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Objectives: The STRATEGE (Therapeutic Strategy in Patients Treated With Methotrexate for Rheumatoid Arthritis) study aimed to describe treatment strategies in current practice in RA biologic DMARD (bDMARD)-naïve patients with an inadequate response to MTX therapy, and to compare clinical efficacy of the different therapeutic strategies on disease activity after 6 months., Methods: The main inclusion criteria of this prospective, observational, multicentre study were confirmed RA diagnosis, treatment by MTX monotherapy and need for therapeutic management modification., Results: The 722 patients included had a mean (s.d.) RA duration of 5.3 (6.7) years, a mean DAS28 of 4.0 (1.1); they were all receiving MTX monotherapy, 68% oral, at a mean dose of 15.0 (4.1) mg/week. Two major strategies were identified: (i) MTX monotherapy dose and/or route optimization (72%) and (ii) bDMARD initiation ± MTX (16%). MTX dosing was modified for 70% of patients, maintained (dose and route) for 28% of patients and interrupted for 2%. bDMARDs were started when the MTX mean dose was 17.4 mg/week, 56% parenterally; MTX was maintained concomitantly for 96% of patients. Six-month follow-up results adjusted by propensity score showed that both options were equally successful in improving disease activity and physical function, with 63 and 68% of good-to-moderate EULAR responses, respectively., Conclusion: The STRATEGE study shows the importance of initial MTX treatment optimization before initiation of a biological treatment and emphasizes the importance of treat-to-target strategy., Trial Registration: ClinicalTrials.gov NCT02288520., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Methotrexate combination therapy improves abatacept efficacy as a first-line biologic agent for the treatment of rheumatoid arthritis, but it is unclear when abatacept is used later on, particularly after non-TNF inhibitor (TNFi) failure., Study Question: The objective of this study was to determine whether treatment response after non-TNFi inadequate response is different in patients with rheumatoid arthritis (RA) treated with abatacept in combination with or not with methotrexate., Methods: Patients treated with abatacept monotherapy or in combination with methotrexate after non-TNFi failure were included., Results: Data from 46 patients aged 56 years [49-61] with 12 years [8-16] of disease duration were examined. Rituximab was the treatment used in the previous line for 75.0% of the combination therapy group (15/20) and 34.6% (9/26) in the monotherapy group. At 12 months, 38.5% (10/26) of patients were in good-to-moderate EULAR response in the monotherapy group compared with 25.0% (5/20) in the combination therapy group (P = 0.33). Treatment persistence at 12 months was 61.5% (16/26) in the monotherapy group and 35.0% (7/20) in the combination therapy group (P = 0.07)., Conclusions: Adding methotrexate to abatacept did not improve treatment response in patients with RA after non-TNFi inadequate response.

Objectives: Anti-TNFα agents are indicated in selected patients with rheumatoid arthritis (RA) who respond inadequately to methotrexate and particularly when glucocorticoids are mandatory. We evaluated whether a glucocorticoid-sparing effect occurred during the first year of anti-TNF-α therapy., Methods: Between 2007 and 2009, the French multicentre, longitudinal, prospective, observational, population-based CORPUS cohort included biologic-naive patients with inflammatory joint disease. Patients with active RA treated with glucocorticoids were included. Patients who received at least one anti-TNFα injection during follow-up were compared to anti-TNF-α non-users., Results: Among the 205 patients, 76.1% were women, mean disease duration was 7.7±8.3 years, mean DAS28 was 5.2±1.3, mean follow-up was 13.1±2.8 months, and mean prednisone dose was 9.9±9.6 mg/day. The 75 (36.6%) anti-TNF-α recipients were younger, had a longer RA duration, more often tested positive for rheumatoid factor and anti-citrullinated peptide antibody, more often received previous DMARDs, received a higher methotrexate dosage, had fewer intra-articular glucocorticoid injections at baseline and were more often followed by hospital practitioners than non-recipients. Mean prednisone dosage decreased from 11.8±12.7 to 5.9±9.7 mg/day in recipients and from 8.7±7.1 to 5.0±4.4 mg/day in non-recipients. Prednisone was stopped more often among recipients (21/59, 35.6%) than among non-recipients (16/94, 17.0%) (p=0.01). By multivariate analysis, factors independently associated with lower prednisone requirements were baseline daily prednisone dosage, a CRP >10 mg/l and not to be followed by an office-based practitioner., Conclusions: This study showed a significantly higher glucocorticoid discontinuation rate among anti-TNF-α recipients than among non-recipients. However, the glucocorticoid-sparing effect was small and not observed by multivariate analysis.

