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ID PMID Title PublicationDate abstract
21295822 Treatment of early rheumatoid arthritis: concepts in management. 2011 Apr OBJECTIVES: The early diagnosis and treatment of rheumatoid arthritis (RA) are important goals for rheumatologists. This article provides a review of the literature describing evolving concepts in the treatment of early RA, studies that evaluate treatment strategies using a predefined target, and methods to identify patients who are at higher risk for progressive joint damage. METHODS: We conducted a PubMed search for randomized trials using the terms "early rheumatoid arthritis" and subsequently "tight control" to compare the outcomes of studies using early intervention with biologics and disease-modifying antirheumatic drugs (DMARDs) in early RA and also to compare outcomes of strategies of treatment using a predefined target. RESULTS: The study designs and outcomes of clinical trials of DMARDs and biologic agents in early RA are presented. Early, prompt therapy with combination DMARDs or biologics combined with methotrexate leads to improved outcomes for patients with early RA. In studies where treatment was targeted to a specific outcome, such as remission, the target was achieved more often with targeted treatment than when patients received routine care. Patients who are more likely to experience a rapid disease course that is associated with joint destruction can be identified based on clinical and laboratory variables shown to be predictors of rapid progression. CONCLUSIONS: Early assessment and close monitoring of patients with early RA, targeting remission where possible, are important to optimize long-term outcomes. Specific treatment can be selected from among the many proven therapies to obtain the best results for the individual patient.
22308630 Methotrexate and post operative complications in patients with rheumatoid arthritis underg 2011 Dec In the 1990's there were concerns that methotrexate might increase the risk of post operative complications following elective orthopaedic surgery; as a result many Units initiated policies to discontinue methotrexate prior to elective orthopaedic surgery. In 2001 we carried out a controlled study of complications after elective surgery in rheumatoid arthritis (RA) patients who either continued or discontinued methotrexate prior to surgery. In this study we showed that continuation of methotrexate therapy prior to orthopaedic surgery did not increase the risk of infection or surgical complication occurring in patients with RA within one year of surgery. The limitation of this study was that complications later than one year were not studied. Sixty-five patients have been followed up. Thirty-one were fully assessed in clinic and 34 underwent a structured telephone interview. There were no incidences of deep bone infection in any patient group so that there is no evidence that continued methotrexate therapy in the perioperative period increases the risk of late deep infections. We adhere to our original advice that in the absence of renal failure or sepsis, methotrexate therapy should not be stopped before elective orthopaedic surgery in patients with RA whose disease is controlled by the drug before surgery.
22137923 B-cell therapies in established rheumatoid arthritis. 2011 Aug B-cell depletion therapy based on rituximab is effective and relatively safe in established rheumatoid arthritis. Rituximab is licensed for the treatment of rheumatoid arthritis in combination with methotrexate and in patients who did not respond or cannot tolerate tumour necrosis factor antagonists. Sustained control of disease activity can be achieved by repeated courses of treatment. The optimal dose and schedule of retreatment are still not established. Nevertheless, data are now available that provide a good base for current clinical practice and a good starting point for further research. In general, rituximab has a good safety profile with most studies showing similar incidences of serious adverse events and infections to placebo. However, reasonable and well-funded doubts remain over the safety of long-term strategies of treatment of rheumatoid arthritis with rituximab, in particular, in relation to the risk of secondary hypogammaglobulinaemia and potential increased risk of infections.
21691744 Methotrexate attenuates the Th17/IL-17 levels in peripheral blood mononuclear cells from h 2012 Aug To investigate whether the inhibition of Th17/interleukin (IL)-17 contributes to the beneficial effects of methotrexate (MTX) in the treatment of rheumatoid arthritis (RA). Peripheral blood mononuclear cells (PBMCs) from healthy donors and RA patients were collected. The cells were stimulated with monoclonal antibodies to CD3 and CD28 in the absence or presence of MTX. After coincubation, IL-17 production was detected at both the mRNA and protein levels, and the percentage of cells positive for both CD4 and IL-17 in PBMCs was analyzed by flow cytometry. PBMCs of healthy donors and RA patients were stimulated with CD3 and CD28 monoclonal antibodies to produce high levels of IL-17. The augmentation of IL-17 at the mRNA and protein levels was significantly inhibited when PBMC cultures were preincubated with MTX. Compared with PBMCs of healthy donors, PBMCs of RA patients produced higher levels of IL-17, and this increase in IL-17 levels was more inhibited by MTX pretreatment. MTX inhibited IL-17 at the mRNA level in a dose-dependent manner, but not at the protein level, in both PBMCs of healthy donors and RA patients. MTX did not affect the percentage of CD4- and IL-17-positive cells in PBMCs. MTX dose dependently suppressed the production of IL-17 at the mRNA level by PBMCs from healthy donors and RA patients. Suppression of IL-17 by MTX may contribute to its potent anti-inflammatory role in RA therapy.
