Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
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| 19882783 | Tocilizumab: new drug. Rheumatoid arthritis: another 'mab', no therapeutic advantage. | 2009 Oct | (1) First-line disease-modifying treatment for rheumatoid arthritis is based on "slow-acting" antirheumatic agents, generally methotrexate. Subsequent options include a TNF-alpha antagonist, followed by rituximab or possibly abatacept; (2) Tocilizumab, a monoclonal antibody, inhibits interleukin-6 receptors. It is licensed in the European Union for patients with rheumatoid arthritis in whom other drugs have failed; (3) Clinical evaluation includes 4 placebo-controlled trials of the methotrexate-tocilizumab combination, after failure of a slow-acting antirheumatic drug (3 trials) or failure of a slow-acting antirheumatic drug and a TNF-alpha antagonist (1 trial). An indirect comparison suggests that tocilizumab is no more effective than rituximab in patients with multiple treatment failure; (4) Tocilizumab, like TNF-alpha antagonists, is an immunosuppressant. It carries a risk of serious infections, haematological disorders (neutropenia, thrombocytopenia), gastrointestinal bleeding, hepatic disorders, and systemic and local reactions during the infusion; (5) the adverse effects of long-term tocilizumab therapy are unknown, particularly the risk of cancer; (6) Tocilizumab carries a risk of interactions with drugs that are metabolised by cytochrome P450 isoenzymes. Clinical consequences cannot be ruled out when co-administered drugs have a narrow therapeutic margin; (7) Tocilizumab is administered intravenously every 4 weeks, making it slightly more convenient that rituximab at the beginning of treatment; (8) In patients with rheumatoid arthritis and multiple treatment failure, it remains to be shown whether tocilizumab has a better risk-benefit balance than rituximab, a drug with which we have more experience. It is therefore better to continue to use rituximab, or possibly abatacept. | |
| 21194591 | Golimumab: Review of the efficacy and tolerability of a recently approved tumor necrosis f | 2010 Sep | BACKGROUND: Golimumab (GLM) is a tumor necrosis factor-α (TNF-α) inhibitor that was approved in the United States in 2009 for use with methotrexate (MTX) in adults with moderate to severe active rheumatoid arthritis (RA), and with or without MTX or other non-biologic disease-modifying antirheumatic drugs in adults with active psoriatic arthritis (PsA) or active ankylosing spondylitis (AS). GLM is administered as a 50-mg subcutaneous injection once a month. OBJECTIVES: The goals of this article were to review the current literature on GLM and to provide recommendations for the use of GLM based on the published information. METHODS: The PubMed, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, International Pharmaceutical Abstracts, and other databases, as well as the Web sites for the American College of Rheumatology (ACR) and the European Union League Against Rheumatism, were searched for relevant articles published in English between the inception of the databases through April 2010. Search terms included golimumab and CNTO 148. Pharmacologic, pharmacokinetic, clinical, outcomes, and economic studies as well as meta-analyses, case reports, and select abstracts were eligible for inclusion. Review articles on GLM were not used except to identify other primary papers. RESULTS: Seven clinical studies were identified and used to evaluate the efficacy and tolerability of GLM: 5 in patients with RA (4 subcutaneous administration and 1 intravenous administration), 1 in patients with PsA (subcutaneous), and 1 in patients with AS (subcutaneous). In MTX-naive patients with RA, the number of patients satisfying the ACR20 response criteria (>20% improvement in ACR response rate) at 24 weeks was significantly higher for the GLM + MTX groups than for the MTX-only groups (62% vs 49%, respectively; P < 0.05). In patients with active RA despite MTX therapy, ACR20 responses at 14 to 16 weeks were significantly higher for the combined GLM + MTX groups than for the MTX groups (50%-79% vs 33%-37%, respectively; P < 0.001). GLM was more effective than placebo, both with and without MTX, in patients with RA and a history of treatment with 1 or 2 TNF-α inhibitors (ACR20 at 14 weeks, 35%-37% vs 18%, respectively; P < 0.001). Studies of other TNF-α inhibitors reported ACR20 responses in 53% to 59% of patients with active RA at 24 weeks. GLM was also more effective than placebo at 24 weeks in patients with PsA (ACR20, 52%-61% vs 12%, respectively; P < 0.001) (ASAS40 [40% improvement based on Assessment in Ankylosing Spondylitis International Working Group criteria], 44%-54% vs 15%, respectively; P < 0.001). Studies of