Objective: To report the 5-year outcome of a large prospective cohort of patients with very early rheumatoid arthritis (RA), and to identify factors predictive of outcome., Methods: Patients were recruited if they had early arthritis of < 6 months' duration, had a high probability of developing RA, and had never been prescribed disease-modifying antirheumatic drugs (DMARD) or steroids. Logistic regression analysis was used to determine factors that predict outcome., Results: We included 813 patients from December 2002 to April 2005. Age was 48.1 ± 12.6 years, delay before referral 103.1 ± 52.4 days, 28-joint Disease Activity Score (DAS28) 5.1 ± 1.3, Health Assessment Questionnaire (HAQ) 1.0 ± 0.7; 45.8% and 38.7% had rheumatoid factor or antibodies to cyclic citrullinated peptide (anti-CCP), respectively; 22% had hand or foot erosions; 78.5% fulfilled the American College of Rheumatology/European League Against Rheumatism criteria for RA at baseline and 93.8% during followup. At 5 years, 573 patients were evaluated. The outcome was mild for most patients: disease activity (median DAS28 = 2.5) and HAQ disability (median 0.3) were well controlled over time; 50.6% achieved DAS28 remission and 64.7% low disease activity. Radiographic progression was low (2.9 Sharp unit/year) and only a few patients required joint surgery. Nevertheless, some patients developed new comorbidities. During the 5 years, 82.7% of patients had received at least 1 DMARD (methotrexate, 65.9%), 18.3% a biological DMARD, and about 60% prednisone at least once. Anti-CCP was the best predictor of remaining in the cohort for 5 years, of prescription of synthetic or biologic DMARD, and of radiographic progression., Conclusion: The 5-year outcome of an early RA cohort in the 2000s was described. Anti-CCP was a robust predictor of outcome. The generally good 5-year outcome could be related to early referral and early effective treatment, key processes in the management of early RA in daily practice.

Objective: To evaluate the prevalence of baseline abnormalities in standard laboratory tests in patients with early arthritis and their impact on selection of disease-modifying antirheumatic drugs according to American College of Rheumatology (ACR) recommendations and/or of nonsteroidal anti-inflammatory drugs., Methods: In three cohorts of patients with early arthritis (the ESPOIR, VErA, and Brittany cohorts), we evaluated the prevalence of anemia (hemoglobin <1 3 g/dL in men and 12 g/dL in women), leukopenia (<3500 per mm(3)), thrombocytopenia (<150000 per mm(3)), renal dysfunction (mild, creatinine clearance [CrCl]=60-89.9 mL/min; moderate, CrCl=30-59.9 mL/min; or severe, CrCl<30 mL/min), liver cytolysis (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]>N or>2N), and systemic inflammation (erythrocyte sedimentation rate [ESR]>20 and C-reactive protein [CRP]>6)., Results: We evaluated 1393 patients (1018 women and 375 men). Anemia was present in 363/1366 (26.5%) patients, leukopenia in 18/1372 (1.3%), and thrombocytopenia in 13/1371 (0.9%). ESR elevation was seen in 50.4% of patients and CRP elevation in 62.7%. The level of AST was above normal in 4% and of ALT in 10% of patients. No patient had severe renal dysfunction, 5.6% had moderate renal dysfunction, and 42.6% had mild renal dysfunction. Among the 1094 patients who had undergone all the tests, only 18 (1.64%, 95% confidence interval, 1-2.64) had a formal contraindication to methotrexate therapy according to ACR recommendations (4 had leukopenia, 12 had high ALT levels, and 2 had high ALT and AST levels)., Conclusion: Patients with recent-onset arthritis often have anemia, mild or moderate renal dysfunction, and