Abstract
Introduction
The primary objective was to describe the therapeutic approach to methotrexate (MTX) use at the initiation of the first biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) in the treatment of rheumatoid arthritis (RA). Secondary objectives included characterising participants initiating b/tsDMARD treatment, examining treatment strategies over time, monitoring disease progression, and identifying factors influencing treatment choices.
Methods
This longitudinal, prospective, non-interventional, multicentre study (STRATEGE2) enrolled adult participants with RA who had been treated with MTX for at least 3 months and required b/tsDMARD treatment due to persistent disease activity. Outcomes were assessed at 12 months (M12) and 24 months (M24) after initiating b/tsDMARD treatment.
Results
At baseline, 173 participants with RA had a mean (SD) disease duration of 5.6 (7.3) years and a mean Disease Activity Score in 28 joints (DAS28) score of 4.3 (1.2). Approximately two-thirds had been on MTX for over a year, with a mean weekly dose of 18.8 (4.2) mg (median 20.0), and 72.3% received it subcutaneously. MTX was continued at the initiation of b/tsDMARD therapy in 97.7% of participants. By M12, 83.2% of participants remained on MTX, with 39.9% (95% CI 32.5–47.6) maintaining the same dosage and route of administration. Discontinuation of MTX was primarily due to participant choice or adverse events. At M24, the mean change in DAS28 score was − 2.0 (1.3), with 66.0% of participants achieving remission. On the basis of European Alliance of Associations for Rheumatology (EULAR) classification criteria, 65.2% had a good response, 19.1% a moderate response, and 15.6% an inadequate response.
Conclusion
The STRATEGE2 study investigators adhered to current clinical guidelines by continuing MTX in combination with b/tsDMARD initiation for the management of RA.
Trial Registration
ClinicalTrials.gov: Therapeutic Strategy Associated with bDMARDs or tsDMARDs in Rheumatoid Arthritis and Psoriatic Arthritis (STRATEGE2), NCT05082805.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40744-025-00806-1.
Keywords: DMARDs, Methotrexate, Rheumatoid arthritis, Treat-to-target
Key Summary Points
| Why carry out this study? |
| Clear guidance is lacking on how to manage methotrexate (MTX) dosage and administration when used in combination with biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients with an inadequate response to MTX monotherapy. |
| The longitudinal, prospective, non-interventional, multicentre STRATEGE2 study investigated MTX therapeutic strategies upon initiation of b/tsDMARDs in rheumatoid arthritis (RA) treatment in real-world clinical practice. |
| What was learned from the study? |
| In the STRATEGE2 study, investigators followed current recommendations by continuing MTX during patient management when initiating a b/tsDMARD. Most patients remained on MTX 2 years after initiating b/tsDMARDs, with one-third maintaining initial treatment modalities. Factors influencing MTX continuation were the participant’s age and perceived disease activity. |
| Decisions regarding tapering MTX are complex, particularly concerning MTX dosage and route of administration. Methotrexate discontinuation was primarily driven by adverse events or patient preference. |
| MTX is the cornerstone of RA treatment and is often combined with bDMARD or tsDMARD to improve patient symptoms and functional capacity. Further research is warranted to explore the rationale behind medical decisions regarding the maintenance or modification of treatments in the management of RA. |
Introduction
Rheumatoid arthritis (RA) is one of the most common chronic inflammatory diseases. A systematic review of population-based studies reported a mean (standard deviation, SD) point prevalence in Europe of 0.53% (0.20), based on 12 studies published between 1989 and 2014 [1]. The period prevalence in Europe was 0.60% (0.41), according to 14 studies published between 1989 and 2013 [1]. In France, data from the national health insurance agency reported that 320,200 cases were recorded in 2022 [2]. Rheumatoid arthritis is more prevalent in women, with a rate of 0.51% compared to 0.09% in men, and shows the highest age-specific prevalence in the 65–74 age group [3]. It leads to joint destruction, significantly impairing the patients’ quality of life and contributing to the development of disabilities [4]. Implementing the treat-to-target approach, capitalising on the window of opportunity for treatment, and optimising background treatment—typically methotrexate (MTX)—have significantly improved the health status of patients [5]. MTX treatment has been associated with reduced mortality in patients with RA and with cardiovascular diseases or associated interstitial lung diseases and, as a result, life expectancy has begun to align with that of the general population [6].
The overall prognosis for patients with RA is strongly influenced by the quality of medical care provided. Timely access to a rheumatologist is essential, as is addressing the gap between clinical guidelines and everyday rheumatology practice, which is often attributed to diagnostic challenges [7–9]. MTX remains the first-line treatment for RA among other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) due to its proven efficacy, tolerability, and relative affordability [10, 11]. For patients with an inadequate response to MTX, intolerance to MTX, or poor prognosis, biologic DMARD (bDMARD) therapy may be initiated, either intravenously or subcutaneously. Despite current European Alliance of Associations for Rheumatology (EULAR) guidelines, bDMARDs are often administered as monotherapy, primarily because of a history of intolerance or contraindications to MTX [12, 13]. Additionally, the availability of targeted synthetic DMARDs (tsDMARDs), such as Janus kinase inhibitors (JAKi), introduced in France in 2017, has supported the trend toward using targeted therapies as monotherapy. However, a knowledge gap persists in current recommendations, which state that all biologic or targeted synthetic DMARDs (b/tsDMARDs) should be preferentially used in association with MTX but lack specific guidance on maintaining MTX dosage and route of administration during combination therapy.
This longitudinal, prospective, non-interventional, multicentre study (STRATEGE2, ClinicalTrials.gov NCT05082805) focused on MTX treatment strategies at the initiation of the first b/tsDMARD. The primary objective was to describe the MTX treatment strategies 1 year after b/tsDMARD initiation. Secondary objectives included characterising patient profiles at the time of b/tsDMARD initiation, examining therapeutic strategies 2 years later, assessing changes in disease activity, and identifying factors influencing the choice of therapeutic strategies.
Methods
Study Design
The STRATEGE2 study (ClinicalTrials.gov NCT05082805) was a longitudinal, prospective, non-interventional, multicentre study conducted in France between February 2019 and February 2023. It did not alter participants’ standard of care or dictate therapeutic strategies. All decisions regarding b/tsDMARD therapy and MTX maintenance were made by the treating rheumatologist, reflecting real-world clinical practice. Fifty-three rheumatologists practising in hospital settings (a requirement for prescribing b/tsDMARDs) were involved. Each participant was followed for up to 2 years, with the inclusion visit corresponding to the initiation of b/tsDMARD therapy, and two follow-up visits at 12 months (M12) and 24 months (M24). Data were collected from medical records, physical examinations, and self-reported participant questionnaires. This final analysis reports on the evolution of disease activity, decisions regarding treatments, and the factors driving therapeutic decisions.