20862678 Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment 2011 Jan OBJECTIVE: To determine whether cigarette smoking influences the response to treatment in patients with early rheumatoid arthritis (RA). METHODS: We retrieved clinical information about patients entering the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) early RA cohort from 1996 to 2006 (n=1,998) who were also in the Swedish Rheumatology Register (until 2007). Overall, 1,430 of the 1,621 registered patients were followed up from the time of inclusion in the EIRA cohort. Of these, 873 started methotrexate (MTX) monotherapy at inclusion, and 535 later started treatment with a tumor necrosis factor (TNF) inhibitor as the first biologic agent. The primary outcome was a good response according to the European League Against Rheumatism criteria at the 3-month visit. The influence of cigarette smoking (current or past) on the response to therapy was evaluated by logistic regression, with never smokers as the referent group. RESULTS: Compared with never smokers, current smokers were less likely to achieve a good response at 3 months following the start of MTX (27% versus 36%; P=0.05) and at 3 months following the start of TNF inhibitors (29% versus 43%; P=0.03). In multivariate analyses in which clinical, serologic, and genetic factors were considered, the inverse associations between current smoking and good response remained (adjusted odds ratio [OR] for MTX response 0.60 [95% CI 0.39-0.94]; adjusted OR for TNF inhibitor response 0.52 [95% CI 0.29-0.96]). The lower likelihood of a good response remained at later followup visits. Evaluating remission or joint counts yielded similar findings. Past smoking did not affect the chance of response to MTX or TNF inhibitors. Evaluating the overall cohort, which reflects all treatments used, current smoking was similarly associated with a lower chance of a good response (adjusted ORs for the 3-month, 6-month, 1-year, and 5-year visits 0.61, 0.65, 0.78, 0.66, and 0.61, respectively). CONCLUSION: Among patients with early RA, current cigarette smokers are less likely to respond to MTX and TNF inhibitors.
22127692 Blood memory B cells are disturbed and predict the response to rituximab in patients with 2011 Dec OBJECTIVE: To examine blood B cell subsets in patients with rheumatoid arthritis (RA) prior to B cell depletion therapy and to assess their potential as predictors of clinical response to rituximab (RTX). METHODS: Blood B cell subsets were assessed by flow cytometry in 208 RA patients included in an RTX retreatment study (assessed prior to RTX treatment) and in 47 age-matched controls. Expression of BAFF receptor (BAFF-R) on B cells and serum B cell biomarkers was also measured. B cell subsets and BAFF-R expression were compared between RA patient and control populations. Univariate and multivariate analyses were performed to identify baseline factors associated with a European League Against Rheumatism response 24 weeks after 1 cycle of RTX. RESULTS: Mean ± SD counts of both CD27- naive and CD27+ memory B cells were decreased in RA patients (188.6 ± 121.4/mm(3)) compared with controls (257.3 ± 154.1/mm(3)) (P = 0.001) and were partially restored in patients treated with methotrexate (MTX) plus anti-tumor necrosis factor compared with patients treated with MTX alone. Within the CD27+ memory B cells, the CD27+IgD- switched memory subtype was selectively decreased, irrespective of treatment. The frequency of CD27+ memory B cells correlated inversely with levels of several B cell activation biomarkers in RA. Serum BAFF level and BAFF-R expression was comparable in RA patients and controls. A low baseline CD27+ memory B cell frequency was associated with a greater clinical response to RTX (odds ratio 0.97 [95% confidence interval 0.95-0.99], P = 0.0015). CONCLUSION: In B cell depletion therapy-naive RA patients, a low frequency of CD27+ memory B cells correlated with levels of serum B cell activation biomarkers and may predict response to RTX. These results suggest that low memory B cell frequency may be indicative of a B cell-driven RA subtype that is more sensitive to B cell depletion therapy.
