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ID PMID Title PublicationDate abstract
22799756 Effect of chronic periodontitis on oxidative status in patients with rheumatoid arthritis. 2013 Jun BACKGROUND: Rheumatoid arthritis (RA) and chronic periodontitis (CP) are the most common chronic inflammatory diseases and have remarkable similar pathologies. The aim of this study is to investigate the impact of periodontal status on oxidative stress in patients with RA by evaluating serum oxidative parameters and prolidase levels. METHODS: For this cross-sectional comparative study, the following four groups were composed of 20 individuals each (80 individuals total): 1) RA with CP (RA-CP group); 2) RA but periodontally healthy (RA-C group); 3) systemically healthy with CP (CP group); and 4) systemically and periodontally healthy (C group). Demographic, periodontal, rheumatological, and serum oxidative parameters as determined by serum total antioxidant status, total oxidant status, oxidative stress index (OSI), lipid hydroperoxide levels, paraoxonase, arylesterase, and ceruloplasmin activity, prolidase level, and total sulfhydryl groups were evaluated. RESULTS: The OSI values of the RA-CP group were statistically significantly higher than those of the C group (P <0.05). The prolidase levels of the RA-C, RA-CP groups and the CP group were statistically higher than those of the C group (P = 0.001, P = 0.007, and P = 0.001, respectively). CONCLUSIONS: Although CP and RA each increase oxidative stress, in a small sample size these effects are only significant when both CP and RA are combined relative to neither exposure. In addition, increased prolidase levels in patients with RA and CP may be related to increased oxidative tissue damage.
24356672 Chronic NSAID use and long-term decline of renal function in a prospective rheumatoid arth 2015 Apr OBJECTIVES: Non-steroidal anti-inflammatory drugs (NSAIDs) may cause kidney damage. This study assessed the impact of prolonged NSAID exposure on renal function in a large rheumatoid arthritis (RA) patient cohort. METHODS: Renal function was prospectively followed between 1996 and 2007 in 4101 RA patients with multilevel mixed models for longitudinal data over a mean period of 3.2 years. Among the 2739 'NSAID users' were 1290 patients treated with cyclooxygenase type 2 selective NSAIDs, while 1362 subjects were 'NSAID naive'. Primary outcome was the estimated glomerular filtration rate according to the Cockroft-Gault formula (eGFRCG), and secondary the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration formula equations and serum creatinine concentrations. In sensitivity analyses, NSAID dosing effects were compared for patients with NSAID registration in ≤/>50%, ≤/>80% or ≤/>90% of assessments. FINDINGS: In patients with baseline eGFRCG >30 mL/min, eGFRCG evolved without significant differences over time between 'NSAID users' (mean change in eGFRCG -0.87 mL/min/year, 95% CI -1.15 to -0.59) and 'NSAID naive' (-0.67 mL/min/year, 95% CI -1.26 to -0.09, p=0.63). In a multivariate Cox regression analysis adjusted for significant confounders age, sex, body mass index, arterial hypertension, heart disease and for other insignificant factors, NSAIDs were an independent predictor for accelerated renal function decline only in patients with advanced baseline renal impairment (eGFRCG <30 mL/min). Analyses with secondary outcomes and sensitivity analyses confirmed these results. CONCLUSIONS: NSAIDs had no negative impact on renal function estimates but in patients with advanced renal impairment.
