and (f) morn- dian disease duration at first DMARD onset of 4 years ing stiffness shorter than 15 min. CR on medication was (IQR 8 years). Antinuclear antibodies (ANA) were de- defined as criteria were fulfilled for at least 6 months. tected in 68% of patients, and HLA B27 in 15% [67% CR off medication was defined as criteria were fulfilled of the enthesitis-related arthritis (ERA)]. Uveitis was for at least 12 months after all medication was with- present in 21% of patients (n = 43). Non-uveitis co- drawn [23, 24]. Relapse was defined as no longer fulfill- morbidities were registered in 20% of patients (n = ing criteria at one or more visits. To analyse CR 41). Of these, 32% were other autoimmune diseases according to the therapeutic approach, treatments with (n = 13), 32% genetic mutations or syndromes (n = DMARD were divided in four groups: 1) synthetic 13), 10% chronic infections (n = 4), 10% congenital DMARD (sDMARD) alone, 2) sDMARD combined with malformations (n = 4), and 16% miscellanea (n = 7). another sDMARD, 3) sDMARD combined with biologic Thirty-two patients associated non-uveitis comorbidi- DMARD (bDMARD), and 4) bDMARD alone. Second- ties with clinical significance (78%), being mild in ary outcome measures were CR predictive factors, 38% of the cases (n = 12), moderate in 34% (n = 11) DMARD dose tapering, tapering method and duration, and severe in 28% (n = 9). DMARD withdrawal due to CR, treatment duration up Patients who achieved CR at least once throughout to withdrawal, relapse after withdrawal, time to relapse study follow-up (Table 1) were predominantly Caucasian and relapse predictive factors. All patients withdrawing (94%), had a persistent oligoarticular JIA (84%), did not any DMARD treatment due to CR fulfilled at least associate non-uveitis comorbidities (87%), had not pre- Wallace’s criteria of CR on medication. sented aprevious DMARD adverse event (75%), and had not required biologic DMARD (58%) (p < 0.05). When Statistical analysis adjusting the analysis according to the JIA category, Qualitative variables were expressed as absolute values these results were confirmed for oligoarticular JIA. ERA and percentages. The normality was explored with the patients achieved CR more frequently in the absence of Kolmogorov-Smirnov test. Considering that all study non-uveitis comorbidities (88%, n = 15) (p = 0.035). The variables presented a non-normal distribution, non- significant variables related to ever achieving CR ob- parametric statistics was applied. Quantitative variables tained in the multivariate analysis were the absence of were expressed with medians and Interquartile Range both non-uveitis comorbidities β 3.12 (CI 95% 1.5–6.51) (IQR). In bivariate analysis, qualitative variables were (p = 0.002) and DMARD adverse event β 2.68 (CI 95% compared using the χ2 test, and the quantitative ones 1.42–5.07) (p = 0.002). with the Mann-Whitney U test. For significant variables, 95% CIs were established. For multivariate analysis, lo- Retrospective study gistic and linear regression models were used. Variables Throughout the retrospective study, with a median finally included in the multivariate model were those follow-up period of 7 years (IQR 9 years), 764 treatments showing statistical significance in the bivariate analysis with DMARD were administered, 75% with sDMARD or those with high clinical plausibility. The level of stat- (n = 570) and 25% with bDMARD (n = 291). istical significance was set to 0.05. Statistical analyses Methotrexate was the sDMARD most frequently dis- were performed using SPSS 25.0 (SPSS Inc., Armonk, pensed overall (n = 283), as the first (n = 169) and second NY, USA). (n = 57) sDMARD, and alone (n = 157). It was more commonly supplied to patients with oligoarticular sub- Results type (n = 157), ANA positivity (n = 197) and uveitis (n = A total of 264 patients meeting the ILAR diagnostic cri- 63). Moreover, CR was the most frequent reason for its teria for JIA were included, of which 254 had received withdrawal (n = 82). Other sDMARD administered were DMARD (synthetic or biologic). 