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ID PMID Title PublicationDate abstract
16705046 Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: 2006 Dec BACKGROUND: Anti-tumour necrosis factor-alpha (TNF-alpha) therapies represent an important advancement in therapy for rheumatoid arthritis (RA). However, there remains a proportion of patients who do not improve despite therapy. These drugs are expensive and have the potential of serious toxicity. Therefore, it would be ideal to predict the patients who will respond, so that the use of these drugs can be targetted. OBJECTIVE: To identify the clinical factors present at the start of anti-TNF-alpha therapy that are associated with response at 6 months in patients with RA. METHODS: The British Society for Rheumatology (BSR) Biologics Register collects detailed data on all patients with a rheumatic disease receiving biologic therapy in the UK. We studied all patients with RA who had started etanercept (ETA) or infliximab (INF) and had achieved a minimum 6 months follow-up by 1 October, 2004. The disease status at the baseline and at 6 months was assessed using the Disease Activity Score (DAS28). The response was classified according to the European League against Rheumatism (EULAR) improvement criteria. The effect of baseline characteristics on response was studied using multivariate ordinal logistic regression. RESULTS: 2879 patients were included in this analysis (1267 ETA, 1612 INF). At the start of therapy, the mean age was 55 yrs, disease duration 14 yrs, baseline DAS28 6.7 and health assessment questionnaire (HAQ) 2.1. In all, 28% of ETA and 86% of INF patients were receiving methotrexate. After 6 months, 18% had a good EULAR response, of whom 9% were considered to be in remission and 50% had a moderate response. There was no overall difference in response rate between the two anti-TNF-alpha therapies. A higher baseline HAQ score correlated with a lower response rate while a better response was associated with the current use of NSAIDs and the use of methotrexate (MTX), although the latter only reached statistical significance with ETA [OR 1.82 (95% CI 1.38-2.40)]. There was a lower response rate among current smokers, particularly in patients receiving INF [OR 0.77 (95% CI 0.60-0.99)]. Age, disease duration, rheumatoid factor and the previous number of disease-modifying antirheumatic drugs (DMARDs) did not predict response to either drug. However, females were less likely to achieve remission. CONCLUSIONS: These data support an improved outcome among patients receiving MTX in combination with anti-TNF-alpha therapies. However, the most disabled patients were less likely to respond, despite concurrent MTX. The benefits of NSAIDs may reflect the relative absence of comorbidities in patients who can tolerate these drugs or the continuing presence of reversible inflammatory symptoms. The association of smoking and poor outcome with INF is a novel finding and may reflect alterations in pharmacokinetics. The inability of other baseline disease characteristics to predict the outcome suggests that other factors, including potential genetic differences in drug metabolism, may be influencing the response to anti-TNF-alpha therapies.
16997599 Use of tumor necrosis factor inhibitors in rheumatoid arthritis: a national survey of prac 2006 Dec OBJECTIVES: To determine the prescribing practices, laboratory monitoring protocols, and perceived barriers of United States rheumatologists in prescribing tumor necrosis factor (TNF) inhibitors in rheumatoid arthritis (RA). METHODS: A survey questionnaire was mailed to 1970 rheumatologists who were randomly selected from a national sample of 3008 rheumatologists. A one-page non-response questionnaire was mailed to approximately 200 randomly selected non-responding rheumatologists to assess non-response bias. RESULTS: Two mailings yielded a response rate of 22.3% (428 completed, usable surveys out of 1922 deliverable surveys). Rheumatologists reported using all three agents in patients with moderate RA (82-87%), severe RA (94-96%), and in newly diagnosed and mild RA patients (10-18%). In patients with severe RA who inadequately responded to methotrexate, 91% of rheumatologists reported using a TNF inhibitor with one other disease modifying anti-rheumatic drug. Over 94% of rheumatologists reported switching patients from one TNF inhibitor to a different TNF inhibitor due to inadequate response or side effects. Most rheumatologists (96%) ordered the purified protein derivative test for tuberculosis, with almost 82% conducting this test at baseline. Costs to patients and insurance coverage were perceived as major barriers to prescribing these agents although the perception was slightly lower with infliximab than with adalimumab or etanercept. CONCLUSIONS: The use of TNF inhibitors is not restricted to patients with moderate and severe RA. Rheumatologists are fairly similar in their utilization of the three TNF inhibitors although some variation exists in terms of laboratory practices and perceived barriers regarding the use of these agents.
