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ID PMID Title PublicationDate abstract
26272058 Views on clinically suspect arthralgia: a focus group study. 2016 May The rheumatology field is moving towards identifying individuals with an increased risk for rheumatoid arthritis (RA) at a stage when arthritis is still absent but persons having clinically suspect arthralgia (CSA). Incorporating patients' views in rheumatologic care is pivotal; however, the views of persons with CSA on their condition are unknown. We aimed to help fill this gap by exploring illness perceptions of persons with CSA and their views on hypothetical prognoses for developing RA. Persons with CSA were invited to participate in a semi-structured focus group discussion. Illness perceptions according to the Common Sense Model (CSM) and four a priori formulated themes were explored in detail during the group discussion. The discussion was audio-taped and transcribed verbatim. Transcripts were analysed in an interpretative phenomenological approach manner, on the basis of the dimensions of the CSM by three researchers independently. The views of four participants with CSA were explored during one focus group discussion. Four dimensions of the CSM were mainly observed: Identity, Consequences, Personal Control and Concern. None of the patients identified themselves as being a patient. They did experience pain and impairments in daily functioning and were concerned that their symptoms would progress. In the absence of physician-initiated treatment, some patients changed lifestyle in order to reduce pain and to promote health. Patients unanimously said that they could not interpret prognostic information on RA development expressed in hypothetical chances. Persons with CSA do not consider themselves patients. Prognostic information related to the development of RA based on risk percentages was considered as not useful by persons with CSA. Understanding of the illness perceptions of persons with CSA by health care professionals might improve medical management and facilitate shared decision-making.
26270516 [The importance of γ-linolenic acid in the prevention and treatment]. 2015 Jul 27 The etiology of diet-related disorders is closely associated with dietary factors. A special role is attributed to intake of fat and fatty acid profile, both quantitative and qualitative. For prevention and treatment of the abovementioned diseases a proper supply of unsaturated fatty acids plays a significant role, because of their particular importance to health. γ-Linolenic acid (GLA), with three double bonds in the carbon chain, also known as all-cis 6,9,12-octadecatrienoic acid, belongs to the n-6 family of fatty acids. It plays biologically important functions in the human body, such as being a substrate for eicosanoids synthesis, involvement in the transport and oxidation of cholesterol, and being one of the components of lipid membrane. Its inadequate dietary intake or impaired formation is the cause of many inflammatory and degenerative diseases. A rich source of this fatty acid is vegetable oils, until recently used mainly in folk medicine. Nowadays, studies conducted both in animal models and in humans suggest its health-promoting properties in the prevention and treatment of atopic dermatitis, cardiovascular diseases, diabetes, cancers and rheumatoid arthritis.
27282428 Pregnancy Outcomes in the Tofacitinib Safety Databases for Rheumatoid Arthritis and Psoria 2016 Aug INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), and is being investigated for the treatment of psoriasis. Both conditions can present in women of child-bearing potential, but pregnancy was an exclusion and discontinuation criterion in tofacitinib randomized controlled trials (RCTs) because of the unknown effects of tofacitinib on mother and child. Tofacitinib is a small molecule that has the potential to cross the placenta. OBJECTIVE: The objective was to report outcomes of pregnancy cases identified through April 2014 from tofacitinib RA/psoriasis RCTs, RA post-approval non-interventional studies, and spontaneous adverse-event reporting. METHODS: Pregnancy outcomes were categorized as follows: healthy newborn, medical termination, fetal death, congenital malformation, spontaneous abortion, or pending/lost to follow-up. RESULTS: Out of 9815 patients, 1821 female patients of child-bearing age were enrolled in the RA/psoriasis RCTs; 47 women became pregnant, including 33 who received tofacitinib monotherapy, 13 who received combination therapy with methotrexate (RA patients only), and one patient whose therapy was still blinded. No fetal deaths were reported. One congenital pulmonary valve stenosis (monotherapy, n = 1), seven spontaneous abortions (monotherapy, n = 4; combination therapy, n = 3), and eight medical terminations (monotherapy, n = 4; combination therapy, n = 3; blinded therapy, n = 1) were identified. Remaining cases reported healthy newborns (n = 25) or were pending/lost to follow-up (n = 6). Forty-four cases of paternal exposure to tofacitinib were reported (monotherapy, n = 43; combination therapy, n = 1), including five spontaneous abortions (monotherapy, n = 4; combination therapy, n = 1), 23 healthy newborns, and 16 pending/lost to follow-up. CONCLUSIONS: The pregnancy outcomes reported in this small number of RA/psoriasis patients appear similar to those observed in the general population and in patients treated with biologic therapies for inflammatory diseases. However, definitive conclusions cannot be drawn, and pregnancy outcomes in patients receiving tofacitinib will continue to be monitored.
