Intervention with methotrexate in patients with arthralgia at risk of rheumatoid arthritis to reduce the development of persistent arthritis and its disease burden (TREAT EARLIER): a randomised, double-blind, placebo-controlled, proof-of-concept trial.

BACKGROUND: Rheumatoid arthritis is the most common autoimmune disease worldwide and requires long-term treatment to suppress inflammation. Currently, treatment is started when arthritis is clinically apparent. We aimed to evaluate whether earlier intervention, in the preceding phase of arthralgia and subclinical joint inflammation, could prevent the development of clinical arthritis or reduce the disease burden. METHODS: We conducted a randomised, double-blind, placebo-controlled, proof-of-concept-trial at the Leiden University Medical Centre, Leiden, Netherlands. Adults aged 18 years or older with arthralgia clinically suspected of progressing to rheumatoid arthritis and MRI-detected subclinical joint inflammation were eligible for enrolment across 13 rheumatology outpatient clinics in the southwest region of the Netherlands and randomly assigned (1:1) to a single intramuscular glucocorticoid injection (120 mg) and a 1-year course of oral methotrexate (up to 25 mg/week), or placebo (single injection and tablets for 1 year). Participants and investigators were masked to group assignment. Follow-up continued for 1 year after the end of the 1-year treatment period. The primary endpoint was development of clinical arthritis (fulfilling the 2010 rheumatoid arthritis classification criteria or involving two or more joints) that persisted for at least 2 weeks. Patient-reported physical functioning, symptoms, and work productivity were secondary endpoints, which were measured every 4 months. Additionally, the course of MRI-detected inflammation was studied. All participants entered the intention-to-treat analysis. This trial is registered with EudraCT, 2014-004472-35, and the Netherlands Trial Register, NTR4853-trial-NL4599. FINDINGS: Between April 16, 2015, and Sept 11, 2019, 901 patients were assessed for eligibility and 236 were enrolled and randomly assigned to active treatment (n=119) or placebo (n=117). At 2 years, the frequency of the primary endpoint was similar between the groups (23 [19%] of 119 participants in the treatment group vs 21 [18%] of 117 in the placebo group; hazard ratio 0·81, 95% CI 0·45 to 1·48). Physical functioning improved more in the treatment group during the first 4 months and remained better than in the placebo group (mean between-group difference in Health Assessment Questionnaire disability index over 2 years: -0·09, 95% CI -0·16 to -0·03; p=0·0042). Similarly, pain (on scale 0-100, mean between-group difference: -8, 95% CI -12 to -4; p<0·0001), morning stiffness of joints (-12, -16 to -8; p<0·0001), presenteeism (-8%, -13 to -3; p=0·0007), and MRI-detected joint inflammation (-1·4 points, -2·0 to -0·9; p<0·0001) showed sustained improvement in the treatment group compared with the placebo group. The number of serious adverse events was equal in both groups; adverse events were consistent with the known safety profile for methotrexate. INTERPRETATION: Methotrexate, the cornerstone treatment of rheumatoid arthritis, initiated at the pre-arthritis stage of symptoms and subclinical inflammation, did not prevent the development of clinical arthritis, but modified the disease course as shown by sustained improvement in MRI-detected inflammation, related symptoms, and impairments compared with placebo. FUNDING: Dutch Research Council (NWO; Dutch Arthritis Society).

Determinants of reaching drug-free remission in patients with early rheumatoid or undifferentiated arthritis after one year of remission-steered treatment.