17847113 Effect of infliximab on the glycosylation of IgG of patients with rheumatoid arthritis. 2007 In patients with rheumatoid arthritis (RA) a decrease in the terminal galactose content of N-linked glycans of the Fc region of agalactosyl immunoglobulin G (IgG) (G0) occurs. The aim of this study was to evaluate, for the first time, the effect of infliximab, a new monoclonal antibody for the treatment of RA, on this phenomenon. A total of 19 patients with active RA were treated with intravenous infliximab (3 mg/kg) in combination with methotrexate (MTX) (10-20 mg). IgG was purified from their serum by caprylic acid. Analysis of IgG glycosylation was performed by lectin blotting/immunoblotting and enzyme linked lectin assay (ELLA)/enzyme linked immunosorbent assay (ELISA) using the Griffonia (bandeiraea) simplicifolia lectin II and protein-A/alkaline phosphatase. The purity of IgG samples obtained was higher than 90%. The sensitivity of the lectin/immunoblotting method was of about 0.25 microg of IgG. The inter- and intraassay coefficients of variation (CV) were 1.3% and 9.0% for lectin blotting, and 4.6% and 8.3% for immunoblotting, respectively. The sensitivity of the ELLA/ELISA approach was 0.025 microg/microL and the inter- and intraassay CV were 6.2% and 7.7% for ELLA, and 5.1% and 14.1% for ELISA, respectively. A good linear correlation (r2=0.18, P<0.05) was obtained between the two different experimental approaches. A decrease of G0 was observed in patients who clinically improved (according to the American College of Rheumatology criteria) following the pharmacological treatment. Our data indicate that infliximab can reduce the concentration of G0 in patients with active RA.
16874796 Antirheumatic drug use and the risk of acute myocardial infarction. 2006 Aug 15 OBJECTIVE: To assess the risk of acute myocardial infarction (AMI) associated with the use of disease-modifying antirheumatic drugs (DMARDs) and other medications commonly used in rheumatoid arthritis (RA). METHODS: We conducted a nested case-control analysis within a cohort of subjects with RA, observed between 1999 and 2003, identified from the PharMetrics claims database. For each first AMI hospitalization identified during followup, 10 controls matched on sex, age, and time of study entry were randomly selected from the cohort. Conditional logistic regression was used to estimate the rate ratio (RR) of AMI associated with the current use of anti-RA therapy, as measured from dispensed prescriptions, after adjustment for AMI risk factors. RESULTS: The cohort included 107,908 subjects (average age 54 years at cohort entry). During followup, 558 AMI cases occurred (3.4 per 1,000 per year). AMI rate was significantly decreased with the current use of any DMARD (adjusted RR 0.80, 95% confidence interval [95% CI] 0.65-0.98). This effect was consistent across all DMARDs, including methotrexate (RR 0.81, 95% CI 0.60-1.08), leflunomide (RR 0.28, 95% CI 0.12-0.65), and other traditional DMARDs (RR 0.67, 95% CI 0.46-0.97), but not biologic agents (RR 1.30, 95% CI 0.92-1.83). AMI rate increased with the use of glucocorticoids (RR 1.32, 95% CI 1.02-1.72) but not with nonselective nonsteroidal antiinflammatory drugs (RR 1.05, 95% CI 0.81-1.36) or cyclooxygenase 2 (COX-2) inhibitors (RR 1.11, 95% CI 0.87-1.43). CONCLUSION: DMARD use is associated with a reduction in AMI risk in patients with RA. No risk increase was found with the COX-2 inhibitors in this population.
