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22071858 Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetam 2011 Nov 9 BACKGROUND: Methotrexate is routinely used in the treatment of inflammatory arthritis. There have been concerns regarding the safety of using concurrent non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, or paracetamol (acetaminophen), or both, in these people. OBJECTIVES: To systematically appraise and summarise the scientific evidence on the safety of using NSAIDs, including aspirin, or paracetamol, or both, with methotrexate in inflammatory arthritis; and to identify gaps in the current evidence, assess the implications of those gaps and to make recommendations for future research to address these deficiencies. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, second quarter 2010); MEDLINE (from 1950); EMBASE (from 1980); the Cochrane Database of Systematic Reviews (CDSR) and the Database of Abstracts of Reviews of Effects (DARE). We also handsearched the conference proceedings for the American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) (2008 to 2009) and checked the websites of regulatory agencies for reported adverse events, labels and warnings. SELECTION CRITERIA: Randomised controlled trials and non-randomised studies comparing the safety of methotrexate alone to methotrexate with concurrent NSAIDs, including aspirin, or paracetamol, or both, in people with inflammatory arthritis. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the search results, extracted data and assessed the risk of bias of the included studies. MAIN RESULTS: Seventeen publications out of 8681 identified studies were included in the review, all of which included people with rheumatoid arthritis using various NSAIDs, including aspirin. There were no identified studies for other forms of inflammatory arthritis.For NSAIDs, 13 studies were included that used concurrent NSAIDs, of which nine studies examined unspecified NSAIDs. The mean number of participants was 150.4 (range 19 to 315), mean duration 2182.9 (range 183 to 5490) days, although the study duration was not always clearly defined, and the studies were mainly of low to moderate quality. Two of these studies reported no evidence for increased risk of methotrexate-induced pulmonary disease; one study assessed the effect of concurrent NSAIDs on renal function and found no adverse effect; one study identified no adverse effect on liver function; three studies demonstrated no increase in methotrexate withdrawal; and one study showed no increase in all adverse events, including major toxic reactions. However, transient thrombocytopenia was demonstrated in one study, specifically when NSAIDs were taken on the same week day as methotrexate. This study was a retrospective review that involved small numbers only and was of moderate quality; these finding have not been replicated since.Four studies looked at specific NSAIDs (etodolac, piroxicam, celecoxib and etoricoxib), with a mean number of participants of 25.8 (range 14 to 50) and mean study duration of 16.8 (range 14 to 23) days. These studies were mainly of moderate quality. The studies were primarily pharmacokinetic studies but also reported adverse events as secondary outcomes. There were no clinically significant adverse effects with concomitant piroxicam or etodolac; and only mild adverse events with celecoxib or etoricoxib, such as nausea and vomiting, and headaches.For aspirin, seven studies provided data on adverse events with the use of aspirin and methotrexate. These studies included a mean number of participants of 100 (range 11 to 232), had a mean duration of 1325 (range 8 to 2928) days and were mainly of low to moderate quality. Two of the studies reported no evidence for increased risk of methotrexate-induced pulmonary disease and two studies showed no increase in all adverse events including major toxic reactions; however, none of these studies specified the dose of aspirin that was used. One study demonstrated that concurrent aspirin adversely affected liver function at a mean dose of 6.84 tablets of aspirin per day, which is a possible daily dose of 2.1 g presuming that 300 mg aspirin tablets were given. A further study described a partially reversible decline in renal function with 2 g daily of aspirin. One study reported no increase in adverse events with 975 g aspirin daily, however the study duration was only one week.For paracetamol, no studies were identified for inclusion. AUTHORS' CONCLUSIONS: In the management of rheumatoid arthritis, the concurrent use of NSAIDs with methotrexate appears to be safe provided appropriate monitoring is performed. The use of anti-inflammatory doses of aspirin should be avoided.
