Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Brazilian recommendations for the use of nonsteroidal anti-inflammatory drugs in patients with axial spondyloarthritis

Brazilian recommendations for the use of nonsteroidal anti-inflammatory drugs in patients with... Spondyloarthritis (SpA) is a group of chronic inflammatory systemic diseases characterized by axial and/or peripheral joints inflammation, as well as extra-articular manifestations. Over some decades, nonsteroidal anti-inflammatory drugs (NSAIDs) have been the basis for the pharmacological treatment of patients with axial spondyloarthritis (axSpA). However, the emergence of the immunobiologic agents brought up the discussion about the role of NSAIDs in the management of these patients. The objective of this guideline is to provide recommendations for the use of NSAIDs for the treatment of axSpA. A panel of experts from the Brazilian Society of Rheumatology conducted a systematic review and meta-analysis of randomized clinical trials for 15 predefined questions. The Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations were used, and at least 70% agreement of the voting panel was needed. Fourteen recommendations for the use of NSAIDs in the treatment of patients with axSpA were elaborated. The purpose of these recommendations is to support clinicians’ decision making, without taking out his/her autonomy when prescribing for an individual patient. Keywords: Spondyloarthritis, Ankylosing spondylitis, Nonsteroidal anti-inflammatory drugs, Systematic review, Meta-analysis, Guidelines * Correspondence: ricolage@gmail.com Universidade Federal de Minas Gerais (UFMG), Alameda Álvaro Celso 175, Ambulatório Bias Fortes, 2° andar, Belo Horizonte, MG 30150-260, Brazil Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 2 of 21 Background Methodology Spondyloarthritis (SpA) is a set of diseases that cause in- Study design flammation of the spine and peripheral joints and may This guideline was conducted in two phases. In the first have extra-articular manifestations, such as anterior uve- phase, a systematic review and meta-analysis of random- itis, psoriasis, and inflammatory bowel disease. The main ized clinical trials (RCTs) were performed. In the second manifestation of SpA is the involvement of the entheses, phase, an expert panel answered predefined questions attachment sites of the tendons, capsules, and ligaments and developed the recommendations. to the bones, especially Achilles’ tendon and plantar fascia. Frequently, axSpA patients have a genetic predis- Systematic review and meta-analysis position linked to human leukocyte antigen (HLA)-B27 Inclusion criteria and are usually seronegative for rheumatoid factor. The We included RCTs, systematic reviews, and meta- set of diseases consists of ankylosing spondylitis (AS), analyses that have evaluated the efficacy and safety of psoriatic arthritis, reactive arthritis, enteropathic arthritis NSAIDs, as monotherapy or in combination with TNFi and undifferentiated spondyloarthritis. Axial spondyloar- or IL17i, in patients older than 18 years of age with thritis (axSpA) is defined as all cases involving the spine axSpA. and/or sacroiliac joints, and peripheral spondyloarthritis is defined as cases involving only peripheral joints and/ or peripheral entheses. When the same patient has both Exclusion criteria types of conditions, he/she should be classified by the Non-randomized comparative studies, non-comparative predominant segment (predominantly axial involvement studies, studies published only as conference abstracts, or predominantly peripheral involvement) [1–4]. narrative reviews, animal studies, in vitro studies were AxSpA comprises the so-called radiographic form or excluded. Additionally, studies that evaluated the efficacy AS, which includes patients who present sacroiliitis on and safety of NSAIDs in populations with peripheral simple radiography according to the modified New York spondyloarthritis (psoriatic arthritis, reactive arthritis, in- criteria, and non-radiographic axial spondyloarthritis flammatory bowel disease) or rheumatoid arthritis were (nr-axSpA), which is diagnosed according to the pres- excluded. ence of HLA-B27 (clinical arm) or positive sacroiliac MRI (imaging arm), according to the 2009 Assessment Definition of therapeutic intervention in Ankylosing Spondylitis (ASAS) classification criteria Studies that evaluated intervention with NSAIDs as a [1–4]. Although there is currently no consensus, the pre- class (total or selective and nonselective COX-2 inhibi- vailing opinion is that axSpA is a single disease in which tors), as well as studies that evaluated NSAID-specific 20–30% of patients with nr-axSpA can develop radio- molecules alone or in combination with TNFi or IL17i graphic changes over time (5 to 10 years) [5]. In fact, were considered. radiographic sacroiliitis artificially splits the axSpA spectrum into two groups, and it is unlikely that its pres- ence alone is critical to the outcome [6]. Thus, the Definition of controls present recommendations will address axSpA as a single The included studies that evaluated the efficacy and entity and combine all relevant data, since most of the safety of NSAIDs were compared to placebo or active available studies included patients with the radiographic treatment. form. Over some decades, nonsteroidal anti-inflammatory Efficacy outcomes drugs (NSAIDs) have been the basis for the pharmaco- The outcomes used are shown in the Suplemmentary logical treatment of axSpA. However, with the emer- Material and included parameters of disease activity, gence of biological agents which have brought great functionality, and progression of axial and peripheral benefit to patients with axSpA, the discussion about the damage. Not all outcomes were reported in all compari- role of NSAIDs, as well as its cost/effectiveness and sons, although most outcomes were included in each of safety has gained attention. them. Recently, the Brazilian Society of Rheumatology has published evidence based recommendations for the diag- nosis and management of axSpA [7]. Our main goal in Safety outcomes the present guideline was to specifically evaluate the role Any adverse events were considered, regardless of sever- of NSAIDs for treating axSpA patients through a sys- ity, causal relationship, and resolution, including renal, tematic review with meta-analysis and critical analysis of cardiovascular, gastrointestinal, neurological, dermato- the published scientific data. logic, hematologic and hepatic events. Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 3 of 21 Data sources Meta-analyses The search was conducted in the electronic databases Meta-analyses were performed for outcomes commonly MEDLINE (via PubMed), EMBASE, and the Cochrane reported by at least two studies. Their results are pre- Library. In addition, ongoing studies were searched in sented in the form of forest plots and are described in the Clinical Trials.gov and World Health Organization the text. Outcomes reported by only one study were also (WHO) trial registration databases. We searched for presented in graphical form (Supplementary Material). other potential studies not retrieved by the search strat- egies by checking the reference list of each eligible study, Measures of association as well as in the electronic databases Health Technology For dichotomous variables, the measure of association Assessment (HTA), Database of Abstracts of Reviews of used was relative risk (RR) with its respective 95% confi- Effects (DARE), and National Institute for Health and dence interval (CI). For continuous variables, the meas- Care Excellence (NICE), in addition to the guidelines of ure of association used was the mean difference (MD) specialty societies. with its respective 95% CI. If the studies evaluated the Search strategies, eligibility assessment, data extraction same outcome, but using different scales, the measure of and risk of bias assessment are shown in the Supplemen- association used was the standardized mean difference tary Material. (SMD) with its respective 95% CI. Statistical methods References eligible for meta-analyses For the outcomes of dichotomous variables, the method Through the search strategies reported above, 1915 ref- used for the meta-analysis was the Mantel-Haenszel erences were retrieved (369 in Medline, 1532 in method. For the outcomes of continuous variables, the EMBASE, and 14 in the Cochrane Library) that were method used for the meta-analysis was the inverse- published from January 1, 2014 until May 31, 2018 (up- variance weighting. date date since the review by Kroon et al., 2015) [8]. After removing duplicates, 1698 references were evalu- Analytical model ated by reading titles and abstracts, of which 1666 were The random-effects model was used when the statistical excluded. Thus, 32 references were evaluated by reading heterogeneity was significant by the Cochrane chi- their complete texts. At this stage, 29 references were squared test (p< 0.1). However, if the statistical hetero- excluded: 18 according to the type of study [9–26] (non- geneity was not significant but was moderate or high comparative studies; observational, single-arm studies; (I ≥30%), the results are presented according to the systematic reviews without meta-analysis or with over- random-effects model. In cases of mild statistical hetero- lapping studies; language other than Portuguese, English, geneity (I < 30%) or lack of statistical heterogeneity, the or Spanish; and abstracts); eight according to the type of fixed-effects model was preferably used to add greater intervention [27–34] (drugs not registered in the country weight to the estimates from studies with larger sample and anti-inflammatory agents other than NSAIDs); two sizes. according to the type of outcome [35, 36] (indirect/in- complete analyses, ineligible outcome); and one accord- ing to the type of population [37] (not AS and not Heterogeneity spondyloarthritis). Thus, three RCTs [38–40] were con- In cases of statistical heterogeneity, such heterogeneity sidered eligible. In addition, through the search of the was explored based on 2 strategies: the clinical- reference list of the studies evaluated, one RCT was demographic differences of the participants among stud- manually included [41]. Therefore, four new eligible ref- ies or study design differences and subgroup analyses. erences were added to those previously analyzed by Some subgroup analyses were defined in advance be- Kroon et al. (2015) [8]. cause they were of clinical interest. These subgroup divi- Also, additional searches were performed into Clinical- sions were present or absent HLA-B27, normal or Trials.gov and WHO International Clinical Trials Regis- elevated C-reactive protein (CRP), normal or elevated try Platform databases. At ClinicalTrials.gov, 19 records erythrocyte sedimentation rate (ESR), present or absent were found, of which 17 reported no results. The two syndesmophyte, and male or female sex. trials with available data, presented results before the re- The description of each included RCT, the risk of bias view of Kroon et al. [8], they were not eligible. In the analyses, the evaluation of the quality of the evidence ac- WHO International Clinical Trials Registry Platform, 18 cording to Grading of Recommendations Assessment, reports of 15 RCT registrations were found. However, as Development and Evaluation (GRADE) [42, 43] and the they did not have available results, they were not in- meta-analyses with all the forest plots are available in cluded in this meta-analysis (Fig. 1). the Supplementary Material. Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 4 of 21 Fig. 1 PRISMA flowchart of selection and eligibility of the studies included in the systematic review (SR) Development of recommendations consequences of alternative management strategies, A panel of 28 rheumatologists with expertise in SpA quality of evidence, variability in values and prefer- elaborated 15 questions divided into 6 sections: efficacy ences, and resource use. Strong recommendations and effect size, window of opportunity and treatment mean that most informed patients would choose the strategy, continuous or on demand use, radiographic recommended management and that clinicians can progression, comparison of different NSAIDs, safety and structure their interactions with patients accordingly. adverse reactions. Regarding not answered questions ac- Weak or conditional recommendations mean that pa- cording to the current evidence, the data from individual tients’ choices will vary according to their values and RCTs were reported. If necessary, a manual search for preferences, and clinicians must ensure that patients’ available evidences, including observational studies, was care is in keeping with their values and preferences. performed to support the recommendations. There was The quality of evidence was assessed using GRADE a hierarchic and standardized sequence to report avail- for predefined key outcomes (Supplementary Material) able evidence: meta-analysis, individual RCTs, and finally [42, 43]. observational studies. Observational studies were always The degree of expert agreement (inter-rater reliability) reported as very low-quality evidence and supported was determined by the Delphi method through an online conditional recommendations. anonymous survey, and a minimum 70% agreement was These recommendations followed the GRADE meth- needed for each recommendation. odology. Strength of recommendation was determined Table 1 summarizes the Brazilian recommendations by the balance between desirable and undesirable for the use of NSAIDs in patients with axSpA. Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 5 of 21 Table 1 Brazilian recommendations for the use of nonsteroidal anti-inflammatory drugs in patients with axial spondyloarthritis Recommendations QoE DoA 1. EFFICACY Recommendation 1. In patients with active axSpA, we strongly recommend treatment with NSAIDs over no low 9.8 treatment, because they are effective for mitigating disease activity measures and improving functional status. Recommendation 2. In patients with persistent active axSpA, we strongly recommend long-term over short-term low 9.3 use of NSAIDs, because they exhibit sustained symptomatic efficacy. We conditionally recommend that disease ac- tivity and adverse events should be regularly monitored, evaluating long-term risks versus benefits. Recommendation 3. In patients with active axSpA, we conditionally recommend treatment with NSAIDs over no very low 8.8 treatment for alleviate symptoms of peripheral arthritis and enthesitis, since few data have shown moderate efficacy in these clinical manifestations. 2. WINDOW OF OPPORTUNITY AND TREATMENT STRATEGY Recommendation 4. In patients with active axSpA, we strongly recommend NSAIDs as the first-line treatment over low 8.6 an immunobiologic agent, considering its low cost and satisfactory efficacy. The benefit of starting an immunobiolo- gic agent in NSAIDs-naïve patients, even in those with poor prognostic criteria, is not proven. Recommendation 5. In patients with active axSpA, we strongly recommend to immediately start a NSAID after the very low 8.8 diagnosis because early treatment may increase the response rate. Recommendation 6. In patients with active axSpA, we strongly recommend to initiate NSAIDs at full dosage over low 9.4 low dosage, because they exhibit a tendency for greater efficacy in achieving ASAS 20, reduction of morning stiffness, BASDAI, pain, patient global assessment of disease activity, and BASFI. We conditionally recommend that the full dosages of NSAIDs should be maintained, with adequate monitoring, until good disease control is achieved. Recommendation 7. In patients with active axSpA, in the absence of a response to the first NSAID at 4 weeks, we low to high 8.6 conditionally recommend switching to a second traditional NSAID or iCOX2. If the therapeutic target is not reached with the use of NSAIDs for 12 weeks, we strongly recommend to start an immunobiologic agent. 3. CONTINUOUS OR ON-DEMAND USE Recommendation 8. In patients with active axSpA, we conditionally recommend to start continuous over on- very low to moderate 9.4 demand NSAIDs until symptoms relief is achieved. After clinical improvement or the clinical target (low disease ac- tivity or remission) has been achieved, the full dosage can be reduced or switched to on-demand strategy. Before prescribing continuous NSAIDs, it is important to take into account: the patient’s opinion, comorbidities and risk factors. 4. RADIOGRAPHIC PROGRESSION Recommendation 9. Regarding radiographic progression, in patients with active axSpA, we conditionally Very low 8.2 recommend continuous over on demand use of NSAIDs. Considering controversial results among the studies, we conditionally recommend switching to on demand strategy in inactive disease. We conditionally recommend against switching NSAIDs to immunobiological therapy when there is radiographic progression without evidence of disease activity, because the risk/benefit ratio of starting an immunobiologic agent in this scenario is not clear. 5. COMPARISON AMONG NSAIDs Recommendation 10. In patients with active axSpA, we conditionally recommend that the choice of specific NSAI low 9.6 D should be based on patient’s profile (age, prior toxicity, comorbidities) and on shared decision making. To date, there is no consistent evidence of efficacy and safety differences among the NSAIDs (non-selective or iCOX2) in axSpA. 6. SAFETY AND ADVERSE REACTIONS Recommendation 11. Regarding safety, in patients with active axSpA, we strongly recommend treatment with low 9.0 NSAIDs over no treatment, because the available evidence showed an overall good safety profile of these drugs in axSpA. We conditionally recommend that NSAIDS should be used with caution in individuals with risk factors (age > 65 years, diabetes mellitus, use of aspirin, corticosteroids and other platelet antiaggregants, renal or liver diseases). The risks and benefits of starting them should be shared and individualized according to the patient’s risk profile. Gastrointestinal Recommendation 12. In patients with active axSpA, we conditionally recommend to avoid NSAIDs (non-selective low 8.9 or iCOX2) and to start an immunobiologic agent in those with current or previous peptic ulcer or gastrointestinal bleeding. We conditionally recommend the use of an iCOX2 agent over a traditional NSAID in patients with gastrointestinal risk factors. We strongly recommend the use of concomitant gastroprotective drugs in symptomatic or high-risk patients. Cardiovascular Recommendation 13. In patients with active axSpA, we conditionally recommend to avoid NSAID therapy and to very low (observational 8.4 start an immunobiologic agent in those with cardiovascular risk factors, mainly in those with previous acute studies) myocardial infarction or stroke, especially if recent (past 12 months). Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 6 of 21 Table 1 Brazilian recommendations for the use of nonsteroidal anti-inflammatory drugs in patients with axial spondyloarthritis (Continued) Recommendations QoE DoA Renal Recommendation 14. In patients with active axSpA, we conditionally recommend to avoid NSAIDs and to start an very low (observa-tional 9.4 immunobiologic agent in thoses with increased risk of renal adverse events. The decision should be individualized studies) and risk/benefits shared with the patient. We strongly recommend caution and regular monitoring of renal function, especially in high-risk individuals (elderly, hypertension, diabetes, kidney dysfunction). NSAIDs nonsteroidal anti-inflammatory drugs, iCOX2 selective COX-2 inhibitor, axSpA axial spondyloarthritis, QoE quality of evidence, DoA degree of agreement Recommendations placebo: 3%, RR: 4.65 (1.39 to 15.55)] [48]. Fig. 2 shows Efficacy and effect size the subgroup analysis for pain VAS by comparing trad- Are NSAIDs effective for treating patients with axSpA? itional NSAIDs, iCOX2, or both versus placebo. Five RCTs evaluated the efficacy of conventional NSAI Ds, and three evaluated cyclooxygenase 2-selective in- Recommendation 1 In patients with active axSpA, we strongly recommend treatment with hibitors (iCOX2) compared to placebo. A total of 2002 NSAIDs over no treatment, because they are effective for mitigating patients with active AS, with a mean age between 40 and disease activity measures and improving functional status. Quality of 45 years and a predominance of men (60%), were in- evidence: low; Degree of agreement: 9.8 cluded in these studies and were followed up for 2 to 52 weeks [44–48]. There was a superiority of traditional NSAIDs over placebo for the following outcomes: pain by VAS (0– Do NSAIDS have sustained symptomatic efficacy in axSpA? 100 mm), patient global assessment (PGA) of disease ac- Most RCTs that evaluated the efficacy of NSAIDs, tivity by VAS (0–100 mm), duration of morning stiffness compared to both placebo and other NSAIDs, had a in minutes, C-reactive protein concentration, at least short duration (8 to 12 weeks) [13, 29, 31, 38, 40, 44, 47, 20% improvement according to the ASAS group re- 49–53]. In two long-term RCTs involving patients with sponse criteria (ASAS 20), at least 50% improvement in AS, the sustained efficacy of NSAIDs was shown in 12 pain, and the Bath Ankylosing Spondylitis Function months. Van der Heijde et al. found an ASAS20 re- Index (BASFI) (Table 2). sponse of 52.5% with naproxen and 65% with etoricoxib Regarding iCOX2, the meta-analyses showed superior- compared to 20% in placebo group. The 1-year mainten- ity over placebo in the following outcomes: pain VAS, ance rate was 90% with etoricoxib and 79% with na- PGA, ASAS 20, and BASFI (Table 2). Individual studies proxen [48]. In another RCT, Dougados et al. evaluated showed superiority of iCOX2 over placebo in the Bath the efficacy of NSAIDs in 473 patients with short- and Ankylosing Spondylitis Disease Activity Index (BASDAI) long-term AS. At 6 weeks, 43, 50, and 47% of patients [− 2.2 (− 2.74 to − 1.66)] [48], at least 50% improvement who received 20 mg of piroxicam, 15 mg of meloxicam, in pain [iCOX2: 47.5% vs placebo: 20%, RR: 2.41 (1.45 to or 22.5 mg of meloxicam, respectively, had ≥ 50% im- 4.00)] [45], and ASAS partial remission [iCOX2: 15% vs provement in PGA, compared to 21% for the placebo, Table 2 Efficacy of traditional NSAIDs or iCOX2 vs. placebo in patients with axial spondyloarthritis: meta-analyses of randomized clinical trials TRADITIONAL NSAIDs iCOX2 n=1289 n=669 PAIN VAS (95% CI) −16.75 (−20.28 to −13.07) −21.68 (−35.94 to −7.42) PGA −17.75 (−24.39 to −11.10) −20.82 (− 39.88 to −11.75) ASAS20 60% vs. 23% (PbO) 57% vs. 20% (PbO) RR=2.49 (1.94 to 3.19) RR=2.51 (1.66 to 3.79) BASFI −9(− 13 to −5) −13.4 (− 17.3 to −5) MS - SMD −0.4 (−0.58 to −0.22) NA CRP mg/L −3.37 (−6.11 to − 0.62) NA PAIN50% 48% vs 21% NA 2.25 (1.75 to 2.89) NSAIDs nonsteroidal anti-inflammatory drugs, iCOX2 COX-2-selective inhibitors, PAIN VAS pain by visual analog scale 0–100 mm, PGA Patient Global Assessment 0– 100 mm, BASFI Bath Ankylosing Spondylitis Function Index 0–100 mm, MS-SMD standardized mean difference in the duration of morning stiffness, CRP C-reactive protein, PAIN50% ≥ 50% improvement in pain, RR relative risk, PbO placebo, N/A meta-analysis not feasible Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 7 of 21 Fig. 2 Spinal pain by visual analogue scale (VAS 0–100 mm): analysis of subgroups of four randomized clinical trials of patients with ankylosing spondylitis (n=1199). Meta-analyses comparing traditional NSAIDs versus placebo, selective COX-2 inhibitors versus placebo, and both NSAID subtypes versus placebo. Subtitle: (1) Ximoprofen 30 mg vs placebo. (2) Meloxicam 15 mg vs placebo. (3) Piroxicam 20 mg vs placebo. (4) Ketoprofen 200 mg vs placebo. (5) Naproxen 1000 mg vs placebo. (6) Celecoxib 200 mg vs placebo. (7) Etoricoxib 90 mg vs placebo with sustained response at 12 months. The discontinu- ation rate due to lack/ loss of efficacy was between 10 Recommendation 2 In patients with persistent active axSpA, we strongly recommend long- and 20%. Only 16% of the responders at 6 weeks had a term over short-term use of NSAIDs, because they exhibit sustained 1-year loss of response [46]. symptomatic efficacy. We conditionally recommend that disease activity In a German population-based cohort, almost 80% of 1080 and adverse events should be regularly monitored, evaluating long-term risks versus benefits. patients with AS were on NSAIDs, of whom 71% had been Quality of evidence: low; Degree of agreement: 9.3 taking it for more than 4 years. The NSAIDs were effective for complete or partial resolution (> 50%) of pain in 19.1 and 61.2% of patients, respectively [54]. In a Swedish cohort, 21, 108 patients with AS were analyzed for 3 years. Approxi- Are NSAIDs effective for treating the peripheral mately 80% of patients used iCOX2, and 63.8% used non- manifestations of axSpA? selective NSAIDs for more than 50% of the follow-up time, Four of the five RCTs of NSAIDs versus placebo did not with a good initial response rate as well as a good response evaluate the efficacy of these drugs on peripheral arthritis or rate over time [17]. In the Netherlands, Carbo et al. followed enthesitis in axSpA. One RCT compared the effect of up 393 patients with AS who were anti-TNF naïve, of whom ximoprofen on peripheral arthritis at several doses with 254 were prescribed some TNF inhibitors (BASDAI=6.1 and placebo as secondary outcome, and there was a significant ASDAS=3.8), while 139 were kept under conventional treat- improvement in peripheral arthritis with a moderate effect ment (BASDAI=3.9 and ASDAS=2.4; 74% with NSAIDs). size (standardized mean difference, SMD=0.62 [95%CI: 0.26 After 12 months of follow-up, both groups had similar activ- to 0.97]) [47, 56]. From the three trials that assessed iCOX2 ity scores (BASDAI=3.4 and ASDAS=2.2 vs. BASDAI=3.7 versus placebo, two of them excluded patients with and ASDAS=2.3, respectively). Among patients who received peripheral manifestations. A post-hoc analysis of a study of conventional treatment, 82% maintained a sustained re- etoricoxib and naproxen versus placebo in axSpA suggested sponse with NSAIDs after 52 weeks [55]. Despite being ob- NSAIDs were effective for treating peripheral arthritis, as servational studies whose primary objective was not to assessed by question 3 of BASDAI, with an improvement on evaluate the response to treatment, the high rate of drug re- the VAS 0–100 mm of − 16.4 (− 20.3 to − 12. 