24092417 Update on the safety profile of certolizumab pegol in rheumatoid arthritis: an integrated 2015 Jan OBJECTIVE: To report the long-term safety data of certolizumab pegol (CZP) in rheumatoid arthritis (RA) accumulated as of 30 November 2011. DESIGN: Data from 10 completed randomised controlled trials (RCT) of CZP in RA and several open-label extensions (OLE) were pooled across all doses. Reported adverse events (AE) occurred between the first dose and 84 days after the last dose. All deaths, serious infectious events (SIE) and malignancies were reviewed by external experts, classified according to predefined rules, and validated by an external steering committee. Incidence rates (IR) and event rates (ER) per 100 patient-years (PY) are presented. RESULTS: 4049 RA patients who received CZP were included in the safety pooling; total exposure 9277 PY, mean exposure 2.1 years (range 0.04-7.6). SIE, most frequently pneumonia (IR 0.73/100 PY), were the most common serious AE, occurring more frequently in CZP compared to placebo-treated patients in RCT (IR 5.61/100 PY vs 1.35/100 PY, odds ratio (OR) 4.35, 95% CI 0.65 to 29.30). SIE rates were lower in the CZP-treated population including OLE (ER 4.33/100 PY). 44 patients developed tuberculosis (IR 0.47/100 PY), 39 from high endemic regions. 58 deaths occurred in CZP-exposed patients (IR 0.63/100 PY) and 70 developed malignancies excluding non-melanoma skin cancer (IR 0.76/100 PY), including five lymphomas (IR 0.05/100 PY). CONCLUSIONS: No new or unexpected safety signals associated with CZP emerged in this updated long-term safety analysis. While SIE rates were higher for CZP than for placebo in RCT, the rate decreased with continued exposure to CZP. These rates are consistent with data previously reported for CZP and other tumour necrosis factor inhibitors.
24297383 Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in 2015 Feb OBJECTIVE: To investigate if erythrocyte-methotrexate-polyglutamate (MTX-PG) concentrations in patients with rheumatoid arthritis (RA) are associated with disease activity or adverse events. METHODS: We used a longitudinal study design with two cohorts. The derivation cohort included 102 and the validation cohort included 285 patients with RA on MTX. We measured erythrocyte-MTX-PG with 1-5 glutamate residues at 3 months, 6 months and 9 months after MTX start with a liquid chromatography (LC)-mass spectrometry (MS)/MS assay. Outcomes were disease activity score in 28 joints (DAS28) and adverse events. Longitudinal associations of MTX-PG concentrations after 3 months, 6 months and 9 months with DAS28 were tested with a linear mixed model adjusted for age, gender, baseline DAS28, MTX dose and comedication. RESULTS: In the derivation cohort, mean DAS28 decreased from 4.26 (SE=0.14) at baseline to 2.72 (SE=0.13) after 9 months. Thirty per cent of patients in the derivation cohort experienced more than three adverse events after 3 months, which decreased to 18% after 9 months. In the validation cohort, DAS28 and adverse events were comparable with the derivation cohort. In the derivation cohort, MTX-PG1 (ß=-0.005), MTX-PG2 (ß=-0.022), MTX-PG3 (β=-0.007) and total MTX-PG (ß=-0.004) were associated (p<0.05) with lower DAS28 over 9 months. In the validation cohort, MTX-PG2 (ß=-0.015), MTX-PG3 (ß=-0.010), MTX-PG4 (ß=-0.008) and total MTX-PG (ß=-0.003) were associated with lower DAS28 over 9 months. None of the MTX-PGs was associated with adverse events. CONCLUSIONS: In this first longitudinal study, we showed that an increase in erythrocyte-MTX-PG concentration was associated with a decreased DAS28 over 9 months in two cohorts, and is therefore a potential tool for therapeutic drug monitoring of MTX in RA.
