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ID PMID Title PublicationDate abstract
16173246 Inclusion criteria as widely used for rheumatoid arthritis clinical trials: patient eligib 2005 Sep OBJECTIVE: To identify the proportion of patients fulfilling the inclusion criteria widely used in most clinical trials for rheumatoid arthritis (RA)--including the recent clinical trials of anti-Tumor Necrosis Factor alpha (TNFalpha) agents--in a Turkish cohort. METHODS: 186 consecutive RA patients attending a routine tertiary rheumatology clinic were evaluated in 2 groups: Early RA group (group E): 31 patients with a disease duration of < or = 3 years (mean: 1.9 +/- 0.9 years); late RA group (group L): 155 patients with a disease duration of > 3 years (mean: 13.3 +/- 8.6 years). Patients were evaluated according to 2 different sets of inclusion criteria: (i) The widely used common inclusion criteria for RA clinical studies, as outlined by Sokka and Pincus; (ii) the criteria of two major anti-TNF clinical studies, ERA and ATTRACT. RESULTS: No patients in group E, and 9 (6%) patients in group L fulfilled the common criteria used in clinical studies for RA. In group E, 28 patients had already been started on methotrexate; 2 patients were on sulphasalazine and one patient was on leflunomide. Nevertheless, even if the criterion for previous use of methotrexate was not applied patients did not fulfill the rest of the criteria of ERA study. In group L, 9 out of 155 patients (6%) met the criteria for the ATTRACT study. CONCLUSION: Only few patients met the widely used inclusion criteria for most RA clinical trials and the recent clinical trials of TNFalpha agents in this Turkish cohort. This may be explained by the milder disease activity in this geographical region, which further emphasizes the need to consider development of new criteria for inclusion in clinical trials.
15940552 Have traditional DMARDs had their day? Effectiveness of parenteral gold compared to biolog 2005 Jun This review tries to answer the question of whether in the face of the recently introduced biologics conventional disease-modifying antirheumatic drugs (DMARDs) can still be recommended in the treatment of rheumatoid arthritis (RA). We start with an overview of the oldest conventional DMARD, injectable gold (Au), which was introduced in the treatment of RA in the 1920s. The effect of gold is directed at a number of different sites of the immune system. A significant improvement of clinical and biochemical disease activity parameters as well as an inhibition of X-ray progression has been shown in many studies. Head-to-head comparisons between gold and high-dose methotrexate (MTX) demonstrated no significant difference but some advantages for gold. Since trials comparing biologics with gold will never be performed, an indirect comparison was done by analyzing the results of trials with gold with those with biologics. Conclusions from such comparisons have to be drawn with caution especially since the methodology for performing trials has changed with time. We selected four trials with gold (two open, one placebo-controlled, and one comparison with MTX) and five trials with biologics (three placebo-controlled, one dose escalation study, and one comparison with MTX). In all these trials baseline data regarding swollen joint count (SJC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were roughly comparable and, with the exception of interleukin (IL)-1 RA, demonstrated a similar improvement of over 50% already after 6 months [with faster onset with tumor necrosis factor (TNF)-alpha blockade]. American College of Rheumatology (ACR) response data were not available for the older gold trials. European League Against Rheumatism (EULAR) response criteria could be calculated for the Au/MTX trial and were-for these compounds-only slightly inferior to the results with adalimumab. X-ray response is especially difficult to compare across studies. Although an inhibition with Au and MTX could be demonstrated, this occurred-similar to corticosteroid treatment-earlier and more pronounced with TNF-alpha blockers. We confirm the statement of Weinblatt that the most modern DMARDs do not appear to be much better than the oldest one indicating that conventional DMARDs are not outdated. Therefore, a sufficient trial of conventional DMARDs should precede the introduction of treatment with the very expensive biologics.
