Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
22975734 Clinical efficacy of abatacept in Japanese rheumatoid arthritis patients. 2013 Sep OBJECTIVES: The purpose of this study was to examine the treatment retention and efficacy of abatacept, the first member of a new class of biologic agents, in Japanese rheumatoid arthritis (RA) patients during clinical practice. METHODS: A retrospective multicenter study was conducted with patients who underwent abatacept therapy for 24 weeks (n = 143). RESULTS: Patients at baseline had a mean age of 63.5 years, a mean disease duration of 11.3 years, and a mean disease activity score in 28 joints (DAS28) of 4.5. Overall retention of abatacept treatment was 83.2 % at 24 weeks, when 46.2 % of patients achieved DAS28-defined low disease activity (LDA; DAS28 <3.2) and 26.6 % achieved DAS28-defined remission (DAS28 <2.6). LDA was achieved in a significantly higher proportion of patients without prior biologics therapy compared to those with prior biologics (60.9 vs. 34.2 %, p = 0.001). There was no significant difference between patients with or without concomitant methotrexate (MTX) therapy (45.2 vs. 47.5 %). CONCLUSIONS: Abatacept therapy appears to be highly effective and well tolerated during clinical treatment of RA. Abatacept was particularly effective in patients with no history of biologics use, and did not appear to be dependent on concomitant MTX therapy.
23326596 A(2A) adenosine receptors are differentially modulated by pharmacological treatments in rh 2013 A(2A) adenosine receptors (ARs) play a key role in the inhibition of the inflammatory process. The purpose of this study was to evaluate the modulation of A(2A)ARs in rheumatoid arthritis (RA) patients after different pharmacological treatments and to investigate the effect of A(2A)AR stimulation in a rat model of arthritis. We investigated A(2A)AR density and functionality in RA progression by using a longitudinal study in RA patients before and after methotrexate (MTX), anti-TNFα agents or rituximab treatments. A(2A)ARs were analyzed by saturation binding assays in lymphocytes from RA patients throughout the 24-month study timeframe. In an adjuvant-induced arthritis model in rats we showed the efficacy of the A(2A)AR agonist, CGS 21680 in comparison with standard therapies by means of paw volume assessment, radiographic and ultrasonographic imaging. Arthritic-associated pain was investigated in mechanical allodynia and thermal hyperalgesia tests. IL-10 release following A(2A)AR stimulation in lymphocytes from RA patients and in serum from arthritic rats was measured. In lymphocytes obtained from RA patients, the A(2A)AR up-regulation was gradually reduced in function of the treatment time and the stimulation of these receptors mediated a significant increase of IL-10 production. In the same cells, CGS 21680 did not affected cell viability and did not produced cytotoxic effects. The A(2A)AR agonist CGS 21680 was highly effective, as suggested by the marked reduction of clinical signs, in rat adjuvant-induced arthritis and associated pain. This study highlighted that A(2A)AR agonists represent a physiological-like therapeutic alternative for RA treatment as suggested by the anti-inflammatory role of A(2A)ARs in lymphocytes from RA patients. The effectiveness of A(2A)AR stimulation in a rat model of arthritis supported the role of A(2A)AR agonists as potential pharmacological treatment for RA.