24941916 The risk of acute coronary syndrome in rheumatoid arthritis in relation to tumour necrosis 2014 Jun 18 INTRODUCTION: The elevated risk of ischaemic heart disease in patients with rheumatoid arthritis (RA) has been linked to inflammation and disease severity. Treatment with tumour necrosis factor inhibitors (TNFis) is often effective in reducing disease activity and could possibly modify cardiovascular risk. Our objective in the study was to evaluate the risk of acute coronary syndrome (ACS) in patients with RA treated with TNFis compared with the risk among biologic-naïve RA patients and the general population. METHODS: By linkage of the Swedish National Patient Register and the Swedish Biologics Register, we identified a cohort of patients who were started on their first biologic, a TNFi, between 2001 and 2010 (N = 7,704), and a cohort comprising matched biologic-naïve RA patient referents at a 3:1 ratio. Furthermore, a matched comparator cohort (5:1 ratio) was extracted from the Swedish population register. The incidence rates of a first ACS event were calculated and compared between cohorts using Cox proportional hazards regression in three different risk windows: 'ever-exposed', 'actively on TNFi' and 'short-term exposure' (active treatment maximized to 2 years). The models were adjusted for disease duration, joint surgery, comorbidity and socioeconomic factors, and, in a sensitivity analysis including a subpopulation started on therapy beginning 1 January 2006 or later, for dispensed drugs. RESULTS: Based on 221 events in 7,704 patients (comprising 32,621 person-years) treated with TNFi biologics, the hazard ratio ((HR); ever-exposed) for ACS among the TNFi-exposed RA patients compared with biologic-naïve RA patients was 0.8 (95% confidence interval (CI) = 0.7 to 0.95). In comparison with the general population referents, statistical analysis using fully adjusted models resulted in a HR of 2.0 (95% CI = 1.8 to 2.3) for biologic-naïve RA patients and a HR of 1.6 (95% CI = 1.4 to 1.9) for the TNFi-exposed group. Similar risk estimates were obtained using the other two risk windows. A sensitivity analysis in which we compared the TNFi-exposed patients included from 1 January 2006 onward with biologic-naïve patients resulted in a HR (ever-exposed) of 0.7 (95% CI = 0.5 to 1.0). CONCLUSIONS: RA patients treated with TNFi had a lower risk of ACS compared with biologic-naïve RA patients. Compared with the general population, the risk among patients with RA was elevated, although the difference was less pronounced among the TNFi-exposed patients. This finding could be attributable to the TNFi as such, or it could correspond to a lower degree of inflammation in the TNFi-treated group.
24882838 Ten-year followup of infliximab therapy in rheumatoid arthritis patients with severe, long 2014 Jul OBJECTIVE: Our study describes the 10-year followup data of the Belgian Expanded Access Program (EAP) for infliximab (IFX), which included patients with active rheumatoid arthritis who were refractory to methotrexate. The objectives of the study were to evaluate the continuation rate, reasons for discontinuation, and longterm disease control under IFX treatment, and to study baseline characteristics associated with longterm successful IFX therapy. METHODS: Between February 2000 and September 2001, 511 patients were enrolled in the Belgian IFX EAP, and 507 effectively started IFX therapy. Previously reported data showed that 160 patients were still treated with IFX after 7 years of followup. We describe the therapy status, reasons for IFX discontinuation, and the level of disease activity of this subgroup after 10 years of followup. Baseline characteristics of the total EAP cohort were used to describe variables associated with longterm successful IFX treatment. RESULTS: After 10 years of followup, 110 of the 507 patients (21.7%) were still receiving IFX treatment. In the 7-year to 10-year period, which is the focus of the current study, 16 patients were lost to followup and 34 patients discontinued IFX treatment, mainly because of loss of efficacy. Patients successfully treated with IFX for 10 years had lower baseline values for 28-joint Disease Activity Score (DAS28), patient pain scale, physician visual analog scale, and Health Assessment Questionnaire in comparison with the rest of the study cohort. The mean DAS28 level of the subgroup still taking IFX after 10 years was 2.55 ± 1.01. CONCLUSION: In the Belgian EAP, 21.7% of patients continued to receive maintenance IFX treatment after 10 years of followup. IFX provided good longterm disease control in these patients.