6) compared tention observed over time suggested a sustained efficacy of to 0.9 (− 5.9 to 7.6) for placebo, as well as in enthesitis NSAIDs. (question 4 of BASDAI), with a shift of − 21.3 (− 25.2 to − Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 8 of 21 17.5) with NSAID versus − 6.5 (− 13.3 to 0.4) with placebo originated from a small sample size [62]. In addition, early in patients with concomitant peripheral arthritis, and of − starting of the NSAID led to a highly significant ASAS partial 27.6 (− 30.8 to − 24.5) versus − 7.3 (− 12.9 to − 1.8) in those remission rate (35%) [59]. without concomitant peripheral arthritis [48, 50]. Considering the low cost, long term experience, and The effect of NSAIDs on enthesitis was not specifically satisfactory response in early disease showed in the evaluated in RCTs of patients with axSpA. The current INFAST trial [59], the expert panel stated that NSAIDs recommendations suggest that they are effective in a should still be the first-line treatment in axSpA. subsample of patients, but that conclusion was extrapolated from studies on psoriatic arthritis or based Recommendation 4 In patients with active axSpA, we strongly recommend NSAIDs as the on expert opinions [57, 58]. first-line treatment over an immunobiologic agent, considering its low cost and satisfactory efficacy. To date, the benefit of starting an immu- Recommendation 3 nobiologic agent in NSAIDs-naïve patients, even in those with poor In patients with active axSpA, we conditionally recommend treatment prognostic criteria, is not proven. Quality of evidence: low; Degree of with NSAIDs over no treatment to alleviate symptoms of peripheral agreement: 8.6 arthritis and enthesitis, since few data have shown moderate efficacy in these clinical manifestations. Quality of evidence: very low; Degree of agreement: 8.8 Should NSAIDs be started immediately after the diagnosis of axSpA? Several studies suggest that the response rates are higher Window of opportunity and treatment strategy with an earlier onset of treatment [39, 63–65]. In the Should NSAIDs be considered first-line treatment in axSpA? INFAST study [59], approximately 35% of patients with In the INFAST study, 158 patients with axSpA were very early (< 2 years of disease on average) axSpA (AS + randomized to receive infliximab + naproxen or placebo + nr-axSpA) achieved ASAS partial remission with na- naproxen for 28 weeks. The interesting aspect of this proxen versus 9% with placebo (only 15% of patients study was that the patients were not refractory to NSAI with AS, with longer disease duration, had achieved this Ds, as in other immunobiologic RCTs (they were NSAID target with etoricoxib in the study by van der Heijde naïve or used low dose of NSAIDs). At week 28, 62% of et al) [48]. Barkham et al. achieved 56% ASAS partial re- the Infliximab + naproxen group had ASAS partial mission with infliximab in patients with early axSpA remission versus 35% of the placebo + naproxen group (average of 1 year and 3 months of symptom duration) [59]. Later, infliximab was discontinued, and patients who compared to 22% in the pivotal study of infliximab [61]. achieved remission were monitored until week 52 under Other RCTs found a 70 to 75% ASAS40 response rate continuous naproxen use or no treatment. A similar after TNF inhibitors in patients with axSpA and disease percentage maintained remission in both the group using duration below 3 years, compared to around 40–45% of naproxen (47.5%) and the group without any treatment ASAS40 response rate in those with established AS [59, (40%) and independent of the initial therapeutic regimen, 66, 67]. Haroon et al. reinforced the importance of early despite small sample for the latter analysis. The response treatment by demonstrating that the delay in the onset rate was higher with anti-TNF, but NSAIDs (with placebo) of anti-TNF treatment increases the rate of radiographic led to remission in more than 1/3 of the cases [60]. progression [68]. These results reinforce the idea of a In an open-label follow-up study, 39 of the 40 patients with “window of opportunity” during the treatment of axSpA very early axSpA from the RCT conducted by Barkham et al and the importance of effective early onset treatment. [61] (who had received infliximab or placebo for 16 weeks) Despite the few available data, the panelists considered were monitored for 5 years. There was no difference in important to immediately start an NSAID as soon as the current disease activity or radiographic progression by diagnosis of axSpA is confirmed. mSASSS among participants receiving infliximab or placebo in the randomized phase. However, approximately 60% (7/ Recommendation 5 12) of patients who initially received infliximab still needed In patients with active axSpA, we strongly recommend to immediately start an NSAID after the diagnosis, because early treatment may increase an anti-TNF after 5 years, while 100% (13/13) of those who the response rate. Quality of evidence: very low; Degree of received placebo remained on anti-TNF treatment [62]. agreement: 8.8 Therearenotavailabledata todefinewhether NSAIDs should remain the first-line treatment in patients with poor prognostic criteria (smokers, with elevated CRP and syndes- When NSAIDs are prescribed for the treatment of patients mophytes on baseline) or whether immunobiologics should with axSpA, should they be used in full dosages or at the be the first choice in these cases. Indeed, the long-term bene- lowest possible dosage for symptomatic control? fit of initiating an immunobiologic agent as first line treat- Six RCTs compared full-dosage versus low-dosage of NSAI ment was not proven, as the data suggesting this benefit Ds in almost 2000 patients with active axial SpA. In two of Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 9 of 21 them the mean disease duration was long (10 to 13 years) treatment of axSpA and the clinical experience, despite [46, 47]. The comparisons were: 1) celecoxib 200 mg x cele- lack of evidence, the panel recommended a second NSAI coxib 400 mg [44, 49]; 2) ximoprofen 5 mg x ximoprofen 30 D, regardless therapeutic class (selective COX-2 or not), mg [47]; 3) meloxicam 15 mg x meloxicam 22.5 mg [46]; 4) could be used if the first one failed after 4 weeks. The total etoricoxib 90 mg x etoricoxib 120 mg [48]; and 5) etoricoxib treatment period with NSAIDs should not exceed 12 60 mg x etoricoxib 90 mg [41]. The meta-analyses showed a weeks, if the predefined target is not achieved [6, 7]. slight superiority of the higher dosages of NSAIDs in redu- cing the duration of morning stiffness [SMD: 0.14 (0.02; Recommendation 7 In patients with active axSpA, in the absence of a response to the first 0.27)] and the proportion of patients who achieved ASAS 20 NSAID at 4 weeks, we conditionally recommend switching to a second [RR: 0.87 (0.77; 0.99)], at the limit of statistical significance. traditional NSAID or iCOX2. If the therapeutic target is not reached with However, there was uncertain risk of bias in four studies [44, the use of NSAIDs for 12 weeks, we strongly recommend to start an immunobiologic agent. Quality of evidence: low to high; Degree of 46, 47, 49]and high risk in onestudy [41]. Regarding the agreement: 8.6 BASDAI and BASFI, the meta-analyses did not demonstrate a significant difference between full- and low-dosage NSAI Ds, but the results of the individual studies were consistent Continuous or on-demand use in favoring higher dosage. Regarding pain outcomes, includ- Is there any significant difference in the reduction of disease ing pain VAS and 50% improvement, CRP serum levels and activity or safety of NSAIDs when comparing the on-demand PGA, thedatawereinconsistent, sometimesfavoringhigh versus continuous use for the treatment of axSpA? doses and other times favoring lower doses of NSAIDs. Only two RCTs compared continuous and on-demand ASAS partial remission [48]and BASMI [49] were reported use of NSAIDs in AS patients. In both studies, the primary in only one RCT each, with no difference between doses. outcome was radiographic progression. Wanders et al. Also, the results of the RCTs cited above should be inter- [69] evaluated celecoxib continuously or on demand in preted with caution, as the 120 mg dose of etoricoxib and 215 patients with AS, and disease activity rates were re- 22.5 mg of meloxicam are not currently in use. ported as a secondary outcome. After 2 years, there was Regarding safety, the meta-analyses showed no differences no significant difference of BASDAI, PGA, overall pain, or among NSAIDs dosages on the occurrence of any adverse C-reactive protein serum levels between two ways of pre- event, serious adverse event, or adverse events per specific scribing NSAIDs. More recently, Sieper et al. evaluated system (cardiovascular, gastrointestinal, neurological, respira- 167 patients with AS and compared the continuous or on- tory, or dermatologic). There was also no difference in the demand use of diclofenac. Although not significant, the proportion of patients who discontinued treatment due to BASDAI decreased from 4.1 to 2.7, in continuous group, unexpected adverse events. Given the low accuracy of the and from 4.2 to 3.2 in on-demand group [70]. Regarding findings, the results were considered inconclusive. adverse events, there was no difference between continu- ous and on-demand use in either study. Recommendation 6 Despite the lack of evidence, the panel recommended In patients with active axSpA, we strongly recommend to initiate NSAI continuous use of NSAIDs in active disease until Ds at full dosage over low dosage, because they exhibit a tendency for greater efficacy in achieving ASAS 20, reduction of morning stiffness, symptoms relief is achieved, based on the previous BASDAI, pain, patient global assessment of disease activity, and BASFI. guidelines and the clinical experience [6, 7, 71]. We conditionally recommend that the full dosages of NSAIDs should be maintained, with adequate monitoring, until good disease control is achieved. Quality of evidence: low; Degree of agreement: 9.4 Recommendation 8 In patients with active axSpA, we conditionally recommend to start continuous over on-demand NSAIDs until symptoms relief is achieved. After clinical improvement or the clinical target (low disease activity or For how long should we wait for initial response to NSAIDs remission) has been achieved, the treatment regimen can be switched in axSpA? to on-demand strategy. Before prescribing continuous NSAIDs, it is im- portant to take into account patient’s opinion, comorbidities and risk The traditional NSAIDs and iCOX2 trials have shown that factors. Quality of evidence: very low to moderate; Degree of agree- pain and stiffness measures differed from placebo in the first ment: 9.4 week and the maximum effect was achieved from 2 to 4 weeks. Themajorityofthe studieshad ashort duration of 2 to 6 weeks [44–48]. The two trials with an extension phase Radiographic progression from 6 to 52 weeks did not show any additional effect size Is there evidence that NSAIDs can delay or minimize the with the use of NSAIDs after 6 weeks [46, 48]. progression of axial damage in axSpA? Should we switch to The panelists considered a period of 2 weeks too short an immunobiologic agent in asymptomatic patients with to evaluate efficacy and recommended a 4-week period as radiographic progression? a reasonable time to change treatment, if no response is Only the two previously cited RCTs had the reduction of observed. Based on the previous guidelines for the radiographic progression through modified Stoke Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 10 of 21 Ankylosing Spondylitis Spine Score (mSASSS) as the Seven trials compared traditional NSAIDs on pain primary outcome. Over a two-year follow-up, Wanders reduction (VAS 0–100 mm) and some statistically et al. observed higher progression in the on-demand significant differences were observed [46, 51, 78, 86, 96– group (+ 1.5 ± 2.5) compared to the continuous-use group 98]: aceclofenac was inferior to indomethacin [SMD: 1.23; (+ 0.4 ± 1.7) (p=0.002) [69]. This result was similarly (95% CI: 0.98 to 1.47)], piroxicam was superior to naproxen found in previous retrospective studies [72, 73]. However, [SMD: − 1.25; (95% CI: − 1.98 to − 0.51)], and diclofenac a post-hoc analysis of the Wanders et al. trial showed a sig- was superior to sulindac [SMD: − 0.54; (95% CI: − 1.06 to nificant difference only in those with elevated CRP, which − 0.03). However, no significant difference was observed brought into discussion if celecoxib reduced the radio- using a Likert pain scale. Two studies [46, 93, 99] measured graphic progression due to the reduction of inflammation the PGA, and only one [93] evaluated the proportion of instead of a specific drug class effect [74]. patients with ≥ 50% pain improvement. However, none of On the other hand, Sieper et al. did not find any them found significant differences in comparison among significant difference on radiographic progression traditional NSAIDs (piroxicam vs. meloxicam and between the continuous and on-demand use of diclofe- ketoprofen vs. phenylbutazone, respectively). nac over 2 years using mSASSS as outcome [70]. Nu- A network meta-analysis, that included 26 RCTs and merically, the progression was higher in continuous 3410 patients with AS, did not find any significant differ- group compared to on-demand group (+ 1.3; 95% CI 0.7 ence among 18 different traditional NSAIDs in short- to 1.9 vs + 0.8; 95%; CI 0.2 to 1.4, respectively), but there term (between 2 and 12 weeks) [25]. was no statistical significance, even when considering To compare coxibs and nonselective NSAIDs, seven subgroups with the worst prognosis, such as those with studies were evaluated [38, 40, 41, 44, 45, 48, 49]. Two higher CRP and previous syndesmophytes. Therefore, RCTs used etoricoxib [41, 48], and the others with the efficacy of NSAIDs in preventing radiographic dam- celecoxib [38, 40, 44, 45, 49]. Three RCTs used diclofenac age remains an open question. Nowadays, there is grow- as comparator, another three used naproxen, and the last ing evidence that immunobiologic agents may reduce used ketoprofen. The meta-analyses did not show signifi- long-term radiographic progression, especially after 4 cant differences between iCOX2 and traditional NSAIDs years of treatment. However to date, the benefit of start- for pain VAS 0–100 mm score (Fig. 3), BASDAI, PGA, the ing an immunobiologic agent in patients with radio- proportion of patients who achieved ASAS20, or BASFI. graphic progression measured by mSASSS, but with a Only the study by van der Heijde et al. found a slight su- good symptom control with NSAID was not addressed periority of etoricoxib 90 mg/day over naproxen 1000 mg/ [75–77]. day for the outcomes pain VAS 0–100 mm and PGA. This same study found no significant difference regarding BAS- Recommendation 9 DAI, BASFI, or ASAS partial remission [48]. Regarding the radiographic progression, we conditionally recommend In the network meta-analysis by Wang et al., 18 trad- continuous over on demand use of NSAIDs in patients with active itional NSAIDs and two iCOX2 agents were compared axSpA. Considering controversial results among the studies, we conditionally recommend switching to on demand strategy in inactive to each other in treatment of AS. Etoricoxib was super- disease. We conditionally recommend against switching NSAIDs to ior to celecoxib, ketoprofen, and tenoxicam with regard immunobiological therapy when there is radiographic progression to pain reduction, but without a significant difference in without evidence of disease activity, because the risk/benefit ratio of starting an immunobiologic agent in this scenario is not clear. Quality the duration of morning stiffness. The superiority of of evidence: very low; Degree of agreement: 8.2 etoricoxib should be interpreted with caution because it was based on only one RCT [25, 48]. Regarding any adverse events, there was no significant Comparison among NSAIDs difference among traditional NSAIDs. In only one of the Is there any difference regarding the efficacy of traditional 19 studies, indomethacin caused more adverse events NSAID versus another traditional NSAID or versus iCOX2 in than oxaprozin [80]. In the analysis by organ system, patients with axSpA? Is there any difference among NSAIDs indomethacin was also associated with a higher rate of regarding adverse events in patients with axSpA? neurological adverse events than aceclofenac, oxaprozin, Twenty-six RCTs compared different traditional NSAI and diclofenac [80, 83, 86]. No difference was observed Ds in patients with axSpA. A total of 2176 participants in adverse events rate (renal, cardiovascular, hepatic, aged 35 to 46 years were evaluated. The overall risk of hematological, respiratory, or dermatologic) in patients bias in these studies was considered high due to lack of with axSpA. information on randomization, allocation concealment, In comparison between iCOX2 and traditional NSAIDs, blinding, and loss to follow-up. Given the data hetero- the meta-analysis did not detect differences for any adverse geneity, a meta-analysis was not possible [46, 51–53, events. In the evaluation by organ system (Fig. 4aand b), 78–95]. there were also no significant differences, except for Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 11 of 21 Fig. 3 Spinal pain by visual analog scale (VAS 0–100 mm) comparing traditional NSAIDs versus iCOX2 in patients with ankylosing spondylitis: meta-analysis of six randomized clinical trials. Subtitle: (1) Celecoxib 200 mg vs ketoprofen 200 mg. (2) Celecoxib 400 mg vs diclofenac 75 mg. (3) Etoricoxib 90 mg vs naproxen 1000 mg. (4) Celecoxib 200 mg vs diclofenac 50 mg. (5) Etoricoxib 90 mg vs naproxen 1000 mg. (6) Celecoxib 200 mg vs diclofenac 75 mg increased hepatic toxicity for iCOX2. However, this finding significant short-term differences (incidence of any adverse was highly imprecise and at the limit of statistical signifi- events, serious adverse events, or discontinuation of treat- cance. Regarding discontinuation of treatment due to adverse ment due to adverse events for iCOX2 compared to placebo) events, there were no differences in the comparison of trad- (Table 3 and Fig. 6). In the single RCT with a longer follow- itional NSAIDs or in the comparison between these and up period (52 weeks), the placebo group was blindly reallo- iCOX2. Systematic reviews that included several diseases cated to receive etoricoxib 90 mg, etoricoxib 120 mg, or na- showed greater gastrointestinal safety of iCOX2 compared to proxen 1000 mg after 6-week follow-up. In the first 6 weeks, traditional NSAIDs and suggested a greater cardiovascular the rates of any adverse events were 39.8, 47.6, 48.9, and safety of naproxen compared to other NSAIDs [100, 101]. 41.4% for placebo, etoricoxib 90 mg, etoricoxib 120 mg, and However, we did not observe any significant difference in the naproxen, respectively. At the end of 1 year, there were no present meta-analysis (see supplementary material). significant differences in any of the adverse events among the three groups (43.5%, 36.1, and 38.5%, respectively), nor in se- Recommendation 10 vere adverse events (7.6, 7.2, and 7.7%, respectively) or dis- In patients with active axSpA, we conditionally recommend that the continuation rate due to adverse events (8.7, 4.8, and 7.7%, choice of a specific NSAID should be based on patient’s profile (age, respectively) [48]. prior toxicity, comorbidities) and on shared decision making. To date, there is no consistent evidence of efficacy and safety differences among Therefore comparing NSAIDs versus placebo, we did not the NSAIDs (non-selective or iCOX2) in axSpA. Quality of evidence: find statistical differences in the overall incidence of adverse low; Degree of agreement: 9.6 events, which suggests a good safety profile. However, considering specific organ system analyses showed in the following sections, caution is recommended when using Safety and adverse reactions NSAIDs, especially regarding gastrointestinal events. Is there any evidence that NSAIDs carry an increased risk of adverse events in patients with axSpA? Recommendation 11 Regarding safety, in patients with active axSpA, we strongly recommend Five studies compared non-selective NSAIDs versus pla- treatment with NSAIDs over no treatment, because the available cebo regarding adverse events, totaling 1289 patients eval- evidence showed an overall good safety profile of these drugs in axSpA. uated [44–48]. The meta-analysis showed no significant We conditionally recommend that NSAIDS should be used with caution in individuals with risk factors (age > 65 years old, diabetes mellitus, use adverse events differences compared to placebo. Further- of aspirin, corticosteroids and other platelet antiaggregants, renal or liver more, there was no significant serious adverse events dif- diseases). The risks and benefits of starting them should be shared and ference or in the discontinuation rate due to adverse individualized according to the patient’s risk profile. Quality of evidence: low, Degree of agreement: 9.0 events in short-term (6–12 weeks) (Table 3 and Fig. 5). Another 52-week study found no significant adverse event difference among piroxicam 20 mg, meloxicam 15 mg, and meloxicam 22.5 mg compared to placebo in 473 pa- Is the use of NSAIDs associated with increased tients with AS (26, 38, 34, and 36%, respectively) [46]. gastrointestinal risk in patients with axSpA? Considering iCOX2, three studies compared the incidence Five studies compared traditional NSAIDs versus of any adverse events versus placebo in 700 patients with placebo regarding gastrointestinal adverse events in 1289 axSpA [44, 45, 48]. Our meta-analysis did not show any patients [44–48]. The frequency of gastrointestinal Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 12 of 21 Fig. 4 (See legend on next page.) Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 13 of 21 (See figure on previous page.) Fig. 4 a and b Incidence of adverse events per organ system in the comparison of COX2 selective inhibitors versus traditional NSAIDs in patients with ankylosing spondylitis: meta-analyses of seven randomized clinical trials. Subtitle: (1) Celecoxib 400 mg vs diclofenac 75 mg. (2) Celecoxib 200 mg vs diclofenac 75 mg (3) Celecoxib 400 mg vs naproxen 500 mg. (4) Celecoxib 200 mg vs ketoprofen 200 mg. (5) Celecoxib 400 mg vs diclofenac 75 mg. (6) Etoricoxib 90 mg vs naproxen 1000 mg. (7) Celecoxib 200 mg vs diclofenac 75 mg. (8) Celecoxib 200 mg vs diclofenac 50 mg (9) Celecoxib 400 mg vs diclofenac 75 mg. (10) Celecoxib 200 mg vs diclofenac 75 mg. (11) Celecoxib 400 mg vs naproxen 500 mg. (12) Celecoxib 200 mg vs ketoprofen 200 mg. (13) Celecoxib 400 mg vs diclofenac 75 mg. (14) Etoricoxib 90 mg vs naproxen 1000 mg. (15) Celecoxib 200 mg vs diclofenac 75 mg (16) Celecoxib 200 mg vs ketoprofen 200 mg. (17) Celecoxib 200 mg vs diclofenac 75 mg. (18) Celecoxib 400 mg vs naproxen 500 mg. (19) Celecoxib 200 mg vs ketoprofen 200 mg. (20) Celecoxib 400 mg vs diclofenac 75 mg. (21) Etoricoxib 90 mg vs naproxen 1000 mg. (22) Celecoxib 200 mg vs diclofenac 75 mg. (23) Celecoxib 200 mg vs diclofenac 50 mg (24) Celecoxib 400 mg vs naproxen 500 mg. (25) Celecoxib 200 mg vs ketoprofen 200 mg (26) Celecoxib 200 mg vs diclofenac 75 mg. (27) Celecoxib 200 mg vs diclofenac 50 mg events was higher with tranditional NSAIDs than placebo. aggregation drugs), history of peptic ulcer, and Helicobac- A similar result was observed with iCOX2 in 769 patients ter pylori infection. An observational study that evaluated when compared to placebo (Table 3,Figs. 7 and 8)[44, 45, 4144 individuals with osteoarthritis (85%), rheumatoid 48]. There was no significant difference in the meta- arthritis (11%), or AS (3%) and at least one gastrointestinal analysis of six RCTs that compared iCOX2 versus trad- risk factor, with a mean follow-up of 6 months, showed an itional NSAIDs (RR=0.89; 0.65–1.2). Most RCTs were incidence of 0.7 severe events per 100 patients-year after short-term (2–12 weeks) [38, 40, 44, 45, 48, 49]. the initiation of NSAIDs. The associated use of gastropro- In the Dougados’ study (1999), the extension phase tective drugs, such as proton pump inhibitors, reduced the lasted from 6th to 52nd week. In the first 6 weeks, the risk in approximately 30% of patients [100, 102, 103]. Sys- authors showed 14% gastrointestinal events with tematic reviews that included several diseases, not re- traditional NSAIDs versus 7% in placebo group. A total stricted to the population with SpA, showed greater of six (1.7%) individuals from NSAID group had gastrointestinal safety of iCOX2 [100, 101], but we did not gastroduodenal ulcers, and no patients were diagnosed find any significant difference between iCOX2 and trad- in placebo group by week 52 [46]. Regarding iCOX2, itional NSAIDs in the present meta-analysis (see Fig. 4a only the RCT by van der Heijde et al. (2005) analyzed and Supplementary Material). adverse events from week 6 to week 52 in the extension phase, not controlled by placebo. The incidence of Recommendation 12 In patients with active axSpA, we conditionally recommend to avoid pyrosis after 1 year of use was 9.8, 7.2, and 7.7% for NSAIDs (non-selective or iCOX2) and to start an immunobiologic agent etoricoxib 90 mg, etoricoxib 120 mg, and naproxen 1000 in those with current or previous peptic ulcer or gastrointestinal mg, respectively. Three (2.4%) patients who received bleeding. We conditionally recommend the use of an iCOX2 agent over a etoricoxib 120 mg and 4 (3.2%) who received naproxen traditional NSAID in patients with gastrointestinal risk factors. had gastroduodenal ulcers at 1 year of follow-up [48]. We strongly recommend the use of concomitant gastroprotective drugs Most data on gastrointestinal risk were from studies in in symptomatic or high-risk patients. Quality of evidence: low; Degree of agreement: 8.9 other populations (osteoarthritis, rheumatoid arthritis, etc.) and there is no evidence that the risk is different in axSpA. Factors considered high-risk for gastrointestinal complications with NSAIDs are age above 65 years, co- Is the use of NSAIDs associated with increased morbidities (diabetes, COPD, coronary disease, coagulopa- cardiovascular risk in axSpA? thies), alcoholism, concomitant medication There is growing evidence that SpA is associated with (corticosteroids, anticoagulants, aspirin, other antiplatelet increased mortality, especially for cardiovascular diseases, Table 3 Incidence of adverse events associated with traditional NSAIDs or iCOX2 compared to placebo in patients with axSpA: meta-analysis of randomized clinical trials TRADITIONAL NSAIDs iCOX2 N=1289 N=669 Adverse events 35.6% vs 36.4% (PbO) 54.6% vs 46.4% (PbO) RR=1.08 (0.93 to 1.25) RR=1.22 (0.93 to 1.62) Severe adverse events 1% vs 0.6% (PbO) 0.6% vs 0.6% (PbO) RR=1.71 (0.37 to 8.01) RR=0.96 (0.17 to 5.53) Gastrointestinal adverse events 18% vs 9.5% (PbO) 17.7% vs 7.5% (PbO) RR=1.92 (1.41 to 2.61) RR=2.55 (1.92 to 4.95) Discontinuation due to adverse events 5% vs 5.5% (PbO) 4.6% vs 3.4% (PbO) RR=0.76 (0.48 to 1.22) RR=2.14 (0.36 to 12.56) NSAIDs nonsteroidal anti-inflammatory drugs, iCOX2 selective cyclooxygenase 2 inhibitors, PbO placebo, RR relative risk Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 14 of 21 Fig. 5 Incidence of any adverse events in the comparison of traditional NSAIDs versus placebo in patients with ankylosing spondylitis: meta- analysis of five randomized clinical trials. Subtitle: (1) Naproxen 500 mg vs placebo. (2) Ximoprofen 30 mg vs placebo. (3) NSAID (meloxicam 15 mg, meloxicam 22.5 mg, or piroxicam) vs placebo. (4) Ketoprofen 200 mg vs placebo. (5) Naproxen 1000 mg vs placebo due to multiple factors such as chronic inflammation, cohort of osteoarthritis (OA) patients. Current use of associated comorbidities and maybe the drugs used to diclofenac (0–180 days prior to index date) compared to treat these patients [104–107]. Regarding NSAIDs, large remote use (more than 365 days prior to index date) was population studies, including a Danish cohort of more associated with an increased risk of AMI both in SpA than 1 million individuals, suggested 2 to 3-fold increase group [adjusted OR=3.32 (95% CI 1.57 to 7.03)] and OA regarding cardiovascular risk (acute myocardial infarction, group [(ORa=1.26 (95% CI 1.14 to 1.39)]. Additionally, the stroke, and death from cardiovascular disease) with the risk was different between the two groups [ORa ratio=2.64 chronic use of iCOX2 or nonselective NSAIDs, except for (95% CI 1.24 to 5.58, OA as reference)], whereas there naproxen. Meta-analysis of observational studies estimates was no increased risk of AMI when naproxen was ana- an absolute risk of major adverse cardiovascular events lyzed, either in patients with SpA [(ORa=1.19 (95% CI (MACE) of approximately 3 per 1000 patients-year with 0.53 to 2.68)] or in those with OA [112]. Interestingly, the use of NSAIDs [100, 101, 108, 109]. Furthermore, other authors have observed a protective effect of NSAIDs NSAIDs have been shown to increase mortality in the first against cardiovascular events in patients with axSpA. 3 to 6 months after acute cardiovascular events [110, 111]. Haroon et al. studied 21,143 patients with AS compared However, in the population with SpA, the relationship to 86,606 controls, based on Canadian database, observed of NSAIDs with cardiovascular mortality risk is less clear. a hazard ratio (HR) of 1.36 (95% CI 1.13 to 1.65) for a Debreuil et al., in a case-control study using a large British composite outcome of cardiovascular death. A subgroup database, compared the incidence of acute myocardial in- analysis of patients older than 65 years demonstrated a farction (AMI) between a cohort of SpA patients with a protective effect of conventional NSAIDs for Fig. 6 Incidence of any adverse events in the comparison of selective COX-2 inhibitors versus placebo in patients with ankylosing spondylitis: meta- analysis of three randomized clinical trials. Subtitle: (1) Celecoxib 400 mg vs placebo. (2) Celecoxib 200 mg vs placebo. (3) Etoricoxib 90 mg vs placebo Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 15 of 21 Fig. 7 Incidence of adverse events per organic system in the comparison of traditional NSAIDs versus placebo in patients with ankylosing spondylitis: meta-analyses of five randomized clinical trials. Subtitle: (1) Naproxen 500 mg vs placebo. (2) Ximoprofen 30 mg vs placebo. (3) NSAIDs (meloxicam 15 mg, meloxicam 22.5 mg, or piroxicam) vs placebo. (4) Ketoprofen 200 mg vs placebo. (5) Naproxen 1000 mg vs placebo. (6) Naproxen 500 mg vs placebo. (7) NSAIDs (meloxicam 15 mg, meloxicam 22.5 mg, or piroxicam) vs placebo. (8) Ketoprofen 200 mg vs placebo. (9) Naproxen 1000 mg vs placebo. (10) Ketoprofen 200 mg vs placebo. (11) Naproxen 500 mg vs placebo. (12) NSAIDs (meloxicam 15 mg, meloxicam 22.5 mg or piroxicam) vs placebo. (13) Ketoprofen 200 mg vs placebo. (14) Naproxen 1000 mg vs placebo. (15) Naproxen 500 mg vs placebo. (16) NSAIDs (meloxicam 15 mg, meloxicam 22.5 mg or piroxicam) vs placebo. (17) Ketoprofen 200 mg vs placebo cardiovascular death [HR=0.1 (95% CI 0.01 to 0.61)] [105]. the observation time) [23]. Another Taiwan case-control Tsai et al., using data from the Taiwan Health Insurance, study found negative association between the use of cele- observed a reduced risk of MACE after 12 months in pa- coxib (versus non-users) and coronary events [OR=0.34 tients with AS who had prolonged use of NSAIDs (> 80% of (95% CI 0.13 to 0.89)] in AS patients [26]. Other publications Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 16 of 21 Fig. 8 Incidence of adverse events per organ system in the comparison of selective COX-2 inhibitors versus placebo in patients with ankylosing spondylitis: meta-analysis of three randomized clinical trials. Subtitle: 1) Celecoxib 400 mg vs placebo. (2) Celecoxib 200 mg vs placebo. (3) Etoricoxib 90 mg vs placebo. (4) Celecoxib 400 mg vs placebo. (5) Celecoxib 200 mg vs placebo. (6) Etoricoxib 90 mg vs placebo. (7) Celecoxib 400 mg vs placebo. (8) Celecoxib 200 mg vs placebo. (9) Etoricoxib 90 mg vs placebo. (10) Celecoxib 400 mg vs placebo. (11) Celecoxib 200 mg vs placebo also suggest the protective effect of NSAIDs against cardio- patients with cardiovascular risks factors, specially in vascular events, but the data should be interpreted with cau- those with a recent myocardial infarction or stroke. tion because patients with more comorbidities and risk factors tend to be less exposed to NSAIDs [17, 106]. In sum- Recommendation 13 In patients with active axSpA, we conditionally recommend to avoid mary, it is still controversial whether the beneficial effect of NSAID therapy and to start an immunobiologic agent in those with reducing inflammation would outweigh the negative effects cardiovascular risk factors, mainly in those with previous acute of NSAIDs per se regarding cardiovascular risk. myocardial infarction or stroke, especially if recent (past 12 months). Quality of evidence: very low; Degree of agreement: 8.4 The present systematic review, which included only RCTs and not observational studies, did not find higher cardiovascular risk when comparing traditional NSAIDs or iCOX2 versus placebo. Two RCTs compared Are NSAIDs associated with increased renal risk in patients traditional NSAIDs versus iCOX2 on cardiovascular with axSpA? events incidence [2% (4/175) and 0% (0/170), respectively] The RCTs selected for this systematic review did not and no significant difference in meta-analysis [RR=0.22 report renal toxicity from NSAIDs in patients with (95% CI 0.03 to 1.93)] was observed [38, 49]. axSpA. Similarly to the cardiovascular toxicity, the renal Furthermore, the panel decided to conditionally adverse events evidences were obtained from data recommend caution when prescribing NSAIDs in including other populations. A large cohort study (183, Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 17 of 21 446 patients; 80% women; mean age of 78 years) found treatment of patients with axSpA, as they are effective in an incidence of 0.5% (1 in 200 new treatments) of acute most part of those patients. kidney injury (AKI), requiring hospitalization, in a There is no doubt that the immunobiologic agents are period of up to 45 days after the onset of NSAIDs [113]. quite effective and brought great benefit for the A meta-analysis evaluated 28,992 patients and demon- management of axSpA, but they carry a high cost which strated a RR of AKI associated with NSAIDs ranging demands the best rationale for prescribing them. Our from 1.25 to 2.21 that was statistically significant for sev- recommendations, in consonance with the most eral NSAIDs [114]. Regarding the possibility of progres- important guidelines, strengthen the statement that sion to chronic kidney disease, a prospective study with NSAIDs are the first line treatment in patients with 10,184 patients (57% women; mean age 76 years) found axSpA and they should be started as soon as the RR=1.26 (95% CI 1.04 to 1.53) for a reduction of glom- diagnosis is confirmed. erular filtration rate of at least 15 ml/min/1.73 m among The benefit of NSAIDs in delaying radiographic NSAID users when compared with non-users during a progression in axSpA and if immunobiologics should be median follow-up of 2.75 years [115]. the first line treatment in patients with poor prognostic criteria (elevated CRP, smokers and those with previous syndesmophytes) remain an open question. Does the use of NSAIDs increase the risk of adverse events This review has also shown that NSAIDs have a good in other organs/systems in axSpA? safety profile and are usually well tolerated for the long- Considering five RCTs of non-selective NSAIDs versus term use. The concerns about the cardiovascular and placebo and three of iCOX2 versus placebo, neither the renal side effects are based mostly in data from other meta-analysis nor individual studies found an increase in populations, but not in patients with axSpA that are usu- respiratory, hematological, dermatologic, or neurological ally younger and have less comorbidities and risk factors adverse events [44–48]. Additionally, no significant dif- than other NSAID’s long-term or frequently users, like ferences were found in the comparison of iCOX2 versus patients with osteoarthritis for example. traditional NSAIDs [38, 40, 44, 45, 48, 49]. In the com- One possible limitation of these recommendations is parison of NSAIDs with other NSAIDs, selective or not that we did not include a patient representative in the for COX-2, only indomethacin was associated with a voting panel. This strategy could be used in future greater number of neurological adverse events [80, 83, guidelines. 86]. Despite data from general population have sug- The purpose of these guidelines was to provide gested some hepatotoxic effect of NSAIDs, no specific recommendations elaborated by a panel of RCTs were found for NSAIDs versus placebo in patients rheumatologists with expertise in the field of SpA, with axSpA [116]. The current meta-analysis found mainly to support clinician’s decision making, without greater hepatic toxicity for iCOX2 compared to non- taking out his/her autonomy to choose the best selective NSAIDs, but with high imprecision data and at therapeutic option for an individual patient. the limit of statistical significance (Figs. 7 and 8). Recommendation 14 Supplementary Information In patients with active axSpA, we conditionally recommend to avoid The online version contains supplementary material available at https://doi. NSAIDs and to start an immunobiologic agent in thoses with increased org/10.1186/s42358-020-00160-6. risk of renal adverse events. The decision should be individualized and risk/benefits shared with the patient. Additional file 1. We strongly recommend caution and regular monitoring of renal function, especially in high-risk individuals (elderly, hypertension, dia- betes, kidney dysfunction). Quality of evidence: very low; Degree of agreement: 9.4 Abbreviations AxSpA: Axial Spondyloarthritis; AS: Ankylosing Spondylitis; PsA: Psoriatic Arthritis; ASAS: Ankylosing Spondylitis Assessment Study Group; RCT: Randomized Clinical Trial; TNFi: Tumor Necrosis Factor inhibitor; Conclusions IL17i: Interleukin-17 inhibitor; NSAID: Nonsteroidal Anti-inflammatory Drug; The most recently published guidelines for the iCOX2: Specific Cycloxigenase-2 inhibitor; BASDAI: Bath Ankylosing management of axSpA recommended NSAIDs as the Spondylitis Disease Activity Index; ASDAS: Ankylosing Spondylitis Disease Activity Score; BASFI: Bath Ankylosing Spondylitis Disease Functional Index; first line treatment, but none of them has addressed PAIN50%: ≥ 50% improvement in pain; MD: Mean Difference; SMD: Standard specifically the current role of NSAIDs in the treatment Mean Difference; CRP: C Reactive Protein; ESR: Erythrocyte Sedimentation of patients with axSpA regarding efficacy, safety and Rate; PAIN-VAS: Pain by Visual Analogue Scale; PGA: Patient Global Assessment of disease activity; ASAS20: At least 20% improvement according therapeutic strategy [6, 7, 71]. The present systematic to ASAS response criteria; ASAS40: At least 40% improvement according to review and critical analysis of the available evidences ASAS response criteria; mSASSS: modified Stoke Ankylosing Spondylitis Spine have confirmed that NSAIDs are still the basis for the Score Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 18 of 21 Acknowledgements Lenise Brandao Pieruccetti has no conflicts of interest. We thank Haliton Alves de Oliveira Junior and Anna Maria Buehler for Michel Alexandre Yazbek received financial support from Abbvie, UCB, technical support in the systematic review, statistical assistance and for Novartis and Lilly. performing the meta-analyses. Penelope Esther Palominos has no conflicts of interest. Rafaela Silva Guimarães Goncalves received fees for lectures from Janssen, Novertis, Abbvie, Apsen, Bristol, and Pfizer; advisory board from Janssen. Authors’ contributions Rodrigo Luppino Assad received fees for lectures and advisory board from All authors made contributions to the acquisition of data, have been Abbvie, Novartis, Janssen, UCB, Lilly, and Bristol; research support from involved in drafting the manuscript or revising it critically for important Abbvie and UCB. intellectual content, participated in the voting rounds, gave final approval of Rubens Bonfiglioli received financial support for clinical research from Roche, the version to be published and have participated sufficiently in the work to Pfizer, Amgen, and Novartis; for scientific advisory from Lilly, Abbvie, Roche, take public responsibility for appropriate portions of the content. and UCB; for support to events from Roche, Pfizer, Abbvie and Novartis; for symposia and sponsored meetings from Roche, Pfizer, and Janssen. Funding Sônia Maria Alvarenga Anti received financial support from Abbvie, Jansen, Brazilian Society of Rheumatology. The funding body had no role in the Novartis, Lilly, and UCB. design of the study and collection, analysis, and interpretation of data and in Sueli Coelho da Silva Carneiro received honorary speaker from Abbvie, writing the manuscript. Janssen, Lilly, Novartis and Pfizer; support to research from CNPq and FAPE RJ; support for congresses from Abbvie, Janssen, Novartis, Pfizer, CNPq and Availability of data and materials FAPERJ; advisory board from Janssen, Lilly, and Novartis. Online supplement. Valderílio Feijó Azevedo is GRAPPA member; Medical diretor of Edumed Biotech; received for clinical research from Pfizer, Roche, Janssen, Bristol, Ethics approval and consent to participate Abbvie, Medimmune, Boehringer, GSK, USB, Sanofi, Takeda, Bird Rock Bio, Not applicable. and NovoNordisk; financial support to events and lectures from Pfizer, Hospira, Roche, MSD, BMS, Merck Senoro, Janssen, Novertis, Celltrion, UCB, Consent for publication and AztraZeneca. Not applicable. Cleandro Pires Albuquerque has no conflicts of interest. Wanderley Marques Bernardo has no conflicts of interest. Competing interests Percival Degrava Sampaio-Barros received for participation in lectures, boards Ricardo da Cruz Lage received lecture fees from Abbvie, Pfizer and Novartis; or scientific events from laboratories Abbvie, Janssen, Novartis, Pfizer and sponsorship for events from Janssen, Novartis, Pfizer and Abbvie; research UCB. payments from Abbvie. Marcelo de Medeiros Pinheiro received financial support for advisory board Cláudia Diniz Lopes Marques received lecture fees from Abbvie, Janssen, from Novartis and Janssen; by lectures from Novartis, Janssen, Abbvie. Pfizer and Novartis; advisory board from Novartis and Abbvie; sponsorship for events from Abbvie, Janssen, Pfizer, Novartis, and Lilly. Author details Thauana Luíza Oliveira received lecturer fees from Abbvie, Novartis and 1 Universidade Federal de Minas Gerais (UFMG), Alameda Álvaro Celso 175, Janssen; support to congresses from Abbvie and Janssen. Ambulatório Bias Fortes, 2° andar, Belo Horizonte, MG 30150-260, Brazil. Gustavo Gomes Resende received lecture fees from Abbvie, Janssen, 2 3 Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil. Universidade Novartis, Pfizer, and UCB; advisory board from Abbvie, Janssen, and Novartis; 4 Federal de São Paulo (UNIFESP/ EPM), São Paulo, SP, Brazil. Universidade Research support from Brazilian Society of Rheumatology, FAPEMIG and UCB; 5 Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. Universidade de clinical research payments from Abbvie and Pfizer; sponsorship for scientific 6 São Paulo (USP), São Paulo, SP, Brazil. Hospital Estadual Geral de Goiania events from Abbvie, Janssen, Lilly, Novartis, Pfizer, and UCB. 7 (HGG), Goiânia, Brazil. Santa Casa de Misericórdia (SCM) do Rio de Janeiro, Charles Lubianca Kohen received financial support for advisory board 8 Rio de Janeiro, RJ, Brazil. Pontifícia Universidade Católica (PUC) de Porto participation from Novartis; speaker fee from Janssen, Abbvie, Novartis, Pfizer, 9 Alegre, Porto Alegre, RS, Brazil. Pontifícia Universidade Católica (PUC) de UCB; support to events from Janssen, Abbvie, Roche, Astra-Zeneca, Novartis. 10 Sorocaba, Sorocaba, SP, Brazil. Santa Casa de Misericórdia (SCM) de São Carla Gonçalves Saad has no conflicts of interest. 11 Paulo, São Paulo, SP, Brazil. Pontifícia Universidade Católica (PUC) de Antônio Carlos Ximenes received payments for participation in clinical 12 Campinas, Campinas, SP, Brazil. Hospital Heliópolis, São Paulo, SP, Brazil. research from Abbvvie, Pfizer, Roche, BMS, and Amgen; on scientific board of 13 Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil. Pfizer, and Abbivie; as a lecturer from AbbVie, Pfizer, and Abbott. 14 15 Ribeirão Preto, Ribeirão Preto, Brazil. Hospital do Servidor Público do Célio Roberto Gonçalves has no conflicts of interest. 16 Estado de São Paulo, São Paulo, SP, Brazil. Universidade Federal do Rio De Washington Alves Bianchi has no conflicts of interest. 17 Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil. Universidade Federal do Paraná Eduardo de Souza Meirelles received payments as a speaker from Novartis, 18 (UFPR), Curitiba, PR, Brazil. Universidade de Brasília (UnB), Brasília, DF, Brazil. Abbvie, Abbott and Marjan; research grants from Novartis and Pfizer; support for conferences and courses from Aché, Pfizer, Novartis, Janssen, Abbvie, Received: 3 July 2020 Accepted: 29 December 2020 Roche, and Lilly; Advisory board fee from Novartis and Marjan. Mauro Waldemar Keiserman received financial support for lectures, advisory bord and clinical research from Abbvie, Actelion, Biogen, Bristol, Celltrion, Lilly, Human Genome Sceiences, Janssen, Pfizer, Novartis, Roche, Sanofi, and References UCB. 1. Rudwaleit M, Landewe R, van der Heijde D, Listing J, Brandt J, Braun J, et al. The Adriano Chiereghin received honoraria as a speaker from Janssen, Novartis, development of Assessment of SpondyloArthritis international Society classification UCB, and Pfizer; support to courses and congresses from Abbvie, Janssen, criteria for axial spondyloarthritis (part I): classification of paper patients by expert Novartis, UCB, and Pfizer; advisory board from Novartis and Janssen. opinion including uncertainty appraisal. Ann Rheum Dis. 2009;68(6):770–6. Cristiano Barbosa Campanholo received financial support for advisory board 2. Rudwaleit M, van der Heijde D, Landewe R, Akkoc N, Brandt J, Chou CT, participation from Janssen, Abbvie, Bristol, Lilly, Novartis, Pfizer, UCB; speaker et al. The Assessment of SpondyloArthritis International Society classification fee from Janssen, Abbvie, Lilly, Novartis, and Pfizer, UCB; support to events criteria for peripheral spondyloarthritis and for spondyloarthritis in general. from Janssen, Abbvie, Bristol, Novartis, and Pfizer. Ann Rheum Dis. 2011;70(1):25–31. Andre Marun Lyrio received payments from Speaker of Janssen and UCB; 3. Rudwaleit M, van der Heijde D, Landewe R, Listing J, Akkoc N, Brandt J, support to courses/congresses from Janssen, Abbvie, Pfizer, UBC, Novartis, et al. The development of Assessment of SpondyloArthritis international and Lily. Society classification criteria for axial spondyloarthritis (part II): validation and Cláudia Goldenstein Schainberg has participated in the pharmaceutical final selection. Ann Rheum Dis. 2009;68(6):777–83. advisory board of AbbVie, Janssen, Lilly, Novartis, and Pfizer; is a speaker 4. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria invited by AbbVie, Janssen, Lilly, Novartis, Pfizer; has no stock of these for ankylosing spondylitis. A proposal for modification of the New York pharmaceutical industries. criteria. Arthritis Rheum. 1984;27(4):361–8. Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 19 of 21 5. Sieper J, van der Heijde D. Review: Nonradiographic axial spondyloarthritis: 24. Varkas G, Jans L, Cypers H, Van Praet L, Carron P, Elewaut D, et al. Brief new definition of an old disease? Arthritis Rheum. 