Serum soluble interleukin-2 receptor predicts early remission in patients with recent-onset rheumatoid arthritis treated with a single disease-modifying antirheumatic drug

OBJECTIVE: To study the value of baseline serum levels of circulating soluble interleukin-2 receptor (sIL-2R) and soluble E-selectin as predictors of early remission in patients with recent-onset rheumatoid arthritis (RA) receiving a single disease-modifying anti-rheumatic drug (DMARD) (SINGLE) or therapy with a combination of DMARDs (COMBI). METHODS: Baseline (n = 157) serum samples originate from the FIN-RACo (FINnish Rheumatoid Arthritis Combination therapy) trial, in which 195 patients with early and clinically active RA were randomly assigned to receive either SINGLE (initially sulfasalazine) with or without prednisolone, or COMBI therapy (sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone). Of the samples, 76 were from SINGLE patients and 81 from COMBI patients. sIL-2R was measured by automated immunoassay analyzer and sE-selectin by enzyme-linked immunosorbent assay. RESULTS: At six months, 7 (9% [95% CI: 4 to 18]) SINGLE and 19 (23% [95% CI: 15 to 34]) COMBI patients were in remission. In multivariate logistic regression analysis, sIL-2R <442 U/ml and COMBI therapy were the only predictors of remission. The area under receiver operating characteristic curve for sIL-2R level was 0.86 (95% CI: 0.62 to 0.95) in SINGLE and 0.57 (95% CI: 0.42 to 0.71) in COMBI (p = 0.006). In SINGLE, the optimal cut offpoint was 442 U/ml, lower levels predicting remission with sensitivity of 83% (95% CI: 73% to 91%) and specificity of 86% (95% CI: 42% to 100%). Likelihood ratio for positive test was 5.9 (95% CI: 1.6 to 32.8). In multivariate logistic regression analysis, sIL-2R <442 U/ml and COMBI therapy were the only predictors of remission. CONCLUSION: Low baseline serum sIL-2R level predicts early remission of patients with active early RA treated with a single DMARD.     

Initiation of disease-modifying antirheumatic drug therapy in minority and disadvantaged patients with rheumatoid arthritis

OBJECTIVE: To evaluate disparities in time to initiation of disease modifying antirheumatic drugs (DMARD) in patients with rheumatoid arthritis (RA) receiving care in public or private healthcare settings. METHODS: We reviewed the records of patients with RA initially seen at one of 2 rheumatology clinics: a clinic in a public county hospital providing care primarily to minority, disadvantaged, or uninsured patients, and a private clinic providing care to patients with health insurance coverage. Both clinics were affiliated with the same medical school. We determined time to initiation of DMARD or steroid therapy using Kaplan-Meier analyses and Cox regression. Time to initiation of therapy was measured from onset of disease until a therapy was prescribed (event) or the patient was seen for the first time at one of the 2 clinics (censored at index visit). Independent variables were ethnicity and clinic setting (public or private). RESULTS:One hundred eighteen new patients with RA were seen in the public setting, 167 in the private setting; 83% of the patients in the public clinic and 18% in the private setting were non-White. Survival analysis (disease duration 相似文献   

Rate and causes of noncompliance with disease-modifying antirheumatic drug regimens in patients with rheumatoid arthritis

Clinical Rheumatology - To determine the prevalence and factors associated with medication noncompliance by Thai patients with rheumatoid arthritis (RA). This prospective cohort study enrolled 443...     

Healing phenomena of erosive changes in rheumatoid arthritis patients undergoing disease-modifying antirheumatic drug therapy

Objective. To describe radiographic healing phenomena and reparative changes of joint destruction in rheumatoid arthritis (RA). Methods. Serial radiographs of 6 patients with erosive RA undergoing long-term treatment with disease-modifying antirheumatic drugs (DMARDs) were studied. Radiographs showing healing phenomena were reproduced, and examples of single joints are shown. Results. The examples show recortication of erosions, filling in of erosions with new bone, and secondary osteoarthrosis with bone sclerosis and osteophyte formation. Commonly used radiographic scoring methods do not have the capacity to account for these reparative changes. Conclusion. Healing phenomena can be observed in RA patients undergoing long-term DMARD treatment. These phenomena can be regarded as clinical end points, and their assessment should be incorporated into existing standardized methods for radiologic evaluation and scoring of RA.     

Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study

OBJECTIVE: To examine the efficacy and safety of the humanized anti-interleukin-6 receptor antibody tocilizumab combined with conventional disease-modifying antirheumatic drugs (DMARDs) in patients with active rheumatoid arthritis (RA). METHODS: A total of 1,220 patients were randomized (2:1 ratio) in the phase III, double-blind, placebo-controlled, multicenter TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy) study. Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo (control group) every 4 weeks for 24 weeks. RESULTS: At week 24, the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20) was significantly greater in the tocilizumab plus DMARD group than in the control group (61% versus 25%; P<0.0001). Secondary end points including 50% or 70% improvement (ACR50/70), the Disease Activity Score in 28 joints (DAS28), DAS28 remission responses (DAS28<2.6), European League Against Rheumatism responses, and systemic markers such as the C-reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone. Seventy-three percent of patients in the tocilizumab group had >or=1 adverse event (AE), compared with 61% of patients in the control group. AEs leading to withdrawal from the study were infrequent (4% of patients in the tocilizumab group and 2% of those in the control group). Serious AEs occurred in 6.7% and 4.3% of patients in the tocilizumab and control groups, respectively, and serious infections occurred in 2.7% and 1.9%, respectively. Elevations in the alanine aminotransferase level, from normal at baseline to >3-fold the upper limit of normal, occurred in 4% of patients in the tocilizumab group and 1% of those in the control group, and elevated total cholesterol levels were observed in 23% and 6% of patients, respectively. Sixteen patients started lipid-lowering therapy during the study. Grade 3 neutropenia occurred in 3.7% of patients receiving tocilizumab and none of the patients in the control group, and no grade 4 neutropenia was reported. CONCLUSION: Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents.     

Down regulation of multidrug resistance protein-1 expression in patients with early rheumatoid arthritis exposed to methotrexate as a first disease-modifying antirheumatic drug

BACKGROUND: Methotrexate (MTX) is the current gold standard conventional disease-modifying antirheumatic drug (DMARD) and is effluxed from cells by several transmembrane proteins, including multidrug resistance protein-1 (MRP1). It is hypothesised that the overexpression of these proteins may mediate reduced efficacy of MTX. To date, it is unclear how expression of these proteins changes over time or after exposure to drugs. AIMS: To compare MRP1 expression in newly diagnosed patients with DMARD-naive rheumatoid arthritis with that in healthy controls and to investigate how MRP1 expression changed after exposure to MTX. METHODS: 18 newly diagnosed patients with DMARD-naive rheumatoid arthritis and 14 healthy controls were recruited. Peripheral blood mononuclear cell counts were taken at baseline and after 6 months' treatment with MTX. Cells were separated by density gradient centrifugation and MRP1 expression was measured using the QCRL-1 monoclonal antibody. RESULTS: MRP1 expression in patients did not seem to be up regulated compared with that in healthy controls. In patients who were positive for MRP1 at baseline (61%), treatment with MTX and folic acid led to a marked down regulation of MRP1 expression at 6 months. CONCLUSION: In patients with rheumatoid arthritis expressing MRP1, treatment with MTX and folic acid led to down regulation of MRP1 expression. Further studies are required to determine the mechanism behind this observation and whether MRP1 expression mediates altered efficacy to MTX.     

Use of nonbiologic disease-modifying antirheumatic drugs and risk of infection in patients with rheumatoid arthritis

OBJECTIVE: Rheumatoid arthritis (RA) is associated with increased frequency of and mortality from infections, which may be related to host factors, RA itself, inflammation, or medication side effects. This study was undertaken to determine the effect of nonbiologic disease-modifying antirheumatic drugs (DMARDs) on infection risk in RA. METHODS: We performed a retrospective, longitudinal study of a population-based RA cohort in British Columbia, Canada, followed from January 1996 to March 2003 using administrative data. We evaluated mild infections (requiring a physician visit or antibiotics) and serious infections (requiring or complicating hospitalization). Adjusted risk of mild and serious infections associated with DMARD exposure was estimated using generalized estimating equation extension of multivariate Poisson regression models, after adjusting for baseline covariates (age, sex, RA duration, socioeconomic status) and time-dependent covariates (corticosteroids, comorbidity, prior infections). RESULTS: A total of 27,710 individuals with RA provided 162,710 person-years of followup. Of these, 25,608 (92%) had at least 1 mild infection and 4,941 (18%) had at least 1 serious infection. Use of DMARDs without corticosteroids was associated with a small decrease in mild infection risk of statistical significance but unclear clinical significance (adjusted rate ratio [RR] 0.90, 95% confidence interval [95% CI] 0.88-0.93 relative to no corticosteroid or DMARD use). Use of DMARDs without corticosteroids was not associated with increased serious infection risk (adjusted RR 0.92, 95% CI 0.85-1.0). Use of corticosteroids increased the risk of mild and serious infections. CONCLUSION: Our results indicate that use of nonbiologic DMARDs, including methotrexate, does not increase the risk of infection in RA, whereas use of corticosteroids does. This has important implications for counseling individuals with RA concerning risks and benefits of DMARDs.     