23463804 Subcutaneous abatacept for the treatment of rheumatoid arthritis. 2013 Jun The efficacy, safety and tolerability of i.v. abatacept are well established in patients with active RA. A s.c. abatacept formulation is now available in some countries. Here, we review clinical data for s.c. abatacept. Six trials are presented (Phase II dose-finding study, ACQUIRE, ALLOW, ACCOMPANY, ATTUNE and AMPLE) and issues important to both patients and clinicians are addressed. The primary focus assesses whether the i.v. and s.c. abatacept formulations have similar efficacy, including whether the recommended fixed dose of s.c. abatacept is comparable to the weight-tiered i.v. dosing and whether efficacy is sustained with long-term treatment. Safety and immunogenicity are also discussed, including the short- and long-term safety of s.c. abatacept, and whether immunogenicity is increased following a switch from i.v. to s.c. abatacept, after withdrawal or reintroduction of s.c. abatacept or in the absence of MTX. Year 1 data from the AMPLE study, comparing s.c. abatacept with the TNF antagonist adalimumab, are discussed. Although fewer patient-years of exposure are available for s.c. compared with i.v. abatacept, observations suggest that s.c. abatacept has a similar long-term efficacy to the i.v. formulation, improving the signs, symptoms, disease activity and physical function in patients with RA. With continued treatment, these improvements are maintained over time with high retention rates, similar to i.v. abatacept. s.c. abatacept is associated with low immunogenicity and short- and long-term safety that is consistent with i.v. abatacept. In addition, s.c. abatacept demonstrates comparable efficacy, kinetics of response, safety and radiographic inhibition to adalimumab.
24642277 Ultrasound screening for interstitial lung disease in rheumatoid arthritis. 2014 Mar OBJECTIVES: As interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients is associated with increased mortality due to loss of diffusion capacity and pulmonary hypertension, regular screening for structural abnormalities of the lung is advised. In addition to standard radiological examination with computed x-ray tomography, ultrasound of the lung could allow non-invasive and radiation-free structural monitoring of the lung. The objective of this study was to test the frequency of abnormalities in lung sonography in patients with RA who did not have clinical signs or symptoms of lung disease. METHODS: In a prospective study of 64 consecutive patients with rheumatoid arthritis and 40 healthy volunteers, we screened the pleura and the pulmonary parenchyma for sonographic abnormalities. All RA patients underwent high resolution computer tomography of the lung. RESULTS: 28% of RA patients showed pleural nodules or B-line phenomena. In these patients, CT scans showed signs of incipient interstitial lung disease. Lung sonography showed sporadic abnormalities in 7% of the healthy controls. CONCLUSIONS: Transthoracic ultrasound of the lung is an inexpensive and safe tool to screen patients with RA for incipient pulmonary structural changes.
23505230 Using lifestyle factors to identify individuals at higher risk of inflammatory polyarthrit 2014 Jan OBJECTIVES: To investigate the association of lifestyle factors with risk of inflammatory polyarthritis (IP) and rheumatoid arthritis (RA). METHODS: The European Prospective Investigation of Cancer, Norfolk, UK (EPIC-Norfolk) gathered lifestyle data from participants aged 40-79 years from 1993 to 1997. Individuals who subsequently developed IP were identified by linkage with the Norfolk Arthritis Register. A Cox proportional hazard model was developed, and a score assigned to each risk factor to calculate the odds of developing IP. RESULTS: 25 455 EPIC participants were followed for a median (IQR) of 14.2 (12.9, 15.3) years; 184 developed incident IP (138 cumulatively fulfilled criteria for RA; 107 were seropositive). Pack-years of smoking were associated with increased risk of IP and RA in men (HR 1.21 (95% CI 1.08 to 1.37) per 10-pack-years) and seropositive IP (HR 1.24 (95% CI 1.10 to 1.41)) for all. Diabetes mellitus was associated with increased risk of IP (HR 2.54 (95% CI 1.26 to 5.09)), while alcohol (HR 0.86 (95% CI 0.74 to 0.99) per unit/day) and higher social class (HR 0.36 (95% CI 0.15 to 0.89) for professionals vs manual workers) were associated with reduced risk. Body mass index was associated with seronegative IP (HR 2.75 (95% CI 1.39 to 5.46) for obese vs normal-weight participants). In women, parity (HR 2.81 (95% CI 1.37 to 5.76) for ≥2 vs no children) was associated with increased risk, and breast feeding (HR 0.66 (95% CI 0.46 to 0.94) for every 52 weeks of breast feeding) was inversely associated with risk. Risk factors from the model were used to generate a 'risk score'. A total of 1159 (8.4%) women had scores reflecting a >3-fold increased risk of IP over those with a score of 0. CONCLUSIONS: Several easily ascertained clinical and lifestyle factors can be used to stratify populations for risk of IP.
