Identifying flare prone Spondyloarthritis – insights from a prospective cohort

Identifying flare prone Spondyloarthritis – insights from a prospective 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 Identifying flare prone Spondyloarthritis – insights from a prospective cohort Abilash Krishnan Vijayakumaran, Sayan Mukherjee, Urmila Dhakad, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7045624/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives: To determine characteristics of flares in spondyloarthritis and to identify differences between flare and non-flare populations. Methods: A cohort of 106 patients (2650 patient-weeks follow-up and 318 visits) who fulfilled the ESSG or ASAS classification criteria for SpA were followed up for 6 months. The diagnosis of flare was made by rheumatologist using patient-reported indices and ruling out confounders. Results: 67/ 106 (63.2%) patients were diagnosed flare at 6 months of which 51 (76.1%) developed major/ generalized flares and 16 (23.9%) developed minor/ localized flares. Shorter time since diagnosis (disease duration less than 6 years), current/ past history of enthesitis at baseline, steroid requirement and high disease activity at baseline were significantly favouring flares and ax-SpA was associated with lower tendency to flare in univariable analyses. Multivariable logistic regression analyses revealed inactive (OR 0.21 [95% CI 0.047–0.942], p = 0.042) or low disease at baseline (OR 0.25 [95% CI 0.089–0.718], p = 0.011) was significantly associated with lower tendency of flare while current/ past enthesitis (OR 11.29 [95% CI 1.3–93.46], p = 0.025) favoured greater tendency to flare, with variable effect size. A general linear model for repeated measures revealed significant differences in longitudinal change in all ASAS validated indices between flare and non-flare groups. Conclusion: The study identifies predictors in spondyloarthritis with increased tendency to flare. The results suggest that patients with low/ inactive disease at baseline may have fewer flares and enthesitis may associate with higher tendency to flare. Figures Figure 1 Key Points 1. Inactive/ low disease at baseline was significantly associated with lower tendency of flare and current/ past enthesitis at baseline favored greater tendency to flare. 2. Longitudinal change in ASAS-coreset measures was significantly different between flare and non-flare populations. 3. In countries where tapering TNF inhibitors is routinely practiced due to financial considerations, identifying flare-prone population would facilitate careful tapering. Introduction Axial Spondyloarthritis (axSpA) is an umbrella term denoting chronic inflammation of the spine and sacroiliac joints that includes polyenthesitis of the vertebral column. Flares are episodes of disease worsening requiring change in treatment. Flares in spondyloarthritis (SpA) are frequent, causing worse outcomes [ 1 ][ 2 ]. Definitions of flares are diverse, owing to the multi-faceted nature of the disease. The ASAS (Assessment of SpondyloArthritis international Society) expert group reached a consensus after analyzing 12 different definitions of clinically important worsening. A worsening of ASDAS-CRP of more than 0.9 points was chosen to define clinically important worsening in axSpA [ 3 ]. A study assessing outcome measures to detect flares identified absolute change of BASDAI more than or equal to 2 or a relative change ≥ 30% in subcomponents of BASDAI may indicate a meaningful symptomatic deterioration [ 4 ]. Agreement between perception of flares by doctors and patients was not high (Cohen’s kappa coefficient of 0.61) [ 5 ]. Another study divided flares into generalized/ major and localized/ minor flares. Minor flares were pain/ swelling restricted to one area with fatigue and stiffness and major flares were ‘generalized pain, hot burning joints, muscle spasm, fever, sweating, extreme fatigue and stiffness’[ 6 ]. Data from discontinuation trials of TNF inhibitors showed that discontinuation caused increase in flares as high as 79% compared to placebo. 2-year data from the ESTHER trial showed that the flare rate was similar in etanercept-treated patients’ group and sulfasalazine-treated patients’ group at a mean duration of 24.4 weeks after drug discontinuation (69% vs 75%) [ 7 ]. It is clear that use of TNF inhibitors has no protective effect in preventing flares after discontinuation, especially in early disease. Also, restarting TNF inhibitors or patients on TNF inhibitors have significantly reduced incidence of flares [ 8 ] [ 9 ]. But TNF inhibitor use for prolonged periods is inaccessible to a large population of SpA patients, especially in India and other developing countries due to high out-of-pocket expenditure. Hence, TNF inhibitor tapering by duration and dose has been a viable option being practiced widely by rheumatologists [ 10 ]. This study becomes pertinent by identifying risk factors of flare and allows the physician to tailor decisions related to tapering of TNF inhibitors based on the risk factors. Our study plans to follow up patients in the clinic atleast for 6 months and track all ASAS validated indices (including patient-reported VAS and ASAS NSAID score) to assess characteristics of flare and predictors of flare. Methods Study design We conducted an observational, longitudinal cohort study at the department of Clinical Immunology and Rheumatology in a tertiary care teaching hospital in North India between 2021 and 2023. Eligible patients were patients above the age of 18 years and diagnosed SpA based on ESSG or ASAS classification criteria [ 11 ]. Patients who were included in the cohort should have details of regular follow-up at our centre for at least past 6 months. Patients with very high disease activity at baseline and pregnant patients were excluded. Data was collected after informed consent and prior ethical approval from institutional ethics committee (Ref code: VII PGTSC- IIA/ P14). Sample: Sample size estimation was done using the formula for sample size for comparing two proportions, where we assume the proportion in untreated group 1 (P1) = 0.90, proportion in treated group 2 (P2) = 0.70, significance level (α) = 0.05, Power (1 - β) = 0.8. Approximately 62 participants per group are needed to detect a difference in flare prevalence of 90% vs. 70% with 80% power and 5% significance (two-tailed test). Since patients are followed up over time (at 0,3 and 6 months), adjusted sample size was calculated for a repeated measures design and a sample size per group of 33 patients was needed (supplementary file). Data collection: Data regarding demographics, duration of illness, Disease activity indices -ASDAS CRP (Ankylosing Spondylitis Disease Activity Score C-reactive protein), BASDAI (Bath Ankylosing Spondylitis Disease Activity Index), MASES (Maastricht Ankylosing Spondylitis Enthesitis Score), tender and swollen joint counts, Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Meteorological Index (BASMI), ASAS NSAID Index were collected at baseline and followed up at 3 and 6 months. We used ASDAS-CRP scores to classify disease activity: inactive disease was defined as ASDAS < 1.3, low disease activity as 1.3–<2.1, high disease activity as 2.1–<3.5, and very high disease activity as ≥ 3.5. History regarding previous flare, recent change in medications, physical therapy, hospitalization, antecedent infection, drug default, current NSAID and DMARD (Disease modifying anti-rheumatic drugs) intake, past inadequate response to biologic/ targeted synthetic DMARD (bDMARD/ tsDMARD IR), requirement of intra-articular and systemic glucocorticoids, uveitis, dactylitis, enthesitis were collected at baseline, 3 and 6 months. In a patient who presented with flare, history was probed further if in the past month, conventional synthetic DMARDs (csDMARDs)/ bDMARDs/ tsDMARDs were stopped/delayed for more than 1 week. Similarly, history of recent/ concurrent infection was elicited within the past 2–3 weeks of flare. DMARD IR was diagnosed by the treating rheumatologist based on patient global assessment VAS and lack of ASAS clinically important improvement. The data consisted of measures enlisted in the ASAS coreset for clinical record keeping. Diagnosis of flare: Flares were characterized as generalized or major flares and localized or minor flares. Minor flares are flares restricted to a single site (single joint or entheses) without constitutional symptoms. Major/ generalized flares are flares that involve worsening of axial symptoms or worsening of pain or discomfort in more than one site with constitutional symptoms. Generalized flares also required worsening of ASDAS CRP of more than or equal to 0.9 (based on ASDAS cut-off for clinically important worsening). The diagnosis of flare was confirmed by the treating physician using the above parameters. Uveitis was diagnosed after consultation with the ophthalmologist and confirmation with slit-lamp and fundus examination according to Standardization of Uveitis Nomenclature [ 12 ]. Active enthesitis/ arthritis requires patient’s symptoms and was confirmed by ultrasound features as per OMERACT enthesitis scoring and OMERACT synovitis scoring [ 13 ]. Our study divided generalized flares into pure axial flare, peripheral arthritis flare, enthesitis flare of more than one site, axial and peripheral flare, axial and enthesitis flare, peripheral arthritis and enthesitis flares. Localized flares were further divided into enthesitis flare of a single site, monoarthritis flare and uveitis flare. Flares were diagnosed after ruling out infective, metabolic, and traumatic causes for acute worsening of symptoms. Laboratory investigations include a complete blood count, ESR (mm/hour), CRP and workup for infections (including blood, urine and sputum culture and sensitivity, routine stool testing) depending on the presentation. Details of treatment: All patients were prescribed NSAID and physical therapy as first line therapy. Study participants were already on csDMARDs, bDMARDs, tsDMARDs, oral and intraarticular glucocorticoids based on institutional practice, ASAS-SAA-SPARTAN guidelines, patient preference, and financial considerations. Physical therapy comprised of unsupervised exercises (after prior education by trained physiotherapist) tailored to the individual. High costs and out-of-pocket expenditure preclude the initiation of TNF inhibitors/ secukinumab early in the disease course. Patients who do not have risk factors for progression (hip involvement, persistent very high disease activity, presence of syndesmophytes at presentation) receive single or combination csDMARDs and NSAIDs. Patients with risk factors for progression were initiated on tsDMARDs/ bDMARDs based on patient preference and financial constraints. On follow-up, patients who did not have a fall in ASDAS CRP of more than 1.1 or significant fall in pain VAS (did not achieve pain VAS < 4) after full dose csDMARDs for 3 months or patients who had rapid progression of damage were shifted to bDMARDs/ tsDMARDs (tofacitinib, adalimumab, infliximab, secukinumab and etanercept). Once a patient achieved sustained inactive disease on a biologic DMARD, tapering of the bDMARD was undertaken on an individualized basis, primarily guided by clinical assessment and in accordance with ASAS-EULAR recommendations. Tapering was done by interval extension after