Moreno et al. Arthritis Research & Therapy (2019) 21:88 https://doi.org/10.1186/s13075-019-1873-3 RESEARCH ARTICLE Open Access Withdrawal of infliximab therapy in ankylosing spondylitis in persistent clinical remission, results from the REMINEA study Mireia Moreno1, Jordi Gratacós1*, Vicenç Torrente-Segarra2, Raimon Sanmarti3, Rosa Morlà4, Caridad Pontes5, Maria Llop1, Xavier Juanola6 and REMINEA study Group Abstract Background: Recent data suggest that anti-TNF doses can be reduced in ankylosing spondylitis (AS) patients. Some authors even propose withdrawing treatment in patients in clinical remission; however, at present there is no evidence to support this. Objective: To assess how long AS patients with persistent clinical remission remained free of flares after anti-TNF withdrawal and to evaluate the effects of treatment reintroduction. We also analyze the characteristics of patients who did not present clinical relapse. Methods: Multicenter, prospective, observational study of a cohort of patients with active AS who had received infliximab as a first anti-TNF treatment and who presented persistent remission (more than 6 months). We recorded at baseline and every 6–8 weeks over the 12-month period the age, gender, disease duration, peripheral arthritis or enthesitis, HLA-B27 status, BASDAI, CRP, ESR, BASFI, and three visual analogue scales, spine global pain, spinal night time pain, and patient’s global assessment. Results: Thirty-six out of 107 patients (34%) presented persistent remission and were included in our study. After treatment withdrawal, 21 of these 36 patients (58%) presented clinical relapse during follow-up. Infliximab therapy was reintroduced and only 52% achieved clinical remission, as they had before the discontinuation of infliximab; in an additional 10%, reintroduction of infliximab was ineffective, obliging us to change the anti-TNF therapy. No clinical or biological factors were associated with the occurrence of relapse during the follow-up. Conclusions: Two thirds of patients in clinical remission presented clinical relapse shortly after infliximab withdrawal. Although the reintroduction of infliximab treatment was safe, half of the patients did not present the same clinical response that they had achieved prior to treatment withdrawal. Keywords: Ankylosing spondylitis, Anti-TNF therapy, Disease activity, Treatment withdrawal Background Ankylosing spondylitis (AS) is the most representative Axial spondyloarthritis (axSpA) comprises a group of disease in this group; its burden has recently been recog- chronic, immune-mediated inflammatory diseases char- nized as severe, frequently leading to invalidity, work acterized by the predominance of inflammation in the loss, and social impairment [1, 2]. sacroiliac joints and spine. Involvement of peripheral The introduction of biological therapy has undoubt- skeletal sites and extra-articular manifestations, such as edly been an important step forward in improving the uveitis, psoriasis, or inflammatory bowel disease (IBD), quality of life, activity, functionality, metrology, and most may develop during the course of the disease [1]. extra-articular manifestations in patients with AS and other forms of spondyloarthropathy [1]. Around 60% of * Correspondence: jgratacosmas@gmail.com patients treated with an anti-TNF achieve a good clinical 1 Rheumatology Department, Parc Taulí Hospital Universitari, I3PT, Universitat response; however, according to the Assessment of Autònoma de Barcelona, 08208 Sabadell, Barcelona, Spain Full list of author information is available at the end of the article Spondyloarthritis International Society (ASAS), only 20– © The Author(s). 