24389293 Performance of four current risk algorithms in predicting cardiovascular events in patient 2015 Apr OBJECTIVE: This study was undertaken to assess the predictive ability of 4 established cardiovascular (CV) risk models for the 10-year risk of fatal and non-fatal CV diseases in European patients with rheumatoid arthritis. METHODS: Prospectively collected data from the Nijmegen early rheumatoid arthritis (RA) inception cohort was used. Discriminatory ability for CV risk prediction was estimated by the area under the receiver operating characteristic curve. Calibration was assessed by comparing the observed versus expected number of events using Hosmer-Lemeshov tests and calibration plots. Sensitivity and specificity were calculated for the cut-off values of 10% and 20% predicted risk. RESULTS: Areas under the receiver operating characteristic curve were 0.78-0.80, indicating moderate to good discrimination between patients with and without a CV event. The CV risk models Systematic Coronary Risk Evaluation (SCORE), Framingham risk score (FRS) and Reynolds risk score (RRS) primarily underestimated CV risk at low and middle observed risk levels, and mostly overestimated CV risk at higher observed risk levels. The QRisk II primarily overestimated observed CV risk. For the 10% and 20% cut-off values used as indicators for CV preventive treatment, sensitivity ranged from 68-87% and 40-65%, respectively and specificity ranged from 55-76% and 77-88%, respectively. Depending on the model, up to 32% of observed CV events occurred in patients with RA who were classified as low risk (<10%) for CV disease. CONCLUSIONS: Established risk models generally underestimate (Systematic Coronary Risk Evaluation score, Framingham Risk Score, Reynolds risk score) or overestimate (QRisk II) CV risk in patients with RA.
25512476 Switching from intravenous to subcutaneous formulation of abatacept: a single-center Itali 2015 Feb OBJECTIVE: Subcutaneous (SC) abatacept (ABA) is comparable to intravenous (IV) formulation in terms of efficacy and safety profile. Our work analyzed the switch to SC formulation from IV administration in patients with rheumatoid arthritis. METHODS: Fifty-one patients treated with SC ABA were included. Clinical data were obtained from clinical charts. RESULTS: Fourteen patients relapsed and needed to return to the IV administration. Neither clinical and laboratory features nor the previous therapies were identified as risk factors for SC formulation inefficacy. Disease activity decreased after the return to IV infusions. CONCLUSION: SC ABA showed a risk of relapse in 27% of cases. The reinsertion of the IV administration quickly reinstated disease control.
23011680 Are changes in bone mineral density different between groups of early rheumatoid arthritis 2013 Apr Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early rheumatoid arthritis (RA) patients receiving preventive treatment for osteoporosis. A small increase in lumbar bone mineral density (BMD) during the first year of treatment was recorded, regardless of use of glucocorticoids. INTRODUCTION: This study aims to describe effects on BMD of treatment according to EULAR guidelines with a methotrexate-based tight control strategy including 10 mg prednisone daily versus the same strategy without prednisone in early RA patients who received preventive therapy for osteoporosis. METHODS: Early RA patients were included in the CAMERA-II trial: a randomized, placebo-controlled, double-blind 2-year trial, in which effects of addition of 10 mg prednisone daily to a methotrexate-based tight control strategy were studied. All patients received calcium, vitamin D and bisphosphonates. Disease activity was assessed every 4 weeks. Radiographs of hands and feet and dual-energy X-ray absorptiometry of lumbar spine and left hip were performed at baseline and after 1 and 2 years of treatment. RESULTS: BMD increased significantly over time in both treatment groups at the lumbar spine with a mean of 2.6% during the first year (p<0.001), but not at the hip; at none of the time points did BMD differ significantly between the prednisone and placebo group. Higher age and lower weight at baseline and higher disease activity scores during the trial, but not glucocorticoid therapy, were associated with lower BMD at both the lumbar spine and the hip in mixed-model analyses. CONCLUSION: Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early RA patients on bisphosphonates. A small increase in lumbar BMD during the first year of treatment was found, regardless of use of glucocorticoids.