24812287 Pretreatment multi-biomarker disease activity score and radiographic progression in early 2015 Jun OBJECTIVES: Prediction of radiographic progression (RP) in early rheumatoid arthritis (eRA) would be very useful for optimal choice among available therapies. We evaluated a multi-biomarker disease activity (MBDA) score, based on 12 serum biomarkers as a baseline predictor for 1-year RP in eRA. METHODS: Baseline disease activity score based on erythrocyte sedimentation rate (DAS28-ESR), disease activity score based on C-reactive protein (DAS28-CRP), CRP, MBDA scores and DAS28-ESR at 3 months were analysed for 235 patients with eRA from the Swedish Farmacotherapy (SWEFOT) clinical trial. RP was defined as an increase in the Van der Heijde-modified Sharp score by more than five points over 1 year. Associations between baseline disease activity measures, the MBDA score, and 1-year RP were evaluated using univariate and multivariate logistic regression, adjusted for potential confounders. RESULTS: Among 235 patients with eRA, 5 had low and 29 moderate MBDA scores at baseline. None of the former and only one of the latter group (3.4%) had RP during 1 year, while the proportion of patients with RP among those with high MBDA score was 20.9% (p=0.021). Among patients with low/moderate CRP, moderate DAS28-CRP or moderate DAS28-ESR at baseline, progression occurred in 14%, 15%, 14% and 15%, respectively. MBDA score was an independent predictor of RP as a continuous (OR=1.05, 95% CI 1.02 to 1.08) and dichotomised variable (high versus low/moderate, OR=3.86, 95% CI 1.04 to 14.26). CONCLUSIONS: In patients with eRA, the MBDA score at baseline was a strong independent predictor of 1-year RP. These results suggest that when choosing initial treatment in eRA the MBDA test may be clinically useful to identify a subgroup of patients at low risk of RP. TRIAL REGISTRATION NUMBER: WHO database at the Karolinska Institute: CT20080004; and clinicaltrials.gov: NCT00764725.
25739846 Teriparatide: an unexpected adjunct for the treatment of a long-standing infected elbow pr 2015 Apr A 76-year-old woman with rheumatoid arthritis, osteoporosis and multiple comorbidities presented with septic left elbow prosthesis. Treatment included combination antibiotic therapy and removal of the prosthesis. Weeks later she was started on teriparatide. Her elbow symptoms resolved. In our experience, this is the first case in the literature reporting teriparatide efficacy in the treatment of septic arthritis.
26698025 Deregulation and therapeutic potential of microRNAs in arthritic diseases. 2016 Apr Epigenetic abnormalities are part of the pathogenetic alterations involved in the development of rheumatic disorders. In this context, the main musculoskeletal cell lineages, which are generated from the pool of mesenchymal stromal cells (MSCs), and the immune cells that participate in rheumatic diseases are deregulated. In this Review, we focus on microRNA (miRNA)-mediated regulatory pathways that control cell proliferation, drive the production of proinflammatory mediators and modulate bone remodelling. The main studies that identify miRNAs as regulators of immune cell fate, MSC differentiation and immunomodulatory properties - parameters that are altered in rheumatoid arthritis (RA) and osteoarthritis (OA) - are also discussed, with emphasis on the importance of miRNAs in the regulation of cellular machinery, extracellular matrix remodelling and cytokine release. A deeper understanding of the involvement of miRNAs in rheumatic diseases is needed before these regulatory pathways can be explored as therapeutic approaches for patients with RA or OA.
26019128 The W620 Polymorphism in PTPN22 Disrupts Its Interaction With Peptidylarginine Deiminase T 2015 Sep OBJECTIVE: A C-to-T single-nucleotide polymorphism (SNP) located at position 1858 of human protein tyrosine phosphatase PTPN22 complementary DNA carries the highest risk of rheumatoid arthritis (RA) among all non-HLA genetic variants. This C1858T SNP converts an arginine (R620) to a tryptophan (W620), but it is unclear why it has such a strong impact on RA, a disease characterized by anti-citrullinated protein antibodies. The aim of this study was to test the hypothesis that PTPN22 regulates protein citrullination. METHODS: The level of citrullinated proteins in immune cells was quantified by Western blotting. The physical interaction between PTPN22 and peptidyl arginine deiminase type 4 (PAD-4), which is one of the enzymes that catalyzes protein citrullination, was examined by coimmunoprecipitation. Neutrophils were collected from healthy donors carrying the C1858T SNP and healthy donors not carrying this SNP. The formation of neutrophil extracellular traps (NETs) was examined by immunocytochemistry. RESULTS: PTPN22 physically interacted with PAD-4, and a deficiency in PTPN22 enhanced protein citrullination. This abnormality was reversed by exogenous wild-type PTPN22 or catalytically dead mutant PTPN22. The R-to-W conversion rendered PTPN22 unable to interact with PAD-4 and suppress citrullination. The C1858T SNP was associated with hypercitrullination in peripheral blood mononuclear cells and a heightened propensity for spontaneous formation of NETs, which is a PAD-4-dependent process. CONCLUSION: PTPN22 is an inhibitor of PAD-4 and protein citrullination. This function of PTPN22 is independent of its phosphatase activity but requires R620. Our data not only establish a molecular link between PTPN22 and PAD-4, but also suggest that the C1858T SNP increases the risk of RA by enhancing protein citrullination and spontaneous formation of NETs.