21941193 Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy: expanding th 2011 Nov BACKGROUND: Hepatosplenic T-cell lymphoma (HSTCL) is a rare, lethal disease generally seen in young male patients with inflammatory bowel disease. The study of biologic and immunomodulator naive patients in Crohn's disease (SONIC), advocates combining infliximab with an immunomodulator in moderate-to-severe Crohn's disease. Unfortunately, combined immunosuppression increases risk for HSTCL. We herein review all cases of HSTCL reported to the Food and Drug Administration (FDA) in patients receiving TNF-α inhibitors. METHODS: Individual reports from the FDA Adverse Event Reporting System database for lymphomas from the biological agents - infliximab, adalimumab, certolizumab, natalizumab, and etanercept were downloaded and analyzed with Microsoft Access. Full reports for all identified HSTCL cases were obtained from the FDA. RESULTS: Twenty-five cases of HSTCL were identified. Twenty-two (88%) patients had inflammatory bowel disease and three had rheumatoid arthritis. Four cases (16%) were in women and four patients were above 65 years of age. Twenty-four cases (96%) also received an immunomodulator (azathioprine, 6-mercaptopurine, or methotrexate). Two patients received adalimumab alone. CONCLUSION: HSTCL is no longer restricted to the previously identified risk group of young male patients, but can also occur in patients with rheumatoid arthritis, females and older adults receiving TNF-α inhibitors and immunomodulators. Improved disease outcomes using combination therapy should be tempered by the risk of developing HSTCL.
21618201 Subcutaneous abatacept versus intravenous abatacept: a phase IIIb noninferiority study in 2011 Oct OBJECTIVE: To compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept. METHODS: In this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [∼10 mg/kg] on day 1) or IV abatacept (∼10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed. RESULTS: Of 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept-treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept-treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval -4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept-treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept-treated group and 65.2% and 4.9%, respectively, in the IV abatacept-treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)-treated patients (2.6%) and 18 IV abatacept (SC placebo)-treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept-treated patients and 2.3% of IV abatacept-treated patients. CONCLUSION: SC abatacept provides efficacy and safety comparable with that of IV abatacept, with low immunogenicity and high retention rates, consistent with the established IV abatacept profile. Rates of injection site reactions were low. SC abatacept will provide additional treatment options, such as an alternative route of administration, for patients with RA.
21724705 Efficacy and safety of CH-1504, a metabolically stable antifolate, in patients with active 2011 Sep OBJECTIVE: To investigate the potential efficacy, safety, and tolerability of daily use of CH-1504 in patients with active rheumatoid arthritis (RA). US National Institutes of Health database no. NCT00658047. METHODS: In our phase II randomized double-blind double-dummy study, patients naive to methotrexate (MTX; n = 201) and having moderate to severe RA received either CH-1504 (0.25 mg, 0.5 mg, or 1.0 mg once-daily oral doses) or MTX (titrated to 20.0 mg once-weekly oral doses). All received weekly 10-mg folate supplementation. Efficacy and safety were assessed at 2, 4, 8, and 12 weeks, with a treatment-free followup at 16 weeks. Safety and tolerability were assessed. Primary efficacy endpoint was proportion of patients achieving ACR20 response at Week 12. Secondary endpoints included difference from baseline in the 28-joint Disease Activity Score (DAS28) and individual components of the American College of Rheumatology (ACR) composite index. RESULTS: Demographic characteristics were similar in all treatment groups: mean age 54.3 ± 11.4 years, female sex 87%, mean baseline DAS28 6.6 ± 0.9. At Week 12, CH-1504 demonstrated comparable efficacy compared to MTX as measured by ACR20, DAS28, and ACR composite core-set measures, including tender and swollen joints. No dose-response relationship was observed. Adverse events across treatment groups were mild. Liver enzyme levels increased from baseline to Week 16 in the MTX group, with qualitatively lesser increases in the CH-1504 groups. Two patients in the MTX group withdrew because of gastrointestinal-related adverse events. CH-1504 appeared safe and well tolerated at all dose levels. CONCLUSION: CH-1504 has comparable efficacy to MTX and is safe and well tolerated. Metabolically stable antifolates are a promising therapeutic option that warrants further study.
