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ID PMID Title PublicationDate abstract
17664952 Combination therapy for rheumatoid arthritis: methotrexate and sulfasalazine together or w 2007 Aug Early aggressive treatment of rheumatoid arthritis is associated with improved disease control, slower radiological progression and improved functional outcomes. Tumor necrosis factor blocking therapy is effective but there remain concerns about long-term risks. Combining disease-modifying antirheumatic drugs (DMARDs) is a widely used therapeutic alternative; however, there is uncertainty surrounding the most effective regimen. A popular combination is methotrexate plus sulfasalazine, but each of these DMARDs can also be used in combination with other DMARDs and in triple therapy regimens. However, wide variations in study size, design, steroid usage and approaches to combination therapy have made it difficult to form firm conclusions regarding their efficacy. Generally, combination therapy is well tolerated and associated with no significant increase in the rate of adverse events compared with monotherapy. Methotrexate-sulfasalazine, methotrexate-chloroquine, methotrexate-cyclosporin, methotrexate-leflunomide, methotrexate-intramuscular-gold and methotrexate-doxycycline are effective combination regimens. Triple DMARD therapy is better than various DMARD monotherapy and dual therapy regimens. Methotrexate and hydroxychloroquine may have synergistic anti-inflammatory properties. Clinical trial evidence to support the use of other methotrexate and sulfasalazine combinations is often weak or lacking. Further investigation is required to determine the most effective regimen and approach to combination therapy.
18504330 N-of-1 trials of expensive biological therapies: a third way? 2008 May 26 In developing policies for use of expensive agents, such as those used for the treatment of rheumatoid arthritis, managed care organizations have invoked "stepped care," in which physicians and patients must first try more established and less costly agents. N-of-1 clinical trials are multiple crossover trials in a single patient. In this cost-minimization analysis, we show that offering patients with rheumatoid arthritis the opportunity to participate in an n-of-1 trial comparing methotrexate with etanercept could save costs relative to open access while preserving clinical freedom relative to mandatory stepped care. In the primary model, the n-of-1 trial option was 15% more expensive than stepped care but 47% cheaper than open access to etanercept. More research is needed on the acceptability, safety, and generalizability of this promising approach.
18625629 Tight control and intensified COBRA combination treatment in early rheumatoid arthritis: 9 2008 Nov OBJECTIVE: To investigate the efficacy and feasibility of an intensive combination treatment in early rheumatoid arthritis (RA) combined with monitoring both disease activity and cartilage degradation. METHODS: In a pilot trial, 21 patients with active early RA (mean DAS28 5.3; mean disease duration 3 months) were treated with COBRA treatment comprising sulfasalazine, methotrexate and high-dose step-down prednisolone, intensified by adding hydroxychloroquine and continued low-dose prednisolone. In addition, based on measurements of disease activity or a marker of cartilage degradation (CTX-II), treatment adjustments were possible with methotrexate intensification after 8 or 21 weeks; and with infliximab after 21 weeks. RESULTS: Nineteen of 21 patients (90%) were in remission (DAS28 <2.6) after 40 weeks (8 weeks, 57%; 21 weeks, 76%). American College of Rheumatology (ACR) criteria, ACR20, 50, 70 and 90 improvements rates were 100%, 95%, 71% and 43% respectively. CTX-II excretion decreased by mean (SD) 347(292) ng/mmol creatinine, but only 50% of patients reduced their CTX-II excretion below the cut-off point. The two monitoring groups showed no significant difference in remission according to DAS score or CTX-II excretion, despite a trend towards more intensive treatment in the CTX-II group. Treatment intensification was feasible according to protocol. CONCLUSIONS: This small pilot study suggests that intensified and tightly controlled COBRA treatment is uniquely effective in early RA. TRIAL REGISTRATION NUMBER: ISRCTN96372677.