17121678 Impact of concomitant DMARD therapy on adherence to treatment with etanercept and inflixim 2006 The objective of this work is to compare the adherence to therapy of patients receiving etanercept and infliximab during first tumour necrosis factor (TNF)-blocking treatment course in rheumatoid arthritis. Special emphasis is placed on potential predictors for treatment termination and the impact of concomitant methotrexate (MTX) or other disease-modifying antirheumatic drugs (DMARDs). Patients (n = 1,161) with active rheumatoid arthritis, not responding to at least two DMARDs including MTX starting etanercept or infliximab therapy for the first time, were included in a structured clinical follow-up protocol. Information on diagnosis, disease duration, previous and ongoing DMARDs, treatment start and termination, as well as cause of withdrawal was prospectively collected during the period of March 1999 through December 2004. Patients were divided into six groups according to TNF-blocking drugs and concomitant DMARDs. Five-year level (one-year) of adherence to therapy was 36% (69%) for patients receiving infliximab in combination with MTX compared with 65% (89%) for patients treated with etanercept and MTX (p < 0.001). Cox regression models showed that the risk for premature treatment termination of patients treated with infliximab was threefold higher than for etanercept (p < 0.001). Also, the regression analysis showed that patients receiving concomitant MTX had better treatment continuation than patients treated solely with TNF blockers (p < 0.001). Moreover, patients receiving concomitant MTX had superior drug survival than patients receiving other concomitant DMARDs (p < 0.010). The superior effect of MTX was associated primarily with fewer treatment terminations because of adverse events. In addition, the study identifies low C-reactive protein level, high age, elevated health assessment questionnaire score, and higher previous number of DMARDs as predictors of premature treatment termination. In summary, treatment with etanercept has higher adherence to therapy than treatment with infliximab. Concomitant MTX is associated with improved treatment continuation of biologics when compared with both TNF blockers as monotherapy and TNF blockers combined with other DMARDs.
16430744 Oral tuberculosis associated with a treatment with anti-rheumatic drugs. 2006 Feb BACKGROUND: The use of immunosuppressive medication is a dominant risk factor for infection in patients with rheumatoid arthritis (RA). Methotrexate (MTX) is one of the traditional disease-modifying antirheumatic drugs. Adalimumab [a human anti-tumor necrosis factor-alpha (anti-TNF-alpha) monoclonal antibody] represent an important advance in the treatment of RA and has been recently come in use. TNF-alpha plays a role in the host defense against Mycobacterium tuberculosis and notably in granuloma formation. Infections occur at a high rate among those who use one or the combination of the two medications. METHOD: We examined a female patient that was referred to our department for evaluation and treatment of a granular lesion on the soft palate and uvula, complaining of mild dysphagia. The patient was treated for 4 months with MTX and adalimumab for RA before the oral lesion appeared. RESULTS: The histopathological examination of a specimen of the oral lesion, taken by biopsy, showed a chronic inflammation characterized by tuberculous granulomas. Polymerase chain reaction test and culture of a new specimen was positive for M. tuberculosis. CONCLUSIONS: The therapeutic use of MTX or/and adalimumab for the treatment of RA or few others diseases, can cause oral tuberculosis.