22354637 Pneumocystis jirovecii pneumonia associated with etanercept treatment in patients with rhe 2012 Nov OBJECTIVES: The association of anti-tumor necrosis factor therapy with opportunistic infections in rheumatoid arthritis (RA) patients has been reported. The goal of this study was to clarify the clinical characteristics and the risk factors of RA patients who developed Pneumocystis jirovecii pneumonia (PCP) during etanercept therapy. METHODS: We conducted a multicenter, case-control study in which 15 RA patients who developed PCP were compared with 74 RA patients who did not develop PCP during etanercept therapy. RESULTS: PCP developed within 26 weeks following the first injection of etanercept in 86.7% of the patients. All PCP patients presented with a rapid and severe clinical course and the overall mortality was 6.7%. Independent risk factors were identified using multivariate analysis and included age ≥65 years [hazard ratio (HR) 3.35, p = 0.037], coexisting lung disease (HR 4.48, p = 0.009), and concomitant methotrexate treatment (HR 4.68, p = 0.005). In patients having a larger number of risk factors, the cumulative probability of developing PCP was significantly higher (p < 0.001 for patients with two or more risk factors vs. those with no risk factor, and p = 0.001 for patients with one risk factor vs. those with no risk factor). CONCLUSION: Physicians must consider the possibility of PCP developing during etanercept therapy in RA patients, particularly if one or more risk factors are present.
22595227 Enhanced COMP catabolism detected in serum of patients with arthritis and animal disease m 2012 Aug OBJECTIVE: The study aimed determining whether assessment of cartilage oligomeric matrix protein (COMP) degradation products could serve as a serological disease course and therapeutic response predictor in arthritis. METHODS: We generated a panel of monoclonal antibodies against COMP fragments and developed a novel capture enzyme-linked immunosorbent assay (ELISA) for detecting COMP fragments in patients with osteoarthritis (OA) and rheumatoid arthritis (RA). This test was also used to monitor COMP fragments in surgically-induced OA, collagen-induced arthritis (CIA), and tumor necrosis factor (TNF) transgenic animal models. RESULTS: Compared with a commercial COMP ELISA kit that detected no significant difference in COMP levels between OA and control groups, a significant increase of the COMP fragments were noted in the serum of OA patients assayed by this newly established ELISA. In addition, serum COMP fragment levels were well correlated with severity in OA patients and the progression of surgically-induced OA in murine models. Furthermore, the serum levels of COMP fragments in RA patients, mice with CIA, and TNF transgenic mice were significantly higher when compared with their controls. Interestingly, treatment with TNFα inhibitors and methotrexate led to a significant decrease of serum COMP fragments in RA patients. Additionally, administration of Atsttrin [Tang, et al., Science 2011;332(6028):478] also resulted in a significant reduction in COMP fragments in arthritis mice models. CONCLUSION: A novel sandwich ELISA is capable of reproducibly measuring serum COMP fragments in both arthritic patients and rodent arthritis models. This test also provides a valuable means to utilize serum COMP fragments for monitoring the effects of interventions in arthritis.
21914628 Clinical response and tolerability to abatacept in patients with rheumatoid arthritis prev 2011 Nov OBJECTIVE: To assess the efficacy and safety of abatacept in biological-naive patients with rheumatoid arthritis and an inadequate response to methotrexate treated in the long-term extension (LTE) of the ATTEST trial. METHODS: Patients randomly assigned to abatacept, placebo or infliximab completing the 1-year double-blind period were eligible to receive abatacept ∼10 mg/kg in the open-label LTE. Efficacy to year 2 is presented for patients randomly assigned to abatacept or infliximab who switched to open-label abatacept. Safety data are presented for all patients entering LTE regardless of double-blind treatment. RESULTS: Of 431 patients randomly assigned, 79.8% remained on abatacept at year 2. At years 1 and 2, 19.7% and 26.1% of abatacept and 13.3% and 28.6% of infliximab-to-abatacept patients achieved disease activity score 28-defined remission (<2.6). Safety with abatacept during the cumulative study period was consistent with the double-blind experience, with no increase in adverse event incidence following the switch to abatacept. CONCLUSION: In methotrexate-inadequate responders, abatacept efficacy was maintained over 2 years. For infliximab-to-abatacept patients, efficacy improvements were seen in year 2 after patients switched to abatacept. Switching directly from infliximab to abatacept was well tolerated. These data demonstrate that abatacept provides sustained responses and consistent safety, suggesting that switching from infliximab to abatacept is a viable treatment option.
