Long-Term Outcomes of Patients With Recent-Onset Rheumatoid Arthritis After 10 Years of Tight Controlled Treatment: A Randomized Trial.

BACKGROUND: Treat-to-target therapy is effective for patients with rheumatoid arthritis (RA), but long-term results of continued targeted treatment are lacking. OBJECTIVE: To evaluate long-term outcomes in patients with early RA after 10 years of targeted treatment in 4 treatment strategies. DESIGN: Randomized trial. (Nederlands Trial Register: NTR262 and NTR265). SETTING: The Netherlands. PATIENTS: 508 patients with early active RA. INTERVENTION: Sequential monotherapy (strategy 1), step-up combination therapy (strategy 2), or initial combination therapy with prednisone (strategy 3) or with infliximab (strategy 4), all followed by targeted treatment aiming at low disease activity. MEASUREMENTS: Functional ability (Health Assessment Questionnaire [HAQ] score) and radiographic progression (Sharp-van der Heijde score) were primary end points. Survival in the study population was compared with the general population using the standardized mortality ratio. RESULTS: 195 of 508 of patients (38%) dropped out of the study (28% in strategy 4 vs. 40% to 45% in strategies 1 to 3, respectively). At year 10, mean HAQ score (SD) was 0.57 (0.56); 53% and 14% of patients were in remission and drug-free remission, respectively, without differences among the strategies. Over 10 years, mean HAQ scores were 0.69, 0.72, 0.64, and 0.58 in strategies 1 to 4, respectively (differences not clinically relevant). Radiographic damage was limited for all strategies, with mean Sharp-van der Heijde estimates during follow-up of 11, 8, 8, and 6 in strategies 1 to 4, respectively (P = 0.15). Standardized mortality ratio was 1.16 (95% CI, 0.92 to 1.46) based on 72 observed and 62 expected deaths, with similar survival among the 4 strategies (P = 0.81). LIMITATION: Dropout rate varied by strategy. CONCLUSION: In patients with early RA, initial (temporary) combination therapy results in faster clinical improvement and targeted treatment determines long-term outcomes. Drug-free remission, with prevention of functional deterioration and clinically relevant radiographic damage, and normalized survival are realistic outcomes. PRIMARY FUNDING SOURCE: Dutch College of Health Insurance Companies, Schering-Plough, and Janssen.

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.

Remission induction therapy with methotrexate and prednisone in patients with early rheumatoid and undifferentiated arthritis (the IMPROVED study).

AIM: Classifying more patients as rheumatoid arthritis (RA) (2010 American College of Rheumatology/European League Against Rheumatism criteria for RA) may improve treatment outcomes but may cause overtreatment in daily practice. The authors determined the efficacy of initial methotrexate (MTX) plus prednisone treatment in patients with 1987 or 2010 classified RA and undifferentiated arthritis (UA). METHOD: 610 recent onset RA or UA patients started with MTX 25 mg/week and prednisone 60 mg/day tapered to 7.5 mg/day in 7 weeks. Percentage remissions after 4 months were compared between RA (1987 or 2010 criteria) and UA. Predictors for remission were identified. RESULTS: With the 2010 criteria, 19% more patients were classified as RA than with the 1987 criteria, but similar remission rates were achieved: 291/479 (61%) 2010 classified RA and 211/264 (58%) 1987 classified RA patients (p=0.52), and 79/122 (65%) UA patients (p=0.46). Anticitrullinated protein antibodies (ACPA) positive RA patients achieved more remission (66%) than ACPA negative RA patients (51%, p=0.001), but also had a lower mean baseline Disease Activity Score (DAS) (3.2 vs 3.6, p<0.001). Independent predictors for remission were male sex, low joint counts, DAS and Health Assessment Questionnaire, low body mass index and ACPA positivity. CONCLUSION: Initial treatment with MTX and a tapered high dose of prednisone results in similarly high remission percentages after 4 months (about 60%) in RA patients, regardless of fulfilling the 1987 or 2010 criteria, and in UA patients. Independent predictors indicate that initiating treatment while disease activity is relatively low results in more remission.

