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21047485 Certolizumab pegol (CIMZIA®) for the treatment of rheumatoid arthritis. 2010 Oct This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of certolizumab pegol (CZP) for adults with active rheumatoid arthritis (RA) that have not responded adequately to treatment with conventional disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX), in accordance with the licensed indication, based upon the evidence submission from the manufacturer to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The outcome measures included American College of Rheumatology (ACR) 20, 50 and 70 response rates and quality of life measures after 3 months and 6 months of treatment. The ERG examined the submission's search strategies and considered they appeared comprehensive and that it was unlikely that relevant studies would have been missed. Only English language studies were considered in the submission and non-English language studies relevant to the decision problem may possibly have been ignored. The ERG analysed the first submitted economic model so as to itemise in detail clarification points that were brought to the attention of the manufacturer. In response the manufacturer submitted a modified cost-effectiveness analysis. The ERG undertook further analysis of this second model and other additional submitted evidence. The clinical evidence was derived from two multicentre blinded randomised controlled trials (RCTs) comparing CZP + MTX to placebo + MTX (the RAPID 1 and RAPID 2 trials). RAPID 1 lasted 52 weeks with 982 patients and RAPID 2 24 weeks with 619 patients. Evidence for clinical effectiveness of CZP in mono-therapy came from the 24-week FAST4WARD trial with 220 patients that compared CZP (400 mg every 4 weeks) versus placebo. The three key RCTs demonstrated statistically significant superiority of CZP + MTX versus placebo + MTX and of CZP versus placebo with respect to a variety of outcomes including ACR 20, ACR 50 and ACR 70 measures and quality of life measures at 3 and 6 months. On the basis of results from the indirect comparison meta-analyses, the manufacturer suggested that CZP may be at least as effective as other 'biological' DMARD (bDMARD) comparators and, in a few ACR measures at 3 and 6 months, more effective. CZP is an effective therapy for adult RA patients whose disease has failed to respond adequately to cDMARDs including MTX or who are intolerant of MTX. The cost-effectiveness of CZP relative to other bDMARDs is unclear because the economic modelling undertaken may have ignored relevant effectiveness data and potential differences between trial populations, and so may have included effectiveness results that were biased in favour of CZP; underestimated uncertainty in the relative effectiveness of compared DMARDs; and ignored the potential influence of differences between bDMARDs with regard to adverse events and their related costs and health impacts. The NICE guidance issued in October 2009 states that: the Committee is minded not to recommend certolizumab pegol as a treatment option for people with RA; and the Committee recommends that NICE asks the manufacturer of CZP for more information on the clinical effectiveness and cost-effectiveness of CZP for the treatment of people with RA. On receipt of this information and details of a patient access scheme NICE issued final guidance recommending CZP, under certain criteria, as a treatment option for people with RA.
19373092 An update on methotrexate. 2009 May PURPOSE OF REVIEW: Methotrexate (MTX) has been used for the treatment of rheumatoid arthritis (RA) for about three decades now. MTX is one of the most effective and commonly used medicines to treat various forms of arthritis and other rheumatic conditions. MTX was shown to improve signs and symptoms of RA, disease activity and function, to a similar degree as the tumor necrosis factor blockers, and it inhibits radiographic progression to a smaller degree than the antitumor necrosis factor agents. MTX is considered as the anchor drug among the disease-modifying antirheumatic agents, and it is internationally accepted as the first choice in the management of RA. This review was performed on the basis of a PubMed literature search looking at all publications on MTX and arthritis in 2008. RECENT FINDINGS: MTX seems to even prolong the life span of patients who tolerate the drug and have clinical benefit from this therapy; this may partly be explained by beneficial effects on cardiovascular mortality. The reason for this may well be the suppression of inflammation, but direct atheroprotective effects of MTX may also play a role. MTX is used as monotherapy and in combination with other disease-modifying antirheumatic agents or biologic agents such as the antitumor necrosis factor agents. The 'early' use of MTX within 5 years after disease onset is clearly associated with improved outcomes. The management of RA should include an early strong suppression of inflammation and continuously a tight control strategy. The pharmacodynamics and kinetics of MTX are still incompletely understood. SUMMARY: In this review, we especially cover the following themes: new clinical studies on the use of MTX in RA, the use of MTX in other rheumatic conditions, prediction of response to MTX, optimal dosage, MTX use in the elderly, the mechanism of action, the pharmacokinetics and the pharmacogenetics of MTX, the prevention of side effects, and the overall long-term safety.
