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ecommendations

ecommendations of the French Society for Rheumatology foranaging rheumatoid arthritis

écile Gaujoux-Vialaa,∗,1, Laure Gossecb,1, Alain Cantagrel c, Maxime Dougadosd,runo Fautrelb, Xavier Mariettee, Henri Nataf f, Alain Sarauxg,h, Sonia Tropei,ernard Combej

Department of Rheumatology, Nîmes University Hospital, EA 2415, Montpellier I University, 30029 Nîmes, FranceSorbonne Universities, UPMC Univ Paris 06, GRC 08, institut Pierre Louis d’épidémiologie et de santé publique; AP–HP, Department of Rheumatology, CHUitié-Salpetrière, 75013 Paris, FranceDepartment of Rheumatology, Purpan Hospital, CHRU de Toulouse, Paul Sabatier Toulouse III University, UMR Inserm 1043-CNRS 5282, 31059 Toulouse,ranceParis Descartes University – Department of Rheumatology –Cochin Hospital, Assistance Publique – Hôpitaux de Paris – INSERM (U1153): épidémiologielinique et biostatistiques, PRES Sorbonne Paris-Cité, 75014 Paris, FranceDepartment of Rheumatology, Paris-Sud Universities Hospital, AP–HP, Inserm U 1012, Paris Sud University, 92276 Le Kremlin Bicêtre, FranceCabinet de rhumatologie, 78200 Mantes la Jolie, Yvelines, FranceDepartment of rheumatology, CHU de la Cavale Blanche, boulevard Tanguy-Prigent, 29609 Brest, FranceEA 2216, Bretagne Occidentale University, 29200 Brest, FranceAssociation nationale de défense contre l’arthrite rhumatoïde (ANDAR), 75014 Paris, FranceDepartment of rheumatology, Lapeyronie Hospital, CHRU de Montpellier, Montpellier I University, UMR 5535, 34295 Montpellier, France

a r t i c l e i n f o

rticle history:ccepted 23 April 2014vailable online xxx

eywords:heumatoid arthritisecommendationsreatmentiologicslucocorticoid therapy

a b s t r a c t

Introduction: This article reports the latest recommendations of the French Society for Rheumatology(SFR) regarding the management of rheumatoid arthritis (RA).Methods: New recommendations were developed by hospital- and community-based rheumatologistshaving extensive experience with RA and a patient self-help organization representative. They rest onthe recently issued EULAR recommendations and a literature review.Results: Points emphasized in the 15 recommendations include the need to share treatment decisionsbetween the rheumatologist and the patient, the acquisition by patients of self-management skills, remis-sion or minimal disease activity as the treatment target, the need for initiating disease-modifying drugsas early as possible, and the usefulness of regular disease activity assessments to allow rapid treatmentadjustments if needed (i.e., tight disease control). First-line methotrexate monotherapy is recommended,with concomitant short-term glucocorticoid therapy if indicated by the risk/benefit ratio. Patients whofail this approach (no response after 3 months or target not achieved after 6 months) can be considered foranother synthetic disease-modifying antirheumatic drug (DMARD: leflunomide or sulfasalazine), com-
bined synthetic DMARD therapy, or methotrexate plus a biologic, depending on the prognostic factorsand patient characteristics. If the first biologic fails, switching to a second biologic is recommended. In theevent of a sustained remission, cautious dosage reduction of the biological and/after synthetic DMARDsis in order.Conclusion: These recommendations are designed to improve the management of patients with RA.
nc ais
© 2014 Société fra
. Introduction

Please cite this article in press as: Gaujoux-Viala C, et al. Recommerheumatoid arthritis. Joint Bone Spine (2014), http://dx.doi.org/10.10

Rheumatoid arthritis (RA) is the most common inflammatoryoint disease in adults, with an estimated prevalence of 0.3% to

∗ Corresponding author. Tel.: +33 4 66 68 31 20.E-mail address: [email protected] (C. Gaujoux-Viala).

1 The first two authors contributed equally to this work.

http://dx.doi.org/10.1016/j.jbspin.2014.05.002297-319X/© 2014 Société franc aise de rhumatologie. Published by Elsevier Masson SAS.

e de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.

1% in the general population of adults [1]. RA runs a chroniccourse marked by flares of synovial membrane inflammationthat can eventually cause joint destruction, thereby impairingquality of life and causing disability. In addition, RA is associ-ated with an estimated decrease in life expectancy of 10 years

ndations of the French Society for Rheumatology for managing16/j.jbspin.2014.05.002

[2–5]. The latest French recommendations for managing RAwere published in 2007 [6]. Since then, there have been sev-eral major changes in concepts (e.g., treat-to-target approach,dynamic treatment adjustment, and treatment optimization) and

All rights reserved.

dx.doi.org/10.1016/j.jbspin.2014.05.002


http://www.sciencedirect.com/science/journal/1297319X

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reatments (new data on existing treatments and introduction ofew drugs). The publication of new recommendations is thereforeimely.

These recommendations are intended for physicians whorovide care to RA patients, i.e., chiefly rheumatologists andrimary-care physicians. They should also prove useful to healthuthorities and patient self-help organizations. They deal with

range of issues extending from the diagnosis to the over-ll management of RA but focus chiefly on the drug treatmenttrategy.