2019 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. Moreno et al. Arthritis Research & Therapy (2019) 21:88 Page 2 of 6 30% achieve criteria of clinical partial remission in which inhabitants. The study included a cohort of patients with the patient is apparently asymptomatic [3, 4]. active AS who had received infliximab as a first Data from uncontrolled studies and from clinical prac- anti-TNF treatment. The study was authorized by the tice support the possibility of reducing anti-TNF doses Ethics Committee of the participating hospitals, and all below the normal levels licensed in AS patients with patients gave informed consent prior to taking part in good clinical response, and especially in patients in clin- the study. ical remission [5–7]. In this sense, a recent consensus Patients were included in the cohort and started inflix- paper from the Spanish Society of Rheumatology and imab treatment if they were aged 18 or over, had a diag- the Spanish Society of Hospital Pharmacy [8] stressed nosis of AS according NY criteria, presented a disease the possibility of withdrawing anti-TNF treatment in duration longer than 1 year, and fulfilled criteria for some patients who maintain good clinical response after anti-TNF treatment according to the Guidelines of the intensive reduction of anti-TNF treatment [8], but the Spanish Society of Rheumatology (SER) (BASDAI ≥ 4, evidence supporting this recommendation is lacking. despite treatment with 2 nonsteroidal anti-inflammatory In this sense, previous classic studies have suggested the drugs (NSAID) for a minimum of 3 months at full dose) need to maintain anti-TNF therapy indefinitely, as the with- [12]. After the infliximab induction period, all patients drawal of this treatment is associated with disease reactiva- who presented persistent clinical remission (BASDAI ≤ tion in around 90% of patients within 12 months, 2, normal CRP, and absence of active arthritis and/or independently of the anti-TNF used or the previous dur- enthesitis and/or any other extra-articular manifestation ation of treatment [9]. The factors associated with these during the last 6 months in the absence of any additional reactivations include the high clinical activity at the time of steroid and/or NSAID treatment) were included in a treatment suspension, especially when measured through prospective study of infliximab withdrawal. Patients with C-reactive protein (CRP), as well as age and disease dur- any other definitive diagnosis of spondyloarthritis (psori- ation [9]. However, the heterogeneity of the clinical symp- atic arthritis, inflammatory bowel disease, or reactive toms of the AS patients included the different drugs and arthritis) were excluded, as were those with any con- doses of anti-TNF prescribed prior to the withdrawal of the comitant rheumatic disease that might modify the clin- treatment and especially the lack of homogeneous criteria ical evaluation of the disease activity. of clinical remission in the different studies published all During the study, in accordance with standard clinical mean that the issue remains highly controversial. practice, we prospectively recorded the following vari- More recently, data from a multicenter, randomized, ables at baseline, and every 6–8 weeks over a follow-up double-blind study in patients with non-radiographic period of 12 months: age, gender, disease duration, the axSpA, who initially achieved sustained remission, presence and number of peripheral arthritis or enthesi- showed that continued therapy with adalimumab was as- tis, the presence of HLA-B27, the BASDAI (Bath Anky- sociated with a significant maintenance of remission losing Spondylitis Disease Activity Index), CRP, compared with treatment withdrawal [10]. erythrocyte sedimentation rate (ESR), Bath Ankylosing Since anti-TNF treatment also presents drawbacks, Spondylitis Functional Index (BASFI), and three visual such as its high cost and the possibility of long-term side analogue scales (VAS), spine global pain, spinal night effects, it seems reasonable to plan a time-limited treat- time pain, and patient’s global assessment. In the ment for some patients. The aim of our study was to pre-study phase, as a secondary objective, we also retro- analyze the consequences of the clinical decision to spectively recorded the data from all the cohort of pa- withdraw anti-TNF treatment in a very homogeneous tients with active AS who had initiated treatment with group of AS patients. In this study, we included only infliximab. data from AS patients who received infliximab as a first Clinical relapse was defined in any time period as