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Factors associated with ASDAS remission in a long-term study of ankylosing spondylitis patients under tumor necrosis factor inhibitors

Factors associated with ASDAS remission in a long-term study of ankylosing spondylitis patients... Objective: To determine the clinical and demographic factors associated with disease remission and drug survival in patients with ankylosing spondylitis (AS) on TNF inhibitors. Methods: Data from a longitudinal electronic database of AS patients under anti-TNF therapy between June/2004 and August/2013. Demographic, clinical parameters, disease activity by ASDAS remission (< 1.3) and inactive/low (< 2.1) were analyzed to characterize reasons for drug survival and switching of anti-TNF. Results: Among 117 AS patients, 69 (59%) were prescribed only one anti-TNF, 48 (41%) switched to a second anti- TNF and 13 (11%) to a third anti-TNF. Considering ASDAS-CRP < 1.3, 31 (39%) patients were inactive at the end of the study. Non-switchers (P = 0.04), younger age (P = 0.004), non-smoking (P= 0.016), shorter disease duration (P = 0.047), more frequent use of SSZ (P =0.037) and lower BASDAI (P = 0.027), BASMI (P =0.034) and BASFI (P = 0.003) at baseline were associated with remission. In the multivariate analysis younger age (P = 0.016) and lower BASDAI (P = 0.032) remained as remission predictors. Conclusion: This study supports that ASDAS-CRP remission is an achievable goal not only for non-switchers but also for second anti-TNF, particularly in patients with younger age and lower BASDAI at baseline. Co- medication and non-smoker status seems to have a beneficial effect in anti-TNF response in this population. Keywords: Ankylosing spondylitis, Anti-TNF, Co-medication, Remission, Switch Introduction (DMARDs) for the treatment of axial involvement. Ac- Ankylosing spondylitis (AS), the most frequent disease cording to the ASAS recommendations, treatment with in the spondyloarthritis (SpA) group, is a chronic anti-TNF drugs is indicated in patients who maintain rheumatic disorder characterized by inflammatory back persistent high disease activity [2]. pain, peripheral arthritis, enthesitis and extra-articular Drug survival of anti-TNF agents in the long-term follow manifestations such as uveitis and inflammatory bowel up is increased in patients with SpA, particularly AS, when disease [1]. Non-steroidal anti-inflammatory drugs compared to rheumatoid arthritis (RA) [3, 4]. In this (NSAIDs) are the first line drugs in the treatment of AS. setting, the identification of predictors of good response is Sulfasalazine (SSZ) and in some cases methotrexate important to optimize therapeutic decisions in AS. Previous (MTX) may be considered in patients with concomitant studies have already demonstrated that younger age, lower peripheral arthritis, but there is no evidence of the Bath Ankylosing Spondylitis Functional Index (BASFI), in- benefits of disease modifying anti-rheumatic drugs creased disease activity with high C reactive protein (CRP) level, and even the presence of HLA-B27, are markers of * Correspondence: goncalves-carla@uol.com.br good response to treatment [5–7]. In case of primary or Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455 3° secondary failure, switching to another anti-TNF is andar - sala 3131 - Cerqueira César, São Paulo, SP Cep: 01246-903, Brazil © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Shimabuco et al. Advances in Rheumatology (2018) 58:40 Page 2 of 8 currently the best therapeuticoption. Although drug sur- Centro de Dispensação de Medicação de Alto Custo) vival with the second anti-TNF is frequently lower than the with indication of biological therapy for disease activity first one, the clinical improvement with the first switch in refractory to conventional treatment were evaluated. AS can vary from 30 to 70% of patients, indicating that the Data of patients from an ongoing electronic database lack or loss of response to a TNF blocker is not a predictor protocol that received anti-TNF therapy between June of failure to another one [8–10]. The Danish nationwide 2004 and August 2013 were retrospectively assessed. All biologic registry (DANBIO) documented therapy with patients fulfilled the modified New York classification anti-TNF drugs in patients with AS and described that criteria for definite AS [23]. Demographic characteristics almost 30% of the 1436 patients switched to a second and as gender, age, HLA-B27 positivity, smoking (current or 10% to a third anti-TNF medication during 10 years of previous), and disease duration were recorded. Assess- follow up; switchers were more frequently women, with ments also included parameters of previous and current shorter disease duration and higher levels of Bath Ankylos- treatment with DMARDs, NSAIDs and prednisone, as ing Spondylitis Disease Activity Index (BASDAI), BASFI well as the presence of peripheral arthritis. and visual-analogue-scale (VAS) global at the beginning of the treatment. At the 2-year visit, 52% of switchers (number Study design needed to treat – NNT = 1.9) and 63% of non-switchers Patients were evaluated using an electronic chart (NNT = 1.6) achieved BASDAI 50 response, compared with database protocol established in 2000 with periodical the baseline visit of the first treatment [11]. There was no assessment of parameters of treatment response and strong evidence of difference between switchers for failure adverse events. Acute phase reactants, as CRP and or adverse events in relation to baseline characteristics and Erythrocyte Sedimentation Rate (ESR) were collected at therapeutic response; however, studies with small group of every visit. Outcome parameters were BASDAI, BASFI, patients have shown a slightly better response in those that Bath Ankylosing Spondylitis Metrology Index (BASMI), switched due to adverse events than due to failure [12, 13]. Ankylosing Spondylitis Quality of Life (ASQoL) [24–28]. Despite the well-known indication of DMARD associ- The analysis of final clinical response was performed ated with anti-TNF drugs in the treatment of RA, there is in patients receiving anti-TNF therapy at the end of the no such consensus in relation to SpA. ASAS recommen- study. Clinical response was measured according to dations do not support the mandatory use of conventional determined levels of Ankylosing Spondylitis Disease DMARDs associated with biological therapy, especially in Activity Score (ASDAS) - CRP and ASDAS – ESR [29] cases of axial involvement [2]. As the formation of and the Ankylosing Spondylitis Disease Activity Score anti-drug antibodies is one of the possible mechanisms of (ASDAS) update of 2018 was used to classify patients ac- lack or loss of blocking TNF response, co-medication with cording disease activity states as inactive disease (< 1.3) DMARDs has been suggested in many inflammatory and low disease activity (1.3–2.1) [30]. diseases, including SpA [14, 15]. In the last decade, many Treatment for less than 24 weeks or patients that studies have addressed the use of concomitant conven- stopped medication due to drug failure, adverse events tional DMARDs in patients with SpA, with contrasting or multiple switches (i.e. use of the same drug for more results. Although two studies each have shown that MTX than one course) were excluded only from response could be associated with longer anti-TNF drug survival in analysis, at final evaluation and remission predictors. psoriatic arthritis [16, 17] and AS [18, 19], three other This study was approved by the Local Ethics Commit- studies showed no benefits of this association [20–22]. tee on Human Research at the University of São Paulo Therefore, there is no definitive conclusion on the benefit (CAPPesq). All participants gave written informed of combined therapy with anti-TNF and DMARDs consid- consent in compliance with the Helsinki Declaration. ering drug retention and effectiveness. The primary aim of this study was to determine the Statistical analysis clinical and demographic factors associated with disease The results were presented as mean and standard devi- remission and prolonged drug survival in patients with ation (SD) for continuous variables (age, disease duration, ankylosing spondylitis (AS) on anti-TNF inhibitors. We also BASDAI, BASMI, ASQol, ESR, CRP and ASDAS - CRP/ evaluated the influence of co-medication in AS patients on ESR) and compared using the T test or Mann-Whitney anti-TNF switching, clinical response and remission. test when comparing two groups and ANOVA for more than two groups. Patients and methods Categorical variables (gender, HLA-B27, peripheral Patients arthritis, smoking, use of DMARD, NSAID or prednis- One hundred seventeen AS patients followed in the one, ASDAS – CRP/ESR) were shown as percentage and Spondyloarthritis Outpatient Clinic and referred to the evaluated through the Fisher Exact Test or Chi square Immunobiological Drugs Infusion Center (CEDMAC – when indicated. Shimabuco et al. Advances in Rheumatology (2018) 58:40 Page 3 of 8 Multivariate analysis was also performed for possible P = 0.039), whereas no difference was observed when MTX factors associated with remission and Kaplan-Meier users were analyzed (18.8% vs. 16.7%, P = 0.811). Groups analysis for drug survival on different anti-TNF courses. with and without SSZ co-medication presented simi- Statistical significance was considered when P < 0.05. lar baseline characteristics, as gender (P= 1.000), age Statistical analyses were performed using SigmaStat (P= 0.869), smoking (P=0.489), peripheral arthritis version 3.1 (2005) and GraphPad/ Prisma Software. (P= 0.839), BASDAI (P= 0.473) and ASDAS-CRP (P = 0.923). The mean dose of SSZ was 2.6 g per day. Results The concomitant use of conventional DMARDs in Baseline demographics the AS patients was quite common due to the high A total of 117 patients treated with TNF