discussing the potential risks and benefits with the patient. TsDMARDs were continued at optimal doses. Economic considerations were also considered where relevant. Treatment of flares: Most localized flares were treated with increasing dose and frequency of NSAIDs. Some patients also required intraarticular or brief oral glucocorticoids. Depending upon the duration and severity of major flares, change/ addition of therapy was considered by the treating team. Statistical analysis: Descriptive data were expressed as median (due to non-normality of data), inter-quartile range (IQR), frequency and proportions. Comparative analyses between patients who developed and who did not develop flares at 6 months were performed. Data normality was assessed using the Shapiro-Wilk test. Based on the distribution, the Mann-Whitney U test was used for non-normally distributed data, while ANOVA was applied for normally distributed data. Categorical variables were analyzed using the chi-squared test. Univariable Analysis: We first conducted univariable logistic regression analyses to assess the association between each candidate predictor and the outcome. These variables included demographic factors (age, sex, duration of disease, family history), disease classification (radiographic vs. non-radiographic SpA), known risk factors for progression (presence of syndesmophytes, bDMARDs at baseline, bDMARD inadequate response prior to enrolment, steroid requirement at baseline, ASAS NSAID index, hip involvement, current or past enthesitis, and disease activity at baseline). The purpose of this initial analysis was to screen variables for potential inclusion in the multivariable model. Variables with a p-value < 0.10 in the univariable analysis were considered for the next stage. This threshold was intentionally liberal to reduce the risk of omitting potentially important predictors. Stepwise Selection for Multivariable Analysis: From the pool of candidate variables identified above, we applied a manual backward stepwise selection approach. Starting with a full model including all eligible variables from the univariable analysis, we iteratively removed variables based on their statistical insignificance (p > 0.05) and lack of substantial improvement to model fit (evaluated using likelihood ratio tests). Variables known to be clinically relevant or previously established in literature (e.g., age, sex, presence of syndesmophytes) were retained regardless of p-value, to preserve clinical interpretability and avoid model misspecification. Variables related to treatment dosage and type of bDMARDs were not included in the analysis due to heterogeneity in treatment regimens and lack of uniform data, which would have introduced significant confounding and potential bias. We assessed the final model for multicollinearity (using VIF) and goodness-of-fit (Hosmer–Lemeshow test). Mean change in ASAS validated indices at 0 and 6 months were compared between the flare and non- flare groups (∆BASFI, ∆BASDAI, ∆BASMI, ∆ASDAS CRP, ∆Patient Global Assessment VAS (∆PGA VAS) and ∆ASAS NSAID index). A general linear statistical model for repeated measures analysis was done to assess longitudinal change in ASAS validated indices between flare and non-flare group. Survival analysis using Kaplan-Meier analysis was performed to assess time to flare between patients on bDMARDs/ tsDMARDs and not on bDMARDs/ tsDMARDs. Results Baseline variables: The median age of our population was 26 years (IQR 22–31) and the duration since diagnosis was 4.5 years (IQR 3–8). 10(9.4%) patients had a family history of SpA and all of them were first-degree relatives. There were 85 (80.1%) males and 21 (19.9%) females enrolled in the study with a male: female ratio of roughly 4:1. 75(70.8%) patients had radiographic SpA whereas 31(29.2%) had nr-axSpA. Among 69 patients tested for HLA-B27, 50 (72.5%) were positive and 19 (27.5%) were negative. HLA-B27 status was unknown in 37 patients (34.9% of the total cohort). 72(68%) patients had SpA with axial and peripheral involvement, 31(29.2%) had pure axial SpA, 2(1.9%) patients had pure peripheral SpA and 1(0.9%) had IBD-associated arthritis. 50(47.2%) had syndesmophytes at baseline and 31(29.2%) patients had root joint (hip/shoulder) disease at baseline. 24 (22.6%) patients had current/ past history of enthesitis (and 14(13.1%) patients had current/ past uveitis at baseline. 84 (79.2%) were on csDMARDs and 32 (30.1%) patients were on bDMARDs at baseline. A total 48 (45.2%) patients did not have a fall of ASDAS CRP of > 1.1 and significant fall in pain VAS (did not achieve pain VAS < 4) on adequate trial of full dose csDMARDs prior to enrolment and 9 (8.5%) patients failed atleast 1 bDMARD/ tsDMARD prior to enrolment. Patients were declared bDMARD/ tsDMARD IR after receiving adequate trial of optimal dose bDMARDs/ tsDMARDs. 13 (12.3%) patients required oral glucocorticoids at baseline (Table 1 ). Table 1 Baseline demographic, clinical, and treatment characteristics of the patient cohort (n = 106) Variable Value Age, years 26 (22–31) Duration of disease, years 4.5 (3–8) Male 85 (80.1) Family history of spondyloarthritis 10 (9.4) Presence of syndesmophytes 50 (47.2) Radiographic classification Radiographic axSpA non-radiographic axSpA 75 (70.8) 31 (29.2) HLA-B27 status available Positive Negative 69 (65) 50 (72.5) 19 (27.5) SpA Axial + Peripheral SpA Peripheral SpA IBD- arthritis Axial SpA 72 (69) 2 (1.9) 1 (0.9) 31 (29.2) Hip involvement 31 (29.2) Enthesitis 24 (22.6) Uveitis 14 (13.2) ASAS NSAID index 25 (1–100) ESR, mm/hour 25 (14–40) CRP, mg/l 6.85 (3–16.95) BASDAI 2.4 (1.2–3.6) ASDAS-CRP 2.5 (1.8–3.2) BASFI 2.2 (0.675–3.4) BASMI 1.8 (1.2–2.625) Systemic corticosteroid use at baseline Median dose 13 (12.3) 5 mg/day prednisolone equivalent. csDMARD at baseline SSZ only MTX only SSZ + MTX 44 (41.5) 22 (20.8) 18 (17) bDMARD at baseline Adalimumab Q2W Q3W Q6W Infliximab Q3M Secukinumab monthly 9 (8.5) 6 (5.7) 3 (2.8) 1 (0.9) 4 (3.8) tsDMARD at baseline Tofacitinib: 8 (7.5) Continuous variables are presented as median [interquartile range]; categorical variables as number (%). Characteristics of flares: 67 patients (63.2%) were developed flare during the course of the study period. 9 different patterns of flare have been identified in the study, namely pure axial flare (17%), axial and peripheral flare (15%), minor enthesitis flare (8%), major arthritis flare (6%), major enthesitis flare (5%), minor arthritis flare (4%), axial and entheseal flare (4%), uveitis (4%) and cutaneous flare (1%). Of the 67 patients who flared, associations of flare were history of in 20 (30%) patients, antecedent infections in 13 (19%) patients (8 patients had viral upper respiratory tract infection, 3 patients had urinary tract infections, and 2 patients had acute gastroenteritis) and unknown cause in 34 (51%) patients. Qualitative variables were analysed and significant association favoring flare was seen with duration since diagnosis of less than 6 years (unadjusted OR 2.174 [95% CI 0.973–4.856], steroid requirement at baseline (unadjusted OR 8.291 [95% CI 1.034–66.462], current/ past history of enthesitis at baseline (unadjusted OR 5.478 [95% CI 1.514–19.821], disease activity at baseline (p = 0.002) and radiographic axSpA (unadjusted OR 0.305 [95% CI 0.112–0.831] was associated with lower tendency of flare (Table 2 ). Multivariable logistic regression analyses revealed inactive (adjusted OR 0.210 [95% CI 0.047–0.942], p = 0.042) or low disease at baseline (adjusted OR 0.253 [95% CI 0.089–0.718], p = 0.011) was significantly associated with lower tendency of flare while current/ past enthesitis at baseline (adjusted OR 11.293 [95% CI 1.3–93.46], p = 0.025) favored greater tendency to flare, although with variable effect size [Table 3 ]. Table 2 Distribution of qualitative variables between flare and non-flare groups: Variables Frequency (%) p-value Flare n = 67 (63.2) Non- flare n = 39 (36.8) Duration of disease 6 years or less 49(73.1) 21(53.8) 0.043 More than 6 years 18(26.8) 18(46.1) Sex Male 50(74.6) 35(89.7) 0.078 Female 17(25.4) 4(10.2) Radiographic 42(62.6) 33(84.6) 0.017 Non-radiographic 25(27.4) 6(15.3) Presence of syndesmophytes at baseline. 30(44.7) 20(51.2) 0.518 Family h/0 4(5.9) 6(15.3) 0.110 bDMARDs/ tsDMARDs at baseline 35(52.2) 16(41) 0.265 Steroid req at baseline 12(17.8) 1(2.6) 0.029 Age group 35 10(14.9) 7(17.9) Hip involvement 18(26.8) 13(33.3) 0.480 bDMARD inadequate response prior to enrolment 6(8.9) 3(7.6) 1.000 Current /Past history of enthesitis 21(31.3) 3(7.6) 0.007 Disease activity at baseline # Inactive 3(4.4) 7(17.9) 0.002 Low 11(16.4) 14(35.9) High 53(79.1) 18(46.1) # Inactive disease was defined as ASDAS < 1.3, low disease activity as 1.3–<2.1, high disease activity as 2.1–<3.5, and very high disease activity as ≥ 3.5. Categorical variables are presented as number (%). Abbreviations: bDMARD – biologic DMARD; tsDMARD – targeted synthetic DMARD. Table 3 Univariable and Multivariable Logistic Regression analysis to compare flare and non-flare groups Variables Univariate analysis Multivariable analysis unadjusted Odds ratio 95% CI p-value Adjusted Odds ratio 95% CI p-value Male Sex 0.336 0.104–1.085 0.060 0.284 0.079–1.025 0.055 Duration less than 6 years 2.174 0.973–4.856 0.043 2.774 0.856–8.993 0.089 Radiographic SpA 0.305 0.112–0.831 0.017 0.518 0.161–1.664 0.269 Glucocorticoid requirement at baseline 8.291 1.034–66.462 0.020 3.950 0.421–37.058 0.229 Disease activity at Baseline* - - 0.002 - - 0.011 • Inactive disease vs high at baseline 0.210 0.047–0.942 0.042 • Low disease vs high at baseline 0.253 0.089–0.718 0.011 Current/ past enthesitis at baseline 5.478 1.514–19.821 0.005 11.293 1.300–93.460 0.025 Note: High disease activity serves as the reference category. *Disease activity at baseline showed significant association with tendency to flare whereas, the adjusted odds ratio of low/ inactive disease developing a flare is indicated in subsequent rows. Change of ASAS validated indices in flare and non-flare groups: The longitudinal change in quantitative variables at 0, 3 and 6 months was compared both as individual medians at different time-points and ∆-change in ASAS validated indices between flare and non-flare groups. Individual medians of ASAS NSAID index, ASDAS CRP, BASDAI and patient global assessment VAS were different between flare and non-flare groups at 0, 3 and 6 months. ∆ASDAS CRP, ∆BASDAI, ∆BASFI, ∆ASAS NSAID index, ∆PGA VAS and ∆BASMI at 3 and 6 months from baseline were compared using Mann Whitney U test to assess the longitudinal change in both the groups. The ∆-change was significant at 6 months in BASDAI, ASDAS CRP and BASFI values. The flare groups not only had significantly higher ASDAS CRP and BASDAI at 0, 3 and 6 months, but also was accompanied by significant fall of ASDAS CRP and BASDAI at 6 months compared to non-flare group. BASFI, though not statistically higher in flare group at 3 and 6 months still had significant fall at 3 and 6 months. A general linear model for repeated measures (two-way ANOVA) revealed that the longitudinal change in means of ASDAS CRP, BASDAI, BASFI, BASMI, ASAS NSAID Index and PGA VAS was statistically significant in both intra-group comparison and between flare and non-flare groups at the three time-points. But, with both time and flare outcome as a combined function, only ASDAS CRP and BASDAI was statistically