19451137 Survival, comorbidities and joint damage 11 years after the COBRA combination therapy tria 2010 May BACKGROUND: COBRA (for 'COmbinatie therapie Bij Rheumatoide Artritis') combination therapy is effective for the treatment of rheumatoid arthritis (RA), but long-term safety is unknown. This study evaluates survival, comorbidities and joint damage in the original COBRA trial cohort. METHODS: In the COBRA trial, 155 patients with early RA were treated with sulfasalazine (SSZ) monotherapy (SSZ group) or a combination of step-down prednisolone, methotrexate (MTX) and SSZ (COBRA group). The current 11-year follow-up study of the COBRA trial invited all original patients and performed protocollised scrutiny of clinical records, questionnaires, physical examination, laboratory and imaging tests. RESULTS: In all, 152 out of 155 patients yielded at least partial data. After a mean of 11 years follow-up, 18 (12%) patients had died, 6 COBRA patients and 12 SSZ patients, HR 0.57 (95% CI 0.21 to 1.52). Treatment for hypertension was significantly more prevalent in the COBRA group (p=0.02) with similar trends for diabetes and cataract. Conversely, hypercholesterolaemia, cancer and infection showed a trend in favour of COBRA. Other comorbidities such as cardiovascular disease and fractures appeared in similar frequency. Radiographic findings suggest as a minimum sustained benefit for COBRA therapy, that is, difference in joint damage but similar subsequent progression rates after 5 years. Imputation to compensate for selective dropout suggests increasing benefit for COBRA, that is, difference in yearly progression rates similar to that seen in the first 5 years of follow-up. CONCLUSIONS: After 11 years, initial COBRA combination therapy resulted in numerically lower mortality and similar prevalence of comorbidity compared with initial SSZ monotherapy. In addition, lower progression of joint damage suggests long-term disease modification.
20726683 Trends in treatment strategies and the usage of different disease-modifying anti-rheumatic 2011 Jan OBJECTIVES: To determine which disease-modifying anti-rheumatic drugs (DMARDs) are currently used by Finnish rheumatologists to treat early rheumatoid arthritis (RA). METHODS: Information on sex, date of birth, and date of special medicine reimbursement decision for all new RA patients was collected from a nationwide register maintained by the Social Insurance Institution (SII) during the time period from 1 January 2000 to 31 December 2007. Patient cohorts were registered in 2-year time periods (2000-01, 2002-03, 2004-05, 2006-07) and DMARDs purchased by the patient cohorts during the first year after the date of reimbursement decision for RA were registered. The frequencies of early drug treatment strategies (combination of DMARDs, single DMARD, or no DMARDs) were evaluated. RESULTS: A total of 14 878 (68.0% female, 62.6% rheumatoid factor (RF)-positive) patients were identified. Between 2000 and 2001 the most commonly used treatment strategy for early RA during the first 3 months was single DMARD treatment (56.1%) and the most commonly used DMARD during the first year was sulfasalazine (63.0%), while between 2006 and 2007 the respective treatments were combination DMARDs (55.3%) and methotrexate (69.0%). The change in treatment strategies as well as in DMARDs used was highly significant (p < 0.001 for linearity). At the end of the study period only 4.9% of the patients with early RA were not receiving DMARDs during the first 3 months. CONCLUSIONS: Currently, combination therapy including methotrexate is the most commonly prescribed treatment strategy for early RA in Finland. In recent years, an increasing number of active drug treatments have been taken into practice.