. Methods

The French Society for Rheumatology (SFR) convened a taskorce composed of 8 hospital-based rheumatologists, 1 community-ased rheumatologist, and 1 representative of a patient self-helprganization. These 10 individuals came from various geographicegions throughout France. Their work referred to the 2007 rec-mmendations issued by the French National Authority for HealthHAS) and the HAS guidebook for chronic diseases (#22) [6] butelied chiefly on the recently published European League Againstheumatism (EULAR) recommendations for managing RA [7]. Inarticular, the task force directed careful attention to the resultsf the three vast systematic literature reviews that were per-ormed to prepare the EULAR recommendations by assessinghe efficacy of synthetic disease-modifying antirheumatic drugsDMARDs) [8], efficacy of biologics [9], and safety data [10],espectively. The task force developed the recommendations in013, improved them by conducting several consensus-buildingounds via email, and submitted them to a review group com-osed of 31 experts who included hospital- and community-basedheumatologists, SFR members, primary-care physicians, and aatient self-help organization representative. The comments anduggestions made by the review group were used to develophe final version of the recommendations. The level of evi-ence and grade of each recommendation were determined11].

. Results

Three general principles and 15 recommendations were devel-ped (Table 1) and recapitulated in algorithm format (Fig. 1).

.1. General principles about the management of rheumatoidrthritis (RA)

.1.1. The optimal management of patients with RA requires aialogue between the rheumatologist and patient to ensure thathe patient receives the information and education needed tohare in his or her management decisions

RA is a chronic disease and therefore requires that the patientontributes to his or her own management and follow-up (Table 1).he sharing of medical decisions is the foundation of the partner-hip between the patient and physician. To take informed decisionsegarding their own management, in partnership with the physi-ian, the patient must receive relevant information and education.herapeutic patient education is at the core of this recommenda-ion: it promotes patient self-sufficiency and the emergence of the


atient as a fully-fledged partner in the management process [6].herapeutic patient education can be delivered during formal ses-ions or via other means, particularly when formal sessions are notvailable.

PRESSe Spine xxx (2014) xxx–xxx

3.1.2. The rheumatologist is the specialist who should be incharge of managing patients with RA. The primary-care physicianplays a crucial role in detecting RA and in providing follow-up inconjunction with the rheumatologist

The rheumatologist is the specialist who should treat and mon-itor patients with RA. However, the primary-care physician is inan unique position to detect potential early RA and to rapidly referpatients with suspected RA to the rheumatologist. An early diag-nosis followed by prompt treatment initiation is key to improvingthe outcomes of RA management. Thus, the availability of effectiveand fast-moving chains of care is imperative [12]. The primary-carephysician also plays an essential role in organizing and coordinatingthe individualized management strategy, most notably regardingtreatment monitoring and comorbidity management. Patients withRA are at high risk not only for disabilities related to their joint dis-ease, but also for cardiovascular and respiratory disease, infection,lymphoma, and osteoporotic fractures [13,14].

3.1.3. The high cost of RA, its consequences, and its treatments forboth the individual and society should be considered whenmaking treatment decisions

The treatment of RA is costly, particularly since the advent ofbiologics [15,16]. However, the disease itself generates high indi-rect costs due to loss of productivity, work incapacitation, andsurgical procedures. The treatment decisions should therefore takeinto account not only the costs of treatment, but also the cost toindividuals and society of suboptimal disease management. Bio-logics are highly effective and can therefore decrease the mid-termand long-term costs of RA, for instance by decreasing the time spentoff work and the need for surgical procedures [17,18]. Thus, thetreatment decisions should be based chiefly on efficacy and safetydata, while also factoring in the costs of management.

3.2. Recommendations

3.2.1. Diagnosis and organization of the management of RA3.2.1.1. Recommendation 1. A diagnosis of RA should be:

• considered in patients with specific clinical findings such as jointswelling (clinical arthritis), morning stiffness lasting longer than30 minutes, and a positive hand or forefoot squeeze test;

• confirmed by laboratory tests (erythrocyte sedimentation rate[ESR], C-reactive protein [CRP], anti-citrullinated protein anti-bodies [ACPA], and rheumatoid factors [RFs]) and imaging studies(radiographs with or without ultrasonography), after ruling outthe differential diagnoses.

Optimal patient outcomes are obtained by initiating DMARDtherapy early after symptom onset [19].

Early recognition of suspected RA by the primary-care physicianfollowed by prompt patient referral to a rheumatologist is thereforecrucial. Clinically, the most telling finding is synovitis, particularlyat the finger joints and wrists. A positive squeeze test provides valu-able orientation: the pain is caused by putting pressure across themetacarpophalangeal and/or metatarsophalangeal joints [20].

Confirmation of the diagnosis of RA relies on a set of converg-ing arguments with special attention to the absence of clinicaland laboratory data pointing to another inflammatory joint dis-ease (Table 2). The most useful criteria are those developed jointlyby the American College of Rheumatology (ACR) and EULAR forclassifying RA [21] (Fig. 2). In patients with clinical synovitis in atleast one joint and no alternative diagnosis that better explains


the findings, a score ≥ 6/10 indicates RA (Fig. 2). Another impor-tant key to the diagnosis is the presence of specific antibodies (RFsand ACPA), which must be assayed (Table 2, Fig. 2). Imaging stud-ies should consist of anteroposterior radiographs of the hands and


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Table 12014 recommendations about the management of rheumatoid arthritis issued by the French Society for Rheumatology (SFR).