other TNF-α inhibitors reported ACR20 responses at 24 weeks in 55% to 57% of patients with PsA and ASAS40 responses in 46% to 47% of patients with AS. The incidence of any adverse effect appeared to be comparable in the GLM (61.2%-93.9%) and placebo groups (59.3%-85.3%), but withdrawals because of adverse effects were higher in the GLM groups (0%-12.1%) than in the placebo groups (0%-5.9%). The incidence of serious infections was comparable for GLM (0%-4.4%) and placebo (0.8%-3.5%). The most frequently reported adverse effects in the GLM groups were injection-site reactions (2.7%-37.1%), nausea (2.7%-22.9%), headache (3.8%-21.2%), nasopharyngitis (1.9%-15.0%), and upper respiratory tract infections (5.7%-13.8%). CONCLUSIONS: Based on the results of the studies included in this review, GLM appeared to be more effective than placebo in patients with RA, PsA, or AS. Clinical studies have not directly compared GLM with other TNF-α inhibitors. However, according to the available efficacy and tolerability data, GLM should be considered as the first or second TNF-α inhibitor for the treatment of PsA or AS and as the second or possibly first TNF-α inhibitor in combination with MTX for the treatment of RA. | |
| 19571519 | Preliminary study to identify the predictive factors for the response to methotrexate ther | 2009 Jul | To identify the major factors predicting the response to Methotrexate (MTX) therapy in rheumatoid arthritis (RA) patients, we evaluated the relationship between the response to MTX and factors such as the concentration of MTX-polyglutamates (MTX-PGs) in erythrocytes (RBCs), genotypes of thymidylate synthase (TYMS) 5'-UTR (2R/3R) and 3'-UTR (-6/+6), 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, and other patient-related factors. Thirty-six Japanese RA patients were enrolled in this cohort study. The concentrations of MTX-PGs in RBCs were measured, and polymorphisms were determined using PCR-RFLP method. As an indicator of the accumulated capacity of MTX-PGs in the RBCs of each patient, the MTX dose/MTX-PGs (AC-MPG, l/week) was calculated. The response to MTX therapy was assessed using the MTX dose for a>or=50% decrease in CRP level (MTX dose for 50%CRP, mg/week), and the relationships between MTX dose for 50%CRP and various other factors were evaluated using multiple linear regression analysis. The MTX dose was 6.9+/-0.3 mg/week and the MTX-PGs concentration in RBCs was 97.3+/-8.1 nmol/l (n=36, blood samples=95, mean+/-S.D.). The range of MTX dose for 50%CRP was 2.0-13.0 mg/week. Most individual AC-MPG levels showed no change during the evaluation period (coefficient of variation=5.9%). Based on the results of multiple linear regression analysis, AC-MPG, TYMS 3'-UTR (-6/+6), and ESR at the start of MTX therapy were associated with the MTX dose for 50%CRP. AC-MPG, TYMS 3'-UTR (-6/+6), and ESR might be the major predictive factors for the response to MTX therapy in Japanese RA patients. | |
| 21365941 | [Adverse effects of cyclosporin a observed in rheumatoid arthritis and psoriatic arthritis | 2010 | INTRODUCTION: Rheumatoid arthritis (RA) and psoriatic arthritis (PA) represent diseases which often demand aggressive therapy in order to control the process and inhibit lesion formation in joints and organs. This kind of therapy can be achieved with cyclosporin A (CsA), particularly when combined with methotrexate (MTX). This combination is far more effective than single-drug therapy and is capable of significantly reducing the number of articular lesions. Considering the fact that monotherapy is associated with many adverse effects, it is feared that both drugs in combination may produce cumulative toxicity. The aim of this work was to determine the frequency of adverse effects caused by CsA in patients treated for RA and PA at the Outpatient Rheumatology Clinic of the First Public Hospital in Szczecin. MATERIAL AND METHODS: Our study group consisted of 61 patients, including 47 with RA--35 females, mean age 51 yrs (range: 21-69 yrs), mean disease duration 9.9 yrs (range: 2-23 yrs); 12 males, mean age 51.8 yrs (range: 33-74 yrs), mean disease duration 8 yrs (range: 3-14 yrs) and 14 with PA--6 females, mean age 41.1 yrs (range: 33-55 yrs), mean disease duration 7.8 yrs (range: 2-16 yrs); 8 males, mean age 42.9 yrs (range: 35-50 yrs), mean disease duration 7.0 yrs (range: 0.5-21 yrs). All patients were on MTX. During 11 years of follow-up, CsA was withdrawn due to adverse effects in 20 patients (32.8%). The following adverse effects were observed: arterial hypertension (n=19), hand tremor (n=11), hirsutism (n=7), elevated creatinine (n=17), gingival hypertrophy (n=9), abnormal appetite (n=2), peripheral neuropathy (n=1), lymphocytosis (n=1), skin lesions (n=1), diarrhea (n=2), recurrent infections (n=1), candidiasis (n=1), zoster (n=1), and neoplasm (n=2). Adverse effects responsible for withdrawal of CsA in 14 patients (23%) appeared more frequently during the first 12 months of therapy. Our observations indicate that CsA is well tolerated. The majority of adverse effects subsided after dose reduction or temporary withdrawal of the drug. | |