significant in multivariate tests [Table 4 ]. Table 4 General Linear Model for repeated measures to assess significance of longitudinal change in indices between flare and non-flare groups and within these groups . Dependent variables Mean at 0,3 and 6 months, respectively Intra-group comparison (sig.) Inter- group comparison (sig.) Multivariate tests (Wilks’ Lambda) Flare No flare Time Time*flare outcome Flare outcome Time Time*flare outcome ASDAS CRP 0 2.7 1.9 0.000 0.030 0.000 0.00 0.015 3 mo 2.34 1.76 6 mo 1.88 1.66 BASDAI 0 3.02 1.43 0.000 0.034 0.000 0.00 0.012 3 mo 2.46 1.25 6 mo 1.77 0.97 ASAS NSAID Index 0 49.9 30.6 0.000 0.321 0.000 0.00 0.228 3 mo 44.2 15.9 6 mo 21.6 4.2 BASMI 0 2.2 1.88 0.000 0.609 0.334 0.000 0.668 3 mo 1.92 1.7 6 mo 1.77 1.51 BASFI 0 3.29 1.64 0.018 0.187 0.026 0.000 0.144 3 mo 2.01 1.36 6 mo 1.47 1.07 Patient General Assessment VAS 0 3.94 2.49 0.001 0.537 0.000 0.000 0.458 3 mo 3.7 2.15 6 mo 2.8 1.7 Abbreviations: ASAS – Assessment of SpondyloArthritis International Society; ASDAS – Ankylosing Spondylitis Disease Activity Score; BASDAI – Bath Ankylosing Spondylitis Disease Activity Index; BASFI – Bath Ankylosing Spondylitis Functional Index; BASMI – Bath Ankylosing Spondylitis Metrology; CRP – C-reactive protein; VAS – visual analog scale. Survival analysis: Survival analysis using Kaplan-Meier analysis showed the median time to flare in the biological/ targeted synthetic DMARD group to be at 88 days compared to 26 days in the group with no biologicals/ targeted synthetic DMARDs at baseline. This did not meet statistical difference (p = 0.249)[figure 1 ]. The difference in the probability of developing a flare did not meet statistical significance because most patients were on suboptimal/ tapering doses of bDMARDs. Discussion The study aimed at exploring the characteristics of flares, relation of disease activity indices to flare episodes and factors affecting flares. Most of the studies on flares in spondyloarthritis were conducted on patient-reported flare using multiple methods namely, online questionnaire [ 6 ], smartphone app [ 14 ], patients’ self-recorded details of NSAID intake and disease activity [ 4 ]and online survey platform [ 15 ]. Comparison between various studies on flare in SpA is tabulated in Table 1 [ 4 ] [ 6 ] [ 14 ] [ 16 ] [ 17 ] [ 18 ] [ 19 ]. The study focused on rheumatologist-diagnosed flares with patient-based indices (BASDAI, ASDAS CRP, ASAS NSAID index, patient global assessment VAS, BASFI) to make the diagnosis of flare. We augmented patient’s perception of disease activity with rheumatologist assessment to bridge the doctor-patient consensus in diagnosis of flare. Also, we relied on ASDAS CRP, a weighted measure, which considers the burden of inflammation. The details were collected through face-to-face interaction which further helped in therapeutic decision making and effective control of flares. Compared to studies on flares in SpA, our cohort was younger and had a relatively shorter disease course (median duration of disease in our population was 4.5 years with IQR of 3–8 and median age of our population was 26 with an IQR of 22–31, providing insights about flares in early course and younger population in SpA. Also, lower median age in our sample population corresponds to the demographic characteristics of Indian population [ 6 ]. The incidence of flares in our study is 63.2%. Associations for flare showed history of drug default in the past month(30%) and antecedent infections in the past 3 weeks (19%). There was positive history of drug default in 20/67 patients of flare group and 3/39 patients of the non-flare group. The flare incidence was relatively low in the study compared to other SpA cohorts [supplementary file]. Almost all our patients were on NSAIDs, except 4 patients (3.8%) who did not require NSAIDs during the study. 84 patients (79.3%) were on csDMARDs and 29.2% were on tapering/ regular course bDMARDs/ tsDMARDs in our study. Survival analysis showed the median time to flare in the biological group to be at 88 days compared to 26 days in the group with no biologicals at baseline, but this did not meet statistical difference. Also, incidence of flares between the groups did not meet statistically significant difference (33% vs 30.2%). Among patients on bDMARDs, 31.2% of our patients were on tapering doses of bDMARDs explaining the lack of difference in incidence of flares in patients receiving bDMARDs. None of the patients on tsDMARDs were on inadequate/ tapering doses. Similarly, comparative analysis of sulfasalazine-treated and etanercept-treated patients from ESTHER trial also showed flare rate was similar in both groups at 24.4 weeks after discontinuation (69% vs 75%)[ 7 ]. A study conducted in south India showed short-course infliximab followed by continuation of methotrexate and sulfasalazine combination can prolong time to disease flare and decrease requirement for additional infliximab dose in axSpA. Also, disease flare occurred only in 33.3% (15/45) of patients after a mean duration of 14.5 months compared to usual time-to-flare of 4–6 months on discontinuation of TNF inhibitors in the study [ 20 ]. This suggests that csDMARDs might have a beneficial role in preventing flares in SpA. Significant association favouring flare was seen with duration since diagnosis of less than 6 years, steroid requirement at baseline, current/ past history of enthesitis at baseline, high disease activity at baseline and ax-SpA was associated with lower tendency to flare in univariable analyses. Jacquemin et al also identified significant statistical association of shorter time since onset of disease, higher BASDAI, less anti-TNF treatment, worse quality of life favouring tendency to flare [ 17 ]. The results of change in ASDAS CRP, BASDAI, BASFI, ASAS NSAID index, at 6 months was similar to study by Danda et al which showed higher fall in peripheral arthritis group with similarly high BASDAI, BASFI, ASDAS CRP, ASAS NSAID index at baseline [ 21 ]. The higher ∆-change or fall in ASDAS CRP, BASDAI and BASFI in the flare group could be attributed to immediate medical attention and subsequent improvement. Limitations include a single center study and limited sample population preventing in-depth analyses regarding effect of drugs/ drug combinations on flare outcomes. Also, the study did not include indices for assessing quality of life, work productivity in relation to flares. The treatment protocol followed in the study does not reflect standard guidelines in SpA, the only reason being financial concerns precluding use of bDMARDs early in the course of the disease. The study was conducted in a North Indian tertiary care cohort, making it difficult to generalize the findings. Additionally, the study design may limit the ability to control for confounders related to the timing of flares. Strengths include 2650 patient-weeks of follow-up and 318 patient visits with close patient interaction and tracking of flares. Also, real world data is generated regarding status of bDMARD/ csDMARD use in populations not affording continuous use of bDMARDs from out-of-pocket health expenditure. Patients with risk factors/ protective factors towards flare can be identified and suitable decisions regarding care plans can be taken with the findings generated by the study. Conclusion Patients with low/ inactive disease activity at baseline have lower odds of developing a flare. Patients with current/ past enthesitis have higher odds of developing flare. ASDAS CRP, BASDAI, Patient general assessment VAS and ASAS NSAID scores are significantly different in patients of axSpA with tendency to flare. Also ∆-change in ASDAS CRP, BASFI and BASDAI at 6 months varied significantly between flare and non-flare groups. In patients who are at high risk of flare as suggested in the study, it would help the rheumatologist to guide the treatment plan carefully to prevent flare. Declarations Ethics approval: Research was performed in accordance with the Declaration of Helsinki and prior ethical approval from institutional ethics committee of King George’s Medical University (Ref code: VII PGTSC- IIA/ P14). Consent to participate: Detailed informed consent for participation was obtained from all participants of the study. Consent for publication: Consent for publication was obtained from all the participants of the study. Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Clinical trial number: Not applicable. Acknowledgements: The authors would like to thank the patients of the cohort. Competing interests: The authors of this study declare they have no competing interests. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author contribution declaration: AKV was involved in Conceptualization, Methodology, Software, SM was involved in Data curation, Writing- Original draft preparation. UD involved in Visualization, Investigation. MKM was involved in Methodology, Software. NK was involved in Validation. APM was involved in Data curation, Writing. PK was involved in Writing- Reviewing and Editing. All authors read and approved the final manuscript References Wendling D, Prati C. Flare in axial spondyloarthritis. The dark side of the outcome. Ann Rheum Dis. 2016;75(6):950–1. Aouad K, Gossec L. Defining and managing flares in axial spondyloarthritis. Curr Opin Rheumatol. 2022;34(4):195. Molto A, Gossec L, Meghnathi B, Landewé RBM, van der Heijde D, Atagunduz P, et al. An Assessment in SpondyloArthritis International Society (ASAS)-endorsed definition of clinically important worsening in axial spondyloarthritis based on ASDAS. Ann Rheum Dis. 2018;77(1):124–7. Dougados M, Wood E, Gossec L, van Der Heijde D, Logeart I. Flare in axial spondyloarthritis: investigation of meaningful changes in symptomatic outcome measures. Clin Exp Rheumatol. 2017;35:209–13. Godfrin-Valnet M, Puyraveau M, Prati C, Wendling D. Flare in spondyloarthritis: Thresholds of disease activity variations. Joint Bone Spine. 2015;82(3):192–5. Cooksey R, Brophy S, Gravenor MB, Brooks CJ, Burrows CL, Siebert S. Frequency and characteristics of disease flares in ankylosing spondylitis. Rheumatology. 2010;49(5):929–32. Song IH, Althoff CE, Haibel H, Hermann KGA, Poddubnyy D, Listing J, et al. Frequency and duration of drug-free remission after 1 year of treatment with etanercept versus sulfasalazine in early axial spondyloarthritis: 2-year data of the ESTHER trial. Ann Rheum Dis. 2012;71(7):1212–5. Proft F, Weiß A, Torgutalp M, Protopopov M, Rodriguez VR, Haibel H, Behmer O, Sieper J, Poddubnyy D. Sustained clinical response and safety of etanercept in patients with early axial spondyloarthritis: 10-year results of the ESTHER trial. Therapeutic Adv Musculoskelet Disease. 2021;13:1759720X20987700. Danve A, Deodhar A. Treatment of axial spondyloarthritis: an update. Nat Rev Rheumatol. 2022;18(4):205–16. Reveille JD, Ximenes A, Ward MM. Economic Considerations of the Treatment of Ankylosing Spondylitis. Am J Med Sci. 2012;343(5):371–4. Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Braun J, Burgos-Vargas R, et al. The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis. 2009;68:ii1–44. Jabs DA, Nussenblatt RB, Rosenbaum JT, Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140(3):509–16. Balint PV, Terslev L, Aegerter P, Bruyn GAW, Chary-Valckenaere I, Gandjbakhch F, et al. Reliability of a consensus-based ultrasound definition and scoring for enthesitis in spondyloarthritis and psoriatic arthritis: an OMERACT US initiative. Ann Rheum Dis. 2018;77(12):1730–5. Barnett R, Ng S, Sengupta R. Understanding flare in axial spondyloarthritis: novel insights from daily self-reported flare experience. Rheumatol Adv Pract. 