Ethics
This study was approved on 12 November 2018 by an independent ethics committee (Comité de Protection des Personnes Sud Méditerranée V; Reference 18.068). All participating study sites accepted the single ethics committee approval. The ethics committee expressly authorized the use of oral non-opposition, as permitted for non-interventional research conducted in France and involving no risk or constraint beyond routine clinical practice. Participants received comprehensive written information about the study objectives, procedures, and their rights, in compliance with Articles L.1121–1 and L.1122–1-1 of the French Public Health Code. Oral non-opposition to the collection of their personal data was obtained prior to participant inclusion and documented in the study records, as required by local regulations governing non-interventional studies in France. All data were processed in compliance with the reference methodology MR-003 from the French Data Protection Authority (Commission Nationale de l’Informatique et des Libertés—CNIL), ensuring the protection of participant privacy and data integrity.
Eligibility Criteria
The eligible population consisted of patients with RA who had been treated with MTX for at least 3 months at the time of study inclusion and required the initiation of their first b/tsDMARD due to the disease activity.
Inclusion criteria were (i) adults aged 18 years or older, (ii) diagnosis of RA according to the American College of Rheumatology (ACR) 1987 classification criteria or the ACR/EULAR 2010 classification criteria; (iii) treatment with MTX (either oral or subcutaneous) for at least 3 months; (iv) naive to b/tsDMARDs and requiring initiation of such treatment due to the disease activity; and (v) informed consent provided for the collection and use of personal data.
Patients enrolled in interventional rheumatology clinical trials were excluded from this study.
Study Outcomes
The primary outcome was the proportion of participants for whom MTX treatment was maintained at the M12 visit, defined as those who did not definitively stop MTX, reduce its dosage, or change the route of administration.
Secondary outcomes were evaluated at both the M12 and M24 follow-up visits and included the proportion of participants maintaining the same MTX treatment (dose and route of administration). Additionally, secondary outcomes encompassed the individual components of the primary outcome definition: the proportions of participants who definitively stopped MTX treatment, reduced its dosage, or changed its route of administration.
Other secondary outcomes captured the adaptation of csDMARDs, bDMARDs, tsDMARDs, and other treatments. These adaptations were reported with respect to treatment modifications, dosage adjustments, modes of administration, and the reasons behind treatment changes.
Global disease activity was assessed at baseline by the physician using a 100-mm scale and at all follow-up visits using the Disease Activity Score in 28 joints (DAS28). Treatment outcomes were assessed according to the EULAR response [14].
Disease activity, fatigue, and pain were assessed using a 100-mm visual analogue scale, based on participant responses collected at baseline, M12, and M24 visits. Physical function was evaluated using the Health Assessment Questionnaire-Disability Index (HAQ-DI), which ranges from 0 to 3. A minimal clinically meaningful improvement in physical function was defined as a mean reduction of at least 0.375 from baseline in the adjusted HAQ-DI score [15].
Study Size
The sample size was calculated on the basis of the primary hypothesis that MTX treatment would be maintained in 20% of participants. To achieve a 95% confidence interval (CI) with a precision of 12–15%, and accounting for an anticipated 10% rate of data loss (due to participants lost to follow-up, screening failure, etc.), this study aimed to include 200 participants with RA.
Statistical Analyses
Baseline participant, disease, and treatment characteristics were summarised using counts and percentages for categorical variables, and means with SD or medians with first (Q1) and third (Q3) quartiles for continuous variables.
The primary outcome was reported as frequency and percentage with 95% CI. For secondary outcomes, categorical variables were reported as counts and percentages, as well as frequency and percentage with a 95% CI (logistic regression). Continuous variables were reported using mean (SD) and/or median (Q1, Q3).
Predictive factors were identified using univariate and multivariable logistic regression models. The multivariable analysis was adjusted for random centre-level clustering effect. Results were displayed as odds ratios (OR) with 95% CI and p values. An alpha threshold of 0.2 was used for inclusion of predictive factors in the final multivariable model, while the significance level (alpha error) for statistical tests was set at 0.05. Missing data were not imputed.
All data analyses were performed using SAS software, version 9.4.
Results
Demographics and Baseline Characteristics
Of the 186 participants screened, 3 were deemed ineligible on the basis of the inclusion criteria, and 3 did not initiate b/tsDMARD therapy despite receiving a prescription at inclusion (Fig. 1). The study enrolled 180 eligible participants; however, 7 participants withdrew prematurely without completing the M12 or M24 follow-up visits. Thus, baseline characteristics were reported, and outcome analyses were conducted on a reference population of 173 participants. Of these, 171 (98.8%) participants completed the M12 visit, and 157 (90.8%) completed the M24 visit. One (0.6%) participant withdrew during the M12 visit, while 15 (8.7%) withdrew before the M24 visit. Among those who withdrew prior to M24, 11 participants were lost to follow-up, 2 participants decided to withdraw, and 2 participants died.
Fig. 1.
Participants disposition
At baseline, the reference population (N = 173) consisted of 130 (75.1%) women and 43 (24.9%) men, with a mean (SD) age of 56.1 (13.7) years (Table 1) and a mean (SD) time since RA diagnosis of 5.6 (7.3) years. The overall mean (SD) DAS28 score was 4.3 (1.2), with 32 (19.0%) participants classified as having low disease activity and 14 (8.3%) participants in remission.
Table 1.
Demographics and baseline characteristics of the study participants
| Characteristics | Reference population (N = 173) |
|---|---|
| Age (years), mean (SD) | 56.1 (13.7) |
| Sex, female/male, n (%) | 130 (75.1)/43 (24.9) |
| BMI (kg/m2), mean (SD) | 25.8 (5.6) |
| Missing, n (%) | 5 (2.9) |
| Tobacco consumption | |
| Non-smoker, n (%) | 86 (50.0) |
| Former smoker, n (%) | 51 (29.7) |
| Current smoker, n (%) | 35 (20.3) |
| Missing, n (%) | 1 (0.6) |
| Time since diagnosis (years), mean (SD) | 5.6 (7.3) |
| RF positive, n (%) | 121 (75.2) |
| High level, n (%) | 91 (52.6) |
| Low level, n (%) | 30 (17.3) |
| RF negative, n (%) | 40 (23.1) |
| RF unknown, n (%) | 12 (6.9) |
| ACPA positive, n (%) | 117 (71.8) |
| High level, n (%) | 102 (59.0) |
| Low level, n (%) | 15 (8.7) |
| ACPA negative, n (%) | 46 (26.6) |
| ACPA unknown, n (%) | 10 (5.8) |
| Participant’s global assessment of disease activity | |
| 0–100 mm scale, mean (SD) | 57.4 (22.0) |
| Missing, n (%) | 7 (4.0) |
| Participant’s assessment of pain | |
| 0–100 mm scale, mean (SD) | 55.8 (22.7) |
| Missing, n (%) | 9 (5.2) |
| Participant’s assessment of fatigue | |
| 0–100 mm scale, mean (SD) | 55.9 (24.1) |
| Missing, n (%) | 20 (11.6) |
| Physician’s global assessment of disease activity | |
| 0–100 mm scale, mean (SD) | 53.9 (20.1) |
| Missing, n (%) | 7 (4.0) |
| CRP level (mg/L), mean (SD) | 31.1 (144.7) |
| Missing, n (%) | 2 (1.2) |
| DAS28 score, mean (SD) | 4.3 (1.2) |
| Low disease activity: DAS28 [2.6–3.2], n (%) | 32 (19.0) |
| Remission: DAS28 < 2.6, n (%) | 14 (8.3) |
| Missing, n (%) | 5 (2.9) |
| Presence of radiographic signs, n (%) | 82 (47.7) |
| Hands, n/N (%) | 48/82 (58.5) |
| Wrists, n/N (%) | 37/82 (45.1) |
| Feet, n/N (%) | 50/82 (61.0) |
| Missing, n (%) | 1 (0.6) |
ACPA anticitrullinated peptide antibody-positive, BMI body mass index, CRP C-reactive protein, DAS28 Disease Activity Score in 28 joints, RF rheumatoid factor, SD standard deviation
Overall, first-line treatment for RA was initiated, on average, 4.3 (SD 5.4) years prior to study inclusion. MTX was prescribed as the first-line treatment for 150 (86.7%) participants (Table 2). Approximately two-thirds (n = 114, 65.8%) of participants had started MTX more than 1 year before inclusion. At baseline, the mean (SD) weekly dose of MTX was 18.8 (4.2) mg (median 20.0), primarily administered subcutaneously (n = 125, 72.3%), while 47 (27.2%) participants took it orally, and only 1 (0.6%) participant received it via intramuscular injection.