| 19402861 | Methotrexate: long-term safety and efficacy in an Australian consultant rheumatology pract | 2009 Apr | BACKGROUND: The aim of this study was to evaluate the rate and cause of methotrexate (MTX) termination in clinical practice, describe the types of toxicities noted, assess the incidence of achieving remission in rheumatoid arthritis (RA) patients and review the appropriateness of current clinical guidelines for monitoring MTX treatment. METHODS: A retrospective, case review of patients seen in a private rheumatology practice attached to a major Sydney Teaching Hospital was undertaken over an 18-year period. The primary outcome was time to cessation of MTX. RESULTS: Seven hundred and ninety patients satisfied the inclusion criteria. MTX was terminated in 272 patients (34.4%). Toxicity-related discontinuation occurred in 93 patients (11.8%) and due to non-adverse reactions in 179 patients. The median duration of therapy in these two groups was 2.0 and 2.9 years, respectively. There was no difference in the average maximum weekly dose of MTX. Of patients with RA, 47.5% were in remission at last follow up. Cox proportional hazards analyses showed that those of the female sex remained on treatment significantly longer than the male sex (hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.57-0.96; P = 0.014); patients with RA remained on treatment significantly longer than patients with seronegative arthritis (HR 0.56, 95%CI 0.42-0.74; P < 0.001). Being of the male sex aged more than 60 years and having a non-RA diagnosis predisposed to stopping MTX earlier. CONCLUSION: MTX is a safe and effective medication. Notable remission rates are achievable in patients with RA with current conventional treatment protocols. MTX has a low toxicity profile and this study stresses the need to re-evaluate and revise the current monitoring guidelines. | |
| 19248121 | Pneumocystis jiroveci pneumonia in patients with rheumatoid arthritis treated with inflixi | 2009 Mar 15 | OBJECTIVE: To establish proper management of Pneumocystis jiroveci pneumonia (PCP) in rheumatoid arthritis (RA) patients treated with infliximab. PCP has been observed in 0.4% of patients with RA treated with infliximab in Japan. METHODS: Data from patients with RA (n = 21) who were diagnosed with PCP during infliximab treatment and from 102 patients with RA who did not develop PCP during infliximab therapy were collected from 14 rheumatology referral centers in Japan. A retrospective review of these patients and a case-control study to compare patients with and without PCP were performed. RESULTS: The median length of time from the first infliximab infusion to the development of PCP was 8.5 weeks. At the onset of PCP, the median dosages of prednisolone and methotrexate were 7.5 mg/day and 8 mg/week, respectively. Pneumocystis jiroveci was microscopically identified in only 2 patients, although the polymerase chain reaction test for the organism was positive in 20 patients. The patients with PCP had significantly lower serum albumin levels (P < 0.001) and lower serum IgG levels (P < 0.001) than the patients without PCP. Computed tomography of the chest in all patients with PCP revealed ground-glass opacity either with sharp demarcation by interlobular septa or without interlobular septal boundaries. Sixteen of the 21 patients with PCP developed acute respiratory failure, but all survived. CONCLUSION: PCP is a serious complication that may occur early in the course of infliximab therapy in patients with RA. For the proper clinical management of this infectious disease, physicians need to be aware of the possibility of PCP developing during infliximab therapy. | |
| 20569501 | 74-week follow-up of safety of infliximab in patients with refractory rheumatoid arthritis | 2010 | INTRODUCTION: The objective was to describe the prevalence, types, and predictors of adverse events (AEs) in rheumatoid arthritis (RA) patients treated with infliximab and methotrexate in a daily clinical setting. METHODS: This was a prospective, multi-center, open-label, 74-week observational study in patients with active RA despite treatment with methotrexate and at least one other disease-modifying anti-rheumatic drug. Patients were treated with 3 mg/kg infliximab at weeks 0, 2, and 6 and then every 8 weeks. At weeks 0, 6, 26, 50, and 74, patients answered a health assessment questionnaire, a swollen joint count was made, and