abnormal liver function. However, fewer than 2% have laboratory test abnormalities contraindicating methotrexate therapy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: Rituximab has been shown to be efficient in the treatment of rheumatoid arthritis (RA) when associated with methotrexate (MTX). The purpose of this study was to evaluate the response to this treatment in daily practice in the following three specific situations: rheumatoid factor (RF)-negative RA patients, rituximab monotherapy patients and TNFα inhibitors-naive patients., Methods: This retrospective observational study is an exploratory analysis of the response to rituximab. One thousand milligrams (1000 mg) of rituximab was administered twice at an interval of 15 days. Therapeutic response was determined at mean 20 weeks after the infusion on the basis of DAS28 scores and EULAR response criteria., Results: One hundred and eight patients were included in the study and the responses of 95 of these were evaluated. Of the latter, 75% were EULAR responders. There was no significant difference in EULAR response between patients treated with rituximab and MTX (73.8%) and those who had received rituximab alone (79.3%). Similarly, there was no difference in the number of EULAR responders between patients who had received TNF inhibitor beforehand (74.1%) and those who had not (78.6%). However, interval to retreatment was significantly shorter in TNF inhibitor-naive patients. Lastly, a significant difference (P=0.02) in EULAR response rate was observed between RF-positive patients (84.8%) and RF-negative patients (57.9%). Interval to retreatment was also significantly shorter in RF-negative patients., Conclusion: In our experience, while our RTX efficacy findings appear to be consistent with the results of comparable controlled trials, whether or not in association with MTX, or with prior administration of one or several TNF inhibitors, RF-positive RA patients exhibited a higher EULAR response rate than RF-negative RA patients., (Copyright © 2011 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Objectives: In early and active RA despite MTX, continuous treatment with TNF blockers in combination with MTX is recommended. To compare this strategy with an initial combination of MTX and adalimumab (ADA) given for 3 months and then adjusted based on the disease activity status., Methods: Prospective unblinded randomized multicentre controlled 1-year trial in which 65 patients with early (<6 months) and active [disease activity score (DAS28(ESR)) >5.1] RA were assigned to Group 1 (32 patients): MTX (0.3 mg/kg/week, maximum of 20 mg/week, without escalating dose regimen) or to Group 2 (33 patients): initial combination therapy with MTX (as in Group 1) and ADA (40 mg eow). In both groups, treatment was adjusted every 3 months. The aim was to achieve a low DAS (DAS28(ESR) <3.2)., Results: From Week 12 until Week 52, seven patients in Group 1 and 11 patients in Group 2 remained in low disease activity state while receiving MTX monotherapy (P = 0.28). The 1-year area under the curve (AUC) of DAS28 was lower in Group 2 owing to an initial better response. The total intake of anti-TNF-alpha and the mean increase in total modified Sharp score was similar in the two groups., Conclusions: Initial combination of MTX and ADA and then an adjusted based on the disease activity status achieved a faster control of disease activity but did not increase the number of patients for whom anti-TNF-alpha treatment was not needed after 12 weeks nor a better subsequent clinical or radiological outcome than a 3-month delayed initiation of anti-TNF in patients with still active disease despite MTX.

