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2017 recommendations of the Brazilian Society of Rheumatology for the pharmacological treatment of rheumatoid arthritis

2017 recommendations of the Brazilian Society of Rheumatology for the pharmacological treatment... The objective of this document is to provide a comprehensive update of the recommendations of Brazilian Society of Rheumatology on drug treatment of rheumatoid arthritis (RA), based on a systematic literature review and on the opinion of a panel of rheumatologists. Four general principles and eleven recommendations were approved. General principles: RA treatment should (1) preferably consist of a multidisciplinary approach coordinated by a rheumatologist, (2) include counseling on lifestyle habits, strict control of comorbidities, and updates of the vaccination record, (3) be based on decisions shared by the patient and the physician after clarification about the disease and the available therapeutic options; (4) the goal is sustained clinical remission or, when this is not feasible, low disease activity. Recommendations: (1) the first line of treatment should be a csDMARD, started as soon as the diagnosis of RA is established; (2) methotrexate (MTX) is the first-choice csDMARD; (3) the combination of two or more csDMARDs, including MTX, may be used as the first line of treatment; (4) after failure of first-line therapy with MTX, the therapeutic strategies include combining MTX with another csDMARD (leflunomide), with two csDMARDs (hydroxychloroquine and sulfasalazine), or switching MTX for another csDMARD (leflunomide or sulfasalazine) alone; (5) after failure of two schemes with csDMARDs, a bDMARD may be preferably used or, alternatively a tsDMARD, preferably combined, in both cases, with a csDMARD; (6) the different bDMARDs in combination with MTX have similar efficacy, and therefore, the therapeutic choice should take into account the peculiarities of each drug in terms of safety and cost; (7)the combination ofa bDMARDandMTX is preferredoverthe useofabDMARDalone; (8)incaseof failure of an initial treatment scheme with a bDMARD, a scheme with another bDMARD can be used; in cases of failure with a TNFi, a second bDMARD of the same class or with another mechanism of action is effective and safe; (9) tofacitinib can be used to treat RA after failure of bDMARD; (10) corticosteroids, preferably at low doses for the shortest possible time, should be considered during periods of disease activity, and the risk-benefit ratio should also be considered; (11) reducing or spacing out bDMARD doses is possible in patients in sustained remission. * Correspondence: liciamhmota@gmail.com Programa de Pós-graduação em Ciências Médicas, Faculdade de Medicina- Universidade de Brasília; Serviço de Reumatologia, Hospital Universitário de Brasília, Universidade de Brasília, Brasília, Brazil Rheos, Centro Médico Lúcio Costa, SGAS 610, bloco 1, salas T50- T51, L2 Sul, Asa Sul, Brasília, DF 70200700, Brazil Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mota et al. Advances in Rheumatology (2018) 58:2 Page 2 of 17 Introduction Table 1 Questions based on clinical scenarios, selected by the rheumatoid arthritis committee of the brazilian society of Rheumatoid arthritis (RA) is a systemic inflammatory rheumatology to guide the development of the recommendations autoimmune disease characterized primarily by the in- Questions about possible clinical scenarios for treating rheumatoid arthritis volvement of the synovial membrane of peripheral joints. in Brazil, considering safety, effectiveness, and cost. The estimated prevalence of RA in the total population is Question 1: Should the first line of treatment be csDMARD (methotrexate, 0.5–1.0%, and the incidence is higher in the 30–50-year- hydroxychloroquine, leflunomide, or sulfasalazine), tsDMARD (tofacitinib), or old age group and among women [1, 2]. In Brazil, a study bDMARD (adalimumab, certolizumab, etanercept, infliximab, golimumab, conducted in Minas Gerais found a prevalence of 0.46% abatacept, rituximab, or tocilizumab)? [3]. The past few decades have introduced a substantial in- Question 2: Is there evidence that a particular csDMARD is more effective crease in the number of RA treatments due to advances in than other csDMARDs? knowledge concerning the pathophysiological mecha- Question 3: Is there evidence that the use of combination therapy with two or more csDMARDs is more effective than csDMARD monotherapy nisms of the disease and the development of new drugs. as the first line of treatment? Moreover, new monitoring and treatment strategies have Question 4: Is there evidence that after failure of a csDMARD monotherapy been implemented, including comprehensive disease con- as the first line of treatment, the best option is to switch to a second trol and early intervention, during the onset of symptoms monotherapy regimen rather than using combination therapy with [4]. In 2012 and 2013, the RA Committee of the Brazilian two or more csDMARDs? Society of Rheumatology (Sociedade Brasileira de Reuma- Question 5: Is there evidence that a particular TNFi (adalimumab, tologia–SBR) published recommendations on RA diagno- certolizumab, etanercept, golimumab, or infliximab) or non-TNFi (abatacept, rituximab, or tocilizumab) bDMARD is more effective sis and treatment in Brazil to provide support to Brazilian than other biological agents? rheumatologists, based upon scientific evidence combined Question 6: Is there evidence that bDMARD (adalimumab, certolizumab, with the experience of a panel of specialists, while safe- etanercept, golimumab, infliximab, abatacept, rituximab, or tocilizumab) guarding the necessary autonomy of physicians in choos- combined with methotrexate is more effective than bDMARD monotherapy? ing among the available therapeutic strategies [5–8]. In Question 7: In the case of failure of a first bDMARD scheme, is there 2015, the recommendations were updated to include the evidence that a second bDMARD scheme is effective? use of target-specific synthetic disease-modifying anti- Question 8: Is there evidence that tsDMARD (tofacitinib) is more rheumatic drugs [9]. effective than bDMARD (adalimumab, certolizumab, etanercept, golimumab, infliximab, abatacept, rituximab, or tocilizumab)? The objective of the current document is to provide a Question 9: Is there evidence that oral, parenteral, or intra-articular use comprehensive update of the recommendations of SBR of corticosteroids improves prognosis when combined with DMARD? on drug treatment of RA in Brazil considering the ad- Question 10: Is there evidence that it is possible to reduce the dose or vances accrued since the last revision. The scope of this increase the dose intervals for bDMARD in patients in remission? work is limited to adult disease because juvenile idio- csDMARD conventional synthetic disease-modifying drugs – methotrexate, pathic arthritis requires distinct and specific approaches. leflunomide, sulfasalazine and antimalarials (hydroxychloroquine and chloroquine) tsDMARD: synthetic target-specific disease-modifying drugs – tofacitinib bDMARD: biological disease-modifying drugs – tumor necrosis factor inhibitors/TNFi Methods (adalimumab, certolizumab, etanercept, golimumab, infliximab), T-lymphocyte costi- The present recommendations were based on a System- mulation modulator (abatacept), anti-CD20 (rituximab), and IL-6 receptor blocker (tocilizumab) atic Literature Review (SLR) and on the opinion of a panel of rheumatologists specialized in RA. In Septem- ber 2016, the RA Committee met to develop questions selected studies, as well as relevant publications in the to guide the SLR based on real-life scenarios, and these area, and the annals of congresses most relevant to the questions were improved by multiple subsequent rounds specialty were also searched. The search included the of online discussion. At the end of the interactive period from 2006 to October 2016 without language re- process, ten questions considered essential for the prep- strictions and was updated monthly until March 2017. aration of the recommendations were selected (Table 1). The studies were selected using the Covidence system Furthermore, four general principles that should guide (www.covidence.org). Two independent researchers ana- the entire RA treatment based on concepts widely estab- lyzed the retrieved publications based on the titles and lished in the literature were formulated. abstracts. Cases of disagreement were resolved by consen- An SLR was undertaken to answer the proposed ques- sus. The risk of bias in clinical trials was assessed using the tions. Randomized clinical trials and systematic reviews of tool proposed by the Cochrane Collaboration [10]. System- randomized clinical trials were considered eligible primar- atic reviews were evaluated using the AMSTAR tool [11]. ily, but controlled observational studies were also consid- The quality of evidence for each outcome (high, moderate, ered acceptable when interventional studies with those low, or very low) was evaluated using the GRADE tool designs were not available. The MEDLINE, EMBASE, and (https://gradepro.org)[12]. The risk of publication bias was SCOPUS databases were searched using specific search assessed by consulting the protocols of the clinical trials strategies (Table 2). In addition, the references of the registered in ClinicalTrials.gov (https://clinicaltrials.gov) Mota et al. Advances in Rheumatology (2018) 58:2 Page 3 of 17 Table 2 Search strategies used in the MEDLINE, EMBASE and SCOPUS databases for obtaining evidence on drug therapies for rheumatoid arthritis Database Strategy MEDLINE (via PubMed) ((((meta analysis[ptyp] OR meta-analysis[tiab] OR meta-analysis[mh] OR (systematic[tiab] AND review[tiab]) NOT ((case[ti] AND report[ti]) OR editorial[ptyp] OR comment[ptyp] OR letter[ptyp] OR newspaper article [ptyp])) OR (randomized controlled trial[Publication Type] OR (randomized[Title/Abstract] AND controlled[Title/Abstract] AND trial[Title/Abstract]))))) AND ((arthritis, rheumatoid[mh:noexp]) or (rheumatoid arthriti*[text word])) Filters: Publication date from 2006/01/01 EMBASE ‘rheumatoid arthritis’/mj AND ([cochrane review]/lim OR [systematic review]/lim OR [controlled clinical trial]/lim OR [randomized controlled trial]/lim OR [meta analysis]/lim) AND [2006–2016]/py NOT [medline]/lim SCOPUS TITLE-ABS-KEY(rheumatoid arthritis) AND((TITLE-ABS-KEY(randomized) AND TITLE-ABS-KEY(controlled) AND TITLE- ABS-KEY(trial)) OR (TITLE-ABS-KEY(meta-analysis) OR (TITLE-ABS-KEY(systematic) AND TITLE-ABS-KEY(review)))) AND (PUBYEAR > 2006) AND NOT (INDEX(medline) or INDEX(embase)) and WHO International Clinical Trials Registry Platform csDMARD: conventional synthetic disease-modifying (http://www.who.int/ictrp/en) when available and by asym- antirheumatic drugs – methotrexate, leflunomide, sulfa- metry analysis of funnel plots. salazine, and antimalarial drugs (hydroxychloroquine and The methodological details of the SLR that supported chloroquine). the present recommendations and the expanded results, tsDMARD: synthetic target-specific disease-modifying together with the rationale of the answers to the formu- antirheumatic drug – tofacitinib. lated questions, will be available as Additional file 1.In bDMARD: biological disease-modifying antirheumatic the present document, a predominantly clinical ap- drugs – tumor necrosis factor inhibitors/TNFi (adali- proach was adopted, in which the SLR findings were mumab, certolizumab, etanercept, golimumab, inflixi- summarized in a technically accessible language as the mab), T-lymphocyte co-stimulation modulator (abatacept) basis for the recommendations. , anti-CD20 (rituximab), and IL-6 receptor blocker Based on the results of the SLR, the RA Committee (tocilizumab). met in June and August 2017 in São Paulo and Belo boDMARD: original biological disease-modifying anti- Horizonte to establish the level of agreement with rheumatic drugs. each general principle and recommendation according bsDMARD: biosimilar biological disease-modifying an- to the methodology described below. After presenting tirheumatic drugs. each statement, a secret ballot was held, in which the participants could agree or disagree with the general General principles proposition of each statement. In cases of agreement General principle 1: Treatment of patients with RA should by at least 70% of the participants present, a new preferably consist of a multidisciplinary approach vote was conducted to assess the level of agreement coordinated by a rheumatologist. (level of agreement: 9.87) with the text using a numerical scale from 0 (“com- Patients with RA should be preferably monitored by a pletely disagree”)to10(“completely agree”). The gen- multidisciplinary team, including a physician, physio- eral principles and recommendations that did not therapist, occupational therapist, psychologist, and nu- reach a minimum rate of agreement of 70% initially tritionist, among others. The rheumatologist, as a were subjected to repeated steps of reformulation and specialist in RA, should be responsible for coordinating voting until this rate was reached, and the level of the treatment. agreement was then determined. This process resulted in the approval of four general principles and eleven recommendations for drug treat- General principle 2: Treatment of patients with RA should ment of RA in Brazil, which are presented in Table 3 include counseling on lifestyle habits, strict control of and discussed below. This document also includes a sec- comorbidities, and updates of the vaccination record. tion on therapeutic strategies, and this section serves as (level of agreement: 10) the basis for the understanding and practical application Smoking, excessive intake of alcoholic beverages, of the recommendations. The therapeutic strategies were obesity, and a sedentary lifestyle should be strongly graphically summarized into the new flowchart for drug discouraged. The active search and appropriate man- treatment of RA in Brazil (Fig. 1). agement of comorbidities, particularly systemic arter- The following abbreviations and nomenclature for ial hypertension, diabetes mellitus, dyslipidemia, and disease-modifying antirheumatic drugs (DMARDs) were osteoporosis, are part of the care of patients with RA. used in this document: The patient’s vaccination record should be updated Mota et al. Advances