adverse events (AEs) occurring during the previous period were registered. RESULTS: Five hundred and seventy-five patients were treated with infliximab, of which 346 were still on infliximab at the study end, 158 discontinued treatment, and 71 were lost to follow-up. Reasons for discontinuation included safety (n=74), elective reasons (n=43), and inefficacy (n=41). Infusion reactions (n=33) and infections (n=20) were the most common AEs causing discontinuation and the most common AEs overall. There were four cases of tuberculosis, all of which occurred in patients negative at screening. Total AEs, serious AEs, and infusion reactions as well as discontinuations for AEs were most frequent during the first 26 weeks. Higher age was a predictor of serious adverse events (SAEs), infection, and discontinuation due to an SAE, but odds ratios were close to one. CONCLUSIONS: AEs and discontinuations due to AEs occur most frequently during the first half year of infliximab treatment in refractory RA patients. The main reasons for discontinuing treatment are infections and infusion reactions. Tuberculosis and other infections remain an important concern in these patients. | |
| 19854710 | Hepatoprotective effect of tumour necrosis factor alpha blockade in psoriatic arthritis: a | 2010 Jun | OBJECTIVE: To evaluate the impact of tumour necrosis factor alpha (TNFalpha) blockers on the presence of liver fibrosis in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with methotrexate (MTX). METHODS: Participants were consecutive patients with RA and PsA who had undergone MTX treatment for at least 1 year + or - TNF blockade for over 6 months. Liver fibrosis was assessed using non-invasive transient elastography (FibroScan). Regression models were used to compare FibroScan values of patients with RA and patients with PsA receiving TNFalpha blockers with those who were not. RESULTS: FibroScan assessments were performed on 51 patients with RA and 43 patients with PsA. Compared to patients with RA, those with PsA were predominantly young men, received lower cumulative dosages of MTX and exhibited a higher incidence of liver steatosis and hyperlipidaemia. An abnormal result was observed in 7.1% of the anti-TNFalpha-naïve and in 13% of the anti-TNFalpha-treated patients in the RA group and in 30% of the anti-TNFalpha-naïve and 4.3% of the anti-TNFalpha-treated patients in the PsA group (OR=0.11, 95% CI 0.02 to 0.98). Results of the PsA group were robust when adjusted for baseline characteristics. CONCLUSION: The results suggest a protective effect of TNFalpha inhibitors against the development of liver fibrosis in patients with PsA. | |
| 20955087 | Small-area variations in sales of TNF inhibitors in Sweden between 2000 and 2009. | 2011 Jan | OBJECTIVE: To measure small-area variations in sales per capita of tumour necrosis factor (TNF) inhibitors. METHODS: For 2000-2009, sales data on etanercept, infliximab, and adalimumab were retrieved from the Swedish National Corporation of Pharmacies, which keeps data on drugs dispensed in ambulatory care and hospitals. As points of reference, data were retrieved on all drugs, non-biologic treatments for chronic inflammatory disorders (sulfasalazine, methotrexate, azathioprine), and for a biologic used in a different therapeutic area (trastuzumab). As a corollary measure to sales per capita, penetration of biologics in the rheumatoid arthritis (RA) population was calculated using nationwide registers. Small areas were defined as the 21 counties of Sweden. RESULTS: From 2000 to 2009, annual TNF inhibitor sales increased 9-fold from 195 to 1779 million SEK (0.7-5.0% of total drug expenditure). The county variation in sales per capita, initially 6.2-fold (coefficient of variation 42%), decreased to 2.3-fold in 2009 (24%). During the same period, total drug expenditure per capita remained at a 1.2-fold county variation (4-6%). Sales per capita variations of non-biologic treatments against chronic inflammatory diseases ranged from 1.5 to 1.8 (12-16%). For trastuzumab, a 3.2-fold variation (30%) was observed in 2009. At the patient level, there was a 2-fold county variation (from 10% to 21%) in biologic penetration in RA. County-specific sales per capita were associated with mean RA duration (r = -0.52, p = 0.015) and C-reactive protein at treatment initiation (r = -0.49, p = 0.025), while pain was borderline significant (r = -0.43, p = 0.055). CONCLUSIONS: Despite universal access to treatment, substantial but decreasing small-area variations were observed. Although geographic variations are anticipated initially, their persistence calls for investigation of patient equity and treatment appropriateness as counties seem to have different initiation thresholds. | |