19861018 QuantiFERON-TB Gold in the identification of latent tuberculosis infection in rheumatoid a 2009 Nov OBJECTIVE: To compare the performance of QuantiFERON-TB Gold (QFT-G) with that of the tuberculin skin test (TST) in detecting latent tuberculosis (LTBI) among patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: A total of 35 RA patients and 15 healthy controls underwent TST, QFT-G assays and chest X-ray and filled out a questionnaire on predisposing conditions for TB disease. Serum interferon gamma (IFN-gamma) levels were tested by an enzyme-linked immunosorbent assay. RESULTS: Forty-five per cent of RA patients had a TST > 5 mm vs. 26% in healthy controls. In the RA patients, QFT-G was positive in 11.4%, negative in 60% and indeterminate in 28.6%. The overall agreement between TST and QFT-G was significantly lower in the RA population than in controls (56% vs. 84%). No correlation was found between the use of prednisone, methotrexate and QFT-G results or agreement between TST and QFT-G. A low IFN-gamma level (<4 pg/ml) was found in 51.5% of the RA patients. No correlation was found between serum IFN-gamma levels and QFT-G results. CONCLUSION: The clinical significance of negative QFT-G in TST-positive patients with low TB risk remains to be assessed. The high rate of indeterminate results questions the clinical utility of QFT-G in the diagnosis of LTBI in RA patients.
20828280 Golimumab: a new anti-TNF-alpha agent for rheumatoid arthritis, psoriatic arthritis and an 2010 Sep Rheumatoid arthritis (RA) is a chronic inflammatory systemic disease characterized by symmetric arthritis leading to progressive erosion of cartilage and bone. Psoriatic arthritis and ankylosing spondylitis are also inflammatory arthritides that belong to the spondyloarthritides. Disease-modifying anti-rheumatic drugs and biologic therapies including anti-TNF agents are used in their treatment. The TNF antagonists have shown rapid and sustained therapeutic responses. However, a substantial number of patients fail to respond to anti-TNF agents or experience side effects. Golimumab is a human monoclonal antibody to TNF-α requiring less frequent administration compared with current anti-TNF products. Various trials have shown promising results in terms of efficacy and safety in methotrexate-naive and -resistant patients with RA as well as in patients previously treated with other anti-TNF agents. The efficacy of golimumab has also been demonstrated in patients with psoriatic arthritis and ankylosing spondylitis.
20444750 EULAR recommendations for the management of rheumatoid arthritis with synthetic and biolog 2010 Jun Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.
21044432 Methotrexate transport mechanisms: the basis for targeted drug delivery and ß-folate-rece 2010 Sep Methotrexate (MTX) plays a pivotal role in the treatment of rheumatoid arthritis (RA). The transport mechanisms with which MTX reaches is target after application are an important part of MTX pharmacology and its concentration in target tissue such as RA synovial membrane might strongly influence the effectiveness of the drug. Physiological plasma protein binding of MTX to albumin is important for the distribution of MTX in the body and relative high concentrations of the drug are found in the liver. However, targeted drug delivery into inflamed joints and increased anti-arthritic efficiency can be obtained by covalent coupling of MTX ex-vivo to human serum albumin (MTX-HSA) or in-vivo to endogenous albumin mediated through the MTX-pro-drug AWO54. High expression of the folate receptor β (FR-β) on synovial macrophages of RA patients and its capacity to mediate binding and uptake of MTX has been demonstrated. To further improve drug treatment of RA, FR-β specific drugs have been developed and were characterised for their therapeutic potency in synovial inflammation. Therefore, different approaches to improve folate inhibitory and FR-β specific therapy of RA beyond MTX are in development and will be described.