23044765 Performance of matrix-based risk models for rapid radiographic progression in a cohort of 2013 Apr OBJECTIVE: Matrix-based risk models have been proposed as a tool to predict rapid radiographic progression (RRP) in rheumatoid arthritis (RA), but the experience with such models is limited. We tested the performance of 3 risk models for RRP in an observational cohort. METHODS: Subjects from an observational RA cohort with hand radiographs and necessary predictor variables to be classified by the risk models were identified (n = 478). RRP was defined as a yearly change in the Sharp/van der Heijde score of ≥5 units. Patients were placed in the appropriate matrix categories, with a corresponding predicted risk of RRP. The mean predicted probability for cases and noncases, integrated discrimination improvement, Hosmer-Lemeshow statistics, and C statistics were calculated. RESULTS: The median age was 59 years (interquartile range [IQR] 50-66 years), the median disease duration was 12 years (IQR 4-23 years), the median swollen joint count was 6 (IQR 2-13), 84% were women, and 86% had erosions at baseline. Twelve percent of patients (32 of 271) treated with synthetic disease-modifying antirheumatic drugs (DMARDs) at baseline and 10% of patients (21 of 207) treated with biologic DMARDs experienced RRP. Most of the predictor variables had a skewed distribution in the population. All models had a suboptimal performance when applied to this cohort, with C statistics of 0.59 (model A), 0.65 (model B), and 0.57 (model C), and Hosmer-Lemeshow chi-square P values of 0.06 (model A), 0.005 (model B), and 0.05 (model C). CONCLUSION: Matrix risk models developed in clinical trials of patients with early RA had limited ability to predict RRP in this observational cohort of RA patients.
23918525 ADAM15 adds to apoptosis resistance of synovial fibroblasts by modulating focal adhesion k 2013 Nov OBJECTIVE: To study the contribution of ADAM15, a disintegrin metalloproteinase that is up-regulated in the rheumatoid arthritis (RA) synovial membrane, to the characteristic resistance of RA synovial fibroblasts (RASFs) to apoptosis induction by genotoxic stress or stimulation with proapoptotic FasL, which is present at high concentrations in RA synovial fluid. METHODS: Caspase 3/7 activity and the total apoptosis rate in RASFs upon exposure to the DNA-damaging agent camptothecin or FasL were determined using enzyme assays and annexin V staining. Phosphorylated signaling proteins were analyzed by immunoblotting. RNA interference was used to silence ADAM15 expression. NF-κB activity was determined by enzyme-linked immunosorbent assay. RESULTS: RASFs displayed significantly higher caspase 3/7 activity upon camptothecin and FasL exposure when ADAM15 had been down-regulated by specific small interfering RNAs. Upon FasL stimulation, RASFs phosphorylated focal adhesion kinase (FAK) and c-Src (Src), and activated phosphatidylinositol 3-kinase as well as the transcription factor NF-κB. This ADAM15-dependent, FasL-induced activation of antiapoptotic kinases and NF-κB was demonstrated by a marked reduction of apoptosis upon knockdown of ADAM15 protein expression. Inhibitors specifically interfering with FAK and Src signaling, such as FAK inhibitor 14 and dasatinib, potently induce apoptosis in RASFs, with significant enhancement by the silencing of ADAM15. CONCLUSION: ADAM15 contributes to apoptosis resistance in RASFs by activating the Src/FAK pathway upon FasL exposure, rendering the FAK/Src signaling pathway an interesting target for potential therapeutic intervention in RA.