24818633 Intensive combination treatment regimens, including prednisolone, are effective in treatin 2015 Jun BACKGROUND: Recently, we documented the likely non-inferiority of Combinatietherapie Bij Reumatoïde Artritis (COBRA)-light therapy (methotrexate increased to 25 mg/week with initial prednisolone 30 mg/day) compared with the original COBRA therapy (methotrexate 7.5 mg/week, sulfasalazine 2 g/day, with initial prednisolone 60 mg/day) after 26 weeks in patients with early active rheumatoid arthritis (RA). OBJECTIVE: To assess the non-inferiority of COBRA-light versus COBRA after 1 year in terms of disease activity (DAS44), functional outcome (Health Assessment Questionnaire (HAQ)) and radiographic progression (Sharp/van der Heijde score (SHS)), and to assess the effect of adding etanercept. METHODS: An open-label, randomised controlled, non-inferiority trial of 162 patients with active early RA, following a treat-to-target protocol incorporating the addition of etanercept if DAS44 ≥1.6 at weeks 26 or 39. RESULTS: Both groups showed major improvements in DAS44 after 52 weeks: mean (SD) -2.41 (1.2) in the COBRA and -2.02 (1.0) in the COBRA-light group (p=ns). In both groups, functional ability improved and radiological progression of joints was minimal. At least one adverse event was reported in 96% of the patients in both groups. In total, 25 serious adverse events occurred: 9 vs 16 in COBRA and COBRA-light, respectively. Treatment actually instituted was often less intensive than required by the protocol: of the total population, 108 patients (67%) required etanercept (more in the COBRA-light group), but only 67 of these (62%) actually received it. CONCLUSIONS: Intensive COBRA or COBRA-light therapy has major, comparably favourable effects on disease activity, functional ability and radiological outcome after 1 year in patients with early RA. Protocolised addition of etanercept was often not implemented by treating rheumatologists, and patients receiving it appeared to have limited added benefit, probably because of low disease activity levels at its initiation. TRIAL REGISTRATION NUMBER: ISRCTN55552928.
24550647 Utilization patterns of disease-modifying antirheumatic drugs in elderly rheumatoid arthri 2014 Feb This study was conducted to investigate disease-modifying antirheumatic drug (DMARD) utilization in Korean elderly patients with rheumatoid arthritis (RA). We used data from January 1, 2005 to June 30, 2006 from the Health Insurance Review and Assessment Service claims database. The study subjects were defined as patients aged 65 yr or older with at least two claims with a diagnosis of RA. DMARD use was compared by the patients' age-group, gender, medical service, and geographic divisions. The patterns of DMARD use in mono- and combination therapy were calculated. RA medication use was calculated by the number of defined daily doses (DDD)/1,000 patients/day. A total of 166,388 patients were identified during the study period. DMARD use in RA patients was 12.0%. The proportion of DMARD use was higher in the younger elderly, females, and patients treated in big cities. Hydroxychloroquine was the most commonly used DMARD in monotherapy, and most of the combination therapies prescribed it with methotrexate. DMARD use in elderly RA patients was noticeably low, although drug prescriptions showed an increasing trend during the study period, clinicians may need to pay more attention to elderly RA patients.
23670804 Serum macrophage migration inhibitory factor levels are correlated with response to tocili 2014 Mar To examine the relationship between serum cytokine levels and response to tocilizumab in patients with RA. The disease status of 21 RA patients was assessed at baseline and after 12 weeks of tocilizumab treatment, using the clinical disease activity index (CDAI). Clinical response to tocilizumab was defined as an improvement of >50% from the baseline CDAI. Serum cytokine levels were quantified using double-ligand ELISA for TNF-α, IL-6, CCL2, CCL3, CXCL8, CXCL10, CX3CL1, and macrophage migration inhibitory factor (MIF). After 12 weeks of tocilizumab treatment, there was a significant overall reduction in RA disease activity (CDAI), from 22.4 ± 11.3 to 9.2 ± 6.6 (p < 0.0001), across the entire patient group. After 12 weeks of tocilizumab treatment, 14 patients achieved a >50% improvement (the responder group), but there were no significant responses in the other 7 patients (the non-responder group). The erythrocyte sedimentation rate levels, the positive % of anti-cyclic citrullinated protein antibody and patients (%) receiving methotrexate in combination with tocilizumab were significantly higher in the responder group than in the non-responder group. Although serum baseline levels of CCL2 and CXCL8 were higher in the responder group than in the non-responder group, there were no significant changes in these chemokine levels after treatment. The serum MIF levels, but not the levels of other cytokines, in the responder group were significantly decreased after tocilizumab treatment. Our results suggest that tocilizumab differentially regulates serum cytokine profiles in patients with RA, and MIF regulation in patients with active RA may be sensitive to anti-IL-6 therapy.