21452922 Methotrexate chronotherapy is effective against rheumatoid arthritis. 2011 Apr Methotrexate (MTX) is the most important drug for treating rheumatoid arthritis (RA). It has been stated that cytokines play an important role in the pathogenesis of RA, and that cytokine levels increase and show 24-h rhythms in RA patients. Previously, we found that arthritis was relieved after the administration of MTX at specific times in synchronization with the 24-h rhythm of tumor necrosis factor (TNF)-α in collagen-induced arthritis (CIA) animals. Based on our findings in an earlier study of the dosing time-dependent effects of MTX in MRL/lpr mice, which develop autoimmune disorders that share similarities with human RA, we examined here the utility of MTX chronotherapy in Japanese RA patients. In an initial animal modeling study, we collected blood from MRL/lpr mice at different times (2, 6, 10, 14, 18, or 22 hours after the light was turned on [HALO]), and we measured TNF-α mRNA expression in leukocytes. MTX was administered to the mice at two different dosing times (6 or 18 HALO), and various blood parameters were measured to estimate arthritis activity. TNF-α mRNA levels showed a clear 24-h rhythm with a peak at 22 HALO and a trough at 18 HALO after RA had developed. In these MRL/lpr mice, inflammation and TNF-α were markedly reduced when the MTX dosing time was matched to the time (18 HALO) when the TNF-α level began to increase. We then applied these findings to Japanese RA patients by switching them from the standard MTX three times/wk (day 1: after breakfast and supper; day 2: after breakfast schedule), to chronotherapy, in which the dose and number of doses/wk were not changed but MTX was administered once-a-day at bedtime. Disease Activity Score (DAS)28, modified health assessment questionnaire (MHAQ), and adverse effects were assessed. With MTX chronotherapy, DAS28, which is commonly used to quantitatively assess RA symptoms, was significantly improved at all follow-up clinical visit times compared with the baseline (vs. 1 mo: p = .0197, 2 mos: p = .0107, 3 mos: p = .0087). Significant symptom recovery was observed in 41.2% of patients, and 23.5% of patients achieved clinical remission during the 3 mos of follow-up. Functional capacity of RA patients, as indicated by the MHAQ, was markedly improved by chronotherapy. There were no severe adverse effects. Thus, we demonstrated (i) inflammation and plasma TNF-α concentrations were significantly reduced in MRL/lpr mice treated with MTX at 18 HALO, the time when TNF-α mRNA level began to increase; and (ii) MTX bedtime chronotherapy was safe, markedly reduced disease activity, and improved the functional capacity of RA patients. The findings on RA patients show that bedtime MTX chronotherapy can improve RA symptoms compared to the current standard dosing methods.
21693740 Association between disease-modifying antirheumatic drugs and diabetes risk in patients wi 2011 Jun 22 CONTEXT: Rheumatoid arthritis (RA) and psoriasis have been linked with insulin resistance and diabetes mellitus (DM). Prior investigations suggest that systemic immunosuppressive drugs may improve insulin resistance and reduce the risk of DM. OBJECTIVE: To compare the risk of newly recorded DM among participants diagnosed with RA or psoriasis based on use of a variety of disease-modifying antirheumatic drugs (DMARDs). DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study among 121,280 patients with a diagnosis of either RA or psoriasis on at least 2 visits. The analyses were conducted in the context of 2 large health insurance programs, 1 in Canada and 1 in the United States, using administrative data. The mean follow-up was 5.8 months and began with the first prescription for a DMARD after study eligibility was met. Drug regimens were categorized into 4 mutually exclusive groups: (1) tumor necrosis factor (TNF) inhibitors with or without other DMARDs; (2) methotrexate without TNF inhibitors or hydroxychloroquine; (3) hydroxychloroquine without TNF inhibitors or methotrexate; or (4) other nonbiologic DMARDs without TNF inhibitors, methotrexate, or hydroxychloroquine (reference exposure). MAIN OUTCOME MEASURE: Newly recorded DM as evidenced by a new diagnosis of DM with use of a DM-specific medication. RESULTS: The study cohort consisted of 13,905 participants with 22,493 treatment episodes starting 1 of the categories of DMARD regimens between January 1996 and June 2008. New diabetes cases and respective incidence rates per 1000 person-years were: other nonbiologic DMARDs (55 cases among 3993 treatment episodes; rate, 50.2; 95% confidence interval [CI], 47.3-53.2); TNF inhibitors (80 cases among 4623 treatment episodes; rate, 19.7; 95% CI, 19.1-20.3); methotrexate (82 cases among 8195 treatment episodes; rate, 23.8; 95% CI, 23.0-24.6); and hydroxychloroquine (50 cases among 5682 treatment episodes; rate, 22.2; 95% CI, 21.3-23.1). The multivariate adjusted hazard ratios for DM were 0.62 (95% CI, 0.42-0.91) for TNF inhibitors, 0.77 (95% CI, 0.53-1.13) for methotrexate, and 0.54 (95% CI, 0.36-0.80) for hydroxychloroquine compared with other nonbiologic DMARDS. CONCLUSION: Among patients with RA or psoriasis, the adjusted risk of DM was lower for individuals starting a TNF inhibitor or hydroxychloroquine compared with initiation of other nonbiologic DMARDs.