anti-TNF treatment and who presented persistent clin- newly appearing BASDAI ≥ 4 and/or PCR ≥ 0.8 mg/dl. ical remission (at least 6 months) in accordance with our For patients with relapse after treatment withdrawal, pre-established definition [11]. The focus of the study infliximab treatment was reintroduced without an induc- was to assess how long patients maintained a good clin- tion phase or any previous premedication. At the end, a ical response defined as the absence of flare after final visit was performed in all patients included in the anti-TNF withdrawal, and to define the characteristics of study. patients who did not present clinical relapse. Frequencies and percentages were given for subjects who achieved initial remission after infliximab treatment Methods and for subjects who did not present a clinical flare after We conducted a prospective observational study in 23 treatment withdrawal during follow-up. Other parame- hospitals with Rheumatology Services in Catalonia, ters including baseline and clinical data during follow-up north-eastern Spain, a region with seven million were described by frequency and percentage, mean and Moreno et al. Arthritis Research & Therapy (2019) 21:88 Page 3 of 6 standard deviation (SD), median and 25 and 75 percen- were associated, in the pre-study period, with clinical re- tiles, and 95% confidence intervals [95%CI], as appropri- mission under infliximab treatment. However, unfortu- ate. No inferential analysis was conducted. nately, we did not find any statistical differences between any clinical or biological parameter in patients Results who remained free of clinical relapse during follow-up One hundred and seven patients, 72% male, with a first after treatment withdrawal compared with those who infliximab prescription, were retrospectively identified. did not (Table 2). The main characteristics of these patients are shown in (Table 1). Among these patients, 36 (34%) achieved per- Discussion sistent clinical remission and were included in the pro- This is the first prospective study to show that the ma- spective study, so infliximab treatment was then jority of longstanding AS patients in persistent clinical discontinued. The period of clinical remission before remission presented clinical relapse after infliximab treatment withdrawal ranged in all cases between 6 and withdrawal within the following 12 months. Moreover, 12 months. After treatment withdrawal, only 12 out of although the reintroduction of infliximab was safe and these 36 subjects (33.3%) remained free of clinical re- effective in most cases, around half of the patients did lapse during the follow-up. Overall, 21 of these 36 pa- not achieve remission after treatment reintroduction and tients (58.3%) presented clinical relapse (three patients in an additional 10% the treatment was ineffective, obli- were lost during the follow-up study). Half of the re- ging us to change the prescription. lapses appeared within 6 months of infliximab with- Data from clinical practice and registries have sug- drawal. In the 21 patients who presented clinical relapse, gested that in patients with sustained clinical remission infliximab therapy was reintroduced and 11 (52%) again (i.e., more than 6 months), reducing the treatment dose achieved clinical remission, but ten (48%) did not. Of may be a desirable therapeutic goal [5–7]. For example, these ten patients, in seven, the reintroduction of inflixi- the recent EULAR guidelines [13] incorporate the taper- mab was associated with good clinical response (absence ing of biological therapy for these patients as a new rec- of flare, BASDAI < 4 and/or CRP < 0.8 mg/dl), but in ommendation, even though the data supporting this three (14%), the treatment was ineffective, and we had to policy are limited due to the absence of randomized change to another anti-TNF treatment (Fig. 1). The re- controlled studies. Recently our group have been com- introduction of infliximab was safe, and no important municated a randomized pragmatical study demonstrat- side effects or infusion reactions were recorded. ing the no inferiority of a regime of dose reduction Analyzing the