18945303 Effect of folic or folinic acid supplementation on methotrexate-associated safety and effi 2009 Mar BACKGROUND: Methotrexate is a folic acid antagonist widely used for the treatment of inflammatory disorders for more than 50 years. Methotrexate is a standard systemic therapy for severe psoriasis and rheumatoid arthritis. Folic acid supplementation has been advocated to limit the toxicity of methotrexate on blood cells, gastrointestinal tract and liver. However, there is still controversy regarding the usefulness of folic acid supplementation. OBJECTIVES: We sought to assess the evidence for the efficacy of folic acid supplementation in patients treated with methotrexate for inflammatory diseases. We also investigated whether folic acid supplementation may decrease the efficacy of methotrexate. METHODS: Cochrane and MEDLINE databases were systematically searched. Randomized controlled trials in patients treated with methotrexate for rheumatoid arthritis or psoriasis with or without arthritis were included. Study selection, assessment of methodological quality, data extraction and analysis were carried out by two independent researchers. We selected double-blind randomized placebo-controlled trials. Analysis was performed for each subgroup of side-effects: gastrointestinal, mucocutaneous, haematological and hepatic. RESULTS: Six randomized controlled trials met the inclusion criteria, with a total sample of 648 patients. There were 257 patients in the placebo group, 198 patients treated with folic acid, and 193 patients treated with folinic acid. The statistical analysis showed a significant reduction of 35.8% of hepatic side-effects induced by methotrexate for patients with supplementation with folic or folinic acid (95% confidence interval -0.467 to -0.248). There was no statistical difference for mucocutaneous and gastrointestinal side-effects although there was a trend in favour of supplementation. The effect of supplementation on haematological side-effects could not be assessed accurately due to a low incidence of these events in the population studied. We were unable to analyse the effect of supplementation on the effectiveness of methotrexate, as markers of activity used in each study were not comparable. CONCLUSIONS: Supplementation with folic acid is an effective measure to reduce hepatic adverse effects associated with methotrexate treatment. There is no difference between folinic acid and folic acid, but the lower cost of the latter promotes its use.
16679432 Adalimumab and methotrexate is more effective than adalimumab alone in patients with estab 2006 Oct OBJECTIVES: To compare the effectiveness of adalimumab monotherapy and adalimumab and methotrexate (MTX) combination therapy in patients with established rheumatoid arthritis. METHODS: Data from an ongoing longitudinal observational study in Norway were used to compare response to treatment with two different adalimumab regimens (monotherapy, n = 84; combination with MTX, n = 99). Patients were assessed with measures of disease activity, health status and utility scores. Within-group changes were analysed from baseline to follow-up at 3 and 6 months and the changes were compared between groups after adjustment for the propensity score. The groups were also compared for the proportions of patients achieving European League Against Rheumatism (EULAR) good response, Disease Activity Score (DAS)28 remission and treatment terminations. RESULTS: The improvement from baseline was significant for all measures in the adalimumab and MTX group, but only for DAS28, joint counts, two Short-form Health Survey with 36 questions (SF-36) dimensions and patient's and investigator's global assessment in the monotherapy group. All between-group differences were numerically in favour of combination therapy and significant for C reactive protein, joint counts, DAS28, Modified Health Assessment Questionnaire, investigator's global assessment, four SF-36 dimensions and Short Form 6D at 6 months. More patients in the combination therapy group reached EULAR good response (p<0.001) and remission (p = 0.07). At 6 months, 80.8% of the patients in the combination therapy group and 59.5% in the monotherapy group remained on treatment (p = 0.002). More withdrawals in the monotherapy group were due to adverse events. CONCLUSIONS: Our results were consistent across several categories of end points and suggest that adalimumab combined with MTX is effective in patients with rheumatoid arthritis treated in daily clinical practice and is superior to adalimumab monotherapy.
16890029 Method for the determination of blood methotrexate by high performance liquid chromatograp 2007 Jan 1 Methotrexate (MTX) has been widely used at low dose for the treatment of different diseases including rheumatoid arthritis. MTX might be present in plasma in free form, and in blood cells in methotrexate polyglutamate (MTXPG). A rapid and sensitive HPLC method was developed for the determination of plasma MTX level, whole-blood MTX level, and whole-blood total MTX (MTX+MTXPG) level. To determine plasma MTX level or whole-blood MTX level, a 0.2-ml aliquot of plasma or whole blood (after a freeze-thaw cycle to break blood cells) was well mixed with 0.8 ml methanol and centrifuged. To determine whole-blood total MTX level, a 0.1-ml aliquot of whole blood (after a freeze-thaw cycle) was mixed with 80 microl ascorbic acid (114 mM) and incubated at 37 degrees C for 2h to enzymatically convert the MTXPG to MTX. Then 20 microl NaOH solution (0.5M) and 0.8 ml methanol were added and mixed well. After centrifugation, a 0.5-ml aliquot of the supernatant was evaporated to dryness and re-dissolved in 0.2 ml hydrochloric acid (10mM). Methylene chloride (0.2 ml) was added and mixed well. After centrifugation, the top aqueous layer was injected to HPLC for analysis. After the MTX was eluted from the HPLC column, it was electrochemically oxidized and detected by a fluorescence detector. Recoveries of spiked MTX at ppb (ng/ml) level were between 87.9 and 118% with within-day relative standard deviation less than 5.2% and day-to-day relative standard deviation less than 9.8%. The limit of detection (LOD) and limit of quantitation (LOQ) of the described method were 1.2 and 2.6 ng/ml, respectively.