2013;65(3):543–51. Report: Six-Week Treatment of Axial Spondyloarthritis Patients With an 6. van der Heijde D, Ramiro S, Landewe R, Baraliakos X, Van den Bosch F, Optimal Dose of Nonsteroidal Antiinflammatory Drugs: Early Response to Sepriano A, et al. 2016 update of the ASAS-EULAR management Treatment in Signal Intensity on Magnetic Resonance Imaging of the recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76(6): Sacroiliac Joints. Arthritis Rheumatol (Hoboken, NJ). 2016;68(3):672–8. 978–91. 25. Wang R, Dasgupta A, Ward MM. Comparative efficacy of non-steroidal anti- inflammatory drugs in ankylosing spondylitis: a Bayesian network meta- 7. Resende GG, Meirelles ES, Marques CDL, Chiereghin A, Lyrio AM, Ximenes analysis of clinical trials. Ann Rheum Dis. 2016;75(6):1152–60. AC, et al. The Brazilian Society of Rheumatology guidelines for axial spondyloarthritis - 2019. Adv Rheumatol. 2020;60(1):19. 26. Wu L-C, Leong P-Y, Yeo K-J, Li T-Y, Wang Y-H, Chiou J-Y, et al. Celecoxib 8. FPB K, der Burg LRA v, Ramiro S, RBM L, Buchbinder R, Falzon L, et al. Non- and sulfasalazine had negative association with coronary artery diseases in steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis patients with ankylosing spondylitis: A nation-wide, population-based case- (ankylosing spondylitis and non-radiographic axial spondyloarthritis). control study. Medicine. 2016;95(36):e4792-e. Cochrane Database Syst Rev. 2015;17(7):CD010952-CD. 27. Couderc M, Pereira B, Molto A, Tiple A, Soubrier M, Dougados M. The 9. Baraliakos X, Kiltz U, Peters S, Appel H, Dybowski F, Igelmann M, et al. Prevalence of Renal Impairment in Patients with Spondyloarthritis: Results Efficiency of treatment with non-steroidal anti-inflammatory drugs from the International ASAS-COMOSPA Study. J Rheumatol. 2018;45(6):795– according to current recommendations in patients with radiographic and 801. non-radiographic axial spondyloarthritis. Rheumatology (Oxford). 2017;56(1): 28. Dregan A, Chowienczyk P, Molokhia M. Cardiovascular and type 2 diabetes 95–102. morbidity and all-cause mortality among diverse chronic inflammatory 10. Bhuvanesh M, Balaji C, Saranya C, Ramesh R, Tamilselvam T, Rajeswari S. disorders. Heart (British Cardiac Society). 2017;103(23):1867–73. Serum levels of tumor necrosis factor-alpha and vascular endothelial growth 29. Fattahi MJ, Jamshidi AR, Mahmoudi M, Vojdanian M, Yekaninejad MS, factor as markers of disease activity in patients with axial spondyloarthritis. Jafarnezhad-Ansariha F, et al. Evaluation of the efficacy and safety of beta-d- Indian J Rheumatol. 2018;13(1):9–13. mannuronic acid in patients with ankylosing spondylitis: A 12-week randomized, placebo-controlled, phase I/II clinical trial. Int 11. Essers I, Stolwijk C, Boonen A, De Bruin ML, Bazelier MT, de Vries F, et al. Immunopharmacol. 2018;54:112–7. Ankylosing spondylitis and risk of ischaemic heart disease: a population- based cohort study. Ann Rheum Dis. 2016;75(1):203–9. 30. Gao G, Lu L, Li Z, Li Y. THU0367 The influences of non-steroidal anti- 12. Gaydukova IZ, Gamayunova Cyrillic A cKA, Dorogoykina KD, Rebrov AP. inflammatory drugs on serum VEGF and BMP-2 levels in patients with axial Efficiency of different celecoxib regimens in patients with active axial spondyloarthritis. Ann Rheum Dis. 2017;76(Suppl 2):344 LP. spondyloarthritis: Results of the 4-week pilot open-label comparative single- 31. Gao G-M, Li Y-M, Zheng X-L, Jiang D-B, Zhang L-L, Xu P-H, et al. The Efficacy center study ‘AIM’. Ter Arkh. 2017;89(6):78–83. of Imrecoxib and Celecoxib in Axial Spondyloarthritis and Their Influence on 13. Gaydukova IZ, Rebrov AP. Efficiency and safety of different etoricoxib Serum Dickopff-Related Protein 1 (DKK-1) Levels. Med Sci Monit. 2017;23: regimens in patients with axial spondyloarthritis, including ankylosing 2985–92. spondylitis. Ter Arkh. 2015;87(3):77–82. 32. Jafarnezhad-Ansariha F, Yekaninejad MS, Jamshidi A-R, Mansouri R, Vojdanian M, Mahmoudi M, et al. The effects of beta-D-mannuronic acid 14. Gratacos J, Moreno Martinez-Losa M, Font P, Montilla C, Fernandez- (M2000), as a novel NSAID, on COX1 and COX2 activities and gene Espartero C, Linares LF, et al. Etoricoxib in ankylosing spondylitis: is there a expression in ankylosing spondylitis patients and the murine monocyte/ role for active patients refractory to traditional NSAIDs? Clin Exp Rheumatol. macrophage, J774 cell line. Inflammopharmacology. 2018;26(2):375–84. 2016;34(1):94–9. 15. Guellec D, Nocturne G, Tatar Z, Pham T, Sellam J, Cantagrel A, et al. Should 33. Bedaiwi M, Thavaneswaran A, Haroon N, Anton A, Inman R. Profiling non-steroidal anti-inflammatory drugs be used continuously in ankylosing ankylosing spondylitis patients likely to respond to NSAID treatment; 2014. spondylitis? Joint Bone Spine. 2014;81(4):308–12. 34. Zengin O, Kısacık B, Kimyon G, Uyar N, Onat AM. AB0751 Treatment 16. Karateev A, Chernikhova E, Erdes S. AB0735 Upper Gastrointestinal Tract Response in Spondylitis Without Sacroiliitis to Nonsteroidal Pathology in Patients with Ankylosing Spondylitis. Ann Rheum Dis. 2015; Antiinflammatory Drugs is More Difficult than Axial Spondyloarthritis. Ann 74(Suppl 2):1144 LP. Rheum Dis. 2015;74(Suppl 2):1150.1. 35. Sánchez MD, Montilla-Morales CA, Gόmez-Castro S, Hidalgo-Calleja C, 17. Kristensen LE, Jakobsen AK, Askling J, Nilsson F, Jacobsson LTH. Safety of Carranco-Medina T, Calero-Paniagua I, et al. AB0705 Nonsteroidal Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Antiinflammatory Drugs and Bone Mineral Density and Fractures in Patients Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A with Ankylosing Spondylitis. Ann Rheum Dis. 2014;73(Suppl 2):1037 LP. Swedish National Population-Based Cohort Study. Arthritis Care Res. 2015; 67(8):1137–49. 36. Shukla A, Rai MK, Prasad N, Agarwal V. Short-term non-steroid anti- 18. Maas F, Spoorenberg A, van der Slik BPG, van der Veer E, Brouwer E, inflammatory drug use in spondyloarthritis patients induces subclinical Bootsma H, et al. Clinical Risk Factors for the Presence and Development of acute kidney injury: biomarkers study. Nephron. 2017;135(4):277–86. Vertebral Fractures in Patients With Ankylosing Spondylitis. Arthritis Care 37. Bedaiwi MK, Sari I, Wallis D, O'Shea FD, Salonen D, Haroon N, et al. Clinical Res. 2017;69(5):694–702. efficacy of celecoxib compared to acetaminophen in chronic nonspecific 19. Molto A, Granger B, Wendling D, Dougados M, Gossec L. Use of low back pain: results of a randomized controlled trial. Arthritis Care Res. nonsteroidal anti-inflammatory drugs in early axial spondyloarthritis in daily 2016;68(6):845–52. practice: Data from the DESIR cohort. Joint Bone Spine. 2017;84(1):79–82. 38. Huang F, Gu J, Liu Y, Zhu P, Zheng Y, Fu J, et al. Efficacy and safety of 20. Regel A, Sepriano A, Baraliakos X, van der Heijde D, Braun J, Landewe R, celecoxib in chinese patients with ankylosing spondylitis: a 6-week et al. Efficacy and safety of non-pharmacological and non-biological randomized, double-blinded study with 6-week open-label extension pharmacological treatment: a systematic literature review informing the treatment. Curr Ther Res Clin Exp. 2014;76:126–33. 2016 update of the ASAS/EULAR recommendations for the management of 39. Sieper J, van der Heijde D, Dougados M, Mease PJ, Maksymowych WP, axial spondyloarthritis. RMD Open. 2017;3(1):e000397-e. Brown MA, et al. Efficacy and safety of adalimumab in patients with non- radiographic axial spondyloarthritis: results of a randomised placebo- 21. Tam H-W, Yeo K-J, Leong P-Y, Chen C-H, Li Y-C, Ma C-M, et al. Sulfasalazine controlled trial (ABILITY-1). Ann Rheum Dis. 2013;72(6):815–22. might reduce risk of cardiovascular diseases in patients with ankylosing spondylitis: A nationwide population-based retrospective cohort study. Int J 40. Walker C, Essex MN, Li C, Park PW. Celecoxib versus diclofenac for the Rheum Dis. 2017;20(3):363–70. treatment of ankylosing spondylitis: 12-week randomized study in 22. Tang M, Xue L, Shen Y, Bo L, Yang R, Wen J, et al. Efficacy of long-term Norwegian patients. J Int Med Res. 2016;44(3):483–95. nonsteroidal antiinflammatory drug treatment on magnetic resonance 41. Balazcs E, Sieper J, Bickham K, Mehta A, Frontera N, Stryszak P, et al. A imaging-determined bone marrow oedema in early, active axial randomized, clinical trial to assess the relative efficacy and tolerability of spondyloarthritis patients. Clin Rheumatol. 2018;37(1):245–50. two doses of etoricoxib versus naproxen in patients with ankylosing 23. Tsai W-C, Ou T-T, Yen J-H, Wu C-C, Tung Y-C. Long-term frequent use of spondylitis. BMC Musculoskelet Disord. 2016;17(1):426. non-steroidal anti-inflammatory drugs might protect patients with 42. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE ankylosing spondylitis from cardiovascular diseases: a nationwide case- guidelines: 1. Introduction-GRADE evidence profiles and summary of control study. PLoS One. 2015;10(5):e0126347-e. findings tables. J Clin Epidemiol. 2011;64(4):383–94. Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 20 of 21 43. Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al. Going 62. Ash Z, Barkham N, McGonagle D, Hensor E, Emery P, Marzo-Ortega H. from evidence to recommendations. Bmj. 2008;336(7652):1049–51. Induction approach to early axial spondyloarthritis: still looking for the 44. Barkhuizen A, Steinfeld S, Robbins J, West C, Coombs J, Zwillich S. Celecoxib window of opportunity. Arthritis Rheum. 2011;63:1285. is efficacious and well tolerated in treating signs and symptoms of 63. Baraliakos X, Koenig AS, Jones H, Szumski A, Collier D, Bananis E. Predictors ankylosing spondylitis. J Rheumatol. 2006;33(9):1805–12. of clinical remission under anti-tumor necrosis factor treatment in patients with ankylosing spondylitis: pooled analysis from large randomized clinical 45. Dougados M, Behier JM, Jolchine I, Calin A, van der Heijde D, Olivieri I, et al. trials. J Rheumatol. 2015;42(8):1418–26. Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis: a six-week controlled study with comparison 64. Robinson PC, Brown MA. The window of opportunity: a relevant concept against placebo and against a conventional nonsteroidal antiinflammatory for axial spondyloarthritis. Arthritis Res Ther. 2014;16(3):109. drug. Arthritis Rheum. 2001;44(1):180–5. 65. Rudwaleit M, Listing J, Brandt J, Braun J, Sieper J. Prediction of a major 46. Dougados M, Gueguen A, Nakache JP, Velicitat P, Veys EM, Zeidler H, et al. clinical response (BASDAI 50) to tumour necrosis factor alpha blockers in Ankylosing spondylitis: what is the optimum duration of a clinical study? A ankylosing spondylitis. Ann Rheum Dis. 2004;63(6):665–70. one year versus a 6 weeks non-steroidal anti-inflammatory drug trial. 66. Song IH, Hermann K, Haibel H, Althoff CE, Listing J, Burmester G, et al. Rheumatology (Oxford). 1999;38(3):235–44. Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on 47. Dougados M, Nguyen M, Caporal R, Legeais J, Bouxin-Sauzet A, Pellegri- active inflammatory lesions as detected by whole-body MRI (ESTHER): a 48- Guegnault B, et al. Ximoprofen in ankylosing spondylitis. A double blind week randomised controlled trial. Ann Rheum Dis. 2011;70(4):590–6. placebo controlled dose ranging study. Scand J Rheumatol. 1994;23(5):243– 67. Song IH, Hermann KG, Haibel H, Althoff CE, Poddubnyy D, Listing J, et al. 8. Consistently good clinical response in patients with early axial 48. van der Heijde D, Baraf HSB, Ramos-Remus C, Calin A, Weaver AL, Schiff M, spondyloarthritis after 3 years of continuous treatment with etanercept: et al. Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: results longterm data of the ESTHER trial. J Rheumatol. 2014;41(10):2034–40. of a fifty-two-week, randomized, controlled study. Arthritis Rheum. 2005; 68. Haroon N, Inman RD, Learch TJ, Weisman MH, Lee M, Rahbar MH, et al. The 52(4):1205–15. impact of tumor necrosis factor alpha inhibitors on radiographic 49. Sieper J, Klopsch T, Richter M, Kapelle A, Rudwaleit M, Schwank S, et al. progression in ankylosing spondylitis. Arthritis Rheum. 2013;65(10):2645–54. Comparison of two different dosages of celecoxib with diclofenac for the 69. Wanders A, Heijde D, Landewe R, Behier JM, Calin A, Olivieri I, et al. treatment of active ankylosing spondylitis: results of a 12-week randomised, Nonsteroidal antiinflammatory drugs reduce radiographic progression in double-blind, controlled study. Ann Rheum Dis. 2008;67(3):323–9. patients with ankylosing spondylitis: a randomized clinical trial. Arthritis 50. Gossec L, van der Heijde D, Melian A, Krupa DA, James MK, Cavanaugh PF, Rheum. 2005;52(6):1756–65. et al. Efficacy of cyclo-oxygenase-2 inhibition by etoricoxib and naproxen 70. Sieper J, Listing J, Poddubnyy D, Song I-H, Hermann K-G, Callhoff J, et al. on the axial manifestations of ankylosing spondylitis in the presence of Effect of continuous versus on-demand treatment of ankylosing spondylitis peripheral arthritis. Ann Rheum Dis. 2005;64(11):1563–7. with diclofenac over 2 years on radiographic progression of the spine: 51. Villa Alcazar LF, de Buergo M, Rico Lenza H, Montull Fruitos E. Aceclofenac results from a randomised multicentre trial (ENRADAS). Ann Rheum Dis. is as safe and effective as tenoxicam in the treatment of ankylosing 2016;75(8):1438–43. spondylitis: a 3 month multicenter comparative trial. Spanish Study Group 71. Ward MM, Deodhar A, Akl EA, Lui A, Ermann J, Gensler LS, et al. American on Aceclofenac in Ankylosing Spondylitis. J Rheumatol. 1996;23(7):1194–9. College of Rheumatology/Spondylitis Association of America/ 52. Ebner W, Poal Ballarin JM, Boussina I. Meclofenamate sodium in the Spondyloarthritis Research and Treatment Network 2015 recommendations treatment of ankylosing spondylitis. Report of a European double-blind for the treatment of ankylosing spondylitis and nonradiographic axial controlled multicenter study. Arzneimittel-Forschung. 1983;33(4A):660–3. spondyloarthritis. Arthritis Rheumatol (Hoboken, NJ). 2016;68(2):282–98. 53. Good A, Mena H. Treatment of ankylosing spondylitis with flurbiprofen and 72. Boersma JW. Retardation of ossification of the lumbar vertebral column in indomethacin. Curr Med Res Opin. 1977;5(1):117–21. ankylosing spondylitis by means of phenylbutazone. Scand J Rheumatol. 54. Zochling J, Bohl-Buhler MH, Baraliakos X, Feldtkeller E, Braun J. Nonsteroidal 1976;5(1):60–4. anti-inflammatory drug use in ankylosing spondylitis--a population-based 73. Poddubnyy D, Rudwaleit M, Haibel H, Listing J, Marker-Hermann E, Zeidler survey. Clin Rheumatol. 2006;25(6):794–800. H, et al. Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the 55. Carbo MJG, Spoorenberg A, Maas F, Brouwer E, Bos R, Bootsma H, et al. German Spondyloarthritis Inception Cohort. Ann Rheum Dis. 2012;71(10): Ankylosing spondylitis disease activity score is related to NSAID use, 1616–22. especially in patients treated with TNF-alpha inhibitors. PLoS One. 2018; 13(4):e0196. 74. Kroon F, Landewe R, Dougados M, van der Heijde D. Continuous NSAID use 56. Zochling J, van der Heijde D, Dougados M, Braun J. Current evidence for reverts the effects of inflammation on radiographic progression in patients the management of ankylosing spondylitis: a systematic literature review for with ankylosing spondylitis. Ann Rheum Dis. 2012;71(10):1623–9. the ASAS/EULAR management recommendations in ankylosing spondylitis. 75. Jeong H, Eun YH, Kim IY, Park EJ, Kim H, Lee J, et al. Effect of tumor necrosis Ann Rheum Dis. 2006;65(4):423–32. factor alpha inhibitors on spinal radiographic progression in patients with 57. Coates LC, Kavanaugh A, Mease PJ, Soriano ER, Laura Acosta-Felquer M, ankylosing spondylitis. Int J Rheum Dis. 2018;21(5):1098–105. Armstrong AW, et al. Group for Research and Assessment of Psoriasis and 76. Molnar C, Scherer A, Baraliakos X, de Hooge M, Micheroli R, Exer P, et al. Psoriatic Arthritis 2015 Treatment Recommendations for Psoriatic Arthritis. TNF blockers inhibit spinal radiographic progression in ankylosing Arthritis Rheum. 2016;68(5):1060–71. spondylitis by reducing disease activity: results from the Swiss Clinical 58. Gossec L, Smolen JS, Ramiro S, de Wit M, Cutolo M, Dougados M, et al. Quality Management cohort. Ann Rheum Dis. 2018;77(1):63–9. European League Against Rheumatism (EULAR) recommendations for the 77. Louie GH, Ward MM. Measurement and treatment of radiographic management of psoriatic arthritis with pharmacological therapies: 2015 progression in ankylosing spondylitis: lessons learned from observational update. Ann Rheum Dis. 2016;75(3):499–510. studies and clinical trials. Curr Opin Rheumatol. 2014;26(2):145–50. 59. Sieper J, Lenaerts J, Wollenhaupt J, Rudwaleit M, Mazurov VI, Myasoutova L, 78. Tannenbaum H, DeCoteau WE, Esdaile JM. A double blind multicenter trial et al. Efficacy and safety of infliximab plus naproxen versus naproxen alone in comparing piroxicam and indomethacin in ankylosing spondylitis with patients with early, active axial spondyloarthritis: results from the double-blind, long-term follow-up. Curr Therapeut Res - Clin Exp. 1984;36(3):426–35. placebo-controlled INFAST study, Part 1. Ann Rheum Dis. 2014;73(1):101–7. 79. Astorga G. Double-blind, parallel clinical trial of tenoxicam (Ro 12–0068) 60. Sieper J, Lenaerts J, Wollenhaupt J, Rudwaleit M, Mazurov VI, Myasoutova L, versus piroxicam in patients with ankylosing spondylitis. Eur J Rheumatol et al. Maintenance of biologic-free remission with naproxen or no Inflamm. 1987;9(2):70–3. treatment in patients with early, active axial spondyloarthritis: results from a 80. Caldwell JR, Altman RD, Burch FX, Calin A. Treatment of ankylosing 6-month, randomised, open-label follow-up study, INFAST Part 2. Ann spondylitis with oxaprozin: a comparison with indomethacin. Semin Arthritis Rheum Dis. 2014;73(1):108–13. Rheum. 1986;15(3, Supplement 2):95–100. 61. Barkham N, Keen HI, Coates LC, O'Connor P, Hensor E, Fraser AD, et al. 81. Calin A, Britton M. Sulindac in ankylosing spondylitis. Double-blind Clinical and imaging efficacy of infliximab in HLA-B27-Positive patients with evaluation of sulindac and indomethacin. JAMA. 1979;242(17):1885–6. magnetic resonance imaging-determined early sacroiliitis. Arthritis Rheum. 82. Heinrichs KK. Treatment of spondylitis ankylosans: controlled comparative 2009;60(4):946–54. study with tiaprofenic acid and diclofenac. Med Klin. 1985;80(21):597–601. Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 21 of 21 83. Khan MA. Diclofenac in the treatment of ankylosing spondylitis: review of 107. Liew JW, Ramiro S, Gensler LS. Cardiovascular morbidity and mortality in worldwide clinical experience and report of a double-blind comparison ankylosing spondylitis and psoriatic arthritis. Best Pract Res Clin Rheumatol. with indomethacin. Semin Arthritis Rheum. 1985;15(2 Suppl 1):80–4. 2018;32(3):369–89. 84. Lomen PL, Turner LF, Lamborn KR, Brinn EL. Flurbiprofen in the treatment of 108. Fosbol EL, Gislason GH, Jacobsen S, Folke F, Hansen ML, Schramm TK, et al. ankylosing spondylitis. a comparison with indomethacin. Am J Med. 1986; Risk of myocardial infarction and death associated with the use of 80(3A):127–32. nonsteroidal anti-inflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther. 2009;85(2):190–7. 85. Lomen PL, Turner LF, Lamborn KR, Brinn EL, Sattler LP. Flurbiprofen in the 109. Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, treatment of ankylosing spondylitis. A comparison with phenylbutazone. et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: Am J Med. 1986;80(3A):120–6. network meta-analysis. Bmj. 2011;342:c7086. 86. Batlle-Gualda E, Figueroa M, Ivorra J, Raber A. The efficacy and tolerability of 110. Gislason GH, Jacobsen S, Rasmussen JN, Rasmussen S, Buch P, Friberg J, aceclofenac in the treatment of patients with ankylosing spondylitis: a et al. Risk of death or reinfarction associated with the use of selective multicenter controlled clinical trial. Aceclofenac Indomethacin Study Group. cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory J Rheumatol. 1996;23(7):1200–6. drugs after acute myocardial infarction. Circulation. 2006;113(25):2906–13. 87. Mena HR, Good AE. Management of ankylosing spondylitis with flurbiprofen 111. Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, or indomethacin. South Med J. 1977;70(8):945–7. et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after 88. Nissila M, Kajander A. Proquazone (Biarison) and indomethacin (Indocid) in cardiac surgery. N Engl J Med. 2005;352(11):1081–91. the treatment of ankylosing spondylitis. Two comparative, clinical, double- 112. Dubreuil M, Louie-Gao Q, Peloquin CE, Choi HK, Zhang Y, Neogi T. Risk of blind studies. Scand J Rheumatol Suppl. 1978;7(21):36–9. myocardial infarction with use of selected non-steroidal anti-inflammatory 89. Palferman TG, Webley M. A comparative study of nabumetone and drugs in patients with spondyloarthritis and osteoarthritis. Ann Rheum Dis. indomethacin in ankylosing spondylitis. Eur J Rheumatol Inflamm. 1991; 2018;77(8):1137–42. 11(2):23–9. 113. Winkelmayer WC, Waikar SS, Mogun H, Solomon DH. Nonselective and 90. Pasero G, Ruju G, Marcolongo R, Senesi M, Seni U, Mannoni A, Mannoni A, cyclooxygenase-2-selective NSAIDs and acute kidney injury. Am J Med. et al. Aceclofenac versus naproxen in the treatment of ankylosing 2008;121(12):1092–8. spondylitis: A double-blind, controlled study. Curr Therapeut Res - Clin Exp. 114. Ungprasert P, Cheungpasitporn W, Crowson CS, Matteson EL. Individual 1994;55(7):833–42. non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A 91. Rejholec V, Vapaatalo H, Tokola O, Gothoni G. Tolfenamic acid in ankylosing systematic review and meta-analysis of observational studies. Eur J Intern spondylarthritis: a double-blind comparison to indomethacin. Scand J Med. 2015;26(4):285–91. Rheumatol Suppl. 1980;36:1–7. 115. Gooch K, Culleton BF, Manns BJ, Zhang J, Alfonso H, Tonelli M, et al. NSAID 92. Franssen MJ, Gribnau FW, van de Putte LB. A comparison of diflunisal and use and progression of chronic kidney disease. Am J Med. 2007;120(3):280 phenylbutazone in the treatment of ankylosing spondylitis. Clin Rheumatol. e1–7. 1986;5(2):210–20. 116. Cao YL, Tian ZG, Wang F, Li WG, Cheng DY, Yang YF, et al. Characteristics 93. Jessop JD. Double-blind study of ketoprofen and phenylbutazone in and clinical outcome of nonsteroidal anti-inflammatory drug-induced acute ankylosing spondylitis. Rheumatol Rehabil. 1976;15(Suppl 5):37–42. hepato-nephrotoxicity among Chinese patients. World J Gastroenterol. 2014; 94. Schwarzer AC, Cohen M, Arnold MH, Kelly D, McNaught P, Brooks PM. 20(38):13956–65. Tenoxicam compared with diclofenac in patients with ankylosing spondylitis. Curr Med Res Opin. 1990;11(10):648–53. 95. Simpson MR, Simpson NR, Scott BO, Beatty DC. A controlled study of Publisher’sNote flufenamic acid in ankylosing spondylitis. A preliminary report. Ann Phys Springer Nature remains neutral with regard to jurisdictional claims in Med. 1966;8(Suppl 1):126–8. published maps and institutional affiliations. 96. Myklebust G. Comparison of naproxen and piroxicam in rheumatoid arthritis and Bechterew's syndrome. A double-blind parallel multicenter study. Tidsskr Nor Laegeforen. 1986;106(17–18):1485–7. 97. Nahir AM, Scharf Y. A comparative study of diclofenac and sulindac in ankylosing spondylitis. Rheumatol Rehabil. 1980;19(3):193–8. 98. Santo JE, Queiroz MV. Oxaprozin versus diclofenac sodium in the treatment of ankylosing spondylitis. J Int Med Res. 1988;16(2):150–6. 99. Ansell BM. A comparative study of Butacote and naproxen in ankylosing spondylitis. J Int Med Res. 1977;5(Suppl 2):95. 100. Coxib, traditional NTC, Bhala N, Emberson J, Merhi A, Abramson S, et al. Vascular and upper gastrointestinal effects of non-steroidal anti- inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769–79. 101. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti- inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. Bmj. 2006;332(7553):1302–8. 102. Lanas A, Boers M, Nuevo J. Gastrointestinal events in at-risk patients starting non-steroidal anti-inflammatory drugs (NSAIDs) for rheumatic diseases: the EVIDENCE study of European routine practice. Ann Rheum Dis. 2015;74(4): 675–81. 103. Poddubnyy D, van der Heijde D. Therapeutic controversies in spondyloarthritis: nonsteroidal anti-inflammatory drugs. Rheum Dis Clin North Am. 2012;38(3):601–11. 104. Bakland G, Gran JT, Nossent JC. Increased mortality in ankylosing spondylitis is related to disease activity. Ann Rheum Dis. 2011;70(11):1921–5. 105. Haroon NN, Paterson JM, Li P, Inman RD, Haroon N. Patients with ankylosing spondylitis have increased cardiovascular and cerebrovascular mortality: a population-based study. Ann Intern Med. 2015;163(6):409–16. 106. Lehtinen K. Mortality and causes of death in 398 patients admitted to hospital with ankylosing spondylitis. Ann Rheum Dis. 1993;52(3):174–6. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Advances in Rheumatology Springer Journals

Loading next page...