retrospective data, we found that age compared with full doses in these patients [14]. (39 ± 12 vs 43 ± 14 years, p = 0.05), disease duration (9 ± Many previous studies have suggested that treatment 8 vs 14 ± 11 years, p = 0.02), and CRP at the start of withdrawal in AS patients leads to a reactivation of the infliximab treatment (3.41 ± 3.65 vs 1.63 ± 2.10, p = 0.02) disease [8, 15–17]. Nonetheless, in most studies, Table 1 Baseline characteristics of the cohort of 107 patients who started infliximab treatment Number of valid values Baseline characteristics Age (years), mean ± SD 104 41.8 ± 12.0 Disease duration (years)†, mean ± SD 91,107 77 11.9 ± 10.4 male sex, n (%) 75 (70.1%) HLA-B27 positive, n (%) 69 (89.6%) Modified Schober test (cm), mean ± SD 87 3.7 ± 1.9 Fingertip to floor distance (cm), mean ± SD 101 19.6 ± 13.9 Number of swollen joints¸ mean ± SD 107 1.13 ± 2.2 CRP (mg/dl), mean ± SD 103 2.23 ± 2.82 ESR (mm/h), mean ± SD 105 35.3 ± 28.0 VAS nocturnal spinal pain (cm), mean ± SD 99 5.7 ± 2.8 VAS spinal pain(cm), mean ± SD 98 6.3 ± 2.4 VAS patient global (cm), mean ± SD 99 7.2 ± 1.8 BASDAI score (cm), mean ± SD 102 6.2 ± 1.9 BASFI score (cm)¸ mean ± SD 100 4.9 ± 2.7 n number, SD standard deviation, CRP C-reactive protein, ESR erythrocyte sedimentation rate, VAS patient’s rating of pain by visual analogue scale ranging from 0 (none) to 10 (worst), BASDAI Bath Ankylosing Spondylitis Disease Activity Index, BASFI Bath Ankylosing Spondylitis Functional Index † 50% of patients had less than 10 years of disease duration Moreno et al. Arthritis Research & Therapy (2019) 21:88 Page 4 of 6 Fig. 1 Flow chart of the patient outcomes included in the REMINEA study. Clinical persistent remission: BASDAI ≤ 2 and normal C-protein reactive (CRP) and the absence of active arthritis and/or enthesitis and/or any other extra-articular manifestation during the last 6 months in the absence of any additional steroid and/or NSAID treatment. Relapse: any time period as newly appearing BASDAI ≥ 4 and/or CRP ≥ 0.8 mg/dl. Good clinical response: BASDAI< 4 and/or CRP < 0.8 mg/dl. Asterisk indicates 3 patients in the study phase of 12 months of follow-up were lost to follow-up Table 2 Comparison of significant variables between patients on infliximab according to remission status and patients after infliximab withdrawal according to the absence of clinical relapse Infliximab treatment Infliximab withdrawal Clinical persistent remission* No remission P value Clinical relapse** Free of clinical P value (n = 36) (n = 71) (n = 21) relapse (n = 12) Age (years), mean ± SD 38.52 ± 11.96 3.39 ± 11.81 0.05 40 ± 12 37 ± 12 ns Disease duration (years)†, 8.94 ± 8.09 13.69 ± 11.29 0.02 9 ± 8.0 9 ± 9.0 ns mean ± SD CRP (mg/dl), mean ± SD 3.41 ± 3.65 1.63 ± 2.10 0.01 3.9 ± 3.5 3.0 ± 3.1 ns BASDAI score (cm), mean ± SD 5.95 ± 1.85 6.4 ± 1.82 ns 6 ± 2.0 6 ± 2.0 ns BASFI score (cm)¸ mean ± SD 4.35 ± 2.44 5.18 ± 2.81 ns 4 ± 3.0 5 ± 2.0 ns SD standard deviation, CRP C-reactive protein, BASDAI Bath Ankylosing Spondylitis Disease Activity Index, BASFI Bath Ankylosing Spondylitis Functional Index *Clinical persistent remission: BASDAI ≤ 2 and normal C-protein reactive (CRP) and the absence of active arthritis and/or enthesitis and/or any otherextra-articular manifestation during the last 6 months in the absence of any additional steroid and/or NSAID treatment, refers to patients under IFX treatment **Relapse: any time period as newly appearing BASDAI ≥ 4 and/or CRP ≥ 0.8 mg/dl after treatment with IFX withdrawal † 50% of patients had less than 10 years of disease duration Moreno et al. Arthritis Research & Therapy (2019) 21:88 Page 5 of 6 withdrawal is performed in patients who are not in clin- propose withdrawal as an objective of the treatment ical remission, and some of them even present high CRP strategy, at least at present, in the absence of any object- serum levels [15, 16]. Recently, a controlled and ran- ive predictive factors of persistent clinical remission after domized study in non-radiographic axSpA patients re- treatment withdrawal. ported in patients who achieved sustained remission The study has certain limitations that