Table 2.
RA treatments at baseline
| Treatments | Reference population (N = 173) |
|---|---|
| MTX as first-line treatment, n (%) | 150 (86.7) |
| Time since the last modification of MTX treatment (months), mean (SD) | 14.9 (35.1) |
| Missing, n (%) | 7 (4.0) |
| MTX dosage (mg per week) depending on the route of administration | |
| Subcutaneous injection (n = 125), mean (SD) | 19.9 (3.7) |
| Oral (n = 47), mean (SD) | 16.0 (4.2) |
| Intramuscular injection (n = 1), mean (SD) | 20.0 (NA) |
| Overall MTX dose (mg/week) | |
| Mean (SD) | 18.8 (4.2) |
| Median (Q1, Q3) | 20.0 (15.0, 20.0) |
| Other conventional synthetic DMARDs associated with MTX, n (%) | 15 (8.7) |
| Sulfasalazine and hydroxychloroquine, n (%) | 1 (6.7) |
| Hydroxychloroquine, n (%) | 9 (60.0) |
| Sulfasalazine, n (%) | 5 (33.3) |
| Corticosteroids associated with MTX, n (%) | 86 (50.0) |
| Missing, n (%) | 1 (0.6) |
| Corticosteroid dosage (mg/day) (n = 84) | |
| Mean (SD) | 9.6 (6.0) |
| Median (Q1, Q3) | 7.5 (5.0, 10.0) |
| ≤ 5 mg per day, n (%) | 35 (41.7) |
| > 5 to 10 mg per day, n (%) | 30 (35.7) |
| > 10 mg per day, n (%) | 19 (22.6) |
| Missing, n (%) | 2 (2.3) |
| NSAIDs associated with MTX, n (%) | 29 (16.9) |
| Missing, n (%) | 1 (0.6) |
| Folates associated with MTX, n (%) | 166 (96.0) |
| Folates dosage (mg/week) (n = 164), mean (SD) | 12.8 (5.4) |
DMARD disease-modifying antirheumatic drug, NA not applicable, NSAIDs non-steroidal anti-inflammatory drugs, MTX methotrexate, Q1 first quartile, Q3 third quartile, RA rheumatoid arthritis, SD standard deviation
Treatments associated with MTX included corticosteroids (CS) for 86 (50.0%) participants, with a mean daily dose of 9.6 mg (median 7.5).
Primary Outcome
Maintenance of MTX Treatment 1 Year After b/tsDMARD Initiation
At the M12 follow-up visit, the same treatment modalities for MTX were maintained in 69 participants, corresponding to 39.9% (95% CI 32.5–47.6) of the study population (Table 3). In contrast, MTX treatment was modified or discontinued for 104 (60.1%, 95% CI 52.4–67.5) participants.
Table 3.
Maintenance, modification, or discontinuation of MTX treatment after b/tsDMARD initiation
| Therapeutic decision | M12 visit | M24 visit |
|---|---|---|
| Primary outcome: Maintenance of the same MTX treatment (dosage and route of administration) | N = 173 | N = 157 |
| n (%) [95% CI] | 69 (39.9) [32.5–47.6]a | 54 (34.4) [27.0–42.4] |
| MTX treatment modification, n (%) | 75 (43.3) | 64 (40.7) |
| Dosage reduction, n (%) | 70 (40.5) | 72 (45.9) |
| Change from subcutaneous injection to oral, n (%) | 30 (17.3) | 32 (20.4) |
| Only dosage reduction, n (%) | 45 (26.0) | 37 (23.6) |
| Only change from subcutaneous injection to oral, n (%) | 5 (2.9) | 4 (2.5) |
| Both dosage reduction and change from subcutaneous injection to oral, n (%) | 25 (14.4) | 23 (14.6) |
| MTX treatment discontinuation, n (%) | 29 (16.8) | 39 (24.8) |
Comparison are done between ongoing treatment at the time of b/tsDMARD initiation and treatment prescribed at the end of each visit
CI confidence interval, b/tsDMARD biologic or targeted synthetic disease-modifying antirheumatic drug, M12 study visit 12 months after b/tsDMARD initiation, M24 study visit 24 months after b/tsDMARD initiation, MTX methotrexate
aResult of the primary outcome analysis
Secondary Outcomes
Maintenance, Modifications, or Discontinuation of MTX Treatment
One year after b/tsDMARD initiation, 144 (83.2%) participants were still treated with MTX (Table 3). Specifically, 69 (39.9%) participants maintained the same dosage and route of administration, while 75 (43.3%) participants experienced changes in their MTX treatment modalities—either in dosage, route of administration, or both. MTX was discontinued in 29 (16.8%) participants at the M12 visit. Modification strategies for MTX treatment, listed in order of prevalence, included a dosage reduction alone (n = 45, 26.0%), a combination of dosage reduction and change from subcutaneous to oral administration (n = 25, 14.4%), and a change from subcutaneous to oral administration alone (n = 5, 2.9%).
Two years after b/tsDMARD initiation, 118 (75.2%) participants remained on MTX (Table 3). A total of 54 (34.4%, 95% CI 27.0–42.4) participants maintained the same dosage and route of administration, while 103 (65.6%, 95% CI 57.6–73.0) participants had either modified their treatment or discontinued MTX by the M24 visit. Specifically, 64 (40.7%) participants received a modified MTX treatment, and 39 (24.8%) discontinued MTX entirely.
Modification strategies at M24 were similar to those employed at M12, including dosage adjustments and changes to the route of administration.