in Rheumatology (2018) 58:2 Page 4 of 17 csDMARD: Conventional synthetic disease-modifying antirheumatic drugs Table 3 General principles and recommendations of the Brazilian (methotrexate, leflunomide, sulfasalazine) and antimalarials (hydroxychloroquine Society of Rheumatology for pharmacological treatment of and chloroquine) rheumatoid arthritis in Brazil tsDMARD: Synthetic target-specific disease-modifying antirheumatic drugs – tofacitinib General principles bDMARD: biological disease-modifying drugs – tumor necrosis factor inhibitors/ General principle 1: Treatment of patients with RA should preferably TNFi (adalimumab, certolizumab, etanercept, golimumab, infliximab), T-lymphocyte consist of a multidisciplinary approach coordinated by a rheumatologist. costimulation modulator (abatacept), anti-CD20 (rituximab), and IL-6 receptor Level of agreement: 9.87 blocker (tocilizumab) General principle 2: RA treatment should include counseling on lifestyle habits, strict control of comorbidities, and updates of the vaccination record. Level of agreement: 10 preferably before the initiation of treatment and kept updated during follow-up. General principle 3: RA treatment should be based on decisions shared by the patient and physician after clarification about the disease and the available therapeutic options. General principle 3: Treatment of patients with RA Level of agreement: 9.93 should be based on decisions that are shared by the General Principle 4: The goal of RA treatment is sustained clinical patient and the physician after clarification about the remission or, when this is not feasible, low disease activity. Level of agreement: 9.87 disease and the available therapeutic options. (level of Recommendations for drug treatment of RA agreement: 9.93) Patients with RA should be informed about the na- Recommendation 1: The first line of treatment should be a csDMARD, started as soon as the diagnosis of RA is established. ture and prognosis of the disease. Moreover, patients Level of agreement: 9.93 should be informed about the available therapeutic Recommendation 2: Methotrexate is the first-choice csDMARD. options, their benefits, potential adverse effects, and Level of agreement: 10 costs. Recommendation 3: Combination of two or more csDMARDs, including methotrexate, may be used as the first line of treatment. Level of agreement: 9.62 General principle 4: The goal of RA treatment is sustained clinical remission or, when this is not feasible, low disease Recommendation 4: After failure of first-line therapy with MTX, the therapeutic strategies include combining MTX with another csDMARD activity. (level of agreement: 9.83) (leflunomide), with two csDMARDs (hydroxychloroquine and The rheumatologist and the patient should acknowledge sulfasalazine), or switching MTX for another csDMARD (leflunomide that the goal of treatment is sustained clinical remission or sulfasalazine) alone. Level of agreement: 9.12 or, in cases where this is not feasible, low disease activity. Recommendation 5: After failure of two schemes with csDMARD, a In the long term, these outcomes are related to the best bDMARD may be preferably used or, alternatively, a tsDMARD, clinical, structural, and functional evolution [13–15]. preferably combined, in both cases, with a csDMARD. Regular monitoring of clinical, laboratory, and imaging pa- Level of agreement: 9.5 rameters is necessary to achieve this goal. In the initial stage Recommendation 6: The different bDMARDs in combination with of RA (the first 6 months of symptoms) and whenever the MTX have similar efficacy, and therefore, the therapeutic choice should take into account the peculiarities of each drug in terms of disease presents with significant inflammatory activity, safety and cost. follow-up should be performed monthly to allow dosage ad- Level of agreement: 9.31 justment or changes in medication for disease management. Recommendation 7: The combination of bDMARD and methotrexate is preferred over the use of bDMARD alone. Level of agreement: 9.87 Recommendations Recommendation 8: In case of failure of an initial treatment scheme Recommendation 1: The first line of treatment should be with bDMARD, a scheme with another bDMARD can be used. In a csDMARD started as soon as the diagnosis of RA is cases of failure with a TNFi, a second bDMARD of the same class or established. (level of agreement: 9.93) with another mechanism of action is effective and safe. Level of agreement: 9.37 The efficacy (ACR50 response) of methotrexate (MTX) Recommendation 9: Tofacitinib can be used to treat RA after failure of monotherapy is similar to that of bDMARD monother- bDMARD. apy, except for tocilizumab, which was more effective Level of agreement: 9.81 than MTX [16–23]. Recommendation 10: Corticosteroids, preferably at low doses for the Although monotherapy with tofacitinib has been shortest possible time, should be considered during periods of shown more effective than with MTX, the limited avail- disease activity, and the risk-benefit ratio should also be considered. Level of agreement: 9.81 ability of long-term safety data on the former requires caution and precludes its use as the first line of treat- Recommendation 11: Reducing or spacing out bDMARD doses is possible in patients in sustained remission. ment, until more data become available [24]. Level of agreement: 9.31 In addition, the lower cost of csDMARD should be taken into account, although few cost-effectiveness Mota et al. Advances in Rheumatology (2018) 58:2 Page 5 of 17 Fig. 1 (See legend on next page.) Mota et al. Advances in Rheumatology (2018) 58:2 Page 6 of 17 (See figure on previous page.) Fig. 1 Flowchart - 2017 Recommendations of the Brazillan Society of Rheumatology for pharmacological treatment of rheumatoid arthritis. 1: Sulfasalazine or leflunomide may be used in cases of contraindication to MTX. Antimalarials (hydroxychloroquine or chloroquine) as monotherapy may be considered in cases of low probability of development of radiographic erosions. 2: The most used combinations in Brazil are MTX + antimalarials, MTX + leflunomide (with or without antimalarials), MTX + sulfasalazine (with or without antimalarials). 3: The goal of treatment is remission according to ACR/EULAR criteria or, in cases where this is not possible, low disease activity, as assessed by one of the composite disease activity indices defined in the 2011 SBR Consensus (5). 4: The use of a third TNFi after failure of two TNFi drugs is not recommended. 5: In Brazil, rituximab is recommended in combination with methotrexate for patients with a poor response or intolerance to one or more TNFi drugs. 6: In case of failure or toxicity to a drug used in the third line of treatment, the next step is switching to another drug (bDMARD or tsDMARD) with the same level of complexity and that has not been used previously studies have evaluated the use of csDMARD as the Recommendation 4: After failure of first-line therapy with firstlineoftreatment.The qualityofevidencefor MTX, therapeutic strategies include combining MTX with this recommendation is low to moderate. another csDMARD (leflunomide), with two csDMARDs (hydroxychloroquine and sulfasalazine), or switching MTX for another csDMARD (leflunomide or sulfasalazine) Recommendation 2: Methotrexate is the first-choice alone. (level of agreement: 9.12) csDMARD. (level of agreement: 10) After failure of MTX as the first line of treatment, lefluno- There were no significant differences in the efficacy of mide (20 mg/day, without a loading dose) or sulfasalazine csDMARD for most of the relevant outcomes (ACR50 (with an increase in dosage to 3 g/day) are monotherapy and ACR70 response, number of painful and swollen alternatives [31, 50, 51]. Both the combination of MTX joints, disease activity, pain, and functional capacity – with leflunomide or with hydroxychloroquine + sulfasala- moderate evidence) [25–36]. zine provided better ACR50 response rates compared with Compared with MTX, leflunomide causes more ad- MTX alone (moderate evidence), with no significant dif- verse events (discontinuation of treatment, rashes, and ference in radiographic progression and discontinuation systemic arterial hypertension– high evidence) [30–33]. of treatment due to adverse events (low evidence) [50]. However, MTX has the highest risk of hepatic and pul- The combination of sulfasalazine with MTX (without monary adverse events (low to very low evidence) [37, 38]. hydroxychloroquine) compared to MTX alone did not Subcutaneous MTX was shown to be superior to oral show an incremental benefit (low evidence) [41]. MTX in ACR70 and pain control, with fewer gastro- After failure of leflunomide, replacement with sulfa- intestinal adverse reactions (moderate evidence) [39]. salazine or the combination of sulfasalazine and lefluno- MTX remains the first-choice drug for the RA treat- mide had no additional benefit in ACR50 response, pain, ment because of its efficacy and safety, possibility of in- quality of life, and treatment dropout (moderate evi- dividualizing the dose and route of administration, and dence) [52]. relatively low cost [30, 40]. After failure of sulfasalazine, the inclusion of MTX did not provide additional benefits in ACR20, ACR50, and ACR70 (moderate evidence), although an improvement Recommendation 3: Combination of two or more of the disease activity score (DAS) with the combination csDMARD, including MTX, may be used as the first line of of csDMARDs was observed after 18 months of treat- treatment. (level of agreement: 9.62) ment [53]. As a first line of treatment, among the possible com- binations of csDMARD, triple therapy with MTX + Recommendation 5: After failure of two schemes with sulfasalazine + hydroxychloroquine, and MTX + leflu- csDMARD, a bDMARD may be preferably used or, nomide, both schemes compared with MTX mono- alternatively, a tsDMARD, preferably combined, in both therapy, showed an improved ACR response (high to cases, with a csDMARD. (level of agreement: 9.5) moderate evidence) [25, 41, 42]. However, the cost of The combination of bDMARD and MTX produces combination therapy is higher [43], and there is no evi- higher ACR20, ACR50, and ACR70 response rates after dence of a clinically significant difference between MTX 6 months of treatment compared with MTX monother- alone and the combination of DMARDs (MTX + lefluno- apy [54]. Higher ACR70 response rates at 6 to 12 months mide, and triple therapy) in other disease activity indices of treatment were also observed with the combination of [25, 42, 44–47] (moderate to low evidence), radiographic bDMARD and csDMARD (not necessarily MTX) versus progression [41, 42, 48] (moderate to low evidence), and csDMARD alone [18]. The addition of bDMARD in therapeutic safety [25, 41, 47, 49](moderate to low cases of a poor response to csDMARD was effective evidence). Mota et al. Advances in Rheumatology (2018) 58:2 Page 7 of 17 [24]. In cases of poor response to a csDMARD, the (high evidence) and did not significantly increase the rate addition of a bDMARD was effective. of treatment dropout due to adverse effects compared with The tsDMARD tofacitinib in monotherapy or in com- adalimumab monotherapy (moderate evidence) [72]. bination with MTX was effective and safe in patients Etanercept + MTX provided a better ACR50 response with a poor response to csDMARD, with improvement and lower radiographic progression compared with eta- in disease activity and physical function and a reduction nercept monotherapy (high evidence) and did not sig- of radiographic progression [55, 56]. nificantly affect the ACR70 response and dropout due to However, long-term safety and real-life data are not adverse events (moderate evidence) [73]. yet available for tsDMARD, and thus, a preference for Golimumab + MTX improved the ACR50 response bDMARD over tofacitinib after csDMARD failure has rate and did not significantly affect the ACR70 response, been proposed. dropout due to adverse events, severe adverse events, and functional capacity compared with golimumab monotherapy (moderate evidence) [76]. Recommendation 6: The different bDMARDs in Abatacept + MTX increased the remission rates (DAS28 combination with MTX have similar efficacy, and < 2.6) compared with abatacept monotherapy [19]. therefore, the therapeutic choice should take into Higher ACR50 and ACR70 response rates were observed account the peculiarities of each drug in terms of safety with rituximab + MTX compared with rituximab alone and cost. (level of agreement: 9.31) (the groups were compared with MTX monotherapy) [75]. The available bDMARDs have similar levels of effective- In a randomized trial, tocilizumab monotherapy was ness for the number of painful or swollen joints, disease not significantly different from tocilizumab + MTX for activity, quality of life, functional capacity, and pain con- ACR50 and ACR70 responses, dropout due to adverse trol [16, 57–62]. However, total annual costs of treat- events, severe adverse events, and functional capacity ment vary among the different bDMARDs and these after 24 weeks of treatment. However, other randomized differences need to be taken into consideration at the trial found higher remission rates (DAS28 < 2.6) and time of drug selection (low to moderate evidence) [63]. lower radiographic progression with tocilizumab + MTX All bDMARDs have consistently demonstrated superior compared with tocilizumab monotherapy [77–79]. efficacy when used in combination with MTX compared The use of csDMARD in combination with bDMARD with MTX monotherapy [24, 40]. appears to reduce the formation of antibodies against Patients using bDMARDs compared with those using the biological agent, secondary failure. Studies that used csDMARDs have an increased risk of severe infections bDMARDs combined with csDMARDs, such as lefluno- [64–68]. In general, different bDMARDs have similar mide, confirmed the efficacy of this combination strat- levels of safety. Some SLRs of randomized trials have re- egy, particularly in patients who presented adverse ported a possible increase in the incidence of severe infec- events or contraindications to MTX [80, 81]. tions with the use of certolizumab in the (indirect) comparison with other bDMARDs (moderate evidence), Recommendation 8: In case of failure of an initial treatment but this result has not been observed in registry studies scheme with bDMARD, a scheme with another bDMARD [65–67, 69]. Lower intestinal perforation was more com- can be used. In cases of failure with TNFi, a second mon in patients treated with tocilizumab (moderate evi- bDMARD of the same class or with another mechanism of dence) [70]. Tuberculosis (TB) was more common in action is effective and safe. (level of agreement: 9.37) TNFi users than non-TNFi users. Among TNFi users, TB The use of another bDMARD is safe and effective after was more common in patients treated with adalimumab therapeutic failure of an initial treatment with bDMARD and infliximab compared with those treated with etaner- [24, 82]. When the first bDMARD was an TNFi agent, cept (moderate evidence) [68]. There were no differences the use of another TNFi agent was safe and effective in among the bDMARD in the incidence of herpes zoster or cases of treatment failure [83, 84]. neoplasia except for a possible increase in the rate of mel- Abatacept (high evidence), rituximab (high evidence), anoma with the use of TNFi (very low evidence) [64, 71]. golimumab (moderate evidence), and tocilizumab (mod- erate evidence) were better than placebo for decreasing Recommendation 7: The combination of bDMARD and the number of painful and swollen joints after failure of MTX is preferred over the use of bDMARD alone. (level of TNFi treatment [82, 85–87]. agreement: 9.87) Indirect comparisons did not allow the determination bDMARDs are more effective when combined with of superiority among abatacept, golimumab, rituximab, csDMARDs, particularly MTX [19, 72–75]. or tocilizumab in ACR50 and ACR70 responses when Adalimumab + MTX improved ACR20, ACR50, ACR70, used after failure of the first bDMARD [88]. The risk of and ACR90 responses and functional capacity and pain adverse events, including severe ones, and severe Mota et al. Advances in Rheumatology (2018) 58:2 Page 8 of 17 infections caused by these four biologicals after failure of dose reduction or dose interval increase, should be the first bDMARD, was similar to placebo. treated with another bDMARD or tsDMARD [113]. Although the use of a second TNFi agent after failure However, in patients with established RA and low dis- of the first is safe and effective, some studies suggest su- ease activity or remission, bDMARD dose reduction or a perior results for the ACR20 response, EULAR response dose interval increase should be evaluated on an individ- criterion, and disease activity reduction when switching ual basis [107–112, 114–116]. to a bDMARD with a different mechanism of action [82, Lowering the bDMARD dose reduces costs (high evi- 87, 89, 90]. These data must be confirmed in further dence) [114, 117]. studies. In other countries, rituximab has been shown to be the most cost-effective alternative among bDMARDs Therapeutic strategies for treating RA in Brazil for the treatment of patients with previous failure to Treatment with DMARDs should be initiated as soon as the TNFi (very low evidence) [82, 85–87, 89, 91]. diagnosis of RA is established. Treatment should be adjusted However, these results cannot be directly applied to as necessary by frequent clinical reassessments at 30–90-day the Brazilian context. intervals. Therapeutic strategies based on specific goals pro- duce better outcomes for disease activity and functional cap- acity, with less radiographic structural damage compared Recommendation 9: Tofacitinib can be used to treat RA with conventional treatments [4, 6, 113]. The goal is sus- after failure of bDMARD. (level of agreement: 9.81) tained remission [118, 119] or at least low disease activity, as Tofacitinib + MTX is effective after failure of TNFi, pro- assessed by a composite measure of disease activity, also tak- moting a rapid and favorable ACR20 response and improv- ing into consideration the absolute decrease in the compos- ing functional capacity and disease remission [92–97]. ite measure score (Tables 4, 5,and 6)[7, 113]. There are no available radiographic progression data for the use of tofacitinib after failure of bDMARD. First-line treatment: csDMARD First scheme Recommendation 10: Corticosteroids, preferably at low MTX is the first-choice csDMARD [6, 40, 120]. MTX doses for the shortest possible time, should be may be initially prescribed as monotherapy or in com- considered during periods of disease activity, and the bination with other csDMARD (example: MTX + lefluno- risk-benefit ratio should also be considered. (level of mide) [17]. Subcutaneous MTX is an alternative to cases agreement: 9.81) of drug intolerance or poor response to oral MTX before Corticosteroids are effective in treating RA when com- changing or adding other csDMARD. Subcutaneous MTX bined with csDMARD. Most of the analyzed studies used is better tolerated and has greater bioavailability, poten- oral prednisone. The use of corticosteroids in RA reduced tially improving clinical efficacy compared with oral ad- pain [98] (moderate evidence) and radiographic progres- ministration at the same dose [39]. sion (high to low evidence) [99–102]. Prednisone + MTX In cases in which MTX is contraindicated, sulfasala- compared with MTX alone reduced the need to switch zine [28] or leflunomide [25] may be used as the first treatment to bDMARD and did not increase the rate of option. Hydroxychloroquine (or when unavailable, adverse events [103]. However, low doses (≤10 mg/day of chloroquine) may be used in monotherapy in cases of prednisone or equivalent) for the shortest possible time undifferentiated arthritis or disease with low potential are recommended for managing periods of increased dis- for the development of radiographic erosions [6]. ease activity and minimizing adverse events. Special cau- tion is necessary in patients with comorbidities that are Second scheme potentially aggravated by corticosteroids. In cases in which there is no clinical response in 3 months or the therapeutic goal (sustained remission or low disease Recommendation 11: Reducing or spacing out bDMARD activity according to a composite measure of disease activ- doses is possible in patients in sustained remission. (level ity) is not achieved within 6 months with an optimum of agreement: 9.31) dose of MTX or in the presence of adverse effects, it is Patients using bDMARD combined with csDMARD and recommended to switch MTX for another csDMARD in in sustained remission (for at least 6 months) according monotherapy, such as leflunomide [25] or sulfasalazine to any composite disease activity index may receive [28], or a combination of MTX and other csDMARDs [41, lower bDMARD doses or the dose interval may be in- 46]. The suggested combinations are MTX + hydroxy- creased (moderate to low evidence) [104–112]. chloroquine + sulfasalazine [41] or MTX + leflunomide Patients with recent-onset RA (less than 6 months of [121]. Therapeutic progression should be rapid, with symptoms) and low disease activity, suggestive of re- monthly assessments in the first 6 months of treatment sidual inflammation, rather than undergoing bDMARD and adjustment of doses and schedules as needed. Mota et al. Advances in Rheumatology (2018) 58:2 Page 9 of 17 Table 4 Composite measures of disease activity used in rheumatoid arthritis: components, calculation formula, and range of results Components SDAI CDAI DAS28 (with 4 variables) Number of swollen joints (0–28) (0–28) Square root of the simple sum Simple sum Simple sum Number of painful joints (0–28) (0–28) Square root of the simple sum Simple sum Simple sum Acute phase reagents CRP – ESR 2–100 mm (0.1–10 mg/dL) or CRP 0.1–10 mg/dL logarithmic transformation Global health assessment – 0–100 mm (Patient) Assessment of disease activity (0–10 cm) (0–10 cm) – (Patient) Assessment of disease activity (0–10 cm) (0–10 cm) – (Examiner) Total index Simple sum Simple sum Calculation formula (requires a calculator) Index variation (0.1–86.0) (0–76) (0.49–9.07) CDAI, clinical disease activity index; DAS28, disease activity index (28 joints); CRP, C-reactive protein; SDAI, simplified disease activity index; ESR, erythrocyte sedimentation rate. Assuming a variation of 2 to 100 mm/h for ESR and of 0.1 to 10 mg/dL for CRP [6, 142]. Corticosteroids, analgesics, and non-steroidal anti- (low evidence) and improve functional capacity (low evi- inflammatory drugs dence) in RA [122–127]. NSAIDs may be useful primarily Low doses of corticosteroids (maximum of 10 mg/day of at disease onset (because DMARDs do not have immedi- prednisone or equivalent) may be used at the beginning of ate action) and in cases of RA exacerbation [128, 129]. treatment or when disease worsens. However, treatment The choice of NSAID should be individualized because for the shortest possible time is recommended to reduce there is no demonstrated superior efficacy of one NSAID the occurrence of adverse events. Intra-articular cortico- over another. Use for the shortest possible time is rec- steroids may be used when necessary for symptom con- ommended. Additional caution is necessary in cases of trol, particularly for monoarticular or oligoarticular risk factors for adverse events caused by NSAIDs, in- arthritis [6]. Common analgesics (paracetamol and dipyr- cluding advanced age, systemic arterial hypertension, one) and weak opioids (tramadol and codeine) may be heart failure, renal or hepatic dysfunction, gastrointes- used on demand for the control of pain symptoms [6]. tinal disease, arterial insufficiency, and coagulation disor- Non-steroidal anti-inflammatory drugs (NSAIDs) re- ders [130]. duce pain (low to moderate evidence) and disease activity Second-line treatment: bDMARD or tsDMARD The use of bDMARD or tsDMARD is recommended in Table 5 Definition of the status of activity of rheumatoid cases in which there is no clinical response after arthritis and respective cutoff points using composite disease 3 months using the second scheme of the first-line treat- activity indices ment, the therapeutic goal is not achieved in 6 months Index Disease activity status Cutoff points (remission or low disease activity according to a com- SDAI Remission ≤5 posite measure of disease activity), or in cases of drug Low > 5 and ≤ 20 toxicity or intolerance. Moderate > 20 and ≤ 40 The bDMARD drugs used in the second-line treat- High > 40 ment are TNFi (adalimumab, certolizumab, etanercept, CDAI Remission ≤2.8 golimumab, or infliximab), T-lymphocyte costimulation modulator (abatacept), and IL-6 receptor blocker (toci- Low ≤10 lizumab), combined with csDMARD (preferably MTX) Moderate > 10 and ≤ 22 [24, 41, 58, 94, 95]. High > 22 Tocilizumab demonstrated similar efficacy in mono- DAS28 Remission ≤2.6 therapy compared to tocilizumab + MTX for most of Low > 2.6 and ≤ 3.2 the relevant clinical outcomes [58, 77, 131]. Moderate > 3.2 and ≤ 5.1 Adalimumab, etanercept, certolizumab, golimumab, and abatacept can be used in monotherapy [16], but High > 5.1 their efficacy may be lower compared with the combina- CDAI, clinical disease activity index; DAS28, disease activity index (28 joints); SDAI, simplified disease activity index [142]. tions with csDMARDs [17]. Mota et al. Advances in Rheumatology (2018) 58:2 Page 10 of 17 Table 6 Classification of the therapeutic response in rheumatoid arthritis according to the variation in scores of the composite disease activity indices Index Response classification EULAR-DAS28 response Good: drop ≥ 1.2 points, reaching DAS28 ≤ 3.2 Moderate: drop > 1.2 points, maintenance of DAS28 > 3.2; or drop > 0.6 and ≤ 1.2 points, reaching DAS28 ≤ 5.1 Unresponsive: drop > 0.6 and ≤ 1.2 points, maintenance of DAS28 > 5.1; or drop ≤0.6 points SDAI and CDAI response Good: drop ≥ 85% in the score value Moderate: decrease ≥70 and < 85% in the score value Weak: drop ≥ 50% and < 70% in the score value Unresponsive: drop < 50% in the score value CDAI, clinical disease activity index; DAS28, disease activity index (28 joints); SDAI, simplified disease activity index [142–144]. Different bDMARDs have similar levels of clinical effi- (indicating primary failure to bDMARD or tsDMARD), cacy and safety [24, 42, 120]. Therefore, bDMARDs or loss of the previous response (secondary failure to should be chosen on an individual basis, taking into ac- bDMARD or tsDMARD), or cases of drug toxicity or count the costs and the presence of comorbidities that intolerance. may be positively or negatively affected by the treatment The drugs available for the third-line treatment are the choice. There is not necessarily a preference for one bDMARDs TNFi (adalimumab, certolizumab, etaner- mechanism of action relative to another for treating RA. cept, golimumab, or infliximab), T-lymphocyte co- The tsDMARD tofacitinib may be prescribed as the stimulation modulator (abatacept), IL-6 receptor blocker second line of treatment, preferably in combination with (tocilizumab), anti-CD20 (rituximab), and the tsDMARD MTX [41] or in monotherapy in cases of contraindica- tofacitinib, combined with csDMARD (preferably MTX) tion to MTX. However, because of the higher availability [96]. Rituximab, when considered, should be indicated of long-term safety and real-life data for bDMARDs, at to patients with positive RF or anti-CCP [96, 132]. present these regimens are preferred as the second-line When a bDMARD is used as the second-line treat- treatment, and tsDMARDs are considered an alternative ment, switching to another bDMARD or to a tsDMARD to bDMARDs [9]. Although evidence supports the use is recommended as the third-line treatment. A second of the bDMARD rituximab after failure of csDMARD, TNFi drug (particularly in cases of secondary failure), anti-CD20 is formally approved for treating RA only switching to a bDMARD with a different mechanism of after TNFi failure and has been used as the third-line action (abatacept, tocilizumab, or rituximab) [82]or treatment in this therapeutic strategy. Nonetheless, ri- switching to a tsDMARD (tofacitinib) is recommended tuximab may be considered as the first choice among in cases in which the first bDMARD is a TNFi [82, 97]. bDMARDs for patients with rheumatoid factor (RF) or Patients with failure to a first TNFi show improvements antibodies against citrullinated cyclic peptide (anti-CCP), with a second TNFi [24, 59, 84, 91]. However, there are with contraindications to other bDMARDs, or an associ- uncertainties about the cost-effectiveness of this strategy ated diagnosis of lymphoma [132]. Patients with poor because it can result in lower response rates compared prognosis