25433042 The EULAR Study Group for Registers and Observational Drug Studies: comparability of the p 2015 Jun OBJECTIVE: Under the auspices of the European League Against Rheumatism (EULAR), a study group of investigators representing European biologic DMARD (bDMARD) registers was convened. The purpose of this initial assessment was to collect and compare a cross section of patient characteristics and collate information on the availability of potential confounders within these registers. METHODS: Baseline characteristics of patients starting their first bDMARD in an arbitrary year (2008) for the treatment of RA, including demographic and disease characteristics, bDMARD drug details and co-morbidities, were collected and compared across 14 European bDMARD registers. RESULTS: A total of 5320 patients were included. Half the registers had restricted recruitment to certain bDMARDs during the study year. All registers` collected data on age, gender, disease duration, seropositivity for IgM-RF and 28-joint DAS (DAS28). The mean DAS28 ranged from 4.2 to 6.6 and the mean HAQ from 0.8 to 1.9. Current smoking ranged from 9% to 34%. Nine registers reported co-morbidities with varying prevalence. CONCLUSION: In addition to demonstrating European-wide collaboration across rheumatology bDMARD registers, this assessment identified differences in prescribing patterns, recruitment strategies and data items collected. These differences need to be considered when applying strategies for combined analysis. The lack of a common data model across Europe calls for further work to harmonize data collection across registers.
23960240 The cellular source and target of IL-21 in K/BxN autoimmune arthritis. 2013 Sep 15 IL-21 is a pluripotent cytokine that regulates B cell and plasma cell differentiation and is thought be an autocrine factor for follicular helper T cell (T(FH)) and Th17 differentiation. Although IL-21 has been implicated in autoimmune diseases, its relevant cellular source and target cells have not been well characterized. We investigated this issue in the K/BxN mouse model of autoimmune arthritis. Adoptive transfer of KRN-transgenic CD4⁺ T cells into appropriate hosts drives germinal center (GC) formation and autoantibody production against glucose-6-phosphate isomerase, leading to joint inflammation and destruction. By comparing transfer of T or B cells deficient in IL-21 or IL-21R, we were able to dissect the contribution of each cell type. T cells deficient in IL-21 did not induce GC formation or autoantibody production, but they went through normal T(FH) differentiation. However, T cells lacking IL-21R induced Ab titers, GC B cell frequency, and arthritis development similar to wild-type T cells, suggesting that IL-21 is not required for T(FH) differentiation and function. IL-21 acts on B cells, because IL-21R expression on B cells was required to induce disease. In contrast, Th17 cells, a T cell subset that also produces IL-21 and can provide help to B cells, are not required for the GC response and arthritis. These data have implications in developing effective therapies for rheumatoid arthritis and other Ab-mediated autoimmune diseases.
22833376 Tolerability and efficacy of abatacept in Japanese patients with rheumatoid arthritis: a p 2013 Jul OBJECTIVE: The primary objective of this study was to evaluate the tolerability of single and multiple doses of abatacept in Japanese patients with rheumatoid arthritis. Secondary objectives included evaluating its pharmacokinetics, pharmacodynamics, immunogenicity, and efficacy. METHODS: This dose-escalation, single- and multiple-dose, multicenter, open-label study was conducted at nine sites in Japan. Seven patients were enrolled at each of three dose levels (2, 8 and 16 mg/kg) and received a single intravenous dose of abatacept on day 1 of the single-dose phase. The multiple-dose phase, at the same dose, started once the patients had completed the single-dose phase and when it was confirmed that there were no safety issues. RESULTS: Twenty patients started the single-dose phase. Single and multiple doses of abatacept were well tolerated, and adverse events were of mild to moderate intensity. There were no discontinuations or deaths due to adverse events. The pharmacokinetics of abatacept were linear, with no notable accumulation. There were no immunogenic effects on the safety, efficacy, or pharmacokinetics of abatacept. Multiple doses of abatacept improved individual items of the American College of Rheumatology core set. CONCLUSION: Single and multiple doses of abatacept showed favorable tolerability and efficacy in Japanese patients with rheumatoid arthritis.