2021;5(3):rkab082. Liew JW, Castillo M, Zaccagnino E, Katz P, Haroon N, Gensler LS. Patient-reported disease activity in an axial spondyloarthritis cohort during the COVID-19 pandemic. ACR Open Rheumatol. 2020;2(9):533–9. Brophy S, Calin A. Definition of disease flare in ankylosing spondylitis: the patients’ perspective. J Rheumatol. 2002;29(5):954–8. Jacquemin C, Maksymowych WP, Boonen A, Gossec L. Patient-reported Flares in Ankylosing Spondylitis: A Cross-sectional Analysis of 234 Patients. J Rheumatol. 2017;44(4):425–30. Yeo J, Kim JY, Park JK, Shin K, Lee EY, Kim TH, Park JW. Flare prediction after tapering the dose of tumour necrosis factor inhibitors in patients with axial spondyloarthritis: a nationwide cohort study. Rheumatology. 2025;64(3):1155–61. Wetterslev M, Georgiadis S, Christiansen SN, Pedersen SJ, Sørensen IJ, Hetland ML, et al. Occurrence and prediction of flare after tapering of tumor necrosis factor inhibitors in patients with axial spondyloarthritis. J Rheumatol. 2024;51(1):39–49. Nair AM, Sandhya P, Yadav B, Danda D. TNFα blockers followed by continuation of sulfasalazine and methotrexate combination: a retrospective study on cost saving options of treatment in Spondyloarthritis. Clin Rheumatol. 2017;36(10):2243–51. Ganapati A, Gowri M, Antonisamy B, Danda D. Combination of methotrexate and sulfasalazine is an efficacious option for axial spondyloarthritis in a resource-limited, real-world clinical setting: a prospective cohort study. Clin Rheumatol. 2021;40(7):1871–9. Additional Declarations No competing interests reported. Supplementary Files supplementJRDrev.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7045624","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":490470789,"identity":"9df2fc79-59e4-4f8c-9fcd-ee5df35cb27f","order_by":0,"name":"Abilash Krishnan Vijayakumaran","email":"","orcid":"","institution":"King George's Medical University","correspondingAuthor":false,"prefix":"","firstName":"Abilash","middleName":"Krishnan","lastName":"Vijayakumaran","suffix":""},{"id":490470790,"identity":"dd25e550-aa34-4cdc-a57d-08fd3c445f0a","order_by":1,"name":"Sayan Mukherjee","email":"","orcid":"","institution":"King George's Medical University","correspondingAuthor":false,"prefix":"","firstName":"Sayan","middleName":"","lastName":"Mukherjee","suffix":""},{"id":490470791,"identity":"f96254f0-bcbf-4e8f-ba44-f65f0a34d824","order_by":2,"name":"Urmila Dhakad","email":"","orcid":"","institution":"King George's Medical University","correspondingAuthor":false,"prefix":"","firstName":"Urmila","middleName":"","lastName":"Dhakad","suffix":""},{"id":490470792,"identity":"8ae139c3-e666-4a67-8862-d21855cc1b6d","order_by":3,"name":"Mukesh Kumar Maurya","email":"","orcid":"","institution":"King George's Medical University","correspondingAuthor":false,"prefix":"","firstName":"Mukesh","middleName":"Kumar","lastName":"Maurya","suffix":""},{"id":490470793,"identity":"fa86395c-459b-4d94-a324-7474846ebaf4","order_by":4,"name":"Nishant Kamble","email":"","orcid":"","institution":"King George's Medical University","correspondingAuthor":false,"prefix":"","firstName":"Nishant","middleName":"","lastName":"Kamble","suffix":""},{"id":490470794,"identity":"0e2fc02d-93bd-45ac-a545-2ad1864796c8","order_by":5,"name":"Ankush PM","email":"","orcid":"","institution":"King George's Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ankush","middleName":"","lastName":"PM","suffix":""},{"id":490470795,"identity":"e2777bbb-7464-49f9-b75a-063162241e3d","order_by":6,"name":"Puneet Kumar","email":"data:image/png;base64,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","orcid":"","institution":"King George's Medical University","correspondingAuthor":true,"prefix":"","firstName":"Puneet","middleName":"","lastName":"Kumar","suffix":""}],"badges":[],"createdAt":"2025-07-04 10:08:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7045624/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7045624/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87849987,"identity":"4a2cef3c-0899-4c90-afc2-c2412862b80b","added_by":"auto","created_at":"2025-07-29 15:47:28","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":142477,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan Meier survival analysis to compare time to flare between patients on bDMARDs/ tsDMARDs/ not on bDMARDs/ tsDMARDS.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNote: \u003c/strong\u003ebDMARDs and tsDMARDs have been clubbed together in this survival curve. Patients who received biologicals/ tsDMARDs were quite heterogenous with patients receiving TNF inhibitors, secukinumab and tofacitinib, many receiving tapering doses.\u003c/p\u003e\n\u003cp\u003eMedian time to flare in the biological/ targeted synthetic DMARD group to be at 88 days compared to 26 days in the group with no biologicals/ targeted synthetic DMARDs at baseline. This did not meet statistical difference (p-value =0.249)\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7045624/v1/d75bb220788cb5813e1a8987.jpg"},{"id":100950846,"identity":"8b47b691-12bd-41ef-a06a-dd488887532f","added_by":"auto","created_at":"2026-01-23 07:09:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1024384,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7045624/v1/cc1487ba-ef8f-4036-9832-74efa35d295f.pdf"},{"id":87849992,"identity":"0771df7d-735f-4d1a-8369-6637502e8e73","added_by":"auto","created_at":"2025-07-29 15:47:28","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23736,"visible":true,"origin":"","legend":"","description":"","filename":"supplementJRDrev.docx","url":"https://assets-eu.researchsquare.com/files/rs-7045624/v1/2487d9aff83109ddd60e7d78.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Identifying flare prone Spondyloarthritis – insights from a prospective cohort","fulltext":[{"header":"Key Points","content":"\u003cp\u003e1. Inactive/ low disease at baseline was significantly associated with lower tendency of flare and current/ past enthesitis at baseline favored greater tendency to flare.\u003c/p\u003e\n\u003cp\u003e2. Longitudinal change in ASAS-coreset measures was significantly different between flare and non-flare populations.\u003c/p\u003e\n\u003cp\u003e3. In countries where tapering TNF inhibitors is routinely practiced due to financial considerations, identifying flare-prone population would facilitate careful tapering.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eAxial Spondyloarthritis (axSpA) is an umbrella term denoting chronic inflammation of the spine and sacroiliac joints that includes polyenthesitis of the vertebral column. Flares are episodes of disease worsening requiring change in treatment. Flares in spondyloarthritis (SpA) are frequent, causing worse outcomes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e][\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Definitions of flares are diverse, owing to the multi-faceted nature of the disease. The ASAS (Assessment of SpondyloArthritis international Society) expert group reached a consensus after analyzing 12 different definitions of clinically important worsening. A worsening of ASDAS-CRP of more than 0.9 points was chosen to define clinically important worsening in axSpA [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. A study assessing outcome measures to detect flares identified absolute change of BASDAI more than or equal to 2 or a relative change\u0026thinsp;\u0026ge;\u0026thinsp;30% in subcomponents of BASDAI may indicate a meaningful symptomatic deterioration [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Agreement between perception of flares by doctors and patients was not high (Cohen\u0026rsquo;s kappa coefficient of 0.61) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Another study divided flares into generalized/ major and localized/ minor flares. Minor flares were pain/ swelling restricted to one area with fatigue and stiffness and major flares were \u0026lsquo;generalized pain, hot burning joints, muscle spasm, fever, sweating, extreme fatigue and stiffness\u0026rsquo;[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eData from discontinuation trials of TNF inhibitors showed that discontinuation caused increase in flares as high as 79% compared to placebo. 2-year data from the ESTHER trial showed that the flare rate was similar in etanercept-treated patients\u0026rsquo; group and sulfasalazine-treated patients\u0026rsquo; group at a mean duration of 24.4 weeks after drug discontinuation (69% vs 75%) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. It is clear that use of TNF inhibitors has no protective effect in preventing flares after discontinuation, especially in early disease. Also, restarting TNF inhibitors or patients on TNF inhibitors have significantly reduced incidence of flares [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. But TNF inhibitor use for prolonged periods is inaccessible to a large population of SpA patients, especially in India and other developing countries due to high out-of-pocket expenditure. Hence, TNF inhibitor tapering by duration and dose has been a viable option being practiced widely by rheumatologists [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This study becomes pertinent by identifying risk factors of flare and allows the physician to tailor decisions related to tapering of TNF inhibitors based on the risk factors. Our study plans to follow up patients in the clinic atleast for 6 months and track all ASAS validated indices (including patient-reported VAS and ASAS NSAID score) to assess characteristics of flare and predictors of flare.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy design\u003c/p\u003e\u003cp\u003e We conducted an observational, longitudinal cohort study at the department of Clinical Immunology and Rheumatology in a tertiary care teaching hospital in North India between 2021 and 2023. Eligible patients were patients above the age of 18 years and diagnosed SpA based on ESSG or ASAS classification criteria [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Patients who were included in the cohort should have details of regular follow-up at our centre for at least past 6 months. Patients with very high disease activity at baseline and pregnant patients were excluded. Data was collected after informed consent and prior ethical approval from institutional ethics committee (Ref code: VII PGTSC- IIA/ P14).\u003c/p\u003e\u003cp\u003eSample:\u003c/p\u003e\u003cp\u003eSample size estimation was done using the formula for sample size for comparing two proportions, where we assume the proportion in untreated group 1 (P1)\u0026thinsp;=\u0026thinsp;0.90, proportion in treated group 2 (P2)\u0026thinsp;=\u0026thinsp;0.70, significance level (α)\u0026thinsp;=\u0026thinsp;0.05, Power (1 - β)\u0026thinsp;=\u0026thinsp;0.8. Approximately 62 participants per group are needed to detect a difference in flare prevalence of 90% vs. 70% with 80% power and 5% significance (two-tailed test). Since patients are followed up over time (at 0,3 and 6 months), adjusted sample size was calculated for a repeated measures design and a sample size per group of 33 patients was needed (supplementary file).