24166792 Association of low baseline levels of erythrocyte folate with treatment nonresponse at thr 2013 Nov OBJECTIVE: To investigate whether baseline concentrations of one-carbon metabolism biomarkers are associated with treatment nonresponse and adverse events in rheumatoid arthritis (RA) patients receiving methotrexate (MTX). METHODS: A prospective derivation cohort (n = 285) and validation cohort (n = 102) of RA patients receiving MTX were studied. Concentrations of plasma homocysteine, serum vitamin B12 , serum folate, erythrocyte vitamin B6 , and erythrocyte folate were determined at baseline and after 3 months of treatment. Nonresponse after 3 months was assessed using the Disease Activity Score in 28 joints (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Adverse events at 3 months were assessed using biochemical parameters and health status questionnaires. Analyses were corrected for baseline DAS28, age, sex, MTX dose, comedications, and presence of the methylenetetrahydrofolate reductase 677TT genotype. RESULTS: In the derivation cohort, the mean DAS28 scores at baseline and 3 months were 4.94 and 3.12, respectively, and 78% of patients experienced adverse events. This was similar between the 2 cohorts, despite a lower MTX dose in the validation cohort. Patients with lower levels of erythrocyte folate at baseline had a higher DAS28 at 3 months in both the derivation cohort (β = -0.15, P = 0.037) and the validation cohort (β = -0.20, P = 0.048). In line with these results, lower baseline erythrocyte folate levels were linearly associated with a 3-month DAS28 of >3.2 in both cohorts (derivation cohort, P = 0.049; validation cohort, P = 0.021) and with nonresponse according to the EULAR criteria (derivation cohort, P = 0.066; validation cohort, P = 0.027). None of the other biomarkers (levels at baseline or changes over 3 months) were associated with the DAS28 or treatment nonresponse. Baseline levels of the biomarkers and changes in levels after 3 months were not associated with incidence of adverse events. CONCLUSION: A low baseline concentration of erythrocyte folate is associated with high disease activity and nonresponse at 3 months after the start of MTX treatment and could be used in prediction models for MTX outcome. None of the investigated one-carbon metabolism biomarkers were associated with incidence of adverse events at 3 months.
24728329 Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in pati 2014 Aug OBJECTIVE: To compare the relative bioavailability, safety and tolerability of oral methotrexate (MTX) and subcutaneous (SC) MTX administered via an auto-injector (MTXAI) in patients with rheumatoid arthritis (RA). METHODS: In this randomised, multicenter, open-label, three-way crossover study, patients ≥18 years with adult RA undergoing treatment with MTX for ≥3 months were assigned to receive MTX 10, 15, 20 and 25 mg weekly in a random sequence of three treatments: oral, SC into the abdomen and SC into the thigh. For 24 h after administration of each treatment, blood samples were collected for pharmacokinetic analysis and injection sites were assessed. RESULTS: Forty-seven patients completed the study. Systemic exposure of oral MTX plateaued at doses ≥15 mg/week. In contrast, SC MTX demonstrated a linear increase in systemic exposure that was greater than oral MTX at each dose. No unexpected AEs were noted for either formulation. CONCLUSIONS: Unlike oral MTX, the systemic exposure of SC MTX did not plateau over the doses studied, particularly at doses ≥15 mg/week. In this study, higher systemic MTX exposure was not associated with increases in AEs. Patients with an inadequate clinical response to oral MTX may benefit from higher drug exposure by switching to SC MTX. TRIAL REGISTRATION NUMBER: NCT01618968.