factors [5], including high disease activity, with switching the mechanism of action [87, 90, 91]. If high number of painful or swollen joints, high RF and/or the first bDMARD is not a TNFi, the options include anti-CCP titers, and early occurrence of radiographic prescribing another bDMARD with a mechanism of ac- erosions, may benefit from a more aggressive treatment, tion distinct from that of the first bDMARD (including including indication of a bDMARD after failure of the TNFi) or the use of tsDMARD. first csDMARD scheme, although more evidence is re- When a tsDMARD is used as the second-line treat- quired to support this indication. ment, the option for the third-line treatment is switching There is no evidence of cost-effectiveness supporting to bDMARDs. However, this strategy requires careful the use of bDMARD as the first-line treatment for RA clinical observation because there is no available evi- in Brazil. The concomitant use of two bDMARDs or one dence to date on the efficacy and safety of the sequential bDMARD combined with a tsDMARD is not recom- use of bDMARDs after failure of tsDMARD (tofacitinib). mended [42]. Until specific information is available, caution is advised on the sequential use of drugs that interfere with IL-6 Third-line treatment: After failure of the first bDMARD or (tocilizumab) and the JAK-STAT signaling pathway (tofa- tsDMARD citinib) in patients with toxicity to any of these medica- The third-line treatment is used in cases the therapeutic tions because the effects of IL-6 are mediated by the goal (sustained remission or low disease activity accord- JAK-STAT pathway [40]. ing to a composite measure of disease activity) is not The treatment sequence depends on the specificities achieved in 6 months using the second-line treatment of each case and the discretion of the physician. In the Mota et al. Advances in Rheumatology (2018) 58:2 Page 11 of 17 case of failure or toxicity to a drug used in the third line defined by the simultaneous presence of two require- of treatment, the next step is to switch to another ments [1]: the expected clinical outcome using the (bDMARD or tsDMARD) with the same level of com- bsDMARD is similar to that produced by the corre- plexity and that has not been used previously. A mini- sponding boDMARD in any patient [2]; repeated switch- mum of 3 months and maximum of 6 months of clinical ing between the boDMARD and the bsDMARD evaluation are recommended before switching a thera- presents no additional safety or efficacy risk compared peutic regimen due to poor clinical response. with the continued use of the reference product [141]. The SBR advocates the need for an objective demon- Gradual reduction of medication dose and treatment stration of interchangeability between any boDMARD discontinuation and its correspondent bsDMARD using studies specific- There are no data to support setting any limit for the ally designed for this purpose. Until such studies are RA treatment duration. However, patients using available and interchangeability conditions are regulated bDMARD in sustained remission may receive a in Brazil, boDMARDs should not be automatically re- bDMARD dose reduction or dose interval increase. Al- placed with bsDMARDs without the consent of the pre- though disease reactivation may occur in some cases, scriber and patient. disease control is usually reestablished with the return to the previous dose schedule (moderate to low evi- Pharmacological treatment flowchart for RA in Brazil dence) [19, 23, 104, 105, 114, 133]. In cases of complete The therapeutic strategies proposed by the RA Commit- and sustained remission (at least 6 months), gradual and tee of the SBR for RA treatment in Brazil are summa- careful treatment withdrawal may be attempted in the rized in Fig. 1. following sequence: first NSAIDs, followed by cortico- steroids, and bDMARD or tsDMARD, but maintaining Treatment monitoring the use of csDMARD. After the withdrawal of For patients with active disease, especially in the initial bDMARD, if sustained clinical remission is maintained, phase of the disease (first 6 months of manifestations), reduction of the csDMARD dose can be carefully intensive follow-up with monthly visits and, when neces- attempted. Exceptionally, withdrawal of csDMARD sary, rapid treatment escalation are recommended [6]. might be feasible in cases in which clinical remission The efficacy and safety of the therapeutic intervention continues to be sustained [40, 116]. should be evaluated at each visit considering the comor- Sustained drug-free remission is rare, and the prob- bidities of the patient and aiming to achieve the lowest ability of disease exacerbation (flares) is higher in pa- possible disease activity (if remission is not possible), as tients with long-standing disease, the presence of well as improve function and quality of life. Visits can be synovitis on ultrasound (gray scale or power Doppler), spaced out for patients with established disease, particu- and a positive anti-CCP [116]. larly those with controlled disease [6]. The clinical history of patients who are eligible for Biosimilar drugs treatment with bDMARD should be analyzed for the Biosimilar bDMARDs (bsDMARDs) are very similar to presence of severe active infection, TB, or untreated la- their original bDMARDs (boDMARDs) regarding qual- tent TB, moderate to severe heart failure, multiple scler- ity, molecular structure, biological activity, clinical effi- osis or optic neuritis, previous hypersensitivity to TNFi, cacy, safety, and immunogenicity in comparability tests, malignancy or lymphoma, and congenital or acquired and these drugs fulfill strict regulatory criteria [134]. immunodeficiency. Complementary examinations to bsDMARDs have been shown to be safe and effective identify hepatitis B virus, hepatitis C virus, and HIV, as when used as an alternative to boDMARDs (moderate well as chest X-ray and the tuberculin test, should be evidence). There were no differences in ACR20 and part of the pretreatment evaluation [6]. ACR70 response rates, disease activity (moderate evi- dence), or severe adverse events of the bsDMARDs Conclusions adalimumab, etanercept, infliximab, and rituximab Advances in RA diagnosis and treatment have allowed compared with their respective boDMARDs [134–140]. improvements in disease outcome. The presence of a The development of anti-drug antibodies was similar rheumatologist is critical in evaluating and treating pa- between bsDMARDs and boDMARDs (moderate evi- tients with RA because these professionals are trained to dence), and lower for the bsDMARD of etanercept make an early diagnosis and are familiar with the avail- compared with the boDMARD (high evidence) [134]. able drug therapies, indications, management, and ad- However, the demonstration of biosimilarity should verse events. not be understood as evidence of interchangeability. The Brazilian scenario has specificities that require Interchangeability, when referring to bsDMARDs, is attention, including the local availability of medications Mota et al. Advances in Rheumatology (2018) 58:2 Page 12 of 17 and the socioeconomic status of the population. Brazil Roche). Financial competing interest: none. Non-financial competing interest: none. is a large country with a growing population, requiring Cleandro Pires de Albuquerque Personal fees and/or non-financial support rational allocation of resources to allow broad and from Pfizer, Abbvie, AstraZeneca, Janssen, Bristol-Myers-Squibb, Roche, equitable access of the population to medications and Novartis and UCB, outside the submitted work. Geraldo da Rocha Castelar Pinheiro Consultants for: Abbvie, Bristol-Myers other health technologies. Squibb, Eli Lilly, Glaxo Smith Kline, Janssen, Pfizer, Sanofi Genzyme and The recommendations presented herein seek to provide Roche. scientific evidence to Brazilian rheumatologists, consider- Ieda Maria Magalhães Laurindo Consultants for Abbvie, Bristol, GSK, Janssen, Lilly, Pfizer and UCB; has received personal or institutional support from ing the therapeutic efficacy, safety, and costs, together Abbvie, Bristol, Janssen, Lilly, Pfizer, UCB; has delivered speeches at events with the critical assessment and experience of a panel of related to this work and sponsored by Abbvie, Bristol, Janssen, Lilly, Pfizer, experts to standardize the management of RA in the na- Roche and UCB. Ivanio Alves Pereira Has received consulting fees,speaking fees and tional socioeconomic context, but maintaining the auton- supporting for internationals congresses from Roche,Pfizer, Janssen, Novartis, omy of the physician in choosing different therapeutic Bristol-Myers-Squibb, UCB Pharma, Eli-Lilly, AbbVie, and EMS. options. These recommendations should be updated peri- Manoel Barros Bertolo Has participated in clinical and/or experimental studies related to this work and sponsored by the PI (Roche); has delivered odically because of the rapid development of this field of speeches at events related to this work and sponsored by the PI (Abbvie, knowledge. The 2017 SBR recommendations and support- Pfizer). Financial competing interest: none. Non-financial competing interest: ing documents could be accessed online none. Mariana Peixoto Guimarães Ubirajara Silva de Souza Support in Congresses: UCB, Roche, Janssen Lectures with fee: UCB, Janssen, Abbvie, Pfizer, Roche, Additional file BMS Clinical research: GSK, UCB, Abbvie Advisory Board: Janssen. Max Vitor Carioca Freitas Speaker at events related to this work and sponsored by Abbvie, Novartis, Roche, Pfizer and UCB. Managing Partner of Additional file 1: Methodological details, expanded results and Integrare Therapeutics. rationale of the answers to the formulated questions of the SLR that Paulo Louzada Júnior Sponsored by: Bristol-Myers Squibb, UCB, Pfizer Board supported the present recommendations. (DOCX 980 kb) Participation: Pfizer. Ricardo Machado Xavier Lectures, consultancies: Abbvie, BMS, GSK, Janssen, Acknowledgements Lilly, Novartis, Pfizer, Roche, UCB Clinical trials: Abbvie, UCB, Pfizer, GSK, Lilly. The authors wish to acknowledge the researchers Tais Freire Galvão and Rina Dalva Neubarth Giorgi Has received consulting fees,speaking fees and Marcus Tolentino Silva, who performed the systematic review that is supporting for internationals congresses from Roche,Pfizer,Bristol-Myers- presented in detail in the Additional file 1, funded by the Brazilian Society of Squibb, UCB Pharma, Eli-Lilly,AbbVie,Abbott and EMS. Rheumatology. Funding Publisher’sNote Brazilian Society of Rheumatology. The funding body had no role in the Springer Nature remains neutral with regard to jurisdictional claims in design of the study and collection, analysis, and interpretation of data and in published maps and institutional affiliations. writing the manuscript. Author details Authors’ contributions 1 Programa de Pós-graduação em Ciências Médicas, Faculdade de Medicina- All authors made substantial contributions to the acquisition of data, have Universidade de Brasília; Serviço de Reumatologia, Hospital Universitário de been involved in drafting the manuscript or revising it critically for important 2 Brasília, Universidade de Brasília, Brasília, Brazil. Disciplina de Reumatologia, intellectual content, gave final approval of the version to be published and Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo have participated sufficiently in the work to take public responsibility for 3 Horizonte, Brazil. Centro Universitário de Brasília- UniCEUB, Brasília, Brazil. appropriate portions of the content; and agreed to be accountable for all 4 5 Universidade Federal de Pernambuco, Recife, Brazil. Hospital Vera Cruz, Belo aspects of the work in ensuring that questions related to the accuracy or 6 Horizonte, Brazil. Serviço de Reumatologia, Departamento de Medicina integrity of any part of the work are appropriately investigated and resolved. Interna, Serviço de Reumatologia, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Serviço de Ethics approval and consent to participate Reumatologia, Hospital Universitário de Brasília, Universidade de Brasília, Not applicable. Brasília, Brazil. Disciplina de Reumatologia, Departamento de Medicina Interna, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil. 9 10 Competing interests Universidade Nove de Julho, São Paulo, Brazil. Universidade do Sul de Licia Maria Henrique da Mota Has received personal or institutional support Santa Catarina, Florianópolis, Brazil. Disciplina de Reumatologia, Faculdade from Abbvie, Janssen, Pfizer and Roche; has delivered speeches at events de Ciências Médicas, Universidade Estadual de Campinas, Campinas, Brazil. 12 13 related to this work and sponsored by Abbvie, Janssen, Pfizer, Roche and Santa Casa de Belo Horizonte, Belo Horizonte, Brazil. Universidade de UCB. Financial competing interest: none. Fortaleza, Fortaleza, Brazil. Disciplina de Reumatologia, Faculdade de Adriana Maria Kakehasi Research funds: CNPq, SBR, FAPEMIG Support for Medicina de Universidade de Ribeirão Preto, Universidade de São Paulo, Scientific Events: Abbvie, BMS, Janssen Lecture Fees: UCB, Janssen, Pfizer, Ribeirão Preto, Brazil. Serviço de Reumatologia, Hospital do Servidor Roche, BMS Clinical research: Roche, Pfizer Advisory board: Janssen, Roche, Público Estadual de São Paulo, Instituto de Assistência Médica ao Servidor BMS, Pfizer. Público Estadual, São Paulo, Brazil. Rheos, Centro Médico Lúcio Costa, SGAS Ana Paula Monteiro Gomides Assistance for participation in events: Pfizer. 610, bloco 1, salas T50- T51, L2 Sul, Asa Sul, Brasília, DF 70200700, Brazil. Angela Luzia Branco Pinto Duarte Lecture Fees: Janssen, BMS. Bóris Afonso Cruz Support for Scientific Events and Lecture Fees: Abbvie, Received: 5 March 2018 Accepted: 18 April 2018 BMS, Janssen, Novartis, Pfizer, Roche. Claiton Viegas Brenol Has participated in clinical and/or experimental studies related to this work and sponsored by the PI (Abbvie, BMS, Janssen, Pfizer and Roche); has received personal or institutional support from the PI References (Abbvie, BMS, Janssen, Pfizer and Roche); has delivered speeches at events 1. Silman A HM. Epidemiology of rheumatic diseases. Oxford University Press; related to this work and sponsored by the PI (Abbvie, Janssen, Pfizer and 2000. Mota et al. Advances in Rheumatology (2018) 58:2 Page 13 of 17 2. Minichiello E, Semerano L, Boissier M-C. 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Medicine & Public Health; Rheumatology