21998118 Predicting low disease activity and remission using early treatment response to antitumour 2012 Feb OBJECTIVE: To derive and validate decision trees to categorise rheumatoid arthritis (RA) patients 12 weeks after starting etanercept with or without methotrexate into three groups: patients predicted to achieve low disease activity (LDA) at 1 year; patients predicted not to achieve LDA at 1 year and patients who needed additional time on therapy to be categorised. METHODS: Data from RA patients enrolled in the TEMPO trial were analysed. Classification and regression trees were used to develop and validate decision tree models with week 12 and earlier assessments that predicted long-term LDA. LDA, defined as disease activity score in 28 joints (DAS28) ≤3.2 or clinical disease activity index ≤10.0, was measured at 52 or 48 weeks. Demographics, laboratory data and clinical data at baseline and to week 12 were analysed as predictors of response. RESULTS: 39% (67/172) of patients receiving etanercept and 60% (115/193) of patients receiving etanercept plus methotrexate achieved LDA at week 52. For patients receiving etanercept, 53% were predicted to have LDA, 39% were predicted not to have LDA and 8% could not be categorised using DAS28 criteria at week 12. For patients receiving etanercept plus methotrexate, 63% were predicted to have LDA, 25% were predicted not to have LDA and 12% could not be categorised. CONCLUSION: Most (80-90%) patients in TEMPO initiating etanercept with or without methotrexate could be predicted within 12 weeks of starting therapy as likely to have LDA or not at week 52. However, approximately 10-20% of patients needed additional time on therapy to decide whether to continue treatment.
22871244 [Prednisone for rheumatoid arthritis: the detriment of the doubt]. 2012 Physicians pride themselves on practicing evidence-based medicine. However, these principles appear not to apply in the case of glucocorticoid therapy for rheumatoid arthritis (RA). Despite a sizable body of evidence, glucocorticoids are underutilised in the treatment of RA. Hench's 1950 acceptance speech for the Nobel Prize (which he shared with Kendall and Reichstein for the discovery of glucocorticoids) illustrated his awareness of the benefits and risks of these agents. Although glucocorticoids have proved beneficial in randomized trials from 1955 onwards, only a perception of harm has endured. The recently published CAMERA-2 trial data could be the final piece of evidence added to the substantial body of literature proving that prednisone 10 mg/d given for 2 years in early RA, in addition to high-dose methotrexate, is better than methotrexate alone in inducing remission and preventing joint damage, and is accompanied by fewer side effects. Existing treatment guidelines need to be urgently updated to reflect these findings.
22382341 Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patient 2012 Apr OBJECTIVE: To evaluate efficacy and safety of CE-224,535, a selective P2X(7) receptor antagonist, versus placebo, in patients with active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX). METHODS: In our phase IIA study (ClinicalTrials.gov no. NCT00628095; A6341009), patients aged ≥ 18 years with active RA were randomized to receive either CE-224,535 (500 mg bid) or placebo for 12 weeks; all patients continued a stable background dose of ≥ 7.5 mg MTX. RESULTS: The American College of Rheumatology 20% (ACR20) response rate (primary efficacy endpoint) was not significantly different from placebo for CE-224,535 (34.0% vs 36.2%; p = 0.591) at Week 12, or at any timepoint over the 12-week treatment period. There was no significant difference at Week 12 for the ACR20 response rate following subgroup analyses by age, sex, baseline disease activity, baseline duration of disease, geographic region, or concomitant use of steroids. ACR50/ACR70 response rates and change from baseline in Disease Activity Score 28-joint C-reactive protein (DAS28-3-CRP) and Health Assessment Questionnaire-Disability Index for CE-224,535 were not significant at Week 12 versus placebo. Treatment-emergent adverse events (AE) were reported by 62.3% (CE-224,535) and 55.3% (placebo) of patients; the most common AE were nausea (11.3%, CE-224,535; 4.3%, placebo) and diarrhea (7.5%, CE-224,535; 4.3%, placebo). The proportion of patients discontinuing due to an AE was 9.4% (CE-224,535) and 6.4% (placebo); no deaths were reported. Serious AE occurred in 3.8% (CE-224,535) and 2.1% (placebo) of patients; none was considered treatment-related. CONCLUSION: CE-224,535 was not efficacious, compared with placebo, for the treatment of RA in patients with an inadequate response to MTX. CE-224,535 demonstrated an acceptable safety and tolerability profile.