24432366 Poor knowledge of methotrexate associated with older age and limited English-language prof 2013 INTRODUCTION: Our objective was to determine rheumatoid arthritis (RA) patients' understanding of methotrexate and assess whether knowledge varies by age, education, English language proficiency, or other disease-related factors. METHODS: Adults with RA (n = 135) who were enrollees of an observational cohort completed a structured telephone interview in their preferred language between August 2007 and July 2009. All subjects who reported taking methotrexate were asked 11 questions about the medication in addition to demographics, education level, and language proficiency. Primary outcome was a total score below the 50th percentile (considered inadequate methotrexate knowledge). Bivariable and multivariable logistic regressions were performed. Covariates included demographics, language proficiency, education, and disease characteristics. RESULTS: Of 135 subjects, 83% were female, with a mean age of 55 ± 14 years. The majority spoke English (64%), followed by 22% Spanish and 14% Cantonese or Mandarin. Limited English language proficiency (LEP) was reported in 42%. Mean methotrexate knowledge score was 5.4 ± 2.6 (range, 0 to 10); 73 (54%) had a score lower than 5 (of 10). Age older than 55, less than high school education, LEP, better function, and biologic use were independently associated with poor knowledge. CONCLUSIONS: In a diverse RA cohort, overall methotrexate knowledge was poor. Older age and limited proficiency in English were significant correlates of poor knowledge. Identification of language barriers and improved clinician-patient communication around methotrexate dosing and side effects may lead to improved safety and enhanced benefits of this commonly used RA medication.
23687260 A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy an 2013 Oct OBJECTIVES: To compare the efficacy and safety of innovator infliximab (INX) and CT-P13, an INX biosimilar, in active rheumatoid arthritis patients with inadequate response to methotrexate (MTX) treatment. METHODS: Phase III randomised, double-blind, multicentre, multinational, parallel-group study. Patients with active disease despite MTX (12.5-25 mg/week) were randomised to receive 3 mg/kg of CT-P13 (n=302) or INX (n=304) with MTX and folic acid. The primary endpoint was the American College of Rheumatology 20% (ACR20) response at week 30. Therapeutic equivalence of clinical response according to ACR20 criteria was concluded if the 95% CI for the treatment difference was within ±15%. Secondary endpoints included ACR response criteria, European League Against Rheumatism (EULAR) response criteria, change in Disease Activity Score 28 (DAS28), Medical Outcomes Study Short-Form Health Survey (SF-36), Simplified Disease Activity Index, Clinical Disease Activity Index, as well as pharmacokinetic (PK) and pharmacodynamic (PD) parameters, safety and immunogenicity. RESULTS: At week 30, ACR20 responses were 60.9% for CT-P13 and 58.6% for INX (95% CI -6% to 10%) in the intention-to-treat population. The proportions in CT-P13 and INX groups achieving good or moderate EULAR responses (C reactive protein (CRP)) at week 30 were 85.8% and 87.1%, respectively. Low disease activity or remission according to DAS28-CRP, ACR-EULAR remission rates, ACR50/ACR70 responses and all other PK and PD endpoints were highly similar at week 30. Incidence of drug-related adverse events (35.2% vs 35.9%) and detection of antidrug antibodies (48.4% vs 48.2%) were highly similar for CT-P13 and INX, respectively. CONCLUSIONS: CT-P13 demonstrated equivalent efficacy to INX at week 30, with a comparable PK profile and immunogenicity. CT-P13 was well tolerated, with a safety profile comparable with that of INX. CLINICALTRIALS.GOV IDENTIFIER: NCT01217086.