Sustained drug-free remission in rheumatoid arthritis after DAS-driven or non-DAS-driven therapy: a comparison of two cohort studies.

OBJECTIVES: To compare the prevalence of and predictors for sustained drug-free remission in two cohorts of patients with recent-onset RA treated with DAS-driven therapy or non-DAS-driven therapy. METHODS: Sustained drug-free remission was assessed after 5 years of follow-up in 508 patients treated with DAS-driven therapy (DAS ≤ 2.4) in a randomized treatment cohort, and in 424 patients who received non-DAS-driven therapy in a prospective inception cohort. The design of the DAS-driven cohort required systematic joint assessments with DAS-driven restart of therapy. Predictors for remission were identified by univariable and multivariable logistic regression in each cohort separately and in a combined multivariate logistic regression analysis corrected for propensity scores, including a sensitivity analysis on patients receiving initial monotherapy. RESULTS: Patients in the DAS-driven cohort had more active disease at baseline, but the prevalence of sustained drug-free remission was similar after DAS-driven (9.8%) and non-DAS-driven therapy (10.6%). Among patients with ACPA, drug-free remission was more frequently achieved after DAS-driven than after non-DAS-driven therapy (5.4 vs. 2.1%, OR = 2.68, 95% CI 0.97, 7.43). Absence of ACPA and short symptom duration were independent predictors for sustained drug-free remission in both cohorts. Initial treatment choice and inclusion period were not predictive. The sensitivity analysis yielded comparable results. CONCLUSION: Retrospectively comparing a DAS-driven to a non-DAS-driven therapy cohort, the occurrence and predictors of sustained drug-free remission were similar. The DAS-driven cohort had a more unfavourable prognosis. DAS-driven therapy may improve the chance of sustained drug-free remission in ACPA-positive patients with recent-onset RA.

The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study.

OBJECTIVE: To compare clinical and radiological outcomes of four dynamic treatment strategies in recent-onset rheumatoid arthritis (RA) after 5 years follow-up. METHODS: 508 patients with recent-onset RA were randomly assigned into four treatment strategies: sequential monotherapy; step-up combination therapy; initial combination with prednisone; initial combination with infliximab. Treatment adjustments were made based on 3-monthly disease activity score (DAS) measurements (if DAS >2.4 next treatment step; if DAS ≤ 2.4 during ≥ 6 months taper to maintenance dose; if DAS <1.6 during ≥ 6 months stop antirheumatic treatment). Primary and secondary outcomes were functional ability, joint damage progression, health-related quality of life and (drug-free) remission percentages. RESULTS: After 5 years, 48% of patients were in clinical remission (DAS <1.6) and 14% in drug-free remission, irrespective of initial treatment. After an earlier improvement in functional ability and quality of life with initial combination therapy, from 1 year onwards clinical outcomes were comparable across the groups and stable during 5 years. The initial combination groups showed less joint damage in year 1. In years 2-5 annual progression was comparable across the groups. After 5 years, initial combination therapy resulted in significantly less joint damage progression, reflecting the earlier clinical response. CONCLUSION: Irrespective of initial treatment, an impressive improvement in clinical and radiological outcomes of RA patients can be achieved with dynamic treatment aimed at reducing disease activity, leading to 48% remission, 14% drug-free remission and sustained functional improvement. Starting with combination therapy resulted in earlier clinical improvement and less joint damage without more toxicity.

Sick leave and work disability in patients with early arthritis.