\u003c/p\u003e\u003cp\u003eData collection:\u003c/p\u003e\u003cp\u003eData regarding demographics, duration of illness, Disease activity indices -ASDAS CRP (Ankylosing Spondylitis Disease Activity Score C-reactive protein), BASDAI (Bath Ankylosing Spondylitis Disease Activity Index), MASES (Maastricht Ankylosing Spondylitis Enthesitis Score), tender and swollen joint counts, Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Meteorological Index (BASMI), ASAS NSAID Index were collected at baseline and followed up at 3 and 6 months. We used ASDAS-CRP scores to classify disease activity: inactive disease was defined as ASDAS\u0026thinsp;\u0026lt;\u0026thinsp;1.3, low disease activity as 1.3\u0026ndash;\u0026lt;2.1, high disease activity as 2.1\u0026ndash;\u0026lt;3.5, and very high disease activity as \u0026ge;\u0026thinsp;3.5. History regarding previous flare, recent change in medications, physical therapy, hospitalization, antecedent infection, drug default, current NSAID and DMARD (Disease modifying anti-rheumatic drugs) intake, past inadequate response to biologic/ targeted synthetic DMARD (bDMARD/ tsDMARD IR), requirement of intra-articular and systemic glucocorticoids, uveitis, dactylitis, enthesitis were collected at baseline, 3 and 6 months. In a patient who presented with flare, history was probed further if in the past month, conventional synthetic DMARDs (csDMARDs)/ bDMARDs/ tsDMARDs were stopped/delayed for more than 1 week. Similarly, history of recent/ concurrent infection was elicited within the past 2\u0026ndash;3 weeks of flare. DMARD IR was diagnosed by the treating rheumatologist based on patient global assessment VAS and lack of ASAS clinically important improvement. The data consisted of measures enlisted in the ASAS coreset for clinical record keeping.\u003c/p\u003e\u003cp\u003eDiagnosis of flare:\u003c/p\u003e\u003cp\u003eFlares were characterized as generalized or major flares and localized or minor flares. Minor flares are flares restricted to a single site (single joint or entheses) without constitutional symptoms. Major/ generalized flares are flares that involve worsening of axial symptoms or worsening of pain or discomfort in more than one site with constitutional symptoms. Generalized flares also required worsening of ASDAS CRP of more than or equal to 0.9 (based on ASDAS cut-off for clinically important worsening). The diagnosis of flare was confirmed by the treating physician using the above parameters. Uveitis was diagnosed after consultation with the ophthalmologist and confirmation with slit-lamp and fundus examination according to Standardization of Uveitis Nomenclature [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Active enthesitis/ arthritis requires patient\u0026rsquo;s symptoms and was confirmed by ultrasound features as per OMERACT enthesitis scoring and OMERACT synovitis scoring [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Our study divided generalized flares into pure axial flare, peripheral arthritis flare, enthesitis flare of more than one site, axial and peripheral flare, axial and enthesitis flare, peripheral arthritis and enthesitis flares. Localized flares were further divided into enthesitis flare of a single site, monoarthritis flare and uveitis flare. Flares were diagnosed after ruling out infective, metabolic, and traumatic causes for acute worsening of symptoms. Laboratory investigations include a complete blood count, ESR (mm/hour), CRP and workup for infections (including blood, urine and sputum culture and sensitivity, routine stool testing) depending on the presentation.\u003c/p\u003e\u003cp\u003eDetails of treatment:\u003c/p\u003e\u003cp\u003eAll patients were prescribed NSAID and physical therapy as first line therapy. Study participants were already on csDMARDs, bDMARDs, tsDMARDs, oral and intraarticular glucocorticoids based on institutional practice, ASAS-SAA-SPARTAN guidelines, patient preference, and financial considerations. Physical therapy comprised of unsupervised exercises (after prior education by trained physiotherapist) tailored to the individual. High costs and out-of-pocket expenditure preclude the initiation of TNF inhibitors/ secukinumab early in the disease course. Patients who do not have risk factors for progression (hip involvement, persistent very high disease activity, presence of syndesmophytes at presentation) receive single or combination csDMARDs and NSAIDs. Patients with risk factors for progression were initiated on tsDMARDs/ bDMARDs based on patient preference and financial constraints. On follow-up, patients who did not have a fall in ASDAS CRP of more than 1.1 or significant fall in pain VAS (did not achieve pain VAS\u0026thinsp;\u0026lt;\u0026thinsp;4) after full dose csDMARDs for 3 months or patients who had rapid progression of damage were shifted to bDMARDs/ tsDMARDs (tofacitinib, adalimumab, infliximab, secukinumab and etanercept). Once a patient achieved sustained inactive disease on a biologic DMARD, tapering of the bDMARD was undertaken on an individualized basis, primarily guided by clinical assessment and in accordance with ASAS-EULAR recommendations. Tapering was done by interval extension after discussing the potential risks and benefits with the patient. TsDMARDs were continued at optimal doses. Economic considerations were also considered where relevant.\u003c/p\u003e\u003cp\u003eTreatment of flares:\u003c/p\u003e\u003cp\u003eMost localized flares were treated with increasing dose and frequency of NSAIDs. Some patients also required intraarticular or brief oral glucocorticoids. Depending upon the duration and severity of major flares, change/ addition of therapy was considered by the treating team.\u003c/p\u003e\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis:\u003c/h2\u003e\u003cp\u003eDescriptive data were expressed as median (due to non-normality of data), inter-quartile range (IQR), frequency and proportions. Comparative analyses between patients who developed and who did not develop flares at 6 months were performed. Data normality was assessed using the Shapiro-Wilk test. Based on the distribution, the Mann-Whitney U test was used for non-normally distributed data, while ANOVA was applied for normally distributed data. Categorical variables were analyzed using the chi-squared test.\u003c/p\u003e\u003cp\u003eUnivariable Analysis:\u003c/p\u003e\u003cp\u003eWe first conducted univariable logistic regression analyses to assess the association between each candidate predictor and the outcome. These variables included demographic factors (age, sex, duration of disease, family history), disease classification (radiographic vs. non-radiographic SpA), known risk factors for progression (presence of syndesmophytes, bDMARDs at baseline, bDMARD inadequate response prior to enrolment, steroid requirement at baseline, ASAS NSAID index, hip involvement, current or past enthesitis, and disease activity at baseline). The purpose of this initial analysis was to screen variables for potential inclusion in the multivariable model. Variables with a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.10 in the univariable analysis were considered for the next stage. This threshold was intentionally liberal to reduce the risk of omitting potentially important predictors.\u003c/p\u003e\u003cp\u003eStepwise Selection for Multivariable Analysis:\u003c/p\u003e\u003cp\u003eFrom the pool of candidate variables identified above, we applied a manual backward stepwise selection approach. Starting with a full model including all eligible variables from the univariable analysis, we iteratively removed variables based on their statistical insignificance (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) and lack of substantial improvement to model fit (evaluated using likelihood ratio tests). Variables known to be clinically relevant or previously established in literature (e.g., age, sex, presence of syndesmophytes) were retained regardless of p-value, to preserve clinical interpretability and avoid model misspecification. Variables related to treatment dosage and type of bDMARDs were not included in the analysis due to heterogeneity in treatment regimens and lack of uniform data, which would have introduced significant confounding and potential bias. We assessed the final model for multicollinearity (using VIF) and goodness-of-fit (Hosmer\u0026ndash;Lemeshow test).\u003c/p\u003e\u003cp\u003eMean change in ASAS validated indices at 0 and 6 months were compared between the flare and non- flare groups (∆BASFI, ∆BASDAI, ∆BASMI, ∆ASDAS CRP, ∆Patient Global Assessment VAS (∆PGA VAS) and ∆ASAS NSAID index). A general linear statistical model for repeated measures analysis was done to assess longitudinal change in ASAS validated indices between flare and non-flare group. Survival analysis using Kaplan-Meier analysis was performed to assess time to flare between patients on bDMARDs/ tsDMARDs and not on bDMARDs/ tsDMARDs.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eBaseline variables:\u003c/p\u003e\u003cp\u003eThe median age of our population was 26 years (IQR 22\u0026ndash;31) and the duration since diagnosis was 4.5 years (IQR 3\u0026ndash;8). 10(9.4%) patients had a family history of SpA and all of them were first-degree relatives. There were 85 (80.1%) males and 21 (19.9%) females enrolled in the study with a male: female ratio of roughly 4:1. 75(70.8%) patients had radiographic SpA whereas 31(29.2%) had nr-axSpA. Among 69 patients tested for HLA-B27, 50 (72.5%) were positive and 19 (27.5%) were negative. HLA-B27 status was unknown in 37 patients (34.9% of the total cohort). 72(68%) patients had SpA with axial and peripheral involvement, 31(29.2%) had pure axial SpA, 2(1.9%) patients had pure peripheral SpA and 1(0.9%) had IBD-associated arthritis. 50(47.2%) had syndesmophytes at baseline and 31(29.2%) patients had root joint (hip/shoulder) disease at baseline. 24 (22.6%) patients had current/ past history of enthesitis (and 14(13.1%) patients had current/ past uveitis at baseline. 84 (79.2%) were on csDMARDs and 32 (30.1%) patients were on bDMARDs at baseline. A total 48 (45.2%) patients did not have a fall of ASDAS CRP of \u0026gt;\u0026thinsp;1.1 and significant fall in pain VAS (did not achieve pain VAS\u0026thinsp;\u0026lt;\u0026thinsp;4) on adequate trial of full dose csDMARDs prior to enrolment and 9 (8.5%) patients failed atleast 1 bDMARD/ tsDMARD prior to enrolment. Patients were declared bDMARD/ tsDMARD IR after receiving adequate trial of optimal dose bDMARDs/ tsDMARDs. 13 (12.3%) patients required oral glucocorticoids at baseline (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline demographic, clinical, and treatment characteristics of the patient cohort (n\u0026thinsp;=\u0026thinsp;106)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eValue\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26 (22\u0026ndash;31)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration of disease, years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.5 (3\u0026ndash;8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e85 (80.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFamily history of spondyloarthritis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (9.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePresence of syndesmophytes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e50 (47.