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Abstract

The objective of this document is to provide a comprehensive update of the recommendations of Brazilian Society of Rheumatology on drug treatment of rheumatoid arthritis (RA), based on a systematic literature review and on the opinion of a panel of rheumatologists. Four general principles and eleven recommendations were approved. General principles: RA treatment should (1) preferably consist of a multidisciplinary approach coordinated by a rheumatologist, (2) include counseling on lifestyle habits, strict control of comorbidities, and updates of the vaccination record, (3) be based on decisions shared by the patient and the physician after clarification about the disease and the available therapeutic options; (4) the goal is sustained clinical remission or, when this is not feasible, low disease activity. Recommendations: (1) the first line of treatment should be a csDMARD, started as soon as the diagnosis of RA is established; (2) methotrexate (MTX) is the first-choice csDMARD; (3) the combination of two or more csDMARDs, including MTX, may be used as the first line of treatment; (4) after failure of first-line therapy with MTX, the therapeutic strategies include combining MTX with another csDMARD (leflunomide), with two csDMARDs (hydroxychloroquine and sulfasalazine), or switching MTX for another csDMARD (leflunomide or sulfasalazine) alone; (5) after failure of two schemes with csDMARDs, a bDMARD may be preferably used or, alternatively a tsDMARD, preferably combined, in both cases, with a csDMARD; (6) the different bDMARDs in combination with MTX have similar efficacy, and therefore, the therapeutic choice should take into account the peculiarities of each drug in terms of safety and cost; (7)the combination ofa bDMARDandMTX is preferredoverthe useofabDMARDalone; (8)incaseof failure of an initial treatment scheme with a bDMARD, a scheme with another bDMARD can be used; in cases of failure with a TNFi, a second bDMARD of the same class or with another mechanism of action is effective and safe; (9) tofacitinib can be used to treat RA after failure of bDMARD; (10) corticosteroids, preferably at low doses for the shortest possible time, should be considered during periods of disease activity, and the risk-benefit ratio should also be considered; (11) reducing or spacing out bDMARD doses is possible in patients in sustained remission. * Correspondence: liciamhmota@gmail.com Programa de Pós-graduação em Ciências Médicas, Faculdade de Medicina- Universidade de Brasília; Serviço de Reumatologia, Hospital Universitário de Brasília, Universidade de Brasília, Brasília, Brazil Rheos, Centro Médico Lúcio Costa, SGAS 610, bloco 1, salas T50- T51, L2 Sul, Asa Sul, Brasília, DF 70200700, Brazil Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Mota et al. Advances in Rheumatology (2018) 58:2 Page 2 of 17 Introduction Table 1 Questions based on clinical scenarios, selected by the rheumatoid arthritis committee of the brazilian society of Rheumatoid arthritis (RA) is a systemic inflammatory rheumatology to guide the development of the recommendations autoimmune disease characterized primarily by the in- Questions about possible clinical scenarios for treating rheumatoid arthritis volvement of the synovial membrane of peripheral joints. in Brazil, considering safety, effectiveness, and cost. The estimated prevalence of RA in the total population is Question 1: Should the first line of treatment be csDMARD (methotrexate, 0.5–1.0%, and the incidence is higher in the 30–50-year- hydroxychloroquine, leflunomide, or sulfasalazine), tsDMARD (tofacitinib), or old age group and among women [1, 2]. In Brazil, a study bDMARD (adalimumab, certolizumab, etanercept, infliximab, golimumab, conducted in Minas Gerais found a prevalence of 0.46% abatacept, rituximab, or tocilizumab)? [3]. The past few decades have introduced a substantial in- Question 2: Is there evidence that a particular csDMARD is more effective crease in the number of RA treatments due to advances in than other csDMARDs? knowledge concerning the pathophysiological mecha- Question 3: Is there evidence that the use of combination therapy with two or more csDMARDs is more effective than csDMARD monotherapy nisms of the disease and the development of new drugs. as the first line of treatment? Moreover, new monitoring and treatment strategies have Question 4: Is there evidence that after failure of a csDMARD monotherapy been implemented, including comprehensive disease con- as the first line of treatment, the best option is to switch to a second trol and early intervention, during the onset of symptoms monotherapy regimen rather than using combination therapy with [4]. In 2012 and 2013, the RA Committee of the Brazilian two or more csDMARDs? Society of Rheumatology (Sociedade Brasileira de Reuma- Question 5: Is there evidence that a particular TNFi (adalimumab, tologia–SBR) published recommendations on RA diagno- certolizumab, etanercept, golimumab, or infliximab) or non-TNFi (abatacept, rituximab, or tocilizumab) bDMARD is more effective sis and treatment in Brazil to provide support to Brazilian than other biological agents? rheumatologists, based upon scientific evidence combined Question 6: Is there evidence that bDMARD (adalimumab, certolizumab, with the experience of a panel of specialists, while safe- etanercept, golimumab, infliximab, abatacept, rituximab, or tocilizumab) guarding the necessary autonomy of physicians in choos- combined with methotrexate is more effective than bDMARD monotherapy? ing among the available therapeutic strategies [5–8]. In Question 7: In the case of failure of a first bDMARD scheme, is there 2015, the recommendations were updated to include the evidence that a second bDMARD scheme is effective? use of target-specific synthetic disease-modifying anti- Question 8: Is there evidence that tsDMARD (tofacitinib) is more rheumatic drugs [9]. effective than bDMARD (adalimumab, certolizumab, etanercept, golimumab, infliximab, abatacept, rituximab, or tocilizumab)? The objective of the current document is to provide a Question 9: Is there evidence that oral, parenteral, or intra-articular use comprehensive update of the recommendations of SBR of corticosteroids improves prognosis when combined with DMARD? on drug treatment of RA in Brazil considering the ad- Question 10: Is there evidence that it is possible to reduce the dose or vances accrued since the last revision. The scope of this increase the dose intervals for bDMARD in patients in remission? work is limited to adult disease because juvenile idio- csDMARD conventional synthetic disease-modifying drugs – methotrexate, pathic arthritis requires distinct and specific approaches. leflunomide, sulfasalazine and antimalarials (hydroxychloroquine and chloroquine) tsDMARD: synthetic target-specific disease-modifying drugs – tofacitinib bDMARD: biological disease-modifying drugs – tumor necrosis factor inhibitors/TNFi Methods (adalimumab, certolizumab, etanercept, golimumab, infliximab), T-lymphocyte costi- The present recommendations were based on a System- mulation modulator (abatacept), anti-CD20 (rituximab), and IL-6 receptor blocker (tocilizumab) atic Literature Review (SLR) and on the opinion of a panel of rheumatologists specialized in RA. In Septem- ber 2016, the RA Committee met to develop questions selected studies, as well as relevant publications in the to guide the SLR based on real-life scenarios, and these area, and the annals of congresses most relevant to the questions were improved by multiple subsequent rounds specialty were also searched. The search included the of online discussion. At the end of the interactive period from 2006 to October 2016 without language re- process, ten questions considered essential for the prep- strictions and was updated monthly until March 2017. aration of the recommendations were selected (Table 1). The studies were selected using the Covidence system Furthermore, four general principles that should guide (www.covidence.org). Two independent researchers ana- the entire RA treatment based on concepts widely estab- lyzed the retrieved publications based on the titles and lished in the literature were formulated. abstracts. Cases of disagreement were resolved by consen- An SLR was undertaken to answer the proposed ques- sus. The risk of bias in clinical trials was assessed using the tions. Randomized clinical trials and systematic reviews of tool proposed by the Cochrane Collaboration [10]. System- randomized clinical trials were considered eligible primar- atic reviews were evaluated using the AMSTAR tool [11]. ily, but controlled observational studies were also consid- The quality of evidence for each outcome (high, moderate, ered acceptable when interventional studies with those low, or very low) was evaluated using the GRADE tool designs were not available. The MEDLINE, EMBASE, and (https://gradepro.org)[12]. The risk of publication bias was SCOPUS databases were searched using specific search assessed by consulting the protocols of the clinical trials strategies (Table 2). In addition, the references of the registered in ClinicalTrials.gov (https://clinicaltrials.gov) Mota et al. Advances in Rheumatology (2018) 58:2 Page 3 of 17 Table 2 Search strategies used in the MEDLINE, EMBASE and SCOPUS databases for obtaining evidence on drug therapies for rheumatoid arthritis Database Strategy MEDLINE (via PubMed) ((((meta analysis[ptyp] OR meta-analysis[tiab] OR meta-analysis[mh] OR (systematic[tiab] AND review[tiab]) NOT ((case[ti] AND report[ti]) OR editorial[ptyp] OR comment[ptyp] OR letter[ptyp] OR newspaper article [ptyp])) OR (randomized controlled trial[Publication Type] OR (randomized[Title/Abstract] AND controlled[Title/Abstract] AND trial[Title/Abstract]))))) AND ((arthritis, rheumatoid[mh:noexp]) or (rheumatoid arthriti*[text word])) Filters: Publication date from 2006/01/01 EMBASE ‘rheumatoid arthritis’/mj AND ([cochrane review]/lim OR [systematic review]/lim OR [controlled clinical trial]/lim OR [randomized controlled trial]/lim OR [meta analysis]/lim) AND [2006–2016]/py NOT [medline]/lim SCOPUS TITLE-ABS-KEY(rheumatoid arthritis) AND((TITLE-ABS-KEY(randomized) AND TITLE-ABS-KEY(controlled) AND TITLE- ABS-KEY(trial)) OR (TITLE-ABS-KEY(meta-analysis) OR (TITLE-ABS-KEY(systematic) AND TITLE-ABS-KEY(review)))) AND (PUBYEAR > 2006) AND NOT (INDEX(medline) or INDEX(embase)) and WHO International Clinical Trials Registry Platform csDMARD: conventional synthetic disease-modifying (http://www.who.int/ictrp/en) when available and by asym- antirheumatic drugs – methotrexate, leflunomide, sulfa- metry analysis of funnel plots. salazine, and antimalarial drugs (hydroxychloroquine and The methodological details of the SLR that supported chloroquine). the present recommendations and the expanded results, tsDMARD: synthetic target-specific disease-modifying together with the rationale of the answers to the formu- antirheumatic drug – tofacitinib. lated questions, will be available as Additional file 1.In bDMARD: biological disease-modifying antirheumatic the present document, a predominantly clinical ap- drugs – tumor necrosis factor inhibitors/TNFi (adali- proach was adopted, in which the SLR findings were mumab, certolizumab, etanercept, golimumab, inflixi- summarized in a technically accessible language as the mab), T-lymphocyte co-stimulation modulator (abatacept) basis for the recommendations. , anti-CD20 (rituximab), and IL-6 receptor blocker Based on the results of the SLR, the RA Committee (tocilizumab). met in June and August 2017 in São Paulo and Belo boDMARD: original biological disease-modifying anti- Horizonte to establish the level of agreement with rheumatic drugs. each general principle and recommendation according bsDMARD: biosimilar biological disease-modifying an- to the methodology described below. After presenting tirheumatic drugs. each statement, a secret ballot was held, in which the participants could agree or disagree with the general General principles proposition of each statement. In cases of agreement General principle 1: Treatment of patients with RA should by at least 70% of the participants present, a new preferably consist of a multidisciplinary approach vote was conducted to assess the level of agreement coordinated by a rheumatologist. (level of agreement: 9.87) with the text using a numerical scale from 0 (“com- Patients with RA should be preferably monitored by a pletely disagree”)to10(“completely agree”). The gen- multidisciplinary team, including a physician, physio- eral principles and recommendations that did not therapist, occupational therapist, psychologist, and nu- reach a minimum rate of agreement of 70% initially tritionist, among others. The rheumatologist, as a were subjected to repeated steps of reformulation and specialist in RA, should be responsible for coordinating voting until this rate was reached, and the level of the treatment. agreement was then determined. This process resulted in the approval of four general principles and eleven recommendations for drug treat- General principle 2: Treatment of patients with RA should ment of RA in Brazil, which are presented in Table 3 include counseling on lifestyle habits, strict control of and discussed below. This document also includes a sec- comorbidities, and updates of the vaccination record. tion on therapeutic strategies, and this section serves as (level of agreement: 10) the basis for the understanding and practical application Smoking, excessive intake of alcoholic beverages, of the recommendations. The therapeutic strategies were obesity, and a sedentary lifestyle should be strongly graphically summarized into the new flowchart for drug discouraged. The active search and appropriate man- treatment of RA in Brazil (Fig. 1). agement of comorbidities, particularly systemic arter- The following abbreviations and nomenclature for ial hypertension, diabetes mellitus, dyslipidemia, and disease-modifying antirheumatic drugs (DMARDs) were osteoporosis, are part of the care of patients with RA. used in this document: The patient’s vaccination record should be updated Mota et al. Advances in Rheumatology (2018) 58:2 Page 4 of 17 csDMARD: Conventional synthetic disease-modifying antirheumatic drugs Table 3 