18590110 [Comparison of efficacy and tolerability of triple combination therapy (methotrexate + sul 2008 AIM: To compare efficacy and tolerability of combined therapy with methotrexate (MTX), sulfasalazine (SSZ) and hydroxychloroquine (HCQ) with MTX-monotherapy in patients with rheumatoid arthritis (RA). MATERIAL AND METHODS: RA patients (n = 60) who had not been treated with the above drugs were randomized (1:1) to receive either the triple drug combination or MTX alone in a 2-year open study. SSZ was given in a dose of 2.0 g/day, HCQ--200 mg/day. A MTX dose was gradually increased from 7.5 mg/week to 17.5 mg/week in an attempt to achieve remission in all the patients. Basic criterion of the treatment efficacy was achievement of a significant clinical effect (> 50% response according to the American College of Rheumatology--ACR criteria) in stability of the positive effect beginning from the ninth month of the study up to its end with no evidence of serious drug toxicity. RESULTS: 13 of 18 patients treated with the triple therapy (72.2%) and 6 of 20 patients treated with MTX alone (30.0%; p = 0.013) achieved an ACR > 50% response by the end of 18 months of therapy. 11 of 18 patients (61.1%) from the combined therapy group and 5 of 20 patients (25%; p = 0.024) from MTX monotherapy group maintained ACR > 50% response from month 9 to 18 of the study without any evidence of major drug toxicity. Two patients (11.1%) in the combined therapy group and 4 patients (20%) in the MTX group discontinued the treatment because of drug toxicity. CONCLUSION: In patients with RA the triple combination therapy with MTX, SSZ and HCQ given during 1.5 year is more effective than MTX alone. The triple combination of MTX, SSZ and HCQ is well tolerated.
17900958 Anti-tumor necrosis factor-alpha therapy in the ordinary clinical setting: Three-year effe 2007 Dec OBJECTIVES: The aim was to estimate the proportion of patients with rheumatoid arthritis (RA) achieving low disease activity by anti-tumor necrosis factor-alpha (TNF-alpha) therapy in an ordinary clinical setting. METHODS: Thirty-three patients with active RA despite methotrexate treatment were included in an open phase IV study of infliximab in combination with methotrexate. The mean age was 53years (range 21-71) and mean disease duration 10.7years (1-32). Treatment was changed in cases of insufficient response or intolerable adverse events. Response status to infliximab was assessed according to the American College of Rheumatology (ACR 20). Disease activity score (DAS28) was assessed at baseline and at weeks 26, 54, 80, 106 and 158. Low disease activity is defined as DAS28
18957621 Tocilizumab: an interleukin-6 receptor inhibitor for the treatment of rheumatoid arthritis 2008 Nov OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trial data, and safety profile of tocilizumab, a new biologic agent targeting the interleukin-6 cytokine receptor. DATA SOURCES: A systematic search of MEDLINE (1998-June 2008) and International Pharmaceutical Abstracts (1970-June 2008) was performed to identify published clinical trials and review articles. Key search terms were tocilizumab, MRA, interleukin-6/receptors, interleukin-6/immunology, and rheumatoid arthritis. The search was limited to studies in humans that were published in the English language. References from articles located during this search were evaluated for other relevant citations. Abstracts from national and international rheumatology meetings (American College of Rheumatology and European League Against Rheumatism) and from unpublished Phase 3 clinical trials in progress (using www.clinicaltrials.gov) were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All available human studies describing the pharmacology, pharmacokinetics, efficacy, safety, and adverse effects of tocilizumab were included. DATA SYNTHESIS: At doses greater than 4 mg/kg, tocilizumab use has resulted in significant improvement in clinical outcomes, including the American College of Rheumatology parameters indicating a patient's level of improvements and disease remission. Improvements were noted when tocilizumab was used as monotherapy or in combination with methotrexate or other disease-modifying antirheumatic drugs. The most effective dose of tocilizumab appears to be 8 mg/kg, which has shown significant improvements in radiographic measures of joint damage. The most common adverse effects have included abnormal results of liver function tests, hyperlipidemia, neutropenia, infections, nasopharyngitis, gastrointestinal complaints, musculoskeletal disorders, headache, rash, and pruritus. CONCLUSIONS: Tocilizumab represents a promising new treatment for rheumatoid arthritis. Additional research is warranted to confirm its radiographic benefits, clarify its safely profile, and identify its place in rheumatoid arthritis treatment relative to current biologic agents.