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRadiographic classification\u003c/p\u003e\u003cp\u003eRadiographic axSpA\u003c/p\u003e\u003cp\u003enon-radiographic axSpA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e75 (70.8)\u003c/p\u003e\u003cp\u003e31 (29.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHLA-B27 status available\u003c/p\u003e\u003cp\u003ePositive\u003c/p\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e69 (65)\u003c/p\u003e\u003cp\u003e50 (72.5)\u003c/p\u003e\u003cp\u003e19 (27.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSpA\u003c/p\u003e\u003cp\u003eAxial\u0026thinsp;+\u0026thinsp;Peripheral SpA\u003c/p\u003e\u003cp\u003ePeripheral SpA\u003c/p\u003e\u003cp\u003eIBD- arthritis\u003c/p\u003e\u003cp\u003eAxial SpA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e72 (69)\u003c/p\u003e\u003cp\u003e2 (1.9)\u003c/p\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003cp\u003e31 (29.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHip involvement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31 (29.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEnthesitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24 (22.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUveitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (13.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eASAS NSAID index\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 (1\u0026ndash;100)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eESR, mm/hour\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25 (14\u0026ndash;40)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRP, mg/l\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.85 (3\u0026ndash;16.95)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBASDAI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.4 (1.2\u0026ndash;3.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eASDAS-CRP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.5 (1.8\u0026ndash;3.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBASFI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.2 (0.675\u0026ndash;3.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBASMI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.8 (1.2\u0026ndash;2.625)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSystemic corticosteroid use at baseline\u003c/p\u003e\u003cp\u003eMedian dose\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (12.3)\u003c/p\u003e\u003cp\u003e5 mg/day prednisolone equivalent.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ecsDMARD at baseline\u003c/p\u003e\u003cp\u003eSSZ only\u003c/p\u003e\u003cp\u003eMTX only\u003c/p\u003e\u003cp\u003eSSZ\u0026thinsp;+\u0026thinsp;MTX\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44 (41.5)\u003c/p\u003e\u003cp\u003e22 (20.8)\u003c/p\u003e\u003cp\u003e18 (17)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ebDMARD at baseline\u003c/p\u003e\u003cp\u003eAdalimumab Q2W\u003c/p\u003e\u003cp\u003eQ3W\u003c/p\u003e\u003cp\u003eQ6W\u003c/p\u003e\u003cp\u003eInfliximab Q3M\u003c/p\u003e\u003cp\u003eSecukinumab monthly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (8.5)\u003c/p\u003e\u003cp\u003e6 (5.7)\u003c/p\u003e\u003cp\u003e3 (2.8)\u003c/p\u003e\u003cp\u003e1 (0.9)\u003c/p\u003e\u003cp\u003e4 (3.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003etsDMARD at baseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTofacitinib: 8 (7.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003eContinuous variables are presented as median [interquartile range]; categorical variables as number (%).\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eCharacteristics of flares:\u003c/p\u003e\u003cp\u003e67 patients (63.2%) were developed flare during the course of the study period. 9 different patterns of flare have been identified in the study, namely pure axial flare (17%), axial and peripheral flare (15%), minor enthesitis flare (8%), major arthritis flare (6%), major enthesitis flare (5%), minor arthritis flare (4%), axial and entheseal flare (4%), uveitis (4%) and cutaneous flare (1%). Of the 67 patients who flared, associations of flare were history of in 20 (30%) patients, antecedent infections in 13 (19%) patients (8 patients had viral upper respiratory tract infection, 3 patients had urinary tract infections, and 2 patients had acute gastroenteritis) and unknown cause in 34 (51%) patients.\u003c/p\u003e\u003cp\u003eQualitative variables were analysed and significant association favoring flare was seen with duration since diagnosis of less than 6 years (unadjusted OR 2.174 [95% CI 0.973\u0026ndash;4.856], steroid requirement at baseline (unadjusted OR 8.291 [95% CI 1.034\u0026ndash;66.462], current/ past history of enthesitis at baseline (unadjusted OR 5.478 [95% CI 1.514\u0026ndash;19.821], disease activity at baseline (p\u0026thinsp;=\u0026thinsp;0.002) and radiographic axSpA (unadjusted OR 0.305 [95% CI 0.112\u0026ndash;0.831] was associated with lower tendency of flare (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Multivariable logistic regression analyses revealed inactive (adjusted OR 0.210 [95% CI 0.047\u0026ndash;0.942], p\u0026thinsp;=\u0026thinsp;0.042) or low disease at baseline (adjusted OR 0.253 [95% CI 0.089\u0026ndash;0.718], p\u0026thinsp;=\u0026thinsp;0.011) was significantly associated with lower tendency of flare while current/ past enthesitis at baseline (adjusted OR 11.293 [95% CI 1.3\u0026ndash;93.46], p\u0026thinsp;=\u0026thinsp;0.025) favored greater tendency to flare, although with variable effect size [Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDistribution of qualitative variables between flare and non-flare groups:\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003eFrequency (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFlare\u003c/p\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;67 (63.2)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNon- flare\u003c/p\u003e\u003cp\u003en\u0026thinsp;=\u0026thinsp;39 (36.8)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eDuration of disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 years or less\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49(73.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e21(53.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003e0.043\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMore than 6 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18(26.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e18(46.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50(74.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e35(89.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0.078\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17(25.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4(10.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eRadiographic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e42(62.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e33(84.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003e0.017\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eNon-radiographic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25(27.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6(15.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003ePresence of syndesmophytes at baseline.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30(44.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e20(51.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.518\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eFamily h/0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4(5.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6(15.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.110\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003ebDMARDs/ tsDMARDs at baseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35(52.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16(41)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.265\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eSteroid req at baseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12(17.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1(2.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.029\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eAge group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32(47.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e20(51.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.777\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25\u0026ndash;35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25(37.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e12(30.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10(14.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7(17.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eHip involvement\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18(26.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13(33.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.480\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003ebDMARD inadequate response prior to enrolment\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6(8.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3(7.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eCurrent /Past history of enthesitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21(31.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3(7.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.007\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eDisease activity at baseline\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInactive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3(4.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7(17.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11(16.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e14(35.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53(79.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e18(46.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e#\u003c/sup\u003e Inactive disease was defined as ASDAS\u0026thinsp;\u0026lt;\u0026thinsp;1.3, low disease activity as 1.3\u0026ndash;\u0026lt;2.1, high disease activity as 2.1\u0026ndash;\u0026lt;3.5, and very high disease activity as \u0026ge;\u0026thinsp;3.5.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eCategorical variables are presented as number (%).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: bDMARD \u0026ndash; biologic DMARD; tsDMARD \u0026ndash; targeted synthetic DMARD.