19960973 [Effects of wenhua juanbi recipe on TNF-alpha and IL-1beta in peripheral blood of rheumato 2009 Sep OBJECTIVE: To observe the clinical effect of Wenhua Juanbi Recipe (WJR) in treating rheumatoid arthritis (RA), its effects in reducing the dosage of Western medicine used and stabilizing condition of disease, as well as its influences on peripheral blood levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta) and anti-cyclic citrullinated peptide antibody (anti-CCP), for the sake of exploring its preliminary acting mechanism. METHODS: One hundred patients with RA were randomly assigned to 2 groups, the control group and the treated group, 50 in each group. All were treated with oral administration of methotrexate (MTX,7.5 mg per week), sulfasalazine (0.5 g, tid) and meloxicam (Mobic, 7.5 mg, bid), but to the treated group WJR was given additionally. The therapeutic course for both groups was 3 months. Clinical effect, changes of symptoms and physical signs, dosages of western medicines used, and laboratory indices in 2 groups after treatment were observed, and cases of relapse 3 months after treatment were figured out. RESULTS: The total effective rate in the treated group was higher than that in the control group (88.0% vs 76.0%, P<0.05). The improvements in scores of symptoms and signs [joint pain (0.61 +/- 0.59), swelling (1.49 +/- 1.20), tenderness (0.90 +/- 0.69), movement (0.68 +/- 0.62), griping strength (68.56 +/- 6.50) mm Hg, morning stiff time (23.26 +/- 9.26) min], and in levels of laboratory indices (TNF-alpha, IL-1beta, anti-CCP, RF, ESR, CRP, PLT and Ig) in the treated group after treatment were significantly superior to those in the control group (P<0.05 or P<0.01). The dosages of MTX [(82.11 +/- 11.35) mg vs (94.75 +/- 10.23) mg] and meloxicam [(108.85 +/- 16.13) mg vs (189.63 +/- 18.44) mg] used, and the relapse rate in the treated group were lower significantly (P<0.05, P<0.01) than those in the control group respectively. CONCLUSIONS: Effect of combined therapy of WJR and Western medicines is superior to that of using Western medicines alone in treating RA; WJR can reduce the dosages of Western medicines used and the relapse rate, as well as stabilize the condition of illness. It has the effects of immune regulating and anti-inflammatory reaction. Its mechanism for treating RA is possibly the inhibition on cytokines of TNF-alpha and IL-1beta.
20132066 Time to methotrexate treatment in patients with rheumatoid arthritis referred to hospital. 2010 OBJECTIVE: To describe time to methotrexate (MTX) treatment among patients with a first-time diagnosis of rheumatoid arthritis (RA) in a hospital-based department of rheumatology. METHODS: Using prescription data, we conducted a large cohort study in the County of Aarhus, Denmark, including all patients with a first-time diagnosis of RA. We used Kaplan-Meier estimates to compute the cumulative probability of MTX treatment start with follow-up starting on the date of referral. We defined early treatment start as MTX initiation within 90 days after referral. RESULTS: Among 1516 RA patients, a total of 703 (46%) started MTX treatment during the study period. The overall median time to treatment start was 120 days [interquartile range (IQR) 19-557]. Patients included in 2000-2006 had an earlier MTX treatment start compared with patients included in 1996-1999 [adjusted incidence rate ratio (IRR) 1.83, 95% confidence interval (CI) 1.55-2.16]. Patients with a C-reactive protein (CRP) level>300 nmol/L had an earlier MTX treatment start compared with patients with a moderate CRP level (adjusted IRR 1.36, 95% CI 1.16-1.73). Only 21% of the patients started MTX within 90 days after referral and those were mainly patients included in later years and patients with a high CRP. CONCLUSIONS: The data suggest that reduction in the time to start MTX treatment after referral to hospital could be improved, especially among patients with less severe symptoms. However, our results show that treatment practice in recent years has changed towards an earlier MTX treatment start.