21821865 Sustained disease remission and inhibition of radiographic progression in methotrexate-nai 2011 Nov OBJECTIVE: To assess the efficacy and safety of abatacept plus methotrexate versus methotrexate alone in early erosive rheumatoid arthritis (RA). METHODS: The AGREE was a 2-year phase IIIb multinational study in early (≤ 2 years) RA. During the double-blind period (year 1), patients were randomly assigned 1:1 to receive abatacept+methotrexate or methotrexate alone; all patients received open-label abatacept+methotrexate during year 2. Clinical outcomes assessed included 28-joint disease activity score (DAS28) defined remission, low disease activity score (LDAS), American College of Rheumatology (ACR) responses and physical function. Radiographic outcomes were assessed using the Genant-modified Sharp total score (TS). Safety was monitored throughout. RESULTS: Of the 459 patients completing year 1, 433 patients (94.3%) completed year 2. DAS28-defined remission, LDAS, ACR and physical function were sustained through year 2 in the original abatacept+methotrexate group, with 55.2% in remission at 2 years. Upon introduction of abatacept in the methotrexate-alone group, additional patients achieved DAS28-defined remission (44.5% vs 26.9%), LDAS (60.4% vs 43.2%) and improved ACR 70 (49.8% vs 31.7%) for year 2 versus year 1. Less radiographic progression was observed at 2 years in the original abatacept+methotrexate group than the methotrexate-alone group (change in TS 0.84 vs 1.75, p<0.001). No new safety issues were seen. Similar rates of serious adverse events, serious infections and autoimmune events were observed in years 1 and 2. CONCLUSIONS: The AGREE trial was the first to examine the impact of T-cell co-stimulation modulation with abatacept in patients with early erosive RA. Early treatment with abatacept+methotrexate resulted in greater sustainable clinical, functional and radiographic benefits than methotrexate alone, with acceptable safety and tolerability. TRIAL REGISTRATION: NCT00122382.
22012969 Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early 2012 Mar BACKGROUND: In the IMAGEstudy, rituximab plus methotrexate (MTX) inhibited joint damage and improved clinical outcomes at 1 year in MTX-naïve patients with early active rheumatoid arthritis. OBJECTIVE: The aim of this study was to assess joint damage progression and clinical outcomes over 2 years. METHODS: Patients (n=755) were randomised to receive rituximab 2×500 mg+MTX, 2×1000 mg+MTX or placebo+MTX. The placebo-controlled period continued to week 104. Two-year end points were defined as secondary or exploratory and included change in total Genant-modified Sharp score (mTSS), total erosion score and joint space narrowing score from baseline to week 104. Clinical efficacy and physical function end points were also assessed. RESULTS: At 2 years, rituximab 2×1000 mg+MTX maintained inhibition of progressive joint damage versus MTX alone (mTSS change 0.41 vs 1.95; p<0.0001 (79% inhibition)), and a higher proportion of patients receiving rituximab 2×1000 mg+MTX had no radiographic progression over 2 years compared with those receiving MTX alone (57% vs 37%; p<0.0001). Contrary to 1-year results, exploratory analysis of rituximab 2×500 mg+MTX at 2 years showed that progressive joint damage was slowed by ∼61% versus placebo+MTX (mTSS, exploratory p=0.0041). Improvements in clinical signs and symptoms and physical function seen after 1 year in rituximab-treated patients versus those receiving placebo were maintained at year 2. Safety profiles were similar between groups. CONCLUSIONS: Treatment with rituximab 2×1000 mg+MTX was associated with sustained improvements in radiographic, clinical and functional outcomes over 2 years. Clinical trials.gov identifier NCT00299104.
