Hand function is already reduced before RA development and reflects subclinical tenosynovitis.

BACKGROUND: Clinically suspect arthralgia (CSA) is characterised by arthralgia of small joints and considered a risk stage for development of rheumatoid arthritis (RA). However, it remains unknown if the function of the hands is already affected and what mechanisms underlie impaired hand-function in CSA. METHODS: We studied various measures of hand function in two CSA populations. CSA patients in the TREAT EARLIER-trial (n=236) were evaluated at baseline for: grip strength on a dynamometer (GS), patient-reported difficulties in the grip domain of the Health Assessment Questionnaire (HAQ) questionnaire and incomplete fist closure at physical examination. Findings were validated in an independent CSA cohort (n=600) where hand function was measured as: GS evaluated by squeezing the examiner's fingers, grip domain of the HAQ questionnaire and fist closure. Contrast-enhanced MRI of the hands measured synovitis, tenosynovitis and bone marrow oedema (summed as subclinical inflammation) in both cohorts. RESULTS: GS (on a dynamometer) was reduced in 75% compared with reference values in healthy controls, 60% reported grip difficulties and 13% had incomplete fist closure. Reduced GS was associated with subclinical inflammation (-0.38 kg/point inflammation, 95% CI -0.68 to -0.08). Studying separate MRI features, GS reduction was independently associated with tenosynovitis, decreasing with -2.63 kg (95% CI -2.26 to -0.33)/point tenosynovitis (range observed tenosynovitis scores: 0-20). Similar relations with tenosynovitis were seen for patient-reported grip difficulties (OR 1.12/point, 95% CI 1.07 to 1.42) and incomplete fist closure (OR 1.36/point, 95% CI 1.03 to 1.79). In the validation cohort, 36% had decreased examiner-assessed GS, 51% reported grip difficulties and 14% incomplete fist closure: all were associated with tenosynovitis. Decreased dynamometer-measured GS was most sensitive for detecting tenosynovitis (75%), while incomplete fist closure was most specific (88%-90%). CONCLUSION: Hand function is already often affected before RA development. These limitations are related to subclinical inflammation and tenosynovitis in particular.

Five-year outcomes of probable rheumatoid arthritis treated with methotrexate or placebo during the first year (the PROMPT study).

OBJECTIVE: To assess long-term disease outcome of undifferentiated arthritis (UA) after initial treatment with methotrexate (MTX) or placebo. METHODS: 110 patients with UA were randomised to receive MTX (n=55) or placebo (n=55) for 1 year. After 5 years the outcomes for diagnosis (rheumatoid arthritis, 1987 criteria (RA (1987)), UA or UA in remission) and radiographic progression were compared between treatment arms and anti-citrullinated protein antibody (ACPA)-positive and -negative patients. Outcomes were recalculated for patients who, with hindsight, might have been classified at baseline as having RA according to the 2010 criteria (RA (2010)). RESULTS: 25 patients in the MTX group and 29 in the placebo group progressed to RA (1987) (p=0.45). MTX delayed progression from UA to RA (1987) but only in ACPA-positive patients. Drug-free remission was achieved in 35 patients, 20 of whom were initially treated with MTX, and 32 were ACPA-negative. ACPA-positive patients had more radiographic progression, regardless of treatment. Forty-three patients (39%) could be reclassified as having had RA (2010) at baseline, 6/24 (25%) of whom achieved remission after placebo treatment. CONCLUSIONS: After 5 years there is no lasting benefit of a 1 year initial course of MTX for patients with undifferentiated arthritis, compared with initial placebo. Progression to classifiable RA was not suppressed, drug-free remission not induced and the progression of radiological damage was similar in both groups. Reclassification at baseline with the 2010 criteria showed that 25% of patients with RA (2010) achieved spontaneous drug-free remission.

Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial.

OBJECTIVE: To determine whether patients with undifferentiated arthritis (UA; inflammatory, nontraumatic arthritis that cannot be diagnosed using current classification criteria) benefit from treatment with methotrexate (MTX). METHODS: The PRObable rheumatoid arthritis: Methotrexate versus Placebo Treatment (PROMPT) study was a double-blind, placebo-controlled, randomized, multicenter trial involving 110 patients with UA who fulfilled the American College of Rheumatology (ACR) 1958 criteria for probable RA. Treatment started with MTX (15 mg/week) or placebo tablets, and every 3 months the dosage was increased if the Disease Activity Score was >2.4. After 12 months, the study medication was tapered and discontinued. Patients were followed up for 30 months. When a patient fulfilled the ACR criteria for RA (primary end point), the study medication was changed to MTX. Joint damage was scored on radiographs of the hands and feet. RESULTS: In 22 of the 55 patients (40%) in the MTX group, UA progressed to RA compared with 29 of 55 patients (53%) in the placebo group. However, in the MTX group, patients fulfilled the ACR criteria for RA at a later time point than in the placebo group (P = 0.04), and fewer patients showed radiographic progression over 18 months (P = 0.046). CONCLUSION: This study provides evidence for the efficacy of MTX treatment in postponing the diagnosis of RA, as defined by the ACR 1987 criteria, and retarding radiographic joint damage in UA patients.

Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis.

OBJECTIVE: The functional role of HLA class II molecules in the pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II molecules are involved in the interaction between T and B lymphocytes required for long-lived B cell responses and generation of high-affinity IgG antibodies. We undertook this study to investigate the relationship between HLA class II gene polymorphisms and RA-specific IgG antibodies against cyclic citrullinated peptides (anti-CCP antibodies). METHODS: High-resolution HLA-DR and DQ typing and anti-CCP-2 antibody testing were performed on 268 RA patients from the Early Arthritis Clinic cohort at the Department of Rheumatology of the Leiden University Medical Center. The presence of anti-CCP antibodies was analyzed in carriers of the different DR and DQ alleles. Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method. RESULTS: Carriership of the individual alleles HLA-DRB1*0401, DRB1*1001, DQB1*0302, and DQB1*0501 was associated with the presence of anti-CCP antibodies. Carriers of DQ-DR genotypes containing proposed RA susceptibility alleles were significantly more often anti-CCP antibody positive. Carriership of one or two HLA-DRB1 shared epitope (SE) alleles was significantly associated with production of anti-CCP antibodies (odds ratio [OR] 3.3, 95% confidence interval [95% CI] 1.8-6.0 and OR 13.3, 95% CI 4.6-40.4, respectively). An increased rate of joint destruction was observed in SE+, anti-CCP+ patients (mean Sharp score 7.6 points per year) compared with that in SE-, anti-CCP+ patients (2.4 points per year) (P = 0.04), SE+, anti-CCP- patients (1.6 points per year) (P < 0.001), and SE-, anti-CCP- patients (1.6 points per year) (P < 0.001). CONCLUSION: HLA class II RA susceptibility alleles are associated with production of anti-CCP antibodies. Moreover, more severe disease progression is found in RA patients with both anti-CCP antibodies and SE alleles.