Objective: To survey rheumatologists' preferences for the choice of a second-line disease-modifying antirheumatic drug (DMARD) after inadequate response with methotrexate (MTX) therapy in rheumatoid arthritis (RA)., Methods: Thirty-six rheumatologists stated their preferences for RA treatment after inadequate response with MTX therapy (optimal dose at least 6 months). From the initial scenario, we derived 54 vignettes varying by rheumatoid factor or anti-cyclic citrullinated peptide antibody presence, swollen joint count, Disease Activity Score in 28 joints, and structural damage. Respondents stated their preference among 5 therapeutic options: MTX continuation, switch to another conventional DMARD, addition of another conventional DMARD, addition of anakinra, or addition of a tumor necrosis factor (TNF) blocker. Presentation by pairs yielded 10 combinations of strategies for each variant, totaling 540 vignettes; participants evaluated a random sample of 180 vignettes. Determinants of each top-ranked option were analyzed by logistic regression. The compilation of these data served to define a therapeutic algorithm., Results: The responses of 33 rheumatologists were analyzable. Therapeutic preferences corresponded to the top-ranked options. For patients with mild or moderately active RA, either a switch or step-up strategy to another conventional DMARD was top ranked. TNF blockers were preferred for RA patients with high disease activity or progressive structural damage. On the basis of these preferences, we developed a simple decision tree for use in daily clinical practice., Conclusion: Our simple, easy-to-use decision tree developed from rheumatologists' preferences for therapy after failure of MTX therapy in RA treatment may guide rheumatologists in daily practice to choose a second-line DMARD.

Objectives: To develop clinical practice guidelines for the use of methotrexate in rheumatoid arthritis (RA), using the evidence-based approach and expert opinion., Methods: A scientific committee used a Delphi procedure to select five questions, which formed the basis for developing recommendations. Evidence providing answers to the five questions was sought in the Cochrane databases, PubMed, and proceedings of meetings of the French Society for Rheumatology, European League Against Rheumatism, and American College of Rheumatology. Using this evidence, a group of rheumatologists developed and validated the recommendations. For each recommendation, the level of evidence and the extent of agreement among experts were specified., Results: The recommendations were as follows: 1: The starting dosage for methotrexate in patients with RA should not be less than 10 mg/week and should be determined based on disease severity and patient-related factors; 2: When a patient with RA shows an inadequate response to methotrexate, the dosage should be increased at intervals of 6 weeks, up to 20 mg/week, according to tolerance and patient-related factors; 3: When starting methotrexate treatment in a patient with RA, preference should be given to the oral route. A switch to the intramuscular or subcutaneous route should be considered in patients with poor compliance, inadequate effectiveness, or gastrointestinal side effects; 4: At present, there is no evidence indicating that a change in methotrexate dosage is in order when a TNF antagonist is given concomitantly; 5: The investigations that are mandatory before starting methotrexate therapy in a patient with RA consist of a full blood cell count, serum transaminase levels, serum creatinine with computation of creatinine clearance, and a chest radiograph. In addition, serological tests for the hepatitis viruses B and C and a serum albumin assay are recommended. In patients with a history of respiratory disease or current respiratory symptoms, lung function tests with determination of the diffusing capacity for carbon monoxide are recommended; 6: Investigations that are mandatory for monitoring methotrexate therapy in patients with RA consist of full blood cell counts and serum transaminase and creatinine assays. These tests should be obtained at least once a month for the first 3 months then every 4-12 weeks; 7: Folate supplementation can be given routinely to patients treated with methotrexate for RA. In practice, a minimal dosage of 5 mg of folic acid once a week, at a distance from the methotrexate dose, is appropriate; 8: In the event of respiratory symptoms possibly related to methotrexate toxicity, the drug must be stopped and symptom severity evaluated. Should evidence of serious disease be found, the patient should be admitted immediately or advice from a pulmonologist should be obtained immediately., Conclusion: Recommendations about methotrexate therapy for RA were developed. These recommendations should help to improve practice uniformity and, ultimately, to improve the management of RA.