General principles and recommendations Level of evidence Group agreementaMean (SD)

General principlesThe optimal management of patients with RA requires a dialogue between the rheumatologist and patient toensure that the patient receives the information and education needed to share in his or her managementdecisions

NA 9.3 (1.2)

The rheumatologist is the specialist who should be in charge of managing patients with RA. The primary-carephysician plays a crucial role in detecting RA and in providing follow-up in conjunction with the rheumatologist

NA 9.6 (0.8)

The high cost of RA, its consequences, and its treatments for both the individual and society should beconsidered when making treatment decisions

NA 9.0 (1.4)

RecommendationsDiagnosis and organization of the management of RA B 9.4 (0.8)

1. A diagnosis of RA should beConsidered in patients with specific clinical findings such as joint swelling (clinical arthritis), morning stiffnesslasting longer than 30 minutes, and a positive hand or forefoot squeeze testConfirmed by laboratory tests (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], anti-citrullinatedprotein antibodies [ACPA], and rheumatoid factors [RFs]) and imaging studies (radiographs with or withoutultrasonography), after ruling out the differential diagnoses

2. As soon as RA is diagnosed, disease-modifying treatment must be initiated A 9.5 (1.0)3. The treatment target is a remission or minimal disease activity in every patient, with the goal of preventing

structural damage progression and the development of disabilitiesA 9.4 (0.8)

4. A clinical remission is defined as the absence of signs and symptoms of significant inflammatory activity.Disease activity should be measured using validated composite criteria, including joint indices

B 9.1 (1.1)

5. Follow-up should be provided at closely spaced intervals (every 1 to 3 months) as long as the disease isactive. Treatment adjustments are in order in patients who fail to improve within 3 months or to achieve theirtreatment target within 6 months

B 9.4 (0.8)

First-line treatment6. Methotrexate is the first-line DMARD in patients with active RA; the optimal dosage should be reached

within no more than 4–8 weeks.A 9.4 (0.9)

7. In DMARD-naive patients who have contraindications or early intolerance to methotrexate, leflunomideand sulfasalazine are good alternatives

A 9.2 (1.0)

8. While awaiting the effects of DMARD therapy, glucocorticoid therapy can be considered, in a lowcumulative dosage, if possible for no longer than 6 months. The glucocorticoid dose should be tapered aspromptly as possible

B 8.9 (1.6)

Second and subsequent lines of treatment9. In patients with an inadequate response or intolerance to methotrexate and

Presence of adverse prognostic factors, add-on biologic therapy may be considered (TNF� antagonist, abatacept,tocilizumab or, in specific situations, rituximabb)Absence of adverse prognostic factors, combined synthetic DMARD therapy(methotrexate/sulfasalazine/hydroxychloroquine) or a switch to another synthetic DMARD (leflunomide orsulfasalazine) are good treatment options. If this strategy fails or is contraindicated, biological therapy should beconsidered

D 9.0 (1.4)

10. All biologics are best used in combination with methotrexate A 9.3 (1.5)11. Patients who fail a first biological agent should be switched to another biological agent; patients having

failed a first TNF� antagonist can be given either a second TNF� antagonist or a biological agent with a differentmechanism of action

A 9.0 (1.2)

Managing disease remission and global patient management12. In patients with a sustained remission, after discontinuation of the glucocorticoid therapy (or tapering to a

dose ≤ 5 mg/day), a decrease in the biological agent dosage can be consideredB 9.1 (1.2)

13. In patients with a prolonged remission, a gradual decrease in the synthetic DMARDs can be considered, asa medical decision shared by the patient and physician

C 8.6 (1.5)

14. Treatment selection and adjustment should factor in a number of considerations in addition to measureddisease activity, such as structural disease progression, comorbidities, tolerance of the drugs, and the patient’swishes

C 9.6 (0.7)

15. Patients with RA should be offered a global management program including not only drug treatments, butalso therapeutic education, comorbidity management and, as appropriate, psychological support, assistancewith social and occupational issues, functional rehabilitation, and/or surgery

C 9.4 (1.0)

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rists, anteroposterior and oblique radiographs of the forefeet, and chest radiograph [6]. Patients who fail to meet the clinical andaboratory ACR/EULAR criteria but who have radiographic erosionsypical for RA can also be classified as having RA (Fig. 2). The EULARecently defined typical RA erosions as the presence of erosions int least three joints among the metacarpophalangeal joints, proxi-al interphalangeal joints, wrists, and metatarsophalangeal joints

22]. Finally, Doppler ultrasonography can be useful to confirm theresence of synovitis, monitor disease activity and progression, and


valuate persistent inflammation [23].