OBJECTIVE: The aim of this study was to assess whether baseline characteristics in patients with undifferentiated arthritis or early RA affect the possibility of achieving drug-free remission after 1 year (DFR1 year) of early remission induction therapy. METHODS: We included 375 patients participating in the IMPROVED study who achieved remission (DAS < 1.6) after 4 months (early remission) and were by protocol able to achieve DFR1 year. Having started with MTX plus prednisone, patients tapered prednisone to zero; after 8 months, those still in remission tapered MTX to zero, while those not in remission restarted prednisone. Characteristics of patients achieving and not achieving DFR1 year were compared. Logistic regression was performed to identify predictors of DFR1 year. RESULTS: After 1 year, 119 patients (32%) were in DFR. Presence of RF, fulfilling the 2010 criteria for RA, and a low tender joint count were associated with achieving DFR1 year, whereas presence of ACPA was not. None of the baseline characteristics was independently associated with DFR1 year. DFR1 year was sustained for 4 months in 65% of the patients. ACPA-positive patients less often had sustained DFR than ACPA-negative patients (58% vs 80%, P = 0.013). CONCLUSION: After 1 year of remission-steered treatment, 32% of the patients who had achieved early remission after 4 months were able to taper medication and achieved DFR. Neither the presence of ACPA nor any other baseline characteristics were independently associated with achieving DFR1 year, but in ACPA-positive patients DFR was less often sustained.

Intra articular injection with corticosteroids in patients with recent onset rheumatoid arthritis: subanalyses from the BeSt study.

To investigate the association between intra-articular (IA) large joint corticosteroid injections and clinical outcomes in patients with recent onset rheumatoid arthritis (RA). We compared pain (visual analog scale (VAS)), the Disease Activity Score (44 joints) (DAS), and swollen and tender joint counts before and after IA injection. Using linear mixed models (LMM), the DAS and the Health Assessment Questionnaire (HAQ) score over time were compared in IA injected versus noninjected patients. In year 1, 93 joints were injected in 44 patients treated with initial methotrexate monotherapy and 16 in patients treated with initial combination therapy (p < 0.01). Three months later, swelling and tenderness were resolved in 58-50 % of the injected joints; but within 12 months after the injection, swelling recurred in 14 % and tenderness in 41 % of the injected joints. Mean (SD) DAS decreased from 4.0 (1.4) before to 3.2 (1.2) 3 months after injection (p < 0.01) and VAS for pain from 49 (26) to 40 (27) (p < 0.01). LMM showed a higher DAS and HAQ in patients injected in year 0-1 compared to those not injected, but no difference in subsequent years, and similar treatment adjustments. Eight-year radiographs showed similar damage in injected joints (17 %) and noninjected joints (14 %). IA corticosteroid injections are associated with symptom relief, sometimes only temporarily, in 50 % of cases. Initially DAS significantly improved, but over time DAS and HAQ were similar in injected versus non-injected patients. After 8 years there was no difference in joint damage.

Evaluation of classical complement pathway activation in rheumatoid arthritis: measurement of C1q-C4 complexes as novel activation products.

OBJECTIVE: Novel activation products that are stable and minimally susceptible to in vitro artefacts have recently been described in the classical complement pathway. The present study assessed circulating levels of these products, i.e., covalent complexes between the recognition molecule of the classical pathway (C1q) and activated C4, in plasma samples from patients with rheumatoid arthritis (RA) to establish the relationship between these levels and the clinical and immunologic parameters in these patients. METHODS: C1q-C4 levels were measured in plasma samples from 41 patients with active RA and 43 patients with inactive RA. These levels were related to other complement activation products and to disease activity according to the Disease Activity Score in 28 joints (DAS28), using Spearman's rank correlations. RESULTS: C1q-C4 plasma levels were significantly higher in patients with active RA as compared with patients with RA in clinical remission (median 3.3 arbitrary units [AU], range 0.4-13.4 versus 1.7 AU, range 0.2-5.5; P=0.0001), suggesting that activation of the classical complement pathway reflects disease activity. This was supported by a significant correlation between C1q-C4 levels and the DAS28 (r=0.398, P=0.0002). Levels of other complement activation products, such as activated C4 (C4b/c), were also significantly elevated in patients with active disease compared with patients with inactive disease (P=0.03), and were correlated with C1q-C4 levels (r=0.329, P=0.002). Levels of C1q-C4 complexes were higher in synovial fluid samples than in plasma samples from the 4 patients tested. CONCLUSION: Systemic complement activation via the classical pathway in patients with RA correlates with disease activity. These results indicate that C1q-C4 complexes may be used as a biomarker for RA.