24786925 Longterm safety, efficacy, and inhibition of structural damage progression over 5 years of 2014 Jun OBJECTIVE: Evaluate the safety and efficacy of longterm abatacept (ABA) treatment over 5 years in methotrexate (MTX)-refractory patients with rheumatoid arthritis (RA). METHODS: Patients from the 1-year, double-blind Abatacept in Inadequate Responders to Methotrexate (AIM) study (NCT00048568) received open-label ABA (∼10 mg/kg) in the longterm extension (LTE). Safety was assessed for patients who received ≥ 1 ABA dose, and efficacy for patients randomized to ABA and treated in the LTE. Radiographs were evaluated for changes in Genant-modified Sharp scores. RESULTS: Out of 652 patients, 539 entered the LTE (ABA, n = 378; placebo, n = 161). At Year 5, 72.4% were ongoing; discontinuation rates declined over time. Incidence rates of serious adverse events, serious infections, malignancies, and autoimmune events were 13.87, 2.84, 1.45, and 0.99 events/100 patient-years exposure, respectively. American College of Rheumatology 20 response was 82.3% (n = 373) and 83.6% (n = 268) at years 1 and 5, respectively. Disease Activity Score 28 C-reactive protein (DAS28-CRP) < 2.6 and ≤ 3.2 were achieved by 25.4% and 44.1% of patients at Year 1 (n = 370), and 33.7% and 54.7% at Year 5 (n = 267), respectively. Mean changes in DAS28-CRP and Health Assessment Questionnaire-Disability Index at Year 1 [-2.83 (n = 365) and -0.68 (n = 369)] were maintained at Year 5 [-3.14 (n = 264) and -0.77 (n = 271)] for patients continuing treatment. Of them, 59.5% (n = 291) and 45.1% (n = 235) remained free from radiographic progression at years 1 and 5, respectively. CONCLUSION: In MTX-refractory patients with RA, longterm ABA treatment was well tolerated and provided consistent safety and sustained efficacy, with high patient retention. Radiographic progression continued to be inhibited with ongoing treatment.
24729113 Metastatic bone lesion due to methotrexate and etanercept 24 years after breast cancer tre 2014 Apr 12 A 72-year-old woman with rheumatoid arthritis presented with lumbar vertebral bone metastasis 24 years after mammectomy and radiotherapy for breast cancer. She was treated with prednisolone and methotrexate (MTX) for 11 months to which 10 mg of etanercept twice a week was added for a further 8 months. On the basis of this result, the possibility of a metastatic bone lesion appearing many years after cancer treatment should be considered when planning MTX and etanercept therapy.
24595497 In vitro efficacy of polysaccharide-based nanoparticles containing disease-modifying antir 2014 Sep PURPOSE: To evaluate the therapeutic efficacy of dexamethasone (DM) and methotrexate (MTX) entrapped within polysialic acid (PSA)-trimethyl chitosan (TMC) nanoparticles using an in vitro model of rheumatoid arthritis (RA). METHODS: The loading capacity of the PSA-TMC nanoparticles was determined. An RA in vitro model was developed by stimulating a synovial cell line with a proinflammatory mediator. Multiplex immunoassay was used to determine changes in the secretion of interleukin-6 (IL-6), interleukin-8 (IL-8), and granulocyte-macrophage colony-stimulating factor (GM-CSF) by the in vitro model following administration of the DM- and MTX-loaded nanoparticles. RESULTS: The loading capacity of the PSA-TMC nanoparticles was approximately 0.1 mg of drug/mg of nanoparticle. When applied to our in vitro model of RA, there were no significant differences in the concentrations of IL-6 and IL-8 when comparing the free drugs and drug-loaded nanoparticles, administered at concentration of 0.1 mg/ml and 1.0 mg/ml, respectively. CONCLUSIONS: The present study verified that MTX and DM are able to retain bioactivity when loaded into PSA-TMC nanoparticles. Although in vitro efficacy was not increased, the in vivo efficacy will likely be enhanced by the site-specific targeting conferred by nanoparticle entrapment.
25546405 Identification of S100A9 as biomarker of responsiveness to the methotrexate/etanercept com 2014 OBJECTIVES: One way to optimize the drug prescription in rheumatoid arthritis (RA) is to identify predictive biomarkers of drug responsiveness. Here, we investigated the potential "theranostic" value of proteins of the S100 family by monitoring levels of both S100A8 and S100A9 in blood samples from RA patients. DESIGN: For proteomic analysis, peripheral blood mononuclear cells (PBMC) and serum samples were collected in patients prior to initiation of the methotrexate/etanercept (MTX/ETA) combination. Firstly, relative mass spectrometry (MS) quantification focusing on S100A8 and S100A9 proteins was carried out from PBMCs samples to identify potential biomarkers. The same approach was also performed from serum samples from responder (R) and non responder (NR) patients. Finally, to confirm these results, an absolute quantification of S100A8, S100A9 proteins and calprotectin (heterodimer of S100A8/S100A9) was carried out on the serum samples using ELISA. RESULTS: MS analyses revealed that both S100A8 and S100A9 proteins were significantly accumulated in PBMC from responders. In contrast to PBMC, only the S100A9 protein was significantly overexpressed in the serum of R patients. Absolute quantification by ELISA confirmed this result and pointed out a similar expression level of S100A8 protein and calprotectin in sera from both R and NR groups. Thus, the S100A9 protein revealed to be predictive of MTX/ETA responsiveness, contrarily to parameters of inflammation and auto-antibodies which did not allow significant discrimination. CONCLUSION: This is the first report of an overexpression of S100A9 protein in both PBMCs and serum of patients with subsequent response to the MTX/ETA combination. This protein thus represents an interesting biomarker candidate of therapeutic response in RA.