16762151 Suppression of circulating interleukin-6 concentrations is associated with decreased endot 2006 Mar BACKGROUND: Circulating interleukin (IL)-6 concentrations are associated with endothelial activation in rheumatoid arthritis (RA). OBJECTIVE: To assess endothelial activation before and after suppression of cytokine production in RA. METHODS: Twenty-one patients (mean (SD) age 59 (9) years; disease duration 6 (4) years) were treated with intraarticular methylprednisolone acetate (417 (152) mg) together with disease modifying agent (DMARD) initiation (n = 10) or intensification (n = 11) employing methotrexate (n = 11), leflunomide (n = 8), minocyclin (n = 6) and sulphasalazine (n = 1). Disease activity, circulating cytokines (IL-1, tumor necrosis factor alpha (TNF-alpha) and IL-6) and biomarkers of endothelial activation (circulating vascular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and endothelial leukocyte adhesion molecule-1 (ELAM-1)) were evaluated before and 2 weeks after treatment. RESULTS: The intervention resulted in reductions in 8 disease activity markers (p < or = 0.002). Serum IL-6 concentrations decreased from 17 (2.9) to 4.9 (4.6) pg/ml (p = 0.0008). Serum IL-1 and TNF-alpha levels did not change (p > or = 0.4). Serum VCAM-1 concentrations decreased from 912 (402) to 752 (252) (p = 0.003), ICAM-1 from 398 (205) to 323 (179) (p = 0.04) and ELAM-1 from 68 (28) to 53 (25) (p = 0.02) pg/ml, respectively. Baseline rheumatoid factor titers were associated with reductions in VCAM-1 (r(s) = 0.481, p = 0.03). In multivariable regression models, decreases in circulating interleukin-6 concentrations were associated with reductions in VCAM-1 (p < 0.0001), ICAM-1 (p = 0.005) and ELAM-1 (p = 0.02) independent of changes in disease activity, weight and blood pressure. CONCLUSION: Our results suggest that suppression of circulating IL-6 concentrations attenuates atherogenesis in active RA.
16892137 [Therapeutic effect and impact on cytokine production by methotrexate in rheumatoid arthri 2006 Aug 18 OBJECTIVE: To examine the clinical benefit and impact on cytokine production by methotrexate in rheumatoid arthritis. METHODS: Thirty patients with RA were treated with oral methotrexate (mean, 15 mg per week) as monotherapy for 24 weeks. Clinical assessment using the American College of Rheumatology (ACR) criteria for improvement was performed at baseline and at the end of 2, 4, 8, 12 and 24 weeks. The pro-inflammation cytokine TNF-alpha, INF-gamma,IL-1beta, IL-6 and anti-inflammation cytokine IL-10 were measured in RA sera at baseline and after 24 weeks of therapy. RESULTS: There was remarkable improvement in disease activity following the MTX treatment. At the end of 24 weeks, the percent age of ACR20 was 70% (21/30), ACR50 30% (9/30) and ACR70 10% (3/30). The levels of IL-6 (46.83+/-35.81 vs. 20.92+/-17.98, P=0.001), TNF-alpha (162.52+/-107.63 vs. 18.32+/-14.36, P=0.026) and INF-gamma (67.79+/-43.76 vs. 35.78+/-27.51, P=0.004) were significantly higher than those of the health control at baseline, respectively. The levels of TNF-alpha (123.36+/-89.61,P=0.018), INF-gamma (41.53+/-13.49, P=0.015), IL-1beta (7.47+/-7.33, P=0.026), IL-6 (26.01+/-25.64, P=0.025) were significantly decreased after treatment with methotrexate. In contrast, IL-10 was remarkably increased (71.76+/-41.01, P=0.02). CONCLUSION: Methotrexate is effective in patients with rheumatoid arthritis. It can suppress the symptoms and joint damage. In addition, methotrexate treatment decreases the levels of pro-inflammatory cytokine, and increases the level of anti-inflammatory cytokine.