22873531 Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. 2012 Aug 9 BACKGROUND: Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis. METHODS: In this 12-month, phase 3 trial, 717 patients who were receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of adalimumab once every 2 weeks, or placebo. At month 3, patients in the placebo group who did not have a 20% reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily; at month 6, all patients still receiving placebo were switched to tofacitinib in a blinded fashion. The three primary outcome measures were a 20% improvement at month 6 in the American College of Rheumatology scale (ACR 20); the change from baseline to month 3 in the score on the Health Assessment Questionnaire-Disability Index (HAQ-DI) (which ranges from 0 to 3, with higher scores indicating greater disability); and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity). RESULTS: At month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%) (P<0.001 for all comparisons). There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28-4(ESR) below 2.6 at month 6 in the active-treatment groups than in the placebo group. Adverse events occurred more frequently with tofacitinib than with placebo, and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group. Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts. CONCLUSIONS: In patients with rheumatoid arthritis receiving background methotrexate, tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy. (Funded by Pfizer; ORAL Standard ClinicalTrials.gov number, NCT00853385.).
21892671 Study protocol of a multicenter registry of patients with rheumatoid arthritis starting bi 2012 Jun Biologic agents have proven to be effective against rheumatoid arthritis (RA) in clinical trials and post-marketing surveillance (PMS) studies. However, limited follow-up periods and strict criteria for recruitment might lead to an underestimation of adverse events. To document the long-term course of patients with RA treated with biologics in clinical settings, we established the Tsurumai Biologics Communication Registry (TBCR). First, we retrospectively collected data of patients registered for any biologic PMS study or clinical trial at participating institutes. Thus far, thirteen institutes have joined the registry and 860 patients have been identified. Comparing baseline characteristics by age and initiation year of biologics, young patients had significantly less joint damage and dysfunction and a higher dose of concomitant methotrexate (MTX) compared to older patients. Older age and functional class were significantly related to the incidence of adverse events that resulted in discontinuation of the 1st biologic treatment. The TBCR is in its initial stages, and information on all patients newly starting biologic therapy at participating institutes is being collected prospectively. Differences in baseline characteristics by age and initiation year of biologics need to be carefully evaluated in order to report on drug-related survival and long-term prognosis, using follow-up data in the near future.
23108887 Tocilizumab in the treatment of the adult-onset Still's disease: current clinical evidence 2013 Jan This study aimed to review and analyze the effectiveness and safety of tocilizumab in the treatment of patients with adult-onset Still's disease (AOSD). We report on two patients with AOSD who were successfully treated with tocilizumab. All published information on the use of tocilizumab in this disease was also retrieved through a systematic review of the English-language literature. Including our cases, 35 patients were given tocilizumab for AOSD (8 mg/kg/month in 22 patients). The main clinical manifestations were arthritis in all 35 patients and systemic symptoms such as fever or skin rash in 28 (80 %). Thirty-three (94 %) patients had unsuccessfully tried other immunosuppressive agents such as methotrexate, tumor necrosis factor-α blockers, or anakinra. Most of the patients achieved a response with tocilizumab, such as a prompt articular improvement in 30/35 (86 %) patients and a disappearance of systemic symptoms in 27/28 (96 %). Twenty-eight (80 %) patients tapered their steroid intakes, including seven (20 %) who were able to discontinue them. Four (11 %) patients relapsed, and two were successfully retreated with tocilizumab. Regarding safety, tocilizumab is a well-tolerated treatment, but severe side effects such as macrophage activation syndrome or cytomegalovirus reactivation are possible and require ongoing vigilance. Our findings suggest that tocilizumab should probably be proposed in refractory AOSD, as it allows for remission to be induced and the dose of steroid intakes to be reduced. It is a well-tolerated treatment that can be administered according to the therapeutic sequence of rheumatoid arthritis. Further prospective studies are required to assess the better use of this treatment (dosage and duration) and its place among other conventional treatments.