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eUnivariable and Multivariable Logistic Regression analysis to compare flare and non-flare groups\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eUnivariate analysis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e\u003cp\u003eMultivariable analysis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"1\" nameend=\"c8\" namest=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eunadjusted Odds ratio\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAdjusted Odds ratio\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale Sex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.336\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.104\u0026ndash;1.085\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.060\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.284\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.079\u0026ndash;1.025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.055\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuration less than 6 years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.174\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.973\u0026ndash;4.856\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.043\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.774\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.856\u0026ndash;8.993\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.089\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRadiographic SpA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.305\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.112\u0026ndash;0.831\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.518\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.161\u0026ndash;1.664\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.269\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGlucocorticoid requirement at baseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.291\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.034\u0026ndash;66.462\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.950\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.421\u0026ndash;37.058\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.229\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease activity at\u003c/p\u003e\u003cp\u003eBaseline*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e0.011\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026bull; Inactive disease vs high at baseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.210\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.047\u0026ndash;0.942\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e0.042\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026bull; Low disease vs high at baseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.253\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e0.089\u0026ndash;0.718\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e0.011\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCurrent/ past enthesitis at baseline\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.478\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.514\u0026ndash;19.821\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e11.293\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cb\u003e1.300\u0026ndash;93.460\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003e0.025\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eNote: High disease activity serves as the reference category.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003e*Disease activity at baseline showed significant association with tendency to flare whereas, the adjusted odds ratio of low/ inactive disease developing a flare is indicated in subsequent rows.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eChange of ASAS validated indices in flare and non-flare groups:\u003c/p\u003e\u003cp\u003eThe longitudinal change in quantitative variables at 0, 3 and 6 months was compared both as individual medians at different time-points and ∆-change in ASAS validated indices between flare and non-flare groups. Individual medians of ASAS NSAID index, ASDAS CRP, BASDAI and patient global assessment VAS were different between flare and non-flare groups at 0, 3 and 6 months. ∆ASDAS CRP, ∆BASDAI, ∆BASFI, ∆ASAS NSAID index, ∆PGA VAS and ∆BASMI at 3 and 6 months from baseline were compared using Mann Whitney U test to assess the longitudinal change in both the groups. The ∆-change was significant at 6 months in BASDAI, ASDAS CRP and BASFI values. The flare groups not only had significantly higher ASDAS CRP and BASDAI at 0, 3 and 6 months, but also was accompanied by significant fall of ASDAS CRP and BASDAI at 6 months compared to non-flare group. BASFI, though not statistically higher in flare group at 3 and 6 months still had significant fall at 3 and 6 months. A general linear model for repeated measures (two-way ANOVA) revealed that the longitudinal change in means of ASDAS CRP, BASDAI, BASFI, BASMI, ASAS NSAID Index and PGA VAS was statistically significant in both intra-group comparison and between flare and non-flare groups at the three time-points. But, with both time and flare outcome as a combined function, only ASDAS CRP and BASDAI was statistically significant in multivariate tests [Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cb\u003eGeneral Linear Model for repeated measures to assess significance of longitudinal change in indices between flare and non-flare groups and within these groups\u003c/b\u003e.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e\u003cp\u003eDependent variables\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003eMean at 0,3\u003c/p\u003e\u003cp\u003eand 6\u003c/p\u003e\u003cp\u003emonths, respectively\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003eIntra-group comparison (sig.)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eInter- group comparison\u003c/p\u003e\u003cp\u003e(sig.)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003eMultivariate tests\u003c/p\u003e\u003cp\u003e(Wilks\u0026rsquo; Lambda)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFlare\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003cp\u003eflare\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTime\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTime*flare\u003c/p\u003e\u003cp\u003eoutcome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFlare\u003c/p\u003e\u003cp\u003eoutcome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eTime\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eTime*flare\u003c/p\u003e\u003cp\u003eoutcome\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eASDAS CRP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003e0.030\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003e0.015\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003cp\u003emo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003cp\u003emo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.66\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eBASDAI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003e0.034\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003e0.012\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003cp\u003emo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.25\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003cp\u003emo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.97\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eASAS NSAID\u003c/p\u003e\u003cp\u003eIndex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.321\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.228\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003cp\u003emo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003cp\u003emo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eBASMI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.609\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.334\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.668\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003cp\u003emo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003cp\u003emo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eBASFI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.187\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.026\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.144\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003cp\u003emo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003cp\u003emo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.07\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003ePatient General Assessment\u003c/p\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.537\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.458\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003cp\u003emo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003cp\u003emo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003eAbbreviations: ASAS \u0026ndash; Assessment of SpondyloArthritis International Society; ASDAS \u0026ndash; Ankylosing Spondylitis Disease Activity Score; BASDAI \u0026ndash; Bath Ankylosing Spondylitis Disease Activity Index; BASFI \u0026ndash; Bath Ankylosing Spondylitis Functional Index; BASMI \u0026ndash; Bath Ankylosing Spondylitis Metrology; CRP \u0026ndash; C-reactive protein; VAS \u0026ndash; visual analog scale.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eSurvival analysis:\u003c/p\u003e\u003cp\u003eSurvival analysis using Kaplan-Meier analysis showed the median time to flare in the biological/ targeted synthetic DMARD group to be at 88 days compared to 26 days in the group with no biologicals/ targeted synthetic DMARDs at baseline. This did not meet statistical difference (p\u0026thinsp;=\u0026thinsp;0.249)[figure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e]. The difference in the probability of developing a flare did not meet statistical significance because most patients were on suboptimal/ tapering doses of bDMARDs.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe study aimed at exploring the characteristics of flares, relation of disease activity indices to flare episodes and factors affecting flares. Most of the studies on flares in spondyloarthritis were conducted on patient-reported flare using multiple methods namely, online questionnaire [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], smartphone app [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], patients\u0026rsquo; self-recorded details of NSAID intake and disease activity [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]and online survey platform [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Comparison between various studies on flare in SpA is tabulated in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The study focused on rheumatologist-diagnosed flares with patient-based indices (BASDAI, ASDAS CRP, ASAS NSAID index, patient global assessment VAS, BASFI) to make the diagnosis of flare. We augmented patient\u0026rsquo;s perception of disease activity with rheumatologist assessment to bridge the doctor-patient consensus in diagnosis of flare. Also, we relied on ASDAS CRP, a weighted measure, which considers the burden of inflammation. The details were collected through face-to-face interaction which further helped in therapeutic decision making and effective control of flares. Compared to studies on flares in SpA, our cohort was younger and had a relatively shorter disease course (median duration of disease in our population was 4.5 years with IQR of 3\u0026ndash;8 and median age of our population was 26 with an IQR of 22\u0026ndash;31, providing insights about flares in early course and younger population in SpA. Also, lower median age in our sample population corresponds to the demographic characteristics of Indian population [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The incidence of flares in our study is 63.2%. Associations for flare showed history of drug default in the past month(30%) and antecedent infections in the past 3 weeks (19%). There was positive history of drug default in 20/67 patients of flare group and 3/39 patients of the non-flare group. The flare incidence was relatively low in the study compared to other SpA cohorts [supplementary file].