206 patients were in- Leflunomide (22%, n = 125), Tacrolimus (7%, n = 41), cluded in the retrospective study, which received 764 Cyclosporine A (7%, n = 39), Sulfasalazine (5%, n = 31), Castillo-Vilella et al. Pediatric Rheumatology (2021) 19:130 Page 4 of 10 Fig. 1 Cohort of JIA patients: retrospective and prospective studies. From follow-up onset to December 31, 2015 Azathioprine (4%, n = 24), Mycophenolate mofetil (3%, performing the analysis according to treatment group n = 15) and Hydroxychloroquine (2%, n = 12). (Table 2), CR was more frequently observed in patients Etanercept was the most dispensed bDMARD overall treated with sDMARD alone (53%). In this group, CR (50%, n = 96), as first course (68%, n = 65), and alone was associated with oligoarticular persistent subtype and (43%, n = 42). Other dispensed bDMARD were Adalimu- Methotrexate treatment (p < 0.05). The absence of HLA mab (42%, n = 55) Infliximab (10%, n = 20), Anakinra B27 and DMARD toxicity were significantly related to (5%, n = 9), Tocilizumab (n = 9) and others (n = 5). higher rates of CR within all treatment groups (p < 0.05). Throughout the retrospective study, 64% of patients DMARD dose tapering was performed in 66% of ad- achieved CR at least once (131 of 206). The median ministered treatments. It was more commonly observed number of times that patients achieved CR was 1 (range in patients treated with sDMARD alone (75%) and com- 1 to 4). A total of 199 treatments were administered bined with bDMARD (60%) groups (p = 0.018). No dif- amid CR status of the disease (199 of 764). When ferences were observed regarding tapering method, Castillo-Vilella et al. Pediatric Rheumatology (2021) 19:130 Page 5 of 10 Table 1 Baseline characteristics of JIA patients according to ever achieving clinical remission of the disease Active Disease Clinical Remission TOTAL p (n = 62) (n = 144) (n = 206) Female sex, n (%) 44 (71) 103 (72) 147 (71) 0.531 a Caucasian ethnicity , n (%) 55 (89) 136 (94) 191 (93) 0.016 JIA subtype n (%) Oligoarticular 24 (39) 83 (58) 107 (52) 0.285 Persistenta 14 (58) 70 (84) 84 (41) 0.016 Extended 10 (42) 13 (16) 23 (12) Poliarticular RF - 9 (15) 11 (8) 20 (10) Poliarticular RF + 2 (3) 5 (4) 7 (3) Psoriatic 6 (10) 11 (8) 17 (8) Systemic 4 (7) 13 (9) 17 (8) Enthesitis-related arthritis 13 (21) 17 (12) 30 (15) Undifferentiated 3 (5) 5 (4) 8 (4) No uveitis, n (%) 47 (76) 116 (81) 163 (79) 0.277 a No comorbidities , n (%) 40 (65) 125 (87) 165 (80) 0.001 Positive ANA, n (%) 36 (58) 103 (72) 139 (68) 0.067 Positive RF, n (%) 3 (5) 6 (4) 9 (4) 0.536 HLA B27 presence, n (%) 13 (21) 18 (13) 31 (15) 0.073 No AE with DMARDa, n (%) 30 (48) 108 (75) 138 (67) 0.001 No biologic DMARDa, n (%) 22 (36) 84 (58) 106 (52) 0.002 n Number, JIA Juvenile idiopathic arthritis, RF- Negative rheumatoid factor, RF+ Positive rheumatoid factor, ANA Antinuclear antibodies, HLA B27 Human leukocyte antigen, AE Adverse event, DMARD Disease modifying antirheumatic drug a p < 0,05 Statistically significant differences using the χ2 order (sDMARD or bDMARD first), or duration [median commonly observed in patients with persistent forms 16 months, (IQR 28)]. Relapse amid dose tapering was (92%), without associated comorbidities (88%), treated scarce in all treatment groups (14%) (p > 0.05). DMARD with MTX (80%) as first DMARD (67%), and when dose withdrawal after dose tapering was significantly higher in was tapered (77%) (p < 0.05). patients receiving sDMARD exclusively, alone or com- Multivariate analysis demonstrated that variables sig- bined (86 and 89%, respectively). No significant associ- nificantly related to CR according to treatment group ation was observed between CR regarding treatment were persistent oligoarticular subtype (p = 0.001) and group and disease duration at DMARD onset, the DMAR DMARD dose tapering (p = 0.002). These results were D dispensed, or the order in which it was administered. confirmed in patients with oligoarticular JIA when A total of 124 DMARD treatments were withdrawn adjusting by ILAR category (p < 0.001). due to CR of the disease (62%). Median treatment dur- At the end of the retrospective study, 18% of patients ation up to withdrawal was significantly shorter in were in CR off treatment (n = 37). Of these, 28 were ex- patients receiving sDMARD alone (31 months, IQR 26 cluded due to maintaining remission and not requiring months). Moreover, of these, 64% relapsed after a DMARD during the prospective study. A total of 236 median time of 14 months (IQR 32 months). Signifi- DMARD were yet being administered, 60 of which were cantly lower relapse rates were observed in patients with dispensed to patients in CR status of the disease. DMAR persistent oligoarticular JIA (93%, n = 38) (p = 0.048) and D treatment continuation predominated in patients in in those in which DMARD dose was tapered before CR receiving bDMARD, alone (63%) and combined with withdrawal (77%, n = 50) (p = 0.001). When performing sDMARD (48%) (p = 0.001). the analysis according to JIA ILAR category, these re- sults were confirmed for oligoarticular JIA. Prospective study Further analysis, adjusting by ILAR category was per- Clinical remission was achieved by 17% of patients formed. Significant variables related to clinical remission throughout the two-year follow-up prospective study (27 in patients with oligoarticular forms of JIA are depicted out of 159 patients). A total of 57 DMARD treatments in Table 3. CR predominated in patients receiving were administered to patients in CR status of the disease sDMARD alone (53%). Within this group, CR was more (57 out of 267). Castillo-Vilella et al. Pediatric Rheumatology (2021) 19:130 Page 6 of 10 Table 2 Clinical remission in JIA patients treated with DMARD according to treatment group. Retrospective study results SDMARD SDMARD SDMARD BDMARD BDMARD Clinical p alone combined combined alone remission n = 106 (53%) n = 37 (19%) n = 48 (24%) n = 8 (4%) n = 199 JIA ILAR category a n (%) Oligoarticular 66 (62) 18 (49) 25 (52) 3 (1) 112 (56) 0.003 Persistent 61 (92) 13 (72) 17 (68) 1 (33) 92 (82) HLA B27 absence a n (%) 89 (84) 33 (89) 25 (52) 6 (75) 153 (85) 0,023 Synthetic DMARD a n (%) Metotrexate 78 (74) 18 (49) 15 (31) 0 108 (54) < 0.001 No AE with DMARD a n (%) 81 (76) 24 (65) 33 (69) 1 (13) 139 (70) 0.005 Dose tapering n = 132 Dose tapering a n (%) 80 (75) 18 (49) 29 (60) 5 (62) 132 (66) 0,018 Tapering method n (%) 0,071 Interval increase 35 (44) 8 (44) 12 (41) 5 (100) 60 (45) Dose decrease 30 (37) 7 (39) 15 (31) 0 46 (35) Both 15 (19) 3 (17) 1 (3) 0 19 (14) Tapering duration, months, median (IQR) 15 (20) 14 (27) 21 (25) 40 (30) 16 (28) 0,190 Relapse amid tapering, n (%) 10 (13) 5 (28) 4 (14) 0 19 (14) 0,330 a Withdrawal after tapering , n (%) 69 (86) 16 (89) 10 (34) 1 (13) 95 (72) < 0,001 Withdrawal due to CR n = 124 Withdrawal due to CR 71 (67) 29 (78) 21 (44) 3 (38) 124 (62) 0,728 Treatment duration to withdrawal due to 31 (26) 42 (43) 34 (54) 68 (71) 31 (30) 0,037 RC a, months, median (IQR) Relapse after withdrawal n (%) 50 (70) 16 (55) 11 (52) 2 (67) 79 (64) 0,783 Time to relapse, months, median (IQR) 13 (25) 42 (41) 10 (18) 14 14 (32) 0,122 SDMARD Synthetic disease modifying drug, BDMARD Biologic disease modifying drug, JIA Juvenile idiopathic arthritis, n Number, HLA B27 Human leukocyte antigen, AE Adverse event, IQR Interquartile range, CR Clinical remission a p < 0,05 Statistically significant differences using the χ2 or Mann Whitney U tests Patients demographic, clinical and treatment variables particularly in patients treated with sDMARD alone (p < significantly related to CR, according to treatment 0.05). When adjusting by JIA category, ANA association group, are summarized in Table 4. Clinical Remission with CR was confirmed for oligoarticular and psoriatic