24114449 Is extrapolation of the safety and efficacy data in one indication to another appropriate 2014 Jan CT-P13, the world's first biosimilar monoclonal antibody to infliximab, was approved for marketing in South Korea for all the six indications of infliximab, which Europe may follow, although the product was tested only in rheumatoid arthritis (RA) with a limited pharmacokinetic comparison in ankylosing spondylitis. However, the extrapolation of the efficacy and safety findings of CT-P13 in RA to the other indications appears scientifically challenging when assessed by the current regulatory requirements. RA is not a sensitive clinical model to detect potential differences between CT-P13 and infliximab, and other mechanisms of action than antagonizing tumor necrosis factor α appear to be also important, which could be different by the approved indications. Furthermore, the immunogenicity and safety profiles of CT-P13 were not sufficiently characterized in that immunogenicity potential was lowest in RA, which was even further suppressed by the concomitant use of methotrexate. Extrapolation of the safety and efficacy data in one indication to another may be inappropriate for biosimilars unless backed up by strong scientific justification, which may include the mechanistic exposure-relationship approach. Therefore, regulatory agencies need to exercise caution before granting extrapolated indications to biosimilars.
23576019 Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease- 2013 Aug As part of the National Institute for Health and Clinical Excellence (NICE) single technology appraisal (STA) process, the manufacturer of golimumab (Simponi(®); Merck Sharp & Dohme, USA) was invited to submit evidence for its clinical and cost effectiveness for the treatment of rheumatoid arthritis (RA) after the failure of previous disease-modifying antirheumatic drugs (DMARDs). The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at The University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). This article provides details of the manufacturer's initial submission, the ERG's clarification questions and the ERG report submitted to NICE. The decision made by NICE is provided alongside a brief comment on additional results produced from an additional analysis requested by NICE on behalf of the Committee. The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based on upon the manufacturer's submission to NICE. The clinical evidence was derived from three randomized controlled trials of golimumab in the treatment of moderate to severe RA: GO-FORWARD and Kay et al. (DMARD-experienced population) and GO-AFTER (tumour necrosis factor [TNF]-α inhibitor-experienced population). The ERG considered that the trials were of reasonable methodological quality and measured a clinically relevant range of outcomes. The trials for golimumab, as well as comparator treatments, were synthesized using mixed-treatment comparison methods for the DMARD-experienced population and an indirect comparison using the Bucher method for the TNF-α inhibitor-experienced population. The trials used were appropriate, although no definitive judgement regarding the comparative efficacy of golimumab with other biologics was possible. The manufacturer provided a DMARD-experienced population model and a TNF-α inhibitor-experienced population model. The models allowed sequences of treatments to be evaluated for each population, although a fully incremental analysis between the use of golimumab following DMARD failure and the use of golimumab following TNF-α inhibitor failure was not possible. Several limitations with the model were identified, and after a request from NICE and suspension of the appraisal, the manufacturer submitted sensitivity analyses with an additional American College of Rheumatology 70 % improvement criteria (ACR70) health state included, using SF-36 data directly from the GO-FORWARD study. The annual rate of the Health Assessment Questionnaire (HAQ) score increase for patients receiving palliative treatment was also changed from 0.09 to 0.06. The further analyses provided highlighted the particular sensitivity of the results to HAQ progression rates and the re-administration frequency for rituximab in the TNF-α inhibitor-experienced population. The Appraisal Committee concluded that golimumab should be recommended in combination with methotrexate as an option for patients with severe active RA who have failed on conventional DMARDs, or who have failed on a TNF-α inhibitor and are contraindicated to or withdrawn from rituximab.