| 19909548 | Rapid and sustained improvements in health-related quality of life, fatigue, and other pat | 2009 | INTRODUCTION: The objective of this study was to assess the impact of certolizumab pegol (CZP) treatment on health-related quality of life (HRQoL), fatigue and other patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA). METHODS: Patients with active RA (N = 982) were randomized 2:2:1 to subcutaneous CZP (400 mg at weeks 0, 2 and 4; followed by CZP 200 mg or 400 mg) plus methotrexate (MTX) every other week, or placebo (PBO) plus MTX. PRO assessments included HRQoL, fatigue, physical function, arthritis pain and disease activity. Adjusted mean changes from baseline in all PROs were obtained using analysis of covariance (ANCOVA) applying last observation carried forward (LOCF) imputation. The proportion of patients achieving clinically meaningful improvements in each PRO was obtained using logistic regression and by applying non-responder imputation to missing values after rescue medication or withdrawal. The correlations between PRO responses and clinical responses were also assessed by tetrachoric correlation using non-responder imputation. RESULTS: Patients treated with CZP plus MTX reported significant (P < 0.001), clinically meaningful improvements in HRQoL at the first assessment (week 12); reductions in fatigue, disease activity and pain and improvements in physical function were reported at week 1. In particular, CZP-treated patients reported improvements in mental health. Mean changes from baseline in the SF-36 Mental Component Summary (MCS) at week 52 for CZP 200 mg and 400 mg plus MTX, and PBO plus MTX were 6.4, 6.4 and 2.1, respectively (P < 0.001). In addition, mental health and vitality scores in CZP-treated patients approached age- and gender-adjusted US population norms. Improvements in all PROs were sustained. Similar benefits were reported with both CZP doses. Changes in SF-36 MCS scores had the lowest correlation with disease activity scores (DAS28) and American College of Rheumatology 20% improvement (ACR20) response rates, while improvements in pain showed the highest correlation. CONCLUSIONS: Treatment with CZP plus MTX resulted in rapid and sustained improvements in all PROs, indicating that the benefits of CZP extend beyond clinical efficacy endpoints into areas that are more relevant and meaningful for patients on a daily basis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00152386. | |
| 19917435 | [Cutaneous infection due to Mycobacterium chelonae during anti-TNF therapy]. | 2009 Nov | BACKGROUND: Mycobacterium chelonae is a ubiquitous, rapidly growing, opportunistic, non-tuberculous mycobacterium that can cause skin and bone tissue infections. We report a case of cutaneous infection due to M. chelonae following anti-TNF therapy. CASE REPORT: A 70-year-old woman with a medical history of rheumatoid arthritis was admitted for several purple nodular cutaneous lesions on her right leg evolving for 2 months. At admission, she was on prednisone, methotrexate and adalimumab for her rheumatoid arthritis. Skin lesions appeared 5 days before etanercept, which was taken for 5 months before being discontinued for adalimumab. Both the histopathological examination and bacterial culture of involved skin showed the presence of M. chelonae. Adalimumab was immediately discontinued and a combination of amoxicillin-clavulanic acid and tigecyclin was started. DISCUSSION: TNF-alpha plays a pivotal role in immune reaction to intracellular pathogens. Very few cases of cutaneous infection involving M. chelonae in association with an anti-TNF-alpha therapy have been reported in the literature. To our knowledge, this is the first case occurring during treatment with etanercept and symptoms worsened with the introduction of adalimumab. In addition, this case underlines the difficulties of effectively treating this mycobacterium. | |
| 19783714 | Examination of the effect of increasing doses of etoricoxib on oral methotrexate pharmacok | 2009 Oct | The authors designed 2 randomized controlled studies to examine the effects of etoricoxib 60 to 120 mg daily on methotrexate pharmacokinetics in 50 rheumatoid arthritis (RA) patients on stable doses of methotrexate (7.5-20 mg). Patients received oral methotrexate at baseline and on days 7 and 14. In study 1, patients received etoricoxib 60 mg (days 1-7) and then 120 mg (days 8-14); in study 2, patients received etoricoxib 90 mg (days 1-7) and then 120 mg (days 8-14). For study 1, the AUC(0-infinity) geometric mean ratio (GMR) (90% confidence interval [CI]) for day 7 versus baseline was 1.01 (0.91, 1.12) for etoricoxib 60 mg; the area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) GMR (90% CI) for day 14 was 1.28 (1.15, 1.42) for etoricoxib 120 mg. For study 2, the AUC(0-infinity) GMR (90% CI) for day 7 versus baseline was 1.07 (1.01, 1.13) for etoricoxib 90 mg; the AUC(0-infinity) GMR (90% CI) for day 14 was 1.05 (0.99, 1.11) for etoricoxib 120 mg. In summary, etoricoxib 60 and 90 mg had no effect on methotrexate plasma concentrations. Although no effect on methotrexate pharmacokinetics was observed with etoricoxib 120 mg in study 2, GMR AUC(0-infinity) fell outside the prespecified bounds in study 1. Standard monitoring of methotrexate-related toxicity should be continued when etoricoxib and methotrexate are administered concurrently, especially with doses >90 mg etoricoxib. | |