must be men- with adalimumab more reactivation of the disease in the tioned. The sample size is too small to assess factors re- treatment withdrawal compared with the control arm lated to the persistence of remission or the presence of a (patients without suspension of anti-TNF) [10]. How- flare after treatment withdrawal; however, other larger ever, some official recommendations, based only on clin- study also failed in this subject [10]. Similarly, since all ical practice and in the expert opinion, suggest the the patients were in treatment with infliximab, the re- possibility of withdrawing treatment in AS patients with sults need to be corroborated in other anti-TNF agents, persistent clinical remission after a notable reduction in but the results published by Landewé et al. [10] using anti-TNF therapy [8, 18]. adalimumab are quite similar. Furthermore, our sched- The data we reported in AS patients were in agreement ule of treatment did not incorporate a strategy of inflixi- with the results previously reported by Landewé et al. in mab reduction doses before treatment withdrawal, so we non-radiographic axSpA [10]. Unfortunately, in our study cannot definitively rule out the possibility of withdrawal as did Landewé et al., the withdrawn of treatment was per- treatment in patients under persistent remission after in- formed without dose reduction. However, all the patients tensive doses reduction. The clinical remission period previous dose reduction were in persistent remission with- before withdrawal of infliximab treatment (6 to 12 out any analgesic or anti-inflammatory treatment that months) does not exclude the possibility of some differ- could mask the clinical symptoms. ent results in patients with a longer period of time in Few studies are focused on the clinical response to clinical remission. Finally, the study began before the re-treatment after withdrawal of anti-TNF therapy in pa- publication of the definite new ASAS remission and re- tients with axSpA, suggesting as overall that the reintro- lapse criteria; however, the criteria applied are widely ac- duction of treatment is comparable to the previously cepted and used in the clinical practice. observed [15, 19, 20]. In contrast, our data indicate that the reintroduction of biological therapy (without previ- Conclusion ous premedication), although it was safe, only half of the In summary, this is the first prospective trial performed patients achieved clinical remission, as they had before in a homogeneous cohort of AS patients to evaluate the the discontinuation of anti-TNF. These data are in effect of anti-TNF withdrawal in patients presenting per- agreement with data recently reported by Landewé et al. sistent clinical remission. Our data of clinical relapse in non-radiographic axSpA using adalimumab [10]. Fur- during the first 12 months in the majority of patients in thermore, in our study, in 10% of the patients, the AS patients are in agreement with the study in re-treatment was ineffective, obliging us to change the non-radiographic axSpA previously published. Moreover, anti-TNF therapy. although the reintroduction of infliximab treatment was The patients we included in the study presented defin- safe, half of the patients did not achieve the same clinical ite AS and had received only infliximab treatment as response as prior to treatment withdrawal. first-line anti-TNF therapy. The baseline characteristics of our patients are quite similar to those in previous Abbreviations AS: Ankylosing spondylitis; ASAS: Assessment of Spondyloarthritis studies of anti-TNF therapy (22, 23). The baseline clin- International Society; AxSpA: Axial spondyloarthritis; BASDAI: Bath Ankylosing ical characteristics we found to be associated with clin- Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis ical remission after infliximab treatment—younger age, Functional Index; CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; IBD: Inflammatory bowel disease; NSAID: Nonsteroidal anti-inflammatory short disease duration, and high CRP levels—were in drugs; NY criteria: New York criteria; SD: Standard deviation; SER: Spanish agreement with the