Therapeutic Decisions After b/tsDMARD Initiation
At inclusion, rheumatologists prescribed the following types of b/tsDMARDs: 100 (57.8%) anti-tumour necrosis factor (anti-TNF), 30 (17.3%) Cytotoxic T-lymphocyte antigen 4 - immunoglobulin (CTLA4-Ig), 18 (10.4%) tsDMARDs (JAKi), and 3 (1.7%) anti-B-cell (anti-CD20) (Table 4). Concomitantly, MTX treatment was maintained for most participants (n = 169, 97.7%), either with unchanged modalities or with modifications to dosage or route of administration. The mean (SD) weekly MTX dosage was 17.8 (4.5) mg, with 112 (66.3%) participants receiving it via subcutaneous injections and 56 (33.1%) via oral administration. Nearly half of the participants (n = 81, 47.1%) continued CS treatment at the time of b/tsDMARD initiation.
Table 4.
Therapeutic decisions since b/tsDMARD initiation
| Therapeutic decisions | Inclusion visit | M12 visit | M24 visit |
|---|---|---|---|
| Therapeutic decision for MTX | N = 173 | N = 173 | N = 157 |
| MTX Maintenance, n (%)a | 169 (97.7) | 144 (83.2) | 118 (75.2) |
| Same MTX, n (%) | 131 (75.7) | 69 (39.9) | 54 (34.4) |
| Modified MTX, n (%) | 38 (22.0) | 75 (43.4) | 64 (40.8) |
| MTX discontinuation, n (%) | 4 (2.3) | 29 (16.8) | 39 (24.8) |
| MTX dosage and route of administration | N = 169 | N = 144 | N = 118 |
| Subcutaneous injection, n (%) | 112 (66.3) | 80 (55.6) | 67 (56.8) |
| Subcutaneous injection dosage (mg/week), mean (SD) | 19.3 (3.9) | 17.6 (4.3) | 17.6 (4.2) |
| Oral, n (%) | 56 (33.1) | 63 (43.8) | 50 (42.4) |
| Oral dosage (mg/week), mean (SD) | 15.0 (4.1) | 13.8 (3.9) | 13.4 (4.2) |
| Intramuscular injection, n (%) | 1 (0.6) | 1 (0.7) | 1 (0.8) |
| Intramuscular injection dosage (mg/week), mean (SD) | 20.0 (NA) | 15.0 (NA) | 15.0 (NA) |
| Overall MTX dosage (mg/week) | N = 169 | N = 144 | N = 118 |
| Mean (SD) | 17.8 (4.5) | 15.9 (4.5) | 15.8 (4.6) |
| Median (Q1, Q3) | 20.0 (15.0, 20.0) | 15.0 (13.8, 20.0) | 15.0 (12.5, 20.0) |
| Prescription of b/tsDMARDs | N = 173 | N = 159 | N = 132 |
| Anti-TNF, n (%) | 100 (57.8) | 74 (46.5) | 54 (40.9) |
| CTLA4-Ig, n (%) | 30 (17.3) | 27 (17.0) | 25 (18.9) |
| Anti-IL-6, n (%) | 22 (12.7) | 27 (17.0) | 25 (18.9) |
| tsDMARD: JAKi, n (%) | 18 (10.4) | 27 (17.0) | 23 (17.4) |
| Anti-CD20, n (%) | 3 (1.7) | 4 (2.5) | 3 (2.3) |
| Anti-IL-17, n (%) | 0 (0.0) | 0 (0.0) | 2 (1.5) |
| Therapeutic decision for b/tsDMARDsb | N = 173 | N = 157 | |
| Yes, n (%) | 159 (91.9) | 132 (84.1) | |
| No, n (%) | 14 (8.1) | 25 (15.9) | |
| Therapeutic decision for corticosteroids | N = 172 | N = 172 | N = 156 |
| Yes, n (%) | 81 (47.1) | 67 (39.0) | 59 (37.8) |
| No, n (%) | 91 (52.9) | 105 (61.0) | 97 (62.2) |
| Corticosteroid dosage (mg/day) | N = 80 | N = 65 | N = 57 |
| Mean (SD) | 9.3 (7.5) | 8.9 (9.0) | 9.3 (9.3) |
| Median (Q1, Q3) | 7.5 (5.0, 10.0) | 5.0 (5.0, 10.0) | 6.0 (5.0, 10.0) |
The inclusion visit corresponds to the initiation of b/tsDMARD therapy
Anti-CD20 anti-B-cell, CTLA4-Ig Cytotoxic T-lymphocyte antigen 4 - immunoglobulin, Anti-IL-6 anti-interleukin-6, Anti-IL-17 anti-interleukin-17, Anti-TNF anti-tumour necrosis factor, bDMARD biological disease-modifying antirheumatic drug, b/tsDMARD biological or targeted synthetic disease-modifying antirheumatic drug, DMARD disease-modifying antirheumatic drug, JAKi Janus kinase inhibitors, tsDMARD targeted synthetic disease-modifying antirheumatic drug, M12 study visit 12 months after b/tsDMARD initiation, M24 study visit 24 months after b/tsDMARD initiation, MTX methotrexate, NA not applicable, Q1 first quartile, Q3 third quartile, SD standard deviation
aMaintenance of MTX treatment at M12 and M24 visits, with identical dosage and route of administration (same MTX), or with either a different dosage or route of administration in comparison with the prescription at the time of b/tsDMARD initiation (modified MTX)
bAll b/tsDMARDs
The continuation of b/tsDMARD therapy was observed in 159 (91.9%) participants at the M12 visit and 132 (84.1%) participants at the M24 visit (Table 4). Of the 132 participants followed at M24, 86 (65.2%) remained on the same b/tsDMARD therapy, while 32 (24.0%) received a second-line treatment, 11 (8.3%) a third-line treatment, and 3 (2.3%) a fourth-line treatment. Anti-TNF therapy remained the most frequently prescribed b/tsDMARD. However, its use tended to decrease compared to baseline, with 74 (46.5%) prescriptions at M12 and 54 (40.9%) at M24. Treatment cessations were primarily reported for anti-TNF therapies. At M12, 31 (19.5%) participants were still treated with other bDMARDs, and this proportion remained stable at M24 (n = 28, 21.2%). Anti-IL-6 therapies represented 27 (17.0%) treatments at M12 and 25 (18.9%) treatments at M24. Furthermore, tsDMARDs comprised 27 (17.0%) treatments at M12 and 23 (17.4%) treatments at M24.
Adaptations to MTX treatment included both dose reductions and changes in the route of administration (Table 4). By M12, the mean (SD) weekly MTX dosage had decreased to 15.9 (4.5) mg. Subcutaneous injections became less common (n = 79, 54.9%), while oral administration increased (n = 63, 43.8%). Similarly, at M24, the mean (SD) weekly MTX dose was 15.8 (4.6) mg, administered subcutaneously to 66 (55.9%) participants and orally to 50 (42.4%) participants.