| 19647103 | Tumour necrosis factor antagonist therapy and cancer development: analysis of the LORHEN r | 2010 Jan | OBJECTIVE: The objective was to compare cancer risk in a RA cohort population treated with TNF antagonists, and identify the characteristics of the patients at higher risk. METHODS: The study involved 1114 RA patients treated with anti-TNF agents after failing to respond to traditional DMARDs, 1064 of whom were evaluable for adverse events over an average observational period of 23.32 months. The relative cancer risks (expressed as hazard ratios) in the anti-TNF treated patients were estimated using univariate and multivariate analyses. The rate of cancer in this cohort was compared with that in the general population using data from the Varese and Milan Cancer Report. RESULTS: There were 18 incident cases (1.7%), 4 of which involved lymphomas. Comparison with the general population showed that the overall cancer risk was similar, but the risk of lymphoma was about five times higher in the RA patients treated with a biological agent. Higher RR were found in males (HR 4.95, 95% CI 1.97-12.48; p=0.001) and patients aged >65 years (HR 2.72, 95% CI 1.08-6.84; p=0.034); combined therapy with methotrexate seemed to be protective (HR 0.31, 95% CI 0.11-0.87; p=0.026). CONCLUSION: The overall cancer risk in RA patients treated with anti-TNF seemed to be similar to that in the general population in the same geographical area, but the risk of haematological cancer was significantly greater. The demographic and clinical factors associated with a higher risk of cancer in our cohort were male gender and an age of >65 years. | |
| 19840317 | Nodulosis in systemic onset juvenile idiopathic arthritis: an uncommon event with spontane | 2009 Sep | Accelerated nodulosis is a rare complication of methotrexate therapy in juvenile idiopathic arthritis. When nodulosis does occur in patients with juvenile idiopathic arthritis on methotrexate, it is almost always seen in patients with polyarthritis with rheumatoid factor seropositivity, but only occasionally in polyarthritis patients who are rheumatoid factor negative. It has been described previously in only one patient with systemic arthritis. In this study, we describe three patients with systemic arthritis, all of whom developed nodulosis while receiving methotrexate. Interestingly, it was not necessary to discontinue methotrexate in any of these patients. In fact, methotrexate dose was escalated without consequences and with complete resolution of nodules. This observation suggests that nodulosis occurring in patients with systemic arthritis already on methotrexate may not be because of methotrexate itself, but may be a component of the disease process. The other likely possibility given the fact that nodulosis occurs with other immunomodulatory agents and is not specifically related to methotrexate is that immunomodulatory agents in general precipitate the development of nodulosis. Thus, we propose that the new terminology "immunomodulatory agents induced nodulosis" rather than "methotrexate-induced nodulosis" be used in the literature. | |
| 20100913 | A proof-of-concept and drug-drug interaction study of pamapimod, a novel p38 MAP kinase in | 2010 Sep | This study evaluated the potential pharmacokinetic interaction of pamapimod, a p38 mitogen-activated protein kinase inhibitor, and methotrexate (MTX) when administered concomitantly in patients with rheumatoid arthritis (RA); the study also evaluated the pharmacodynamic effects of pamapimod. Twenty-two RA patients on a stable regimen of MTX (10-25 mg/wk; administered on days 1 and 8) were randomized to receive 300 mg of pamapimod (n = 17) or placebo (n = 5) once daily (qd) for 10 days (days 5-14). Blood and urine samples were collected pre- and postdose on days 1 (MTX alone), 7 (pamapimod alone), and 8 (MTX and pamapimod coadministered). No clinically significant changes were observed in plasma exposures and renal clearance of pamapimod, MTX, or their metabolites, whether administered separately or concomitantly. The combination of pamapimod (300 mg qd) for 10 days and weekly MTX was generally well tolerated. Parameters of RA disease--namely, tender joint count, swollen joint count, erythrocyte sedimentation rate, and C-reactive protein--generally decreased between days 5 and 14. The results of this study suggest that dose adjustments for either drug are not necessary when concomitantly administered and that pamapimod can decrease pharmacodynamic markers of disease activity. | |