We studied the occurrence of sick leave and work disability, the presence of workplace adaptations and the usage of professional guidance related to working problems in patients with early arthritis. Inclusion criteria were arthritis symptoms of less than 2 years duration and a paid job at the time of diagnosis. Assessments were done in connection with an early arthritis clinic (EAC) at entry into the cohort and 12 months thereafter by means of a questionnaire comprising questions on sick leave (absenteeism from work reported to the employer), work disability (receiving a full or partial work disability pension), unemployment, work adaptations and professional guidance related to working problems. Fifty-seven of the 69 participants (83%) had an arthritis symptom duration of <6 months. The number of patients with sick leave due to arthritis in the past 12 months decreased from 28 (41%) at study entry to 18 (26%) after 12 months of follow-up. The number of patients receiving a work disability pension increased from 5 (7%) at study entry to 13 (19%) after 12 months of follow-up (10 partial and 3 full). Sick leave in the 12 months before study entry appeared to be the most important predictor of the institution or increase in a work disability pension (odds ratio, 16.1; 95%CI, 1.8-142.8). Between study entry and follow-up, the number of patients with workplace adaptations increased from 20 (29%) to 28 (42%), whereas the number of patients receiving vocational guidance decreased from 48 (70%) to 36 (52%). In patients with early arthritis and a paid job, arthritis-related sick leave was common and occurred in part before patients entered the EAC and a diagnosis was made. About 20% of the patients became permanently work disabled, with partial work disability being more common than full work disability. Considerable proportions of patients received workplace adaptations and professional guidance with working problems.

The usage of functional wrist orthoses in patients with rheumatoid arthritis.

OBJECTIVE: To describe the usage of functional wrist orthoses and to identify factors contributing to usage in patients with rheumatoid arthritis (RA). METHODS: A multicentre, cross-sectional study, including a random selection of patients with RA visiting outpatient clinics. A total of 240/362 eligible patients (66%) completed questionnaires, a semi-structured interview and a clinical assessment. Usage was registered according to eight categories ranging from 'always' to 'never'. Factors potentially associated with usage included demographic variables, the presence of wrist and hand complaints, general disease characteristics, mental and physical functioning, coping strategies and satisfaction with functional wrist orthoses. Logistic regression analyses were used to determine which factors were associated with the usage of wrist splints. RESULTS: One hundred twenty-eight patients (53%) possessed functional wrist orthoses, whereas 74/128 (58%) were actually using them. Patients used them mainly during house keeping and cycling/driving. Main reasons for using the orthoses were relief of pain and joint protection, and main reasons for not using them were no need and problems with ease of use. Factors significantly associated with usage included the presence of wrist and hand complaints, worse physical functioning and greater satisfaction with comfort of the wrist orthoses. CONCLUSION: About half of patients with RA possessed functional wrist orthoses, with 58% of them actually being used. Apart from local complaints and general functional ability, satisfaction with comfort of the functional wrist orthoses appears to be an important factor for their usage. These results point at the need for additional research regarding modifiable factors associated with compliance, such as comfort and ease of use.

Erosions in the foot at baseline are predictive of orthopaedic shoe use after 10 years of treat to target therapy in patients with recent onset rheumatoid arthritis.

The objective of this study is to investigate if foot joint damage due to rheumatoid arthritis (RA) can predict whether patients will start wearing orthopaedic shoes (OS) within 10 years after treatment start. Data from recent onset RA patients with 10 years follow-up from the BeSt (Dutch acronym for treatment strategies) study were used. Treatment was tightly controlled, targeted at disease activity score (DAS) ≤2.4, according to 1 of 4 pre-specified treatment strategies. After 10 years of follow-up, orthopaedic shoe use was recorded in 285/508 patients (responders to questionnaires at 10 years). Between-group differences for orthopaedic shoe users and non-users were calculated at baseline, after 10 years, and change scores over the 10-year period were calculated. Predictors for orthopaedic shoe use were identified by univariable and multivariable logistic regression analyses. Orthopaedic shoe use was reported by 57/285 patients after 10 years. Orthopaedic shoe users had more joint damage, joint swelling and pain in the feet already at baseline and after 10 years. At both time points, DAS of orthopaedic shoe users and non-users was similar. Multivariable logistic regression showed that dichotomized foot erosions score (cut-off ≥1 erosion) (OR 2.42), anti-citrullinated protein antibodies (ACPA) (OR 4.64) and DAS (OR 1.77) were independent predictors of orthopaedic shoe use. Despite intensive targeted treatment, 57/285 recent onset RA patients started using orthopaedic shoes over 10 year of follow-up. Presence of foot erosions at treatment start predicts orthopaedic shoe use after 10 years. The risk of orthopedic shoe use increased for ACPA-positive patients and for those with higher baseline disease activity.