19916579 Benefit-risk assessment of leflunomide: an appraisal of leflunomide in rheumatoid arthriti 2009 Evidence is accumulating for the early sustained usage of disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis. Leflunomide was licensed for the treatment of rheumatoid arthritis in 1998. Postmarketing surveillance, case reports and observational studies have highlighted less common or unexpected adverse events. Therefore, it is appropriate that we review the benefit-risk profile of leflunomide after 10 years of widespread usage. A wide-based search of relevant literature was performed to formulate this assessment. The improvements in rheumatoid arthritis shown by double-blind, randomized controlled trials (RCTs) of leflunomide have now been shown to be maintained beyond 4 years in open-label extension studies. Leflunomide is comparable to methotrexate, but better than sulfasalazine at 24 months in only one study. However, tolerance in clinical practice research shows higher than expected withdrawal rates due to both toxicity and lack of efficacy when compared with methotrexate and placebo. Adverse events reported include gastrointestinal upset, hypertension, headache, hepatotoxicity and hair loss, as well as predisposition to infection and peripheral neuropathy. The incidence of gastrointestinal adverse effects for leflunomide is similar to sulfasalazine but higher than those seen with methotrexate. Serious drug-induced hepatotoxicity leading to hospitalization is rare (0.02%), but isolated fatalities from liver failure have been documented. It is considered likely, but not yet proven, that there may be an increased incidence of weight loss and interstitial lung disease with leflunomide. Leflunomide in combination with methotrexate or sulfasalazine is an effective regimen in RCTs utilizing placebo controls, but more research is needed to confirm its effectiveness in combination with other DMARDs, particularly biologicals. The active metabolite of leflunomide is teratogenic in animal studies and is also found in breast milk. Therefore, contraception is advised in both males and females of child-bearing potential. There are genetic, pharmacokinetic and biochemical reasons to explain variation in both patient response and adverse event profile. Hence, blood and blood pressure monitoring are recommended and therapeutic drug monitoring should be considered in clinical nonresponders. Leflunomide is an effective DMARD that sustains a clinical and radiological response comparable to sulfasalazine and methotrexate. However, adverse effects necessitate frequent monitoring. It should be used with caution in those of child-bearing potential and with pre-existing lung and liver disease.
19147618 TWEAK and its receptor Fn14 in the synovium of patients with rheumatoid arthritis compared 2010 Jan OBJECTIVE: To investigate the expression of tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor inducible 14 (Fn14) in the inflamed synovium of patients with arthritis, as TWEAK blockade has been observed to have a beneficial effect in an animal model of rheumatoid arthritis (RA). METHODS: Synovial tissue (ST) biopsies were obtained from 6 early, methotrexate-naive patients with RA as well as 13 patients with RA and 16 patients with psoriatic arthritis (PsA) who were matched for treatment and disease duration. Serial ST samples were obtained from a separate cohort of 13 patients with RA before and after infliximab treatment. TWEAK and Fn14 expression was evaluated by immunohistochemistry and digital image analysis. RESULTS: TWEAK and Fn14 were clearly expressed in ST of patients with RA and PsA. TWEAK expression was significantly higher in RA (sub)lining samples compared to PsA (p = 0.005 and p = 0.014, respectively), but Fn14 expression was comparable. Double immunofluorescence showed TWEAK and Fn14 expression on fibroblast-like synoviocytes and macrophages, but not T cells. Of interest, persistent TWEAK and Fn14 expression was found after anti-TNF therapy. CONCLUSIONS: TWEAK and Fn14 are abundantly expressed in the inflamed synovium of patients with RA and PsA. This raises the possibility that blocking TWEAK/Fn14 signalling could be of therapeutic benefit in inflammatory arthritis.
19333993 Choice of second-line disease-modifying antirheumatic drugs after failure of methotrexate 2009 Apr 15 OBJECTIVE: To survey rheumatologists' preferences for the choice of a second-line disease-modifying antirheumatic drug (DMARD) after inadequate response with methotrexate (MTX) therapy in rheumatoid arthritis (RA). METHODS: Thirty-six rheumatologists stated their preferences for RA treatment after inadequate response with MTX therapy (optimal dose at least 6 months). From the initial scenario, we derived 54 vignettes varying by rheumatoid factor or anti-cyclic citrullinated peptide antibody presence, swollen joint count, Disease Activity Score in 28 joints, and structural damage. Respondents stated their preference among 5 therapeutic options: MTX continuation, switch to another conventional DMARD, addition of another conventional DMARD, addition of anakinra, or addition of a tumor necrosis factor (TNF) blocker. Presentation by pairs yielded 10 combinations of strategies for each variant, totaling 540 vignettes; participants evaluated a random sample of 180 vignettes. Determinants of each top-ranked option were analyzed by logistic regression. The compilation of these data served to define a therapeutic algorithm. RESULTS: The responses of 33 rheumatologists were analyzable. Therapeutic preferences corresponded to the top-ranked options. For patients with mild or moderately active RA, either a switch or step-up strategy to another conventional DMARD was top ranked. TNF blockers were preferred for RA patients with high disease activity or progressive structural damage. On the basis of these preferences, we developed a simple decision tree for use in daily clinical practice. CONCLUSION: Our simple, easy-to-use decision tree developed from rheumatologists' preferences for therapy after failure of MTX therapy in RA treatment may guide rheumatologists in daily practice to choose a second-line DMARD.