 
/lp/springer-journals/brazilian-recommendations-for-the-use-of-nonsteroidal-anti-SwA00Afei8

References (122)

Publisher
Springer Journals
Copyright
Copyright © The Author(s) 2021
eISSN
2523-3106
DOI
10.1186/s42358-020-00160-6
Publisher site
See Article on Publisher Site

Abstract

Spondyloarthritis (SpA) is a group of chronic inflammatory systemic diseases characterized by axial and/or peripheral joints inflammation, as well as extra-articular manifestations. Over some decades, nonsteroidal anti-inflammatory drugs (NSAIDs) have been the basis for the pharmacological treatment of patients with axial spondyloarthritis (axSpA). However, the emergence of the immunobiologic agents brought up the discussion about the role of NSAIDs in the management of these patients. The objective of this guideline is to provide recommendations for the use of NSAIDs for the treatment of axSpA. A panel of experts from the Brazilian Society of Rheumatology conducted a systematic review and meta-analysis of randomized clinical trials for 15 predefined questions. The Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations were used, and at least 70% agreement of the voting panel was needed. Fourteen recommendations for the use of NSAIDs in the treatment of patients with axSpA were elaborated. The purpose of these recommendations is to support clinicians’ decision making, without taking out his/her autonomy when prescribing for an individual patient. Keywords: Spondyloarthritis, Ankylosing spondylitis, Nonsteroidal anti-inflammatory drugs, Systematic review, Meta-analysis, Guidelines * Correspondence: ricolage@gmail.com Universidade Federal de Minas Gerais (UFMG), Alameda Álvaro Celso 175, Ambulatório Bias Fortes, 2° andar, Belo Horizonte, MG 30150-260, Brazil Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 2 of 21 Background Methodology Spondyloarthritis (SpA) is a set of diseases that cause in- Study design flammation of the spine and peripheral joints and may This guideline was conducted in two phases. In the first have extra-articular manifestations, such as anterior uve- phase, a systematic review and meta-analysis of random- itis, psoriasis, and inflammatory bowel disease. The main ized clinical trials (RCTs) were performed. In the second manifestation of SpA is the involvement of the entheses, phase, an expert panel answered predefined questions attachment sites of the tendons, capsules, and ligaments and developed the recommendations. to the bones, especially Achilles’ tendon and plantar fascia. Frequently, axSpA patients have a genetic predis- Systematic review and meta-analysis position linked to human leukocyte antigen (HLA)-B27 Inclusion criteria and are usually seronegative for rheumatoid factor. The We included RCTs, systematic reviews, and meta- set of diseases consists of ankylosing spondylitis (AS), analyses that have evaluated the efficacy and safety of psoriatic arthritis, reactive arthritis, enteropathic arthritis NSAIDs, as monotherapy or in combination with TNFi and undifferentiated spondyloarthritis. Axial spondyloar- or IL17i, in patients older than 18 years of age with thritis (axSpA) is defined as all cases involving the spine axSpA. and/or sacroiliac joints, and peripheral spondyloarthritis is defined as cases involving only peripheral joints and/ or peripheral entheses. When the same patient has both Exclusion criteria types of conditions, he/she should be classified by the Non-randomized comparative studies, non-comparative predominant segment (predominantly axial involvement studies, studies published only as conference abstracts, or predominantly peripheral involvement) [1–4]. narrative reviews, animal studies, in vitro studies were AxSpA comprises the so-called radiographic form or excluded. Additionally, studies that evaluated the efficacy AS, which includes patients who present sacroiliitis on and safety of NSAIDs in populations with peripheral simple radiography according to the modified New York spondyloarthritis (psoriatic arthritis, reactive arthritis, in- criteria, and non-radiographic axial spondyloarthritis flammatory bowel disease) or rheumatoid arthritis were (nr-axSpA), which is diagnosed according to the pres- excluded. ence of HLA-B27 (clinical arm) or positive sacroiliac MRI (imaging arm), according to the 2009 Assessment Definition of therapeutic intervention in Ankylosing Spondylitis (ASAS) classification criteria Studies that evaluated intervention with NSAIDs as a [1–4]. Although there is currently no consensus, the pre- class (total or selective and nonselective COX-2 inhibi- vailing opinion is that axSpA is a single disease in which tors), as well as studies that evaluated NSAID-specific 20–30% of patients with nr-axSpA can develop radio- molecules alone or in combination with TNFi or IL17i graphic changes over time (5 to 10 years) [5]. In fact, were considered. radiographic sacroiliitis artificially splits the axSpA spectrum into two groups, and it is unlikely that its pres- ence alone is critical to the outcome [6]. Thus, the Definition of controls present recommendations will address axSpA as a single The included studies that evaluated the efficacy and entity and combine all relevant data, since most of the safety of NSAIDs were compared to placebo or active available studies included patients with the radiographic treatment. form. Over some decades, nonsteroidal anti-inflammatory Efficacy outcomes drugs (NSAIDs) have been the basis for the pharmaco- The outcomes used are shown in the Suplemmentary logical treatment of axSpA. However, with the emer- Material and included parameters of disease activity, gence of biological agents which have brought great functionality, and progression of axial and peripheral benefit to patients with axSpA, the discussion about the damage. Not all outcomes were reported in all compari- role of NSAIDs, as well as its cost/effectiveness and sons, although most outcomes were included in each of safety has gained attention. them. Recently, the Brazilian Society of Rheumatology has published evidence based recommendations for the diag- nosis and management of axSpA [7]. Our main goal in Safety outcomes the present guideline was to specifically evaluate the role Any adverse events were considered, regardless of sever- of NSAIDs for treating axSpA patients through a sys- ity, causal relationship, and resolution, including renal, tematic review with meta-analysis and critical analysis of cardiovascular, gastrointestinal, neurological, dermato- the published scientific data. logic, hematologic and hepatic events. Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 3 of 21 Data sources Meta-analyses The search was conducted in the electronic databases Meta-analyses were performed for outcomes commonly MEDLINE (via PubMed), EMBASE, and the Cochrane reported by at least two studies. Their results are pre- Library. In addition, ongoing studies were searched in sented in the form of forest plots and are described in the Clinical Trials.gov and World Health Organization the text. Outcomes reported by only one study were also (WHO) trial registration databases. We searched for presented in graphical form (Supplementary Material). other potential studies not retrieved by the search strat- egies by checking the reference list of each eligible study, Measures of association as well as in the electronic databases Health Technology For dichotomous variables, the measure of association Assessment (HTA), Database of Abstracts of Reviews of used was relative risk (RR) with its respective 95% confi- Effects (DARE), and National Institute for Health and dence interval (CI). For continuous variables, the meas- Care Excellence (NICE), in addition to the guidelines of ure of association used was the mean difference (MD) specialty societies. with its respective 95% CI. If the studies evaluated the Search strategies, eligibility assessment, data extraction same outcome, but using different scales, the measure of and risk of bias assessment are shown in the Supplemen- association used was the standardized mean difference tary Material. (SMD) with its respective 95% CI. Statistical methods References eligible for meta-analyses For the outcomes of dichotomous variables, the method Through the search strategies reported above, 1915 ref- used for the meta-analysis was the Mantel-Haenszel erences were retrieved (369 in Medline, 1532 in method. For the outcomes of continuous variables, the EMBASE, and 14 in the Cochrane Library) that were method used for the meta-analysis was the inverse- published from January 1, 2014 until May 31, 2018 (up- variance weighting. date date since the review by Kroon et al., 2015) [8]. After removing duplicates, 1698 references were evalu- Analytical model ated by reading titles and abstracts, of which 1666 were The random-effects model was used when the statistical excluded. Thus, 32 references were evaluated by reading heterogeneity was significant by the Cochrane chi- their complete texts. At this stage, 29 references were squared test (p< 0.1). However, if the statistical hetero- excluded: 18 according to the type of study [9–26] (non- geneity was not significant but was moderate or high comparative studies; observational, single-arm studies; (I ≥30%), the results are presented according to the systematic reviews without meta-analysis or with over- random-effects model. In cases of mild statistical hetero- lapping studies; language other than Portuguese, English, geneity (I < 30%) or lack of statistical heterogeneity, the or Spanish; and abstracts); eight according to the type of fixed-effects model was preferably used to add greater intervention [27–34] (drugs not registered in the country weight to the estimates from studies with larger sample and anti-inflammatory agents other than NSAIDs); two sizes. according to the type of outcome [35, 36] (indirect/in- complete analyses, ineligible outcome); and one accord- ing to the type of population [37] (not AS and not Heterogeneity spondyloarthritis). Thus, three RCTs [38–40] were con- In cases of statistical heterogeneity, such heterogeneity sidered eligible. In addition, through the search of the was explored based on 2 strategies: the clinical- reference list of the studies evaluated, one RCT was demographic differences of the participants among stud- manually included [41]. Therefore, four new eligible ref- ies or study design differences and subgroup analyses. erences were added to those previously analyzed by Some subgroup analyses were defined in advance be- Kroon et al. (2015) [8]. cause they were of clinical interest. These subgroup divi- Also, additional searches were performed into Clinical- sions were present or absent HLA-B27, normal or Trials.gov and WHO International Clinical Trials Regis- elevated C-reactive protein (CRP), normal or elevated try Platform databases. At ClinicalTrials.gov, 19 records erythrocyte sedimentation rate (ESR), present or absent were found, of which 17 reported no results. The two syndesmophyte, and male or female sex. trials with available data, presented results before the re- The description of each included RCT, the risk of bias view of Kroon et al. [8], they were not eligible. In the analyses, the evaluation of the quality of the evidence ac- WHO International Clinical Trials Registry Platform, 18 cording to Grading of Recommendations Assessment, reports of 15 RCT registrations were found. However, as Development and Evaluation (GRADE) [42, 43] and the they did not have available results, they were not in- meta-analyses with all the forest plots are available in cluded in this meta-analysis (Fig. 1). the Supplementary Material. Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 4 of 21 Fig. 1 PRISMA flowchart of selection and eligibility of the studies included in the systematic review (SR) Development of recommendations consequences of alternative management strategies, A panel of 28 rheumatologists with expertise in SpA quality of evidence, variability in values and prefer- elaborated 15 questions divided into 6 sections: efficacy ences, and resource use. Strong recommendations and effect size, window of opportunity and treatment mean that most informed patients would choose the strategy, continuous or on demand use, radiographic recommended management and that clinicians can progression, comparison of different NSAIDs, safety and structure their interactions with patients accordingly. adverse reactions. Regarding not answered questions ac- Weak or conditional recommendations mean that pa- cording to the current evidence, the data from individual tients’ choices will vary according to their values and RCTs were reported. If necessary, a manual search for preferences, and clinicians must ensure that patients’ available evidences, including observational studies, was care is in keeping with their values and preferences. performed to support the recommendations. There was The quality of evidence was assessed using GRADE a hierarchic and standardized sequence to report avail- for predefined key outcomes (Supplementary Material) able evidence: meta-analysis, individual RCTs, and finally [42, 43]. observational studies. Observational studies were always The degree of expert agreement (inter-rater reliability) reported as very low-quality evidence and supported was determined by the Delphi method through an online conditional recommendations. anonymous survey, and a minimum 70% agreement was These recommendations followed the GRADE meth- needed for each recommendation. odology. Strength of recommendation was determined Table 1 summarizes the Brazilian recommendations by the balance between desirable and undesirable for the use of NSAIDs in patients with axSpA. Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 5 of 21 Table 1 Brazilian recommendations for the use of nonsteroidal anti-inflammatory drugs in patients with axial spondyloarthritis Recommendations QoE DoA 1. EFFICACY Recommendation 1. In patients with active axSpA, we strongly recommend treatment with NSAIDs over no low 9.8 treatment, because they are effective for mitigating disease activity measures and improving functional status. Recommendation 2. In patients with persistent active axSpA, we strongly recommend long-term over short-term low 9.3 use of NSAIDs, because they exhibit sustained symptomatic efficacy. We conditionally recommend that disease ac- tivity and adverse events should be regularly monitored, evaluating long-term risks versus benefits. Recommendation 3. In patients with active axSpA, we conditionally recommend treatment with NSAIDs over no very low 8.8 treatment for alleviate symptoms of peripheral arthritis and enthesitis, since few data have shown moderate efficacy in these clinical manifestations. 2. WINDOW OF OPPORTUNITY AND TREATMENT STRATEGY Recommendation 4. In patients with active axSpA, we strongly recommend NSAIDs as the first-line treatment over low 8.6 an immunobiologic agent, considering its low cost and satisfactory efficacy. The benefit of starting an immunobiolo- gic agent in NSAIDs-naïve patients, even in those with poor prognostic criteria, is not proven. Recommendation 5. In patients with active axSpA, we strongly recommend to immediately start a NSAID after the very low 8.8 diagnosis because early treatment may increase the response rate. Recommendation 6. In patients with active axSpA, we strongly recommend to initiate NSAIDs at full dosage over low 9.4 low dosage, because they exhibit a tendency for greater efficacy in achieving ASAS 20, reduction of morning stiffness, BASDAI, pain, patient global assessment of disease activity, and BASFI. We conditionally recommend that the full dosages of NSAIDs should be maintained, with adequate monitoring, until good disease control is achieved. Recommendation 7. In patients with active axSpA, in the absence of a response to the first NSAID at 4 weeks, we low to high 8.6 conditionally recommend switching to a second traditional NSAID or iCOX2. If the therapeutic target is not reached with the use of NSAIDs for 12 weeks, we strongly recommend to start an immunobiologic agent. 3. CONTINUOUS OR ON-DEMAND USE Recommendation 8. In patients with active axSpA, we conditionally recommend to start continuous over on- very low to moderate 9.4 demand NSAIDs until symptoms relief is achieved. After clinical improvement or the clinical target (low disease ac- tivity or remission) has been achieved, the full dosage can be reduced or switched to on-demand strategy. Before prescribing continuous NSAIDs, it is important to take into account: the patient’s opinion, comorbidities and risk factors. 4. RADIOGRAPHIC PROGRESSION Recommendation 9. Regarding radiographic progression, in patients with active axSpA, we conditionally Very low 8.2 recommend continuous over on demand use of NSAIDs. Considering controversial results among the studies, we conditionally recommend switching to on demand strategy in inactive disease. We conditionally recommend against switching NSAIDs to immunobiological therapy when there is radiographic progression without evidence of disease activity, because the risk/benefit ratio of starting an immunobiologic agent in this scenario is not clear. 5. COMPARISON AMONG NSAIDs Recommendation 10. In patients with active axSpA, we conditionally recommend that the choice of specific NSAI low 9.6 D should be based on patient’s profile (age, prior toxicity, comorbidities) and on shared decision making. To date, there is no consistent evidence of efficacy and safety differences among the NSAIDs (non-selective or iCOX2) in axSpA. 6. SAFETY AND ADVERSE REACTIONS Recommendation 11. Regarding safety, in patients with active axSpA, we strongly recommend treatment with low 9.0 NSAIDs over no treatment, because the available evidence showed an overall good safety profile of these drugs in axSpA. We conditionally recommend that NSAIDS should be used with caution in individuals with risk factors (age > 65 years, diabetes mellitus, use of aspirin, corticosteroids and other platelet antiaggregants, renal or liver diseases). The risks and benefits of starting them should be shared and individualized according to the patient’s risk profile. Gastrointestinal Recommendation 12. In patients with active axSpA, we conditionally recommend to avoid NSAIDs (non-selective low 8.9 or iCOX2) and to start an immunobiologic agent in those with current or previous peptic ulcer or gastrointestinal bleeding. We conditionally recommend the use of an iCOX2 agent over a traditional NSAID in patients with gastrointestinal risk factors. We strongly recommend the use of concomitant gastroprotective drugs in symptomatic or high-risk patients. Cardiovascular Recommendation 13. In patients with active axSpA, we conditionally recommend to avoid NSAID therapy and to very low (observational 8.4 start an immunobiologic agent in those with cardiovascular risk factors, mainly in those with previous acute studies) myocardial infarction or stroke, especially if recent (past 12 months). Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 6 of 21 Table 1 Brazilian recommendations for the use of nonsteroidal anti-inflammatory drugs in patients with axial spondyloarthritis (Continued) Recommendations QoE DoA Renal Recommendation 14. In patients with active axSpA, we conditionally recommend to avoid NSAIDs and to start an very low (observa-tional 9.4 immunobiologic agent in thoses with increased risk of renal adverse events. The decision should be individualized studies) and risk/benefits shared with the patient. We strongly recommend caution and regular monitoring of renal function, especially in high-risk individuals (elderly, hypertension, diabetes, kidney dysfunction). NSAIDs nonsteroidal anti-inflammatory drugs, iCOX2 selective COX-2 inhibitor, axSpA axial spondyloarthritis, QoE quality of evidence, DoA degree of agreement Recommendations placebo: 3%, RR: 4.65 (1.39 to 15.55)] [48]. Fig. 2 shows Efficacy and effect size the subgroup analysis for pain VAS by comparing trad- Are NSAIDs effective for treating patients with axSpA? itional NSAIDs, iCOX2, or both versus placebo. Five RCTs evaluated the efficacy of conventional NSAI Ds, and three evaluated cyclooxygenase 2-selective in- Recommendation 1 In patients with active axSpA, we strongly recommend treatment with hibitors (iCOX2) compared to placebo. A total of 2002 NSAIDs over no treatment, because they are effective for mitigating patients with active AS, with a mean age between 40 and disease activity measures and improving functional status. Quality of 45 years and a predominance of men (60%), were in- evidence: low; Degree of agreement: 9.8 cluded in these studies and were followed up for 2 to 52 weeks [44–48]. There was a superiority of traditional NSAIDs over placebo for the following outcomes: pain by VAS (0– Do NSAIDS have sustained symptomatic efficacy in axSpA? 100 mm), patient global assessment (PGA) of disease ac- Most RCTs that evaluated the efficacy of NSAIDs, tivity by VAS (0–100 mm), duration of morning stiffness compared to both placebo and other NSAIDs, had a in minutes, C-reactive protein concentration, at least short duration (8 to 12 weeks) [13, 29, 31, 38, 40, 44, 47, 20% improvement according to the ASAS group re- 49–53]. In two long-term RCTs involving patients with sponse criteria (ASAS 20), at least 50% improvement in AS, the sustained efficacy of NSAIDs was shown in 12 pain, and the Bath Ankylosing Spondylitis Function months. Van der Heijde et al. found an ASAS20 re- Index (BASFI) (Table 2). sponse of 52.5% with naproxen and 65% with etoricoxib Regarding iCOX2, the meta-analyses showed superior- compared to 20% in placebo group. The 1-year mainten- ity over placebo in the following outcomes: pain VAS, ance rate was 90% with etoricoxib and 79% with na- PGA, ASAS 20, and BASFI (Table 2). Individual studies proxen [48]. In another RCT, Dougados et al. evaluated showed superiority of iCOX2 over placebo in the Bath the efficacy of NSAIDs in 473 patients with short- and Ankylosing Spondylitis Disease Activity Index (BASDAI) long-term AS. At 6 weeks, 43, 50, and 47% of patients [− 2.2 (− 2.74 to − 1.66)] [48], at least 50% improvement who received 20 mg of piroxicam, 15 mg of meloxicam, in pain [iCOX2: 47.5% vs placebo: 20%, RR: 2.41 (1.45 to or 22.5 mg of meloxicam, respectively, had ≥ 50% im- 4.00)] [45], and ASAS partial remission [iCOX2: 15% vs provement in PGA, compared to 21% for the placebo, Table 2 Efficacy of traditional NSAIDs or iCOX2 vs. placebo in patients with axial spondyloarthritis: meta-analyses of randomized clinical trials TRADITIONAL NSAIDs iCOX2 n=1289 n=669 PAIN VAS (95% CI) −16.75 (−20.28 to −13.07) −21.68 (−35.94 to −7.42) PGA −17.75 (−24.39 to −11.10) −20.82 (− 39.88 to −11.75) ASAS20 60% vs. 23% (PbO) 57% vs. 20% (PbO) RR=2.49 (1.94 to 3.19) RR=2.51 (1.66 to 3.79) BASFI −9(− 13 to −5) −13.4 (− 17.3 to −5) MS - SMD −0.4 (−0.58 to −0.22) NA CRP mg/L −3.37 (−6.11 to − 0.62) NA PAIN50% 48% vs 21% NA 2.25 (1.75 to 2.89) NSAIDs nonsteroidal anti-inflammatory drugs, iCOX2 COX-2-selective inhibitors, PAIN VAS pain by visual analog scale 0–100 mm, PGA Patient Global Assessment 0– 100 mm, BASFI Bath Ankylosing Spondylitis Function Index 0–100 mm, MS-SMD standardized mean difference in the duration of morning stiffness, CRP C-reactive protein, PAIN50% ≥ 50% improvement in pain, RR relative risk, PbO placebo, N/A meta-analysis not feasible Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 7 of 21 Fig. 2 Spinal pain by visual analogue scale (VAS 0–100 mm): analysis of subgroups of four randomized clinical trials of patients with ankylosing spondylitis (n=1199). Meta-analyses comparing traditional NSAIDs versus placebo, selective COX-2 inhibitors versus placebo, and both NSAID subtypes versus placebo. Subtitle: (1) Ximoprofen 30 mg vs placebo. (2) Meloxicam 15 mg vs placebo. (3) Piroxicam 20 mg vs placebo. (4) Ketoprofen 200 mg vs placebo. (5) Naproxen 1000 mg vs placebo. (6) Celecoxib 200 mg vs placebo. (7) Etoricoxib 90 mg vs placebo with sustained response at 12 months. The discontinu- ation rate due to lack/ loss of efficacy was between 10 Recommendation 2 In patients with persistent active axSpA, we strongly recommend long- and 20%. Only 16% of the responders at 6 weeks had a term over short-term use of NSAIDs, because they exhibit sustained 1-year loss of response [46]. symptomatic efficacy. We conditionally recommend that disease activity In a German population-based cohort, almost 80% of 1080 and adverse events should be regularly monitored, evaluating long-term risks versus benefits. patients with AS were on NSAIDs, of whom 71% had been Quality of evidence: low; Degree of agreement: 9.3 taking it for more than 4 years. The NSAIDs were effective for complete or partial resolution (> 50%) of pain in 19.1 and 61.2% of patients, respectively [54]. In a Swedish cohort, 21, 108 patients with AS were analyzed for 3 years. Approxi- Are NSAIDs effective for treating the peripheral mately 80% of patients used iCOX2, and 63.8% used non- manifestations of axSpA? selective NSAIDs for more than 50% of the follow-up time, Four of the five RCTs of NSAIDs versus placebo did not with a good initial response rate as well as a good response evaluate the efficacy of these drugs on peripheral arthritis or rate over time [17]. In the Netherlands, Carbo et al. followed enthesitis in axSpA. One RCT compared the effect of up 393 patients with AS who were anti-TNF naïve, of whom ximoprofen on peripheral arthritis at several doses with 254 were prescribed some TNF inhibitors (BASDAI=6.1 and placebo as secondary outcome, and there was a significant ASDAS=3.8), while 139 were kept under conventional treat- improvement in peripheral arthritis with a moderate effect ment (BASDAI=3.9 and ASDAS=2.4; 74% with NSAIDs). size (standardized mean difference, SMD=0.62 [95%CI: 0.26 After 12 months of follow-up, both groups had similar activ- to 0.97]) [47, 56]. From the three trials that assessed iCOX2 ity scores (BASDAI=3.4 and ASDAS=2.2 vs. BASDAI=3.7 versus placebo, two of them excluded patients with and ASDAS=2.3, respectively). Among patients who received peripheral manifestations. A post-hoc analysis of a study of conventional treatment, 82% maintained a sustained re- etoricoxib and naproxen versus placebo in axSpA suggested sponse with NSAIDs after 52 weeks [55]. Despite being ob- NSAIDs were effective for treating peripheral arthritis, as servational studies whose primary objective was not to assessed by question 3 of BASDAI, with an improvement on evaluate the response to treatment, the high rate of drug re- the VAS 0–100 mm of − 16.4 (− 20.3 to − 12. 