18050387 Requirement of methotrexate in combination with anti-tumor necrosis factor-alpha therapy f 2007 Dec OBJECTIVE: To determine that concomitant use of methotrexate (MTX) is required to achieve adequate suppression of bone destruction in treating rheumatoid arthritis (RA) with tumor necrosis factor-alpha (TNF-alpha)-inhibiting biologic therapy. We quantitatively compared the suppressive effects of treatment with a combination of infliximab and MTX and treatment with each of these 2 agents alone on bone destruction in SCID-HuRAg-pit mice. METHODS: Tissue derived from human RA pannus was implanted with a slice of dentin subcutaneously in the backs of SCID mice (SCID-HuRAg-pit model). Infliximab was administered daily to SCID-HuRAg-pit mice using an osmotic pump for 2 weeks with or without oral administration of MTX. Histological changes in tissue and the pits formed on the dentin slice were examined 8 weeks after transplant. Serum concentrations of TNF-alpha and interleukin 6 (IL-6) were also measured. RESULTS: Treatment with a combination of infliximab and MTX suppressed pit formation significantly, while treatment with neither infliximab alone nor MTX alone had a significant effect on pit formation. Synovial inflammation and serum TNF-alpha and IL-6 levels were suppressed by infliximab with or without MTX. CONCLUSION: This is the first evidence in an animal model of arthritis that concomitant use of MTX is required to achieve adequate suppression of bone destruction when treating RA with a TNF-alpha-inhibiting biologic. Our findings suggest that infliximab suppresses bone destruction through a mechanism of action different from that mediating its antiinflammatory effects in the treatment of RA.
17284392 [Therapeutic maintenance level of methotrexate in rheumatoid arthritis]. 2006 Jul OBJECTIVES: To determine the probability of drug continuation, the reasons for discontinuation of methotrexate (MTX), and risk factors of treatment termination in rheumatoid arthritis. MATERIALS AND METHODS: Retrospective cohort study of a 100 case follow-up between 1983 and 2003, all treated with MTX. Factors associated with toxicity, and efficacy of MTX were studied. Logistic regression was used to study the relation between baseline variables and various dependent factors. RESULTS: Eighty three women and seventeen men were included in this study. The mean age at commencement of MTX was 45+/-13.7 (18-81) years. The mean duration of disease was 9.5+/-8.7 (0.25-40) years. The mean weekly dose of MTX was 9.8+/-3.4 mg/week. The therapeutic maintenance level of MTX was 76% at one year, 63% at 2 years and 45% at 5 years. The median of treatment duration was 10 (0. 5-40) months. Reasons for patients stopping MTX were: Adverse effects (15), lack of effect (1), non medical reasons (14) essentially because of financial difficulties. Baseline white blood cell counts >9 giga/mm3 (RR: 3.17) [95 %:1.03-9.74] (p=0.04) and baseline serum creatinine level >72 micromol/L (RR: 8.6) [95 %:1.04-71.17] (p=0.04) were associated with an increased risk of treatment termination. CONCLUSION: The continuation rate of methotrexate in our study was good, despite the poor compliance with the treatment due to financial difficulties.