19137355 Expression of multidrug resistance-1 protein correlates with disease activity rather than 2009 Apr Disease-modifying antirheumatic drugs (DMARDs) improve the disability and slow the progression of the joint damage in rheumatoid arthritis (RA). However, a large proportion of patients experience inefficacy by the end of 2 years. This loss of efficacy may be due to expression of multidrug resistance (MDR) proteins on lymphocytes. The objective is to study the expression of MDR protein on the peripheral blood lymphocytes in patients with RA and correlate it with the disease status and response to treatment. Twenty-eight patients were enrolled. Expression of MDR-1 by flow cytometry was carried out on lymphocytes at baseline and after 4 months of therapy. This expression was correlated with disease activity scores (DAS 28). There were 25 females with mean age of 48.13 years and median disease duration of 48 months. Eighteen patients were DMARD naive and ten were refractory to DMARD (methotrexate). The percentage of cells expressing MDR-1 in the DMARD-naive (p<0.O5) and DMARD-refractory (p<0.05) groups were significantly higher than the healthy controls at the baseline. The relative fluorescence intensity was significantly higher in the DMARD-refractory group (p<0.05) as compared to the DMARD-naive group. After 4 months of therapy, there was significant improvement in the D value (p<0.01) in the DMARD-naive group (treated with methotrexate only) and DMARD-refractory group (p<0.05). A significant correlation (r=0.563) between the DAS 28 scores and the D value (p=0.003) was observed. Expression of MDR-1 in RA correlated with disease activity status and improved with DMARD therapy. It is not related to the refractoriness to therapy with methotrexate.
19684150 Plasma adiponectin in patients with active, early, and chronic rheumatoid arthritis who ar 2009 Sep OBJECTIVE: Rheumatoid arthritis (RA) is a systemic chronic inflammatory joint disease, whereas osteoarthritis (OA) is a local joint disease with low-level inflammatory activity. The pathogenic role of the adipocytokine adiponectin is largely unknown in these diseases. We hypothesized (1) that plasma adiponectin concentrations differ in healthy controls and patients with early disease-modifying antirheumatic drug (DMARD)-naive RA, chronic RA, and OA; (2) that changes in adiponectin are observed during methotrexate (MTX) treatment of chronic RA; and (3) that adiponectin correlates to disease activity measures in RA. METHODS: Plasma adiponectin was analyzed with a validated in-house immunoassay. We measured adiponectin in healthy controls (n = 45) and patients with early DMARD-naive RA (n = 40), chronic RA (n = 74), and OA (n = 35). In a subgroup of patients with chronic RA (n = 31), the longitudinal effect of MTX treatment on adiponectin (Week 0 vs Week 28) was investigated. RESULTS: Adiponectin differed significantly between healthy controls (mean 4.8 +/- SD 2.7 mg/l) and the 3 groups, with 8.9 +/- 4.8 mg/l in early RA, 11.6 +/- 5.6 mg/l in chronic RA, and 14.1 +/- 6.4 mg/l in OA. Longitudinally, MTX treatment increased adiponectin significantly from 9.7 +/- 4.5 mg/l at Week 0 to 11.0 +/- 4.5 mg/l at Week 28 in chronic RA. No correlations to disease activity measures were found. CONCLUSION: Both early DMARD-naive and chronic RA were associated with higher plasma adiponectin compared to healthy controls, but lower plasma adiponectin than OA. Adiponectin increased 13% during MTX treatment. In patients with RA and OA body mass index, age, sex, and disease activity measures failed to explain the findings.