Comparing the long-term clinical outcome of treatment with methotrexate or sulfasalazine prescribed as the first disease-modifying antirheumatic drug in patients with inflammatory polyarthritis

OBJECTIVE: To compare the clinical and functional outcome at 2 and 5 years in patients with inflammatory polyarthritis treated with either methotrexate (MTX) or sulfasalazine (SSZ) as the first disease-modifying antirheumatic drug (DMARD). METHODS: Patients recruited to a primary-care-based inception cohort of patients with inflammatory polyarthritis were eligible for this analysis if they were started on either SSZ (n = 331) or MTX (n = 108) as their first DMARD within 3 months. Outcomes assessed included the Disease Activity Score (DAS)28, Health Assessment Questionnaire, radiological erosions (Larsen Score) and cumulative mortality with the proportions still on the original treatment. To overcome potential bias in allocation to these two treatments, a propensity score was calculated based on baseline disease status variables. RESULTS: are expressed as the mean difference between MTX and SSZ, both unadjusted and adjusted for propensity score. RESULTS: The baseline differences between the two groups disappeared after adjusting for propensity score. At 2 and 5 years there were few differences in the clinical outcomes, either unadjusted or after adjustment for propensity. By contrast, at 5 years the proportion that was erosive was lower in the MTX group: odds ratio 0.3 (95% confidence interval 0.1 to 0.8), with a 31% lower Larsen Score after adjustment. At both time points, those treated with MTX were at least twice as likely to remain on that drug as those treated with SSZ. CONCLUSION: Long-term clinical outcome is similar in patients prescribed MTX and SSZ, although it would seem that MTX has greater potential to suppress erosions, which supports it being the first DMARD of choice.     

The importance of the disease process and disease-modifying antirheumatic drug treatment in the development of septic arthritis in patients with rheumatoid arthritis

OBJECTIVE: To evaluate the effect of disease-modifying antirheumatic drugs (DMARDs) on the likelihood of patients with rheumatoid arthritis (RA) developing septic arthritis (SA). METHODS: The United Kingdom General Practice Research Database (GPRD) was used to identify adults with RA, and age-, sex-, and practice-matched control subjects. Subjects were studied between 1987 and 2002. The risk of developing SA (excluding infected joint replacements) for individuals with RA was calculated and the effect of DMARD use determined. RESULTS: A total of 136,977 subjects (34,250 patients with RA, 102,747 controls) were identified. SA was identified in 345 subjects, of which 321 (236 in patients with RA, 85 in controls) cases occurred during the study period. The incidence rate of SA was 12.9 times higher in subjects with RA than in those without (95% confidence interval [95% CI] 10.1-16.5, P < 0.001). The incident rate ratios (IRRs) for developing SA while receiving DMARDs compared with receiving no DMARDs were different for different medications. Penicillamine (adjusted IRR 2.51, 95% CI 1.29-4.89, P = 0.004), sulfasalazine (adjusted IRR 1.74, 95% CI 1.04-2.91, P = 0.03), and prednisolone (adjusted IRR 2.94, 95% CI 1.93-4.46, P < 0.001) were associated with an increased incidence of SA when compared with not receiving any DMARD. The use of other DMARDs including methotrexate showed no such effect. CONCLUSION: Individuals with RA have an increased risk of developing SA. This increased risk can be attributed to both the disease process and the use of DMARDs.     

Overall survival in patients with rheumatoid arthritis and solid malignancies receiving biologic disease-modifying antirheumatic therapy

Clinical Rheumatology - The effects of biologic disease–modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA) and cancer are largely unknown. We examined overall...     