inhibitors were prevalence of peripheral joint involvement (70%) in identified. Forty-five patients maintained the first agent our patients with axial SpA. Thirty-five patients (29.9%) during the study period; 48 patients switched to a sec- used more than one DMARD at the introduction of the ond anti-TNF, due to failure in 58% and adverse effects anti-TNF drug; MTX and SSZ was the main combination. in 42% of the cases; and 13 patients were treated with a High disease activity was associated with maintenance of third anti-TNF, 62% due to failure and 38% due to ad- combined DMARDs at the study entry as there was no verse effects (Fig. 1). The most common first anti-TNF other treatment option at that time. was infliximab in 88 patients (75.2%), with adalimumab in 20 (17.1%) and etanercept in 9 patients (7.7%), Disease characteristics at baseline of the second anti-TNF indicating the drug availability in our country at that Switchers’ characteristics at baseline of the second moment. Adalimumab was the most frequently used anti-TNF were also assessed and compared between second drug (67%) and etanercept was the common patients who remained receiving the second and those third line treatment (69%). The median of follow-up who have not responded and switched to the third duration was 41.5 months (0.5 to 116.1 months). anti-TNF. Groups were similar with respect to demo- At baseline, demographic data and clinical parameters graphic data and characteristics of disease, except for the were similar in switchers and non-switchers (Table 1). higher scores of BASDAI at baseline of the 2nd There was no difference regarding gender, age, presence of anti-TNF in patients who required the third therapy (6.4 HLA-B27, smoking (current or previous), disease duration ± 1.7 vs. 4.1 ± 2.5, P = 0.012), suggesting worse disease and disease parameters. With regard to co-medication, activity in patients who evolved with failure to the non-switchers used more often DMARD (88.9% vs. 72.9%, second anti-TNF. The choice of the first switch did not P= 0.023); among those patients who used concomitant influence the maintenance of the second treatment; it was DMARDs, the use of SSZ was also more frequent in pa- comparable among patients who started and switched to tients who maintained the first treatment (37.7% vs. 18.8%, monoclonal antibody (infliximab or adalimumab) and Fig. 1 Flow-chart of treatment courses in Ankylosing Spondylitis patients. AE: adverse events Shimabuco et al. Advances in Rheumatology (2018) 58:40 Page 4 of 8 Table 1 Patients characteristics at baseline Table 2 Comparison at final evaluation between non-switchers and switchers Variable Non-switchers Switchers P (n = 69) (n = 48) Non-switchers Switchers P (n = 42) (n = 36) Male gender 61/69 (88.4%) 38/48 (79.2%) 0.199 BASDAI 1.7 ± 1.6 2.6 ± 2.0 0.041* Age, years 37.3 ± 13.2 38.3 ± 11.2 0.665 BASFI 2.8 ± 2.7 4.2 ± 3.0 0.034* HLA-B27 positivity 38/46 (82.6%) 34/40 (85.0%) 1.000 BASMI 2.9 ± 2.2 3.2 ± 2.1 0.635 Smoking 17/45 (37.8%) 13/36 (36.1%) 1.000 ASQoL 3.5 (1.0, 8.0) 6.0 (1.5, 10.5) 0.057 Disease duration, years 11.4 (6.2, 17.7) 9.2 (5.7, 19.2) 0.840 CRP, mg/l 2.8 (1.3, 5.0) 4.0 (1.7, 8.6) 0.148 Peripheral involvement 45/69 (65.2%) 37/48 (77.1%) 0.218 ESR, mm/hr 4.0 (2.0, 8.0) 5.0 (2.0, 15.5) 0.363 Pure axial involvement 24/69 (34.8%) 11/48 (22.9%) 0.218 ASDAS – CRP 1.5 ± 0.7 2.0 ± 1.0 0.012* BASDAI 5.2 ± 2.0 5.5 ± 2.1 0.482 Last anti-TNF treatment 206.6 (96.9, 287.9) 171.9 (101.6, 210.3) 0.146 BASFI 5.2 ± 2.5 5.9 ± 2.4 0.199 duration, weeks BASMI 3.9 ± 2.8 4.5 ± 2.7 0.290 Values are expressed as mean (SD) and median (quartile). ASDAS Ankylosing ASQoL 10.4 ± 5.5 12.7 ± 4.7 0.058 Spondylitis Disease Activity Score, ASQoL Ankylosing Spondylitis Quality of Life, BASDAI Bath Ankylosing Spondylitis Disease Activity Index, BASFI Bath CRP, mg/l 21.6 (12.8, 38.0) 20.6 (12.6, 40.0) 0.397 Ankylosing Spondylitis Functional Index, BASMI Bath Ankylosing Spondylitis Metrology Index, CRP C Reactive Protein, ESR Erythrocyte Sedimentation Rate, ESR, mm/hr 20.5 (11.0, 34.5) 25.0 (13.1, 48.5) 0.268 * P < 0.05 ASDAS – CRP 3.8 ± 0.9 3.9 ± 1.0 0.714 non-switchers more often achieved inactive/low disease ASDAS – ESR 3.3 ± 0.9 3.6 ± 1.0 0.175 activity (ASDAS< 2.1) by ASDAS - CRP (80.1% vs. 55.9%, Concomitant use of: P = 0.024) and ASDAS - ESR (88.1% vs. 57.6%, P= 0.003) NSAID 50/69 (72.4%) 41/48 (85.4%) 0.117 and remission (ASDAS < 1.3) by ASDAS - ESR (61.9% vs. DMARD 62/69 (88.9%) 35/48 (72.9%) 0.023* 36.4%, P= 0.037) and ASDAS - CRP (42.8% vs. SSZ only 26/69 (37.7%) 9/48 (18.8%) 0.039* 26.5%, P = 0.156). Considering ASDAS - CRP < 1.3, 31 (39%) patients MTX only 13/69 (18.8%) 8/48 (16.7%) 0.811 were inactive at the end of the study. Thereby the NNT Cyclosporine 1/69 (1.4%) 1/48 (2.1%) 1.000 was 5.57 for non-switchers and 5.33 for second and 13 Leflunomide 7/69 (10.1%) 8/48 (16.7%) 0.400 for the third anti-TNF. Prednisone 23/69 (33.3%) 15/48 (31.2%) 0.844 Switchers due to failure or adverse effects were Values are expressed as mean (SD), median (quartile) and percentages. BASDAI comparable regarding demographic data and baseline Bath Ankylosing Spondylitis Disease Activity Index, BASFI Bath Ankylosing characteristics, as disease activity parameters and Spondylitis Functional Index, BASMI Bath Ankylosing Spondylitis Metrology Index, ASQoL Ankylosing Spondylitis Quality of Life, CRP C Reactive Protein, co-medication. In the final evaluation, 14 switchers due ESR Erythrocyte Sedimentation Rate, ASDAS Ankylosing Spondylitis Disease to adverse effects and 14 patients due to lack or loss of Activity Score, NSAID Non-steroidal Anti-Inflammatory Drug, SSZ Sulfasalazine, MTX Methotrexate, *P < 0.05 efficacy were on treatment with second anti-TNF. Response to treatment and status of disease were those who started with monoclonal antibody and switched comparable between the groups (ASDAS - CRP < 2.1: to etanercept (66% vs. 77%, P =0.716). 64.3% vs. 66.7%, P = 1.000). Final evaluation and disease status Inactive disease and predictors At the end of the study, 78 patients (42 non-switchers Patients that achieved remission at the final evaluation and 36 switchers) were using their last TNF inhibitors with ASDAS-CRP < 1.3 were evaluated for the presence for more than 6 months; among the 36 switchers, 28 pa- of predictors of remission at baseline. Younger age (32.3 tients were receiving the second and 8 patients the third ± 9.9 vs. 39.8 ± 11.8 years, P = 0.004), non-smoking anti-TNF. Table 2 shows the final parameters of disease (smoking: 16.0% vs. 46.3%, P= 0.016), shorter disease activity and clinical status. The effectiveness of the first duration (10.6 ± 9.3 vs. 14.7 ± 9.8 years, P = 0.047), more TNF inhibitor was more evident in non-switchers, since frequent use of SSZ (70.9% vs. 44.9%, P = 0.037), lower this group had at final evaluation lower scores of BASDAI (4.6 ± 2.2 vs. 5.8 ± 2.0, P = 0.027), lower BASFI BASDAI (1.7 ± 1.6 vs. 2.6 ± 2.0, P = 0.041), BASFI (2.8 ± (4.4 ± 2.0 vs. 6.2 ± 2.5, P = 0.003) and lower BASMI (3.6 2.7 vs. 4.2 ± 3.0, P = 0.034), ASDAS - CRP (1.5 ± 0.7 vs. ± 2.8 vs. 5.0 ± 2.7, P = 0.034) at the moment of anti-TNF 2.0 ± 1.0, P = 0.012) and ASDAS - ESR (1.3 ± 0.7 vs. 1.8 drug introduction were associated with remission ± 1.0, P= 0.050) compared to switchers, in spite of (Table 3). Of note, 71% of the patients that achieved comparable duration of the last anti-TNF treatment for remission remained in the first anti-TNF and none the switchers and non-switchers (P = 0.146). Of note, achieved remission in the third anti-TNF. Shimabuco et al. Advances in Rheumatology (2018) 58:40 Page 5 of 8 Table 3 Baseline comparison between patients according to patients without this co-medication. Non-smokers AS inactive disease criteria (ASDAS – CRP < 1.3) patients also achieved remission more frequently than ASDAS CRP < 1.3 ASDAS CRP ≥ 1.3 P smoker patients (ASDAS-CRP < 1.3, 48.8% vs. 17.4%, (n = 31) (n = 49) P = 0.016) and seemed to present lower disease activ- Male gender 27/31 (87.1%) 39/49 (79.6%) 0.548 ity (ASDAS-CRP, 1.5 ± 0.8 vs. 1.9 ± 0.8, P = 0.056) at HLA-B27 positivity 20/27 (74.1%) 37/42 (88.1%) 0.193 the end of the study. Smoking 4/25 (16.0%) 19/41 (46.3%) 0.016* Retention to therapy Baseline: The mean anti-TNF drug survival for non-switchers was Age, years 32.3 ± 9.9 39.8 ± 11.8 0.004* 5.2 years (95% CI 4.4 to 6.0 years) and for switchers was Duration of disease, 10.6 ± 9.3 14.7 ± 9.8 0.047* 1.7 years (95% CI 1.3 to 2.1 years) on first anti-TNF, 4.9 years years (95% CI 3.9 to 5.9 years) on second anti-TNF and Co-medication: 3.8 years (95% CI 2.5 to 5.2 years) on third anti-TNF. NSAID 23/31 (74.2%) 35/49 (71.4%) 1.000 Retention to therapy was superior for non-switchers DMARD 27/31 (87.1%) 37/49 (75.5%) 0.259 when compared to switchers to the second (log rank test P = 0.007) and to the third anti-TNF (log rank test MTX 11/31 (35.5%) 21/49 (42.9%) 0.640 P = 0.02). The retention to therapy between switchers SSZ 22/31 (70.9%) 22/49 (44.9%) 0.037* on the second or third course presented no difference BASDAI 4.6 ± 2.2 5.8 ± 2.0 0.027* (log rank test P =0.07) (Fig. 2). BASFI 4.4 ± 2.0 6.2 ± 2.5 0.003* BASMI 3.6 ± 2.8 5.0 ± 2.7 0.034* Discussion ASQol 10.6 ± 5.6 11.2 ± 4.8 0.669 This is the first long-term study to evaluate AS patients under anti-TNF agents focusing on ASDAS inactive ASDAS – CRP 3.5 ± 0.9 3.9 ± 1.0 0.126 disease, demonstrating an overall 40% remission. We CRP (mg/L) 20.3 (9.7, 36.7) 24.6 (14.9, 38.9) 0.664 further identified that younger age and lower BASDAI at ESR (mm/h) 23.0 (10.3, 32.0) 21.0 (12.5, 36.5) 0.650 baseline were predictors of long-term remission. 