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.
22763150 Efficacy of leflunomide 100mg weekly compared to low dose methotrexate in patients with ac 2012 Sep OBJECTIVE: To determine the clinical efficacy and safety of Leflunomide (LFN) 100 mg/week compared to low dose Methotrexate (MTX) 10 mg/week in a double-blind, randomized, controlled trial with 52 weeks of follow up in Rheumatoid Arthritis (RA) patients. PATIENTS AND METHODS: Patients who met ARC1987 criteria for RA were included. All patients had medical records, including laboratory tests and hand X-rays. Clinical evaluations for improvement and ACR and EULAR response criteria were performed. Statistical analysis for independent's samples between both groups defined a P value of ≤.05. Safety was evaluated by comparing the proportion of adverse events (AE) registered. RESULTS: Of 90 patients screened; five were withdrawn; the remaining 85 patients were randomised: 43 LFN and 42 MTX. Sixty-three patients completed the study; 72% in the LFN group and 74.4% in the MTX group. ACR20 improvement criteria were achieved by LFN group in 90.3%, and in MTX 78.1% (P=.14) at week 52. EULAR improvement criteria applied at the end point showed a DAS28 score for the LFN group of 3.45, and for the MTX group was 3.67(P=.43). Total withdrawals, including loss during follow up, AE and lack of efficacy for each group was 12 patients in the LFN group, and 10 patients in the MTX group. Regarding safety, no serious AE of a life threatening nature were reported. CONCLUSIONS: These outcomes confirm that LFN 100 mg/week offers an adequate and sustained improvement effect on the clinical manifestations of RA, similar to low dose treatment with MTX 10 mg/every week after 52 weeks of follow up; it may be a good therapeutic option alone or in combination with others anti-rheumatic drugs.
21736857 Cost-effectiveness of etanercept treatment in early active rheumatoid arthritis followed b 2011 Jul OBJECTIVES: To explore the cost-effectiveness of early biologic treatment, followed by dose-reduction in the case of remission, of active rheumatoid arthritis (RA), compared with standard treatment with methotrexate (MTX) in Sweden. METHODS: Effectiveness (function, disease activity, erosions) in early RA for both alternatives was taken from a clinical trial comparing etanercept (ETA) combined with MTX to MTX alone. Patients discontinuing treatment can switch to another or their first biologic treatment. For patients in remission (Disease Activity Score [DAS28] < 2.6), ETA is reduced to half the dose. Return to full dose occurs when DAS28 reaches ≥ 3.2 again. Costs and utilities by level of functional capacity from an observational study are used. The model is analyzed as a micro-simulation and results are presented from the societal perspective for Sweden, for 10 years; costs (€2008) and effects are discounted at 3 percent. Sensitivity analysis was performed for the perspective, the time horizon, switching, and dose-reduction. RESULTS: The main analysis conservatively assumes 50 percent switching at discontinuation. The cost per quality-adjusted life-year (QALY) gained with early ETA/MTX treatment is €13,500 (societal perspective, incremental cost of €15,500 and incremental QALYs of 1.15). With 75 percent switching, the cost per QALY gained was €10,400. Over 20 years, the cost per QALY gained was €8,200. Results were further sensitive to the time patients remained on half dose and the perspective. CONCLUSIONS AND POLICY IMPLICATIONS: This study combines clinical trial and clinical practice data to explore cost-effective treatment scenarios in early RA, including the use of biologics. Our results indicate that a situation where a considerable proportion of patients achieve remission, dose-adjustments will increase the cost-effectiveness of treatment.