| 20713496 | Red blood cell methotrexate polyglutamates emerge as a function of dosage intensity and ro | 2010 Dec | OBJECTIVE: MTX is a prodrug producing anti-arthritic effects through a folylpolyglutamate synthase-mediated activation to MTX polyglutamates (MTXPGs). Our objective was to characterize the pharmacokinetics of intracellular MTXPGs and the factors associated with their accumulation in adult RA patients treated with MTX weekly. METHODS: MTX pharmacokinetics were evaluated in 47 MTX-naïve patients enrolled in an MTX dose-escalation study for an average of 20 weeks and 223 patients enrolled in a cross-sectional study under long-term MTX therapy. Short-chain (MTXPG1-2), long-chain (MTXPG3) and very long-chain (MTXPG4-5) concentrations were measured in circulating red blood cells using liquid chromatography. Statistical analyses consisted of non-linear mixed models, multivariate regression analyses and Wilcoxon signed-rank test. RESULTS: The accumulation of MTXPG1-5 was sigmoidal and steady-state concentrations were achieved after 7 weeks of therapy. However, additional exposure and MTX dosage escalation produced a selective redistribution towards longer chain MTXPGs at the expense of shorter chain MTXPGs. Age, glomerular filtration rate and route of MTX administration were the most important predictors of MTXPG accumulation. In 10 patients, a switch from oral to parenteral MTX was associated with a 37% increase in long-chain MTXPGs, a 132% increase in very long-chain MTXPGs and a concomitant 31% reduction in disease activity (P<0.02). CONCLUSION: The selective emergence of long-chain MTXPGs is function of dose, time of exposure and hence dosage intensity. Switching from oral to parenteral MTX produces a selective accumulation of longer chain MTXPGs that are known to be more potent inhibitors of de novo purine biosynthesis than shorter chain MTXPGs. | |
| 19153737 | Adding low dose tacrolimus in rheumatoid arthritis patients with an inadequate response to | 2009 Sep | In the present study, we retrospectively evaluate the efficacy of low dose tacrolimus (TAC) as add-on therapy in refractory rheumatoid arthritis (RA) despite a combination of tumor necrosis factor (TNF) inhibitor and methotrexate (MTX) using consecutive case series of five patients with active RA (mean disease duration 2.3 years) despite MTX and TNF inhibitors for at least 3 months (mean 9.5 months) treated with low dose TAC (1.5-2 mg/day) for at least 6 months (mean 1.8 years). Clinical and radiographic efficacy was assessed according to the European league against rheumatism response criteria and the modified Sharp method, respectively. At 1 year, three patients reached to remission. The mean yearly progression of radiographic joint damage of all five patients after the onset of TAC was significantly decreased compared to that observed during anti-TNF therapy without TAC (p = 0.04). One patient temporally discontinued the treatment because of herpes zoster. In RA patients with inadequate response to MTX and a TNF inhibitor, additions of low dose TAC markedly improved clinical variables including radiographic scores without remarkable detrimental effects. It seems that TAC in combination with MTX and TNF inhibitors may be a hopeful treatment option for RA patients with inadequate response to anti-TNF therapy. | |
| 19147616 | Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthriti | 2010 Jan | INTRODUCTION: Potential hepatotoxicity associated with disease-modifying antirheumatic drugs (DMARDs) requires laboratory monitoring. In patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA), the incidence of elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) enzymes associated with methotrexate (MTX), leflunomide (LEF) and MTX+LEF versus other DMARDs was examined. METHODS: Patients with RA and PsA enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) initiating DMARDs were identified. Abnormalities were identified when either was 1- or 2-fold times above the upper limits of normal (ULN). Odds ratios (OR) between MTX/LEF dose and elevated ALT/AST enzymes were estimated using generalised estimating equations. Interaction terms for use of MTX+LEF quantified the incremental risk of the combination compared with each individually. RESULTS: Elevated ALT/AST levels (>1x ULN) occurred in 22%, 17%, 31% and 14% of patients with RA receiving MTX, LEF, MTX+LEF or