Rheumatologists suspended CS therapy in 91 (52.9%) participants at the initiation of b/tsDMARD (Table 4). This proportion increased to 105 (61.0%) participants at M12 and 97 (62.2%) participants at M24. Nevertheless, among those who continued CS therapy, the mean (SD) daily dose remained relatively high throughout the study: 9.3 (7.5) mg at b/tsDMARD initiation, 8.9 (9.0) mg at M12, and 9.3 (9.3) mg at M24.
Reasons Driving MTX Discontinuation
MTX discontinuation was reported in 29 (16.8%) participants during the first year and 39 (24.8%) participants during the second year following b/tsDMARD initiation. At both time points, the primary reasons for discontinuation were participant decisions (M12: n = 11, 39.2%; M24: n = 14, 35.9%) and adverse events (M12: n = 10, 35.7%; M24: n = 13, 33.3%) (Supplementary Table S1). No unexpected safety concerns or serious adverse events related to MTX or b/tsDMARDs were reported during the study (Supplementary Table S2).
Factors Favouring the Maintenance of MTX Treatment
The factors associated with the decision to maintain MTX treatment with the same modalities, from the initiation of b/tsDMARDs to the M24 follow-up visit, were investigated using univariate logistic regression analysis (Supplementary Table S3). Factors with a p > 0.200 were excluded from further analysis to focus on significant predictors. Among the factors assessed, receiving a prescription at baseline for combination therapy versus b/tsDMARD monotherapy (reference) was not significantly associated with MTX maintenance during the first 2 years of b/tsDMARD therapy (OR (95% CI) 1.02 (0.53–1.98), p = 0.952).
Multivariable analysis identified two significant predictors for MTX maintenance at M24. Participant age was identified as a factor, with each additional year of age significantly increasing the likelihood of maintaining MTX (OR (95% CI) 1.04 (1.01–1.08), p = 0.011, Supplementary Table S4). Furthermore, each additional unit on the visual analogue scale measuring participant-perceived disease activity was significantly associated with an increased likelihood of maintaining MTX (OR (95% CI) 1.02 (1.00–1.04), p = 0.005).
Non-smoking was not significantly associated with MTX maintenance (OR (95% CI) 1.95 (0.66–5.78), p = 0.231), although it was included as a potential predictor in the analysis. Therapeutic decisions made by rheumatologists practising exclusively in hospital-based settings, as opposed to those in private practice with partial hospital involvement (reference), were also not significantly associated with MTX maintenance (OR (95% CI) 2.94 (0.98–8.85), p = 0.055). Finally, given the multicentric design of this study, the centre effect was tested and found to be non-significant, indicating that rheumatologist practices were consistent across geographic locations.
Evolution of Disease Activity and Participants’ Physical Function Since b/tsDMARD Initiation
Since b/tsDMARD initiation, the DAS28 score progressively decreased over time, with mean (SD) changes from baseline of − 1.7 (1.4) at M12 and − 2.0 (1.3) at M24 (Table 5). The number of participants in remission increased from 14 (8.3%) at baseline to 81 (53.3%) at M12, and further to 95 (66.0%) at M24. In contrast, 49 (34.7%) participants did not achieve low disease activity by M24, with 27 (19.1%) displaying a moderate response and 22 (15.6%) showing no response to therapy. Reduction in disease activity (DAS28) and improvement in physical function (HAQ-DI) were observed within similar ranges across groups, regardless of whether MTX was maintained, modified, or discontinued. We can hypothesize that MTX was reduced (modification or discontinuation group) when the patient’s condition had improved.
Table 5.
Disease activity and participants’ physical function: evolution at 12 months and 24 months
| Parameter | Evolution at M12 and M24 | Evolution at M12 | Evolution at M24 | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| All participants (N = 173) | Maintenance (N = 69) | Modification (N = 75) | Discontinuation (N = 29) | Maintenance (N = 54) | Modification (N = 64) | Discontinuation (N = 39) | |||||||||
| Baseline | M12 | M24 | Baseline | M12 | Baseline | M12 | Baseline | M12 | Baseline | M24 | Baseline | M24 | Baseline | M24 | |
| Disease activity | N = 168 | N = 152 | N = 144 | N = 68 | N = 60 | N = 74 | N = 66 | N = 26 | N = 26 | N = 52 | N = 49 | N = 63 | N = 62 | N = 37 | N = 33 |
| Mean (SD) | 4.3 (1.2) | 2.6 (1.1) | 2.4 (1.1) | 4.4 (1.2) | 2.8 (1.1) | 4.4 (1.2) | 2.4 (1.0) | 4.3 (1.2) | 2.9 (1.2) | 4.5 (1.2) | 2.7 (1.2) | 4.2 (1.1) | 2.3 (0.9) | 4.4 (1.3) | 2.3 (1.0) |
| MC (SD)(1) | − 1.7 (1.4) | − 2.0 (1.3) | − 1.6 (1.4) | − 2.0 (1.3) | − 1.4 (1.3) | − 1.8 (1.5) | − 2.0 (1.1) | − 2.3 (1.4) | |||||||
| Remission, n (%) | 14 (8.3) | 81 (53.3) | 95 (66.0) | 6 (8.8) | 31 (51.7) | 5 (6.8) | 40 (60.6) | 3 (11.5) | 10 (38.5) | 2(3.8) | 29 (59.2) | 6 (9.5) | 41 (66.1) | 3 (8.1) | 25 (75.8) |
| EULAR criteria | |||||||||||||||
| Good response, n (%) | 84 (56.0) | 92 (65.2) | 31 (51.7) | 43 (66.2) | 10 (40.0) | 27 (56.3) | 41 (67.2) | 24 (75.0) | |||||||
| Moderate response, n (%) | 32 (21.3) | 27 (19.1) | 14 (23.3) | 10 (15.4) | 8 (32.0) | 11 (22.9) | 13 (21.3) | 3 (9.4) | |||||||
| No response, n (%) | 34 (22.7) | 22 (15.6) | 15 (25.0) | 12 (18.5) | 7 (28.0) | 10 (20.8) | 7 (11.5) | 5 (15.6) | |||||||
| Physical function (HAQ-DI) | N = 148 | N = 141 | N = 119 | N = 56 | N = 50 | N = 69 | N = 67 | N = 23 | N = 24 | N = 42 | N = 35 | N = 61 | N = 55 | N = 32 | N = 29 |
| Mean (SD)(2) | 1.0 (0.7) | 0.7 (0.7) | 0.6 (0.6) | 1.1 (0.6) | 0.8 (0.7) | 0.9 (0.7) | 0.6 (0.7) | 1.0 (0.8) | 0.6 (0.6) | 1.1 (0.6) | 0.8 (0.7) | 0.9 (0.7) | 0.6 (0.6) | 1.0 (0.8) | 0.4 (0.6) |
| MC (SD) | − 0.3 (0.6) | − 0.3 (0.6) | − 0.4 (0.4) | − 0.3 (0.7) | − 0.4 (0.6) | − 0.3 (0.5) | − 0.3 (0.6) | − 0.5 (0.6) | |||||||
| Clinically meaningful improvement, n (%) | 61 (48.4) | 60 (54.5) | 21 (47.7) | 31 (50.0) | 9 (45.0) | 20 (62.5) | 28 (52.8) | 12 (48.0) | |||||||
Disease activity is reported as DAS28 score. Physical function is reported as adjusted HAQ-DI. The minimal clinically meaningful improvement in the physical function was defined as a mean decrease of at least 0.375 from baseline in the adjusted HAQ-DI. Maintenance, modification, and discontinuation refer to decisions regarding MTX treatment
For all participants: (1) Change from baseline in DAS28 score, reflecting the disease activity, was calculated for 150 and 141 participants at M12 and M24 visits, respectively. (2) Change from baseline in adjusted HAQ-DI, reflecting the evolution of the participants’ physical function, was calculated for 126 and 110 participants at M12 and M24 visits, respectively
For participants maintaining MTX treatment at the M12 visit: (1) Change from baseline in DAS28 score was calculated for 60 participants. (2) Change from baseline in adjusted HAQ-DI was calculated for 44 participants
For participants modifying their MTX treatment at the M12 visit: (1) Change from baseline in DAS28 score was calculated for 65 participants. (2) Change from baseline in adjusted HAQ-DI was calculated for 62 participants
For participants discontinuing MTX at the M12 visit: (1) Change from baseline in DAS28 score was calculated for 25 participants. (2) Change from baseline in adjusted HAQ-DI was calculated for 20 participants
For participants maintaining MTX treatment at the M24 visit: (1) Change from baseline in DAS28 score was calculated for 48 participants. (2) Change from baseline in adjusted HAQ-DI was calculated for 32 participants