1st anti-TNF 22/31 (71.0%) 23/49 (46.9%) 0.040* Switching was a frequent event during long-term retention anti-TNF therapy in our cohort, occurring in more than Last anti-TNF 176.9 ± 85.2 182.1 ± 106.2 0.820 a third of our patients and mainly due to treatment treatment, weeks failure (lack or loss of efficacy). In the Danish registry Values are expressed as mean (SD), median (quartile) and percentages. BASDAI (DANBIO) [11], and in a Dutch [31] and a Spanish [32] Bath Ankylosing Spondylitis Disease Activity Index, BASFI Bath Ankylosing Spondylitis Functional Index, BASMI Bath Ankylosing Spondylitis Metrology cohort a high frequency of switching was also observed, Index, ASQoL Ankylosing Spondylitis Quality of Life, CRP C Reactive Protein, mostly associated with lack/loss of effect. In contrast, in ESR Erythrocyte Sedimentation Rate, ASDAS Ankylosing Spondylitis Disease Activity Score, DMARD Disease Modifying Antirheumatic Drug, the Norwegian registry (NOR-DMARD) [10] and in the NSAID Non-steroidal Anti-Inflammatory Drug, SSZ Sufasalazine, Leeds cohort [33] a very low frequency of switching/ MTX Methotrexate, *P <0.05 discontinuation was reported. In the multivariate analysis the variables that remained We have not identified demographic and baseline dis- as predictor of remission were younger age (OR = 0.935; ease parameters as relevant predictive factors for switch- CI 95% 0.886–0.987; P = 0.016) and lower BASDAI (OR ing in our patients opposing to previous report that = 0.725; CI 95% 0.541–0.972; P = 0.032) (Table 4). female gender, MTX use, higher BASFI and BASDAI Further analysis of significant parameters in univariate were associated with the second anti-TNF therapy [11]. demonstrated that patients treated with SSZ and Although a previous report has shown that peripheral anti-TNF achieved more often at the end of the study involvement was a predictive factor of switching [18], it inactive disease (ASDAS-CRP < 1.3, 47.7% vs. 25.0%, was not observed in this study, probably because that P = 0.040) and lower disease activity according to represents a common finding in Brazilian axial SpA ASDAS – CRP (1.5 ± 0.9 vs. 1.9 ± 0.9, P = 0.009) than patients [43]. With regard to the third anti-TNF, we identified that patients with higher BASDAI at the time Table 4 Remission predictors: multivariate analysis of introduction of the second anti-TNF agent were more Baseline OR CI (95%) P likely to switch to the third TNF inhibitor, suggesting a Age 0.935 0.886 0.987 0.016* refractory disease in these patients. Sulfasalazine 2.849 0.857 9.472 0.088 Although response rates decreased after switching for the second anti-TNF agent, many patients presented satisfac- BASDAI 0.725 0.541 0.972 0.032* tory improvement in the follow-up with a NNT very simi- BASDAI Bath Ankylosing Spondylitis Disease Activity Index, OR Odds Ratio, CI confidence interval,*P < 0.05 lar to the first anti-TNF agent. In contrast, the very high Shimabuco et al. Advances in Rheumatology (2018) 58:40 Page 6 of 8 Fig. 2 Retention to therapy (Kaplan-Meier analysis); log-rank test: non-switchers vs switchers - second anti-TNF (P = 0.007) and non-switchers vs switchers - third anti-TNF (P = 0.02) NNT for the third TNF blockers and complete absence of disease and CRP or ESR parameters, we consider that remission in this group does not support this switch. At baseline ASDAS index may not have been associated the final evaluation, non-switchers achieved lower levels of with remission due to similar values of CRP and ESR at BASDAI, BASFI and ASDAS-CRP compared to switchers. baseline between the groups and limited number of pa- Similar trends of reduced response in switchers have been tients with ASDAS evaluation at baseline in our cohort, demonstrated [9, 11, 34], but none of these studies consid- since ASDAS index was published in 2009. ered ASDAS inactive disease as a target. In fact, ASDAS is We suggested and extended recent observations that the only validated and discriminatory instrument for concomitant DMARD use was associated with a better first assessing disease activity in AS [29, 30]. anti-TNF persistent rate [19, 20, 37]. The non-exclusion of The reason for change (lack/loss of efficacy or adverse patients who discontinued without switching anti-TNF events) to the second TNF antagonist did not influence due to other causes precludes a definitive conclusion about anti-TNF response. At the final assessment, both groups concomitant DMARD use effectiveness in AS in a previous presented comparable indexes, including BASDAI, study [37]. ASDAS-CRP and frequency of ASDAS inactivity/moder- Non-smokers AS patients also achieved remission ate disease activity. Previous studies reported similar more frequently than smoker patients at the end of the results [10, 11, 35, 36]; however, some demonstrated study, in agreement to published data. Previous studies slightly better clinical improvement in switchers due to indicate that this factor has a dose-dependent impact on adverse events [11, 34]. structural damage progression and in worse treatment In this study, we presented novel evidence of predict- response of SpA patients [38–41]. ive factors considering ASDAS score as remission cri- The treatment response analysis performed herein was teria. Unlike other studies that considered BASDAI50 or limited to patients under anti-TNF treatment at the final ASAS40 (4–6), ours considered ASDAS-CRP < 1.3 as evaluation and with at least 24 weeks of therapy. This remission response. Younger age, non-smoking, shorter strict study design provided novel data demonstrating disease duration, more frequent use of SSZ, lower that SSZ co-medication was more often associated with BASDAI, BASFI and BASMI at the time of anti-TNF remission. In the Swiss cohort, a benefit in drug survival drug introduction were identified as possible predictors was reported, but it was only demonstrated for DMARD of remission and only younger age and lower BASDAI at on the clinical response in patients treated with inflixi- baseline remained significant in the multivariate analysis. mab and methotrexate [20]. Taking into account that ASDAS considers 3 answers Baseline disease and activity parameters were alike in of BASDAI questionnaire plus global assessment of patients with and without SSZ minimizing the chance Shimabuco et al. Advances in Rheumatology (2018) 58:40 Page 7 of 8 that these factors might have influenced SSZ effect in Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in anti-TNF treatment. In fact, more than 2/3 of our pa- published maps and institutional affiliations. tients have associated peripheral involvement in AS, and the concomitant use of conventional DMARD, as SSZ, is Received: 19 June 2018 Accepted: 23 November 2018 quite common in our daily practice in Brazil [42–44]. References Conclusion 1. Braun J, Sieper J. Ankylosing spondylitis. Lancet. 2007;369:1379–90. This long-term longitudinal study supports that 2. van der Heijde D, Ramiro S, Landewé R, Baraliakos X, Van den Bosch F, ASDAS-CRP remission is an achievable goal not only Sepriano A, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76(6): for non-switchers but also for the second anti-TNF, par- 978–991. ticularly in patients with younger age and lower BASDAI 3. Sampaio-Barros PD, van der Horst-Bruinsma IE. Adverse effects of TNF at baseline therapy. Co-medication and non-smoker inhibitors in SpA: are they different from RA? Best Pract Res Clin Rheumatol. 2014;28:747–63. status seems to have a beneficial effect on anti-TNF re- 4. Arends S, Brouwer E, Efde M, van der Veer E, Bootsma H, Wink F, et al. sponse in this population. Long-term drug survival and clinical effectiveness of etanercept treatment in patients with ankylosing spondylitis in daily clinical practice. Clin Exp Abbreviations Rheumatol. 2017;35(1):61–8 Epub 2016 Oct 7. AS: Ankylosing spondylitis; ASDAS: Ankylosing Spondylitis Disease Activity 5. Rudwaleit M, Claudepierre P, Wordsworth P, Cortina EL, Sieper J, Kron M, et Score; ASQoL: Ankylosing Spondylitis Quality of Life; BASDAI: Bath Ankylosing al. Effectiveness, safety, and predictors of good clinical response in 1250 Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis patients treated with adalimumab for active ankylosing spondylitis. J Functional Index; BASMI: Bath Ankylosing Spondylitis Metrology Index; CRP: C Rheumatol. 2009;36:801–8. Reactive Protein; ESR: Erythrocyte Sedimentation Rate; MTX: Methotrexate; 6. Glintborg B, Ostergaard M, Krogh NS, Dreyer L, Kristensen HL, Hetland ML. NSAID: Non-steroidal Anti-Inflammatory Drug; SpA: Spondyloarthritis; Predictors of treatment response and drug continuation in 842 patients SSZ: Sulfasalazine with ankylosing spondylitis treated with anti-tumour necrosis factor: results from 8 years' surveillance in the Danish nationwide DANBIO registry. Ann Rheum Dis. 2010;69:2002–8. Acknowledgements 7. Arends S, van der Veer E, Kallenberg CG, Brouwer E, Spoorenberg A. Not applicable. Baseline predictors of response to TNF-α blocking therapy in ankylosing spondylitis. Curr Opin Rheumatol. 2012;24:290–8. Funding 8. Baraliakos X, Braun J. Spondyloarthritides. Best Pract Res Clin Rheumatol. This work was supported by grants from Fundação de Amparo à Pesquisa 2011;25:825–42. do Estado de São Paulo (FAPESP #2015/03756–4 to EB), Conselho Nacional 9. Cantini F, Niccoli L, Benucci M, Chindamo D, Nannini C, Olivieri I, et al. de Desenvolvimento Cientifico e Tecnológico (#305068/2014–8 to EB) and Switching from infliximab to once-weekly administration of 50 mg the Frederico Foundation (to PDSB, EB and CGSS). etanercept in resistant or intolerant patients with ankylosing spondylitis: results of a fifty-four-week study. Arthritis Rheum. 2006;55:812–6. 