Continued participation in a ten-year tight control treat-to-target study in rheumatoid arthritis: why keep patients doing their best?

OBJECTIVE: To identify risk factors for early study termination and motivators for adherence to a long-term followup trial and to improve completeness of long-term studies. METHODS: Risk factors for early termination in 508 included patients were identified through Cox regression analysis. Patients completing the 10-year followup filled in a questionnaire on possible motives for continued study participation. RESULTS: Risk factors for early termination were higher age (hazard ratio [HR] 1.03, 95% confidence interval [95% CI] 1.02-1.04), functional disability during the preceding year (HR 1.54, 95% CI 1.20-1.99), having achieved drug-free remission (HR 6.62, 95% CI 2.07-21.14), limited joint damage (HR 0.98, 95% CI 0.97-0.995 for actual damage; HR 0.83, 95% CI 0.73-0.94 for damage progression), and few adverse events (HR 0.35, 95% CI 0.26-0.47). A total of 288 of 313 patients (92%) attending the last visit answered the questionnaire. The majority mentioned contributing to scientific research (97% agreed), helping other patients (91%), and learning about new treatment strategies (84%) and their disease (85%) as reasons to continue participation. Next, patients mentioned tight control (202 of 278 patients), good treatment strategy (128 of 278), good medication (117 of 278), and good half-term results (102 of 278) as motivators. More than 95% of patients experienced participation "as expected" or "better than expected." Additional examinations during yearly visits (extra questionnaires, imaging) were mentioned as "worse than expected" (10%), as was answering routine questionnaires (7%). CONCLUSION: Continued participation was relatively high in the Treatment Strategies for Rheumatoid Arthritis (BeSt) Study. Higher age, functional disability, drug-free remission, little joint damage, and few adverse events predicted early study termination. Main motives for continued participation were a willingness to contribute to research, help future patients, and because patients had good experiences with the study protocol.

Disease flares in rheumatoid arthritis are associated with joint damage progression and disability: 10-year results from the BeSt study.

INTRODUCTION: Flares in patients with rheumatoid arthritis are suggested to sometimes spontaneously resolve. Targeted therapy could then entail possible overtreatment. We aimed to determine the flare prevalence in patients who are treated-to-target and to evaluate associations between flares and patient-reported outcomes and radiographic progression. METHODS: In the BeSt study, 508 patients were treated-to-target for 10 years. After initial treatment adjustments to achieve disease activity score ≤2.4, a flare was defined from the second year of follow-up onwards, according to three definitions. The first definition is a disease activity score >2.4 with an increase of ≥0.6 regardless of the previous disease activity score. The other definitions will be described in the manuscript. RESULTS: The flare prevalence was 4-11 % per visit; 67 % of the patients experienced ≥1 flare during 9 years of treatment (median 0 per patient per year). During a flare, functional ability decreased with a mean difference of 0.25 in health assessment questionnaire (p < 0.001), and the odds ratios (95 % confidence intervals) for an increase in patients' assessment of disease activity, pain and morning stiffness of ≥20 mm on a visual analogue scale were 8.5 (7.3-9.8), 8.4 (7.2-9.7) and 5.6 (4.8-6.6), respectively, compared to the absence of a flare. The odds ratio for radiographic progression was 1.7 (1.1-2.8) in a year with a flare compared to a year without a flare. The more flares a patient experienced, the higher the health assessment questionnaire at year 10 (p < 0.001) and the more radiographic progression from baseline to year 10 (p = 0.005). CONCLUSION: Flares were associated with concurrent increase in patient's assessment of disease activity, pain and morning stiffness, functional deterioration and development of radiographic progression with a dose-response-effect, both during the flare and long term. This suggests that intensifying treatment during a flare outweighs the risk of possible overtreatment. TRIAL REGISTRATION: Dutch trial registry NTR262 (7 September 2005) and NTR265 (8 September 2005).