22089073 [How to effectively use methotrexate in rheumatoid arthritis?]. 2012 Jan Methotrexate (MTX) is the first choice disease modifying anti-rheumatic drugs for rheumatoid arthritis. In spite of its generalized use by rheumatologists worldwide, there is a general lack of agreement regarding the route of administration, the start-up dose and the way to increase the same. In this article we propose a simplified outline for the use of the drug that should be individualized, based on it's pharmacological aspects, guidelines and recommendations published in high impact factor journals during the past few years. Adverse reactions and side effects, as well as their follow up are also reviewed.
22338476 [Association of TNF-alpha polymorphism (-308 A/G) with high activity of rheumatoid arthrit 2011 Nov INTRODUCTION: Genetic markers are significant predictive factors in the assessment of therapeutic response of rheumatoid arthritis (RA) to biological medication. OBJECTIVE: The aim of the study was to determinate the association of TNF-alpha -308 G/A polymorphism with a high RA activity and its predictive value in therapeutic response after 12 months of treatment with Etanercept. METHODS: The study enrolled 132 patients with RA treated with Methotrexate (MTX) and 58 control subjects. The -308 TNF polymorphism was examined using the polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP). The patients were divided into two groups: group A with A/A and A/G genotype and group G with G/G genotype. After 12 months, beside MTX, Etanercept was introduced in 36 patients. We compared clinical activity among the groups at the beginning and after one year of therapy by using DAS28 SE (Disease activity score with sedimentation). RESULTS: There was no significant difference found in the distribution of G and A allele in the RA group compared to the control group. A significantly higher disease activity was noticed in A compared to the G group (DAS28 SE: 6.31 to 5.81; p < 0.05). The patients with A allele kept the majority of the disease activity even after a year of study (DAS28 SE: 5.25 to 3.89). After a year of MTX and Etanercept therapy, a significantly larger proportion of patients in the G group displayed a good clinical response to treatment compared to the A group (81.5% to 25%; p < 0.05). The average change of DAS28 SE in G group was 2.24, while in the A group DAS 28 reduction was significantly lower (1.17; p = 0.005). CONCLUSION: There was no significant difference in the frequency of A in the patients with RA compared to healthy subjects. The presence of A allele is associated with more serious clinical presentation of the disease and lower therapeutic response to Etanercept.
23095111 Pharmacogenetic polymorphisms contributing to toxicity induced by methotrexate in the sout 2012 Nov Abstract Rheumatoid arthritis (RA) is a common illness of global significance for public health. Methotrexate (MTX) is the most broadly used disease-modifying antirheumatic drug for the treatment of RA, but it displays marked person-to-person variation in its propensity for toxicity. Several studies have suggested that polymorphisms in methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, reduced folate carrier (RFC1) G80A, and ABCB1 C3435T, could be related to methotrexate toxicity. This prospective study examined the different frequencies of MTHFR, RFC1, and ABCB1 pharmacogenetic variations between patients who have RA and those without RA. We also sought to assess the association between these polymorphisms and MTX toxicity. Four single-nucleotide polymorphisms (SNPs) were genotyped: C677T and A1298C from MTHFR, G80A from RFC1, and C3435T from ABCB1. The efficacy and toxicity of MTX were evaluated through clinical follow-up during 1 year of treatment. RA patients showed a higher frequency of the T allele at MTHFR C677T than patients without RA (p=0.049). There was a significant association between the presence of both the T allele at MTHFR C677T (p=0.006), and the C allele at ABCB1 C3435T (p=0.046), with toxicity development after 12 months of MTX treatment. However, there was no correlation between MTX toxicity and either the A allele at MTHFR A1298C or the G allele at RFC1 A80G. These data suggest that the presence of the MTHFR C677T and ABCB1 C3435T SNPs contribute to MTX toxicity in patients with RA. These observations contribute to a rapidly-growing knowledge base on the pharmacogenetics of RA and personalized medicine.