10. Lie E, van der Heijde D, Uhlig T, Mikkelsen K, Rødevand E, Koldingsnes W, et al. Availability of data and materials Effectiveness of switching between TNF inhibitors in ankylosing spondylitis: The datasets generated and / or analyzed during the current study are not data from the NOR-DMARD register. Ann Rheum Dis. 2011;70:157–63. publicly available because they belong to electronic database of the institution 11. Glintborg B, Østergaard M, Krogh NS, Tarp U, Manilo N, Loft AG, et al. but are available from the corresponding author on reasonable request. Clinical response, drug survival and predictors thereof in 432 ankylosing spondylitis patients after switching tumour necrosis factor α inhibitor Authors’ contributions therapy: results from the Danish nationwide DANBIO registry. Ann Rheum AYS: study concept and design, assist in subject recruitment, acquisition of Dis. 2013;72(7):1149–5. subject and data, interpretation of data and drafting the manuscript. CRG: 12. Pradeep DJ, Keat AC, Gaffney K, Brooksby A, Leeder J, Harris C. study concept and design, assist in subject recruitment, interpretation of Switching anti-TNF therapy in ankylosing spondylitis. Rheumatology data and revising the manuscript. JCBM: assist in subject recruitment, (Oxford). 2008;47:1726–7. interpretation of data and revising the manuscript. MGW: assist in subject 13. Haberhauer G, Strehblow C, Fasching P. Observational study of switching recruitment and revising the manuscript. ACMR: assist in subject recruitment, anti-TNF agents in ankylosing spondylitis and psoriatic arthritis versus interpretation of data and revising the manuscript. PDS: study concept and rheumatoid arthritis. Wien Med Wochenschr. 2010;160:220–4. design, assist in subject recruitment, interpretation of data and drafting the 14. de Vries MK, Wolbink GJ, Stapel SO, de Groot ER, Dijkmans BA, Aarden LA, manuscript. CGS: assist in subject recruitment, acquisition of data and et al. Inefficacy of infliximab in ankylosing spondylitis is correlated with revising the manuscript. EB: study concept and design, interpretation of data antibody formation. Ann Rheum Dis. 2007;66:133–4. and drafting the manuscript. CGSS: study concept and design, assist in 15. de Vries MK, Brouwer E, van der Horst-Bruinsma IE, Spoorenberg A, van subject recruitment, interpretation of data and drafting the manuscript. All Denderen JC, Jamnitski A, et al. Decreased clinical response to adalimumab authors read and approved the final manuscript. in ankylosing spondylitis is associated with antibody formation. Ann Rheum Dis. 2009;68:1787–8. 16. Kristensen LE, Gülfe A, Saxne T, Geborek P. Efficacy and tolerability of Ethics approval and consent to participate This study was approved by the Local Ethics Committee on Human Research anti-tumour necrosis factor therapy in psoriatic arthritis patients: results at the University of São Paulo (CAPPesq). All participants gave written from the south Swedish arthritis treatment group register. Ann Rheum informed consent in compliance with the Helsinki Declaration. Dis. 2008;67:364–9. 17. Fagerli KM, Lie E, van der Heijde D, Heiberg MS, Lexberg AS, Rødevand E, et al. The role of methotrexate co-medication in TNF-inhibitor treatment in Consent for publication patients with psoriatic arthritis: results from 440 patients included in the Not applicable. NOR-DMARD study. Ann Rheum Dis. 2014;73:132–7. 18. Kristensen LE, Karlsson JA, Englund M, Petersson IF, Saxne T, Geborek P. Competing interests Presence of peripheral arthritis and male sex predicting continuation of The authors declare that they have no competing interests. anti-tumor necrosis factor therapy in ankylosing spondylitis: an Shimabuco et al. Advances in Rheumatology (2018) 58:40 Page 8 of 8 observational prospective cohort study from the South Swedish Arthritis treatment of ankylosing spondylitis: a prospective cohort study. J Treatment Group Register. Arthritis Care Res (Hoboken). 2010;62:1362–9. Rheumatol. 2015;42(12):2339–46. 19. Lie E, Kristensen LE, Forsblad-d'Elia H, Zverkova-Sandström T, Askling J, 38. Villaverde-García V, Cobo-Ibáñez T, Candelas-Rodríguez G, Seoane-Mato D, Jacobsson LT, ARTIS Study Group. The effect of co-medication with Campo-Fontecha PDD, Guerra M, et al. The effect of smoking on clinical conventional synthetic disease modifying antirheumatic drugs on TNF and structural damage in patients with axial spondyloarthritis: A systematic inhibitor drug survival in patients with ankylosing spondylitis and literature review. Semin Arthritis Rheum. 2016;46(5):569–583. undifferentiated spondyloarthritis: results from a nationwide prospective 39. Jones GT, Ratz T, Dean LE, Macfarlane GJ, Atzeni F. In axial spondyloarthritis, study. Ann Rheum Dis. 2015;74:970–8. never smokers, ex-smokers and current smokers show a gradient of increasing disease severity - results from the Scotland registry for ankylosing 20. Nissen MJ, Ciurea A, Bernhard J, Tamborrini G, Mueller R, Weiss B, et al. The spondylitis (SIRAS). Arthritis Care Res (Hoboken). 2017;69(9):1407–1413. effect of Comedication with a conventional synthetic disease-modifying 40. Zhao S, Challoner B, Khattak M, Moots RJ, Goodson NJ. Increasing smoking Antirheumatic drug on drug retention and clinical effectiveness of anti- intensity is associated with increased disease activity in axial tumor necrosis factor therapy in patients with axial Spondyloarthritis. spondyloarthritis. Rheumatol Int. 2017;37(2):239–44. Arthritis Rheumatol. 2016;68(9):2141–50. 41. Glintborg B, Højgaard P, Lund Hetland M, Steen Krogh N, Kollerup G, 21. Sepriano A, Ramiro S, van der Heijde D, Ávila-Ribeiro P, Fonseca R, Borges J, Jensen J, et al. Impact of tobacco smoking on response to tumour et al. Effect of Comedication with conventional synthetic disease-modifying necrosis factor-alpha inhibitor treatment in patients with ankylosing Antirheumatic drugs on retention of tumor necrosis factor inhibitors in spondylitis: results from the Danish nationwide DANBIO registry. patients with Spondyloarthritis: a prospective cohort study. Arthritis Rheumatology (Oxford). 2016;55(4):659–68. Rheumatol. 2016;68(11):2671–9. 42. Benegas M, Muñoz-Gomariz E, Font P, Burgos-Vargas R, Chaves J, Palleiro D, 22. Fabbroni M, Cantarini L, Caso F, Costa L, Pagano VA, Frediani B, et al. Drug et al. RESPONDIA group; ASPECT study group; REGISPONSER study group. retention rates and treatment discontinuation among anti-TNF-α agents in Comparison of the clinical expression of patients with ankylosing spondylitis psoriatic arthritis and ankylosing spondylitis in clinical practice. Mediat from Europe and Latin America. J Rheumatol. 2012;39:2315–20. Inflamm. 2014;2014:862969. 43. Saad CG, Gonçalves CR, Sampaio-Barros PD. Seronegative arthritis in Latin 23. Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria America: a current review. Curr Rheumatol Rep. 2014;16:438. for ankylosing spondylitis. A proposal for modification of the New York 44. Kohem CL, Bortoluzzo AB, Gonçalves CR, Braga da Silva JA, Ximenes AC, criteria. Arthritis Rheum. 1984;27:361–8. Bértolo MB, et al. Profile of the use of disease modifying drugs in the 24. Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Braun J, Burgos-Vargas R, et al. Brazilian registry of Spondyloartrhritis. Braz J Rheumatol. 2014;54:33–7. The Assessment of Spondyloarthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis. 2009;68:ii1–ii44. 25. Garret S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath ankylosing spondylitis disease activity index. J Rheumatol. 1994;21:2286–91. 26. Calin A, Jones SD, Garrett SL, Kennedy LG. Bath ankylosing spondylitis functional index. Br J Rheumatol. 1995;34:793–4. 27. Jenkinson TR, Mallorie PA, Whitelock HC, Kennedy LG, Garrett SL, Calin A. Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS Metrology Index. J Rheumatol. 1994;21:1694–8. 28. Doward LC, Spoorenberg A, Cook A, Whalley D, Helliwell PS, Kay LJ, et al. Development of the ASQol: a quality of life instrument specific to ankylosing spondylitis. Ann Rheum Dis. 2003;63:20–6. 29. Machado P, Landewé R, Lie E, Kvien TK, Braun J, Baker D, et al. Ankylosing spondylitis disease activity score (ASDAS): defining cut-off values for disease activity states and improvement scores. Ann Rheum Dis. 2011;70:47–53. 30. Machado PM, Landewé R, Heijde DV; Assessment of SpondyloArthritis international Society (ASAS). Ankylosing Spondylitis Disease Activity Score (ASDAS): 2018 update of the nomenclature for disease activity states. Ann Rheum Dis. 2018 Feb 16: annrheumdis-2018-213184. [Epub ahead of print]. 31. Arends S, Brouwer E, van der Veer E, Groen H, Leijsma MK, Houtman PM, et al. Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: a prospective longitudinal observational cohort study. Arthritis Res Ther. 2011;13:R94. 32. Rosales-Alexander JL, Aznar JB, Perez-Vicente S, Magro-Checa C. Drug survival of anti-tumour necrosis factor α therapy: results from the Spanish - AR II study. Rheumatology (Oxford). 2015;54:1459–63. 33. Coates LC, Cawkwell LS, Ng NW, Bennett AN, Bryer DJ, Fraser AD, et al. Real-life experience confirms sustained response to long-term biologics and switching in ankylosing spondylitis. Rheumatology (Oxford). 2008;47:897–900. 34. Rudwaleit M, Van den Bosch F, Kron M, Kary S, Kupper H. Effectiveness and safety of adalimumab in patients with ankylosing spondylitis or psoriatic arthritis and history of anti-tumor necrosis factor therapy. Arthritis Res Ther. 2010;12:R117. 35. Paccou J, Solau-Gervais E, Houvenagel E, Salleron J, Luraschi H, Philippe P, et al. Efficacy in current practice of switching between anti-tumour necrosis factor- α agents in spondyloarthropathies. Rheumatology (Oxford). 2011;50:714–20. 36. Conti F, Ceccarelli F, Marocchi E, Magrini L, Spinelli FR, Spadaro A, et al. Switching tumour necrosis factor alpha antagonists in patients with ankylosing spondylitis and psoriatic arthritis: an observational study over a 5-year period. Ann Rheum Dis. 2007;66:1393–7. 37. Heinonen AV, Aaltonen KJ, Joensuu JT, Lähteenmäki JP, Pertovaara MI, Romu MK, et al. Effectiveness and drug survival of TNF inhibitors in the http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Advances in Rheumatology Springer Journals

Factors associated with ASDAS remission in a long-term study of ankylosing spondylitis patients under tumor necrosis factor inhibitors