predominated in female patients in all treatment groups, subtypes and HLA B27 for oligoarticular and ERA sub- except in the sDMARD and bDMARD combined group types in those patients treated with sDMARD alone (p < (p = 0.037). Persistent oligoarticular forms, ANA positiv- 0.05). Two variables were significantly related to CR ac- ity, HLA B27 and uveitis absence were related to CR, cording to treatment group in multivariable model: Table 3 Clinical remission according to treatment group in patients with oligoarticular JIA SDMARD SDMARD SDMARD BDMARD BDMARD Clinical p alone combined combined alone remission n = 66 n = 18 n = 25 n =3 n = 112 Persistent 61 (92) 13 (72) 17 (68) 1 (33) 92 (46) 0.003 b Comorbidities absence, n (%) 58 (88) 15 (83) 23 (92) 1 (33) 97 (87) 0.042 Synthetic DMARD a, n (%) Metotrexate 53 (80) 9 (50) 8 (50) 0 70 (35) 0.025 First DMARD course c, n (%) 44 (67) 6 (28) 11 (44) 0 60 (54) 0.014 DMARD dose tapering a, n (%) 51 (77) 8 (44) 15 (60) 3 (100) 77 (69) 0.024 SDMARD Synthetic disease modifying drug, BDMARD Biologic disease modifying drug, JIA Juvenile idiopathic arthritis, n Number; a p < 0,05 Statistically significant differences using the χ2 test b Comorbidities other than uveitis and not related to drug toxicity c First DMARD course = DMARD dispensed in the first place, chronologically Castillo-Vilella et al. Pediatric Rheumatology (2021) 19:130 Page 7 of 10 Table 4 Clinical remission in JIA patients treated with DMARD according to treatment group. Prospective study results SDMARD SDMARD SDMARD BDMARD BDMARD Clinical p alone combined combined alone remission n = 33 (43%) n = 6 (8%) n = 23 (30%) n = 14 (18%) n = 76 Female sex a, n (%) 24 (73) 4 (67) 8 (35) 9 (64) 45 (59) 0.037 a Persistent oligoarticular , n (%) 19 (91) 6 (100) 4 (57) 2 (50) 31 (82) 0.048 ANA positivity a, n (%) 26 (79) 6 (100) 12 (52) 6 (43) 50 (66) 0.013 HLA B27 absence a, n (%) 31 (94) 0 12 (52) 8 (57) 57 (75) 0.005 Uveitis absence a, n (%) 27 (82) 2 (33) 21 (91) 13 (93) 63 (83) 0.006 Biologic DMARD a, n (%) Etanercept 0 0 5 (36) 10 (71) 15 (54) 0.040 a DMARD dose tapering , n (%) 29 (88) 3 (50) 14 (61) 11 (79) 57 (75) 0.050 SDMARD Synthetic disease modifying drug, BDMARD Biologic disease modifying drug, JIA Juvenile idiopathic arthritis, n Number; ANA Antinuclear antibodies, HLA B27 Human leukocyte antigen, AE Adverse event; IQR Interquartile range, CR Clinical remission a p < 0,05 Statistically significant differences using the χ2 or Mann Whitney U tests ANA (p = 0.034) and HLA B27 (p = 0.033). ANA nega- Greater CR rates were observed along retrospective tivity demonstrated a negative association with CR in pa- study, which might be explained by the longer follow-up tients treated with sDMARD alone β − 1.59 (CI 95% duration. In accordance with this observation, two stud- 0.43–0.955) (p = 0.044). ies have hypothesized, based on study results observed DMARD dose was tapered in 74% of treatments, with throughout last decade, that CR on medication increases median of two reductions per treatment (range 1 to 5). with longer disease duration [9, 17]. Dose tapering predominated in patients treated with In our study, patients were predominantly Caucasian synthetic or biologic DMARD administered alone (88 females, with early JIA onset (< 5 years), oligoarticular and 79%, respectively) (p = 0.050). No differences in persistent JIA, ANA positivity and early age at DMARD method, order, or duration (median 24 months, IQR 29) onset (< 6 years). MTX was the most frequently adminis- were observed among treatment groups. Relapse tered sDMARD and the most commonly administered throughout dose tapering was scarce (11%) and 39% of alone. DMARD treatments were subsequently withdrawn, Ever attaining CR was related to persistent oligoarticu- showing no significant differences regarding treatment lar subtype, absence of coexisting comorbidities (other (p > 0.05). Out of 267 treatments administered, 34% were than uveitis) and not