16906378 Development of interstitial pneumonia in a rheumatoid arthritis patient treated with infli 2006 Infliximab, an anti-tumor necrosis factor (TNF)-alpha antibody, was introduced to a 66-year-old woman with methotrexate (MTX)-resistant rheumatoid arthritis (RA). Although the TNF-blocking therapy was successful, she developed noninfectious interstitial pneumonia (IP) after a second infusion of infliximab. In most cases reported previously, infliximab-associated noninfectious IP occurred after a second or third infusion of infliximab, and this type of IP was more fatal in comparison with cases associated with MTX treatment alone. Keeping a sharp lookout on IP development during this period is crucial to the success of infliximab treatment. After MTX discontinuation and steroid pulse therapy, our patient made a dramatic recovery from IP.
18246698 Primary cutaneous Cryptococcosis during therapy with methotrexate and adalimumab. 2008 Jan Primary cutaneous infection with Cryptococcus neoformans is uncommon, but can occur following an inoculation injury to the skin. Tumor necrosis factor-alpha (TNF-alpha) is important in the immune response to Cryptococcus, and patients taking inhibitors of TNF-alpha may have increased susceptibility to cryptococcal infection. We report a case of primary cutaneous cryptococcosis in a patient taking adalimumab, methotrexate, and hydroxychloroquine for rheumatoid arthritis.
17562570 Effects of thymoquinone (volatile oil of black cumin) on rheumatoid arthritis in rat model 2007 Sep Many studies have been carried out in recent years on the pharmacological effects of Nigella sativa seeds that have uncovered their antiinflammatory and immunological effects. The objective of this study was to explore the antiinflammatory effects of thymoquinone on arthritis in rat models. Rats with arthritis induced by Freund's incomplete adjuvant were assigned to five groups: group 1: controls 0.9% NaCl (n = 7); group 2: 2.5 mg/kg thymoquinone (n = 7); group 3: 5 mg/kg thymoquinone (n = 7); group 4: Bacilli Chalmette Guerin (BCG) 6 x 105 CFU (n = 7); group 5: methotrexate 0.3 mg/kg (n = 7). Signs of inflammation on the claw and radiological signs were searched for and TNF-alpha and IL-1beta were measured. The results of the control and other groups were compared. As a result, thymoquinone, confirmed clinically and radiologically, suppressed adjuvant-induced arthritis in rats.
17563271 Etanercept: long-term clinical experience in rheumatoid arthritis and other arthritis. 2007 Jun Etanercept is a dimeric fusion protein based on the p75 TNF-alpha receptor. It binds to TNF-alpha and blocks its biologic activity. In randomized, double-blind, placebo-controlled trials, etanercept has therapeutic activity in rheumatoid arthritis, psoriatic arthritis, polyarticular-course juvenile idiopathic arthritis and ankylosing spondylitis. Etanercept improves joint inflammation, physical function and slows/halts structural damage, especially when combined with methotrexate. A sustained response is observed in a substantial percentage of patients. Although some safety issues should be considered before starting etanercept treatment, in general terms, etanercept is a well tolerated drug with an acceptable safety profile. The use of any TNF-alpha antagonist must be in agreement with the National Recommendations for Biologic Therapy, and in difficult clinical situations, a balance between risk/benefit needs to be obtained.
19095031 Construction and characterization of a novel DNA vaccine that is potent antigen-specific t 2009 Jan 29 Currently available treatments for rheumatoid arthritis (RA) are often ineffective in ameliorating the progression of disease, particularly the invasive destruction of articular cartilage and bone, and RA remains incurable. Therefore, vaccinotherapy of RA with an antigen-specific tolerizing DNA vaccine may offer new promise for overcoming this difficulty. Using recombinant technology, the DNA sequences encoding chicken type II collagen (CCOL2A1) with deleted N-propeptides were obtained from the plasmid pPIC9K/pCalpha(1)(II), and then cloned into pcDNA3.1(+). The resulting recombinant plasmid pcDNA-CCOL2A1 was produced in Escherichia coli, purified, characterized and used as a tolerizing DNA vaccine for the treatment of collagen-induced arthritis (CIA). Therapeutic efficacy and potential action mechanisms of pcDNA-CCOL2A1 tolerizing DNA vaccine against CIA were studied. Here we demonstrate that a single intravenous treatment with novel tolerizing DNA vaccine pcDNA-CCOL2A1 can induce potent immune tolerance against CIA. The efficacy of this therapy was verified by clinical visual scoring, radiographic X-ray, histopathological examination, and anti-CII IgG levels. Furthermore, the action mechanism behind this efficacy can be at least partially attributed to increased CD4(+)CD25(+) T regulatory cells, which specifically down-modulate the T lymphocyte proliferative response to CCII, induce a shift of Th1 to Th2 cells, as well as down-regulate Th1-cytokine TNF-alpha, while up-regulating both Th2-cytokine IL-10 and Th3-cytokine TGF-beta. More importantly, pcDNA-CCOL2A1 alone seems to be as effective as the current "golden standard" treatment, methotrexate (MTX). Taken together, these results suggest that we have successfully developed a novel tolerizing DNA vaccine encoding CCII, which is the first description of a tolerizing DNA vaccine encoding CCII for antigen-specific tolerizing therapy but not prophylactic against CIA.