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Springer Journals
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Copyright © 2018 by The Author(s)
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Medicine & Public Health; Rheumatology
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2523-3106
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10.1186/s42358-018-0040-x
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Abstract

Objective: To determine the clinical and demographic factors associated with disease remission and drug survival in patients with ankylosing spondylitis (AS) on TNF inhibitors. Methods: Data from a longitudinal electronic database of AS patients under anti-TNF therapy between June/2004 and August/2013. Demographic, clinical parameters, disease activity by ASDAS remission (< 1.3) and inactive/low (< 2.1) were analyzed to characterize reasons for drug survival and switching of anti-TNF. Results: Among 117 AS patients, 69 (59%) were prescribed only one anti-TNF, 48 (41%) switched to a second anti- TNF and 13 (11%) to a third anti-TNF. Considering ASDAS-CRP < 1.3, 31 (39%) patients were inactive at the end of the study. Non-switchers (P = 0.04), younger age (P = 0.004), non-smoking (P= 0.016), shorter disease duration (P = 0.047), more frequent use of SSZ (P =0.037) and lower BASDAI (P = 0.027), BASMI (P =0.034) and BASFI (P = 0.003) at baseline were associated with remission. In the multivariate analysis younger age (P = 0.016) and lower BASDAI (P = 0.032) remained as remission predictors. Conclusion: This study supports that ASDAS-CRP remission is an achievable goal not only for non-switchers but also for second anti-TNF, particularly in patients with younger age and lower BASDAI at baseline. Co- medication and non-smoker status seems to have a beneficial effect in anti-TNF response in this population. Keywords: Ankylosing spondylitis, Anti-TNF, Co-medication, Remission, Switch Introduction (DMARDs) for the treatment of axial involvement. Ac- Ankylosing spondylitis (AS), the most frequent disease cording to the ASAS recommendations, treatment with in the spondyloarthritis (SpA) group, is a chronic anti-TNF drugs is indicated in patients who maintain rheumatic disorder characterized by inflammatory back persistent high disease activity [2]. pain, peripheral arthritis, enthesitis and extra-articular Drug survival of anti-TNF agents in the long-term follow manifestations such as uveitis and inflammatory bowel up is increased in patients with SpA, particularly AS, when disease [1]. Non-steroidal anti-inflammatory drugs compared to rheumatoid arthritis (RA) [3, 4]. In this (NSAIDs) are the first line drugs in the treatment of AS. setting, the identification of predictors of good response is Sulfasalazine (SSZ) and in some cases methotrexate important to optimize therapeutic decisions in AS. Previous (MTX) may be considered in patients with concomitant studies have already demonstrated that younger age, lower peripheral arthritis, but there is no evidence of the Bath Ankylosing Spondylitis Functional Index (BASFI), in- benefits of disease modifying anti-rheumatic drugs creased disease activity with high C reactive protein (CRP) level, and even the presence of HLA-B27, are markers of * Correspondence: goncalves-carla@uol.com.br good response to treatment [5–7]. In case of primary or Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455 3° secondary failure, switching to another anti-TNF is andar - sala 3131 - Cerqueira César, São Paulo, SP Cep: 01246-903, Brazil © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Shimabuco et al. Advances in Rheumatology (2018) 58:40 Page 2 of 8 currently the best therapeuticoption. Although drug sur- Centro de Dispensação de Medicação de Alto Custo) vival with the second anti-TNF is frequently lower than the with indication of biological therapy for disease activity first one, the clinical improvement with the first switch in refractory to conventional treatment were evaluated. AS can vary from 30 to 70% of patients, indicating that the Data of patients from an ongoing electronic database lack or loss of response to a TNF blocker is not a predictor protocol that received anti-TNF therapy between June of failure to another one [8–10]. The Danish nationwide 2004 and August 2013 were retrospectively assessed. All biologic registry (DANBIO) documented therapy with patients fulfilled the modified New York classification anti-TNF drugs in patients with AS and described that criteria for definite AS [23]. Demographic characteristics almost 30% of the 1436 patients switched to a second and as gender, age, HLA-B27 positivity, smoking (current or 10% to a third anti-TNF medication during 10 years of previous), and disease duration were recorded. Assess- follow up; switchers were more frequently women, with ments also included parameters of previous and current shorter disease duration and higher levels of Bath Ankylos- treatment with DMARDs, NSAIDs and prednisone, as ing Spondylitis Disease Activity Index (BASDAI), BASFI well as the presence of peripheral arthritis. and visual-analogue-scale (VAS) global at the beginning of the treatment. At the 2-year visit, 52% of switchers (number Study design needed to treat – NNT = 1.9) and 63% of non-switchers Patients were evaluated using an electronic chart (NNT = 1.6) achieved BASDAI 50 response, compared with database protocol established in 2000 with periodical the baseline visit of the first treatment [11]. There was no assessment of parameters of treatment response and strong evidence of difference between switchers for failure adverse events. Acute phase reactants, as CRP and or adverse events in relation to baseline characteristics and Erythrocyte Sedimentation Rate (ESR) were collected at therapeutic response; however, studies with small group of every visit. Outcome parameters were BASDAI, BASFI, patients have shown a slightly better response in those that Bath Ankylosing Spondylitis Metrology Index (BASMI), switched due to adverse events than due to failure [12, 13]. Ankylosing Spondylitis Quality of Life (ASQoL) [24–28]. Despite the well-known indication of DMARD associ- The analysis of final clinical response was performed ated with anti-TNF drugs in the treatment of RA, there is in patients receiving anti-TNF therapy at the end of the no such consensus in relation to SpA. ASAS recommen- study. Clinical response was measured according to dations do not support the mandatory use of conventional determined levels of Ankylosing Spondylitis Disease DMARDs associated with biological therapy, especially in Activity Score (ASDAS) - CRP and ASDAS – ESR [29] cases of axial involvement [2]. As the formation of and the Ankylosing Spondylitis Disease Activity Score anti-drug antibodies is one of the possible mechanisms of (ASDAS) update of 2018 was used to classify patients ac- lack or loss of blocking TNF response, co-medication with cording disease activity states as inactive disease (< 1.3) DMARDs has been suggested in many inflammatory and low disease activity (1.3–2.1) [30]. diseases, including SpA [14, 15]. In the last decade, many Treatment for less than 24 weeks or patients that studies have addressed the use of concomitant conven- stopped medication due to drug failure, adverse events tional DMARDs in patients with SpA, with contrasting or multiple switches (i.e. use of the same drug for more results. Although two studies each have shown that MTX than one course) were excluded only from response could be associated with longer anti-TNF drug survival in analysis, at final evaluation and remission predictors. psoriatic arthritis [16, 17] and AS [18, 19], three other This study was approved by the Local Ethics Commit- studies showed no benefits of this association [20–22]. tee on Human Research at the University of São Paulo Therefore, there is no definitive conclusion on the benefit (CAPPesq). All participants gave written informed of combined therapy with anti-TNF and DMARDs consid- consent in compliance with the Helsinki Declaration. ering drug retention and effectiveness. The primary aim of this study was to determine the Statistical analysis clinical and demographic factors associated with disease The results were presented as mean and standard devi- remission and prolonged drug survival in patients with ation (SD) for continuous variables (age, disease duration, ankylosing spondylitis (AS) on anti-TNF inhibitors. We also BASDAI, BASMI, ASQol, ESR, CRP and ASDAS - CRP/ evaluated the influence of co-medication in AS patients on ESR) and compared using the T test or Mann-Whitney anti-TNF switching, clinical response and remission. test when comparing two groups and ANOVA for more than two groups. Patients and methods Categorical variables (gender, HLA-B27, peripheral Patients arthritis, smoking, use of DMARD, NSAID or prednis- One hundred seventeen AS patients followed in the one, ASDAS – CRP/ESR) were shown as percentage and Spondyloarthritis Outpatient Clinic and referred to the evaluated through the Fisher Exact Test or Chi square Immunobiological Drugs Infusion Center (CEDMAC – when indicated. Shimabuco et al. Advances in Rheumatology (2018) 58:40 Page 3 of 8 Multivariate analysis was also performed for possible P = 0.039), whereas no difference was observed when MTX factors associated with remission and Kaplan-Meier users were analyzed (18.8% vs. 16.7%, P = 0.811). Groups analysis for drug survival on different anti-TNF courses. with and without SSZ co-medication presented simi- Statistical significance was considered when P < 0.05. lar baseline characteristics, as gender (P= 1.000), age Statistical analyses were performed using SigmaStat (P= 0.869), smoking (P=0.489), peripheral arthritis version 3.1 (2005) and GraphPad/ Prisma Software. (P= 0.839), BASDAI (P= 0.473) and ASDAS-CRP (P = 0.923). The mean dose of SSZ was 2.6 g