For participants modifying their MTX treatment at the M24 visit: (1) Change from baseline in DAS28 score was calculated for 61 participants. (2) Change from baseline in adjusted HAQ-DI was calculated for 53 participants
For participants discontinuing MTX at the M24 visit: (1) Change from baseline in DAS28 score was calculated for 32 participants. (2) Change from baseline in adjusted HAQ-DI was calculated for 25 participants
DAS28 Disease Activity Score in 28 joints, EULAR European Alliance of Associations for Rheumatology, HAQ-DI Health Assessment Questionnaire-Disability Index, M12 study visit 12 months after b/tsDMARD initiation, M24 study visit 24 months after b/tsDMARD initiation, MC mean change from baseline, SD standard deviation
From the participants’ perspective, physical function improved at M12 and stabilised at M24, with mean changes (SD) from baseline in the adjusted HAQ-DI of − 0.3 (0.6) at both time points (Table 5). Up to 61 (48.4%) participants reported a clinically meaningful improvement in physical function.
Discussion
This longitudinal, prospective, non-interventional, multicentre study conducted in France examined MTX therapeutic strategies at the initiation of b/tsDMARDs for the treatment of RA in real-world clinical settings. At baseline, the 173 participants had been diagnosed with RA for approximately 5.6 (7.3) years, with a DAS28 score of 4.3 (1.2). Approximately two-thirds of participants had been receiving MTX therapy for over 1 year, with a mean weekly dose of 18.8 (4.2) mg, and 72.3% were treated via subcutaneous administration. At the time of b/tsDMARD initiation, 97.7% of participants continued MTX therapy. After 1 year, 83.2% of participants remained on MTX, with 39.9% (95% CI 32.5–47.6) maintaining the same treatment modalities. MTX discontinuation was primarily attributed to participant preferences or adverse events. By the 2-year follow-up, the mean change from baseline in the DAS28 score was − 2.0 (1.3), with 66.0% of participants achieving remission. According to EULAR criteria, 65.2% of participants demonstrated a good response to treatment, 19.1% had a moderate response, and 15.6% had an inadequate response.
At baseline, prior to b/tsDMARD initiation, most participants were receiving MTX via subcutaneous injection, while nearly one-third were using oral administration. These participants may have benefited from optimising their treatment modalities before considering b/tsDMARD therapy. This is supported by real-world data from the ESPOIR cohort study, which reported 3–4 times higher remission rates and improved functional outcomes after MTX optimisation [16]. Additionally, a recent study by Jung et al. suggested that incomplete utilisation of MTX and other csDMARDs may impede the achievement of remission or low disease activity [17]. All national and international treatment guidelines—including the recommendations of the French Society for Rheumatology (SFR) from 2014 [7], 2019 [4], and 2024 [11], the EULAR recommendations (2022 update) [10], and the 2021 ACR guideline [18]—consistently advise that if a patient demonstrates an inadequate response following MTX optimisation, a combination therapy with MTX and a b/tsDMARD should be initiated, as maintaining MTX is the preferred strategy. In the STRATEGE2 study, three-quarters of participants continued MTX therapy 2 years after initiating b/tsDMARD, regardless of any changes in treatment modalities. This outcome aligns with the SFR guidelines available at the time, which recommended prescribing b/tsDMARD in combination with MTX [4].
Firstly, within 2 years after initiating b/tsDMARD, rheumatologists maintained the initial MTX treatment modalities for one-third of participants. Factors associated with this decision-making process were investigated but only a few stood out. Participant age was a factor associated with the maintenance of MTX treatment modalities. Younger patients with a recent RA diagnosis may be more inclined to request MTX discontinuation, whereas older patients typically exhibit better treatment adherence, as they are more accustomed to it. Furthermore, a previous study has shown that older patients have a reduced risk of suspending b/tsDMARD treatment [19]. Finally, perceived disease activity reported by participants was also identified as a contributing factor. It can be argued that patients who sense a flare are more likely to advocate for the continuation of MTX to manage their symptoms effectively.
Secondly, rheumatologists reduced the dosage, adapted the route of administration of MTX, or both, for 40% of participants within 2 years of initiating targeted therapy. When remission is achieved with combination therapy, the question arises as to whether MTX or b/tsDMARD therapy should be tapered or discontinued. Evidence from the TARA trial indicates no significant difference in clinical outcomes when tapering either the csDMARD or the bDMARD first. The proportion of patients experiencing a flare-up within 2 years was similar between the two groups: 61% (95% CI 50–71) following csDMARD discontinuation versus 62% (95% CI 52–72) following anti-TNF discontinuation (p = 0.840) [20]. Although tapering bDMARDs was previously recommended for cost-related considerations, this assumption is still being investigated [21]. According to the latest SFR guidelines (2024), progressive tapering of cs/b/tsDMARDs should only be considered once sustained remission is achieved without the use of corticosteroids [11]. However, the definition of remission varies depending on the assessment tool employed. Achieving remission based on the DAS28 score has been associated with sustained remission, improved quality of life, and reduced cardiovascular issues. As a result, DAS28 remission is recognised as the treatment target across all guidelines. In this study, a significant proportion of participants achieved DAS28 remission, with 53.3% at 12 months and 66.0% at 24 months of follow-up. In parallel, a clinically meaningful improvement in participants’ health was reported in half of the study population, consistent with the association between DAS28 remission and functional, clinical, and structural improvements [22]. Remission as defined by the DAS28 score is considered the most permissive criterion compared to stricter frameworks, such as the EULAR criteria, Clinical Disease Activity Index (CDAI), or Simplified Disease Activity Index (SDAI). This may explain why treatments for some participants remained unchanged, with no tapering, despite achieving DAS28 remission. EULAR recommendations suggest tapering either the background csDMARD or the targeted therapy (bDMARD), without a preference, for patients in DAS28 remission, as flare rates are comparable after 1 year of follow-up [23]. However, caution is warranted when tapering MTX, particularly when administered subcutaneously. Tapering subcutaneous MTX is associated with a higher risk of flare-ups and requires closer monitoring compared to tapering oral MTX [24]. Findings from the RETRO study further confirmed the ability to maintain DAS28 remission after tapering or discontinuing either biologic DMARDs or conventional synthetic DMARDs [25]. However, relapses were most likely to occur within the first 6 months following treatment adjustments and were associated with anticitrullinated peptide antibody-positive (ACPA) status [25].