neither, respectively; elevations were 2.76-fold (95% CI 1.84 to 4.15) more likely in patients with PsA. Elevations >2x ULN occurred in 1-2% of patients on MTX or LEF monotherapy compared with 5% with the combination. After multivariable adjustment and compared with either monotherapy, the combination of MTX and LEF was associated with a greater risk according to MTX dose used as part of the combination: MTX 10-17.5 mg/week, OR 2.91 (95% CI 1.23 to 6.90); MTX > or =20 mg/week, OR 3.98 (95% CI 1.72 to 9.24). CONCLUSIONS: Abnormal ALT/AST levels developed in 14-35% of patients with RA or PsA initiating DMARD therapy. The risks were incrementally greater in those with PsA and in those receiving MTX (> or =10 mg/day) + LEF. These findings should help inform monitoring for potential hepatotoxicity in these patient populations. | |
| 20448284 | Risk of elevated liver enzymes associated with TNF inhibitor utilisation in patients with | 2010 Sep | OBJECTIVE: Liver function test (LFT) elevations are reported with the use of tumour necrosis factor inhibitors (TNF-Is). The aim of this study was to compare LFT elevations in patients with rheumatoid arthritis receiving adalimumab (ADA), etanercept (ETN) or infliximab (INF) enrolled in the Consortium of Rheumatology Researchers of North America from October 2001 to March 2007. METHODS: Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels >1x upper limit of normal (ULN) were considered elevations and ALT/AST levels >2x ULN were considered abnormalities. Treatments included TNF-Is, methotrexate (MTX), leflunomide and other disease-modifying antirheumatic agents (DMARDs). Patients were censored after their first LFT elevation. Three analytical models were evaluated: (1) individual TNF-I vs non-biological DMARDs (primary model); (2) individual TNF-I plus MTX vs MTX monotherapy; and (3) limited to new users of individual TNF-I vs non-biological DMARDs. ORs for LFT elevations were estimated using generalised estimating equation logistic regression. RESULTS: 6861 patients (ADA: 849; ETN: 1383; INF: 1449) with 22 522 determinations were analysed. LFT elevations >1x ULN with TNF-I use were seen in 5.9% of AST/ALT determinations and abnormalities >2x ULN in 0.77%. In the primary model the adjusted ORs for LFT elevations >1x ULN were ADA 1.35 (95% CI 1.09 to 1.66), ETN 1.00 (95% CI 0.83 to 1.21) and INF 1.58 (95% CI 1.35 to 1.86). For 2x ULN, adjusted ORs were ADA 1.72 (95% CI 0.99 to 3.01), ETN 1.10 (95% CI 0.64 to 1.88) and INF 2.40 (95% CI 1.53 to 3.76). Similar results were obtained in other models. CONCLUSION: The overall incidence of LFT elevations >1x ULN with TNF-I use was uncommon and abnormalities >2x ULN were rarely observed. Significant differences were most consistently observed with INF, less commonly with ADA and were not observed with ETN compared with comparator DMARDs. | |
| 21161534 | Causes of DMARD withdrawal following ADR within 6 months of initiation among Indian rheuma | 2012 Mar | The present study was conducted in Indian rheumatoid arthritis (RA) patients prescribed disease-modifying anti-rheumatic drugs (DMARDs) to determine the incidence and type of adverse drug reactions (ADRs) leading to their withdrawal in the initial 6 months of therapy. This was considered important as pharmacogenetic variations in the pattern of RA in different populations and genetic differences in efficacy and safety to drugs demand separate studies to be conducted in different populations. Hospital records were used to identify 1,000 consecutive patients with RA fulfilling the American College of Rheumatology criteria and having at least 6-month follow-up. Age, gender, duration of arthritis, drug usage and ADR-related drug withdrawal were recorded from the charts. Most of the patients were put on single DMARD. Combined use of DMARD was less frequent and non-use of DMARD was common; however, disease control was good. The commonest DMARD used in our hospital was hydroxychloroquine 444 (44%) and the commonest combination used was methotrexate with hydroxychloroquine by 55 (6%). Sulphasalazine use showed preference to young and males. Supportive drugs used were NSAIDs by 883 (88%), corticosteroids by 646 (65%), paracetamol by 594 (59%) and amitriptyline by 88 (9%). Incidence of ADR-related DMARD withdrawal was maximum with leflunomide 2/15 (13.33%) followed by methotrexate 9/116 (7.76%), sulphasalazine 6/185 (3.24%), chloroquine 3/131 (2.29%) and hydroxychloroquine 8/444 (1.8%). Severity and symptomatology of disease, genetic pattern of patients, financial status, previous experience of the clinicians and patients, availability of drugs, patient expectations and compliance were the main factors that lead to a difference in pattern of therapy in our patients compared to other population. |