21384675 [Clinical study of pneumocystis pneumonia in patients with rheumatoid arthritis]. 2011 Jan We reviewed case of pneumocystis pneumonia (PCP) with rheumatoid arthritis. We administered the antirheumatic drug methotrexate (MTX) at the time of to 13 patients, corticosteroids to 11 patients and a tumor necrosis factor (TNF) inhibitor to 3 patients. Treatment for PCP was started on admission in all cases. We administered adrenocorticosteroids to all 13 patients with a PaO2 level < 70 Torr. Three patients were under respiratory management, and 4 patients died. By univariate analysis, prognostic indicators of death were: presence of acute respiratory distress syndrome (ARDS), peripheral blood neutrophil/lymphocyte ratio, serum albumin value, serum beta-D-glucan value, and AaDO2 and PaO2/FiO2 ratios. Readministration of a TNF inhibitor in 2 patients and MTX in 3 patients was possible after PCP remission. Even though we began treatment for PCP on the day of admission, 25% of patients died. PCP may occur in patients who are given MTX or a TNF inhibitor or both, and the clinician should endeavor to detect its onset as early as possible. Elucidation of the prognostic indicators of recovery may require multivariate analysis of many cases.
22183962 Methotrexate increases expression of cell cycle checkpoint genes via JNK activation. 2012 Jun OBJECTIVE: To assess defects in expression of critical cell cycle checkpoint genes and proteins in patients with rheumatoid arthritis (RA) relative to presence or absence of methotrexate (MTX) treatment, and to investigate the role of JNK in induction of these genes by MTX. METHODS: Flow cytometric analysis was used to quantify changes in levels of intracellular proteins, measure reactive oxygen species (ROS), and determine apoptosis in different lymphoid populations. Quantitative reverse transcription-polymerase chain reaction was used to identify changes in cell cycle checkpoint target genes. RESULTS: RA patients expressed reduced baseline levels of MAPK9, TP53, CDKN1A, CDKN1B, CHEK2, and RANGAP1 messenger RNA (mRNA) and JNK total protein. The reduction in expression of mRNA for MAPK9, TP53, CDKN1A, and CDKN1B was greater in patients not receiving MTX than in those receiving low-dose MTX, with no difference in expression levels of CHEK2 and RANGAP1 mRNA between MTX-treated and non-MTX-treated patients. Further, JNK levels were inversely correlated with C-reactive protein levels in RA patients. In tissue culture, MTX induced expression of both p53 and p21 by JNK-2- and JNK-1-dependent mechanisms, respectively, while CHEK2 and RANGAP1 were not induced by MTX. MTX also induced ROS production, JNK activation, and sensitivity to apoptosis in activated T cells. Supplementation with tetrahydrobiopterin blocked these MTX-mediated effects. CONCLUSION: Our findings support the notion that MTX restores some, but not all, of the proteins contributing to cell cycle checkpoint deficiencies in RA T cells, via a JNK-dependent pathway.
20921970 A genetic marker at the OLIG3/TNFAIP3 locus associates with methotrexate continuation in e 2012 Apr Whole-genome association studies in rheumatoid arthritis have identified single-nucleotide polymorphisms (SNPs) predisposing to disease with moderate risk. We aimed to investigate the role of these markers in predicting methotrexate (MTX) response, measured by continuation on MTX monotherapy in patients with recent onset inflammatory polyarthritis (IP). In all, 19 SNPs were genotyped in 736 patients treated with MTX following registration, or not more than 3 months before registration, to the Norfolk Arthritis Register. The association of SNPs with MTX continuation by year 1 and by year 2 was investigated using Cox proportional hazard regression models. A SNP within the OLIG3/TNFAIP3 locus (rs6920220) was associated with being less likely to maintain MTX monotherapy at year 1, hazards ratio (HR) 1.73 (1.18, 2.52) and year 2, HR 1.49 (1.11, 2.00); correlating with an increased in adverse events. Weak evidence for an effect at the PTPN22 locus was also observed. These findings require replication in other large datasets.