17117491 Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 2007 Feb OBJECTIVE: Individuals with rheumatoid arthritis (RA) with or without methotrexate (MTX) medication occasionally develop lymphoproliferative disorders (MTX-LPD and non-MTX-LPD, respectively). The hyperimmune state of RA itself or the immunosuppressive state induced by MTX administration might contribute to development of LPD. Our objective was to characterize MTX-LPD in comparison to non-MTX-LPD and sporadic LPD in patients with RA. METHODS: We compared MTX-LPD to non-MTX-LPD and sporadic LPD by evaluating 48 cases of MTX-LPD, 28 non-MTX-LPD, and 150 sporadic LPD. RESULTS: Later onset age of LPD and female predominance were evident in patients with RA-LPD compared to sporadic LPD. The interval between the diagnosis of RA and LPD in MTX-LPD (median 132 mo) was significantly shorter than that in non-MTX-LPD (240 mo). The frequency of diffuse large B cell lymphoma (DLBCL) and positive rate of Epstein-Barr virus (EBV) in RA-LPD was significantly higher than in sporadic LPD (57.9% vs 42.7%, 27.6% vs 9.9%, respectively). After withdrawal of MTX, 11 of the MTX-LPD cases showed a spontaneous regression of tumors. The 5-year survival rate in RA-LPD (59.2%) was significantly worse than that in sporadic LPD (74.6%). CONCLUSION: The majority of cases of RA-LPD show similar clinicopathological characteristics irrespective of MTX medication, except for spontaneous regression of LPD after withdrawal of MTX in MTX-LPD, and a shorter interval between the diagnosis of RA and LPD in MTX-LPD than in non-MTX-LPD. RA-LPD cases showed younger age of onset, female predominance, unfavorable prognosis, and higher frequencies of DLBCL and EBV positivity compared to sporadic LPD.
18657665 Tumor necrosis factor-alpha antagonist use and heart failure in elderly patients with rheu 2008 Aug BACKGROUND: Clinical trials have shown that tumor necrosis factor-alpha antagonists (TNFAs) confer little benefit, and some may cause potential harm in advanced heart failure (HF). Although TNFAs had significant benefits in treating rheumatoid arthritis (RA), little is known whether the drugs pose an increased risk of HF in older patients with RA. METHODS: A cohort study was conducted using data from Medicare and drug benefit programs in 2 states (1994-2004). We identified patients with RA aged > or =65 who received TNFA or methotrexate (MTX). The cohort was divided into patients with and without previous HF. We considered demographic variables, cardiovascular risk factors, RA severity-related measures, and other comorbidities. The primary end point was hospitalization with HF. We used stratified Cox proportional hazards regression to estimate the adjusted effect of TNFAs on HF hospitalization. RESULTS: The cohort consisted of 1,002 TNFA users and 5,593 MTX users. There were 59 HF admissions during 1,680 person-years of TNFA use and 227 HF admissions during 10,623 person-years of MTX use. Comparing TNFA with MTX users, the adjusted hazard ratio for HF hospitalization was 1.70 (95% confidence interval 1.07-2.69). We found similar results in patients with and without previous HF. Among patients with previous HF, the adjusted hazard ratio for death was 4.19 (95% confidence interval 1.48-11.89). CONCLUSIONS: TNFAs may increase the risk of both first hospitalization and exacerbation of HF in elderly patients with RA. The potential for residual confounding in our study cannot be ruled out; larger and more detailed studies are needed to confirm the findings.