per day. Results The concomitant use of conventional DMARDs in Baseline demographics the AS patients was quite common due to the high A total of 117 patients treated with TNF inhibitors were prevalence of peripheral joint involvement (70%) in identified. Forty-five patients maintained the first agent our patients with axial SpA. Thirty-five patients (29.9%) during the study period; 48 patients switched to a sec- used more than one DMARD at the introduction of the ond anti-TNF, due to failure in 58% and adverse effects anti-TNF drug; MTX and SSZ was the main combination. in 42% of the cases; and 13 patients were treated with a High disease activity was associated with maintenance of third anti-TNF, 62% due to failure and 38% due to ad- combined DMARDs at the study entry as there was no verse effects (Fig. 1). The most common first anti-TNF other treatment option at that time. was infliximab in 88 patients (75.2%), with adalimumab in 20 (17.1%) and etanercept in 9 patients (7.7%), Disease characteristics at baseline of the second anti-TNF indicating the drug availability in our country at that Switchers’ characteristics at baseline of the second moment. Adalimumab was the most frequently used anti-TNF were also assessed and compared between second drug (67%) and etanercept was the common patients who remained receiving the second and those third line treatment (69%). The median of follow-up who have not responded and switched to the third duration was 41.5 months (0.5 to 116.1 months). anti-TNF. Groups were similar with respect to demo- At baseline, demographic data and clinical parameters graphic data and characteristics of disease, except for the were similar in switchers and non-switchers (Table 1). higher scores of BASDAI at baseline of the 2nd There was no difference regarding gender, age, presence of anti-TNF in patients who required the third therapy (6.4 HLA-B27, smoking (current or previous), disease duration ± 1.7 vs. 4.1 ± 2.5, P = 0.012), suggesting worse disease and disease parameters. With regard to co-medication, activity in patients who evolved with failure to the non-switchers used more often DMARD (88.9% vs. 72.9%, second anti-TNF. The choice of the first switch did not P= 0.023); among those patients who used concomitant influence the maintenance of the second treatment; it was DMARDs, the use of SSZ was also more frequent in pa- comparable among patients who started and switched to tients who maintained the first treatment (37.7% vs. 18.8%, monoclonal antibody (infliximab or adalimumab) and Fig. 1 Flow-chart of treatment courses in Ankylosing Spondylitis patients. AE: adverse events Shimabuco et al. Advances in Rheumatology (2018) 58:40 Page 4 of 8 Table 1 Patients characteristics at baseline Table 2 Comparison at final evaluation between non-switchers and switchers Variable Non-switchers Switchers P (n = 69) (n = 48) Non-switchers Switchers P (n = 42) (n = 36) Male gender 61/69 (88.4%) 38/48 (79.2%) 0.199 BASDAI 1.7 ± 1.6 2.6 ± 2.0 0.041* Age, years 37.3 ± 13.2 38.3 ± 11.2 0.665 BASFI 2.8 ± 2.7 4.2 ± 3.0 0.034* HLA-B27 positivity 38/46 (82.6%) 34/40 (85.0%) 1.000 BASMI 2.9 ± 2.2 3.2 ± 2.1 0.635 Smoking 17/45 (37.8%) 13/36 (36.1%) 1.000 ASQoL 3.5 (1.0, 8.0) 6.0 (1.5, 10.5) 0.057 Disease duration, years 11.4 (6.2, 17.7) 9.2 (5.7, 19.2) 0.840 CRP, mg/l 2.8 (1.3, 5.0) 4.0 (1.7, 8.6) 0.148 Peripheral involvement 45/69 (65.2%) 37/48 (77.1%) 0.218 ESR, mm/hr 4.0 (2.0, 8.0) 5.0 (2.0, 15.5) 0.363 Pure axial involvement 24/69 (34.8%) 11/48 (22.9%) 0.218 ASDAS – CRP 1.5 ± 0.7 2.0 ± 1.0 0.012* BASDAI 5.2 ± 2.0 5.5 ± 2.1 0.482 Last anti-TNF treatment 206.6 (96.9, 287.9) 171.9 (101.6, 210.3) 0.146 BASFI 5.2 ± 2.5 5.9 ± 2.4 0.199 duration, weeks BASMI 3.9 ± 2.8 4.5 ± 2.7 0.290 Values are expressed as mean (SD) and median (quartile). ASDAS Ankylosing ASQoL 10.4 ± 5.5 12.7 ± 4.7 0.058 Spondylitis Disease Activity Score, ASQoL Ankylosing Spondylitis Quality of Life, BASDAI Bath Ankylosing Spondylitis Disease Activity Index, BASFI Bath CRP, mg/l 21.6 (12.8, 38.0) 20.6 (12.6, 40.0) 0.397 Ankylosing Spondylitis Functional Index, BASMI Bath Ankylosing Spondylitis Metrology Index, CRP C Reactive Protein, ESR Erythrocyte Sedimentation Rate, ESR, mm/hr 20.5 (11.0, 34.5) 25.0 (13.1, 48.5) 0.268 * P < 0.05 ASDAS – CRP 3.8 ± 0.9 3.9 ± 1.0 0.714 non-switchers more often achieved inactive/low disease ASDAS – ESR 3.3 ± 0.9 3.6 ± 1.0 0.175 activity (ASDAS< 2.1) by ASDAS - CRP (80.1% vs. 55.9%, Concomitant use of: P = 0.024) and ASDAS - ESR (88.1% vs. 57.6%, P= 0.003) NSAID 50/69 (72.4%) 41/48 (85.4%) 0.117 and remission (ASDAS < 1.3) by ASDAS - ESR (61.9% vs. DMARD 62/69 (88.9%) 35/48 (72.9%) 0.023* 36.4%, P= 0.037) and ASDAS - CRP (42.8% vs. SSZ only 26/69 (37.7%) 9/48 (18.8%) 0.039* 26.5%, P = 0.156). Considering ASDAS - CRP < 1.3, 31 (39%) patients MTX only 13/69 (18.8%) 8/48 (16.7%) 0.811 were inactive at the end of the study. Thereby the NNT Cyclosporine 1/69 (1.4%) 1/48 (2.1%) 1.000 was 5.57 for non-switchers and 5.33 for second and 13 Leflunomide 7/69 (10.1%) 8/48 (16.7%) 0.400 for the third anti-TNF. Prednisone 23/69 (33.3%) 15/48 (31.2%) 0.844 Switchers due to failure or adverse effects were Values are expressed as mean (SD), median (quartile) and percentages. BASDAI comparable regarding demographic data and baseline Bath Ankylosing Spondylitis Disease Activity Index, BASFI Bath Ankylosing characteristics, as disease activity parameters and Spondylitis Functional Index, BASMI Bath Ankylosing Spondylitis Metrology Index, ASQoL Ankylosing Spondylitis Quality of Life, CRP C Reactive Protein, co-medication. In the final evaluation, 14 switchers due ESR Erythrocyte Sedimentation Rate, ASDAS Ankylosing Spondylitis Disease to adverse effects and 14 patients due to lack or loss of Activity Score, NSAID Non-steroidal Anti-Inflammatory Drug, SSZ Sulfasalazine, MTX Methotrexate, *P < 0.05 efficacy were on treatment with second anti-TNF. Response to treatment and status of disease were those who started with monoclonal antibody and switched comparable between the groups (ASDAS - CRP < 2.1: to etanercept (66% vs. 77%, P =0.716). 64.3% vs. 66.7%, P = 1.000). Final evaluation and disease status Inactive disease and predictors At the end of the study, 78 patients (42 non-switchers Patients that achieved remission at the final evaluation and 36 switchers) were using their last TNF inhibitors with ASDAS-CRP < 1.3 were evaluated for the presence for more than 6 months; among the 36 switchers, 28 pa- of predictors of remission at baseline. Younger age (32.3 tients were receiving the second and 8 patients the third ± 9.9 vs. 39.8 ± 11.8 years, P = 0.004), non-smoking anti-TNF. Table 2 shows the final parameters of disease (smoking: 16.0% vs. 46.3%, P= 0.016), shorter disease activity and clinical status. The effectiveness of the first duration (10.6 ± 9.3 vs. 14.7 ± 9.8 years, P = 0.047), more TNF inhibitor was more evident in non-switchers, since frequent use of SSZ (70.9% vs. 44.9%, P = 0.037), lower this group had at final evaluation lower scores of BASDAI (4.6 ± 2.2 vs. 5.8 ± 2.0, P = 0.027), lower BASFI BASDAI (1.7 ± 1.6 vs. 2.6 ± 2.0, P = 0.041), BASFI (2.8 ± (4.4 ± 2.0 vs. 6.2 ± 2.5, P = 0.003) and lower BASMI (3.6 2.7 vs. 4.2 ± 3.0, P = 0.034), ASDAS - CRP (1.5 ± 0.7 vs. ± 2.8 vs. 5.0 ± 2.7, P = 0.034) at the moment of anti-TNF 2.0 ± 1.0, P = 0.012) and ASDAS - ESR (1.3 ± 0.7 vs. 1.8 drug introduction were associated with remission ± 1.0, P= 0.050) compared to switchers, in spite of (Table 3). Of note, 71% of the patients that achieved comparable duration of the last anti-TNF treatment for remission remained in the first anti-TNF and none the switchers and non-switchers (P = 0.146). Of note, achieved remission in the third anti-TNF. Shimabuco et al. Advances in Rheumatology (2018) 58:40 Page 5 of 8 Table 3 Baseline comparison between patients according to patients without this co-medication. Non-smokers AS inactive disease criteria (ASDAS – CRP < 1.3) patients also achieved remission more frequently than ASDAS CRP < 1.3 ASDAS CRP ≥ 1.3 P smoker patients (ASDAS-CRP < 1.3, 48.8% vs. 17.4%, (n = 31) (n = 49) P = 0.016) and seemed to present lower disease activ- Male gender 27/31 (87.1%) 39/49 (79.6%) 0.548 ity (ASDAS-CRP, 1.5 ± 0.8 vs. 1.9 ± 0.8, P = 0.056) at HLA-B27 positivity 20/27 (74.1%) 37/42 (88.1%) 0.193 the end of the study. Smoking 4/25 (16.0%) 19/41 (46.3%) 0.016* Retention to therapy Baseline: The mean anti-TNF drug survival for non-switchers was Age, years 32.3 ± 9.9 39.8 ± 11.8 0.004* 5.2 years (95% CI 4.4 to 6.0 years) and for switchers was Duration of disease, 10.6 ± 9.3 14.7 ± 9.8 0.047* 1.7 years (95% CI 1.3 to 2.1 years) on first anti-TNF, 4.9 years years (95% CI 3.9 to 5.9 years) on second anti-TNF and Co-medication: 3.8 years (95% CI 2.5 to 5.2 years) on third anti-TNF. NSAID 23/31 (74.2%) 35/49 (71.4%) 1.000 Retention to therapy was superior for non-switchers DMARD 27/31 (87.1%) 37/49 (75.5%) 0.259 when compared to switchers to the second (log rank test P = 0.007) and to the third anti-TNF (log rank test MTX 11/31 (35.5%) 21/49 (42.9%) 0.640 P = 0.02). The retention to therapy between switchers SSZ 22/31 (70.9%) 22/49 (44.9%) 0.037* on the second or third course presented no difference BASDAI 4.6 ± 2.2 5.8 ± 2.0 0.027* (log rank test P =0.07) (Fig. 2). BASFI 4.4 ± 2.0 6.2 ± 2.5 0.003* BASMI 3.6 ± 2.8 5.0 ± 2.7 0.034* Discussion ASQol 10.6 ± 5.6 11.2 ± 4.8 0.669 This is the first long-term study to evaluate AS patients under anti-TNF agents focusing on ASDAS inactive ASDAS – CRP 3.5 ± 0.9 3.9 ± 1.0 0.126 disease, demonstrating an overall 40% remission. We CRP (mg/L) 20.3 (9.7, 36.7) 24.6 (14.9, 38.9) 0.664 further identified that younger age and lower BASDAI at ESR (mm/h) 23.0 (10.3, 32.0) 21.0 (12.5, 36.5) 0.650 baseline were predictors of long-term remission. 