General principles and recommendations of the Brazilian (methotrexate, leflunomide, sulfasalazine) and antimalarials (hydroxychloroquine Society of Rheumatology for pharmacological treatment of and chloroquine) rheumatoid arthritis in Brazil tsDMARD: Synthetic target-specific disease-modifying antirheumatic drugs – tofacitinib General principles bDMARD: biological disease-modifying drugs – tumor necrosis factor inhibitors/ General principle 1: Treatment of patients with RA should preferably TNFi (adalimumab, certolizumab, etanercept, golimumab, infliximab), T-lymphocyte consist of a multidisciplinary approach coordinated by a rheumatologist. costimulation modulator (abatacept), anti-CD20 (rituximab), and IL-6 receptor Level of agreement: 9.87 blocker (tocilizumab) General principle 2: RA treatment should include counseling on lifestyle habits, strict control of comorbidities, and updates of the vaccination record. Level of agreement: 10 preferably before the initiation of treatment and kept updated during follow-up. General principle 3: RA treatment should be based on decisions shared by the patient and physician after clarification about the disease and the available therapeutic options. General principle 3: Treatment of patients with RA Level of agreement: 9.93 should be based on decisions that are shared by the General Principle 4: The goal of RA treatment is sustained clinical patient and the physician after clarification about the remission or, when this is not feasible, low disease activity. Level of agreement: 9.87 disease and the available therapeutic options. (level of Recommendations for drug treatment of RA agreement: 9.93) Patients with RA should be informed about the na- Recommendation 1: The first line of treatment should be a csDMARD, started as soon as the diagnosis of RA is established. ture and prognosis of the disease. Moreover, patients Level of agreement: 9.93 should be informed about the available therapeutic Recommendation 2: Methotrexate is the first-choice csDMARD. options, their benefits, potential adverse effects, and Level of agreement: 10 costs. Recommendation 3: Combination of two or more csDMARDs, including methotrexate, may be used as the first line of treatment. Level of agreement: 9.62 General principle 4: The goal of RA treatment is sustained clinical remission or, when this is not feasible, low disease Recommendation 4: After failure of first-line therapy with MTX, the therapeutic strategies include combining MTX with another csDMARD activity. (level of agreement: 9.83) (leflunomide), with two csDMARDs (hydroxychloroquine and The rheumatologist and the patient should acknowledge sulfasalazine), or switching MTX for another csDMARD (leflunomide that the goal of treatment is sustained clinical remission or sulfasalazine) alone. Level of agreement: 9.12 or, in cases where this is not feasible, low disease activity. Recommendation 5: After failure of two schemes with csDMARD, a In the long term, these outcomes are related to the best bDMARD may be preferably used or, alternatively, a tsDMARD, clinical, structural, and functional evolution [13–15]. preferably combined, in both cases, with a csDMARD. Regular monitoring of clinical, laboratory, and imaging pa- Level of agreement: 9.5 rameters is necessary to achieve this goal. In the initial stage Recommendation 6: The different bDMARDs in combination with of RA (the first 6 months of symptoms) and whenever the MTX have similar efficacy, and therefore, the therapeutic choice should take into account the peculiarities of each drug in terms of disease presents with significant inflammatory activity, safety and cost. follow-up should be performed monthly to allow dosage ad- Level of agreement: 9.31 justment or changes in medication for disease management. Recommendation 7: The combination of bDMARD and methotrexate is preferred over the use of bDMARD alone. Level of agreement: 9.87 Recommendations Recommendation 8: In case of failure of an initial treatment scheme Recommendation 1: The first line of treatment should be with bDMARD, a scheme with another bDMARD can be used. In a csDMARD started as soon as the diagnosis of RA is cases of failure with a TNFi, a second bDMARD of the same class or established. (level of agreement: 9.93) with another mechanism of action is effective and safe. Level of agreement: 9.37 The efficacy (ACR50 response) of methotrexate (MTX) Recommendation 9: Tofacitinib can be used to treat RA after failure of monotherapy is similar to that of bDMARD monother- bDMARD. apy, except for tocilizumab, which was more effective Level of agreement: 9.81 than MTX [16–23]. Recommendation 10: Corticosteroids, preferably at low doses for the Although monotherapy with tofacitinib has been shortest possible time, should be considered during periods of shown more effective than with MTX, the limited avail- disease activity, and the risk-benefit ratio should also be considered. Level of agreement: 9.81 ability of long-term safety data on the former requires caution and precludes its use as the first line of treat- Recommendation 11: Reducing or spacing out bDMARD doses is possible in patients in sustained remission. ment, until more data become available [24]. Level of agreement: 9.31 In addition, the lower cost of csDMARD should be taken into account, although few cost-effectiveness Mota et al. Advances in Rheumatology (2018) 58:2 Page 5 of 17 Fig. 1 (See legend on next page.) Mota et al. Advances in Rheumatology (2018) 58:2 Page 6 of 17 (See figure on previous page.) Fig. 1 Flowchart - 2017 Recommendations of the Brazillan Society of Rheumatology for pharmacological treatment of rheumatoid arthritis. 1: Sulfasalazine or leflunomide may be used in cases of contraindication to MTX. Antimalarials (hydroxychloroquine or chloroquine) as monotherapy may be considered in cases of low probability of development of radiographic erosions. 2: The most used combinations in Brazil are MTX + antimalarials, MTX + leflunomide (with or without antimalarials), MTX + sulfasalazine (with or without antimalarials). 3: The goal of treatment is remission according to ACR/EULAR criteria or, in cases where this is not possible, low disease activity, as assessed by one of the composite disease activity indices defined in the 2011 SBR Consensus (5). 4: The use of a third TNFi after failure of two TNFi drugs is not recommended. 5: In Brazil, rituximab is recommended in combination with methotrexate for patients with a poor response or intolerance to one or more TNFi drugs. 6: In case of failure or toxicity to a drug used in the third line of treatment, the next step is switching to another drug (bDMARD or tsDMARD) with the same level of complexity and that has not been used previously studies have evaluated the use of csDMARD as the Recommendation 4: After failure of first-line therapy with firstlineoftreatment.The qualityofevidencefor MTX, therapeutic strategies include combining MTX with this recommendation is low to moderate. another csDMARD (leflunomide), with two csDMARDs (hydroxychloroquine and sulfasalazine), or switching MTX for another csDMARD (leflunomide or sulfasalazine) Recommendation 2: Methotrexate is the first-choice alone. (level of agreement: 9.12) csDMARD. (level of agreement: 10) After failure of MTX as the first line of treatment, lefluno- There were no significant differences in the efficacy of mide (20 mg/day, without a loading dose) or sulfasalazine csDMARD for most of the relevant outcomes (ACR50 (with an increase in dosage to 3 g/day) are monotherapy and ACR70 response, number of painful and swollen alternatives [31, 50, 51]. Both the combination of MTX joints, disease activity, pain, and functional capacity – with leflunomide or with hydroxychloroquine + sulfasala- moderate evidence) [25–36]. zine provided better ACR50 response rates compared with Compared with MTX, leflunomide causes more ad- MTX alone (moderate evidence), with no significant dif- verse events (discontinuation of treatment, rashes, and ference in radiographic progression and discontinuation systemic arterial hypertension– high evidence) [30–33]. of treatment due to adverse events (low evidence) [50]. However, MTX has the highest risk of hepatic and pul- The combination of sulfasalazine with MTX (without monary adverse events (low to very low evidence) [37, 38]. hydroxychloroquine) compared to MTX alone did not Subcutaneous MTX was shown to be superior to oral show an incremental benefit (low evidence) [41]. MTX in ACR70 and pain control, with fewer gastro- After failure of leflunomide, replacement with sulfa- intestinal adverse reactions (moderate evidence) [39]. salazine or the combination of sulfasalazine and lefluno- MTX remains the first-choice drug for the RA treat- mide had no additional benefit in ACR50 response, pain, ment because of its efficacy and safety, possibility of in- quality of life, and treatment dropout (moderate evi- dividualizing the dose and route of administration, and dence) [52]. relatively low cost [30, 40]. After failure of sulfasalazine, the inclusion of MTX did not provide additional benefits in ACR20, ACR50, and ACR70 (moderate evidence), although an improvement Recommendation 3: Combination of two or more of the disease activity score (DAS) with the combination csDMARD, including MTX, may be used as the first line of of csDMARDs was observed after 18 months of treat- treatment. (level of agreement: 9.62) ment [53]. As a first line of treatment, among the possible com- binations of csDMARD, triple therapy with MTX + Recommendation 5: After failure of two schemes with sulfasalazine + hydroxychloroquine, and MTX + leflu- csDMARD, a bDMARD may be preferably used or, nomide, both schemes compared with MTX mono- alternatively, a tsDMARD, preferably combined, in both therapy, showed an improved ACR response (high to cases, with a csDMARD. (level of agreement: 9.5) moderate evidence) [25, 41, 42]. However, the cost of The combination of bDMARD and MTX produces combination therapy is higher [43], and there is no evi- higher ACR20, ACR50, and ACR70 response rates after dence of a clinically significant difference between MTX 6 months of treatment compared with MTX monother- alone and the combination of DMARDs (MTX + lefluno- apy [54]. Higher ACR70 response rates at 6 to 12 months mide, and triple therapy) in other disease activity indices of treatment were also observed with the combination of [25, 42, 44–47] (moderate to low evidence), radiographic bDMARD and csDMARD (not necessarily MTX) versus progression [41, 42, 48] (moderate to low evidence), and csDMARD alone [18]. The addition of bDMARD in therapeutic safety [25, 41, 47, 49](moderate to low cases of a poor response to csDMARD was effective evidence). Mota et al. Advances in Rheumatology (2018) 58:2 Page 7 of 17 [24]. In cases of poor response to a csDMARD, the (high evidence) and did not significantly increase the rate addition of a bDMARD was effective. of treatment dropout due to adverse effects compared with The tsDMARD tofacitinib in monotherapy or in com- adalimumab monotherapy (moderate evidence) [72]. bination with MTX was effective and safe in patients Etanercept + MTX provided a better ACR50 response with a poor response to csDMARD, with improvement and lower radiographic progression compared with eta- in disease activity and physical function and a reduction nercept monotherapy (high evidence) and did not sig- of radiographic progression [55, 56]. nificantly affect the ACR70 response and dropout due to However, long-term safety and real-life data are not adverse events (moderate evidence) [73]. yet available for tsDMARD, and thus, a preference for Golimumab + MTX improved the ACR50 response bDMARD over tofacitinib after csDMARD failure has rate and did not significantly affect the ACR70 response, been proposed. dropout due to adverse events, severe adverse events, and functional capacity compared with golimumab monotherapy (moderate evidence) [76]. Recommendation 6: The different bDMARDs in Abatacept + MTX increased the remission rates (DAS28 combination with MTX have similar efficacy, and < 2.6) compared with abatacept monotherapy [19]. therefore, the therapeutic choice should take into Higher ACR50 and ACR70 response rates were observed account the peculiarities of each drug in terms of safety with rituximab + MTX compared with rituximab alone and cost. (level of agreement: 9.31) (the groups were compared with MTX monotherapy) [75]. The available bDMARDs have similar levels of effective- In a randomized trial, tocilizumab monotherapy was ness for the number of painful or swollen joints, disease not significantly different from tocilizumab + MTX for activity, quality of life, functional capacity, and pain con- ACR50 and ACR70 responses, dropout due to adverse trol [16, 57–62]. However, total annual costs of treat- events, severe adverse events, and functional capacity ment vary among the different bDMARDs and these after 24 weeks of treatment. However, other randomized differences need to be taken into consideration at the trial found higher remission rates (DAS28 < 2.6) and time of drug selection (low to moderate evidence) [63]. lower radiographic progression with tocilizumab + MTX All bDMARDs have consistently demonstrated superior compared with tocilizumab monotherapy [77–79]. efficacy when used in combination with MTX compared The use of csDMARD in combination with bDMARD with MTX monotherapy [24, 40]. appears to reduce the formation of antibodies against Patients using bDMARDs compared with those using the biological agent, secondary failure. Studies that used csDMARDs have an increased risk of severe infections bDMARDs combined with csDMARDs, such as lefluno- [64–68]. In general, different bDMARDs have similar mide, confirmed the efficacy of this combination strat- levels of safety. Some SLRs of randomized trials have re- egy, particularly in patients who presented adverse ported a possible increase in the incidence of severe infec- events or contraindications to MTX [80, 81]. tions with the use of certolizumab in the (indirect) comparison with other bDMARDs (moderate evidence), Recommendation 8: In case of failure of an initial treatment but this result has not been observed in registry studies scheme with bDMARD, a scheme with another bDMARD [65–67, 69]. Lower intestinal perforation was more com- can be used. In cases of failure with TNFi, a second mon in patients