16906370 Acceptability and usefulness of mizoribine in the management of rheumatoid arthritis in me 2006 This report documents the results of a study performed to examine clinical use of mizoribine (MZR), using data from a large-scale prospective cohort study, IORRA (Institute of Rheumatology Rheumatoid Arthritis). The number of patients with RA entered in this study from October 2000 through October 2003 was 6238. Three hundred and six patients (4.9%) received MZR therapy. Mizoribine users who were taking methotrexate (MTX) (MTX-MZR group, n = 94) and over 70 years of age (elderly group, n = 45) were collected. Cumulative retention rates of MZR were calculated by Kaplan-Meier analysis. Median drug survival of MZR was 28 months for the poor responders to MTX and 43 months for the poor responders to MZR, with no significant difference between these groups. Cumulative retention rate of MZR in the elderly group did not show a significant difference compared to that in patients aged under 70 years. Ten patients (10.6%) in the MTX-MZR group and 10 patients (22.2%) in the elderly group experienced adverse effects of MZR. None of these adverse effects was serious. This study indicated that, although MZR has not been frequently prescribed for RA patients, it may be useful and relatively safe for patients who are poor responders to MTX as an additional regimen to MTX therapy as well as for elderly patients.
17080518 An index of patient reported outcomes (PRO-Index) discriminates effectively between active 2006 Nov OBJECTIVE: To analyze 2 indices composed of the 3 patient reported outcomes (PRO) in the American College of Rheumatology (ACR) Core Data Set--physical function, pain, and global estimate--without joint count or laboratory data, for capacities to distinguish active from control treatments in 4 pivotal clinical trials. METHODS: Data from 4 clinical trials involving adalimumab, in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARD) or as monotherapy, versus control treatment were made available to analyze properties of various indices. A categorical PRO-Index M was defined as "majority" improvement in 2 of the 3 PRO measures at 20%, 50%, and 70% levels; results were evaluated to analyze agreement with ACR20, ACR50, ACR70 responses and an "all Core Data Set measures" index based on 4 of the 7 measures having such levels of improvement. A continuous PRO-Index C was defined as the median or 2nd highest of 3 percentage differences from baseline to endpoint; results were evaluated to analyze agreement with a continuous ACR-N, "all Core Data Set measures" index, and Disease Activity Score 28 (DAS28). RESULTS: All indices distinguished active versus control treatment at similar levels, including PRO-Index M versus ACR20, ACR50, and ACR70 responses, and PRO-Index C versus DAS28. CONCLUSION: PRO indices based only on patient questionnaire data, without joint counts or laboratory tests, may be useful quantitative measures of therapeutic efficacy for use in standard rheumatology clinical care.
16034967 Adalimumab for treating rheumatoid arthritis. 2005 Jul 20 BACKGROUND: Adalimumab is a fully human anti-TNFalpha monoclonal antibody. Published studies indicate that its use in patients with RA can be effective and safe. OBJECTIVES: The aim of this review was to assess the efficacy and safety of adalimumab in the treatment of RA. SEARCH STRATEGY: Electronic databases were searched up to August, 2004: MEDLINE, CINAHL, EBM Reviews (CDSR, ACP Journal Club, DARE and CENTRAL) and Health STAR. Conference proceedings were hand searched and pharmaceutical companies were contacted to obtain additional unpublished data from published trials. Adalimumab was searched as a text word as it is not currently indexed. The search was not limited by language, year of publication or type of publication. SELECTION CRITERIA: All randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing adalimumab alone or in combination with DMARDs to placebo or other DMARDs. DATA COLLECTION AND ANALYSIS: Two reviewers independently collected the data in a standardized form and assessed the methodological quality of the trial using validated criteria. Outcome measures included ACR and EULAR responses, DAS 28 and components of ACR response and radiographic data. Safety data were also included. Continuous data were reported as weighted mean difference (WMD) with 95% confidence interval (95%CI), absolute benefit (AB) and relative difference (RD). Dichotomous outcomes were reported as relative risk (RR) with 95% CI, absolute risk difference (ARD) or risk difference (RDiff) with 95%CI and number needed to treat (NNT) or to harm (NNH). When significant heterogeneity was not found, data were pooled. MAIN RESULTS: Six studies with 2381 patients were included in this review. Two comparisons were done: A. adalimumab subcutaneously (sc) + methotrexate (or DMARDs) versus placebo sc + methotrexate (or DMARDs). B. adalimumab sc in monotherapy versus placebo sc. In the comparison A, with adalimumab 40 mg every other week (e.o.w.), the RR to achieve an ACR 20 response at 24 weeks ranged in the included studies from 1.52 to 4.63, and the NNT ranged from 