22400711 RF positivity has substantial influence on the peripheral memory B-cell compartment and it 2012 May OBJECTIVES: The role of B cells in rheumatoid arthritis (RA) has been well established with the advent of B-cell targeted therapies. Alterations of peripheral B-cell subsets in RA and heterogeneous modulations of the B-cell compartment under tumour necrosis factor (TNF) inhibition have been described. In this study we examined the influence of rheumatoid factor (RF) positivity on the peripheral B-cell compartment and its modulation under TNF blockade. METHODS: Consecutive patients with RA and inadequate response to methotrexate (MTX) were stratified according to RF status and a subset of them was included in a prospective study of weekly etanercept treatment. RESULTS: At baseline, RF-negative patients had a significant higher percentage of overall CD27+ B cells compared to healthy controls (HC) and RF-positive patients. In detail, RF-negative patients had 46.6% (range 15.7-86.8%) CD27+ B cells compared to 31.3% (12.9-56.9%, p = 0.026) in HC and 29.8% (19-73.3%, p = 0.04) in RF-positive patients. Within the CD27+ compartment, CD27+/immunoglobulin (Ig)D+ memory B cells were significantly increased to 26.4% (range 5.9-54.7%) in RF-negative patients compared to 14.9% (4.1-27.3%, p = 0.006) in HC and 10.5% (3.4-41.1%, p = 0.003) in RF-positive patients. During anti-TNF therapy, memory B cells increased significantly in relative and absolute numbers only in RF-negative patients. CONCLUSIONS: In RF-negative patients, we observed an enhanced frequency of peripheral memory B cells and an accumulation of pre-switch memory B cells. During anti-TNF therapy, memory B cells increased significantly only in RF-negative patients, suggesting that the peripheral memory B-cell compartment is more amenable to TNF inhibition in these patients.
21331576 Safety and effectiveness of switching from infliximab to etanercept in patients with rheum 2012 Jun Finding an effective treatment strategy for rheumatoid arthritis (RA) patients who have not benefited from previous tumor necrosis factor-α antagonist treatment is important for minimizing RA disease activity and improving patient outcomes. The aim of this study was to compare the safety and effectiveness of etanercept in patients with and without infliximab (IFX) treatment experience. Patients (n = 7,099) from a large postmarketing observational study of etanercept use in Japan were divided into 2 cohorts based on previous IFX use (pre-IFX and non-IFX). Baseline characteristics were assessed in each cohort. Adverse events (AEs) and European League Against Rheumatism (EULAR) responses were monitored every 4 weeks for 24 weeks. At baseline, pre-IFX patients were younger and had fewer comorbidities and a shorter RA duration than non-IFX patients. During the study, pre-IFX patients received concomitant methotrexate more often than non-IFX patients. The incidence of AEs and serious AEs were significantly lower in pre-IFX patients, as was the percentage of patients who discontinued treatment. Both cohorts had significant improvement (P < 0.001) in EULAR responses at the end of the treatment period. This study demonstrated that etanercept was effective and well tolerated in active RA patients with and without prior IFX treatment.
22763757 Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the 2013 Mar PURPOSE: Gamma-glutamyl hydrolase (GGH), cyclin D1 (CCND1) and thymidylate synthase (TS) genes encode enzymes that are involved in methotrexate (MTX) action. In a group of 184 RA patients treated with MTX, we have investigated whether selected polymorphisms in these genes modulate MTX efficacy and/or have impact on adverse drug effects (ADEs). METHODS: The efficacy of the MTX therapy has been estimated using the disease activity score in 28 joints (DAS28-ESR) based on EULAR criteria and relative DAS28 values (rDAS28). All adverse drug events were recorded. Patients were genotyped for selected polymorphisms of the GGH (-354 G > T and 452 C > T), CCND1 (870 A > G) and TYMS (variable number of tandem repeats, VNTR, and G to C substitution of triple repeat, 3R allele) gene. Association studies have been performed between obtained genotypes and the efficacy and toxicity of MTX. RESULTS: According to the EULAR response criteria, 146 RA patients (79.3 %) were classified as responders (good/moderate response) and 38 (20.7 %) as non-responders (poor response). Higher frequency of the TYMS 3 G/3 G genotype has been found among non-responders as compared to individuals with remaining genotypes (p = 0.02). ADEs were recorded in 53 patients. Among those patients eight experienced bone marrow toxicity, all of them carried GGH -354GG genotype (p = 0.003). No other significant association were observed. CONCLUSION: The 3 G/3 G genotype of the TYMS gene may indicate predisposition of poor response to MTX and GG genotype of GGH -354 T > G polymorphism may have high predictive value for myelosuppression in RA patients.