A multibiomarker disease activity score for rheumatoid arthritis predicts radiographic joint damage in the BeSt study.

OBJECTIVE: To determine whether a multibiomarker disease activity (MBDA) score predicts radiographic damage progression in the subsequent year in patients with early rheumatoid arthritis. METHODS: There were 180 serum samples available in the BeSt study (trial numbers NTR262, NTR 265): 91 at baseline (84 with radiographs available) and 89 at 1-year followup (81 with radiographs available). Radiographs were assessed using the Sharp/van der Heijde Score (SvdH). Twelve serum biomarkers were measured to determine MBDA scores using a validated algorithm. Receiver-operating curves and Poisson regression analyses were performed, with Disease Activity Score (DAS) and MBDA score as independent variables, and radiographic progression as dependent variable. RESULTS: At baseline, MBDA scores discriminated more between patients who developed radiographic progression (increase in SvdH≥5 points) and patients who did not [area under the curve (AUC) 0.767, 95% CI 0.639-0.896] than did DAS (AUC 0.521, 95% CI 0.358-0.684). At 1 year, MBDA score had an AUC of 0.691 (95% CI 0.453-0.929) and DAS had an AUC of 0.649 (95% CI 0.417-0.880). Adjusted for anticitrullinated protein antibody status and DAS, higher MBDA scores were associated with an increased risk for SvdH progression [relative risk (RR) 1.039, 95% CI 1.018-1.059 for baseline MBDA score; 1.037, 95% CI 1.009-1.065 for Year 1 MBDA score]. Categorized high MBDA scores were also correlated with SvdH progression (RR for high MBDA score at baseline 3.7; low or moderate MBDA score as reference). At 1 year, high MBDA score gave a RR of 4.6 compared to low MBDA score. CONCLUSION: MBDA scores predict radiographic damage progression at baseline and during disease course.

Early local swelling and tenderness are associated with large-joint damage after 8 years of treatment to target in patients with recent-onset rheumatoid arthritis.

OBJECTIVE: To assess whether early swelling and tenderness in large joints in patients with rheumatoid arthritis (RA) is predictive of later local damage and whether this leads to functional disability. METHODS: Two-year clinical and 8-year radiological followup data from the BeSt study (trial numbers NTR262 and NTR265), a randomized controlled treat-to-target trial, were used. The association between early local joint swelling and/or tenderness (at least once, or for ≥ 2 consecutive visits) and later large-joint damage (Larsen score ≥ 1) was assessed using generalized estimating equations. The association between large-joint damage and functional ability [by Health Assessment Questionnaire (HAQ)] was assessed using logistic and linear regression analysis. RESULTS: Clinical and 8-year radiological data were available for 290 patients. Concomitant local joint swelling and tenderness at least once in the first 2 years was independently associated with damage of the large joints (OR 2.5, 95% CI 1.7-3.6), as was swelling without tenderness (OR 2.0, 95% CI 1.1-3.6). Stronger effects were seen for persistent swelling and/or tenderness. Other independent predictors for joint damage were baseline erythrocyte sedimentation rate (OR 1.01, 95% CI 1.01-1.02) and the presence of rheumatoid factor and/or anticitrullinated protein antibodies (OR 2.5, 95% CI 1.5-4.1; and OR 2.2, 95% CI 1.3-3.8, respectively). Patients with large-joint damage had a higher HAQ score after 8 years than patients without (difference 0.15). CONCLUSION: Early local swelling and tenderness are independent predictors of later joint damage in these joints after 8 years of Disease Activity Score-guided treatment in patients with RA. This suggests that suppression of local inflammation could help prevent local damage and functional disability.