1.9 to 5.4. The RR (95%CI) to achieve an ACR 50 response was 4.63 (3.04-7.05), and the NNT was 3.0 (95%CI 2.0-6.0). The RR (95%CI) to achieve an ACR 70 response was 5.14 (3.14-8.41) and the number needed to treat was 7.0 (95%CI 5.0-13.0). At 52 weeks, the RRs (95%CI) to achieve an ACR 20, 50, and 70 response were 2.46 (1.87-3.22), 4.37 (2.77-6.91), and 5.15 (2.60-10.22), with NNTs of 2.9, 3.1, and 5.3, respectively. At 52 weeks, adalimumab 40 mg e.o.w. and 20 mg every week (e.w.) significantly slowed the radiological progression including Sharp modified index, erosion score, and joint space score (only with 40 mg e.o.w.). In the comparison B, with adalimumab 40 mg e.o w. , the RRs to achieve an ACR 20, 50, and 70 response at 24/26 weeks were 1.91 (1.17-3.10), 2.84 (1.58-5.12), and 7.33 (2.25-33.90) with NNTs of 5.0 (95%CI 3.0-9.0), 7.0 (4.0-20.0), and 9.0 (3.0-38.0), respectively. In most of the analysed studies and comparisons, there were not significant differences in safety outcomes between adalimumab and control groups. The development of positive antinuclear antibodies was significantly more frequent in adalimumab patients than in placebo patients. Serious infections were significantly more frequent in adalimumab patients in only one study (Keystone 2004) with a RR (95%CI) of 7.64(1.02-57.18) and a NNH of 30.2. AUTHORS' CONCLUSIONS: On the basis of the studies reviewed here, adalimumab in combination with methotrexate is efficacious and safe in the treatment of the rheumatoid arthritis. Adalimumab 40 mg sc e.o.w. and 20 mg e.w. slows the radiographic progression at 52 weeks. Adalimumab in combination with DMARDs other than methotrexate is also efficacious and safe, even though data from one only study are available and the number of patients in each group is low. Adalimumab in monotherapy is efficacious and safe in the treatment of the rheumatoid arthritis but the effect size is lower than with combined therapy.
16670074 Atypical lymphoproliferation progressing into B-cell lymphoma in rheumatoid arthritis trea 2006 May A patient with rheumatoid arthritis (RA) developed an atypical lymphoproliferative disorder (LPD) after methotrexate and cyclosporine A, which regressed after suspension of both drugs. After subsequent treatment with rituximab, the LPD was still undetectable. Anti-tumor necrosis factor a therapy was used when the arthritis relapsed, but an aggressive B-cell non Hodgkin's lymphoma developed. Molecular analyses showed an oligoclonal B-cell expansion at the LPD step. A minor clone with significant sequence homology to B-cell lymphomas arising in Sjogren's syndrome and mixed cryoglobulinemia syndrome, given rise to the non-Hodgkin's lymphoma. Treatment of rheumatoid arthritis associated with lymphoproliferation represents a clinical challenge, and common pathogenetic pathways to lymphoma may occur in different autoimmune diseases.
16013943 [Pharmaceutical care of patients with rheumatoid and psoriatic arthritis receiving etanerc 2005 May OBJECTIVE: To evaluate a pharmaceutical care protocol for patients with rheumatoid arthritis (RA) or psoriatic arthritis who begin treatment with etanercept with the objective of identifying potential medication-related problems and implementing therapeutic measures to improve the way this drug is used. METHOD: An observational, prospective, 3-month study of patients with RA receiving etanercept therapy from March to December 2003 was conducted and a pharmaceutical care protocol was set up. During the first visit, a pharmacotherapeutic record was initiated for each patient, including socio-demographic data, personal history, diagnosis, DMARDs (disease-modifying anti-rheumatic drugs) previously received, and concomitant therapies for other underlying conditions. Patients were briefed on dosage, administration route, and potential adverse events both orally and in writing. Correct drug administration and preservation were verified during the second visit, where potential adverse effects were identified, treatment adherence was confirmed, and, if needed, potential drug interactions with other ongoing medications were disclosed. During the third visit, adherence was assessed, adverse events were recorded, and patients evaluated their response to treatment. RESULTS: Fifty patients were included, 40 with a diagnosis of rheumatoid arthritis (80%) and 10 diagnosed with psoriatic arthritis (20%). In all, 72% had received previous treatment with methotrexate (MTX), 40% with leflunomide, 20% with infliximab, 56% with corticoids, 2% with analgesics, 56% with NSAIDs, and 30% with other DMARDs. CONCLUSIONS: No significant drug interactions were found. Regarding adherence to treatment, 7.7% of patients skipped one or more doses, with travelling being the most common reason. Adverse events reported included: injection site reaction (27%), headache (7.7%) and nausea (7.7%). At 3 months after treatment onset, a reduction of MTX doses was seen in 18% of patients, of leflunomide dosage in 8%, of corticoids in 18%, of analgesic usage in 6%, and of NSAIDs in 8% of patients. In agreement with these results, 92% of patients reported having experienced improvment.