18230627 The effectiveness of leflunomide as a co-therapy of tumour necrosis factor inhibitors in r 2009 Jan BACKGROUND: Randomised trials have demonstrated that the efficacy of anti-tumour necrosis factor (TNF) agents is significantly increased by concomitant methotrexate (MTX) in rheumatoid arthritis (RA). In clinical routine, anti-TNF agents are commonly prescribed with other disease-modifying antirheumatic drugs (DMARDs) than MTX, however their effectiveness in combination with anti-TNF agents is not well established. OBJECTIVE: To compare the effectiveness of leflunomide (LEF) and other conventional DMARDs with MTX as co-therapy to anti-TNF agents in RA. METHODS: All patients on anti-TNF agents and conventional DMARDs within the Swiss Clinical Quality Management (SCQM)-RA database were included (n = 1218) and categorised according to the type of co-therapy into anti-TNF+MTX (n = 842), anti-TNF+LEF (n = 260) and anti-TNF+other DMARDs (n = 116). Drug discontinuation rates and incidence of toxic side effects were analysed using Cox proportional hazard models. Progression of radiographic damage, the evolution of functional disability and the improvement of RA disease activity were analysed using longitudinal regression models, adjusting for potential confounders. RESULTS: The overall discontinuation rates of anti-TNF and conventional DMARD combination therapies were relatively high with a median survival of only 16 months (interquartile range (IQR): 10-37), but they did not differ between the three regimens (p = 0.69). The progression of radiographic damage (p = 0.77), functional disability (p = 0.09) and RA disease activity (p = 0.33) were also similar between the different regimen. In addition, no significant difference in the frequency of adverse events emerged. CONCLUSION: Overall these results suggest that LEF and potentially other conventional DMARDs offer an effective and safe alternative to MTX as co-therapy in combination with anti-TNF agents.
17977488 Safety of T-cell co-stimulation modulation with abatacept in patients with rheumatoid arth 2007 Sep Abatacept selectively modulates the CD80/CD86:CD28 co-stimulatory signal required for full T-cell activation, and has been approved for the treatment of rheumatoid arthritis (RA) in combination with methotrexate in a number of countries, including the United States, Canada, and the European Union. As with any new agent, it is important to assess the safety and tolerability of abatacept, and hence an integrated safety analysis of five randomized, placebo-controlled, double-blind core abatacept clinical trials was performed. The 2,944 patients enrolled had active RA and were receiving a variety of biologic and non-biologic background disease-modifying antirheumatic drugs. Overall, 1,955 patients were treated with abatacept during the double-blind periods, and 2,688 during the cumulative double-blind and open-label periods (yielding 4764 patient-years of exposure in total). Overall frequencies of adverse events (AEs; 88.8% vs. 85.1%), serious AEs (SAEs14.0% vs. 12.5%) and malignancies (1.4% vs. 1.1%) were similar in abatacept- versus placebo-treated patients, respectively (regardless of the potential relationship to the study therapy). Discontinuations due to SAEs were 2.8% in the abatacept group vs. 1.6% in the placebo group. The frequency of serious infections was low overall (3.0% vs. 1.9% in abatacept- versus placebo-treated patients, respectively). Acute infusional AEs (9.8% vs. 6.7% in the abatacept versus placebo groups, respectively) were mostly mild-to-moderate in intensity. Safety data through cumulative exposure were consistent with those from the double-blind periods; there was no evidence of an increase in the incidence of serious infections or malignancies with increasing exposure to abatacept. Abatacept was associated with low levels of immunogenicity, with no detectable association between immunogenicity and safety or efficacy. Abatacept treatment did not result in a higher rate of seroconversion for anti-nuclear or anti-dsDNA antibodies versus placebo, and was associated with a similar frequency of autoimmune events versus placebo (1.4% vs. 1.8%, respectively). Moreover, treatment with abatacept may not markedly impair the response to vaccination in healthy volunteers or RA patients. Overall, these findings suggest that abatacept has acceptable safety and tolerability in patients with RA. Ongoing follow-up will monitor whether these features are maintained over long-term abatacept use.