22516985 [Sulphasalazine in patients with rheumatoid arthritis in China: a cross-sectional study]. 2012 Apr 18 OBJECTIVE: To investigate the medication status of rheumatoid arthritis (RA) patients and to analyze the clinical use of sulphasalazine (SSZ) and the adverse effect. METHODS: A total of 1 096 outpatients and inpatients diagnosed with RA were investigated in 21 hospitals all over China from July 2009 to December 2010, including gender, age of onset, clinical manifestations, as well as the clinical characteristics and medication status of 160 RA patients who received SSZ therapy. RESULTS: In the group of 160 patients who received SSZ, the male-to-female ratio was 1:7, The average age at onset was (46.1±15.0) years, while the average course was (9.9±7.8) years. The average dose of sulphasalazine was (1.87±0.52) g/d for a mean duration of (26.3± 14.6) months. Only 17% (27/160) of the patients received SSZ monotherapy. Methotrexate (63.1%), leflunomide (36.2%) and hydroxychloroquine (18.1%) were most commonly used combination drugs. And 36.2% (58/160) of the patients used the two-drug combination of methotrexate plus sulphasalazine .In this group, 41.9% (67/160) once used SSZ but withdrew for adverse events and other reasons, while 17.5% (28/160) withdrew for adverse events, of which the most common were gastrointestinal (8.8%), skin (3.8%) and liver toxicity (3.1%). CONCLUSION: Sulphaszlazine is not a common choice in the RA therapeutics in China, and the average dose of SSZ is lower than the standard dose of 2 to 3 g/d . The adverse events of SSZ are common; however, there are few severe adverse events or threat to life,SSZ is relatively safe in clinical practice.
22923753 Efficacy and safety of certolizumab pegol in a broad population of patients with active rh 2012 Dec OBJECTIVE: To investigate the efficacy and safety of certolizumab pegol (CZP) in a broad population of patients with active RA. METHODS: In this 12-week, double-blind period of the phase IIIb trial, RA patients with inadequate response to at least one DMARD were randomized 4:1 to CZP (400 mg at weeks 0, 2 and 4, followed by 200 mg every 2 weeks) or placebo (every 2 weeks) plus current therapy stratified by previous TNF inhibitor use, concomitant methotrexate use and disease duration (<2 vs ≥2 years). The primary outcome was ACR20 response rate at week 12. RESULTS: Of 1063 patients (CZP = 851; placebo = 212), 37.6% had previous TNF inhibitor use. Baseline mean HAQ Disability Index (HAQ-DI) and DAS 28-joint assessment-ESR [DAS28(ESR)] values were 1.5 and 6.4 in the CZP group, and 1.6 and 6.4 in the placebo group, respectively. The primary endpoint was significant (week 12 ACR20, CZP vs placebo: 51.1 vs 25.9%; P < 0.001); differences were noted at week 2 (31.8 vs 8.5%; P < 0.001). HAQ-DI and DAS28(ESR) change from baseline and ACR50 were significant from week 2. Week 12 ACR20 responses were similar across CZP patient subgroups regardless of concomitant DMARD use at baseline. Adverse and serious adverse events were comparable between CZP and placebo, with no new safety signals. CONCLUSION: CZP was associated with rapid and consistent clinical responses and improved physical function in a diverse group of RA patients, irrespective of concomitant or previous therapy. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00717236.
22876713 [Liver diseases in rheumatoid and psoriatic arthritis]. 2012 Jun OBJECTIVE: The aim of this study was to evaluate the prevalence, risk factors and features of liver diseases (LD) in rheumatoid and psoriatic arthritis. PATIENTS AND METHODS: From July 2007 to January 2010, 118 non-selected patients were consecutively examined. The assessment consisted of a medical record, biochemical studies and abdominal ultrasounds. The diagnosis of fatty liver disease was based on the ultrasound drug induced liver injury (DILI) was evaluated by the Maria-Victorino system criteria. Liver biopsy associated with chronic administration of methotrexate was performed using the histological classification of Kleiner et al. For the statistical analysis chi square test with Yates correction, Student's t test or Mann-Whitney test were applied when appropriate. In the multivariate analysis a binary logistic regression was used. The threshold of significance was P < 0.05. RESULTS: LD was diagnosed in 47 patients (39.8%). The most frequent LD was fatty liver disease in 35 patients (29.7%), followed by DILI in 15 (12.7%), associated with non-steroidal anti-inflammatory drugs (NSAID). In the multivariate analysis, obesity was the only independent risk factor associated with fatty liver disease [Odds ratio (OR) 6.4 (confidence interval (CI) 95%: 2.5-16.1; P = 0.000)] and fatty liver disease was the only risk factor associated with DILI [OR 7.7 (CI 95%: 2.0-30.0; P = 0.003)]. CONCLUSIONS: In our series, there was a high prevalence of LD, being fatty liver disease associated with obesity the most frequent finding. The second frequent disease was DILI, being fatty liver disease its main risk factor. The presence of obesity and the use of NSAIDs, especially in patients with steatosis, arise from our results as two conditions that require special care in handling this particular population.