1st anti-TNF 22/31 (71.0%) 23/49 (46.9%) 0.040* Switching was a frequent event during long-term retention anti-TNF therapy in our cohort, occurring in more than Last anti-TNF 176.9 ± 85.2 182.1 ± 106.2 0.820 a third of our patients and mainly due to treatment treatment, weeks failure (lack or loss of efficacy). In the Danish registry Values are expressed as mean (SD), median (quartile) and percentages. BASDAI (DANBIO) [11], and in a Dutch [31] and a Spanish [32] Bath Ankylosing Spondylitis Disease Activity Index, BASFI Bath Ankylosing Spondylitis Functional Index, BASMI Bath Ankylosing Spondylitis Metrology cohort a high frequency of switching was also observed, Index, ASQoL Ankylosing Spondylitis Quality of Life, CRP C Reactive Protein, mostly associated with lack/loss of effect. In contrast, in ESR Erythrocyte Sedimentation Rate, ASDAS Ankylosing Spondylitis Disease Activity Score, DMARD Disease Modifying Antirheumatic Drug, the Norwegian registry (NOR-DMARD) [10] and in the NSAID Non-steroidal Anti-Inflammatory Drug, SSZ Sufasalazine, Leeds cohort [33] a very low frequency of switching/ MTX Methotrexate, *P <0.05 discontinuation was reported. In the multivariate analysis the variables that remained We have not identified demographic and baseline dis- as predictor of remission were younger age (OR = 0.935; ease parameters as relevant predictive factors for switch- CI 95% 0.886–0.987; P = 0.016) and lower BASDAI (OR ing in our patients opposing to previous report that = 0.725; CI 95% 0.541–0.972; P = 0.032) (Table 4). female gender, MTX use, higher BASFI and BASDAI Further analysis of significant parameters in univariate were associated with the second anti-TNF therapy [11]. demonstrated that patients treated with SSZ and Although a previous report has shown that peripheral anti-TNF achieved more often at the end of the study involvement was a predictive factor of switching [18], it inactive disease (ASDAS-CRP < 1.3, 47.7% vs. 25.0%, was not observed in this study, probably because that P = 0.040) and lower disease activity according to represents a common finding in Brazilian axial SpA ASDAS – CRP (1.5 ± 0.9 vs. 1.9 ± 0.9, P = 0.009) than patients [43]. With regard to the third anti-TNF, we identified that patients with higher BASDAI at the time Table 4 Remission predictors: multivariate analysis of introduction of the second anti-TNF agent were more Baseline OR CI (95%) P likely to switch to the third TNF inhibitor, suggesting a Age 0.935 0.886 0.987 0.016* refractory disease in these patients. Sulfasalazine 2.849 0.857 9.472 0.088 Although response rates decreased after switching for the second anti-TNF agent, many patients presented satisfac- BASDAI 0.725 0.541 0.972 0.032* tory improvement in the follow-up with a NNT very simi- BASDAI Bath Ankylosing Spondylitis Disease Activity Index, OR Odds Ratio, CI confidence interval,*P < 0.05 lar to the first anti-TNF agent. In contrast, the very high Shimabuco et al. Advances in Rheumatology (2018) 58:40 Page 6 of 8 Fig. 2 Retention to therapy (Kaplan-Meier analysis); log-rank test: non-switchers vs switchers - second anti-TNF (P = 0.007) and non-switchers vs switchers - third anti-TNF (P = 0.02) NNT for the third TNF blockers and complete absence of disease and CRP or ESR parameters, we consider that remission in this group does not support this switch. At baseline ASDAS index may not have been associated the final evaluation, non-switchers achieved lower levels of with remission due to similar values of CRP and ESR at BASDAI, BASFI and ASDAS-CRP compared to switchers. baseline between the groups and limited number of pa- Similar trends of reduced response in switchers have been tients with ASDAS evaluation at baseline in our cohort, demonstrated [9, 11, 34], but none of these studies consid- since ASDAS index was published in 2009. ered ASDAS inactive disease as a target. In fact, ASDAS is We suggested and extended recent observations that the only validated and discriminatory instrument for concomitant DMARD use was associated with a better first assessing disease activity in AS [29, 30]. anti-TNF persistent rate [19, 20, 37]. The non-exclusion of The reason for change (lack/loss of efficacy or adverse patients who discontinued without switching anti-TNF events) to the second TNF antagonist did not influence due to other causes precludes a definitive conclusion about anti-TNF response. At the final assessment, both groups concomitant DMARD use effectiveness in AS in a previous presented comparable indexes, including BASDAI, study [37]. ASDAS-CRP and frequency of ASDAS inactivity/moder- Non-smokers AS patients also achieved remission ate disease activity. Previous studies reported similar more frequently than smoker patients at the end of the results [10, 11, 35, 36]; however, some demonstrated study, in agreement to published data. Previous studies slightly better clinical improvement in switchers due to indicate that this factor has a dose-dependent impact on adverse events [11, 34]. structural damage progression and in worse treatment In this study, we presented novel evidence of predict- response of SpA patients [38–41]. ive factors considering ASDAS score as remission cri- The treatment response analysis performed herein was teria. Unlike other studies that considered BASDAI50 or limited to patients under anti-TNF treatment at the final ASAS40 (4–6), ours considered ASDAS-CRP < 1.3 as evaluation and with at least 24 weeks of therapy. This remission response. Younger age, non-smoking, shorter strict study design provided novel data demonstrating disease duration, more frequent use of SSZ, lower that SSZ co-medication was more often associated with BASDAI, BASFI and BASMI at the time of anti-TNF remission. In the Swiss cohort, a benefit in drug survival drug introduction were identified as possible predictors was reported, but it was only demonstrated for DMARD of remission and only younger age and lower BASDAI at on the clinical response in patients treated with inflixi- baseline remained significant in the multivariate analysis. mab and methotrexate [20]. Taking into account that ASDAS considers 3 answers Baseline disease and activity parameters were alike in of BASDAI questionnaire plus global assessment of patients with and without SSZ minimizing the chance Shimabuco et al. Advances in Rheumatology (2018) 58:40 Page 7 of 8 that these factors might have influenced SSZ effect in Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in anti-TNF treatment. In fact, more than 2/3 of our pa- published maps and institutional affiliations. tients have associated peripheral involvement in AS, and the concomitant use of conventional DMARD, as SSZ, is Received: 19 June 2018 Accepted: 23 November 2018 quite common in our daily practice in Brazil [42–44]. References Conclusion 1. Braun J, Sieper J. Ankylosing spondylitis. Lancet. 2007;369:1379–90. This long-term longitudinal study supports that 2. van der Heijde D, Ramiro S, Landewé R, Baraliakos X, Van den Bosch F, ASDAS-CRP remission is an achievable goal not only Sepriano A, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76(6): for non-switchers but also for the second anti-TNF, par- 978–991. ticularly in patients with younger age and lower BASDAI 3. Sampaio-Barros PD, van der Horst-Bruinsma IE. Adverse effects of TNF at baseline therapy. Co-medication and non-smoker inhibitors in SpA: are they different from RA? Best Pract Res Clin Rheumatol. 2014;28:747–63. status seems to have a beneficial effect on anti-TNF re- 4. Arends S, Brouwer E, Efde M, van der Veer E, Bootsma H, Wink F, et al. sponse in this population. Long-term drug survival and clinical effectiveness of etanercept treatment in patients with ankylosing spondylitis in daily clinical practice. Clin Exp Abbreviations Rheumatol. 2017;35(1):61–8 Epub 2016 Oct 7. AS: Ankylosing spondylitis; ASDAS: Ankylosing Spondylitis Disease Activity 5. Rudwaleit M, Claudepierre P, Wordsworth P, Cortina EL, Sieper J, Kron M, et Score; ASQoL: Ankylosing Spondylitis Quality of Life; BASDAI: Bath Ankylosing al. Effectiveness, safety, and predictors of good clinical response in 1250 Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis patients treated with adalimumab for active ankylosing spondylitis. J Functional Index; BASMI: Bath Ankylosing Spondylitis Metrology Index; CRP: C Rheumatol. 2009;36:801–8. Reactive Protein; ESR: Erythrocyte Sedimentation Rate; MTX: Methotrexate; 6. Glintborg B, Ostergaard M, Krogh NS, Dreyer L, Kristensen HL, Hetland ML. NSAID: Non-steroidal Anti-Inflammatory Drug; SpA: Spondyloarthritis; Predictors of treatment response and drug continuation in 842 patients SSZ: Sulfasalazine with ankylosing spondylitis treated with anti-tumour necrosis factor: results from 8 years' surveillance in the Danish nationwide DANBIO registry. Ann Rheum Dis. 2010;69:2002–8. Acknowledgements 7. Arends S, van der Veer E, Kallenberg CG, Brouwer E, Spoorenberg A. Not applicable. Baseline predictors of response to TNF-α blocking therapy in ankylosing spondylitis. Curr Opin Rheumatol. 2012;24:290–8. Funding 8. Baraliakos X, Braun J. Spondyloarthritides. Best Pract Res Clin Rheumatol. This work was supported by grants from Fundação de Amparo à Pesquisa 2011;25:825–42. do Estado de São Paulo (FAPESP #2015/03756–4 to EB), Conselho Nacional 9. Cantini F, Niccoli L, Benucci M, Chindamo D, Nannini C, Olivieri I, et al. de Desenvolvimento Cientifico e Tecnológico (#305068/2014–8 to EB) and Switching from infliximab to once-weekly administration of 50 mg the Frederico Foundation (to PDSB, EB and CGSS). etanercept in resistant or intolerant patients with ankylosing spondylitis: results of a fifty-four-week study. Arthritis Rheum. 2006;55:812–6. 