.2.1.2. As soon as RA is diagnosed, disease-modifying treatment muste initiated (recommendation 2). RA is a therapeutic emergency:

eing the highest possible grade. NA: not applicable.

early, specialized, personalized, multidisciplinary managementmust be provided immediately. The promptness with which treat-ment is initiated largely governs the patient outcomes. Abundantpublished data support the existence of this window of opportunityfor effectively treating RA [19,24–26]. Rapid initiation of effectivetreatment may increase the chances of achieving a remission, limitthe functional impairments, and decrease the degree of structuraldamage [12,27–29].


3.2.1.3. The treatment target is a remission or minimal disease activ-ity in every patient, with the goal of preventing structural damageprogression and the development of disabilities (recommendation3). Achieving a remission or minimal disease activity improves


Please cite this article in press as: Gaujoux-Viala C, et al. Recommendations of the French Society for Rheumatology for managingrheumatoid arthritis. Joint Bone Spine (2014), http://dx.doi.org/10.1016/j.jbspin.2014.05.002

ARTICLE IN PRESSG ModelBONSOI-4041; No. of Pages 11

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Fig. 1. Algorithm for the management of rheumatoid arthritis based on the 2014 recommendations issued by the French Society for Rheumatology (SFR).


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Table 2Routine laboratory tests required in patients with recent-onset polyarthritis [6].

Erythrocyte sedimentation rate and C-reactive proteinBlood cell countsTransaminasesSerum creatinine; urinary dipstick (proteinuria, hematuria)

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Rheumatoid factors and anti-citrullinated peptide antibodies (ACPA)Antinuclear antibodies (ANA)Viral serological tests: hepatitis B and C (as part of the pretreatment workup)

id-term and long-term structural and functional outcomes [30]nd may diminish the excess mortality, particularly due to cardio-ascular disease [31].

Achieving a remission should be the main treatment objectiven every patient, particularly in early-onset RA. The chances ofchieving a remission are lower in patients with advanced RAnd/or marked structural damage, and achieving minimal diseasectivity is an acceptable alternative in this situation [7].

.2.1.4. A clinical remission is defined as the absence of signs andymptoms of significant inflammatory activity. Disease activity shoulde measured using validated composite criteria, including joint indicesrecommendation 4). A clinical remission can be defined as thebsence of clinical signs and symptoms of inflammation. In practice,atients should be evaluated using composite activity indices suchs the Disease Activity Score 28 (DAS28), with values no greaterhan 2.6 indicating a remission and values no greater than 3.2 min-mal disease activity [32]. Other composite indices that includeoint counts can be used such as the Simplified Disease Activityndex (SDAI), with scores no greater than 3.3 indicating a remissionnd scores in the 3.3–11 range indicating minimal disease activity33]; or the Clinical Disease Activity Index (CDAI), for which theorresponding score values are ≤ 2.8 and 2.8–10 [34]. It is worthoting that the DAS28 is the least restrictive in defining a remis-ion [35] and that the DAS28-CRP, which is less restrictive thanhe DAS28-ESR, has no validated cutoffs for remission or minimalisease activity [36,37]. The new ACR/EULAR definition of RA remis-ion issued in 2011 requires values ≤ 1 for the tender and swollenoint counts, CRP level (mg/dL), and global evaluation by the patient0–10 visual analog scale [VAS]) [38]. However, even in the absencef objective evidence of inflammation, a non-negligible proportion


f patients have a global VAS score > 1/10 [39]. Thus, the ACR/EULARefinition of disease remission may be excessively restrictive forveryday practice. In situations that are challenging to evaluatee.g., fibromyalgia or pain due to sequelae), particular importance

ig. 2. Classification criteria for rheumatoid arthritis developed by the Americanollege of Rheumatology (ACR) and European League Against Rheumatism (EULAR)21].

PRESSe Spine xxx (2014) xxx–xxx 5

should be given to joint swelling and laboratory evidence of sys-temic inflammation. Other items not considered in these indicesmay be helpful such as morning stiffness duration, nocturnal awak-enings, pain intensity, and extra-articular manifestations.

3.2.1.5. Follow-up should be provided at closely spaced intervals(every 1 to 3 months) as long as the disease is active. Treatmentadjustments are in order in patients who fail to improve within 3months or to achieve their treatment target within 6 months (recom-mendation 5). Closely spaced follow-up evaluations and frequenttreatment adjustments (every 1 to 3 months) are required aslong as the treatment target has not been achieved. This con-cept of tight disease control with a dynamic treatment strategy[40] and a clearly defined objective constitutes the treat-to-targetapproach [41]. Tight disease control involves matching the treat-ment to the activity of the disease. The usefulness of this strategyhas been confirmed in numerous studies including meta-analyses[42]. Tight disease control improves the quality of disease control,decreases the need for surgical procedures, and decreases the riskof death and cardiovascular events such as myocardial infarction[43–45].

In patients who are not improved after 3 months (e.g., who donot have an at least 1.2-point improvement in the DAS28 or a tran-sition from high to moderate disease activity) and those who havenot achieved their treatment target (remission or minimal diseaseactivity) after 6 months, the treatment strategy should be reap-praised and, in most cases, the disease-modifying treatment shouldbe adjusted or changed.

The functional impact of the disease should be evaluated once ayear (e.g., using the Health Assessment Questionnaire). This eval-uation not only provides a snapshot of the current status of thepatient, but also predicts future outcomes (in terms of clinical man-ifestations, structural damage, work ability, and risk of death) [17].Structural disease progression should be evaluated on radiographsof the hands and feet obtained every 6–12 months the first yearthen once a year for 3–5 years, and subsequently at wider intervalsand whenever the treatment is changed.