23456676 Targeting interleukin-6 in rheumatoid arthritis. 2013 Mar Interleukin (IL)-6 is a potent pro-inflammatory agent that plays a crucial role in the pathogenesis of systemic inflammatory disease. Targeting this pathway in rheumatoid arthritis (RA) seems an attractive option as IL-6 is important for both joint destruction and systemic manifestations. Currently, tocilizumab, which binds the IL-6 receptor, is licensed for treatment in active, moderate to severe disease in RA and systemic juvenile idiopathic arthritis (JIA). Several other promising IL-6 blocking agents as well as a subcutaneous form of tocilizumab are currently undergoing phase III clinical trials. The aim of this article is to provide an up-to-date analysis of clinical efficacy and tolerability data concerning the use of IL-6 inhibitors. Data from clinical trials demonstrated that clinical efficacy for tocilizumab, which included improvement in physical function and halting radiographic progression, were comparable to other biologics licensed for use in RA. Patients who should gain most are RA patients with systemic features such as high inflammatory markers and anaemia. Perhaps, the strongest selling point lies in its effectiveness as a monotherapy. This is particularly useful in those who are not tolerating combination treatment with methotrexate. Tocilizumab is one of a few biologics that have been shown to be superior to methotrexate in head-to-head studies. The safety profile of tocilizumab also is comparable to other currently available biologics. There is a small but significant increase in adverse events including infections in patients treated with tocilizumab compared to placebo, particularly in patients who are elderly and those with multiple comorbidities. Elevated lipid profiles are frequent but have not been associated with major cardiovascular events. IL-6 blockade is a major advancement in the treatment of RA as it targets a unique molecule. Over the next few years, evidence will be available on the long-term cardiovascular safety and efficacy of subcutaneous IL-6 blocking agents.
23934385 The impact of conventional DMARD and biological therapies on CD4+ cell subsets in rheumato 2014 Feb Rheumatoid arthritis (RA) is an autoimmune disease characterized by abnormal prevalence of Th1, Th2, Th17, and regulatory (Treg) subsets. Some data suggest that these subsets are influenced by anti-RA agents. Follow-up studies monitoring T cell phenotype in response to therapy are limited. We investigated the alteration of CD4+ T cell subset distribution after the initiation of disease-modifying antirheumatic drug (DMARD) (with glucocorticosteroid (GCS) and methotrexate (MTX)) and anti-TNFα therapy. We enrolled 19 treatment naive (early) RA patients and initiated GCS (in a dose of 16 mg/day for 4 weeks; then 8 mg/day). MTX, 10 mg/week, was started at week 4. We also enrolled 32 RA patients unresponsive to DMARD and initiated anti-TNFα therapy: adalimumab (ADA), 40 mg/2 weeks, n = 12; etanercept (ETA), 50 mg/weeks, n = 12; or infliximab (IFX) on week 0, 2, and 6, 3 mg/kg bw, n = 8. Blood was taken before and 4 and 8 weeks after the initiation of therapy. Ten volunteers served as controls. The T cell phenotype was assessed with flow cytometry. In early RA, Th1, Th2, and Th17 prevalence was higher, while Treg prevalence was lower than normal. GCS alone decreased Th2 prevalence. GCS + MTX decreased Th17 prevalence. Immune phenotype in unresponsive RA before anti-TNF therapy was as in early RA. Four and 8 weeks after initiating anti-TNF therapy, Th1 prevalence was higher than baseline in ETA or IFX, while it was stable in ADA groups. Th2 prevalence was higher than normal in ADA or IFX, while normalized in ETA group. In each group, Treg prevalence increased, while Th17 prevalence was at the baseline. The proinflammatory immune phenotype is normalized only under GCS + MTX combination in early RA. Anti-TNFα therapy exhibit marked effects on all the cell populations investigated (except Th17); some slight differences in this action exist between ADA, ETA, and IFX therapy.