16282050 [Correlations of clinical symptoms and treatment efficacy in patients with rheumatoid arth 2005 Nov OBJECTIVE: To evaluate the correlations between clinical symptoms and treatment efficacy in patients with rheumatoid arthritis (RA). METHODS: Four hundred and thirteen patients were included in the clinical trial from 9 clinical centers. They were randomly divided into Western medicine-treated group with 204 cases and Chinese herbal drug-treated group with 209 cases. Eighteen clinical symptoms were evaluated before and after treatment. The Western medicine therapy included voltaren extended release tablets, methotrexate and sulfasalazine. The Chinese herbal drug therapy included glucosidorum Tripterygii totorum tablets and Yishen Juanbi Tablets combined with treatment based on syndrome differentiation. The American College of Rheumatology 20 (ACR20) was used as efficacy evaluation criteria. RESULTS: In the Chinese herbal drug-treated group, clinical symptoms such as arthralgia and tenderness of joints were positively correlated with the efficacy after 12-week treatment, while frequent urination at night was negatively correlated. In the same group, tenderness of joints and fever were positively correlated with the efficacy after 24-week treatment, while deep-colored and turbid urine was negatively correlated. In the Western medicine-treated group, tenderness of joints and thirst were positively correlated with the efficacy after 12-week treatment, while vertigo was negatively correlated. And in the same group, tenderness of joints was positively correlated with the efficacy after 24-week treatment, while heaviness of limbs was negatively correlated to the efficacy. The statistical results showed that the treatment efficacy was improved when the correlated symptoms were included in the indications. CONCLUSION: The treatment efficacy of RA is correlated with some symptoms, so further studies should proceed on these correlations in order to achieve better treatment outcome.
15695306 A dose adjustment in patients with rheumatoid arthritis not optimally responding to a stan 2005 Apr OBJECTIVES: To analyse the effect of a dose increase in patients with severe rheumatoid arthritis (RA) with insufficient clinical response to 3 mg/kg infliximab every 8 weeks. METHODS: Patients suffering from active refractory RA despite methotrexate, were treated with i.v. infusions of infliximab (3 mg/kg) on week 0, 2, 6 and every 8 weeks thereafter. Based on the clinical judgement at week 22, patients received a dose increase of 100 mg from week 30 on. The American College of Rheumatology (ACR) core set for disease activity measures was regularly assessed. RESULTS: Five hundred and eleven RA patients were included. At week 22, 61.4, 34 and 14.1% of all patients met ACR 20, ACR 50 and ACR 70 criteria, respectively, and 6.1% of patients were in remission. A low swollen joint count at baseline was correlated with improvement at week 22 for ACR 20 (P < 0.06), ACR 50 (P < 0.06) and ACR 70 (P < 0.005). The change in HAQ score between weeks 0 and 22 was predictive for response at week 54 (P < 0.01). The dose of infliximab was increased by 100 mg in 22% of the patients. Most baseline values of patients requiring dose increase were higher (P < or = 0.001) than the baseline values of the remaining patients. Increasing the dose of infliximab by one vial from week 30 on could circumvent the partial loss of response in these patients. CONCLUSION: Infliximab use in this large out-patient cohort resulted in a significant clinical improvement. A subgroup that partially lost response during the first 22 weeks could regain response by adding 100 mg of infliximab to the subsequent doses. Due to the current study design, however, a regression to the mean like effect could not be ruled out.