16914096 Altered production of IFN-gamma? And other inflammation-related cytokines by mycobacteria- 2006 May 15 Peripheral blood mononuclear cells taken from 32 patients with Rheumatoid Arthritis (RA) receiving neither steroids nor methotrexate and 34 healthy controls were examined for lymphoproliferation in the presence of ultrasonic extracts of 14 different mycobacterial species or serotypes, of an extract of Candida albicans and of 2 mitogens. Additionally, cells were incubated for 96 hours alone, or with Mycobacterium tuberculosis (M.tb) sonicate or Concanavalin-A (Con-A), and supernatants were tested for a range of cytokines. Lymphocytes of rheumatoid patients were less reactive than controls to all the mycobacterial preparations, but no different in their responses to mitogens. Stimulation of patients' cells with M.tb sonicate induced significantly less interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) but more transforming growth factor- beta (TGF-beta) than controls. Even stimulation with Con-A induced much less IFN-gamma in patient's cells than in those of controls. The combination of reduced responses to the mycobacterial reagents and reduced stimulation of type 1 cytokines by the sonicate of M.tb, suggests reduced responsiveness to group i, common mycobacterial antigens. Such findings need not indicate involvement of mycobacteria specifically in the disease aetiology, but provide novel information on the immunopathological abnormalities, which may explain the reported increased susceptibility to mycobacteria of RA patients.
16501834 Malignant lymphoma in patients with systemic rheumatic disease (rheumatoid arthritis, syst 2006 Jan We conducted clinicopathologic and immunohistochemical analyses of the prevalence of Epstein-Barr virus (EBV) among 24 patients with malignant lymphoma complicating systemic rheumatic diseases. (SRD) These 24 patients included 17 with rheumatoid arthritis (RA), 3 with systemic lupus erythematosus (SLE), 2 with systemic sclerosis (SS), and 2 with dermatomyositis (DM). There were 2 men and 22 women ranging in age from 30 to 86 years (mean: 64 years). The interval between the onset of rheumatic disease and that of malignant lymphomas ranged from 3 months to 35 years (mean: 142 months). The use of immunosuppressive drugs before the onset of malignant lymphoma was recorded in 15 patients. Among them, 5 patients received methotrexate (MTX) therapy. Malignant lymphomas were found at extranodal sites in 9 patients, and the disease was in the advanced stage in 17 patients. Histologic and immunohistochemical studies demonstrated that 18 cases (75%) were B-cell lymphoma (RA=12, SLE=2, SS=2, DM=2), 3 (12.5%) were peripheral T-cell lymphoma (RA=3), and 3 (12.5%) were classical Hodgkin lymphoma (RA=2, SLE=1). As in previous reports, there was an increased frequency of diffuse large B-cell lymphoma (50%) in the present series. Moreover, a majority of the diffuse large B-cell lymphomas exhibited activated B-cell phenotype. EBV-encoded small RNAs (Epstein-Barr early region [EBER]-) and/or LMP-1+tumor cells were identified in only 3 cases of classical Hodgkin lymphomas. Our findings suggested EBV-associated lymphoma comprised only a small fraction of all non-Hodgkin's lymphomas in the general SRD patient population.
17357801 Massive myelinolytic leukoencephalopathy in a patient medicated with low-dose oral methotr 2007 Oct The authors describe a 68-year-old female who developed a rapidly progressing leukoencephalopathy involving the cerebrum and brain stem. The disease appeared during low-dose oral methotrexate (MTX) therapy for rheumatoid arthritis. An extensive clinical investigation discounted other possible causes of white matter lesions. Autopsy identified an uninterrupted severe demyelinating, partially liquefactive necrosis-like lesion in the white matter accompanied by astrogliosis and occasional swollen axons therein. The lesion was generally symmetrical, and distributed throughout the whole cerebral white matter except for the bilateral temporal lobes and the rostral part of the frontal lobes. The internal capsules and cerebral peduncles were spongy, and the central and lateral parts of the pons, especially the transverse cerebellopontine tracts, were affected similarly. It was of note that the lesion was accompanied by neither vascular diseases nor lymphocyte infiltration. Thus, the pathological findings were similar to those of a severe form of central and extrapontine myelinolysis, and clearly different from ordinary MTX leukoencephalopathy reported in patients receiving intrathecal or intravenous MTX therapy, known as "disseminated necrotizing leukoencephalopathy". Another possibility is that synergistic effects of several white-matter-damaging disorders may have contributed to the hitherto unknown lesion. To our knowledge, this is the first autopsy record that describes an oral MTX-associated neurological disorder.