19565542 Multicenter, randomized, double-blind, controlled trial of treatment of active rheumatoid 2009 Jul 15 OBJECTIVE: To assess the efficacy and safety of T-614 versus methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: In this multicenter, double-blind trial, 489 patients randomly received either T-614 25 mg/day for the first 4 weeks and 50 mg/day for the subsequent 20 weeks (group 1, n = 163), T-614 50 mg/day for 24 weeks (group 2, n = 163), or MTX 10 mg/week for the first 4 weeks and 15 mg/week for the subsequent 20 weeks (n = 163). Clinical and laboratory parameters were analyzed at baseline and at 4, 10, 17, and 24 weeks. RESULTS: After 24 weeks of treatment, the American College of Rheumatology 20% improvement criteria response rate for patients in T-614 group 2 (63.8%) was not statistically significantly different from that for patients receiving MTX treatment (62.0%), and was superior to that for patients in T-614 group 1 (50.9%). The result of the noninferiority analysis indicated that the efficacy of T-614 (50 mg/day) was not lower than that of MTX by <10%. Rheumatoid factor and IgA, IgG, and IgM demonstrated a statistically significant decrease in all groups. Frequently reported adverse events included hematologic disorder, skin reactions, gastrointestinal symptoms, and transient liver enzyme elevations in the T-614 therapy groups. Side effects in the T-614 groups were generally fewer and milder than in the MTX group, except for skin reactions. There were no prominent cardiovascular adverse events and gastrointestinal ulcers found in the T-614 groups. CONCLUSION: Results indicate that T-614 therapy 50 mg/day is effective and well tolerated, and represents a new option for the treatment of patients with active RA.
21298986 [Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy in Po 2010 Dec Results of a multicenter, non-interventional, observational study assessing efficacy and safety of 1st course rituximab treatment with methotrexate in patients with rheumatoid arthritis and a history of inadequate response to anti-TNF-therapies, in the routine clinical settings in Poland (MIRACLE-POL 1). The aim of the study was to determine the efficacy and safety of treatment with rituximab and methotrexate in patients with active rheumatoid arthritis (RA) who had inadequate response to anti-TNF-therapies in routine clinical settings in Poland. MATERIAL AND METHODS: We evaluated effectiveness and safety of RTX and MTX therapy in 73 patients enrolled in the multicenter, non-interventional, observational study. Patients with active RA had a history of an inadequate response to 1 or more anti-TNF-alpha agents received 1st course of rituximab consisting of 2 intravenous infusions of 1000 mg each. The end points were: EULAR response criteria at 180 days, changes of Disease Activity Scores in 28 joints (DAS28) from the original baseline at 180 days, rate of remission, rate of low disease activity according to EULAR criteria and rate of adverse events (AEs) during treatment. RESULTS: At 180 days 22% of treated patients demonstrated good-to-moderate EULAR response and 12% of patients demonstrated moderate response. In 77% of cases DAS28 decreased > 1.2. 16% of patients achieved remission according to EULAR criteria and 23% of patients achieved low disease activity. After 180 days mean DAS28 score decreased from 6.33 to 4.06. In 16% of patients AEs occurred with the first rituximab infusion, in 12% of patients with the second rituximab one, and in 43% of patients afterwards. All AEs were mild or moderate in severity. There were no serious AEs including serious infections. Infusion-associated AEs occurred in a higher proportion during the first infusion. CONCLUSIONS: Results of this multicenter, non-interventional, observational study confirm efficacy and safety of 1st course rituximab treatment with concomitant methotrexate in patients with rheumatoid arthritis who had inadequate response to anti-TNF-therapies in the routine clinical settings in Poland.
21190991 How I treat LGL leukemia. 2011 Mar 10 Large granular lymphocyte (LGL) leukemia is characterized by a clonal expansion of either CD3(+) cytotoxic T or CD3(-) NK cells. Prominent clinical features of T-LGL leukemia include neutropenia, anemia and rheumatoid arthritis (RA). The terminal effector memory phenotype (CD3(+)/CD45RA(+)/CD62L(-)CD57(+)) of T-LGL suggests a pivotal chronic antigen-driven immune response. LGL survival is then promoted by platelet-derived growth factor and interleukin-15, resulting in global dysregulation of apoptosis and resistance to normal pathways of activation-induced cell death. These pathogenic features explain why treatment of T-LGL leukemia is based on immunosuppressive therapy. The majority of these patients eventually need treatment because of severe or symptomatic neutropenia, anemia, or RA. No standard therapy has been established because of the absence of large prospective trials. The authors use low-dose methotrexate initially for T-LGL leukemia patients with neutropenia and/or RA. We recommend either methotrexate or oral cyclophosphamide as initial therapy for anemia. If treatment is not successful, patients are switched to either the other agent or cyclosporine. The majority of patients experience an indolent clinical course. Deaths infrequently occur because of infections related to severe neutropenia. As there are no curative therapeutic modalities for T-LGL leukemia, new treatment options are needed.