treated with tocilizumab (moderate evi- bDMARD of the same class or with another mechanism of dence) [70]. Tuberculosis (TB) was more common in action is effective and safe. (level of agreement: 9.37) TNFi users than non-TNFi users. Among TNFi users, TB The use of another bDMARD is safe and effective after was more common in patients treated with adalimumab therapeutic failure of an initial treatment with bDMARD and infliximab compared with those treated with etaner- [24, 82]. When the first bDMARD was an TNFi agent, cept (moderate evidence) [68]. There were no differences the use of another TNFi agent was safe and effective in among the bDMARD in the incidence of herpes zoster or cases of treatment failure [83, 84]. neoplasia except for a possible increase in the rate of mel- Abatacept (high evidence), rituximab (high evidence), anoma with the use of TNFi (very low evidence) [64, 71]. golimumab (moderate evidence), and tocilizumab (mod- erate evidence) were better than placebo for decreasing Recommendation 7: The combination of bDMARD and the number of painful and swollen joints after failure of MTX is preferred over the use of bDMARD alone. (level of TNFi treatment [82, 85–87]. agreement: 9.87) Indirect comparisons did not allow the determination bDMARDs are more effective when combined with of superiority among abatacept, golimumab, rituximab, csDMARDs, particularly MTX [19, 72–75]. or tocilizumab in ACR50 and ACR70 responses when Adalimumab + MTX improved ACR20, ACR50, ACR70, used after failure of the first bDMARD [88]. The risk of and ACR90 responses and functional capacity and pain adverse events, including severe ones, and severe Mota et al. Advances in Rheumatology (2018) 58:2 Page 8 of 17 infections caused by these four biologicals after failure of dose reduction or dose interval increase, should be the first bDMARD, was similar to placebo. treated with another bDMARD or tsDMARD [113]. Although the use of a second TNFi agent after failure However, in patients with established RA and low dis- of the first is safe and effective, some studies suggest su- ease activity or remission, bDMARD dose reduction or a perior results for the ACR20 response, EULAR response dose interval increase should be evaluated on an individ- criterion, and disease activity reduction when switching ual basis [107–112, 114–116]. to a bDMARD with a different mechanism of action [82, Lowering the bDMARD dose reduces costs (high evi- 87, 89, 90]. These data must be confirmed in further dence) [114, 117]. studies. In other countries, rituximab has been shown to be the most cost-effective alternative among bDMARDs Therapeutic strategies for treating RA in Brazil for the treatment of patients with previous failure to Treatment with DMARDs should be initiated as soon as the TNFi (very low evidence) [82, 85–87, 89, 91]. diagnosis of RA is established. Treatment should be adjusted However, these results cannot be directly applied to as necessary by frequent clinical reassessments at 30–90-day the Brazilian context. intervals. Therapeutic strategies based on specific goals pro- duce better outcomes for disease activity and functional cap- acity, with less radiographic structural damage compared Recommendation 9: Tofacitinib can be used to treat RA with conventional treatments [4, 6, 113]. The goal is sus- after failure of bDMARD. (level of agreement: 9.81) tained remission [118, 119] or at least low disease activity, as Tofacitinib + MTX is effective after failure of TNFi, pro- assessed by a composite measure of disease activity, also tak- moting a rapid and favorable ACR20 response and improv- ing into consideration the absolute decrease in the compos- ing functional capacity and disease remission [92–97]. ite measure score (Tables 4, 5,and 6)[7, 113]. There are no available radiographic progression data for the use of tofacitinib after failure of bDMARD. First-line treatment: csDMARD First scheme Recommendation 10: Corticosteroids, preferably at low MTX is the first-choice csDMARD [6, 40, 120]. MTX doses for the shortest possible time, should be may be initially prescribed as monotherapy or in com- considered during periods of disease activity, and the bination with other csDMARD (example: MTX + lefluno- risk-benefit ratio should also be considered. (level of mide) [17]. Subcutaneous MTX is an alternative to cases agreement: 9.81) of drug intolerance or poor response to oral MTX before Corticosteroids are effective in treating RA when com- changing or adding other csDMARD. Subcutaneous MTX bined with csDMARD. Most of the analyzed studies used is better tolerated and has greater bioavailability, poten- oral prednisone. The use of corticosteroids in RA reduced tially improving clinical efficacy compared with oral ad- pain [98] (moderate evidence) and radiographic progres- ministration at the same dose [39]. sion (high to low evidence) [99–102]. Prednisone + MTX In cases in which MTX is contraindicated, sulfasala- compared with MTX alone reduced the need to switch zine [28] or leflunomide [25] may be used as the first treatment to bDMARD and did not increase the rate of option. Hydroxychloroquine (or when unavailable, adverse events [103]. However, low doses (≤10 mg/day of chloroquine) may be used in monotherapy in cases of prednisone or equivalent) for the shortest possible time undifferentiated arthritis or disease with low potential are recommended for managing periods of increased dis- for the development of radiographic erosions [6]. ease activity and minimizing adverse events. Special cau- tion is necessary in patients with comorbidities that are Second scheme potentially aggravated by corticosteroids. In cases in which there is no clinical response in 3 months or the therapeutic goal (sustained remission or low disease Recommendation 11: Reducing or spacing out bDMARD activity according to a composite measure of disease activ- doses is possible in patients in sustained remission. (level ity) is not achieved within 6 months with an optimum of agreement: 9.31) dose of MTX or in the presence of adverse effects, it is Patients using bDMARD combined with csDMARD and recommended to switch MTX for another csDMARD in in sustained remission (for at least 6 months) according monotherapy, such as leflunomide [25] or sulfasalazine to any composite disease activity index may receive [28], or a combination of MTX and other csDMARDs [41, lower bDMARD doses or the dose interval may be in- 46]. The suggested combinations are MTX + hydroxy- creased (moderate to low evidence) [104–112]. chloroquine + sulfasalazine [41] or MTX + leflunomide Patients with recent-onset RA (less than 6 months of [121]. Therapeutic progression should be rapid, with symptoms) and low disease activity, suggestive of re- monthly assessments in the first 6 months of treatment sidual inflammation, rather than undergoing bDMARD and adjustment of doses and schedules as needed. Mota et al. Advances in Rheumatology (2018) 58:2 Page 9 of 17 Table 4 Composite measures of disease activity used in rheumatoid arthritis: components, calculation formula, and range of results Components SDAI CDAI DAS28 (with 4 variables) Number of swollen joints (0–28) (0–28) Square root of the simple sum Simple sum Simple sum Number of painful joints (0–28) (0–28) Square root of the simple sum Simple sum Simple sum Acute phase reagents CRP – ESR 2–100 mm (0.1–10 mg/dL) or CRP 0.1–10 mg/dL logarithmic transformation Global health assessment – 0–100 mm (Patient) Assessment of disease activity (0–10 cm) (0–10 cm) – (Patient) Assessment of disease activity (0–10 cm) (0–10 cm) – (Examiner) Total index Simple sum Simple sum Calculation formula (requires a calculator) Index variation (0.1–86.0) (0–76) (0.49–9.07) CDAI, clinical disease activity index; DAS28, disease activity index (28 joints); CRP, C-reactive protein; SDAI, simplified disease activity index; ESR, erythrocyte sedimentation rate. Assuming a variation of 2 to 100 mm/h for ESR and of 0.1 to 10 mg/dL for CRP [6, 142]. Corticosteroids, analgesics, and non-steroidal anti- (low evidence) and improve functional capacity (low evi- inflammatory drugs dence) in RA [122–127]. NSAIDs may be useful primarily Low doses of corticosteroids (maximum of 10 mg/day of at disease onset (because DMARDs do not have immedi- prednisone or equivalent) may be used at the beginning of ate action) and in cases of RA exacerbation [128, 129]. treatment or when disease worsens. However, treatment The choice of NSAID should be individualized because for the shortest possible time is recommended to reduce there is no demonstrated superior efficacy of one NSAID the occurrence of adverse events. Intra-articular cortico- over another. Use for the shortest possible time is rec- steroids may be used when necessary for symptom con- ommended. Additional caution is necessary in cases of trol, particularly for monoarticular or oligoarticular risk factors for adverse events caused by NSAIDs, in- arthritis [6]. Common analgesics (paracetamol and dipyr- cluding advanced age, systemic arterial hypertension, one) and weak opioids (tramadol and codeine) may be heart failure, renal or hepatic dysfunction, gastrointes- used on demand for the control of pain symptoms [6]. tinal disease, arterial insufficiency, and coagulation disor- Non-steroidal anti-inflammatory drugs (NSAIDs) re- ders [130]. duce pain (low to moderate evidence) and disease activity Second-line treatment: bDMARD or tsDMARD The use of bDMARD or tsDMARD is recommended in Table 5 Definition of the status of activity of rheumatoid cases in which there is no clinical response after arthritis and respective cutoff points using composite disease 3 months using the second scheme of the first-line treat- activity indices ment, the therapeutic goal is not achieved in 6 months Index Disease activity status Cutoff points (remission or low disease activity according to a com- SDAI Remission ≤5 posite measure of disease activity), or in cases of drug Low > 5 and ≤ 20 toxicity or intolerance. Moderate > 20 and ≤ 40 The bDMARD drugs used in the second-line treat- High > 40 ment are TNFi (adalimumab, certolizumab, etanercept, CDAI Remission ≤2.8 golimumab, or infliximab), T-lymphocyte costimulation modulator (abatacept), and IL-6 receptor blocker (toci- Low ≤10 lizumab), combined with csDMARD (preferably MTX) Moderate > 10 and ≤ 22 [24, 41, 58, 94, 95]. High > 22 Tocilizumab demonstrated similar efficacy in mono- DAS28 Remission ≤2.6 therapy compared to tocilizumab + MTX for most of Low > 2.6 and ≤ 3.2 the relevant clinical outcomes [58, 77, 131]. Moderate > 3.2 and ≤ 5.1 Adalimumab, etanercept, certolizumab, golimumab, and abatacept can be used in monotherapy [16], but High > 5.1 their efficacy may be lower compared with the combina- CDAI, clinical disease activity index; DAS28, disease activity index (28 joints); SDAI, simplified disease activity index [142]. tions with csDMARDs [17]. Mota et al. Advances in Rheumatology (2018) 58:2 Page 10 of 17 Table 6 Classification of the therapeutic response in rheumatoid arthritis according to the variation in scores of the composite disease activity indices Index Response classification EULAR-DAS28 response Good: drop ≥ 1.2 points, reaching DAS28 ≤ 3.2 Moderate: drop > 1.2 points, maintenance of DAS28 > 3.2; or drop > 0.6 and ≤ 1.2 points, reaching DAS28 ≤ 5.1 Unresponsive: drop > 0.6 and ≤ 1.2 points, maintenance of DAS28 > 5.1; or drop ≤0.6 points SDAI and CDAI response Good: drop ≥ 85% in the score value Moderate: decrease ≥70 and < 85% in the score value Weak: drop ≥ 50% and < 70% in the score value Unresponsive: drop < 50% in the score value CDAI, clinical disease activity index; DAS28, disease activity index (28 joints); SDAI, simplified disease activity index [142–144]. Different bDMARDs have similar levels of clinical effi- (indicating primary failure to bDMARD or tsDMARD), cacy and safety [24, 42, 120]. Therefore, bDMARDs or loss of the previous response (secondary failure to should be chosen on an individual basis, taking into ac- bDMARD or tsDMARD), or cases of drug toxicity or count the costs and the presence of comorbidities that intolerance. may be positively or negatively affected by the treatment The drugs available for the third-line treatment are the choice. There is not necessarily a preference for one bDMARDs TNFi (adalimumab, certolizumab, etaner- mechanism of action relative to another for treating RA. cept, golimumab, or infliximab), T-lymphocyte co- The tsDMARD tofacitinib may be prescribed as the stimulation modulator (abatacept), IL-6 receptor blocker second line of treatment, preferably in combination with (tocilizumab), anti-CD20 (rituximab), and the tsDMARD MTX [41] or in monotherapy in cases of contraindica- tofacitinib, combined with csDMARD (preferably MTX) tion to MTX. However, because of the higher availability [96]. Rituximab, when considered, should be indicated of long-term safety and real-life data for bDMARDs, at to patients with positive RF or anti-CCP [96, 132]. present these regimens are preferred as the second-line When a bDMARD is used as the second-line treat- treatment, and tsDMARDs are considered an alternative ment, switching to another bDMARD or to a tsDMARD to bDMARDs [9]. Although evidence supports the use is recommended as the third-line treatment. A second of the bDMARD rituximab after failure of csDMARD, TNFi drug (particularly in cases of secondary failure), anti-CD20 is formally approved for treating RA only switching to a bDMARD with a different mechanism of after TNFi failure and has been used as the third-line action (abatacept, tocilizumab, or rituximab) [82]or treatment in this therapeutic strategy. Nonetheless, ri- switching to a tsDMARD (tofacitinib) is recommended tuximab may be considered as the first choice among in cases in which the first bDMARD is a TNFi [82, 97]. bDMARDs for patients with rheumatoid factor (RF) or Patients with failure to a first TNFi show improvements antibodies against citrullinated cyclic peptide (anti-CCP), with a second TNFi [24, 59, 84, 91]. However, there are with contraindications to other bDMARDs, or an associ- uncertainties about the cost-effectiveness of this strategy ated diagnosis of lymphoma [132]. Patients with poor because it can result in lower response rates compared prognosis factors [5], including high disease activity, with switching the mechanism of action [87, 90, 91]. If high number of