20838203 Disseminated tuberculosis secondary to adalimumab. 2012 Jul A 62-year-old woman with rheumatoid arthritis presented with fever (T-103.9°F). Vital signs and physical examination were normal. She was taking adalimumab, methotrexate, and prednisone for the past 9 months. Blood and urine cultures, human immunodeficiency virus, rapid plasma reagin, purified protein derivative, and cerebrospinal fluid test findings were negative. Computed tomography showed scattered 0.2-cm nodules in the lungs and innumerable subcentimeter lesions in the liver and spleen. Broad-spectrum antibiotics were started empirically. Liver biopsy findings revealed necrotizing granulomas and were negative for acid fast bacilli and fungi on staining. As the patient was persistently febrile despite antibiotics, the antibiotics were discontinued, and an antituberculous regimen including INH, ethambutol, and pyrazinamide was initiated empirically on day 40 of hospitalization. Fourteen days after liver biopsy, acid-fast bacilli grew in the tissue culture. Disseminated tuberculosis (TB) was diagnosed. Fever subsided after 1 week of anti-TB treatment. Antitumor necrosis factor alpha therapy in rheumatoid arthritis increases the risk of TB 5-fold. This is mostly as a result of reactivation of latent TB and commonly presents as disseminated TB. It usually occurs in the early stage of treatment. In our patient, the screening test results for TB before initiation of Adalimumab could have been falsely negative due to immunosuppression secondary to steroids. Our case emphasizes that current screening tests can miss latent TB especially in immunosuppressed patients. As it is difficult to diagnose TB with polymerase chain reaction and culture, histopathology should be sought early. Patients on antitumor necrosis factor alpha therapy presenting with fever of unknown origin should be considered for empirical anti-TB treatment regardless of microbiological and tissue diagnosis.
21496415 Efficacy and safety of leflunomide or methotrexate plus subcutaneous tumour necrosis facto 2011 Jan Several smaller retrospective case series have concluded that leflunomide (LEF) in combination with anti-TNF-alpha blocking agents appears to be effective and safe. Prospective case series and cohort studies have generally confirmed the efficacy of this combination. Overall, there is currently no evidence from controlled trials that an anti-TNF-alpha combination with LEF is as effective as an anti-TNF-alpha combination with methotrexate (MTX). We compared the effectiveness and safety of a therapeutic regimen associating subcutaneous anti-TNF-alpha agents, etanercept (ETN) and adalimumab (ADA), with leflunomide (LEF) or methotrexate (MTX), in a two year open-label study performed in clinical practice. We evaluated 96 patients with active rheumatoid arthritis undergoing therapy with ADA at the dose of 40 mg every other week, or with ETN at the dose of 50 mg/week for two years added to prednisolone (PDN) at the mean dose of 5.2±2.6 mg/day. Fifty-four of these patients were also undergoing therapy with MTX at the mean dose of 11.7±2.6 mg/week, while 42 patients were undergoing therapy with LEF at the daily dose of 20 mg. At 12 months, the analysis of variance showed an improvement of DAS28 in both groups (p<0.001), with a reduction in 33.3% of the patients in treatment with LEF and in 51.8% of the patients in treatment with MTX (p = 0.20). At 18 months, improvement was present in 33.3% of the patients in the LEF group and in 81.5% of the patients in the MTX group (p=0.001). This improvement seems to be independent of the anti-TNF-alpha agent, even if MTX produces the highest DAS28 reduction when used in association with ETN (p<0.078). We found no difference in drug discontinuation rates or in effectiveness measures between anti-TNFalpha+MTX and anti-TNFalpha+LEF. Our data showed a greater reduction of DAS28 in the MTX group and, in combination with ETN, better results after two years of therapy.