16963793 Methotrexate in rheumatoid arthritis. 2006 Jul A variety of disease-modifying antirheumatic drugs (DMARDs) are available to control the clinical activity of rheumatoid arthritis (RA). Methotrexate (MTX), an analogue of folic acid and of aminopterin, is the most commonly used DMARD and is now prescribed worldwide to at least 500,000 patients with RA. The mechanism by which MTX used at a low dose modulates inflammation in RA is still unknown. Monitoring of the therapy in terms of MTX concentration in patients with RA seems not to have a significant influence on the effectiveness of the treatment. Two meta-analyses showed that MTX has one of the best efficacy/toxicity ratios. It should be the first DMARD used in the majority of patients with RA at this time. However, a significant number of patients treated only with MTX fail to achieve optimal disease control, so there are many combinations of DMARD regimes. It is hoped that more aggressive use of conventional DMARDs and biological agents will result in less disability and a higher proportion of patients achieving remission. The therapy of RA is a dynamic process and requires maintaining a delicate balance between benefits and risks. Even with the newer biological agents, MTX continues to serve as a reference point and there is still a role for MTX in the treatment of RA patients.
16622718 Lack of increase in postoperative complications with low-dose methotrexate therapy in pati 2006 To determine the potential contribution of intermittent low-dose methotrexate (MTX) treatment (2-8 mg/week) to postoperative complications, we studied 122 patients with rheumatoid arthritis (RA) who had 201 surgical procedures. The patients with treatment with MTX were allocated to two groups: those who continued MTX (group A, 77 procedures) and those who discontinued MTX more than 1 week (group B, 21 procedures). The patients who had no treatment with MTX were allocated to group C (103 procedures). The incidence of postoperative infection, poor wound healing, and flare-up of RA was compared between the three groups. Postoperative infection occurred in 3.9%, 4.8%, and 3.9% in groups A, B, and C, respectively. Poor wound healing was experienced in 1.3%, 9.5%, and 7.8% in groups A, B, and C, respectively. At 4 weeks postoperatively, 3.9%, 14.3%, and 6.8% of flares were seen in groups A, B, and C, respectively. No significant difference was found in the patients with or without perioperative use of MTX. From these results, it is unlikely that continuation of intermittent low-dose MTX treatment increases the risk of postoperative complications in patients with RA. Continued treatment with MTX during perioperative period could suppress disease flares, especially in severe RA patients.
17014006 Reduction of inflammatory biomarker response by abatacept in treatment of rheumatoid arthr 2006 Nov OBJECTIVE: Abatacept, a soluble selective costimulation modulator, selectively modulates T cell activation via the CD80/CD86:CD28 costimulation pathway. Data from a Phase II trial showed efficacy in patients with active rheumatoid arthritis (RA) and inadequate response to methotrexate when treated with abatacept (10 mg/kg or 2 mg/kg). To determine the mechanism of action of abatacept, we analyzed changes in the serum levels of inflammatory biomarkers in the patients enrolled in this trial. RESULTS: Following 12 months' treatment, serum levels of interleukin 6 (IL-6), soluble IL-2 receptor, C-reactive protein, soluble E-selectin, and soluble intercellular adhesion molecule-1 were significantly lower in patients receiving abatacept 10 mg/kg versus placebo. Smaller reductions in tumor necrosis factor-a and rheumatoid factor were also observed in the abatacept 10 mg/kg group compared with the placebo group. Although there was no evidence for efficacy of the 2 mg/kg dose, small reductions in inflammatory biomarkers at this dosage support the biologic effect of this therapy. CONCLUSION: These findings reveal the antiinflammatory and immunomodulatory effects of abatacept in patients with RA, and are consistent with the concept that modulating T cell activation improves clinical signs and symptoms and inhibits the progression of structural damage. These data suggest that selective modulation of the CD80/CD86:CD28 pathway with abatacept may affect several inflammatory cell types and cytokines that are involved in the proinflammatory cascade.