16932953 The effect of 3435C>T MDR1 gene polymorphism on rheumatoid arthritis treatment with diseas 2006 Nov OBJECTIVE: Rheumatoid arthritis (RA) is a multifactorial disease, with immunological, genetical as well as environmental factors being implicated in its pathogenesis. Treatment of RA is based mainly on drugs modulating the course of the disease, e.g. methotrexate (MTX) or sulfasalazine (SL). The MDR1 gene product, P-glycoprotein (P-gp), is probably one of the most important and best defined transporters for drug delivery in humans. P-gp transports a wide range of substrates with diverse chemical structures, among them anticancer agents, cardiac drugs, and immunosuppressants. The aim of this study was to examine the effect of the 3435C>T MDR1 gene polymorphism on the efficacy of RA treatment with disease-modifying antirheumatic drugs, i.e. MTX plus methylprednisolone (MP), and SL. METHODS: The study was carried out on 255 patients with RA treated according to two regimes: (1) MTX (7.5-15.0 mg weekly) plus low doses of MP (n=174), (2) SL (1.5-3 g daily, n=81). RESULTS: The probability of remission of RA symptoms after MTX plus MP therapy was 4.65-fold higher in carriers of the TT genotype compared to patients with CC genotype (P=0.003, OR 4.65, 95%CI 1.66-13.05), whereas the probability of remission of RA symptoms in patients treated with SL was 2-fold higher in carriers of TT genotype compared to patients with CC genotype, but did not reach statistical significance (P=0.358, OR=2.00 95% CI=0.58-6.87). CONCLUSION: The results from the present study suggest that the 3435C>T MDR1 gene polymorphism may influence the efficacy of RA therapy with disease-modifying antirheumatic drugs.
17540047 Aspects of early arthritis. Biological therapy in early arthritis--overtreatment or the wa 2007 The availability of newer, and more expensive, therapies for patients with rheumatoid arthritis has changed treatment beyond recognition. Disease remission is the goal for all new patients. Studies have shown that a combination of tumour necrosis factor (TNF)-blocking drugs and methotrexate produces superior outcomes over monotherapy alone; however, use is limited by cost and potential side-effects. Currently, anti-TNF therapy is normally reserved for patients who have failed traditional disease-modifying anti-rheumatic drugs. The question that remains is whether TNF-blocking drugs are better used if given early; the high direct costs are countered by both direct and indirect savings in healthcare costs from optimal control of disease, and the benefits of early control outweigh the increased risk of infection and malignancy.
18306977 Asymptomatic carriage of Pneumocystis jiroveci in elderly patients with rheumatoid arthrit 2008 Low-dose methotrexate (MTX) has been used effectively for rheumatoid arthritis (RA) because of its favorable risk-benefit ratio. One of the recent concerns arising from this therapy is a possible increase in the rate of opportunistic infections, particularly Pneumocystis jiroveci pneumonia (PCP). In this study, we report two cases of PCP occurring during low-dose methotrexate therapy for RA and review 13 additional cases from the literature on Japanese patients with RA. The average age of these patients was 67.7 years, and most were over the age of 60. MTX-associated PCP appears to occur more frequently in elderly individuals in Japan. To identify individuals with a high risk of PCP, we performed a polymerase chain reaction on specimens from induced sputum or bronchoalveolar lavage fluids from 55 patients with RA. At that point in time, they showed no evidence of PCP development. We found six patients (10.9%) having asymptomatic carriage of P. jiroveci. The mean age of the P. jiroveci-positive patients was 74.7 years, which was significantly older than the P. jiroveci-negative patients (mean age 63.6 years). Of the RA patients over the age of 65, 18.8% (6 cases out of 32) were carriers of P. jiroveci. There were no significant differences in RA duration or counts of white blood cells or lymphocytes between the positive and negative groups. Notably, we encountered a case of PCP occurring in an asymptomatic carrier of P. jiroveci during low-dose MTX therapy for RA. This case appeared to be a reactivation of latent infection. By careful follow-up on the carriers of P. jiroveci, we succeeded in promptly diagnosing PCP, and we employed the appropriate therapeutic strategies for this possibly life-threatening complication.