6) compared tention observed over time suggested a sustained efficacy of to 0.9 (− 5.9 to 7.6) for placebo, as well as in enthesitis NSAIDs. (question 4 of BASDAI), with a shift of − 21.3 (− 25.2 to − Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 8 of 21 17.5) with NSAID versus − 6.5 (− 13.3 to 0.4) with placebo originated from a small sample size [62]. In addition, early in patients with concomitant peripheral arthritis, and of − starting of the NSAID led to a highly significant ASAS partial 27.6 (− 30.8 to − 24.5) versus − 7.3 (− 12.9 to − 1.8) in those remission rate (35%) [59]. without concomitant peripheral arthritis [48, 50]. Considering the low cost, long term experience, and The effect of NSAIDs on enthesitis was not specifically satisfactory response in early disease showed in the evaluated in RCTs of patients with axSpA. The current INFAST trial [59], the expert panel stated that NSAIDs recommendations suggest that they are effective in a should still be the first-line treatment in axSpA. subsample of patients, but that conclusion was extrapolated from studies on psoriatic arthritis or based Recommendation 4 In patients with active axSpA, we strongly recommend NSAIDs as the on expert opinions [57, 58]. first-line treatment over an immunobiologic agent, considering its low cost and satisfactory efficacy. To date, the benefit of starting an immu- Recommendation 3 nobiologic agent in NSAIDs-naïve patients, even in those with poor In patients with active axSpA, we conditionally recommend treatment prognostic criteria, is not proven. Quality of evidence: low; Degree of with NSAIDs over no treatment to alleviate symptoms of peripheral agreement: 8.6 arthritis and enthesitis, since few data have shown moderate efficacy in these clinical manifestations. Quality of evidence: very low; Degree of agreement: 8.8 Should NSAIDs be started immediately after the diagnosis of axSpA? Several studies suggest that the response rates are higher Window of opportunity and treatment strategy with an earlier onset of treatment [39, 63–65]. In the Should NSAIDs be considered first-line treatment in axSpA? INFAST study [59], approximately 35% of patients with In the INFAST study, 158 patients with axSpA were very early (< 2 years of disease on average) axSpA (AS + randomized to receive infliximab + naproxen or placebo + nr-axSpA) achieved ASAS partial remission with na- naproxen for 28 weeks. The interesting aspect of this proxen versus 9% with placebo (only 15% of patients study was that the patients were not refractory to NSAI with AS, with longer disease duration, had achieved this Ds, as in other immunobiologic RCTs (they were NSAID target with etoricoxib in the study by van der Heijde naïve or used low dose of NSAIDs). At week 28, 62% of et al) [48]. Barkham et al. achieved 56% ASAS partial re- the Infliximab + naproxen group had ASAS partial mission with infliximab in patients with early axSpA remission versus 35% of the placebo + naproxen group (average of 1 year and 3 months of symptom duration) [59]. Later, infliximab was discontinued, and patients who compared to 22% in the pivotal study of infliximab [61]. achieved remission were monitored until week 52 under Other RCTs found a 70 to 75% ASAS40 response rate continuous naproxen use or no treatment. A similar after TNF inhibitors in patients with axSpA and disease percentage maintained remission in both the group using duration below 3 years, compared to around 40–45% of naproxen (47.5%) and the group without any treatment ASAS40 response rate in those with established AS [59, (40%) and independent of the initial therapeutic regimen, 66, 67]. Haroon et al. reinforced the importance of early despite small sample for the latter analysis. The response treatment by demonstrating that the delay in the onset rate was higher with anti-TNF, but NSAIDs (with placebo) of anti-TNF treatment increases the rate of radiographic led to remission in more than 1/3 of the cases [60]. progression [68]. These results reinforce the idea of a In an open-label follow-up study, 39 of the 40 patients with “window of opportunity” during the treatment of axSpA very early axSpA from the RCT conducted by Barkham et al and the importance of effective early onset treatment. [61] (who had received infliximab or placebo for 16 weeks) Despite the few available data, the panelists considered were monitored for 5 years. There was no difference in important to immediately start an NSAID as soon as the current disease activity or radiographic progression by diagnosis of axSpA is confirmed. mSASSS among participants receiving infliximab or placebo in the randomized phase. However, approximately 60% (7/ Recommendation 5 12) of patients who initially received infliximab still needed In patients with active axSpA, we strongly recommend to immediately start an NSAID after the diagnosis, because early treatment may increase an anti-TNF after 5 years, while 100% (13/13) of those who the response rate. Quality of evidence: very low; Degree of received placebo remained on anti-TNF treatment [62]. agreement: 8.8 Therearenotavailabledata todefinewhether NSAIDs should remain the first-line treatment in patients with poor prognostic criteria (smokers, with elevated CRP and syndes- When NSAIDs are prescribed for the treatment of patients mophytes on baseline) or whether immunobiologics should with axSpA, should they be used in full dosages or at the be the first choice in these cases. Indeed, the long-term bene- lowest possible dosage for symptomatic control? fit of initiating an immunobiologic agent as first line treat- Six RCTs compared full-dosage versus low-dosage of NSAI ment was not proven, as the data suggesting this benefit Ds in almost 2000 patients with active axial SpA. In two of Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 9 of 21 them the mean disease duration was long (10 to 13 years) treatment of axSpA and the clinical experience, despite [46, 47]. The comparisons were: 1) celecoxib 200 mg x cele- lack of evidence, the panel recommended a second NSAI coxib 400 mg [44, 49]; 2) ximoprofen 5 mg x ximoprofen 30 D, regardless therapeutic class (selective COX-2 or not), mg [47]; 3) meloxicam 15 mg x meloxicam 22.5 mg [46]; 4) could be used if the first one failed after 4 weeks. The total etoricoxib 90 mg x etoricoxib 120 mg [48]; and 5) etoricoxib treatment period with NSAIDs should not exceed 12 60 mg x etoricoxib 90 mg [41]. The meta-analyses showed a weeks, if the predefined target is not achieved [6, 7]. slight superiority of the higher dosages of NSAIDs in redu- cing the duration of morning stiffness [SMD: 0.14 (0.02; Recommendation 7 In patients with active axSpA, in the absence of a response to the first 0.27)] and the proportion of patients who achieved ASAS 20 NSAID at 4 weeks, we conditionally recommend switching to a second [RR: 0.87 (0.77; 0.99)], at the limit of statistical significance. traditional NSAID or iCOX2. If the therapeutic target is not reached with However, there was uncertain risk of bias in four studies [44, the use of NSAIDs for 12 weeks, we strongly recommend to start an immunobiologic agent. Quality of evidence: low to high; Degree of 46, 47, 49]and high risk in onestudy [41]. Regarding the agreement: 8.6 BASDAI and BASFI, the meta-analyses did not demonstrate a significant difference between full- and low-dosage NSAI Ds, but the results of the individual studies were consistent Continuous or on-demand use in favoring higher dosage. Regarding pain outcomes, includ- Is there any significant difference in the reduction of disease ing pain VAS and 50% improvement, CRP serum levels and activity or safety of NSAIDs when comparing the on-demand PGA, thedatawereinconsistent, sometimesfavoringhigh versus continuous use for the treatment of axSpA? doses and other times favoring lower doses of NSAIDs. Only two RCTs compared continuous and on-demand ASAS partial remission [48]and BASMI [49] were reported use of NSAIDs in AS patients. In both studies, the primary in only one RCT each, with no difference between doses. outcome was radiographic progression. Wanders et al. Also, the results of the RCTs cited above should be inter- [69] evaluated celecoxib continuously or on demand in preted with caution, as the 120 mg dose of etoricoxib and 215 patients with AS, and disease activity rates were re- 22.5 mg of meloxicam are not currently in use. ported as a secondary outcome. After 2 years, there was Regarding safety, the meta-analyses showed no differences no significant difference of BASDAI, PGA, overall pain, or among NSAIDs dosages on the occurrence of any adverse C-reactive protein serum levels between two ways of pre- event, serious adverse event, or adverse events per specific scribing NSAIDs. More recently, Sieper et al. evaluated system (cardiovascular, gastrointestinal, neurological, respira- 167 patients with AS and compared the continuous or on- tory, or dermatologic). There was also no difference in the demand use of diclofenac. Although not significant, the proportion of patients who discontinued treatment due to BASDAI decreased from 4.1 to 2.7, in continuous group, unexpected adverse events. Given the low accuracy of the and from 4.2 to 3.2 in on-demand group [70]. Regarding findings, the results were considered inconclusive. adverse events, there was no difference between continu- ous and on-demand use in either study. Recommendation 6 Despite the lack of evidence, the panel recommended In patients with active axSpA, we strongly recommend to initiate NSAI continuous use of NSAIDs in active disease until Ds at full dosage over low dosage, because they exhibit a tendency for greater efficacy in achieving ASAS 20, reduction of morning stiffness, symptoms relief is achieved, based on the previous BASDAI, pain, patient global assessment of disease activity, and BASFI. guidelines and the clinical experience [6, 7, 71]. We conditionally recommend that the full dosages of NSAIDs should be maintained, with adequate monitoring, until good disease control is achieved. Quality of evidence: low; Degree of agreement: 9.4 Recommendation 8 In patients with active axSpA, we conditionally recommend to start continuous over on-demand NSAIDs until symptoms relief is achieved. After clinical improvement or the clinical target (low disease activity or For how long should we wait for initial response to NSAIDs remission) has been achieved, the treatment regimen can be switched in axSpA? to on-demand strategy. Before prescribing continuous NSAIDs, it is im- portant to take into account patient’s opinion, comorbidities and risk The traditional NSAIDs and iCOX2 trials have shown that factors. Quality of evidence: very low to moderate; Degree of agree- pain and stiffness measures differed from placebo in the first ment: 9.4 week and the maximum effect was achieved from 2 to 4 weeks. Themajorityofthe studieshad ashort duration of 2 to 6 weeks [44–48]. The two trials with an extension phase Radiographic progression from 6 to 52 weeks did not show any additional effect size Is there evidence that NSAIDs can delay or minimize the with the use of NSAIDs after 6 weeks [46, 48]. progression of axial damage in axSpA? Should we switch to The panelists considered a period of 2 weeks too short an immunobiologic agent in asymptomatic patients with to evaluate efficacy and recommended a 4-week period as radiographic progression? a reasonable time to change treatment, if no response is Only the two previously cited RCTs had the reduction of observed. Based on the previous guidelines for the radiographic progression through modified Stoke Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 10 of 21 Ankylosing Spondylitis Spine Score (mSASSS) as the Seven trials compared traditional NSAIDs on pain primary outcome. Over a two-year follow-up, Wanders reduction (VAS 0–100 mm) and some statistically et al. observed higher progression in the on-demand significant differences were observed [46, 51, 78, 86, 96– group (+ 1.5 ± 2.5) compared to the continuous-use group 98]: aceclofenac was inferior to indomethacin [SMD: 1.23; (+ 0.4 ± 1.7) (p=0.002) [69]. This result was similarly (95% CI: 0.98 to 1.47)], piroxicam was superior to naproxen found in previous retrospective studies [72, 73]. However, [SMD: − 1.25; (95% CI: − 1.98 to − 0.51)], and diclofenac a post-hoc analysis of the Wanders et al. trial showed a sig- was superior to sulindac [SMD: − 0.54; (95% CI: − 1.06 to nificant difference only in those with elevated CRP, which − 0.03). However, no significant difference was observed brought into discussion if celecoxib reduced the radio- using a Likert pain scale. Two studies [46, 93, 99] measured graphic progression due to the reduction of inflammation the PGA, and only one [93] evaluated the proportion of instead of a specific drug class effect [74]. patients with ≥ 50% pain improvement. However, none of On the other hand, Sieper et al. did not find any them found significant differences in comparison among significant difference on radiographic progression traditional NSAIDs (piroxicam vs. meloxicam and between the continuous and on-demand use of diclofe- ketoprofen vs. phenylbutazone, respectively). nac over 2 years using mSASSS as outcome [70]. Nu- A network meta-analysis, that included 26 RCTs and merically, the progression was higher in continuous 3410 patients with AS, did not find any significant differ- group compared to on-demand group (+ 1.3; 95% CI 0.7 ence among 18 different traditional NSAIDs in short- to 1.9 vs + 0.8; 95%; CI 0.2 to 1.4, respectively), but there term (between 2 and 12 weeks) [25]. was no statistical significance, even when considering To compare coxibs and nonselective NSAIDs, seven subgroups with the worst prognosis, such as those with studies were evaluated [38, 40, 41, 44, 45, 48, 49]. Two higher CRP and previous syndesmophytes. Therefore, RCTs used etoricoxib [41, 48], and the others with the efficacy of NSAIDs in preventing radiographic dam- celecoxib [38, 40, 44, 45, 49]. Three RCTs used diclofenac age remains an open question. Nowadays, there is grow- as comparator, another three used naproxen, and the last ing evidence that immunobiologic agents may reduce used ketoprofen. The meta-analyses did not show signifi- long-term radiographic progression, especially after 4 cant differences between iCOX2 and traditional NSAIDs years of treatment. However to date, the benefit of start- for pain VAS 0–100 mm score (Fig. 3), BASDAI, PGA, the ing an immunobiologic agent in patients with radio- proportion of patients who achieved ASAS20, or BASFI. graphic progression measured by mSASSS, but with a Only the study by van der Heijde et al. found a slight su- good symptom control with NSAID was not addressed periority of etoricoxib 90 mg/day over naproxen 1000 mg/ [75–77]. day for the outcomes pain VAS 0–100 mm and PGA. This same study found no significant difference regarding BAS- Recommendation 9 DAI, BASFI, or ASAS partial remission [48]. Regarding the radiographic progression, we conditionally recommend In the network meta-analysis by Wang et al., 18 trad- continuous over on demand use of NSAIDs in patients with active itional NSAIDs and two iCOX2 agents were compared axSpA. Considering controversial results among the studies, we conditionally recommend switching to on demand strategy in inactive to each other in treatment of AS. Etoricoxib was super- disease. We conditionally recommend against switching NSAIDs to ior to celecoxib, ketoprofen, and tenoxicam with regard immunobiological therapy when there is radiographic progression to pain reduction, but without a significant difference in without evidence of disease activity, because the risk/benefit ratio of starting an immunobiologic agent in this scenario is not clear. Quality the duration of morning stiffness. The superiority of of evidence: very low; Degree of agreement: 8.2 etoricoxib should be interpreted with caution because it was based on only one RCT [25, 48]. Regarding any adverse events, there was no significant Comparison among NSAIDs difference among traditional NSAIDs. In only one of the Is there any difference regarding the efficacy of traditional 19 studies, indomethacin caused more adverse events NSAID versus another traditional NSAID or versus iCOX2 in than oxaprozin [80]. In the analysis by organ system, patients with axSpA? Is there any difference among NSAIDs indomethacin was also associated with a higher rate of regarding adverse events in patients with axSpA? neurological adverse events than aceclofenac, oxaprozin, Twenty-six RCTs compared different traditional NSAI and diclofenac [80, 83, 86]. No difference was observed Ds in patients with axSpA. A total of 2176 participants in adverse events rate (renal, cardiovascular, hepatic, aged 35 to 46 years were evaluated. The overall risk of hematological, respiratory, or dermatologic) in patients bias in these studies was considered high due to lack of with axSpA. information on randomization, allocation concealment, In comparison between iCOX2 and traditional NSAIDs, blinding, and loss to follow-up. Given the data hetero- the meta-analysis did not detect differences for any adverse geneity, a meta-analysis was not possible [46, 51–53, events. In the evaluation by organ system (Fig. 4aand b), 78–95]. there were also no significant differences, except for Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 11 of 21 Fig. 3 Spinal pain by visual analog scale (VAS 0–100 mm) comparing traditional NSAIDs versus iCOX2 in patients with ankylosing spondylitis: meta-analysis of six randomized clinical trials. Subtitle: (1) Celecoxib 200 mg vs ketoprofen 200 mg. (2) Celecoxib 400 mg vs diclofenac 75 mg. (3) Etoricoxib 90 mg vs naproxen 1000 mg. (4) Celecoxib 200 mg vs diclofenac 50 mg. (5) Etoricoxib 90 mg vs naproxen 1000 mg. (6) Celecoxib 200 mg vs diclofenac 75 mg increased hepatic toxicity for iCOX2. However, this finding significant short-term differences (incidence of any adverse was highly imprecise and at the limit of statistical signifi- events, serious adverse events, or discontinuation of treat- cance. Regarding discontinuation of treatment due to adverse ment due to adverse events for iCOX2 compared to placebo) events, there were no differences in the comparison of trad- (Table 3 and Fig. 6). In the single RCT with a longer follow- itional NSAIDs or in the comparison between these and up period (52 weeks), the placebo group was blindly reallo- iCOX2. Systematic reviews that included several diseases cated to receive etoricoxib 90 mg, etoricoxib 120 mg, or na- showed greater gastrointestinal safety of iCOX2 compared to proxen 1000 mg after 6-week follow-up. In the first 6 weeks, traditional NSAIDs and suggested a greater cardiovascular the rates of any adverse events were 39.8, 47.6, 48.9, and safety of naproxen compared to other NSAIDs [100, 101]. 41.4% for placebo, etoricoxib 90 mg, etoricoxib 120 mg, and However, we did not observe any significant difference in the naproxen, respectively. At the end of 1 year, there were no present meta-analysis (see supplementary material). significant differences in any of the adverse events among the three groups (43.5%, 36.1, and 38.5%, respectively), nor in se- Recommendation 10 vere adverse events (7.6, 7.2, and 7.7%, respectively) or dis- In patients with active axSpA, we conditionally recommend that the continuation rate due to adverse events (8.7, 4.8, and 7.7%, choice of a specific NSAID should be based on patient’s profile (age, respectively) [48]. prior toxicity, comorbidities) and on shared decision making. To date, there is no consistent evidence of efficacy and safety differences among Therefore comparing NSAIDs versus placebo, we did not the NSAIDs (non-selective or iCOX2) in axSpA. Quality of evidence: find statistical differences in the overall incidence of adverse low; Degree of agreement: 9.6 events, which suggests a good safety profile. However, considering specific organ system analyses showed in the following sections, caution is recommended when using Safety and adverse reactions NSAIDs, especially regarding gastrointestinal events. Is there any evidence that NSAIDs carry an increased risk of adverse events in patients with axSpA? Recommendation 11 Regarding safety, in patients with active axSpA, we strongly recommend Five studies compared non-selective NSAIDs versus pla- treatment with NSAIDs over no treatment, because the available cebo regarding adverse events, totaling 1289 patients eval- evidence showed an overall good safety profile of these drugs in axSpA. uated [44–48]. The meta-analysis showed no significant We conditionally recommend that NSAIDS should be used with caution in individuals with risk factors (age > 65 years old, diabetes mellitus, use adverse events differences compared to placebo. Further- of aspirin, corticosteroids and other platelet antiaggregants, renal or liver more, there was no significant serious adverse events dif- diseases). The risks and benefits of starting them should be shared and ference or in the discontinuation rate due to adverse individualized according to the patient’s risk profile. Quality of evidence: low, Degree of agreement: 9.0 events in short-term (6–12 weeks) (Table 3 and Fig. 5). Another 52-week study found no significant adverse event difference among piroxicam 20 mg, meloxicam 15 mg, and meloxicam 22.5 mg compared to placebo in 473 pa- Is the use of NSAIDs associated with increased tients with AS (26, 38, 34, and 36%, respectively) [46]. gastrointestinal risk in patients with axSpA? Considering iCOX2, three studies compared the incidence Five studies compared traditional NSAIDs versus of any adverse events versus placebo in 700 patients with placebo regarding gastrointestinal adverse events in 1289 axSpA [44, 45, 48]. Our meta-analysis did not show any patients [44–48]. The frequency of gastrointestinal Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 12 of 21 Fig. 4 (See legend on next page.) Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 13 of 21 (See figure on previous page.) Fig. 4 a and b Incidence of adverse events per organ system in the comparison of COX2 selective inhibitors versus traditional NSAIDs in patients with ankylosing spondylitis: meta-analyses of seven randomized clinical trials. Subtitle: (1) Celecoxib 400 mg vs diclofenac 75 mg. (2) Celecoxib 200 mg vs diclofenac 75 mg (3) Celecoxib 400 mg vs naproxen 500 mg. (4) Celecoxib 200 mg vs ketoprofen 200 mg. (5) Celecoxib 400 mg vs diclofenac 75 mg. (6) Etoricoxib 90 mg vs naproxen 1000 mg. (7) Celecoxib 200 mg vs diclofenac 75 mg. (8) Celecoxib 200 mg vs diclofenac 50 mg (9) Celecoxib 400 mg vs diclofenac 75 mg. (10) Celecoxib 200 mg vs diclofenac 75 mg. (11) Celecoxib 400 mg vs naproxen 500 mg. (12) Celecoxib 200 mg vs ketoprofen 200 mg. (13) Celecoxib 400 mg vs diclofenac 75 mg. (14) Etoricoxib 90 mg vs naproxen 1000 mg. (15) Celecoxib 200 mg vs diclofenac 75 mg (16) Celecoxib 200 mg vs ketoprofen 200 mg. (17) Celecoxib 200 mg vs diclofenac 75 mg. (18) Celecoxib 400 mg vs naproxen 500 mg. (19) Celecoxib 200 mg vs ketoprofen 200 mg. (20) Celecoxib 400 mg vs diclofenac 75 mg. (21) Etoricoxib 90 mg vs naproxen 1000 mg. (22) Celecoxib 200 mg vs diclofenac 75 mg. (23) Celecoxib 200 mg vs diclofenac 50 mg (24) Celecoxib 400 mg vs naproxen 500 mg. (25) Celecoxib 200 mg vs ketoprofen 200 mg (26) Celecoxib 200 mg vs diclofenac 75 mg. (27) Celecoxib 200 mg vs diclofenac 50 mg events was higher with tranditional NSAIDs than placebo. aggregation drugs), history of peptic ulcer, and Helicobac- A similar result was observed with iCOX2 in 769 patients ter pylori infection. An observational study that evaluated when compared to placebo (Table 3,Figs. 7 and 8)[44, 45, 4144 individuals with osteoarthritis (85%), rheumatoid 48]. There was no significant difference in the meta- arthritis (11%), or AS (3%) and at least one gastrointestinal analysis of six RCTs that compared iCOX2 versus trad- risk factor, with a mean follow-up of 6 months, showed an itional NSAIDs (RR=0.89; 0.65–1.2). Most RCTs were incidence of 0.7 severe events per 100 patients-year after short-term (2–12 weeks) [38, 40, 44, 45, 48, 49]. the initiation of NSAIDs. The associated use of gastropro- In the Dougados’ study (1999), the extension phase tective drugs, such as proton pump inhibitors, reduced the lasted from 6th to 52nd week. In the first 6 weeks, the risk in approximately 30% of patients [100, 102, 103]. Sys- authors showed 14% gastrointestinal events with tematic reviews that included several diseases, not re- traditional NSAIDs versus 7% in placebo group. A total stricted to the population with SpA, showed greater of six (1.7%) individuals from NSAID group had gastrointestinal safety of iCOX2 [100, 101], but we did not gastroduodenal ulcers, and no patients were diagnosed find any significant difference between iCOX2 and trad- in placebo group by week 52 [46]. Regarding iCOX2, itional NSAIDs in the present meta-analysis (see Fig. 4a only the RCT by van der Heijde et al. (2005) analyzed and Supplementary Material). adverse events from week 6 to week 52 in the extension phase, not controlled by placebo. The incidence of Recommendation 12 In patients with active axSpA, we conditionally recommend to avoid pyrosis after 1 year of use was 9.8, 7.2, and 7.7% for NSAIDs (non-selective or iCOX2) and to start an immunobiologic agent etoricoxib 90 mg, etoricoxib 120 mg, and naproxen 1000 in those with current or previous peptic ulcer or gastrointestinal mg, respectively. Three (2.4%) patients who received bleeding. We conditionally recommend the use of an iCOX2 agent over a etoricoxib 120 mg and 4 (3.2%) who received naproxen traditional NSAID in patients with gastrointestinal risk factors. had gastroduodenal ulcers at 1 year of follow-up [48]. We strongly recommend the use of concomitant gastroprotective drugs Most data on gastrointestinal risk were from studies in in symptomatic or high-risk patients. Quality of evidence: low; Degree of agreement: 8.9 other populations (osteoarthritis, rheumatoid arthritis, etc.) and there is no evidence that the risk is different in axSpA. Factors considered high-risk for gastrointestinal complications with NSAIDs are age above 65 years, co- Is the use of NSAIDs associated with increased morbidities (diabetes, COPD, coronary disease, coagulopa- cardiovascular risk in axSpA? thies), alcoholism, concomitant medication There is growing evidence that SpA is associated with (corticosteroids, anticoagulants, aspirin, other antiplatelet increased mortality, especially for cardiovascular diseases, Table 3 Incidence of adverse events associated with traditional NSAIDs or iCOX2 compared to placebo in patients with axSpA: meta-analysis of randomized clinical trials TRADITIONAL NSAIDs iCOX2 N=1289 N=669 Adverse events 35.6% vs 36.4% (PbO) 54.6% vs 46.4% (PbO) RR=1.08 (0.93 to 1.25) RR=1.22 (0.93 to 1.62) Severe adverse events 1% vs 0.6% (PbO) 0.6% vs 0.6% (PbO) RR=1.71 (0.37 to 8.01) RR=0.96 (0.17 to 5.53) Gastrointestinal adverse events 18% vs 9.5% (PbO) 17.7% vs 7.5% (PbO) RR=1.92 (1.41 to 2.61) RR=2.55 (1.92 to 4.95) Discontinuation due to adverse events 5% vs 5.5% (PbO) 4.6% vs 3.4% (PbO) RR=0.76 (0.48 to 1.22) RR=2.14 (0.36 to 12.56) NSAIDs nonsteroidal anti-inflammatory drugs, iCOX2 selective cyclooxygenase 2 inhibitors, PbO placebo, RR relative risk Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 14 of 21 Fig. 5 Incidence of any adverse events in the comparison of traditional NSAIDs versus placebo in patients with ankylosing spondylitis: meta- analysis of five randomized clinical trials. Subtitle: (1) Naproxen 500 mg vs placebo. (2) Ximoprofen 30 mg vs placebo. (3) NSAID (meloxicam 15 mg, meloxicam 22.5 mg, or piroxicam) vs placebo. (4) Ketoprofen 200 mg vs placebo. (5) Naproxen 1000 mg vs placebo due to multiple factors such as chronic inflammation, cohort of osteoarthritis (OA) patients. Current use of associated comorbidities and maybe the drugs used to diclofenac (0–180 days prior to index date) compared to treat these patients [104–107]. Regarding NSAIDs, large remote use (more than 365 days prior to index date) was population studies, including a Danish cohort of more associated with an increased risk of AMI both in SpA than 1 million individuals, suggested 2 to 3-fold increase group [adjusted OR=3.32 (95% CI 1.57 to 7.03)] and OA regarding cardiovascular risk (acute myocardial infarction, group [(ORa=1.26 (95% CI 1.14 to 1.39)]. Additionally, the stroke, and death from cardiovascular disease) with the risk was different between the two groups [ORa ratio=2.64 chronic use of iCOX2 or nonselective NSAIDs, except for (95% CI 1.24 to 5.58, OA as reference)], whereas there naproxen. Meta-analysis of observational studies estimates was no increased risk of AMI when naproxen was ana- an absolute risk of major adverse cardiovascular events lyzed, either in patients with SpA [(ORa=1.19 (95% CI (MACE) of approximately 3 per 1000 patients-year with 0.53 to 2.68)] or in those with OA [112]. Interestingly, the use of NSAIDs [100, 101, 108, 109]. Furthermore, other authors have observed a protective effect of NSAIDs NSAIDs have been shown to increase mortality in the first against cardiovascular events in patients with axSpA. 3 to 6 months after acute cardiovascular events [110, 111]. Haroon et al. studied 21,143 patients with AS compared However, in the population with SpA, the relationship to 86,606 controls, based on Canadian database, observed of NSAIDs with cardiovascular mortality risk is less clear. a hazard ratio (HR) of 1.36 (95% CI 1.13 to 1.65) for a Debreuil et al., in a case-control study using a large British composite outcome of cardiovascular death. A subgroup database, compared the incidence of acute myocardial in- analysis of patients older than 65 years demonstrated a farction (AMI) between a cohort of SpA patients with a protective effect of conventional NSAIDs for Fig. 6 Incidence of any adverse events in the comparison of selective COX-2 inhibitors versus placebo in patients with ankylosing spondylitis: meta- analysis of three randomized clinical trials. Subtitle: (1) Celecoxib 400 mg vs placebo. (2) Celecoxib 200 mg vs placebo. (3) Etoricoxib 90 mg vs placebo Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 15 of 21 Fig. 7 Incidence of adverse events per organic system in the comparison of traditional NSAIDs versus placebo in patients with ankylosing spondylitis: meta-analyses of five randomized clinical trials. Subtitle: (1) Naproxen 500 mg vs placebo. (2) Ximoprofen 30 mg vs placebo. (3) NSAIDs (meloxicam 15 mg, meloxicam 22.5 mg, or piroxicam) vs placebo. (4) Ketoprofen 200 mg vs placebo. (5) Naproxen 1000 mg vs placebo. (6) Naproxen 500 mg vs placebo. (7) NSAIDs (meloxicam 15 mg, meloxicam 22.5 mg, or piroxicam) vs placebo. (8) Ketoprofen 200 mg vs placebo. (9) Naproxen 1000 mg vs placebo. (10) Ketoprofen 200 mg vs placebo. (11) Naproxen 500 mg vs placebo. (12) NSAIDs (meloxicam 15 mg, meloxicam 22.5 mg or piroxicam) vs placebo. (13) Ketoprofen 200 mg vs placebo. (14) Naproxen 1000 mg vs placebo. (15) Naproxen 500 mg vs placebo. (16) NSAIDs (meloxicam 15 mg, meloxicam 22.5 mg or piroxicam) vs placebo. (17) Ketoprofen 200 mg vs placebo cardiovascular death [HR=0.1 (95% CI 0.01 to 0.61)] [105]. the observation time) [23]. Another Taiwan case-control Tsai et al., using data from the Taiwan Health Insurance, study found negative association between the use of cele- observed a reduced risk of MACE after 12 months in pa- coxib (versus non-users) and coronary events [OR=0.34 tients with AS who had prolonged use of NSAIDs (> 80% of (95% CI 0.13 to 0.89)] in AS patients [26]. Other publications Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 16 of 21 Fig. 8 Incidence of adverse events per organ system in the comparison of selective COX-2 inhibitors versus placebo in patients with ankylosing spondylitis: meta-analysis of three randomized clinical trials. Subtitle: 1) Celecoxib 400 mg vs placebo. (2) Celecoxib 200 mg vs placebo. (3) Etoricoxib 90 mg vs placebo. (4) Celecoxib 400 mg vs placebo. (5) Celecoxib 200 mg vs placebo. (6) Etoricoxib 90 mg vs placebo. (7) Celecoxib 400 mg vs placebo. (8) Celecoxib 200 mg vs placebo. (9) Etoricoxib 90 mg vs placebo. (10) Celecoxib 400 mg vs placebo. (11) Celecoxib 200 mg vs placebo also suggest the protective effect of NSAIDs against cardio- patients with cardiovascular risks factors, specially in vascular events, but the data should be interpreted with cau- those with a recent myocardial infarction or stroke. tion because patients with more comorbidities and risk factors tend to be less exposed to NSAIDs [17, 106]. In sum- Recommendation 13 In patients with active axSpA, we conditionally recommend to avoid mary, it is still controversial whether the beneficial effect of NSAID therapy and to start an immunobiologic agent in those with reducing inflammation would outweigh the negative effects cardiovascular risk factors, mainly in those with previous acute of NSAIDs per se regarding cardiovascular risk. myocardial infarction or stroke, especially if recent (past 12 months). Quality of evidence: very low; Degree of agreement: 8.4 The present systematic review, which included only RCTs and not observational studies, did not find higher cardiovascular risk when comparing traditional NSAIDs or iCOX2 versus placebo. Two RCTs compared Are NSAIDs associated with increased renal risk in patients traditional NSAIDs versus iCOX2 on cardiovascular with axSpA? events incidence [2% (4/175) and 0% (0/170), respectively] The RCTs selected for this systematic review did not and no significant difference in meta-analysis [RR=0.22 report renal toxicity from NSAIDs in patients with (95% CI 0.03 to 1.93)] was observed [38, 49]. axSpA. Similarly to the cardiovascular toxicity, the renal Furthermore, the panel decided to conditionally adverse events evidences were obtained from data recommend caution when prescribing NSAIDs in including other populations. A large cohort study (183, Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 17 of 21 446 patients; 80% women; mean age of 78 years) found treatment of patients with axSpA, as they are effective in an incidence of 0.5% (1 in 200 new treatments) of acute most part of those patients. kidney injury (AKI), requiring hospitalization, in a There is no doubt that the immunobiologic agents are period of up to 45 days after the onset of NSAIDs [113]. quite effective and brought great benefit for the A meta-analysis evaluated 28,992 patients and demon- management of axSpA, but they carry a high cost which strated a RR of AKI associated with NSAIDs ranging demands the best rationale for prescribing them. Our from 1.25 to 2.21 that was statistically significant for sev- recommendations, in consonance with the most eral NSAIDs [114]. Regarding the possibility of progres- important guidelines, strengthen the statement that sion to chronic kidney disease, a prospective study with NSAIDs are the first line treatment in patients with 10,184 patients (57% women; mean age 76 years) found axSpA and they should be started as soon as the RR=1.26 (95% CI 1.04 to 1.53) for a reduction of glom- diagnosis is confirmed. erular filtration rate of at least 15 ml/min/1.73 m among The benefit of NSAIDs in delaying radiographic NSAID users when compared with non-users during a progression in axSpA and if immunobiologics should be median follow-up of 2.75 years [115]. the first line treatment in patients with poor prognostic criteria (elevated CRP, smokers and those with previous syndesmophytes) remain an open question. Does the use of NSAIDs increase the risk of adverse events This review has also shown that NSAIDs have a good in other organs/systems in axSpA? safety profile and are usually well tolerated for the long- Considering five RCTs of non-selective NSAIDs versus term use. The concerns about the cardiovascular and placebo and three of iCOX2 versus placebo, neither the renal side effects are based mostly in data from other meta-analysis nor individual studies found an increase in populations, but not in patients with axSpA that are usu- respiratory, hematological, dermatologic, or neurological ally younger and have less comorbidities and risk factors adverse events [44–48]. Additionally, no significant dif- than other NSAID’s long-term or frequently users, like ferences were found in the comparison of iCOX2 versus patients with osteoarthritis for example. traditional NSAIDs [38, 40, 44, 45, 48, 49]. In the com- One possible limitation of these recommendations is parison of NSAIDs with other NSAIDs, selective or not that we did not include a patient representative in the for COX-2, only indomethacin was associated with a voting panel. This strategy could be used in future greater number of neurological adverse events [80, 83, guidelines. 86]. Despite data from general population have sug- The purpose of these guidelines was to provide gested some hepatotoxic effect of NSAIDs, no specific recommendations elaborated by a panel of RCTs were found for NSAIDs versus placebo in patients rheumatologists with expertise in the field of SpA, with axSpA [116]. The current meta-analysis found mainly to support clinician’s decision making, without greater hepatic toxicity for iCOX2 compared to non- taking out his/her autonomy to choose the best selective NSAIDs, but with high imprecision data and at therapeutic option for an individual patient. the limit of statistical significance (Figs. 7 and 8). Recommendation 14 Supplementary Information In patients with active axSpA, we conditionally recommend to avoid The online version contains supplementary material available at https://doi. NSAIDs and to start an immunobiologic agent in thoses with increased org/10.1186/s42358-020-00160-6. risk of renal adverse events. The decision should be individualized and risk/benefits shared with the patient. Additional file 1. We strongly recommend caution and regular monitoring of renal function, especially in high-risk individuals (elderly, hypertension, dia- betes, kidney dysfunction). Quality of evidence: very low; Degree of agreement: 9.4 Abbreviations AxSpA: Axial Spondyloarthritis; AS: Ankylosing Spondylitis; PsA: Psoriatic Arthritis; ASAS: Ankylosing Spondylitis Assessment Study Group; RCT: Randomized Clinical Trial; TNFi: Tumor Necrosis Factor inhibitor; Conclusions IL17i: Interleukin-17 inhibitor; NSAID: Nonsteroidal Anti-inflammatory Drug; The most recently published guidelines for the iCOX2: Specific Cycloxigenase-2 inhibitor; BASDAI: Bath Ankylosing management of axSpA recommended NSAIDs as the Spondylitis Disease Activity Index; ASDAS: Ankylosing Spondylitis Disease Activity Score; BASFI: Bath Ankylosing Spondylitis Disease Functional Index; first line treatment, but none of them has addressed PAIN50%: ≥ 50% improvement in pain; MD: Mean Difference; SMD: Standard specifically the current role of NSAIDs in the treatment Mean Difference; CRP: C Reactive Protein; ESR: Erythrocyte Sedimentation of patients with axSpA regarding efficacy, safety and Rate; PAIN-VAS: Pain by Visual Analogue Scale; PGA: Patient Global Assessment of disease activity; ASAS20: At least 20% improvement according therapeutic strategy [6, 7, 71]. The present systematic to ASAS response criteria; ASAS40: At least 40% improvement according to review and critical analysis of the available evidences ASAS response criteria; mSASSS: modified Stoke Ankylosing Spondylitis Spine have confirmed that NSAIDs are still the basis for the Score Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 18 of 21 Acknowledgements Lenise Brandao Pieruccetti has no conflicts of interest. We thank Haliton Alves de Oliveira Junior and Anna Maria Buehler for Michel Alexandre Yazbek received financial support from Abbvie, UCB, technical support in the systematic review, statistical assistance and for Novartis and Lilly. performing the meta-analyses. Penelope Esther Palominos has no conflicts of interest. Rafaela Silva Guimarães Goncalves received fees for lectures from Janssen, Novertis, Abbvie, Apsen, Bristol, and Pfizer; advisory board from Janssen. Authors’ contributions Rodrigo Luppino Assad received fees for lectures and advisory board from All authors made contributions to the acquisition of data, have been Abbvie, Novartis, Janssen, UCB, Lilly, and Bristol; research support from involved in drafting the manuscript or revising it critically for important Abbvie and UCB. intellectual content, participated in the voting rounds, gave final approval of Rubens Bonfiglioli received financial support for clinical research from Roche, the version to be published and have participated sufficiently in the work to Pfizer, Amgen, and Novartis; for scientific advisory from Lilly, Abbvie, Roche, take public responsibility for appropriate portions of the content. and UCB; for support to events from Roche, Pfizer, Abbvie and Novartis; for symposia and sponsored meetings from Roche, Pfizer, and Janssen. Funding Sônia Maria Alvarenga Anti received financial support from Abbvie, Jansen, Brazilian Society of Rheumatology. The funding body had no role in the Novartis, Lilly, and UCB. design of the study and collection, analysis, and interpretation of data and in Sueli Coelho da Silva Carneiro received honorary speaker from Abbvie, writing the manuscript. Janssen, Lilly, Novartis and Pfizer; support to research from CNPq and FAPE RJ; support for congresses from Abbvie, Janssen, Novartis, Pfizer, CNPq and Availability of data and materials FAPERJ; advisory board from Janssen, Lilly, and Novartis. Online supplement. Valderílio Feijó Azevedo is GRAPPA member; Medical diretor of Edumed Biotech; received for clinical research from Pfizer, Roche, Janssen, Bristol, Ethics approval and consent to participate Abbvie, Medimmune, Boehringer, GSK, USB, Sanofi, Takeda, Bird Rock Bio, Not applicable. and NovoNordisk; financial support to events and lectures from Pfizer, Hospira, Roche, MSD, BMS, Merck Senoro, Janssen, Novertis, Celltrion, UCB, Consent for publication and AztraZeneca. Not applicable. Cleandro Pires Albuquerque has no conflicts of interest. Wanderley Marques Bernardo has no conflicts of interest. Competing interests Percival Degrava Sampaio-Barros received for participation in lectures, boards Ricardo da Cruz Lage received lecture fees from Abbvie, Pfizer and Novartis; or scientific events from laboratories Abbvie, Janssen, Novartis, Pfizer and sponsorship for events from Janssen, Novartis, Pfizer and Abbvie; research UCB. payments from Abbvie. Marcelo de Medeiros Pinheiro received financial support for advisory board Cláudia Diniz Lopes Marques received lecture fees from Abbvie, Janssen, from Novartis and Janssen; by lectures from Novartis, Janssen, Abbvie. Pfizer and Novartis; advisory board from Novartis and Abbvie; sponsorship for events from Abbvie, Janssen, Pfizer, Novartis, and Lilly. Author details Thauana Luíza Oliveira received lecturer fees from Abbvie, Novartis and 1 Universidade Federal de Minas Gerais (UFMG), Alameda Álvaro Celso 175, Janssen; support to congresses from Abbvie and Janssen. Ambulatório Bias Fortes, 2° andar, Belo Horizonte, MG 30150-260, Brazil. Gustavo Gomes Resende received lecture fees from Abbvie, Janssen, 2 3 Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil. Universidade Novartis, Pfizer, and UCB; advisory board from Abbvie, Janssen, and Novartis; 4 Federal de São Paulo (UNIFESP/ EPM), São Paulo, SP, Brazil. Universidade Research support from Brazilian Society of Rheumatology, FAPEMIG and UCB; 5 Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. Universidade de clinical research payments from Abbvie and Pfizer; sponsorship for scientific 6 São Paulo (USP), São Paulo, SP, Brazil. Hospital Estadual Geral de Goiania events from Abbvie, Janssen, Lilly, Novartis, Pfizer, and UCB. 7 (HGG), Goiânia, Brazil. Santa Casa de Misericórdia (SCM) do Rio de Janeiro, Charles Lubianca Kohen received financial support for advisory board 8 Rio de Janeiro, RJ, Brazil. Pontifícia Universidade Católica (PUC) de Porto participation from Novartis; speaker fee from Janssen, Abbvie, Novartis, Pfizer, 9 Alegre, Porto Alegre, RS, Brazil. Pontifícia Universidade Católica (PUC) de UCB; support to events from Janssen, Abbvie, Roche, Astra-Zeneca, Novartis. 10 Sorocaba, Sorocaba, SP, Brazil. Santa Casa de Misericórdia (SCM) de São Carla Gonçalves Saad has no conflicts of interest. 11 Paulo, São Paulo, SP, Brazil. Pontifícia Universidade Católica (PUC) de Antônio Carlos Ximenes received payments for participation in clinical 12 Campinas, Campinas, SP, Brazil. Hospital Heliópolis, São Paulo, SP, Brazil. research from Abbvvie, Pfizer, Roche, BMS, and Amgen; on scientific board of 13 Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil. Pfizer, and Abbivie; as a lecturer from AbbVie, Pfizer, and Abbott. 14 15 Ribeirão Preto, Ribeirão Preto, Brazil. Hospital do Servidor Público do Célio Roberto Gonçalves has no conflicts of interest. 16 Estado de São Paulo, São Paulo, SP, Brazil. Universidade Federal do Rio De Washington Alves Bianchi has no conflicts of interest. 17 Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil. Universidade Federal do Paraná Eduardo de Souza Meirelles received payments as a speaker from Novartis, 18 (UFPR), Curitiba, PR, Brazil. Universidade de Brasília (UnB), Brasília, DF, Brazil. Abbvie, Abbott and Marjan; research grants from Novartis and Pfizer; support for conferences and courses from Aché, Pfizer, Novartis, Janssen, Abbvie, Received: 3 July 2020 Accepted: 29 December 2020 Roche, and Lilly; Advisory board fee from Novartis and Marjan. Mauro Waldemar Keiserman received financial support for lectures, advisory bord and clinical research from Abbvie, Actelion, Biogen, Bristol, Celltrion, Lilly, Human Genome Sceiences, Janssen, Pfizer, Novartis, Roche, Sanofi, and References UCB. 1. Rudwaleit M, Landewe R, van der Heijde D, Listing J, Brandt J, Braun J, et al. The Adriano Chiereghin received honoraria as a speaker from Janssen, Novartis, development of Assessment of SpondyloArthritis international Society classification UCB, and Pfizer; support to courses and congresses from Abbvie, Janssen, criteria for axial spondyloarthritis (part I): classification of paper patients by expert Novartis, UCB, and Pfizer; advisory board from Novartis and Janssen. opinion including uncertainty appraisal. Ann Rheum Dis. 2009;68(6):770–6. Cristiano Barbosa Campanholo received financial support for advisory board 2. Rudwaleit M, van der Heijde D, Landewe R, Akkoc N, Brandt J, Chou CT, participation from Janssen, Abbvie, Bristol, Lilly, Novartis, Pfizer, UCB; speaker et al. The Assessment of SpondyloArthritis International Society classification fee from Janssen, Abbvie, Lilly, Novartis, and Pfizer, UCB; support to events criteria for peripheral spondyloarthritis and for spondyloarthritis in general. from Janssen, Abbvie, Bristol, Novartis, and Pfizer. Ann Rheum Dis. 2011;70(1):25–31. Andre Marun Lyrio received payments from Speaker of Janssen and UCB; 3. Rudwaleit M, van der Heijde D, Landewe R, Listing J, Akkoc N, Brandt J, support to courses/congresses from Janssen, Abbvie, Pfizer, UBC, Novartis, et al. The development of Assessment of SpondyloArthritis international and Lily. Society classification criteria for axial spondyloarthritis (part II): validation and Cláudia Goldenstein Schainberg has participated in the pharmaceutical final selection. Ann Rheum Dis. 2009;68(6):777–83. advisory board of AbbVie, Janssen, Lilly, Novartis, and Pfizer; is a speaker 4. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria invited by AbbVie, Janssen, Lilly, Novartis, Pfizer; has no stock of these for ankylosing spondylitis. A proposal for modification of the New York pharmaceutical industries. criteria. Arthritis Rheum. 1984;27(4):361–8. Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 19 of 21 5. Sieper J, van der Heijde D. Review: Nonradiographic axial spondyloarthritis: 24. Varkas G, Jans L, Cypers H, Van Praet L, Carron P, Elewaut D, et al. Brief new definition of an old disease? Arthritis Rheum. 