\u003c/p\u003e\u003cp\u003eAlmost all our patients were on NSAIDs, except 4 patients (3.8%) who did not require NSAIDs during the study. 84 patients (79.3%) were on csDMARDs and 29.2% were on tapering/ regular course bDMARDs/ tsDMARDs in our study. Survival analysis showed the median time to flare in the biological group to be at 88 days compared to 26 days in the group with no biologicals at baseline, but this did not meet statistical difference. Also, incidence of flares between the groups did not meet statistically significant difference (33% vs 30.2%). Among patients on bDMARDs, 31.2% of our patients were on tapering doses of bDMARDs explaining the lack of difference in incidence of flares in patients receiving bDMARDs. None of the patients on tsDMARDs were on inadequate/ tapering doses. Similarly, comparative analysis of sulfasalazine-treated and etanercept-treated patients from ESTHER trial also showed flare rate was similar in both groups at 24.4 weeks after discontinuation (69% vs 75%)[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. A study conducted in south India showed short-course infliximab followed by continuation of methotrexate and sulfasalazine combination can prolong time to disease flare and decrease requirement for additional infliximab dose in axSpA. Also, disease flare occurred only in 33.3% (15/45) of patients after a mean duration of 14.5 months compared to usual time-to-flare of 4\u0026ndash;6 months on discontinuation of TNF inhibitors in the study [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This suggests that csDMARDs might have a beneficial role in preventing flares in SpA.\u003c/p\u003e\u003cp\u003eSignificant association favouring flare was seen with duration since diagnosis of less than 6 years, steroid requirement at baseline, current/ past history of enthesitis at baseline, high disease activity at baseline and ax-SpA was associated with lower tendency to flare in univariable analyses. Jacquemin et al also identified significant statistical association of shorter time since onset of disease, higher BASDAI, less anti-TNF treatment, worse quality of life favouring tendency to flare [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The results of change in ASDAS CRP, BASDAI, BASFI, ASAS NSAID index, at 6 months was similar to study by Danda et al which showed higher fall in peripheral arthritis group with similarly high BASDAI, BASFI, ASDAS CRP, ASAS NSAID index at baseline [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The higher ∆-change or fall in ASDAS CRP, BASDAI and BASFI in the flare group could be attributed to immediate medical attention and subsequent improvement.\u003c/p\u003e\u003cp\u003eLimitations include a single center study and limited sample population preventing in-depth analyses regarding effect of drugs/ drug combinations on flare outcomes. Also, the study did not include indices for assessing quality of life, work productivity in relation to flares. The treatment protocol followed in the study does not reflect standard guidelines in SpA, the only reason being financial concerns precluding use of bDMARDs early in the course of the disease. The study was conducted in a North Indian tertiary care cohort, making it difficult to generalize the findings. Additionally, the study design may limit the ability to control for confounders related to the timing of flares. Strengths include 2650 patient-weeks of follow-up and 318 patient visits with close patient interaction and tracking of flares. Also, real world data is generated regarding status of bDMARD/ csDMARD use in populations not affording continuous use of bDMARDs from out-of-pocket health expenditure. Patients with risk factors/ protective factors towards flare can be identified and suitable decisions regarding care plans can be taken with the findings generated by the study.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePatients with low/ inactive disease activity at baseline have lower odds of developing a flare. Patients with current/ past enthesitis have higher odds of developing flare. ASDAS CRP, BASDAI, Patient general assessment VAS and ASAS NSAID scores are significantly different in patients of axSpA with tendency to flare. Also ∆-change in ASDAS CRP, BASFI and BASDAI at 6 months varied significantly between flare and non-flare groups. In patients who are at high risk of flare as suggested in the study, it would help the rheumatologist to guide the treatment plan carefully to prevent flare.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval: Research was performed in accordance with the Declaration of Helsinki and prior ethical approval from institutional ethics committee of King George’s Medical University (Ref code: VII PGTSC- IIA/ P14).\u003c/p\u003e\n\u003cp\u003eConsent to participate: Detailed informed consent for participation was obtained from all participants of the study.\u003c/p\u003e\n\u003cp\u003eConsent for publication: Consent for publication was obtained from all the participants of the study.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eClinical trial number: Not applicable.\u003c/p\u003e\n\u003cp\u003eAcknowledgements: The authors would like to thank the patients of the cohort.\u003c/p\u003e\n\u003cp\u003eCompeting interests: The authors of this study declare they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003eAuthor contribution declaration: AKV was involved in Conceptualization, Methodology, Software, SM was involved in Data curation, Writing- Original draft preparation. UD involved in Visualization, Investigation. MKM was involved in Methodology, Software. NK was involved in Validation. APM was involved in Data curation, Writing. PK was involved in Writing- Reviewing and Editing. All authors read and approved the final manuscript\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWendling D, Prati C. Flare in axial spondyloarthritis. The dark side of the outcome. Ann Rheum Dis. 2016;75(6):950\u0026ndash;1.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAouad K, Gossec L. Defining and managing flares in axial spondyloarthritis. Curr Opin Rheumatol. 2022;34(4):195.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMolto A, Gossec L, Meghnathi B, Landew\u0026eacute; RBM, van der Heijde D, Atagunduz P, et al. An Assessment in SpondyloArthritis International Society (ASAS)-endorsed definition of clinically important worsening in axial spondyloarthritis based on ASDAS. Ann Rheum Dis. 2018;77(1):124\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDougados M, Wood E, Gossec L, van Der Heijde D, Logeart I. Flare in axial spondyloarthritis: investigation of meaningful changes in symptomatic outcome measures. Clin Exp Rheumatol. 2017;35:209\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGodfrin-Valnet M, Puyraveau M, Prati C, Wendling D. Flare in spondyloarthritis: Thresholds of disease activity variations. Joint Bone Spine. 2015;82(3):192\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCooksey R, Brophy S, Gravenor MB, Brooks CJ, Burrows CL, Siebert S. Frequency and characteristics of disease flares in ankylosing spondylitis. Rheumatology. 2010;49(5):929\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSong IH, Althoff CE, Haibel H, Hermann KGA, Poddubnyy D, Listing J, et al. 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J Rheumatol. 2017;44(4):425\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYeo J, Kim JY, Park JK, Shin K, Lee EY, Kim TH, Park JW. Flare prediction after tapering the dose of tumour necrosis factor inhibitors in patients with axial spondyloarthritis: a nationwide cohort study. Rheumatology. 2025;64(3):1155\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWetterslev M, Georgiadis S, Christiansen SN, Pedersen SJ, S\u0026oslash;rensen IJ, Hetland ML, et al. Occurrence and prediction of flare after tapering of tumor necrosis factor inhibitors in patients with axial spondyloarthritis. J Rheumatol. 2024;51(1):39\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNair AM, Sandhya P, Yadav B, Danda D. TNFα blockers followed by continuation of sulfasalazine and methotrexate combination: a retrospective study on cost saving options of treatment in Spondyloarthritis. Clin Rheumatol. 2017;36(10):2243\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGanapati A, Gowri M, Antonisamy B, Danda D. Combination of methotrexate and sulfasalazine is an efficacious option for axial spondyloarthritis in a resource-limited, real-world clinical setting: a prospective cohort study. Clin Rheumatol. 2021;40(7):1871\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7045624/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7045624/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives:\u003c/h2\u003e\u003cp\u003eTo determine characteristics of flares in spondyloarthritis and to identify differences between flare and non-flare populations.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e\u003cp\u003eA cohort of 106 patients (2650 patient-weeks follow-up and 318 visits) who fulfilled the ESSG or ASAS classification criteria for SpA were followed up for 6 months. The diagnosis of flare was made by rheumatologist using patient-reported indices and ruling out confounders.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e\u003cp\u003e67/ 106 (63.2%) patients were diagnosed flare at 6 months of which 51 (76.1%) developed major/ generalized flares and 16 (23.9%) developed minor/ localized flares. Shorter time since diagnosis (disease duration less than 6 years), current/ past history of enthesitis at baseline, steroid requirement and high disease activity at baseline were significantly favouring flares and ax-SpA was associated with lower tendency to flare in univariable analyses. Multivariable logistic regression analyses revealed inactive (OR 0.21 [95% CI 0.047\u0026ndash;0.942], p\u0026thinsp;=\u0026thinsp;0.042) or low disease at baseline (OR 0.25 [95% CI 0.089\u0026ndash;0.718], p\u0026thinsp;=\u0026thinsp;0.011) was significantly associated with lower tendency of flare while current/ past enthesitis (OR 11.29 [95% CI 1.3\u0026ndash;93.46], p\u0026thinsp;=\u0026thinsp;0.025) favoured greater tendency to flare, with variable effect size. A general linear model for repeated measures revealed significant differences in longitudinal change in all ASAS validated indices between flare and non-flare groups.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e\u003cp\u003eThe study identifies predictors in spondyloarthritis with increased tendency to flare. The results suggest that patients with low/ inactive disease at baseline may have fewer flares and enthesitis may associate with higher tendency to flare.\u003c/p\u003e","manuscriptTitle":"Identifying flare prone Spondyloarthritis – insights from a prospective cohort","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-29 15:47:24","doi":"10.21203/rs.3.rs-7045624/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9b043481-c168-4fe2-a41c-37e0ab58a427","owner":[],"postedDate":"July 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-22T16:41:41+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-29 15:47:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7045624","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7045624","identity":"rs-7045624","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}