Thirdly, in this study, approximately one-quarter of participants discontinued MTX at the 2-year follow-up. This was frequently a therapeutic adaptation requested by participants, with adverse events cited as the primary reason for discontinuing MTX therapy. A systematic review published in 2021 identified predictors of adverse events associated with MTX discontinuation, including rheumatoid factor status, body mass index, and HAQ scores [26]. MTX was also discontinued by participants attempting to conceive. However, the latest data suggest that MTX does not cause testicular toxicity, indicating that it is safe for men to continue treatment while attempting conception [27]. Remission was cited only twice as a reason for discontinuing MTX, likely due to the short-term follow-up period of 2 years, as sustained remission of at least 6–12 months is typically required before discontinuation can be considered as a therapeutic option. Additionally, there was a notable decline in the proportion of participants using anti-TNF as part of b/tsDMARD treatment strategies. Despite this decrease, anti-TNF therapies still accounted for half of the prescribed b/tsDMARDs at the 24-month follow-up visit. Between the initiation of the STRATEGE2 study and the 2-year follow-up visit, a safety alert was issued concerning the use of JAKi in patients with cardiovascular risks or those who smoke. During this time, tofacitinib became a recommended third-line treatment [10, 28, 29]. The decision to discontinue MTX is influenced by the level of disease activity observed during combination therapy, as demonstrated by a retrospective Canadian study examining MTX de-escalation patterns in patients with RA treated concomitantly with b/tsDMARDs [30]. In patients with an inadequate response to treatment, MTX withdrawal has been reported to be either less effective or comparable to maintaining combination therapy with anti-TNF and MTX [31]. For patients with a moderate response to bDMARD and MTX combination therapy, continuing MTX is preferable as it helps prevent radiographic progression. In contrast, for patients achieving low disease activity, MTX withdrawal does not significantly worsen disease activity or progression in the short term [30–32]. However, when patients experienced relapse following MTX discontinuation, regaining remission became a prolonged process, with some patients only able to return to low disease activity. Therefore, tapering or discontinuing treatments should be approached gradually and with great caution.
Finally, one of the key benefits of using MTX in combination with targeted therapies is its ability to prevent the formation of antibodies against bDMARDs, thereby improving the survival of anti-TNF drugs. The CONCERTO study demonstrated that an MTX dose of 10 mg weekly is beneficial when combined with the anti-TNF drug adalimumab [33]. Indeed, anti-TNF monotherapy has been linked to a high risk of treatment failure. However, the immunogenicity-limiting effect of MTX may be questioned in older individuals, potentially due to a decline in immunogenicity associated with immuno-senescence in aging [34].
Concerning treatments adjunct to MTX, half of the participants were receiving CS at baseline, with a relatively high mean daily dose of 9.6 mg. While this dosage remained consistent throughout the study, the proportion of participants treated with CS decreased by 24 months. The long-term impacts of low-dose CS have been investigated over a 10-year period, revealing cumulative negative outcomes after more than 5 years of continuous use [35]. Furthermore, side effects were found to increase with each additional year of use [35]. CS therapy should ideally be prescribed for short-term use during the initiation or modification of csDMARD therapy, with the aim of tapering off CS as rapidly as clinically feasible. This approach minimises safety risks such as osteoporotic fractures, serious infections, and diabetes, which are exacerbated by higher doses and prolonged use [36]. In patients with early inflammatory arthritis, the initial prescribed dose of CS tends to be higher compared to its use as background treatment. Yet, when used in combination with DMARDs, CS therapy does not appear to increase mortality or hospitalisations rates [37]. Current recommendations indicate that the persistent need for CS therapy suggests inadequate efficacy of DMARD treatment. Furthermore, they advise against the concurrent use of CS alongside b/tsDMARDs, despite evidence supporting its benefits in RA management [36]. Potential reasons for maintaining CS therapy as a background treatment include its stimulant effect, its ability to address concomitant diseases, and the risk of withdrawal syndrome, which can lead to a resurgence of pain. Nevertheless, tapering and eventually discontinuing CS therapy has been demonstrated to be both feasible and safe [38].
A key limitation of this study lies within its observational nature, which relies on physician-guided treatment decision without standardised protocol. This approach may introduce potential selection bias, limit external validity, and imposes cautiousness with the generalization of the results. Furthermore, the study design restricts our ability to assess the direct impact of MTX modifications on clinical outcomes. These highlight the need for future analytical or longitudinal studies to validate and expand upon these findings. Another limitation of this study was the reliance on the DAS28 score, which may overestimate remission compared to more stringent criteria, such as the ACR/EULAR criteria (Boolean definition), SDAI, or CDAI [39, 40]. Additionally, detailed data on structural progression of RA were not monitored (e.g., radiologic surveillance frequency, date of the latest radiographic examination, and radiographic progression), and tolerance-related data were also not collected during the study period. Lastly, the final part of the enrolment period coincided with the coronavirus disease (COVID-19) pandemic (March 2020 to December 2020). A recent retrospective study evaluated the impact of COVID-19 on the initiation of biologics for chronic inflammatory diseases in France. The authors reported a marked increase in the prescription of IL-6 antagonists [41], medications thought at the time to offer potential benefits on COVID-19 outcomes [42]. Consequently, one cannot rule out that the COVID-19 pandemic may have impacted the selection of targeted therapy during the period covered by STRATEGE2.
Conclusion
MTX is the cornerstone of RA treatment and is often combined with bDMARD or tsDMARD to improve patient symptoms and functional capacity. The investigators of the STRATEGE2 study adhered to recommendations by maintaining MTX in patient management when initiating a b/tsDMARD. Further studies are warranted to explore the rationale behind medical decisions regarding the maintenance or modification of treatments in the management of RA.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors thank the patients and caregivers in addition to the investigators and their teams who contributed to this study.