18666381 Persistent clinical response of infliximab therapy in patients with refractory rheumatoid 2006 Jan Infliximab, a chimeric monoclonal anti-tumor necrosis factor alpha antibody is approved for the treatment of patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX) therapy. This report provides analyses by using infliximab in combination with various disease modifying anti-rheumatic drugs, infliximab "survival" over a period of three years, and its effectiveness on synovial tissue damage using magnetic resonance (MR) imaging. The study was started in 1999 as an open label study using infliximab in combination with cyclosporin A (CsA) in refractory RA patients who were unable to tolerate MTX. A total of 18 RA patients were investigated. After a year of treatment, 80% of patients achieved the 20% American College of Rheumatology Response criteria. Two patients dropped out; one because of an immediate hypersensitivity reaction and the other because of the development of pulmonary tuberculosis. In a subsequent study we investigated infliximab "survival" over a period of 3 years. A total of 84 RA patients were included in the study. After 3 years of therapy, 59% of patients still continued receiving infliximab. The factor that was associated with infliximab "survival" was the concomitant use of MTX. A total of 28 (33%) patients discontinued this study. More specifically, 16 (19%) presented adverse drug reactions, 9 (11%) had drug failure, and 3 (3%) were lost from follow-up. Finally, to evaluate by MR imaging the inflammatory tissue changes in refractory RA patients treated with infliximab, 16 patients were examined with MR imaging of the dominant affected wrist and hand before and one year after therapy. The volume of the enhancing inflammatory tissue (VEIT) was evaluated. A significant decrease of VEIT was observed in 88% of patients after therapy. We conclude that in refractory RA patients infliximab was proved to be efficacious and well tolerated in combination with CsA. The clinical response of infliximab was persistent over a 3-year period and was associated with the concomitant use of MTX. This clinical improvement was also associated with the reduction of inflammatory disease tissue damage.
17100028 Serum leptin levels in rheumatoid arthritis and relationship with disease activity. 2006 Oct OBJECTIVES: This study was performed to evaluate serum leptin levels in rheumatoid arthritis (RA) patients and investigate the correlation with serum tumor necrosis factor alpha (TNF-alpha) levels and clinical and laboratory parameters of disease activity. METHODS: Fifty patients with RA and 34 control subjects were included. Disease activity score 28 (DAS28) was calculated for each patient. Laboratory activity was assessed by examining erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Immunoradiometric assay was used for measuring serum leptin levels (ng/mL). Serum TNF-alpha levels (pg/mL) were measured by sandwich enzyme-linked immunosorbent assay method in 41 of 50 RA patients and in 24 control subjects. RESULTS: Age, sex and body mass index (BMI) did not show a statistically significant difference between RA and control subjects (P > 0.05). Serum leptin levels were higher in RA (P = 0.000). In RA patients, there were no correlations between serum leptin levels and disease duration, swollen and tender joint counts, DAS28, CRP, ESR, serum TNF-alpha levels, oral glucocorticoid and methotrexate usage (P > 0.05). There was no statistically significant serum leptin level difference between patients with high disease activity and mild and low disease activity (P = 0.892). Serum leptin levels positively correlated with BMI in both patient and control groups (P < 0.05). In both groups, mean serum leptin levels were higher in women than men. CONCLUSIONS: Even though serum leptin levels were found to be significantly higher in RA patients than in control subjects in this study, there was no correlation between serum leptin levels and TNF-alpha levels, clinical and laboratory parameters of disease activity. However serum leptin levels positively correlated with BMI in both patient and control groups. In RA, circulating leptin levels do not seem to reflect disease activity.
16982117 [Aspergillosis in systemic diseases treated with steroids and/or immunosuppressive drugs: 2006 Nov This is a multicentric retrospective study of aspergillosis in patients treated by corticosteroids and/or immunosuppressive drugs for systemic diseases and a review of the literature. Nine patients, 5 men and 4 women, mean age of 62.8 years old were included among which Horton's diseases (3 cases), systemic lupus erythematosus (2), polymyositis (1), microscopic polyangiitis (1), idiopathic thrombocytopenic purpura (1), rheumatoid polyarthritis (1). Aspergillosis occurred in average 28.4 month after the diagnosis of systemic disease, and 28 months after the beginning of its treatment: corticosteroids in all cases, at a dose of 50.8 mg/day (equivalent prednisone) in average, cyclophosphamide (2 cases), methotrexate (1), intravenous immunoglobulins (1), leflunomide (1). All cases were invasive or chronic pulmonary aspergillosis located in the lungs (6 cases), or in the brain (3). Revealing symptoms were mild and non specific. Lymphopenia was severe in most cases, in average 472 lymphocytes/mm3 and 283 CD4+/mm3. The diagnosis was confirmed 20.75 days after the first symptoms in invasive aspergillosis, and 18.5 months in the chronic pulmonary cases, by cultures in 7 cases (broncho-alveolar lavage: 4; cerebral biopsy: 3), and direct microscopy examination of broncho-alveolar lavage in 2 cases. Specific serology was positive in 4 cases. Patients were treated by voriconazole (4 cases), itraconazole (2), amphotericin B (1), association of caspofungin and voriconazole (1), successive voriconazole and itraconazole (1). Six patients recovered from aspergillosis with 10.8 months of following time, 3 patients died a few days after confirmation of the diagnosis. Fifty-four cases of the literature are analysed.