3.2.2. First-line treatment3.2.2.1. Methotrexate is the first-line DMARD in patients with activeRA; the optimal dosage should be reached within no more than4–8 weeks (recommendation 6). Methotrexate is the recommendedfirst-line DMARD in RA based on its effectiveness, fairly goodsafety profile, and moderate cost [7,46–50]. The recommendedstarting dosage is 10–15 mg/week orally followed by rapid doseescalation (e.g., 5-mg increments every 1–4 weeks) to achieve theoptimal dosage of about 0.3 mg/Kg/week, i.e., 15–25 mg/week inmost patients, depending on effectiveness and safety, as well ason the specific characteristics of each patient. In the event of aninadequate treatment response or failure to tolerate methotrexate,subcutaneous administration of the drug can be considered. Finally,supplementation with at least 5 mg/week of folic acid at a distancefrom the methotrexate dose is recommended [51].

Methotrexate is thus the first-line drug in patients with activeRA. A major issue is whether methotrexate should be usedalone or combined with other synthetic DMARDs. A CochraneCollaboration meta-analysis published in 2010 found no improve-ment in the risk/benefit ratio with drug combinations comparedto methotrexate alone [52]. Two recent studies compared theclinical and structural efficacy of the triple drug combinationmethotrexate + sulfasalazine + hydroxychloroquine to methotrex-ate alone [53,54]. One of these studies, tREACH, was a randomized


controlled single-blind trial in patients with recent-onset RA athigh risk for progression to established RA but without specificcriteria of adverse prognostic significance [53]. Glucocorticoid ther-apy was given also. Some of the study parameters showed greater


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mprovements with the triple drug combination. The other study,EAR, involved tight disease control with dynamic treatmentdjustments to achieve a predefined target and found no differ-nces in clinical or radiographic outcomes between triple therapynd methotrexate alone [54]. The CareRA study done in Belgiumrovided new information in late 2013 [55]. This randomized con-rolled trial found no evidence that triple DMARD therapy wasetter than methotrexate alone (with glucocorticoid therapy inoth treatment arms) [55]. Finally, patient acceptance of triple ther-py is sometimes poor (e.g., due to the large number of tablets anddverse events), a fact that translates into low treatment continu-tion rates [56].

Thus, given the inadequate amount of consistent data,ethotrexate alone is recommended for the first-line treatment

f active RA.

.2.2.2. In DMARD-naive patients who have contraindications or earlyntolerance to methotrexate, leflunomide and sulfasalazine are goodlternatives (recommendation 7). In patients with contraindicationsr intolerance to methotrexate, leflunomide and sulfasalazine haveeen proven effective in alleviating the symptoms and decreasinghe structural damage [57]. A meta-analysis of randomized con-rolled trials showed similar efficacy of leflunomide or sulfasalazinend methotrexate, although the methotrexate dosages were subop-imal [57]. The usual dosage is 3 g/day for sulfasalazine [58,59] and0 mg/day for leflunomide. The absence of contraindications andood tolerance of these treatments should be checked. Hydrox-chloroquine can be useful in combination with other syntheticMARDs or with biologics but is not recommended alone in RAue to its weak and delayed clinical efficacy and absence of proventructural effects [57].

.2.2.3. While awaiting the effects of DMARD therapy, glucocorticoidherapy can be considered, in a low cumulative dosage, if possible foro longer than 6 months. The glucocorticoid dose should be tapered asromptly as possible (recommendation 8). Nearly one of every threeatients with RA receives long-term glucocorticoid therapy [60].owever, the risk/benefit ratio of glucocorticoid therapy remainsontroversial.

In addition to symptomatic effects, structural effects of glu-ocorticoids were documented in several studies [61–65]. Thetructural efficacy of glucocorticoid therapy has been proven onlyn recent-onset RA and over a treatment duration of 1–2 years [65].

recently reported 2-year randomized controlled trial (CAMERAI) compared methotrexate alone to methotrexate plus prednisone0 mg/day [66]. After 2 years, the modified Sharp erosion scoreprimary outcome measure) was significantly lower in the gluco-orticoid group, which also had significantly fewer patients free ofadiographic disease progression (78% versus 67% with the placebo)66]. However, the use of a 10-mg prednisone dose for 2 years raisesoncerns, particularly regarding safety.

In a meta-analysis, the rate of adverse events in RA patientseceiving glucocorticoid therapy was 43/100 patient-years (95%onfidence interval, 30–55) [67]. A case-control study in RA patientslder than 65 years of age showed an increased risk of severe infec-ion that was proportional not only to the current glucocorticoidosage but also to the cumulative dosage over 2–3 years [68].he excess risk of severe infection occurred even with low-doserednisone therapy (5 mg/day). In addition, two recent studies doc-mented an increase in mortality among patients taking more than

mg/day of glucocorticoids [31,69].The task force took into account these data on the efficacy and


id-term safety of glucocorticoid therapy combined with DMARDs.ecommendation #8 supports low-dose prednisone therapy, inombination with a DMARD, in patients with active RA, mostotably early in the course of the disease; but also advises


restrictions regarding the dosage and duration of prednisone ther-apy. A daily dosage of 0.15 mg/Kg can be suggested as a guide butshould be tapered as promptly as possible. The maximum treat-ment duration of 6 months, although not substantiated by strongevidence, nevertheless generated a consensus among the task forcemembers given the data in the literature. Although the cumulativedose is important to consider in individual patients, a strict rec-ommendation applicable to the majority of patients is difficult todevelop. An alternative to daily oral glucocorticoid therapy is par-enteral methylprednisolone therapy, 80 to 120 mg, which has theadvantage of avoiding weaning difficulties [53].