Progression of radiologic damage in patients with rheumatoid arthritis in clinical remission.

OBJECTIVE: To assess whether radiologic progression occurs during clinical remission in patients with rheumatoid arthritis (RA). METHODS: One hundred eighty-seven patients with RA in clinical remission were followed up clinically and radiologically for 2 years. Clinical remission was defined according to a modification of the American College of Rheumatology criteria (i.e., the criterion of fatigue was omitted, and patients had to fulfill 4 of the 5 remaining criteria). Radiologic joint damage was assessed by the Sharp/van der Heijde method. RESULTS: After 2 years of followup, remission persisted in 52% of patients. The median radiologic score for the total group of patients increased from 21 (interquartile range [IQR] 5, 65) at the time of entry to 25 (IQR 7, 72) after 2 years (P < 0.001). The median score for radiologic progression between baseline and 2 years was 0.5 (IQR 0, 2.5). Among patients with an exacerbation of RA (n = 86), the median score for progression over 2 years was 1.0 (IQR 0, 4.5) (P < 0.001), and in patients with a persistent remission (n = 93) it was 0 (IQR -0.5, 2.0) (P < 0.001). Clinically relevant progression of damage was more frequent in patients with exacerbation (23%) than in those with persistent remission (7%) (P = 0.001). However, in 15% of patients with persistent remission, an erosion developed in a previously unaffected joint. In the logistic regression analysis, the area under the curve of the Disease Activity Score, a continuous measure, was related to the chance of radiologic progression, regardless of the absolute disease activity level. Results were similar when other definitions of remission were used. CONCLUSION: Although rare, clinically relevant progression of joint damage does occur in patients with RA in prolonged remission. This suggests the need for markers that predict progression during periods of low disease activity and for drugs that prevent damage that is independent of disease activity.

Functional disability in relation to radiological damage and disease activity in patients with rheumatoid arthritis in remission.

OBJECTIVE: To investigate the relationship between functional disability, disease activity and radiological damage in patients with rheumatoid arthritis (RA) in remission. METHODS: One hundred and eighty-six patients with RA in remission or with low disease activity were studied. The following variables were assessed at one time point: joint count, visual analog scale for pain, functional disability, i.e., health assessment questionnaire (HAQ) score, radiological joint damage as assessed by radiographs of hands and feet and scored according the Sharp-van der Heijde method, and presence of comorbidity. Disease activity was expressed as the disease activity score (DAS). Correlations were calculated by Spearman's rho coefficient of correlation. In addition, variables associated with the score were analyzed by logistic regression. RESULTS: The median HAQ score was 0.25 [interquartile (IQR) range 0-0.75] and the median DAS was 1.0 (IQR 0.7-1.5). Of the 186 RA patients included, 82% were in remission according to the DAS. The median joint damage as assessed by the Sharp-van der Heijde score was 21 (IQR 9-74). Functional disability was significantly correlated with pain (rho 0.48, p < 0.001), disease activity (rho 0.42; p < 0.001), disease duration (rho 0.39; p < 0.001), radiographic joint damage (rho 0.37; p < 0.001), and age (rho 0.19; p = 0.01). In a logistic regression model functional disability was independently related to presence of pain, disease activity, radiographic joint damage and disease duration in decreasing order of strength, but not to age. sex and co-morbidity. CONCLUSION: Patients with RA who are in remission might experience minimal functional disability and radiographic joint damage. Functional disability in RA patients in remission is most strongly related to the presence of pain and in lesser extent to disease activity, radiographic joint damage, and disease duration.