Promoting physical activity in patients with rheumatoid arthritis: rheumatologists' and health professionals' practice and educational needs.

Despite the proven health benefits, patients with rheumatoid arthritis (RA) are found to be less physically active than their healthy peers. The aim of this study was to examine to what extent and how physical activity, defined as any bodily movement resulting in energy expenditure, is currently promoted by health care providers in patients with RA and how they perceive their competencies and educational needs. For this cross-sectional study, Dutch rheumatologists, rheumatology clinical nurse specialists, and expert physical therapists were sent a postal survey including four domains: attitudes towards physical activity in RA, advices given to patients with RA, and perceived competencies and educational needs. A total of 126 rheumatologists (50%), 132 clinical nurse specialists (56%), and 112 physical therapists (53%) returned the questionnaire. More than 90% agreed that physical activity is an important health goal for RA patients and regularly advised their patients to engage in physical activity. Public health recommendations for moderate-intensity physical activity were found attainable in RA patients by 66%, 74%, and 65% and were by used by 19%, 41%, and 49% of them, respectively. On average, respondents rated their competency to promote physical activity as low to medium, and 54%, 85%, and 72% of the respondents expressed a need for additional education regarding this topic. Rheumatologists, nurses, and physical therapists considered regular physical activity to be an important health goal for RA patients. The majority of them commonly gave advice on physical activity but felt not sufficiently competent and indicated a need for additional education.

Effect of self-efficacy and physical activity goal achievement on arthritis pain and quality of life in patients with rheumatoid arthritis.

OBJECTIVE: To examine physical activity and achievement of physical activity goals in relation to self-reported pain and quality of life among patients with rheumatoid arthritis (RA). METHODS: At baseline, 271 patients with RA were asked to specify a physical activity goal, and filled in questionnaires assessing physical activity, motivation, and self-efficacy for physical activity, arthritis pain, and quality of life. Six months later, patients indicated to what extent they had achieved their baseline physical activity goal and completed the same set of questionnaires. These data were used to construct multiple mediation models that placed physical activity and physical activity goal achievement as mediators between self-efficacy and motivation on one hand, and arthritis pain and quality of life on the other. RESULTS: A total of 106 patients with RA completed both questionnaires. Self-efficacy at baseline predicted subsequent level of physical activity and achievement of physical activity goals. Goal achievement had a direct effect upon quality of life outcomes. Bootstrapping confidence intervals revealed indirect effects of self-efficacy upon arthritis pain and quality of life through goal achievement, but not through physical activity. CONCLUSION: Higher levels of self-efficacy for physical activity increase the likelihood that patients will achieve their physical activity goals. Achievement of physical activity goals seems to be related to lower self-reported arthritis pain, and higher levels of quality of life. In practice, clinicians can foster self-efficacy and goal achievement by assisting patients in setting realistic and attainable exercise goals, developing action plans, and by providing feedback on goal progress.

Accelerated hand bone mineral density loss is associated with progressive joint damage in hands and feet in recent-onset rheumatoid arthritis.

INTRODUCTION: To investigate whether accelerated hand bone mineral density (BMD) loss is associated with progressive joint damage in hands and feet in the first year of rheumatoid arthritis (RA) and whether it is an independent predictor of subsequent progressive total joint damage after 4 years. METHODS: In 256 recent-onset RA patients, baseline and 1-year hand BMD was measured in metacarpals 2-4 by digital X-ray radiogrammetry. Joint damage in hands and feet were scored in random order according to the Sharp-van der Heijde method at baseline and yearly up to 4 years. RESULTS: 68% of the patients had accelerated hand BMD loss (>-0.003 g/cm2) in the first year of RA. Hand BMD loss was associated with progressive joint damage after 1 year both in hands and feet with odds ratios (OR) (95% confidence intervals [CI]) of 5.3 (1.3-20.9) and 3.1 (1.0-9.7). In univariate analysis, hand BMD loss in the first year was a predictor of subsequent progressive total joint damage after 4 years with an OR (95% CI) of 3.1 (1.3-7.6). Multivariate analysis showed that only progressive joint damage in the first year and anti-citrullinated protein antibody positivity were independent predictors of long-term progressive joint damage. CONCLUSIONS: In the first year of RA, accelerated hand BMD loss is associated with progressive joint damage in both hands and feet. Hand BMD loss in the first year of recent-onset RA predicts subsequent progressive total joint damage, however not independent of progressive joint damage in the first year.