15208176 Long term safety of methotrexate in routine clinical care: discontinuation is unusual and 2005 Feb OBJECTIVE: To analyse patients with rheumatoid arthritis, treated with methotrexate in a weekly academic rheumatology clinic over 13 years, for continuation of courses and reasons for discontinuation. METHODS: All 248 patients with an analysable longitudinal course who took methotrexate in standard care between 1990 and 2003 were studied. Continuation of courses was analysed using life tables. All abnormal and severely abnormal values for aspartate aminotransferase (AST) >40 U/l, >80 U/l, albumin <35 g/l, <30 g/l, white blood cell (WBC) count <4.0 x 10(9)/l, <3.0 x 10(9)/l, and platelet count <150 x 10(9)/l, <100 x 10(9)/l, were identified. Responses of the clinician and subsequent laboratory values were reviewed. RESULTS: Over 1007 person-years, the probability of continuing methotrexate over five years was 79% (95% confidence interval, 72% to 84%). Severe laboratory abnormalities occurred in 2.9 per 100 person-years, specifically 0.9 for AST >80 U/l, 1.1 for albumin <30 g/l, 0.7 for WBC <3.0 x 10(9)/l, and 0.3 for platelets <100 x 10(9)/l. No severe laboratory abnormality progressed to further severity or clinical disease. Permanent discontinuations of methotrexate occurred in 46 patients (19%), 26 (10% of all patients) for adverse effects, 15 (32.6%) for inefficacy; only two discontinuations resulted from laboratory abnormalities, both of WBC, possibly from other sources. CONCLUSIONS: Methotrexate was associated with a high rate of continuation, and few clinically significant laboratory abnormalities. Discontinuation primarily reflected clinical rather than laboratory findings. Vigilance for methotrexate toxicity is required but methotrexate appears among the safest treatments for rheumatoid arthritis.
16008691 Epstein--Barr virus-associated B-cell lymphoma in the setting of iatrogenic immune dysregu 2005 Aug BACKGROUND: Epstein-Barr virus (EBV) has been implicated in B-cell lymphoma associated with iatrogenic immune dysregulation, primarily in the context of extracutaneous lymphoma. METHODS: We describe six patients, five transplant recipients receiving cyclosporine and one patient with rheumatoid arthritis receiving methotrexate, who developed cutaneous presentations of EBV-associated B-cell lymphoma. Human herpesvirus 8 (HHV8) and EBV thymidine kinase (vTK) expression were also explored. RESULTS: The cases comprised plasmablastic lymphoma (one case), plasmacytic marginal zone lymphoma (two cases), and diffuse large B-cell lymphoma (three cases). There was a monoclonal gammopathy in one and concurrent extracutaneous disease in two of the six patients. EBV-associated latent small nuclear RNA was detected in all cases with coexpression of HHV8 in one of the five cases and of vTK in three of the six cases. Three patients responded to a reduction in the immunosuppressive regimen and antiviral therapy. Recurrent disease developed in two, with one patient succumbing to multiorgan dissemination. CONCLUSIONS: EBV-associated cutaneous B-cell lymphoma is characterized by a long interval between the initiation of immunosuppression and the development of lymphoma. Although previous reports have reported an indolent clinical course, an aggressive clinical course may occur. HHV8 and lytic phase EBV antigens are detected in some cases, possibly suggesting a pathogenetic role.