17766699 Rituximab pharmacokinetics in patients with rheumatoid arthritis: B-cell levels do not cor 2007 Sep This study characterized the relationship between clinical response, serum rituximab concentrations, and peripheral B-cell levels in patients with rheumatoid arthritis treated with rituximab. Data were analyzed from a double-blind, phase IIa trial in which 161 patients with active rheumatoid arthritis despite continuing methotrexate were randomized to methotrexate alone (10-25 mg/wk), rituximab alone (single course: 1000 mg administered intravenously on days 1 and 15), rituximab plus cyclophosphamide (750 mg administered intravenously on days 3 and 17), or rituximab plus methotrexate. Serum samples for pharmacokinetic analysis were collected through 24 weeks, and peripheral circulating CD19+ B-cell levels were measured through 48 weeks. All treatments were generally well tolerated, with no clinically relevant excess of adverse events leading to withdrawal among patients who received rituximab compared with those who received methotrexate alone. The proportions of patients who achieved an American College of Rheumatology score of 50 at week 24 were 13% (methotrexate alone), 33% (rituximab alone), 41% (rituximab plus cyclophosphamide), and 43% (rituximab plus methotrexate). Peripheral B-cell depletion occurred by day 15 in all patients treated with rituximab. There was no relationship between B-cell depletion and clinical response. Recovery of peripheral B cells was variable and showed no relationship with return of disease activity in patients who responded to rituximab. The mean terminal half-life of rituximab was 19 to 22 days; pharmacokinetic parameters were similar whether rituximab was administered alone or with methotrexate or cyclophosphamide. Because the level of peripherally circulating B cells does not appear to correlate with a maintained clinical response in patients with rheumatoid arthritis, the timing of rituximab retreatment should be based on clinical symptoms rather than peripheral B-cell levels.
17014062 Rituximab for rheumatoid arthritis. 2006 Sep (1) Rituximab (RTX), a monoclonal antibody, selectively targets CD20+ B-cells that are implicated in the pathogenesis of rheumatoid arthritis (RA). (2) The use of RTX with methotrexate (MTX) results in statistically significant clinical improvements among RA patients who have an inadequate response to standard therapies, when compared to the use of MTX alone. (3) The optimal dose, duration of treatment or retreatment, long-term efficacy and safety, and placement of RTX in RA treatment algorithms need to be further investigated. (4) Health Canada has approved the combination of RTX with MTX for use in adult patients with moderate to severe active RA, who have had an inadequate response or intolerance to >1 tumour necrosis factor (TNF) inhibitor therapies.
17391602 Purulent pericarditis in a patient with rheumatoid arthritis treated with etanercept and m 2007 Jan Purulent pericarditis is rarely seen in this post-antibiotic era. We report a case of spontaneous purulent pericarditis in a patient with rheumatoid arthritis being treated with etanercept, a tumour necrosis factor-alpha (TNF-alpha) antagonist, and methotrexate, an immunosuppressant. Both are disease-modifying anti-rheumatic drugs. We discuss the pathophysiology of purulent pericarditis and the recent literature on the infectious complications of TNF-alpha antagonists.