10. Lie E, van der Heijde D, Uhlig T, Mikkelsen K, Rødevand E, Koldingsnes W, et al. Availability of data and materials Effectiveness of switching between TNF inhibitors in ankylosing spondylitis: The datasets generated and / or analyzed during the current study are not data from the NOR-DMARD register. Ann Rheum Dis. 2011;70:157–63. publicly available because they belong to electronic database of the institution 11. Glintborg B, Østergaard M, Krogh NS, Tarp U, Manilo N, Loft AG, et al. but are available from the corresponding author on reasonable request. Clinical response, drug survival and predictors thereof in 432 ankylosing spondylitis patients after switching tumour necrosis factor α inhibitor Authors’ contributions therapy: results from the Danish nationwide DANBIO registry. Ann Rheum AYS: study concept and design, assist in subject recruitment, acquisition of Dis. 2013;72(7):1149–5. subject and data, interpretation of data and drafting the manuscript. CRG: 12. Pradeep DJ, Keat AC, Gaffney K, Brooksby A, Leeder J, Harris C. study concept and design, assist in subject recruitment, interpretation of Switching anti-TNF therapy in ankylosing spondylitis. Rheumatology data and revising the manuscript. JCBM: assist in subject recruitment, (Oxford). 2008;47:1726–7. interpretation of data and revising the manuscript. MGW: assist in subject 13. Haberhauer G, Strehblow C, Fasching P. Observational study of switching recruitment and revising the manuscript. ACMR: assist in subject recruitment, anti-TNF agents in ankylosing spondylitis and psoriatic arthritis versus interpretation of data and revising the manuscript. PDS: study concept and rheumatoid arthritis. Wien Med Wochenschr. 2010;160:220–4. design, assist in subject recruitment, interpretation of data and drafting the 14. de Vries MK, Wolbink GJ, Stapel SO, de Groot ER, Dijkmans BA, Aarden LA, manuscript. CGS: assist in subject recruitment, acquisition of data and et al. Inefficacy of infliximab in ankylosing spondylitis is correlated with revising the manuscript. EB: study concept and design, interpretation of data antibody formation. Ann Rheum Dis. 2007;66:133–4. and drafting the manuscript. CGSS: study concept and design, assist in 15. de Vries MK, Brouwer E, van der Horst-Bruinsma IE, Spoorenberg A, van subject recruitment, interpretation of data and drafting the manuscript. All Denderen JC, Jamnitski A, et al. Decreased clinical response to adalimumab authors read and approved the final manuscript. in ankylosing spondylitis is associated with antibody formation. Ann Rheum Dis. 2009;68:1787–8. 16. Kristensen LE, Gülfe A, Saxne T, Geborek P. Efficacy and tolerability of Ethics approval and consent to participate This study was approved by the Local Ethics Committee on Human Research anti-tumour necrosis factor therapy in psoriatic arthritis patients: results at the University of São Paulo (CAPPesq). All participants gave written from the south Swedish arthritis treatment group register. Ann Rheum informed consent in compliance with the Helsinki Declaration. Dis. 2008;67:364–9. 17. Fagerli KM, Lie E, van der Heijde D, Heiberg MS, Lexberg AS, Rødevand E, et al. The role of methotrexate co-medication in TNF-inhibitor treatment in Consent for publication patients with psoriatic arthritis: results from 440 patients included in the Not applicable. NOR-DMARD study. Ann Rheum Dis. 2014;73:132–7. 18. Kristensen LE, Karlsson JA, Englund M, Petersson IF, Saxne T, Geborek P. Competing interests Presence of peripheral arthritis and male sex predicting continuation of The authors declare that they have no competing interests. anti-tumor necrosis factor therapy in ankylosing spondylitis: an Shimabuco et al. Advances in Rheumatology (2018) 58:40 Page 8 of 8 observational prospective cohort study from the South Swedish Arthritis treatment of ankylosing spondylitis: a prospective cohort study. J Treatment Group Register. Arthritis Care Res (Hoboken). 2010;62:1362–9. Rheumatol. 2015;42(12):2339–46. 19. Lie E, Kristensen LE, Forsblad-d'Elia H, Zverkova-Sandström T, Askling J, 38. Villaverde-García V, Cobo-Ibáñez T, Candelas-Rodríguez G, Seoane-Mato D, Jacobsson LT, ARTIS Study Group. The effect of co-medication with Campo-Fontecha PDD, Guerra M, et al. The effect of smoking on clinical conventional synthetic disease modifying antirheumatic drugs on TNF and structural damage in patients with axial spondyloarthritis: A systematic inhibitor drug survival in patients with ankylosing spondylitis and literature review. Semin Arthritis Rheum. 2016;46(5):569–583. undifferentiated spondyloarthritis: results from a nationwide prospective 39. Jones GT, Ratz T, Dean LE, Macfarlane GJ, Atzeni F. In axial spondyloarthritis, study. Ann Rheum Dis. 2015;74:970–8. never smokers, ex-smokers and current smokers show a gradient of increasing disease severity - results from the Scotland registry for ankylosing 20. Nissen MJ, Ciurea A, Bernhard J, Tamborrini G, Mueller R, Weiss B, et al. The spondylitis (SIRAS). Arthritis Care Res (Hoboken). 2017;69(9):1407–1413. effect of Comedication with a conventional synthetic disease-modifying 40. Zhao S, Challoner B, Khattak M, Moots RJ, Goodson NJ. Increasing smoking Antirheumatic drug on drug retention and clinical effectiveness of anti- intensity is associated with increased disease activity in axial tumor necrosis factor therapy in patients with axial Spondyloarthritis. spondyloarthritis. Rheumatol Int. 2017;37(2):239–44. Arthritis Rheumatol. 2016;68(9):2141–50. 41. Glintborg B, Højgaard P, Lund Hetland M, Steen Krogh N, Kollerup G, 21. Sepriano A, Ramiro S, van der Heijde D, Ávila-Ribeiro P, Fonseca R, Borges J, Jensen J, et al. Impact of tobacco smoking on response to tumour et al. Effect of Comedication with conventional synthetic disease-modifying necrosis factor-alpha inhibitor treatment in patients with ankylosing Antirheumatic drugs on retention of tumor necrosis factor inhibitors in spondylitis: results from the Danish nationwide DANBIO registry. patients with Spondyloarthritis: a prospective cohort study. Arthritis Rheumatology (Oxford). 2016;55(4):659–68. Rheumatol. 2016;68(11):2671–9. 42. Benegas M, Muñoz-Gomariz E, Font P, Burgos-Vargas R, Chaves J, Palleiro D, 22. Fabbroni M, Cantarini L, Caso F, Costa L, Pagano VA, Frediani B, et al. Drug et al. RESPONDIA group; ASPECT study group; REGISPONSER study group. retention rates and treatment discontinuation among anti-TNF-α agents in Comparison of the clinical expression of patients with ankylosing spondylitis psoriatic arthritis and ankylosing spondylitis in clinical practice. Mediat from Europe and Latin America. J Rheumatol. 2012;39:2315–20. Inflamm. 2014;2014:862969. 43. Saad CG, Gonçalves CR, Sampaio-Barros PD. Seronegative arthritis in Latin 23. Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria America: a current review. Curr Rheumatol Rep. 2014;16:438. for ankylosing spondylitis. A proposal for modification of the New York 44. Kohem CL, Bortoluzzo AB, Gonçalves CR, Braga da Silva JA, Ximenes AC, criteria. Arthritis Rheum. 1984;27:361–8. Bértolo MB, et al. Profile of the use of disease modifying drugs in the 24. Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Braun J, Burgos-Vargas R, et al. Brazilian registry of Spondyloartrhritis. Braz J Rheumatol. 2014;54:33–7. The Assessment of Spondyloarthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis. 2009;68:ii1–ii44. 25. Garret S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath ankylosing spondylitis disease activity index. J Rheumatol. 1994;21:2286–91. 26. Calin A, Jones SD, Garrett SL, Kennedy LG. Bath ankylosing spondylitis functional index. Br J Rheumatol. 1995;34:793–4. 27. Jenkinson TR, Mallorie PA, Whitelock HC, Kennedy LG, Garrett SL, Calin A. Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS Metrology Index. J Rheumatol. 1994;21:1694–8. 28. Doward LC, Spoorenberg A, Cook A, Whalley D, Helliwell PS, Kay LJ, et al. Development of the ASQol: a quality of life instrument specific to ankylosing spondylitis. Ann Rheum Dis. 2003;63:20–6. 29. Machado P, Landewé R, Lie E, Kvien TK, Braun J, Baker D, et al. Ankylosing spondylitis disease activity score (ASDAS): defining cut-off values for disease activity states and improvement scores. Ann Rheum Dis. 2011;70:47–53. 30. Machado PM, Landewé R, Heijde DV; Assessment of SpondyloArthritis international Society (ASAS). Ankylosing Spondylitis Disease Activity Score (ASDAS): 2018 update of the nomenclature for disease activity states. Ann Rheum Dis. 2018 Feb 16: annrheumdis-2018-213184. [Epub ahead of print]. 31. Arends S, Brouwer E, van der Veer E, Groen H, Leijsma MK, Houtman PM, et al. Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: a prospective longitudinal observational cohort study. Arthritis Res Ther. 2011;13:R94. 32. Rosales-Alexander JL, Aznar JB, Perez-Vicente S, Magro-Checa C. Drug survival of anti-tumour necrosis factor α therapy: results from the Spanish - AR II study. Rheumatology (Oxford). 2015;54:1459–63. 33. Coates LC, Cawkwell LS, Ng NW, Bennett AN, Bryer DJ, Fraser AD, et al. Real-life experience confirms sustained response to long-term biologics and switching in ankylosing spondylitis. Rheumatology (Oxford). 2008;47:897–900. 34. Rudwaleit M, Van den Bosch F, Kron M, Kary S, Kupper H. Effectiveness and safety of adalimumab in patients with ankylosing spondylitis or psoriatic arthritis and history of anti-tumor necrosis factor therapy. Arthritis Res Ther. 2010;12:R117. 35. Paccou J, Solau-Gervais E, Houvenagel E, Salleron J, Luraschi H, Philippe P, et al. Efficacy in current practice of switching between anti-tumour necrosis factor- α agents in spondyloarthropathies. Rheumatology (Oxford). 2011;50:714–20. 36. Conti F, Ceccarelli F, Marocchi E, Magrini L, Spinelli FR, Spadaro A, et al. Switching tumour necrosis factor alpha antagonists in patients with ankylosing spondylitis and psoriatic arthritis: an observational study over a 5-year period. Ann Rheum Dis. 2007;66:1393–7. 37. Heinonen AV, Aaltonen KJ, Joensuu JT, Lähteenmäki JP, Pertovaara MI, Romu MK, et al. Effectiveness and drug survival of TNF inhibitors in the

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