In every case, as with all treatments, glucocorticoid therapyrequires a careful risk/benefit assessment in each individual patientand routine measures to prevent adverse effects, most notablyglucocorticoid-induced osteoporosis [70].

Intra-articular glucocorticoid injections are often used as analternative or adjunct to systemic glucocorticoid therapy. They canalleviate the local symptoms and inflammation and induce few sideeffects [71].

3.2.3. Second and subsequent lines of treatment3.2.3.1. Inadequate response or intolerance to methotrexate (rec-ommendation 9). In patients with an inadequate response orintolerance to methotrexate and:

• presence of adverse prognostic factors, add-on biologic therapymay be considered (TNF� antagonist, abatacept, tocilizumab or,in specific situations, rituximab2);

• absence of adverse prognostic factors, combined syntheticDMARD therapy (methotrexate/sulfasalazine/hydroxychloro-quine) or a switch to another synthetic DMARD (leflunomide orsulfasalazine) are good treatment options. If this strategy fails oris contraindicated, biological therapy should be considered.

This recommendation differentiates two strategies based on theprognostic factors. Outcome prediction relies in particular on thecombination of the following criteria: presence or progression ofstructural damage (the main criterion), marked clinical and/or lab-oratory activity, and high titers of rheumatoid factors and/or ACPA[72–75].

In patients with an inadequate response or intolerance tomethotrexate but no factors of adverse prognostic significance,the recommended treatment is either combined synthetic DMARDtherapy (e.g., methotrexate + sulfasalazine + hydroxychloroquine)or substitution of another synthetic DMARD for the methotrexate.The role for combination synthetic DMARD therapy was recentlya focus of controversy, as discussed in part in recommendation #6(Section 3.2.2.1). The task force considered that the triple drug com-bination should not be used for the first-line treatment of RA but issupported by recent data for the second-line treatment of patientswho have no factors of adverse prognostic significance. A suggestedalternative consists in switching to another synthetic DMARD usedalone [76].

In patients with factors of adverse prognostic significance(structural damage, marked clinical and/or laboratory activity, highRF and/or ACPA titers), add-on biological therapy can be consid-ered. The biologics licensed for use in this indication are TNF�antagonists (four given subcutaneously, namely, adalimumab,


All these biological agents have been proven effective in alleviat-

2 In particular, in the event of contraindications to other biologics.


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ng the symptoms and slowing structural disease progression inatients with RA refractory to methotrexate [9,77]. The task forceas unable to identify one of these biologics as preferable over the

thers, since the efficacy and safety profiles were similar in severaleta-analyses and a few head-to-head trials; and since no factors

redicting the response to a given biologic are available to date foruiding drug selection [78–80]. It is worth noting, however, thaturrent practice favors the initial use of a TNF� antagonist, givenhe 15 years of clinical experience and excellent structural efficacyhat characterize this drug class.

Rituximab is not licensed for use as a first-line biological agent inA. However, rituximab therapy can be considered in uncommonituations that generate difficulties in using other biological agents.n particular, the task force pointed out that rituximab may be aood choice in patients with a history of cancer within the past

years, a history of lymphoma, latent tuberculosis with an obstacleo effective chemoprophylaxis, a high risk of tuberculosis, and aistory of multiple sclerosis.

.2.3.2. All biologics are best used in combination with methotrex-te (recommendation 10). There is no published evidence that

TNF� antagonist, rituximab, or abatacept alone is superiorver methotrexate alone. In contrast, adding at least 10 mg/weekf methotrexate increases the efficacy of biologic therapy81,82].

In addition, combining methotrexate with a biologic agentmproves the biologic treatment continuation rate in RA. In theutch DREAM registry, for instance, the 1337 patients given a TNF�ntagonist combined with methotrexate had better continuationates compared to the 355 patients given a TNF� antagonist andnother synthetic DMARD, and continuation was lowest in the 261atients given a TNF� antagonist alone [83].

Tocilizumab is in a unique position, as several studies foundetter outcomes with tocilizumab alone than with methotrexatelone [84–87]. In the ACT-RAY randomized controlled trial in 556atients with RA refractory to methotrexate therapy alone, add-onocilizumab was compared to switching to tocilizumab. Whereashe 6-month data suggested similar efficacy with these two strate-ies, after 1 year a trend was found toward better outcomes withocilizumab plus methotrexate compared to methotrexate alone88].

Thus, regardless of the biologic chosen, a synthetic DMARD,hiefly methotrexate, should be given concomitantly. Other syn-hetic DMARD options are leflunomide and even sulfasalazine89,90]. However, should a biological agent have to be usedlone, there is evidence that tocilizumab may constitute the besthoice.