Medical Writing, Editorial, and Other Assistance
The authors also acknowledge the contract research organisation RCTS for their contributions in the study conduct and statistical assistance, and Camille Dejos and Yann Fardini (Soladis Clinical Studies) for medical writing assistance. This assistance was funded by Nordic Pharma, Paris, France.
Author Contributions
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. No honoraria or payments were made for authorship. Substantial contributions to the conception or design of the work: Cécile Gaujoux-Viala and René-Marc Flipo. Substantial contributions to the acquisition, analysis, or interpretation of data for the work: Cécile Gaujoux-Viala, Emmanuelle Dernis, Eric Senbel, Hélène Herman-Demars, Jennifer Becker, and René-Marc Flipo. Drafting the work: Cécile Gaujoux-Viala and René-Marc Flipo. Revising the work critically for important intellectual content: Cécile Gaujoux-Viala, Emmanuelle Dernis, Eric Senbel, Hélène Herman-Demars, Jennifer Becker, and René-Marc Flipo. Final approval of the version to be published: Cécile Gaujoux-Viala, Emmanuelle Dernis, Eric Senbel, Hélène Herman-Demars, Jennifer Becker, and René-Marc Flipo. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: Cécile Gaujoux-Viala, Emmanuelle Dernis, Eric Senbel, Hélène Herman-Demars, Jennifer Becker, and René-Marc Flipo.
Funding
This study was funded by Nordic Pharma (Paris, France). Nordic Pharma sponsored the study and the development of this manuscript and reviewed the text to ensure that from Nordic Pharma’s perspective, the data presented in the publication are scientifically, technically, and medically supportable, that they do not contain any information that has the potential to damage the intellectual property of Nordic Pharma, and that the publication complies with applicable laws, regulations, guidelines, and good industry practice. Sponsorship for this study and Rapid Service Fee were funded by Nordic Pharma. The authors approved the final version to be published after critically revising the manuscript for important intellectual content. No honoraria or payments were made for authorship.
Data Availability
According to the French law, the datasets can only be shared through a controlled access; the reuse of these health data at the individual level would require an agreement with Nordic Pharma (helene.herman-demars@nordicpharma.com), and application to the French Health Data Hub (https://www.health-data-hub.fr/), with examination by the committee of experts (CESREES, Ethics and Scientific Committee for Research, Studies and Evaluations in the field of Health) and the French National Commission for Data Protection (CNIL). The French Data Protection Act and the Public Health Code restrict access to research of public interest.
Declarations
Conflict of Interest
Cécile Gaujoux-Viala: AbbVie; Alfasigma; Amgen; Biocon; Biogen; Boehringer Ingelheim, Bristol-Myers Squibb; Celgene; Celltrion; Eli Lilly; Galapagos; Gilead Sciences; Janssen; Medac; Merck-Serono; Mylan; Nordic Pharma; Novartis; Pfizer; Roche; Sandoz; Sanofi; UCB Pharma and Viatrix. Emmanuelle Dernis: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, MSD, Nordic Pharma, Novartis, Pfizer, Roche, Roche-Chugaï, Sandoz, Sanofi and UCB Pharma. Eric Senbel: Abbvie, Celltrion, Fresenius Kabi, Lilly, Medac, Nordic Pharma, Novartis, Pfizer, Sandoz and UCB. Hélène Herman-Demars and Jennifer Becker: employees Nordic Pharma France. René-Marc Flipo: Abbvie, Bristol-Myers Squibb, Eli-Lilly, Janssen, MSD, Nordic Pharma, Novartis, Pfizer, Roche-Chugaï, Sandoz and Sanofi.
Ethical Approval
This study was approved on 12 November 2018, by an independent ethics committee (Comité de Protection des Personnes Sud Méditerranée V; Reference 18.068). All participating study sites accepted the single ethics committee approval. The ethics committee expressly authorized the use of oral non-opposition, as permitted for non-interventional research conducted in France and involving no risk or constraint beyond routine clinical practice. Participants received comprehensive written information about the study objectives, procedures, and their rights, in compliance with Articles L.1121-1 and L.1122-1-1 of the French Public Health Code. Oral non-opposition to the collection of their personal data was obtained prior to participant inclusion and documented in the study records, as required by local regulations governing non-interventional studies in France. All data were processed in compliance with the reference methodology MR-003 from the French Data Protection Authority (CNIL), ensuring the protection of participant privacy and data integrity.
Footnotes
Prior Presentation: Results from this study were presented in part at the following French and international congresses: A poster (PE.Lu-071) was presented at SFR 2021 (12–14 December 2021) in Paris, France. A Guided Poster Tour (PC42) was presented during SFR 2022 (11–13 December 2022) in Paris, France. A Poster Tour was presented during EULAR 2022 (1–4 June 2022) in Copenhagen, Denmark, and published as a Scientific Abstract in the Congress Abstract Book: Gaujoux-Viala et al. (POS0698), Annals of the Rheumatic Disease, 10.1136/annrheumdis-2022-eular.3719; additionally, a Scientific Abstract (Publication Only) was published: Gaujoux-Viala et al. (AB1449), Annals of the Rheumatic Disease, 10.1136/annrheumdis-2022-eular.3683. An Oral Communication (Gaujoux-Viala; Abstract n°000288) was presented at SFR 2023 (10–12 December 2023) in Paris, France. A Poster Tour Results was presented during EULAR 2023 (31 May–3 June 2023) in Milan, Italy, and published as a Scientific Abstract in the Congress Abstract Book: Gaujoux-Viala et al. (POS0635), Annals of the Rheumatic Disease, 10.1136/annrheumdis-2023-eular.3939; additionally, a Scientific Abstract (Publication Only) was published: Gaujoux-Viala et al. (AB0461), Annals of the Rheumatic Disease, 10.1136/annrheumdis-2023-eular.3982. Two Scientific Abstracts (Publication Only) were published in EULAR 2024 (12–15 June 2024, Vienna, Austria) Congress Abstract Book: Gaujoux-Viala et al. (AB0520), Annals of the Rheumatic Disease, 10.1136/annrheumdis-2024-eular.2185; Gaujoux-Viala et al. (AB0683), Annals of the Rheumatic Disease, 10.1136/annrheumdis-2024-eular.2275. Two posters were presented at ACR Convergence 2024 (14–19 November 2024) in Washington, DC, USA: Gaujoux-Viala et al. (Abstract number 0360), Arthritis Rheumatol. 2024; 76 (suppl 9), and Gaujoux-Viala et al. (Abstract number 1366), Arthritis Rheumatol. 2024; 76 (suppl 9).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
According to the French law, the datasets can only be shared through a controlled access; the reuse of these health data at the individual level would require an agreement with Nordic Pharma (helene.herman-demars@nordicpharma.com), and application to the French Health Data Hub (https://www.health-data-hub.fr/), with examination by the committee of experts (CESREES, Ethics and Scientific Committee for Research, Studies and Evaluations in the field of Health) and the French National Commission for Data Protection (CNIL). The French Data Protection Act and the Public Health Code restrict access to research of public interest.