2013;65(3):543–51. Report: Six-Week Treatment of Axial Spondyloarthritis Patients With an 6. van der Heijde D, Ramiro S, Landewe R, Baraliakos X, Van den Bosch F, Optimal Dose of Nonsteroidal Antiinflammatory Drugs: Early Response to Sepriano A, et al. 2016 update of the ASAS-EULAR management Treatment in Signal Intensity on Magnetic Resonance Imaging of the recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76(6): Sacroiliac Joints. Arthritis Rheumatol (Hoboken, NJ). 2016;68(3):672–8. 978–91. 25. Wang R, Dasgupta A, Ward MM. Comparative efficacy of non-steroidal anti- inflammatory drugs in ankylosing spondylitis: a Bayesian network meta- 7. Resende GG, Meirelles ES, Marques CDL, Chiereghin A, Lyrio AM, Ximenes analysis of clinical trials. Ann Rheum Dis. 2016;75(6):1152–60. AC, et al. The Brazilian Society of Rheumatology guidelines for axial spondyloarthritis - 2019. Adv Rheumatol. 2020;60(1):19. 26. Wu L-C, Leong P-Y, Yeo K-J, Li T-Y, Wang Y-H, Chiou J-Y, et al. Celecoxib 8. FPB K, der Burg LRA v, Ramiro S, RBM L, Buchbinder R, Falzon L, et al. Non- and sulfasalazine had negative association with coronary artery diseases in steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis patients with ankylosing spondylitis: A nation-wide, population-based case- (ankylosing spondylitis and non-radiographic axial spondyloarthritis). control study. Medicine. 2016;95(36):e4792-e. Cochrane Database Syst Rev. 2015;17(7):CD010952-CD. 27. Couderc M, Pereira B, Molto A, Tiple A, Soubrier M, Dougados M. The 9. Baraliakos X, Kiltz U, Peters S, Appel H, Dybowski F, Igelmann M, et al. Prevalence of Renal Impairment in Patients with Spondyloarthritis: Results Efficiency of treatment with non-steroidal anti-inflammatory drugs from the International ASAS-COMOSPA Study. J Rheumatol. 2018;45(6):795– according to current recommendations in patients with radiographic and 801. non-radiographic axial spondyloarthritis. Rheumatology (Oxford). 2017;56(1): 28. Dregan A, Chowienczyk P, Molokhia M. Cardiovascular and type 2 diabetes 95–102. morbidity and all-cause mortality among diverse chronic inflammatory 10. Bhuvanesh M, Balaji C, Saranya C, Ramesh R, Tamilselvam T, Rajeswari S. disorders. Heart (British Cardiac Society). 2017;103(23):1867–73. Serum levels of tumor necrosis factor-alpha and vascular endothelial growth 29. Fattahi MJ, Jamshidi AR, Mahmoudi M, Vojdanian M, Yekaninejad MS, factor as markers of disease activity in patients with axial spondyloarthritis. Jafarnezhad-Ansariha F, et al. Evaluation of the efficacy and safety of beta-d- Indian J Rheumatol. 2018;13(1):9–13. mannuronic acid in patients with ankylosing spondylitis: A 12-week randomized, placebo-controlled, phase I/II clinical trial. Int 11. Essers I, Stolwijk C, Boonen A, De Bruin ML, Bazelier MT, de Vries F, et al. Immunopharmacol. 2018;54:112–7. Ankylosing spondylitis and risk of ischaemic heart disease: a population- based cohort study. Ann Rheum Dis. 2016;75(1):203–9. 30. Gao G, Lu L, Li Z, Li Y. THU0367 The influences of non-steroidal anti- 12. Gaydukova IZ, Gamayunova Cyrillic A cKA, Dorogoykina KD, Rebrov AP. inflammatory drugs on serum VEGF and BMP-2 levels in patients with axial Efficiency of different celecoxib regimens in patients with active axial spondyloarthritis. Ann Rheum Dis. 2017;76(Suppl 2):344 LP. spondyloarthritis: Results of the 4-week pilot open-label comparative single- 31. Gao G-M, Li Y-M, Zheng X-L, Jiang D-B, Zhang L-L, Xu P-H, et al. The Efficacy center study ‘AIM’. Ter Arkh. 2017;89(6):78–83. of Imrecoxib and Celecoxib in Axial Spondyloarthritis and Their Influence on 13. Gaydukova IZ, Rebrov AP. Efficiency and safety of different etoricoxib Serum Dickopff-Related Protein 1 (DKK-1) Levels. Med Sci Monit. 2017;23: regimens in patients with axial spondyloarthritis, including ankylosing 2985–92. spondylitis. Ter Arkh. 2015;87(3):77–82. 32. Jafarnezhad-Ansariha F, Yekaninejad MS, Jamshidi A-R, Mansouri R, Vojdanian M, Mahmoudi M, et al. The effects of beta-D-mannuronic acid 14. Gratacos J, Moreno Martinez-Losa M, Font P, Montilla C, Fernandez- (M2000), as a novel NSAID, on COX1 and COX2 activities and gene Espartero C, Linares LF, et al. Etoricoxib in ankylosing spondylitis: is there a expression in ankylosing spondylitis patients and the murine monocyte/ role for active patients refractory to traditional NSAIDs? Clin Exp Rheumatol. macrophage, J774 cell line. Inflammopharmacology. 2018;26(2):375–84. 2016;34(1):94–9. 15. Guellec D, Nocturne G, Tatar Z, Pham T, Sellam J, Cantagrel A, et al. Should 33. Bedaiwi M, Thavaneswaran A, Haroon N, Anton A, Inman R. Profiling non-steroidal anti-inflammatory drugs be used continuously in ankylosing ankylosing spondylitis patients likely to respond to NSAID treatment; 2014. spondylitis? Joint Bone Spine. 2014;81(4):308–12. 34. Zengin O, Kısacık B, Kimyon G, Uyar N, Onat AM. AB0751 Treatment 16. Karateev A, Chernikhova E, Erdes S. AB0735 Upper Gastrointestinal Tract Response in Spondylitis Without Sacroiliitis to Nonsteroidal Pathology in Patients with Ankylosing Spondylitis. Ann Rheum Dis. 2015; Antiinflammatory Drugs is More Difficult than Axial Spondyloarthritis. Ann 74(Suppl 2):1144 LP. Rheum Dis. 2015;74(Suppl 2):1150.1. 35. Sánchez MD, Montilla-Morales CA, Gόmez-Castro S, Hidalgo-Calleja C, 17. Kristensen LE, Jakobsen AK, Askling J, Nilsson F, Jacobsson LTH. Safety of Carranco-Medina T, Calero-Paniagua I, et al. AB0705 Nonsteroidal Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Antiinflammatory Drugs and Bone Mineral Density and Fractures in Patients Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A with Ankylosing Spondylitis. Ann Rheum Dis. 2014;73(Suppl 2):1037 LP. Swedish National Population-Based Cohort Study. Arthritis Care Res. 2015; 67(8):1137–49. 36. Shukla A, Rai MK, Prasad N, Agarwal V. Short-term non-steroid anti- 18. Maas F, Spoorenberg A, van der Slik BPG, van der Veer E, Brouwer E, inflammatory drug use in spondyloarthritis patients induces subclinical Bootsma H, et al. Clinical Risk Factors for the Presence and Development of acute kidney injury: biomarkers study. Nephron. 2017;135(4):277–86. Vertebral Fractures in Patients With Ankylosing Spondylitis. Arthritis Care 37. Bedaiwi MK, Sari I, Wallis D, O'Shea FD, Salonen D, Haroon N, et al. Clinical Res. 2017;69(5):694–702. efficacy of celecoxib compared to acetaminophen in chronic nonspecific 19. Molto A, Granger B, Wendling D, Dougados M, Gossec L. Use of low back pain: results of a randomized controlled trial. Arthritis Care Res. nonsteroidal anti-inflammatory drugs in early axial spondyloarthritis in daily 2016;68(6):845–52. practice: Data from the DESIR cohort. Joint Bone Spine. 2017;84(1):79–82. 38. Huang F, Gu J, Liu Y, Zhu P, Zheng Y, Fu J, et al. Efficacy and safety of 20. Regel A, Sepriano A, Baraliakos X, van der Heijde D, Braun J, Landewe R, celecoxib in chinese patients with ankylosing spondylitis: a 6-week et al. Efficacy and safety of non-pharmacological and non-biological randomized, double-blinded study with 6-week open-label extension pharmacological treatment: a systematic literature review informing the treatment. Curr Ther Res Clin Exp. 2014;76:126–33. 2016 update of the ASAS/EULAR recommendations for the management of 39. Sieper J, van der Heijde D, Dougados M, Mease PJ, Maksymowych WP, axial spondyloarthritis. RMD Open. 2017;3(1):e000397-e. Brown MA, et al. Efficacy and safety of adalimumab in patients with non- radiographic axial spondyloarthritis: results of a randomised placebo- 21. Tam H-W, Yeo K-J, Leong P-Y, Chen C-H, Li Y-C, Ma C-M, et al. Sulfasalazine controlled trial (ABILITY-1). Ann Rheum Dis. 2013;72(6):815–22. might reduce risk of cardiovascular diseases in patients with ankylosing spondylitis: A nationwide population-based retrospective cohort study. Int J 40. Walker C, Essex MN, Li C, Park PW. Celecoxib versus diclofenac for the Rheum Dis. 2017;20(3):363–70. treatment of ankylosing spondylitis: 12-week randomized study in 22. Tang M, Xue L, Shen Y, Bo L, Yang R, Wen J, et al. Efficacy of long-term Norwegian patients. J Int Med Res. 2016;44(3):483–95. nonsteroidal antiinflammatory drug treatment on magnetic resonance 41. Balazcs E, Sieper J, Bickham K, Mehta A, Frontera N, Stryszak P, et al. A imaging-determined bone marrow oedema in early, active axial randomized, clinical trial to assess the relative efficacy and tolerability of spondyloarthritis patients. Clin Rheumatol. 2018;37(1):245–50. two doses of etoricoxib versus naproxen in patients with ankylosing 23. Tsai W-C, Ou T-T, Yen J-H, Wu C-C, Tung Y-C. Long-term frequent use of spondylitis. BMC Musculoskelet Disord. 2016;17(1):426. non-steroidal anti-inflammatory drugs might protect patients with 42. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE ankylosing spondylitis from cardiovascular diseases: a nationwide case- guidelines: 1. Introduction-GRADE evidence profiles and summary of control study. PLoS One. 2015;10(5):e0126347-e. findings tables. J Clin Epidemiol. 2011;64(4):383–94. Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 20 of 21 43. Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al. Going 62. Ash Z, Barkham N, McGonagle D, Hensor E, Emery P, Marzo-Ortega H. from evidence to recommendations. Bmj. 2008;336(7652):1049–51. Induction approach to early axial spondyloarthritis: still looking for the 44. Barkhuizen A, Steinfeld S, Robbins J, West C, Coombs J, Zwillich S. Celecoxib window of opportunity. Arthritis Rheum. 2011;63:1285. is efficacious and well tolerated in treating signs and symptoms of 63. Baraliakos X, Koenig AS, Jones H, Szumski A, Collier D, Bananis E. Predictors ankylosing spondylitis. J Rheumatol. 2006;33(9):1805–12. of clinical remission under anti-tumor necrosis factor treatment in patients with ankylosing spondylitis: pooled analysis from large randomized clinical 45. Dougados M, Behier JM, Jolchine I, Calin A, van der Heijde D, Olivieri I, et al. trials. J Rheumatol. 2015;42(8):1418–26. Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis: a six-week controlled study with comparison 64. Robinson PC, Brown MA. The window of opportunity: a relevant concept against placebo and against a conventional nonsteroidal antiinflammatory for axial spondyloarthritis. Arthritis Res Ther. 2014;16(3):109. drug. Arthritis Rheum. 2001;44(1):180–5. 65. Rudwaleit M, Listing J, Brandt J, Braun J, Sieper J. Prediction of a major 46. Dougados M, Gueguen A, Nakache JP, Velicitat P, Veys EM, Zeidler H, et al. clinical response (BASDAI 50) to tumour necrosis factor alpha blockers in Ankylosing spondylitis: what is the optimum duration of a clinical study? A ankylosing spondylitis. Ann Rheum Dis. 2004;63(6):665–70. one year versus a 6 weeks non-steroidal anti-inflammatory drug trial. 66. Song IH, Hermann K, Haibel H, Althoff CE, Listing J, Burmester G, et al. Rheumatology (Oxford). 1999;38(3):235–44. Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on 47. Dougados M, Nguyen M, Caporal R, Legeais J, Bouxin-Sauzet A, Pellegri- active inflammatory lesions as detected by whole-body MRI (ESTHER): a 48- Guegnault B, et al. Ximoprofen in ankylosing spondylitis. A double blind week randomised controlled trial. Ann Rheum Dis. 2011;70(4):590–6. placebo controlled dose ranging study. Scand J Rheumatol. 1994;23(5):243– 67. Song IH, Hermann KG, Haibel H, Althoff CE, Poddubnyy D, Listing J, et al. 8. Consistently good clinical response in patients with early axial 48. van der Heijde D, Baraf HSB, Ramos-Remus C, Calin A, Weaver AL, Schiff M, spondyloarthritis after 3 years of continuous treatment with etanercept: et al. Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: results longterm data of the ESTHER trial. J Rheumatol. 2014;41(10):2034–40. of a fifty-two-week, randomized, controlled study. Arthritis Rheum. 2005; 68. Haroon N, Inman RD, Learch TJ, Weisman MH, Lee M, Rahbar MH, et al. The 52(4):1205–15. impact of tumor necrosis factor alpha inhibitors on radiographic 49. Sieper J, Klopsch T, Richter M, Kapelle A, Rudwaleit M, Schwank S, et al. progression in ankylosing spondylitis. Arthritis Rheum. 2013;65(10):2645–54. Comparison of two different dosages of celecoxib with diclofenac for the 69. Wanders A, Heijde D, Landewe R, Behier JM, Calin A, Olivieri I, et al. treatment of active ankylosing spondylitis: results of a 12-week randomised, Nonsteroidal antiinflammatory drugs reduce radiographic progression in double-blind, controlled study. Ann Rheum Dis. 2008;67(3):323–9. patients with ankylosing spondylitis: a randomized clinical trial. Arthritis 50. Gossec L, van der Heijde D, Melian A, Krupa DA, James MK, Cavanaugh PF, Rheum. 2005;52(6):1756–65. et al. Efficacy of cyclo-oxygenase-2 inhibition by etoricoxib and naproxen 70. Sieper J, Listing J, Poddubnyy D, Song I-H, Hermann K-G, Callhoff J, et al. on the axial manifestations of ankylosing spondylitis in the presence of Effect of continuous versus on-demand treatment of ankylosing spondylitis peripheral arthritis. Ann Rheum Dis. 2005;64(11):1563–7. with diclofenac over 2 years on radiographic progression of the spine: 51. Villa Alcazar LF, de Buergo M, Rico Lenza H, Montull Fruitos E. Aceclofenac results from a randomised multicentre trial (ENRADAS). Ann Rheum Dis. is as safe and effective as tenoxicam in the treatment of ankylosing 2016;75(8):1438–43. spondylitis: a 3 month multicenter comparative trial. Spanish Study Group 71. Ward MM, Deodhar A, Akl EA, Lui A, Ermann J, Gensler LS, et al. American on Aceclofenac in Ankylosing Spondylitis. J Rheumatol. 1996;23(7):1194–9. College of Rheumatology/Spondylitis Association of America/ 52. Ebner W, Poal Ballarin JM, Boussina I. Meclofenamate sodium in the Spondyloarthritis Research and Treatment Network 2015 recommendations treatment of ankylosing spondylitis. Report of a European double-blind for the treatment of ankylosing spondylitis and nonradiographic axial controlled multicenter study. Arzneimittel-Forschung. 1983;33(4A):660–3. spondyloarthritis. Arthritis Rheumatol (Hoboken, NJ). 2016;68(2):282–98. 53. Good A, Mena H. Treatment of ankylosing spondylitis with flurbiprofen and 72. Boersma JW. Retardation of ossification of the lumbar vertebral column in indomethacin. Curr Med Res Opin. 1977;5(1):117–21. ankylosing spondylitis by means of phenylbutazone. Scand J Rheumatol. 54. Zochling J, Bohl-Buhler MH, Baraliakos X, Feldtkeller E, Braun J. Nonsteroidal 1976;5(1):60–4. anti-inflammatory drug use in ankylosing spondylitis--a population-based 73. Poddubnyy D, Rudwaleit M, Haibel H, Listing J, Marker-Hermann E, Zeidler survey. Clin Rheumatol. 2006;25(6):794–800. H, et al. Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the 55. Carbo MJG, Spoorenberg A, Maas F, Brouwer E, Bos R, Bootsma H, et al. German Spondyloarthritis Inception Cohort. Ann Rheum Dis. 2012;71(10): Ankylosing spondylitis disease activity score is related to NSAID use, 1616–22. especially in patients treated with TNF-alpha inhibitors. PLoS One. 2018; 13(4):e0196. 74. Kroon F, Landewe R, Dougados M, van der Heijde D. Continuous NSAID use 56. Zochling J, van der Heijde D, Dougados M, Braun J. Current evidence for reverts the effects of inflammation on radiographic progression in patients the management of ankylosing spondylitis: a systematic literature review for with ankylosing spondylitis. Ann Rheum Dis. 2012;71(10):1623–9. the ASAS/EULAR management recommendations in ankylosing spondylitis. 75. Jeong H, Eun YH, Kim IY, Park EJ, Kim H, Lee J, et al. Effect of tumor necrosis Ann Rheum Dis. 2006;65(4):423–32. factor alpha inhibitors on spinal radiographic progression in patients with 57. Coates LC, Kavanaugh A, Mease PJ, Soriano ER, Laura Acosta-Felquer M, ankylosing spondylitis. Int J Rheum Dis. 2018;21(5):1098–105. Armstrong AW, et al. Group for Research and Assessment of Psoriasis and 76. Molnar C, Scherer A, Baraliakos X, de Hooge M, Micheroli R, Exer P, et al. Psoriatic Arthritis 2015 Treatment Recommendations for Psoriatic Arthritis. TNF blockers inhibit spinal radiographic progression in ankylosing Arthritis Rheum. 2016;68(5):1060–71. spondylitis by reducing disease activity: results from the Swiss Clinical 58. Gossec L, Smolen JS, Ramiro S, de Wit M, Cutolo M, Dougados M, et al. Quality Management cohort. Ann Rheum Dis. 2018;77(1):63–9. European League Against Rheumatism (EULAR) recommendations for the 77. Louie GH, Ward MM. Measurement and treatment of radiographic management of psoriatic arthritis with pharmacological therapies: 2015 progression in ankylosing spondylitis: lessons learned from observational update. Ann Rheum Dis. 2016;75(3):499–510. studies and clinical trials. Curr Opin Rheumatol. 2014;26(2):145–50. 59. Sieper J, Lenaerts J, Wollenhaupt J, Rudwaleit M, Mazurov VI, Myasoutova L, 78. Tannenbaum H, DeCoteau WE, Esdaile JM. A double blind multicenter trial et al. Efficacy and safety of infliximab plus naproxen versus naproxen alone in comparing piroxicam and indomethacin in ankylosing spondylitis with patients with early, active axial spondyloarthritis: results from the double-blind, long-term follow-up. Curr Therapeut Res - Clin Exp. 1984;36(3):426–35. placebo-controlled INFAST study, Part 1. Ann Rheum Dis. 2014;73(1):101–7. 79. Astorga G. Double-blind, parallel clinical trial of tenoxicam (Ro 12–0068) 60. Sieper J, Lenaerts J, Wollenhaupt J, Rudwaleit M, Mazurov VI, Myasoutova L, versus piroxicam in patients with ankylosing spondylitis. Eur J Rheumatol et al. Maintenance of biologic-free remission with naproxen or no Inflamm. 1987;9(2):70–3. treatment in patients with early, active axial spondyloarthritis: results from a 80. Caldwell JR, Altman RD, Burch FX, Calin A. Treatment of ankylosing 6-month, randomised, open-label follow-up study, INFAST Part 2. Ann spondylitis with oxaprozin: a comparison with indomethacin. Semin Arthritis Rheum Dis. 2014;73(1):108–13. Rheum. 1986;15(3, Supplement 2):95–100. 61. Barkham N, Keen HI, Coates LC, O'Connor P, Hensor E, Fraser AD, et al. 81. Calin A, Britton M. Sulindac in ankylosing spondylitis. Double-blind Clinical and imaging efficacy of infliximab in HLA-B27-Positive patients with evaluation of sulindac and indomethacin. JAMA. 1979;242(17):1885–6. magnetic resonance imaging-determined early sacroiliitis. Arthritis Rheum. 82. Heinrichs KK. Treatment of spondylitis ankylosans: controlled comparative 2009;60(4):946–54. study with tiaprofenic acid and diclofenac. Med Klin. 1985;80(21):597–601. Cruz Lage et al. Advances in Rheumatology (2021) 61:4 Page 21 of 21 83. Khan MA. Diclofenac in the treatment of ankylosing spondylitis: review of 107. Liew JW, Ramiro S, Gensler LS. Cardiovascular morbidity and mortality in worldwide clinical experience and report of a double-blind comparison ankylosing spondylitis and psoriatic arthritis. Best Pract Res Clin Rheumatol. with indomethacin. Semin Arthritis Rheum. 1985;15(2 Suppl 1):80–4. 2018;32(3):369–89. 84. Lomen PL, Turner LF, Lamborn KR, Brinn EL. Flurbiprofen in the treatment of 108. Fosbol EL, Gislason GH, Jacobsen S, Folke F, Hansen ML, Schramm TK, et al. ankylosing spondylitis. a comparison with indomethacin. Am J Med. 1986; Risk of myocardial infarction and death associated with the use of 80(3A):127–32. nonsteroidal anti-inflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study. Clin Pharmacol Ther. 2009;85(2):190–7. 85. Lomen PL, Turner LF, Lamborn KR, Brinn EL, Sattler LP. Flurbiprofen in the 109. Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, treatment of ankylosing spondylitis. A comparison with phenylbutazone. et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: Am J Med. 1986;80(3A):120–6. network meta-analysis. Bmj. 2011;342:c7086. 86. Batlle-Gualda E, Figueroa M, Ivorra J, Raber A. The efficacy and tolerability of 110. Gislason GH, Jacobsen S, Rasmussen JN, Rasmussen S, Buch P, Friberg J, aceclofenac in the treatment of patients with ankylosing spondylitis: a et al. Risk of death or reinfarction associated with the use of selective multicenter controlled clinical trial. Aceclofenac Indomethacin Study Group. cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory J Rheumatol. 1996;23(7):1200–6. drugs after acute myocardial infarction. Circulation. 2006;113(25):2906–13. 87. Mena HR, Good AE. Management of ankylosing spondylitis with flurbiprofen 111. Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, or indomethacin. South Med J. 1977;70(8):945–7. et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after 88. Nissila M, Kajander A. Proquazone (Biarison) and indomethacin (Indocid) in cardiac surgery. N Engl J Med. 2005;352(11):1081–91. the treatment of ankylosing spondylitis. Two comparative, clinical, double- 112. Dubreuil M, Louie-Gao Q, Peloquin CE, Choi HK, Zhang Y, Neogi T. Risk of blind studies. Scand J Rheumatol Suppl. 1978;7(21):36–9. myocardial infarction with use of selected non-steroidal anti-inflammatory 89. Palferman TG, Webley M. A comparative study of nabumetone and drugs in patients with spondyloarthritis and osteoarthritis. Ann Rheum Dis. indomethacin in ankylosing spondylitis. Eur J Rheumatol Inflamm. 1991; 2018;77(8):1137–42. 11(2):23–9. 113. Winkelmayer WC, Waikar SS, Mogun H, Solomon DH. Nonselective and 90. Pasero G, Ruju G, Marcolongo R, Senesi M, Seni U, Mannoni A, Mannoni A, cyclooxygenase-2-selective NSAIDs and acute kidney injury. Am J Med. et al. Aceclofenac versus naproxen in the treatment of ankylosing 2008;121(12):1092–8. spondylitis: A double-blind, controlled study. Curr Therapeut Res - Clin Exp. 114. Ungprasert P, Cheungpasitporn W, Crowson CS, Matteson EL. Individual 1994;55(7):833–42. non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A 91. Rejholec V, Vapaatalo H, Tokola O, Gothoni G. Tolfenamic acid in ankylosing systematic review and meta-analysis of observational studies. Eur J Intern spondylarthritis: a double-blind comparison to indomethacin. Scand J Med. 2015;26(4):285–91. Rheumatol Suppl. 1980;36:1–7. 115. Gooch K, Culleton BF, Manns BJ, Zhang J, Alfonso H, Tonelli M, et al. NSAID 92. Franssen MJ, Gribnau FW, van de Putte LB. A comparison of diflunisal and use and progression of chronic kidney disease. Am J Med. 2007;120(3):280 phenylbutazone in the treatment of ankylosing spondylitis. Clin Rheumatol. e1–7. 1986;5(2):210–20. 116. Cao YL, Tian ZG, Wang F, Li WG, Cheng DY, Yang YF, et al. Characteristics 93. Jessop JD. Double-blind study of ketoprofen and phenylbutazone in and clinical outcome of nonsteroidal anti-inflammatory drug-induced acute ankylosing spondylitis. Rheumatol Rehabil. 1976;15(Suppl 5):37–42. hepato-nephrotoxicity among Chinese patients. World J Gastroenterol. 2014; 94. Schwarzer AC, Cohen M, Arnold MH, Kelly D, McNaught P, Brooks PM. 20(38):13956–65. Tenoxicam compared with diclofenac in patients with ankylosing spondylitis. Curr Med Res Opin. 1990;11(10):648–53. 95. Simpson MR, Simpson NR, Scott BO, Beatty DC. A controlled study of Publisher’sNote flufenamic acid in ankylosing spondylitis. A preliminary report. Ann Phys Springer Nature remains neutral with regard to jurisdictional claims in Med. 1966;8(Suppl 1):126–8. published maps and institutional affiliations. 96. Myklebust G. Comparison of naproxen and piroxicam in rheumatoid arthritis and Bechterew's syndrome. A double-blind parallel multicenter study. Tidsskr Nor Laegeforen. 1986;106(17–18):1485–7. 97. Nahir AM, Scharf Y. A comparative study of diclofenac and sulindac in ankylosing spondylitis. Rheumatol Rehabil. 1980;19(3):193–8. 98. Santo JE, Queiroz MV. Oxaprozin versus diclofenac sodium in the treatment of ankylosing spondylitis. J Int Med Res. 1988;16(2):150–6. 99. Ansell BM. A comparative study of Butacote and naproxen in ankylosing spondylitis. J Int Med Res. 1977;5(Suppl 2):95. 100. Coxib, traditional NTC, Bhala N, Emberson J, Merhi A, Abramson S, et al. Vascular and upper gastrointestinal effects of non-steroidal anti- inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769–79. 101. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti- inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. Bmj. 2006;332(7553):1302–8. 102. Lanas A, Boers M, Nuevo J. Gastrointestinal events in at-risk patients starting non-steroidal anti-inflammatory drugs (NSAIDs) for rheumatic diseases: the EVIDENCE study of European routine practice. Ann Rheum Dis. 2015;74(4): 675–81. 103. Poddubnyy D, van der Heijde D. Therapeutic controversies in spondyloarthritis: nonsteroidal anti-inflammatory drugs. Rheum Dis Clin North Am. 2012;38(3):601–11. 104. Bakland G, Gran JT, Nossent JC. Increased mortality in ankylosing spondylitis is related to disease activity. Ann Rheum Dis. 2011;70(11):1921–5. 105. Haroon NN, Paterson JM, Li P, Inman RD, Haroon N. Patients with ankylosing spondylitis have increased cardiovascular and cerebrovascular mortality: a population-based study. Ann Intern Med. 2015;163(6):409–16. 106. Lehtinen K. Mortality and causes of death in 398 patients admitted to hospital with ankylosing spondylitis. Ann Rheum Dis. 1993;52(3):174–6.

Journal

Advances in RheumatologySpringer Journals

Published: Jan 19, 2021

There are no references for this article.