having undergone an adverse event withdrawn due to CR of the disease (n = 26) with me- with DMARD therapy. These results were confirmed for dian treatment duration to withdrawal of 12 months oligoarticular JIA patients, among which CR predomi- (IQR 11) and 12% of relapse (n = 3). Median time to nated in those treated with Methotrexate alone and as relapse was 10 months, comparable in all treatment first DMARD. Patients with oligoarticular JIA, particu- groups (p > 0.05). larly those with persistent subtype, have achieved the To conclude, when the follow-up was completed, 70% highest CR rates on and off medication in various stud- of the patients in the cohort had attained CR at least ies, being treated in most cases with MTX as DMARD once (144 out of 206), and 29% were in CR off all medi- of choice [17, 25–27]. cation (59 out of 206). Of these, 69% achieved CR off On the other hand, coexisting comorbidities in JIA pa- medication throughout the retrospective study and tients, including other autoimmune diseases, genetic maintained it along the 24-month prospective study syndromes, or chronic infections, among others, could (n = 41). Clinical remission off medication (n = 59), re- lead to both: a higher occurrence of DMARD toxicity garding JIA subtype, was attained by 30 oligoarticular, and inefficacy. Raab et al. studied associated comorbidi- 11 ERA, 10 systemic, 4 poliarticular RF negative, 3 un- ties in young adult JIA patients of the JuMBO register differentiated and 1 poliarticular RF positive patients. and concluded that comorbidities have a significant im- pact on disease activity and global health status [28]. Furthermore, Simon et al. have recently put in evidence Discussion that patients with JIA are more likely to have concurrent Clinical remission of the disease, based on Wallace cri- autoimmune diseases, and this association might have teria, was achieved at least once by 70% of the JIA pa- an important role in JIA treatment decisions and out- tients included in the cohort along a median of 9-year comes [29]. follow-up, and was the main reason of DMARD with- Lastly, the negative influence of DMARD toxicity in drawal in both studies. ever achieving CR in JIA patients could be explained in Castillo-Vilella et al. Pediatric Rheumatology (2021) 19:130 Page 8 of 10 those having a more aggressive course of the disease. In Dose tapering was performed in two thirds of patients these, higher DMARD doses and therapeutic targets are in CR on medication. Relapse throughout dose tapering combined, leading to a greater likelihood of DMARD was scarce in both studies. Two thirds of DMARD treat- withdrawal due to drug toxicity and subsequent poorer ments administered along CR of the disease were with- control of disease activity. drawn throughout our retrospective study, with a According to therapeutic approach, CR was observed in subsequent relapse observed in two thirds of the cases, patients treated with synthetic DMARD alone more than after a median time to relapse of about 12 months with half of the times, being Methotrexate the most adminis- comparable results in all treatment groups. Significant tered sDMARD and being CR the predominant reason of lower rates of relapse after withdrawal were observed in its withdrawal. These findings support that Methotrexate patients with persistent oligoarticular JIA, treated with is still the DMARD of choice in most JIA categories, even sDMARD alone (mostly Methotrexate) in which the in the biologic era [10, 30, 31]. Within this group CR was drug dose was previously tapered. Nonetheless, no dif- associated with female sex, persistent oligoarticular sub- ferences in method, order (sDMARD or bDMARD first) type, absence of comorbidities (other than uveitis) and or duration (median longer than 12 months in both Methotrexate treatment as first DMARD course. ANA studies) of dose tapering were observed within treatment positivity, the absence of HLA B27, uveitis and