23961669 [Etanercept]. 2013 Jul Etanercept (ETN) is a fusion protein of the receptor (CD120b) for tumor necrosis factor (TNF) and the Fc portion of IgG1. A phase III trail and the JESMR study, both performed in Japan, implicated the importance of concomitant methotrexate (MTX) use in the treatment of rheumatoid arthritis (RA). Further evidences, including the TEAR study and the PRESERVE study, supported the recent treatment strategy for RA, being divided into at least two phases: remission induction phase(step-up or initial combination) and its maintenance phase (step-down). Thus, optimization of RA treatment chiefly based on MTX and anti-TNF biological agents is in progress.
23445732 [Case of successful pregnancy and childbirth in a rheumatoid arthritis patient treated wit 2013 The patient was a 34-year-old woman who, at age 23, was diagnosed with rheumatoid arthritis (RA) presenting with morning stiffness, swelling and tenderness of bilateral knee joints and metacarpophalangeal (MP) joints of the right second and third fingers, increased C-reactive protein (CRP) levels, and a high level of rheumatoid factor (RF). The patient was maintaining remission with oral dose of bucillamine (BUC; 300 mg/day); however, due to the deterioration of arthralgia at age 26, she was additionally administered 8 mg/week of methotrexate (MTX), which improved the symptoms. Thereafter, the prescription of BUC was discontinued. At age 31, she experienced onsets of swelling and tenderness in both the knee joints and wrists and in MP joints of the right second and third fingers; further, CRP levels increased to 5.44 mg/dL, resulting in increased RA activity. The concomitant administration of infliximab was started at a dose of 3 mg/kg, which helped achieve favorable RA control. At age 32, approximately 2 years before childbirth, the prescription of infliximab was changed to 25 mg/dose of etanercept administered twice a week because the patient wished to conceive. Remission was maintained even after the drug change; therefore, MTX was discontinued and the patient was treated with etanercept alone. After she was confirmed to be pregnant in March of the following year, administration of etanercept was continued for treating of RA even during pregnancy. During that time, RA was favorably controlled, and the patient gave birth to a baby boy weighing 3192 g in October of the same year. The Apgar score of the baby was favorable. This case is considered important because, to the best of our knowledge, this may be the first report of a planned pregnancy and childbirth in a patient under administration of a biological preparation.
23716132 Tofacitinib: a review of its use in adult patients with rheumatoid arthritis. 2013 Jun Tofacitinib (Xeljanz(®)) is the first approved drug in a new class of disease modifying antirheumatic drugs (DMARDs), the Janus kinase (JAK) inhibitors. JAKs have a pivotal role in triggering cytokine-induced signal transduction pathways that influence normal and pathological cellular processes of haematopoiesis and immune cell function, including pathogenic mechanisms involved in rheumatoid arthritis (RA). Selective inhibition of JAKs by tofacitinib potentially modulates inflammatory processes and provides a novel approach for the treatment of RA. Oral tofacitinib is indicated for the treatment of adult patients with active RA who have had an inadequate response to methotrexate and/or other DMARDs. In several large well designed trials, tofacitinib, in combination with methotrexate or other nonbiological DMARDs or as monotherapy, was an effective and generally well tolerated DMARD for the treatment of adult patients with moderately to severely active RA who had had an inadequate response to previous DMARDs, including tumour necrosis factor-α inhibitors. Direct head-to-head trials and/or further clinical experience (including long-term safety data), along with robust pharmacoeconomic studies, are required to more definitively position tofacitinib relative to other currently available DMARDs. In the meantime, tofacitinib (alone or in combination with nonbiological DMARDs) is an emerging option for the treatment of DMARD-experienced adult patients with moderately to severely active RA who have had an inadequate response to or are intolerant of methotrexate or other DMARDs.