Objective: To evaluate the proportion of patients with rheumatoid arthritis (RA) visiting office-based rheumatologists for persistently active RA despite past or current methotrexate (MTX) treatment, and to describe the management of these patients in France in 2003., Methods: All French rheumatologists were invited to participate in a cross-sectional postal survey. During a predetermined week, they were to include the first 2 patients seen for RA with a history of past or current MTX treatment. Adequacy of current treatment was assessed based on the 28-joint Disease Activity Score 28 (DAS28) and on current MTX and corticosteroid regimens., Results: Of the 1800 French rheumatologists, 492 returned 838 assessable patient questionnaires. Mean patient age was 58 years and mean time since RA diagnosis was 10 years; 77% of patients were currently taking MTX, and 51% a corticosteroid. High dosages were noted for MTX (> 15 mg/week) in 20% of patients and for corticosteroid therapy (> 10 mg/day) in 5%. Nevertheless, 41% of patients had active RA (DAS28 score 3.2 to 5.1) and 7% had very active RA (DAS28 score > 5.1). The treatment was left unchanged in 78% of patients, and biological therapy was contemplated in only 16% of patients., Conclusion: Although half of MTX-treated patients with RA visiting office-based rheumatologists had active or very active disease, a change in treatment was rarely considered.

Unlabelled: Few prospective placebo-controlled studies have evaluated disease-modifying antirheumatic drugs (DMARDs) in the treatment of peripheral psoriatic arthritis., Objective: To evaluate second-line treatments used in clinical practice in patients with psoriatic arthritis., Method: We studied a cross-section of 100 consecutive patients seen by hospital-based or office-based rheumatologists for psoriatic arthritis., Patients: The 55 men and 45 women had a mean age of 48 years (range, 17-79 years) and a mean disease duration of 7 years (range, 1-24 years)., Results: The most commonly used DMARDs were sulfasalazine, gold, methotrexate, and hydroxychloroquine (64, 43, 41 et 17 patients, respectively). These drugs had been stopped because of inefficacy in 31%, 31%, 12%, and 53% of patients, respectively, and because of adverse events in 23%, 44%, 22%, and 41% of patients, respectively. At the time of the study, mean treatment durations were 15, 21, 34, and 12 months, respectively, and the drugs were still being used in 45%, 21%, 66%, and 6% of patients., Conclusion: Our data confirm the value of methotrexate and salazopyrine. Methotrexate had the best risk/benefit ratio. Gold was often responsible for side effects. Hydroxychloroquine was inadequately effective and poorly tolerated.

Use of methotrexate to treat rheumatoid arthritis is associated with pulmonary adverse effects in 3% to 5% of cases. In addition to immunoallergic lung disease, bronchitis and pneumonia due to pyogenic organisms, opportunistic lower respiratory tract infections have been reported, including, to our knowledge, 18 cases of Pneumocystis carinii pneumonia. We report two new cases of P. carinii pneumonia in methotrexate-treated rheumatoid arthritis patients. One case occurred in a 62-year-old woman with a nine-year history of seropositive rheumatoid arthritis treated for the last seven months with methotrexate, 15 mg per week, and prednisone, 10 mg/d. The other patient was a 58-year-old woman who had been diagnosed with rheumatoid arthritis 18 months earlier and had been receiving 15 mg per week of methotrexate for eight months in combination with 12.5 mg of prednisone per day. Both patients had negative tests for the human immunodeficiency virus. Symptoms consisted of fever, cough and dyspnea, with interstitial infiltrates on chest films, hypoxia, and lymphopenia (700 and 600/mm3, respectively). The diagnosis was confirmed by bronchoalveolar lavage. Both patients recovered under treatment with trimethoprim-sulfamethoxazole. An analysis of the 20 cases of P. carinii pneumonia reported to date in methotrexate-treated rheumatoid arthritis patients demonstrated a number of characteristics: the rheumatoid arthritis was of recent onset in some cases (a few months in one patient); lymphopenia was present in two thirds of cases; one-third of patients were not receiving corticosteroid therapy; the dosage and duration of methotrexate therapy varied widely, from 5 to 30 mg per week and two to 48 months; and four patients died.