painful or swollen joints, high RF and/or the first bDMARD is not a TNFi, the options include anti-CCP titers, and early occurrence of radiographic prescribing another bDMARD with a mechanism of ac- erosions, may benefit from a more aggressive treatment, tion distinct from that of the first bDMARD (including including indication of a bDMARD after failure of the TNFi) or the use of tsDMARD. first csDMARD scheme, although more evidence is re- When a tsDMARD is used as the second-line treat- quired to support this indication. ment, the option for the third-line treatment is switching There is no evidence of cost-effectiveness supporting to bDMARDs. However, this strategy requires careful the use of bDMARD as the first-line treatment for RA clinical observation because there is no available evi- in Brazil. The concomitant use of two bDMARDs or one dence to date on the efficacy and safety of the sequential bDMARD combined with a tsDMARD is not recom- use of bDMARDs after failure of tsDMARD (tofacitinib). mended [42]. Until specific information is available, caution is advised on the sequential use of drugs that interfere with IL-6 Third-line treatment: After failure of the first bDMARD or (tocilizumab) and the JAK-STAT signaling pathway (tofa- tsDMARD citinib) in patients with toxicity to any of these medica- The third-line treatment is used in cases the therapeutic tions because the effects of IL-6 are mediated by the goal (sustained remission or low disease activity accord- JAK-STAT pathway [40]. ing to a composite measure of disease activity) is not The treatment sequence depends on the specificities achieved in 6 months using the second-line treatment of each case and the discretion of the physician. In the Mota et al. Advances in Rheumatology (2018) 58:2 Page 11 of 17 case of failure or toxicity to a drug used in the third line defined by the simultaneous presence of two require- of treatment, the next step is to switch to another ments [1]: the expected clinical outcome using the (bDMARD or tsDMARD) with the same level of com- bsDMARD is similar to that produced by the corre- plexity and that has not been used previously. A mini- sponding boDMARD in any patient [2]; repeated switch- mum of 3 months and maximum of 6 months of clinical ing between the boDMARD and the bsDMARD evaluation are recommended before switching a thera- presents no additional safety or efficacy risk compared peutic regimen due to poor clinical response. with the continued use of the reference product [141]. The SBR advocates the need for an objective demon- Gradual reduction of medication dose and treatment stration of interchangeability between any boDMARD discontinuation and its correspondent bsDMARD using studies specific- There are no data to support setting any limit for the ally designed for this purpose. Until such studies are RA treatment duration. However, patients using available and interchangeability conditions are regulated bDMARD in sustained remission may receive a in Brazil, boDMARDs should not be automatically re- bDMARD dose reduction or dose interval increase. Al- placed with bsDMARDs without the consent of the pre- though disease reactivation may occur in some cases, scriber and patient. disease control is usually reestablished with the return to the previous dose schedule (moderate to low evi- Pharmacological treatment flowchart for RA in Brazil dence) [19, 23, 104, 105, 114, 133]. In cases of complete The therapeutic strategies proposed by the RA Commit- and sustained remission (at least 6 months), gradual and tee of the SBR for RA treatment in Brazil are summa- careful treatment withdrawal may be attempted in the rized in Fig. 1. following sequence: first NSAIDs, followed by cortico- steroids, and bDMARD or tsDMARD, but maintaining Treatment monitoring the use of csDMARD. After the withdrawal of For patients with active disease, especially in the initial bDMARD, if sustained clinical remission is maintained, phase of the disease (first 6 months of manifestations), reduction of the csDMARD dose can be carefully intensive follow-up with monthly visits and, when neces- attempted. Exceptionally, withdrawal of csDMARD sary, rapid treatment escalation are recommended [6]. might be feasible in cases in which clinical remission The efficacy and safety of the therapeutic intervention continues to be sustained [40, 116]. should be evaluated at each visit considering the comor- Sustained drug-free remission is rare, and the prob- bidities of the patient and aiming to achieve the lowest ability of disease exacerbation (flares) is higher in pa- possible disease activity (if remission is not possible), as tients with long-standing disease, the presence of well as improve function and quality of life. Visits can be synovitis on ultrasound (gray scale or power Doppler), spaced out for patients with established disease, particu- and a positive anti-CCP [116]. larly those with controlled disease [6]. The clinical history of patients who are eligible for Biosimilar drugs treatment with bDMARD should be analyzed for the Biosimilar bDMARDs (bsDMARDs) are very similar to presence of severe active infection, TB, or untreated la- their original bDMARDs (boDMARDs) regarding qual- tent TB, moderate to severe heart failure, multiple scler- ity, molecular structure, biological activity, clinical effi- osis or optic neuritis, previous hypersensitivity to TNFi, cacy, safety, and immunogenicity in comparability tests, malignancy or lymphoma, and congenital or acquired and these drugs fulfill strict regulatory criteria [134]. immunodeficiency. Complementary examinations to bsDMARDs have been shown to be safe and effective identify hepatitis B virus, hepatitis C virus, and HIV, as when used as an alternative to boDMARDs (moderate well as chest X-ray and the tuberculin test, should be evidence). There were no differences in ACR20 and part of the pretreatment evaluation [6]. ACR70 response rates, disease activity (moderate evi- dence), or severe adverse events of the bsDMARDs Conclusions adalimumab, etanercept, infliximab, and rituximab Advances in RA diagnosis and treatment have allowed compared with their respective boDMARDs [134–140]. improvements in disease outcome. The presence of a The development of anti-drug antibodies was similar rheumatologist is critical in evaluating and treating pa- between bsDMARDs and boDMARDs (moderate evi- tients with RA because these professionals are trained to dence), and lower for the bsDMARD of etanercept make an early diagnosis and are familiar with the avail- compared with the boDMARD (high evidence) [134]. able drug therapies, indications, management, and ad- However, the demonstration of biosimilarity should verse events. not be understood as evidence of interchangeability. The Brazilian scenario has specificities that require Interchangeability, when referring to bsDMARDs, is attention, including the local availability of medications Mota et al. Advances in Rheumatology (2018) 58:2 Page 12 of 17 and the socioeconomic status of the population. Brazil Roche). Financial competing interest: none. Non-financial competing interest: none. is a large country with a growing population, requiring Cleandro Pires de Albuquerque Personal fees and/or non-financial support rational allocation of resources to allow broad and from Pfizer, Abbvie, AstraZeneca, Janssen, Bristol-Myers-Squibb, Roche, equitable access of the population to medications and Novartis and UCB, outside the submitted work. Geraldo da Rocha Castelar Pinheiro Consultants for: Abbvie, Bristol-Myers other health technologies. Squibb, Eli Lilly, Glaxo Smith Kline, Janssen, Pfizer, Sanofi Genzyme and The recommendations presented herein seek to provide Roche. scientific evidence to Brazilian rheumatologists, consider- Ieda Maria Magalhães Laurindo Consultants for Abbvie, Bristol, GSK, Janssen, Lilly, Pfizer and UCB; has received personal or institutional support from ing the therapeutic efficacy, safety, and costs, together Abbvie, Bristol, Janssen, Lilly, Pfizer, UCB; has delivered speeches at events with the critical assessment and experience of a panel of related to this work and sponsored by Abbvie, Bristol, Janssen, Lilly, Pfizer, experts to standardize the management of RA in the na- Roche and UCB. Ivanio Alves Pereira Has received consulting fees,speaking fees and tional socioeconomic context, but maintaining the auton- supporting for internationals congresses from Roche,Pfizer, Janssen, Novartis, omy of the physician in choosing different therapeutic Bristol-Myers-Squibb, UCB Pharma, Eli-Lilly, AbbVie, and EMS. options. These recommendations should be updated peri- Manoel Barros Bertolo Has participated in clinical and/or experimental studies related to this work and sponsored by the PI (Roche); has delivered odically because of the rapid development of this field of speeches at events related to this work and sponsored by the PI (Abbvie, knowledge. The 2017 SBR recommendations and support- Pfizer). Financial competing interest: none. Non-financial competing interest: ing documents could be accessed online none. Mariana Peixoto Guimarães Ubirajara Silva de Souza Support in Congresses: UCB, Roche, Janssen Lectures with fee: UCB, Janssen, Abbvie, Pfizer, Roche, Additional file BMS Clinical research: GSK, UCB, Abbvie Advisory Board: Janssen. Max Vitor Carioca Freitas Speaker at events related to this work and sponsored by Abbvie, Novartis, Roche, Pfizer and UCB. Managing Partner of Additional file 1: Methodological details, expanded results and Integrare Therapeutics. rationale of the answers to the formulated questions of the SLR that Paulo Louzada Júnior Sponsored by: Bristol-Myers Squibb, UCB, Pfizer Board supported the present recommendations. (DOCX 980 kb) Participation: Pfizer. Ricardo Machado Xavier Lectures, consultancies: Abbvie, BMS, GSK, Janssen, Acknowledgements Lilly, Novartis, Pfizer, Roche, UCB Clinical trials: Abbvie, UCB, Pfizer, GSK, Lilly. The authors wish to acknowledge the researchers Tais Freire Galvão and Rina Dalva Neubarth Giorgi Has received consulting fees,speaking fees and Marcus Tolentino Silva, who performed the systematic review that is supporting for internationals congresses from Roche,Pfizer,Bristol-Myers- presented in detail in the Additional file 1, funded by the Brazilian Society of Squibb, UCB Pharma, Eli-Lilly,AbbVie,Abbott and EMS. Rheumatology. Funding Publisher’sNote Brazilian Society of Rheumatology. The funding body had no role in the Springer Nature remains neutral with regard to jurisdictional claims in design of the study and collection, analysis, and interpretation of data and in published maps and institutional affiliations. writing the manuscript. Author details Authors’ contributions 1 Programa de Pós-graduação em Ciências Médicas, Faculdade de Medicina- All authors made substantial contributions to the acquisition of data, have Universidade de Brasília; Serviço de Reumatologia, Hospital Universitário de been involved in drafting the manuscript or revising it critically for important 2 Brasília, Universidade de Brasília, Brasília, Brazil. Disciplina de Reumatologia, intellectual content, gave final approval of the version to be published and Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo have participated sufficiently in the work to take public responsibility for 3 Horizonte, Brazil. Centro Universitário de Brasília- UniCEUB, Brasília, Brazil. appropriate portions of the content; and agreed to be accountable for all 4 5 Universidade Federal de Pernambuco, Recife, Brazil. Hospital Vera Cruz, Belo aspects of the work in ensuring that questions related to the accuracy or 6 Horizonte, Brazil. Serviço de Reumatologia, Departamento de Medicina integrity of any part of the work are appropriately investigated and resolved. Interna, Serviço de Reumatologia, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Serviço de Ethics approval and consent to participate Reumatologia, Hospital Universitário de Brasília, Universidade de Brasília, Not applicable. Brasília, Brazil. Disciplina de Reumatologia, Departamento de Medicina Interna, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil. 9 10 Competing interests Universidade Nove de Julho, São Paulo, Brazil. Universidade do Sul de Licia Maria Henrique da Mota Has received personal or institutional support Santa Catarina, Florianópolis, Brazil. Disciplina de Reumatologia, Faculdade from Abbvie, Janssen, Pfizer and Roche; has delivered speeches at events de Ciências Médicas, Universidade Estadual de Campinas, Campinas, Brazil. 12 13 related to this work and sponsored by Abbvie, Janssen, Pfizer, Roche and Santa Casa de Belo Horizonte, Belo Horizonte, Brazil. Universidade de UCB. Financial competing interest: none. Fortaleza, Fortaleza, Brazil. Disciplina de Reumatologia, Faculdade de Adriana Maria Kakehasi Research funds: CNPq, SBR, FAPEMIG Support for Medicina de Universidade de Ribeirão Preto, Universidade de São Paulo, Scientific Events: Abbvie, BMS, Janssen Lecture Fees: UCB, Janssen, Pfizer, Ribeirão Preto, Brazil. Serviço de Reumatologia, Hospital do Servidor Roche, BMS Clinical research: Roche, Pfizer Advisory board: Janssen, Roche, Público Estadual de São Paulo, Instituto de Assistência Médica ao Servidor BMS, Pfizer. Público Estadual, São Paulo, Brazil. Rheos, Centro Médico Lúcio Costa, SGAS Ana Paula Monteiro Gomides Assistance for participation in events: Pfizer. 610, bloco 1, salas T50- T51, L2 Sul, Asa Sul, Brasília, DF 70200700, Brazil. Angela Luzia Branco Pinto Duarte Lecture Fees: Janssen, BMS. Bóris Afonso Cruz Support for Scientific Events and Lecture Fees: Abbvie, Received: 5 March 2018 Accepted: 18 April 2018 BMS, Janssen, Novartis, Pfizer, Roche. Claiton Viegas Brenol Has participated in clinical and/or experimental studies related to this work and sponsored by the PI (Abbvie, BMS, Janssen, Pfizer and Roche); has received personal or institutional support from the PI References (Abbvie, BMS, Janssen, Pfizer and Roche); has delivered speeches at events 1. Silman A HM. Epidemiology of rheumatic diseases. Oxford University Press; related to this work and sponsored by the PI (Abbvie, Janssen, Pfizer and 2000. Mota et al. Advances in Rheumatology (2018) 58:2 Page 13 of 17 2. Minichiello E, Semerano L, Boissier M-C. 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Published: May 24, 2018

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