previously published data [21]. Un- Society of Rheumatology; VAS: Visual analogue scales fortunately, a complete study of clinical and biological factors associated with the presence of relapse during Acknowledgements REMINEA study Group the following 12 months did not yield any positive re- Arturo Rodriguez-de-la-Serna (Hospital Universitario Santa Creu i Sant Pau, sults. The sample size of our study seems to be the main Barcelona), Victoria Hernandez (Hospital Universitario Clínic, Barcelona), Elena factor associated with the negative results observed; Riera (Hospital Universitario Germans Trias i Pujol, Barcelona), Vera Ortiz (Hospital General de Granollers, Barcelona), Teresa Clavaguera (Hospital de however, other larger studies also failed to obtain any re- Palamós, Girona), Patricia Reyner (Hospital Doctor Josep Trueta, Girona), sults in this regard [10, 20]. Miquel Sala (Hospital Figueres, Girona), Agustí Sellas (Hospital Universitario Overall, the results we reported here suggest that the Vall d'Hebron, Barcelona), Concepció Pitarch (Hospital Esperit Sant, Barcelona), Delia Reina (Hospital Sant Camil, Barcelona), Jordi Blanco (Hospital decision to withdraw treatment should be taken with Sant Jaume de Calella, Barcelona), Montse Centelles (Consorci Sanitari del considerable caution, and it seems unreasonable to Maresme, Barcelona), Ramon Figuls (Hospital Dos de Maig, Barcelona), Mario Moreno et al. Arthritis Research & Therapy (2019) 21:88 Page 6 of 6 Gelman (Hospital Sant Joan de Déu de Manresa, Barcelona), Xavier Arasa 7. De Stefano R, Frati E, De Quattro D, Menza L, Manganelli S. Low doses of (Hospital Tortosa Verge de la Cinta, Tarragona), Maria Bonet (Hospital etanercept can be effective to maintain remission in ankylosing spondylitis Comarcal d'Alt Penedès, Barcelona), Manel Ciria (Hospital La Seu d'Urgell, patients. Clin Rheumatol. 2014;33(5):707–11. Barcelona). 8. Gonzalez-Alvaro I, Martinez-Fernandez C, Dorantes-Calderon B, Garcia-Vicuna R, Hernandez-Cruz B, Herrero-Ambrosio A, et al. Spanish Rheumatology Funding Society and Hospital Pharmacy Society Consensus on recommendations for This work is conducted under the umbrella of the Rheumatology Society of biologics optimization in patients with rheumatoid arthritis, ankylosing Catalonia and supported by Merck Research Laboratories. spondylitis and psoriatic arthritis. Rheumatology (Oxford). 2015;54(7):1200–9. 9. Baraliakos X, Listing J, Brandt J, Zink A, Alten R, Burmester G, et al. Clinical Availability of data and materials response to discontinuation of anti-TNF therapy in patients with ankylosing For information of availability of data included in REMINEA database, contact spondylitis after 3 years of continuous treatment with infliximab. Arthritis Dr. Juanola. Res Ther. 2005;7(3):R439–44. 10. Landewe R, Sieper J, Mease P, Inman RD, Lambert RG, Deodhar A, et al. Declarations Efficacy and safety of continuing versus withdrawing adalimumab therapy We confirm that the article has not been published before and is not under in maintaining remission in patients with non-radiographic axial consideration for publication elsewhere, and that it is approved by all the spondyloarthritis (ABILITY-3): a multicentre, randomised, double-blind study. authors mentioned. Lancet. 2018;392(10142):134–44. 11. Anderson JJ, Baron G, van der Heijde D, Felson DT, Dougados M. Ankylosing spondylitis assessment group preliminary definition of short- Authors’ contributions term improvement in ankylosing spondylitis. Arthritis Rheum. 2001;44(8): MM and JG analyzed and wrote the paper; XJ supervised and directed the 1876–86. paper writing; ML reviewed the paper; RM, CP, and VT collected the data and 12. Mulero J. Primer documento de consenso de la Sociedad Española de reviewed the database. All authors read and approved the final manuscript. Reumatología sobre el uso de antagonistas del TNF-α en las espondiloartritis. Reumatologia clinica. 