17364199 Tuberculous uveitis after treatment with etanercept. 2007 Sep BACKGROUND: Etanercept is a tumor necrosis factor (TNF) inhibitor that has been licensed in the United States for the treatment of adult and juvenile rheumatoid arthritis as well as psoriatic arthritis. Reactivation of tuberculosis is a complication of its use. We report the first case of tuberculous uveitis due to etanercept. METHODS: We performed a clinical chart review. CASE: A 58-year-old Caucasian woman was referred to our hospital for chronic unilateral granulomatous panuveitis of the right eye (RE). She was on etanercept and methotrexate for rheumatoid arthritis. Since the patient was immunosuppressed with etanercept and since the uveitis was granulomatous we considered tuberculosis as a possible etiology. An aqueous humor tap was performed and sent for polymerase chain reaction analyses of Herpes simplex, Herpes zoster, and Mycobacterium tuberculosis (MT). This last test was positive. Another aqueous humor sample was taken and sent for microscopic examination of sputum for acid-fast bacilli and culture, both of which were positive for MT. A diagnosis of tuberculous uveitis was established; the patient was treated with rifampin, isoniazid pyrazinamide, and ethambutol and etanercept was stopped. Four months later there were no cells in the anterior chamber and the vitreous was clear. DISCUSSION: To our knowledge this is the first reported case of tuberculous uveitis following treatment with etanercept. This etiology has to be considered in patients taking this drug who present with intraocular inflammation.
17943257 Meta-analysis of the combination of TNF inhibitors plus MTX compared to MTX monotherapy, a 2008 Apr This present study was designed to examine (1) whether a combination therapy of TNF (tumor necrosis factor) blockers and methotrexate (MTX) is better than MTX monotherapy, and (2) if the TNF inhibitors such as etanercept, infliximab and adalimumab are all same for treating patients with active rheumatoid arthritis (RA). We performed meta-analysis of a combination therapy of TNF-blockers and MTX compared to MTX monotherapy and we performed adjusted indirect comparison of the TNF-blocking agents for their efficacy and toxicity. Three studies met the inclusion criteria for the analysis. Meta-analysis showed that the combination of MTX with anti-TNF inhibitors was more effective than MTX monotherapy and this indicated that combination therapy of anti-TNF inhibitors and MTX was comparable with MTX monotherapy in terms of withdrawal due to the side effects (RR: 1.05, 95% CI: 0.52-2.09, P = 0.86). The adjusted indirect comparison did not show any differences between infliximab and adalimumab. However, there was a significant difference for clinical efficacy and side effects between etanercept, adalimumab and infliximab. The RRs for achieving ACR20, ACR50 and ACR70 responses and withdrawal due to the side effect in the etanercept group were lower when compared with the adalimumab group. The RR for achieving an ACR20 response in the etanercept group was lower when compared with the infliximab group. The adjusted indirect comparison analysis suggests that the TNF-blocking agents all are not the same with respect to effectiveness and toxicity for the treatment of active RA.
17611987 Good clinical response, remission, and predictors of remission in rheumatoid arthritis pat 2007 Aug OBJECTIVE: To assess the prevalence of good clinical response and remission in rheumatoid arthritis (RA) patients with longstanding disease treated with anti-tumor necrosis factor-alpha (TNF-alpha) drugs at outpatient clinics. METHODS: Retrospective national study of 14 academic tertiary referral rheumatology medical centers. RA patients with a Disease Activity Score (DAS28) > 3.2 were defined as having active disease and could start TNF-alpha blockers. All patients received one TNF-alpha blocker plus methotrexate (10-20 mg/wk). At the third month the patients were categorized as responders or nonresponders, based on improvement of at least 0.25 of the Health Assessment Questionnaire (HAQ). Those who had improved by at least 0.25 HAQ were analyzed for possible predictors of DAS28 remission at the sixth month. RESULTS: A total of 1257 patients started TNF-alpha blockers. Of these, 591 (46.7%) reached the sixth month with an improvement of HAQ of 0.25 at the third month. In the cohort of patients reaching HAQ of 0.25, DAS28 remission was seen in 24% of rheumatoid factor (RF)-positive and 36% of RF-negative patients (p = 0.03). Logistic regression analysis for predictors of remission identified age at baseline, HAQ < 1.63, and RF negativity as positive predictors of remission at 6 months along with sex (male). CONCLUSION: We show that only a minority of patients with longstanding RA achieve a good clinical response or remission at the outpatient community level. Predictors of remission identify characteristics commonly observed in subsets with less severe RA.