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.

A comparison of the OARSI response criteria with patient's global assessment in patients with osteoarthritis of the hip treated with a non-pharmacological intervention.

OBJECTIVE: To compare the Osteoarthritis Research Society International (OARSI) response criteria for clinical trials with patient's global assessment in patients with osteoarthritis (OA) of the hip receiving a non-pharmacological intervention, i.e., manual therapy or exercise therapy. METHODS: Data of a randomized clinical trial on manual therapy and exercise therapy in patients with OA of the hip (n = 109) were used. Change scores of measures of hip function, range of joint motion and pain were compared between patients who were differently classified by the OARSI response criteria and the patient's global assessment (using a t test, 95% CI). Furthermore, risk ratios (with 95% CI) were calculated for the contrast between treatment outcome, using the OARSI criteria or patient's global assessment. RESULTS: Few patients were classified as improved (i.e., responders) with the OARSI response criteria as compared to patient's global assessment. Significantly worse outcome for hip function and pain was observed in patients who were classified as non-responders (OARSI criteria), but who considered themselves as improved (patient's global assessment). Risk ratios for the contrast between the two treatment programs (manual therapy vs exercise therapy) were similar, when using the OARSI criteria or patient's global assessment. CONCLUSION: The validity of the OARSI response criteria has been previously demonstrated in OA patients treated with pharmacological interventions. The present study demonstrates the validity of the OARSI response criteria in OA patients treated with a non-pharmacological intervention, i.e., manual therapy and exercise therapy.

Activation of receptor for advanced glycation end products in osteoarthritis leads to increased stimulation of chondrocytes and synoviocytes.

OBJECTIVE: The major risk factor for osteoarthritis (OA) is aging, but the mechanisms underlying this risk are only partly understood. Age-related accumulation of advanced glycation end products (AGEs) could be one of these mechanisms. We undertook this study to investigate the role of the receptor for AGEs (RAGE) in mediating the cellular effects of AGEs on chondrocytes and fibroblast-like synoviocytes (FLS). METHODS: AGE levels in human cartilage were determined by fluorescence, browning, and pentosidine levels. Chondrocyte activation by AGEs was assessed as the release of proteoglycans and the synthesis of matrix metalloproteinase 1 (MMP-1) and type II collagen messenger RNA (mRNA). The activation of FLS by AGEs was measured by MMP-1 production and invasion through matrix proteins. RESULTS: Patients with focal degeneration of cartilage showed increased AGE levels in their healthy cartilage compared with the levels in healthy cartilage from donors without cartilage degeneration (P < 0.01 for both fluorescence and browning; P not significant for pentosidine content). Stimulation of bovine chondrocytes with glycated albumin increased the release of proteoglycans by 110% (P < 0.001) and the production of MMP-1 mRNA by 200% (P = 0.028). In addition, OA FLS produced 240% more MMP-1 when stimulated with glycated albumin (P < 0.001). Glycated matrix or albumin increased the catabolic activity of OA FLS, which was assessed as invasive behavior, by 150% and 140% (P = 0.001 and P = 0.010), respectively. Effects of stimulation with AGEs were blocked by a neutralizing antibody against RAGE, but not by an isotype control. CONCLUSION: This study shows that AGEs trigger RAGE on chondrocytes and FLS, leading to increased catabolic activity and therefore to cartilage degradation. AGEs, via RAGE, could therefore contribute to the development and/or progression of OA.