16127012 Pathogenesis of rheumatoid arthritis: targeting cytokines. 2005 Jun Although considerable progress has been made by adequate treatment with traditional disease-modifying antirheumatic drugs (DMARDs), therapy of rheumatoid arthritis (RA) still remains difficult. The discovery of the importance of cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-15 (IL-15), which are also stimulated by consequences of autoimmune responses, has led to the development of anticytokine therapies ("biologicals"). Blocking TNF or also, to some extent, IL-1 has proved beneficial in DMARD-resistant RA patients in multiple clinical trials. Along with clinical improvement, TNF blockade has been shown to halt radiographic disease progression, a major risk factor for disability. Recently, clinical trials have shown a significant therapeutic benefit of biological inhibitors of IL-6, and also of IL-15, with an efficacy comparable to that of TNF blockers. All these agents are particularly efficacious when combined with methotrexate. Although clinical remission is difficult to achieve even with anticytokine treatment, these drugs offer the potential to decrease disease activity and improve quality of life in a majority of RA patients, and it is conceivable that combinations of biological therapies may pave the path to even better success, which ultimately is remission or even cure.
16945726 An unusual presentation of methotrexate-induced B-cell lymphoma of the metacarpophalangeal 2006 Sep We report a unusual presentation of B-cell lymphoma in the chronically inflamed synovium of a 64-year-old man with an 18-year history of rheumatoid arthritis that was treated with methotrexate.
16372823 Clinical pharmacology of lumiracoxib: a selective cyclo-oxygenase-2 inhibitor. 2005 Lumiracoxib (Prexige) is a selective cyclo-oxygenase (COX)-2 inhibitor developed for the treatment of osteoarthritis, rheumatoid arthritis and acute pain. Lumiracoxib possesses a carboxylic acid group that makes it weakly acidic (acid dissociation constant [pKa] 4.7), distinguishing it from other selective COX-2 inhibitors. Lumiracoxib has good oral bioavailability (74%). It is rapidly absorbed, reaching maximum plasma concentrations 2 hours after dosing, and is highly plasma protein bound. Lumiracoxib has a short elimination half-life from plasma (mean 4 hours) and demonstrates dose-proportional plasma pharmacokinetics with no accumulation during multiple dosing. In patients with rheumatoid arthritis, peak lumiracoxib synovial fluid concentrations occur 3-4 hours later than in plasma and exceed plasma concentrations from 5 hours after dosing to the end of the 24-hour dosing interval. These data suggest that lumiracoxib may be associated with reduced systemic exposure, while still reaching sites where COX-2 inhibition is required for pain relief. Lumiracoxib is metabolised extensively prior to excretion, with only a small amount excreted unchanged in urine or faeces. Lumiracoxib and its metabolites are excreted via renal and faecal routes in approximately equal amounts. The major metabolic pathways identified involve oxidation of the 5-methyl group of lumiracoxib and/or hydroxylation of its dihaloaromatic ring. Major metabolites of lumiracoxib in plasma are the 5-carboxy, 4'-hydroxy and 4'-hydroxy-5-carboxy derivatives, of which only the 4'-hydroxy derivative is active and COX-2 selective. In vitro, the major oxidative pathways are catalysed primarily by cytochrome P450 (CYP) 2C9 with very minor contribution from CYP1A2 and CYP2C19. However, in patients genotyped as poor CYP2C9 metabolisers, exposure to lumiracoxib (area under the plasma concentration-time curve) is not significantly increased compared with control subjects, indicating no requirement for adjustment of lumiracoxib dose in these subjects. Lumiracoxib is selective for COX-2 compared with COX-1 in the human whole blood assay with a ratio of 515 : 1 in healthy subjects and in patients with osteoarthritis or rheumatoid arthritis. COX-2 selectivity was confirmed by a lack of inhibition of arachidonic acid and collagen-induced platelet aggregation. COX-2 selectivity of lumiracoxib is associated with a reduced incidence of gastroduodenal erosions compared with naproxen and a lack of effect on both small and large bowel permeability. Lumiracoxib does not exhibit any clinically meaningful interactions with a range of commonly used medications including aspirin (acetylsalicylic acid), fluconazole, an ethinylestradiol- and levonorgestrel-containing oral contraceptive, omeprazole, the antacid Maalox, methotrexate and warfarin (although, as in common practice, routine monitoring of coagulation is recommended when lumiracoxib is co-administered with warfarin). As such, dose adjustments are not required when co-administering these agents with lumiracoxib. In addition, moderate hepatic impairment and mild to moderate renal impairment do not appear to influence lumiracoxib exposure.