Introduction: Over the last three years, there have been over twenty case reports of lymphoma in patients given low-dose methotrexate for rheumatoid arthritis. We observed the first case of cutaneous pseudolymphoma., Case Report: A 56-year-old man had been treated with methotrexate (15 mg/day) for 6 years due to rheumatoid arthritis. He developed three isolated papulonodular ulcerations on the limbs. The histology and immunohistochemical examinations demonstrated T and B lymphoplasmocyte infiltration without epidermotropism nor destruction of the annexes. Immunolabelling for anti-Epstein-Barr virus was negative. There was a IgG lambda type monoclonal hypergammaglobulinaemia, Bence-Jones proteinuria and an increase in beta 2-microglobulin. The thoracoabdominal scan, bone marrow biopsy and gallium scintigraphy were normal. There was no sign of a Gougerot-Sjögren syndrome nor of a Felty syndrome. The skin lesions and the Bence-Jones proteinuria disappeared rapidly after withdrawal of methotrexate. There has been no recurrence with a follow-up of 16 months., Discussion: The diagnosis of pseudolymphoma was retained on the basis of the clinical features, the histological and immunohistochemical evidence and especially on the clinical course after methotrexate withdrawal, i.e. spontaneous regression of the lesions within 3 weeks. A similar course has been observed in three cases of lymphocyte proliferation suggesting that this immunosuppressor would be the most probable causative agent. Lymphocyte proliferation, mainly B-cell lymphomas in haematopoietic organs occurring under methotrexate administration have occurred mainly in patients with rheumatoid arthritis. Three cases have also been described in patients with dermatomyositis, but none have been reported in patients with psoriasis. This would suggest that cofactors involved in these autoimmune diseases could also have an effect: immunodepression, potentialization due to associated treatment (corticosteroids), Epstein-Barr virus..., Conclusion: Data on these observations should be combined in order to analyse the question of the safety of low-dose methotrexate in these patients.

Eric Senbel,1 Sonia Tropé,2 Hélène Herman-Demars,3 Elena Zinovieva,3 Agnès Courbeyrette,3 Pierre Clerson,4 Yann Fardini,4 René-Marc Flipo5 1Rheumatology Office, Marseille, France; 2French National Patient Organization Against Rheumatoid Arthritis (ANDAR), Montpellier, France; 3Medical Department, Nordic Pharma, Paris, France; 4Soladis Clinical Studies, Roubaix, France; 5University of Lille, Rheumatology Department, Hôpital Roger Salengro, Lille, FranceCorrespondence: Yann FardiniSoladis Clinical Studies, 15 Boulevard Du Général Leclerc, Roubaix, 59100, FranceTel +33 6 46 32 95 85Fax +33 3 28 09 94 76Email yfardini@soladis.frPurpose: The purpose of the APRIM study (for Adherence Polyarthrite Rhumatoïde Injection Methotrexate) was to investigate the change in treatment adherence of patients with rheumatic arthritis (RA) who switched from oral to subcutaneous methotrexate (MTX).Patients and Methods: Prospective, observational study in RA patients treated with MTX and switching from oral to subcutaneous (SC) route in real-life conditions. Data on motivations for switch, disease activity (DAS28-CRP), quality of life (AISM-2 SF), disability (HAQ-DI), and adherence to MTX were collected at inclusion (M0) and 6 months later (M6). Adherence was assessed by the 8-item Morisky Medication Adherence Scale (MMAS-8) and defined as high (MMAS-8 = 8), medium (MMAS-8 = 6 or ≤ 8) or low (MMAS-8 < 6). The primary evaluation criterion was the proportion of patients who maintained strong adherence or improved adherence by at least one category (from low to medium or strong or from medium to strong) between M0 and M6.Results: The analysis involved 207 patients (age 60.4± 12.7 years, 75.2% females). 6.7% were in remission and 15.5% had low disease activity (LDA) at baseline. 58.5% reached the primary criterion and strong adherence rate increased from 42.0% to 50.7%. Change of route was combined with increased MTX dose in 34.8% of patients. Switch to SC route increased the proportion of patients with remission or LDA from 22.8% to 52.9% and increased quality of life even in patients with unchanged MTX dose.Conclusion: Overall, change from oral to SC route improved adherence to MTX, RA control and quality of life independently of change in MTX dose.Keywords: rheumatoid arthritis, methotrexate, oral, subcutaneous, compliance, switch