24010514 Multiple eruptive keratoacanthomas associated with leflunomide. 2013 Jul 14 A 78-year-old woman diagnosed with rheumatoid arthritis without a history of skin tumors or immunosuppressive medication, started treatment with leflunomide. One month after the introduction of the drug, and for two consecutive years, she developed multiple crateriform nodules and papules on her lower extremities . Biopsy specimens showed keratoacanthomas and squamous-cell carcinomas. Owing to suspicion that the drug could be implicated in the appearance of these tumors, the patient decided to suspend the drug. No new skin lesions have appeared in seventeen months of clinical follow-up. There have been several published case reports of multiple keratoacanthomas associated with immunosuppressive therapy such as sorafenib and imiquimod. However, we found no mention in the literature of the eruption of multiple keratoacanthomas in patients with rheumatoid arthritis treated with leflunomide. We suggest, that the the sudden appearance of skin tumors in our patient is related to the introduction of leflunomide, but additional case reports are required to confirm this association.
23961674 [JAK inhibitor]. 2013 Jul Biologics targeting inflammatory cytokine has become a standardized tool for remission induction in rheumatoid arthritis (RA). However, it is handled under restricted conditions and their cost of acquisition is high. Small molecule drugs targeting Janus kinase (JAK), a molecule involved in intracellular signaling pathway has shown similar treatment effect as biologics. Moreover, inhibitory effect on bone destruction has been demonstrated and has been approved in 2012 as a new disease modifying anti-rheumatic drug in USA. However, since the inhibition of JAK results in inhibition of multiple cytokine signaling pathways, the clinical studies have also shown adverse events differing from biologics.
23378469 Validation of a self-administered inflammatory arthritis detection tool for rheumatology t 2013 Apr OBJECTIVE: The benefits of early intensive treatment of inflammatory arthritis (IA) are dependent on timely and accurate case identification. In our study, a scoring algorithm for a self-administered IA detection tool was developed and validated for the rheumatology triage clinical setting. METHODS: A total of 143 consecutive consenting adults, newly referred to 2 outpatient rheumatology practices, completed the tool. A scoring algorithm was derived from the best-fit logistic regression model using age, sex, and responses to the 12 tool items as candidate predictors of the rheumatologists' blinded classification of IA. Bootstrapping was used to internally validate and refine the model. RESULTS: The 30 IA cases were younger than the 113 non-cases (p < 0.0001) and included clinical diagnoses of early IA (n = 10), rheumatoid arthritis (n = 9), and spondyloarthropathies (n = 11). Non-cases included osteoarthritis (n = 46), pain syndromes (n = 19), systemic lupus erythematosus (n = 5), and miscellaneous, noninflammatory musculoskeletal complaints (n = 43). The best-fit model included younger age, male sex, "trouble making a fist," "morning stiffness," "ever told you have RA," and "psoriasis diagnosis." The overall predictive performance (standard error, SE) of the derivation model was 0.91 (0.03). Internal validation of the derivation model across 200 bootstrap samples resulted in a mean predictive performance (SE) of 0.904 (0.002). The refined tool had a mean predictive performance (SE) of 0.915 (0.002), a sensitivity of 0.855 (0.005), and specificity of 0.873 (0.003). CONCLUSION: A simple, self-administered tool was developed and internally validated for the sensitive and specific detection of IA in a rheumatology waiting list sample. The tool may be used to triage IA from rheumatology referrals.