.2.3.3. Patients who fail a first biological agent should be switched tonother biological agent; patients having failed a first TNF antagonistan be given either a second TNF antagonist or a biological agent with

different mechanism of action (recommendation 11). Failure of arst biological agent warrants a switch to another biological agent

f warranted by the activity of the disease.After failing a TNF� antagonist, patients may be given another

NF� antagonist, abatacept, rituximab, or tocilizumab. In thisituation, there is no clear evidence that one biological agent pro-ides better efficacy than the others [91] and the choice thereforeepends chiefly on the medical history of the patient and theharacteristics of the drug (route of administration, half-life, anddverse events). For instance, rituximab may be useful in patientsith a recent history of cancer or recent treatment for active tuber-


ulosis. The preliminary data from the French ROC trial of treatmenttrategies in patients with an inadequate response to TNF� antag-nist therapy suggest that a biological agent having a differentechanism of action (abatacept, rituximab, or tocilizumab) may


provide greater efficacy than a second TNF� antagonist [92]. How-ever, this finding was not confirmed in a Dutch study comparing asecond TNF� antagonist to abatacept or rituximab [83]. It may beof interest to distinguish primary failure (no response to the TNF�antagonist) and secondary escape phenomenon (initial responsethat wanes over time). The probability of a response to a secondTNF� antagonist may be greater when the first TNF� antagonistwas stopped because of escape phenomenon as opposed to pri-mary failure [93,94]. The task force considered that studies of TNF�antagonist therapy monitoring (serum drug assays and assays ofantibodies to biologics) should be continued to try to assist clini-cians in selecting the best second-line biologic after failure of TNF�antagonist therapy [95].

3.2.4. Managing disease remission and global patientmanagement3.2.4.1. In patients with a sustained remission, after discontinuationof the glucocorticoid therapy (or tapering to a dose ≤ 5 mg/day), adecrease in the biological agent dosage can be considered (recommen-dation 12). The definition of a sustained remission is not universallyagreed on but is usually considered as involving the persistence ofthe remission for at least 6 months. Studies of patients with long-standing RA showed that relapses were common after abrupt TNF�antagonist therapy discontinuation [96–98] and that a strongerand more lasting therapeutic response before discontinuation pre-dicted a greater probability of a sustained response with syntheticDMARD therapy alone [96]. Biological agent dosage de-escalationmay be a better strategy than sudden discontinuation [99]. TheFrench STRASS study is a randomized controlled double-blind trialcomparing a gradual increase in the TNF� antagonist dosing inter-val to keeping the interval unchanged in patients on etanercept oradalimumab combined with a glucocorticoid ≤ 5 mg/day after atleast 6 months of DAS28 remission [100]. After 18 months, increas-ing the TNF� antagonist dosing interval had proven feasible inthree-fourths of patients and TNF� antagonist discontinuation in37.5% [100]. In recent-onset RA, although the treatment goal isclearly to achieve a remission, some de-escalation studies focusedon patients with minimal disease activity. Despite differences in themethodologies and results, the data indicate that de-escalation (viadosage reduction or wider dosing intervals) is often feasible but thatabrupt discontinuation is frequently followed by a relapse and thata remission without treatment is rarely achieved [101–103]. Thedata on de-escalation of biologics other than TNF� antagonists arescarce but suggest similar conclusions [104–106]. Interestingly, thereintroduction of biological therapy in the event of a relapse mayallow the return to a favorable outcome [96,104,107].

In some patients, a clinical remission may coincide with con-tinued structural disease progression [108–110]. Consequently,radiographs should be obtained before and throughout de-escalation to check that the clinical remission is accompanied witha halt in radiographic lesion progression.

Importantly, before considering de-escalation via a dosagereduction or increased dosing intervals, the glucocorticoid ther-apy should first be stopped or brought down to the minimal dose(≤ 5 mg/day) if complete discontinuation proves impossible.

3.2.4.2. In patients with a prolonged remission, a gradual decrease inthe synthetic DMARDs can be considered, as a medical decision sharedby the patient and physician (recommendation 13). Currently avail-able data suggest that methotrexate dosage reduction may deserveconsideration in patients in remission for at least 6 months undermethotrexate therapy [111,112]. Again, dosage reduction seems


preferable over the abrupt discontinuation of methotrexate or anyother synthetic DMARD. Abrupt discontinuation is associated witha high relapse rate of about 70%, i.e., 2-fold that seen with contin-ued treatment [113–115], and the reintroduction of the synthetic


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MARD only inconsistently restores the previous status [116]. Itould seem important to define a sustained remission using a strict

omposite criterion including the absence of synovitis, systemicnflammation, and structural disease progression [38,108–110].

.2.4.3. Treatment selection and adjustment should factor in a num-er of considerations in addition to measured disease activity, such astructural disease progression, comorbidities, tolerance of the drugs,nd the patient’s wishes (recommendation 14). Before making treat-ent decisions, the results of disease activity indices should be

nterpreted based not only on an analysis of the individual indexomponents, but also on the patient’s characteristics, most notablyhe comorbidity profile. It should be borne in mind, however, thatigh RA activity is often associated with a heavier comorbidityurden [117,118] and that effective RA treatment may prevent cer-ain comorbidities [119,120]. Other important considerations arehe tolerance of the drugs by the patient and the patient’s wishes,hich are strongly relevant to shared decision-making and good

reatment adherence. Finally, some patients have low disease activ-ty yet continue to experience structural disease progression, asiscussed in recommendation 12 (Section 3.2.4.1).