DMARD groups in both studies, and neither was associated with toxicity, and having performed DMARD dose tapering CR of the disease nor relapse after withdrawal. Regard- were related to higher CR rates within all treatment ing patients in CR on medication, our therapeutic groups, but more significantly to patients treated with strategy is comparable to the one performed by most sDMARD alone. Furthermore, ANA association with CR rheumatologists participating in two survey studies, who was confirmed for oligoarticular and psoriatic subtypes would wait at least 12 months while in CR on medica- and HLA B27 for oligoarticular and ERA subtypes in those tion to start considering DMARD tapering or withdrawal patients treated with sDMARD alone. However, the re- [14, 15]. Furthermore, given that CR was more fre- sults must be considered cautiously, since the number of quently achieved in patients treated with MTX alone in patients in some categories was scarce. our study, these results would support that maintaining The role of ANA positivity in the likelihood of achiev- MTX at least for 12 months after achieving CR before ing and sustaining CR, and therefore, in short and long- withdrawal is associated with a higher likelihood of term outcomes, has not yet been clarified. Some studies maintaining remission off treatment, as suggested by suggest that ANA negativity would lead to a poorer re- Klotscheet al [43]. One of the limitations of our study is sponse to MTX throughout the first 6 months of the dis- that the exact date of clinical remission start was un- ease, a higher active joint count along the first 6 to 24 available in most patients, and therefore, total duration months, regardless on active joint count, and to a per- of CR on treatment could not be measured. Duration of sistent active disease through the first 3 years from JIA CR on medication remains currently of significant inter- onset [25, 32–34]. The possible association between est given that its association with relapse after treatment ANA positivity and a better MTX response would ex- discontinuation has shown conflicting results [13]. plain that oligoarticular patients included in the study, When the study finalised after a median follow-up and not having coexistent comorbidities (uveitis or time of 9 years, more than two thirds had attained CR at others), would have solely required treatment with least once, and nearly one third of patients were in clin- Methotrexate alone to attain CR. These results would ical remission off all medication, which is slightly lower support what has been recently suggested in two studies than the 42% observed in Nordalet al. study [44]. Con- which showed that JIA patients with early onset, ANA sidering that in our study persistent oligoarticular JIA is positivity and lower active joint count, constitute a the most prevalent JIA subtype, we might have underes- homogeneous JIA subtype with less aggressive course of timated CR rates through follow-up losses, given that the disease, higher likelihood of achieving CR and subse- patients lost to follow up would more likely be in remis- quently better outcome [35, 36]. Nevertheless, our re- sion than those who maintain it. sults contravene the results obtained in two other On the other hand, two thirds were still on DMARD studies which suggest that ANA status does not alter re- therapy. It should be noted that in those patients treated mission rates nor JIA outcome [37, 38]. with sDMARD and bDMARD combined, tapering dur- Regarding HLA B27, several studies have put in evi- ation and number of times the dose was tapered were dence that HLA B27 presence in JIA patients leads to a greater, whereas subsequent withdrawal and following higher risk of bone erosions and radiologic structural flares were less frequently observed in the prospective damage appearance [39, 40], a more persistent and ex- study. This fact would support the recently growing be- tended course of