Response-driven combination therapy with conventional disease-modifying antirheumatic drugs can achieve high response rates in early rheumatoid arthritis with minimal glucocorticoid and nonsteroidal anti-inflammatory drug use

OBJECTIVES: To assess the safety and efficacy of combination therapy in recent-onset rheumatoid arthritis (RA), with dose adjustments determined by response, in a clinic setting over 3 years. METHODS: Disease-modifying antirheumatic drug (DMARD)-naive patients with RA of median duration of 12 weeks (n = 61) attending an early arthritis clinic were treated with methotrexate, sulfasalazine, hydroxychloroquine, and fish oil. Dosage adjustments and additions of further DMARDs were contingent on response to therapy and tolerance. Outcome measures for efficacy were Disease Activity Score (DAS28), clinical remission, and modified Sharp radiographic score and for safety, adverse events, and DMARD withdrawal. RESULTS: At baseline, subjects had at least moderately active disease (mean +/- SD DAS28 was 5.3 +/- 1.1), impaired function as measured by the modified Health Assessment Questionnaire (mHAQ) (0.9 +/- 0.5), and 37% had bone erosions. By 3 months, 29% were in remission; this increased to 54% at 3 years. The greatest fall in DAS28 and improvement in mHAQ scores occurred in the first 12 months. Erosions were detected in 62% at 3 years. The mean dose of parenteral glucocorticoid was equivalent to 0.1 mg/d of prednisolone. After 3 years, 48% remained on triple therapy; fish oil was consumed by 75% of patients, and 21% used nonsteroidal anti-inflammatory drugs. Gastrointestinal intolerance was the most frequent unwanted event (leading to DMARD withdrawal in 17 patients). Sulfasalazine was most frequently withdrawn (30%). CONCLUSION: This implementation study demonstrates the feasibility, safety, and efficacy of combination therapy with inexpensive DMARDs, fish oil, and minimal glucocorticoid use, in routine clinical practice using predefined rules for dosage adjustment.     

An unusual association: anti-Jo1 and anti-SRP antibodies in the serum of a patient with polymyositis

The idiopathic inflammatory myopathies are systemic autoimmune diseases characterized by chronic inflammation, resulting in the progressive weakness of the proximal muscles. Myositis-specific or myositis-associated autoantibodies can often be found in serum of polymyositis and dermatomyositis patients. This autoantibody presence may play a significant role in patient diagnosis and classification. We present a female polymyositis patient characterized with serious muscle weakness and lung involvement. Anti-Jo1 antibodies were detected in the patient’s serum at the time of diagnosis. After 5 years of treatment and surveillance, recent laboratory analysis showed the presence anti-SRP antibody in her serum.     

Combination therapy with multiple disease-modifying antirheumatic drugs in rheumatoid arthritis: a preventive strategy

The traditional "pyramid" or sequential approach to treatment of patients with rheumatoid arthritis involved use of a nonsteroidal anti-inflammatory drug for months to years while seeking to avoid use of second-line antirheumatic drugs until evidence of joint damage was seen. This approach led to short-term reduction of inflammation and a few remissions. However, long-term remissions were rare, and most patients experienced poor long-term outcomes, including joint destruction, severe functional declines, considerable economic losses, work disability, and premature mortality. At this time, a "preventive" strategy is evolving in which early aggressive treatment with disease-modifying antirheumatic drugs is used, seeking to minimize long-term joint damage. When residual inflammation remains after maximum doses of single agents, as is usually the case, combinations of disease-modifying antirheumatic drugs appear to be a reasonable consideration for many patients. Methotrexate is the most commonly used "anchor drug" in combination therapy. Evidence from randomized, controlled clinical trials and observational studies have indicated increased efficacy and acceptable (and often lower) toxicity for combinations of methotrexate plus cyclosporine, hydroxychloroquine, sulfasalazine, leflunomide, etanercept, and infliximab. Further studies lasting 5 years or more are needed to determine the long-term effectiveness, toxicities, and optimal clinical use of disease-modifying antirheumatic drug combinations. At this time, such combinations are taken by at least some patients under care of almost all rheumatologists, and it appears likely that they will be used increasingly in the coming decades.     

Multidrug resistance proteins in rheumatoid arthritis, role in disease-modifying antirheumatic drug efficacy and inflammatory processes: an overview

Drug resistance is generally accepted as an important cause of treatment failure for patients with neoplastic or infectious diseases. Molecular mechanisms underlying drug resistance include the action of drug efflux pumps belonging to the super-family of ATP binding cassette (ABC) proteins, which mediate the cellular extrusion of a large variety of therapeutic drugs, a phenotype that is referred to as multidrug resistance (MDR). Unlike neoplastic and infectious diseases, chronic inflammatory diseases have received little attention. The potential role of ABC transporters in determining the efficacy of anti-rheumatic drugs, notably disease modifying anti-rheumatic drugs (DMARDs), in patients with rheumatoid arthritis is unclear. Based on knowledge from the field of oncology and immunology, this review concentrates on the pharmacological role of MDR proteins in the (clinical) efficacy of several DMARDs, as well as the physiological role of MDR proteins in transporting signalling molecules important in inflammatory processes.