19565512 Disease remission state in patients treated with the combination of tumor necrosis factor 2009 Jul OBJECTIVE: For patients with rheumatoid arthritis (RA) in remission who are receiving disease-modifying antirheumatic drugs (DMARDs), radiographic progression correlates with imaging-detected synovitis as measured by power Doppler activity. In contrast, patients with disease in remission who are receiving the combination of tumor necrosis factor (TNF) blockade with methotrexate (MTX) (combination treatment) have reduced radiographic damage for the equivalent clinical state. We undertook this study to determine whether the difference in radiographic outcome is a result of more complete suppression of imaging-detected synovitis. METHODS: One hundred patients with RA in remission (Disease Activity Score in 28 joints [DAS28] <2.6) for at least 6 months while receiving either combination treatment (n = 50) or DMARDs (n = 50) were matched for clinical variables. Ultrasound of metacarpophalangeal joints 1-5 and the wrist joints was performed. Remission according to imaging results was defined as a score of 0 for both grey scale synovitis and power Doppler activity. RESULTS: In patients receiving combination treatment or DMARDs (median DAS28 1.65 versus 1.78, median disease duration 120 months versus 90 months, and median duration of remission 13 months versus 18 months), the proportion with remission according to imaging results was not significantly different (10% versus 16%, respectively). The combination treatment group had more grey scale synovitis (P < 0.001) but similar power Doppler activity (48% versus 60%, respectively; P = 0.229) in any joint as compared with the DMARD group. Results were not affected by stratification for duration of disease or remission. CONCLUSION: In RA patients with disease in remission, imaging-detected synovitis persists, with power Doppler activity seen in >or=48% of the patients regardless of therapy. These results suggest that superior radiographic outcomes in patients treated with the combination of TNF blockade and MTX may not be due to complete suppression of imaging-detected synovitis.
20217173 Incidence of and risk factors for interstitial pneumonia in patients with rheumatoid arthr 2010 Jun Interstitial lung disease (ILD) is a frequently encountered and sometimes life-threatening complication among patients with rheumatoid arthritis (RA). In this study, we aim to clarify the incidence of and risk factors for ILD using a large observational cohort of RA patients. We analyzed the database from a large observational cohort of Japanese RA patients, the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort. We defined as interstitial pneumonia (IP) computed tomography (CT) pattern of nonspecific interstitial pneumonia or diffuse alveolar damage. Newly developed IP was identified from patient reports over 2.5 years (April 2004 to October 2006) and was confirmed by extensive medical record, chest X-ray radiograph, and CT. The raw and age/gender-adjusted incidence of IP were reported. IP risk factors were analyzed using a nested case-control design was employed using conditional logistic regression analysis with a stepwise method. Thirty-seven patients among 5,699 RA patients were diagnosed with newly developed IP, including 18 cases with methotrexate-induced pneumonitis (MTX-IP) and 15 cases with IP associated with RA (RA-IP). The age-adjusted incidence of MTX-IP among total patients, males, and females was 3.775, 6.667, and 1.013 per 1,000 cases, respectively, and of RA-IP among total patients, males, and females was 1.056, 1.452, and 0.677 per 1,000 cases, respectively. Conditional logistic regression analysis after stepwise variable selection identified male gender, increased Japanese version of the Health Assessment Questionnaire (J-HAQ) score, decreased pain visual analog scale (VAS), and elevated erythrocyte sedimentation rate as significant risk factors for MTX-IP, while the only risk factor for RA-IP was male gender. The incidence of and risk factors for IP in RA patients were determined in a large observational cohort of RA patients in Japan.