the disease [41, 42], and a lower likeli- lief that in some patients, especially those with persistent hood of achieving clinical remission [12, 25]. and extended poliarticular RF positive, systemic or ERA Castillo-Vilella et al. Pediatric Rheumatology (2021) 19:130 Page 9 of 10 JIA, the disease behaves more aggressively, needing more Availability of data and materials specific therapeutic targets and a sustained treatment The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. over time, even when CR is achieved. In those scenarios, maintaining a minimum and progressively tapered dose Declarations for at least 12 months (before even considering with- drawal) would appear to be a good therapeutic approach Ethics approval and consent to participate this study was done in accordance with Ethics Research Committees of Vall to minimize subsequent relapses. d’Hebron University Hospital and Mútua Terrassa University Hospital, in the The main limitation of our study is its observational corresponding phases of the study. mono-centric and non-controlled design. This fact might have led to selection bias, having a lower number of Consent for publication Written consent was obtained from all patients and/or parents. patients included in a predominantly oligoarticular JIA cohort. Consequently, the depicted results should be ap- Competing interests plied cautiously to other JIA categories. That being said, None declared. the coincidence of the results obtained in both retro- spective and prospective studies grants coherence to the Author details 1 Department of Rheumatology, Hospital UniversitariSagrat Cor, C/ Londres, conclusions provided. Lastly, this study fails to describe 28-38 3rd floor, 08029 Barcelona, Spain. 2Department of Rheumatology, total duration of CR both on and off medication as the Hospital UniversitariMútua Terrassa, Terrassa, Spain. 3Department of exact date of CR onset was unavailable in most patients. Rheumatology, Pediatric Rheumatology Unit, Hospital UniversitariValld’Hebrón, Barcelona, Spain. 4Departament de Farmacologia, Clinical remission’s survival in JIA patients remains an Terapèutica i Toxicologia, UniversitatAutònoma de Barcelona, Barcelona, issue of great concern given the complexity of establish- Spain. 5Research Unit, University Hospital of Mútua Terrassa, Research ing and defining when CR itself begins. Foundation Mútua Terrassa, Universitat de Barcelona, Barcelona, Spain. 6 Hospital Sant Jaume de Calella, Laboratori de Referència de Catalunya i Corporació de Salut del Maresme i la Selva, Barcelona, Spain. 7Departament of Rheumatology and Systemic Autoimmune Diseases, Hospital de la Santa Conclusions Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. 8 More than two thirds of JIA patients attained CR along Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, the 9 years of follow-up, and nearly one third achieved Spain. 9Retired, Barcelona, Spain. 10Department of Rheumatology, Hospital Universitario de Cruces, Barakaldo, Spain. CR off medication. Females with early JIA onset, lower active joint count and ANA positivity were the ones Received: 28 January 2021 Accepted: 31 May 2021 achieving and sustaining remission more frequently, es- pecially when receiving synthetic DMARD alone and in References the absence of HLA B27, comorbidities or previous 1. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369(9563):767– DMARD toxicity. In patients who already have attained 78. https://doi.org/10.1016/S0140-6736(07)60363-8. remission, a progressive DMARD dose tapering for at 2. Martini A, Ravelli A, Avcin T, Beresford MW, Burgos-Vargas R, Cuttica R, et al. Toward new classification criteria for juvenile idiopathic arthritis: least 1 year before considering withdrawal would first steps. Pediatric rheumatology international trials organization minimize the probability of subsequent relapse, particu- international consensus. 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