.2.4.4. Patients with RA should be offered a global managementrogram including not only drug treatments, but also therapeutic edu-ation, comorbidity management and, as appropriate, psychologicalupport, assistance with social and occupational issues, functionalehabilitation, and/or surgery (recommendation 15). The manage-ent approach should be global: pharmacotherapy, physical

herapy, psychotherapy and, if needed, surgery act complementar-ly and are inseparable from appropriate assistance with social andccupational issues. Non-pharmacological interventions shoulde considered and may include [6] physical treatments (physio-herapy, occupational therapy, and pedicures or podiatric care);ehabilitation and changes to the environment; therapeutic patientducation, psychological support, and dietary therapy.

In addition, the high prevalence of cardiovascular morbid-ty in RA patients mandates routine and regular evaluations ofther cardiovascular risk factors, which should be corrected when-ver possible (smoking cessation and treatments for dyslipidemia,ypertension, diabetes, and obesity). Given the reported associ-tions between RA and periodontal disease, attention to dentalygiene is recommended [121,122]. Referral for advice from a sur-eon may be order, most notably in patients at risk for tendinopathynd in those with severe joint destruction.

Finally, patients with RA should be informed about the existencef self-help organizations, particularly at the time of diagnosis, andontact information should be supplied if agrees by the patient.

. Discussion

The management of RA has benefited over the last 15 years fromajor breakthroughs in the field of drug therapy, including opti-ization of synthetic DMARD therapy, commercial availability of

iological DMARDs, low-dose glucocorticoid therapy, and combi-ations of drugs belonging to different classes. No less importantre the conceptual advances achieved in recent years, which under-ine the pivotal role for the rheumatologist as the physician ofeference for the management of RA, the importance of sharedecision-making in which the patient is viewed as a partner, the

dentification of a therapeutic window, and the desirability of tightisease control.

The SFR recommendations are recapitulated in a simple and


asy-to-use algorithm for managing RA (Fig. 1). They are intendedor all physicians involved in caring for patients with RA. Theseew SFR recommendations are consistent with existing recom-endations [6] and incorporate recently published data [8–10].


Nevertheless, they encompass a vaster field than do the Euro-pean recommendations, since they extend from the diagnosis toglobal patient management, despite a strong emphasis on treat-ment. Importantly, the high level of evidence underlying most ofthe recommendations results in strong adhesion and high recom-mendation grades. Nevertheless, a few items rely on expert opinionor on a combination of scientific evidence and expert opinion,indicating a need for a vast array of research projects designedto resolve these points. A number of situations encountered inRA patients continue to raise challenges and warrant continuedwork to develop new treatments. Several drugs are being devel-oped (e.g., JAK inhibitors, IL-6 antagonists, and biosimilars). Thus,the present recommendations reflect currently available scientificevidence and will need to be updated regularly.

Disclosure of interest

C.G.V. has received honoraria or research grants from AbbVie,BMS, Janssen, MSD, Pfizer, UCB, and Roche-Chugai.

L.G. has received honoraria or research grants from AbbVie,Janssen, MSD, Pfizer, UCB, and Roche-Chugai.

A.C. has received honoraria or research grants from AbbVie, BMS,Merck, Nordic-Pharma, Novartis, Pfizer, Roche-Chugai, and UCB.

M.D. has received honoraria or research grants from AbbVie,BMS, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB.

B.F. has received honoraria or research grants from AbbVie, BMS,MSD, Nordic-Pharma, Pfizer, Roche-Chugai, and UCB.

X.M. has received honoraria or research grants from BMS, GSK,Merck, Pfizer, Roche-Chugai, and UCB.

H.N. has received honoraria or research grants from Abbvie,BMS, Pfizer, and Roche-Chugai.

A.S. has received honoraria or research grants from AbbVie, BMS,Lilly, Merck, Novartis, Pfizer, Roche-Chugai, and UCB.

L’ANDAR has received funding from Abbvie, BMS, MSD, Nordic,Pfizer, Roche-Chugai, and UCB.

B.C. has received honoraria or research grants from AbbVie, BMS,Lilly, Merck, Novartis, Pfizer, Roche-Chugai, and UCB.

Acknowledgments

We thank the review group members who revised andcommented on the recommendations: the patient self-helporganization Association Franc aise des Polyarthritiques (AFP),Berenbaum F, Berthelot J-M, Baudens G, Boissier M-C, BoumierP, Brocq O, Constantin A, Damade R, Dernis E, Desmoulins F,Devauchelle-Pensec V, Flipo R-M, Gaudin P, Gibert E, GottenbergJ-E, Goupille P, Grange L, Hudry C, Lassoued S, Ludot I, Meyer O,Miossec P, Morand B, Morel J, Moura B, Perdriger A, Pham T, Rist S,Senbel E, Sibilia J, and Wendling D.

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