2005;1(1):32–7. Ethics approval and consent to participate 13. van der Heijde D, Ramiro S, Landewe R, Baraliakos X, Van den Bosch F, All patients included signed an informed consent to participate in REMINEA Sepriano A, et al. 2016 update of the ASAS-EULAR management and the project was approved by ethical committee of all participant hospitals. recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76(6): 978–91. Consent for publication 14. Gratacos J, Pontes C, Juanola X, Sanz J, Torres F, Avendano C, et al. Non- Not applicable. inferiority of dose reduction versus standard dosing of TNF-inhibitors in axial spondyloarthritis. Arthritis Res Ther. 2019;21(1):11. Competing interests 15. Brandt J, Listing J, Haibel H, Sorensen H, Schwebig A, Rudwaleit M, et al. The authors declare that they have no competing interests. Long-term efficacy and safety of etanercept after readministration in patients with active ankylosing spondylitis. Rheumatology (Oxford). 2005; 44(3):342–8. Publisher’s Note 16. Brandt J, Haibel H, Cornely D, Golder W, Gonzalez J, Reddig J, et al. Springer Nature remains neutral with regard to jurisdictional claims in Successful treatment of active ankylosing spondylitis with the anti-tumor published maps and institutional affiliations. necrosis factor alpha monoclonal antibody infliximab. Arthritis Rheum. 2000; 43(6):1346–52. Author details 1 17. Breban M, Vignon E, Claudepierre P, Devauchelle V, Wendling D, Rheumatology Department, Parc Taulí Hospital Universitari, I3PT, Universitat Lespessailles E, et al. Efficacy of infliximab in refractory ankylosing Autònoma de Barcelona, 08208 Sabadell, Barcelona, Spain. 2Rheumatology spondylitis: results of a six-month open-label study. Rheumatology (Oxford). Department, Hospital Comarcal de l’Alt Penedès, Vilafranca, Barcelona, Spain. 3 2002;41(11):1280–5. Rheumatology Department, Hospital Clínic de Barcelona, Universitat de 18. Gonzalez-Alvaro I, Blasco AJ, Lazaro P, Sanchez-Piedra C, Almodovar R, Barcelona, Barcelona, Spain. 4Rheumatology Department, Hospital del Bachiller-Corral J, et al. REDOSER project: optimising biological therapy dose Vendrell, Tarragona, Spain. 5Clinical Pharmacology Department, ParcTaulí for rheumatoid arthritis and spondyloarthritis patients. Heliyon. 2017;3(11): Hospital Universitari, I3PT, Universitat Autònoma de Barcelona, Sabadell, e00452. Barcelona, Spain. 6Rheumatology Department, Hospital Universitari de 19. Baraliakos X, Listing J, Rudwaleit M, Brandt J, Alten R, Burmester G, et al. Bellvitge, IDIBELL, Universitat de Barcelona, L’Hospitalet de Llobregat, Safety and efficacy of readministration of infliximab after longterm Barcelona, Spain. continuous therapy and withdrawal in patients with ankylosing spondylitis. J Rheumatol. 2007;34(3):510–5. Received: 27 November 2018 Accepted: 22 March 2019 20. Haibel H, Heldmann F, Braun J, Listing J, Kupper H, Sieper J. Long-term efficacy of adalimumab after drug withdrawal and retreatment in patients with active non-radiographically evident axial spondyloarthritis who References experience a flare. Arthritis Rheum. 2013;65(8):2211–3. 1. Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet. 2017;390(10089):73–84. 21. Baraliakos X, Koenig AS, Jones H, Szumski A, Collier D, Bananis E. Predictors 2. Braun J, Pincus T. Mortality, course of disease and prognosis of patients with of clinical remission under anti-tumor necrosis factor treatment in patients ankylosing spondylitis. Clin Exp Rheumatol. 2002;20(6 Suppl 28):S16–22. with ankylosing spondylitis: pooled analysis from large randomized clinical 3. van der Heijde D, Dijkmans B, Geusens P, Sieper J, DeWoody K, Williamson trials. J Rheumatol. 2015;42(8):1418–26. P, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum. 2005;52(2):582–91. 4. Zochling J, Braun J. Remission in ankylosing spondylitis. Clin Exp Rheumatol. 2006;24(6 Suppl 43):S88–92. 5. Yates M, Hamilton LE, Elender F, Dean L, Doll H, MacGregor AJ, et al. Is etanercept 25 mg once weekly as effective as 50 mg at maintaining response in patients with ankylosing spondylitis? A randomized control trial. J Rheumatol. 2015;42(7):1177–85. 6. Navarro-Compan V, Moreira V, Ariza-Ariza R, Hernandez-Cruz B, Vargas- Lebron C, Navarro-Sarabia F. Low doses of etanercept can be effective in ankylosing spondylitis patients who achieve remission of the disease. Clin Rheumatol. 2011;30(7):993–6.