27987496 [Detection of peripheral follicular helper T cells in rheumatoid arthritis]. 2016 Dec 18 OBJECTIVE: To detect cell frequency and surface markers of peripheral CD4(+)CXCR5+ follicular helper T (Tfh) cells and analyze the correlation between CD4(+)CXCR5(+)Tfh cells and rheumatoid arthritis (RA) disease activity. METHODS: Forty RA patients meeting the American College of Rheumatology classification criteria for RA and twenty healthy controls (HC) were included. The peripheral blood mononuclear cells and sera were collected. The expressions of CD4+CXCR5(+)Tfh cells (CXCR5, C-X-C chemokine receptor type 5) and inducible T cell costimulator (ICOS), programmed death 1 positive (PD-1), interleukin-21 receptor (IL-21R) and CD40 ligand (CD40L) positive on CD4(+)CXCR5(+)Tfh cells were analyzed by flow cytometry. The transcript levels of B-cell lymphoma 6 (Bcl-6), as well as IL-21 and IL-21R, were measured by real-time polymerase chain reaction. Besides, serum IL-21 and CXCL13 concentrations were determined by enzyme-linked immunosorbent assay. The potential association between Tfh cells and RA disease activity was detected. RESULTS: The cell surface marker of CXCR5(+) on CD4(+) cells was significantly increasingly higher across the following groups versus HC: total RA patients (16.75±3.92 vs.7.49±1.84, P<0.001); RA patients with low disease activity or remission (16.62±3.43 vs. 7.49±1.84, P<0.001); RA patients with moderate disease activity (16.82±3.07 vs. 7.49±1.84, P<0.001) and RA patients with high disease activity (16.87±5.50 vs. 7.49±1.84, P<0.001). Besides, the percentages of ICOS+, PD-1(+), IL-21R(+) on CD4(+)CXCR5(+)Tfh cells in the RA patients were significantly higher than that of HC (ICOS(+)CD4(+)CXCR5(+)cells, 8.37±4.28 vs. 3.72±1.81, P<0.001; PD-1(+)CD4(+)CXCR5(+)cells, 1.57±1.10 vs. 0.24±0.30, P=0.035; IL-21R(+)CD4(+)CXCR5(+) cells, 4.60 ±4.05 vs. 0.20±0.19, P=0.006). But the percentage of CD40L(+) on CXCR5(+)CD4(+)Tfh cells in the RA patients was not significantly higher than that of HC (3.38±3.71 vs. 0.54±0.34, P=0.135). The IL-21R mRNA expression was elevated significantly (5.00±4.94 vs. 0.74±0.55, P<0.001) in the RA patients but not in Bcl-6 mRNA[4.54(3.33, 7.23) vs. 5.31(2.81, 7.44), P=0.329]or IL-21 mRAN[0.72(0.26, 3.45) vs. 0.56(0.27, 3.71), P=0.195]. Additionally, the serum interleukin-21 (IL-21) and CXCL13 levels in the RA patients were higher than in the healthy controls [IL-21, (200.49±154.56) ng/L vs. (8.21±5.95) ng/L, P<0.001; CXCL13, (93.72±49.72) ng/L vs. (43.09±1.28) ng/L, P<0.001] and were both positively correlated with RA disease activity indexes, including erythrocyte sedimentation rate, the disease activity score in 28 joints (ESR-based or CRP-based), clinical disease activity index, and simplified disease activity index. However, none of the Tfh cells, anti-citrullinated protein antibody or rheumatoid factor had any relationship with RA disease activity. CONCLUSION: Peripheral Tfh cells and their relevant cytokines are higher in RA patients than healthy controls, indicating Tfh cells may participate in the pathogenesis of RA, therefore, blocking the pathway of Tfh cells may be reasonable cellular targets for therapeutic intervention.
27906048 Comparative effectiveness of abatacept versus tocilizumab in rheumatoid arthritis patients 2016 Dec 1 BACKGROUND: We compared the effectiveness of abatacept (ABA) vs tocilizumab (TCA) in tumor necrosis factor inhibitor (TNFi) experienced patients. METHODS: We identified rheumatoid arthritis (RA) patients from a large observational US cohort (1 January 2010-31 May 2014) who had discontinued at least one TNFi and initiated ABA or TCZ in moderate or high disease activity based on the Clinical Disease Activity Index (CDAI) and had no prior exposure to the comparator drug. Using propensity score matching (1:1) stratified by prior TNF use (1 TNFi vs ≥2 TNFis), effectiveness at 6 months after initiation was evaluated. Mean change in CDAI over 6 months following initiation was the primary outcome, with secondary outcomes of achievement of low disease activity/remission (CDAI ≤ 10) and mean change in modified Health Assessment Questionnaire (mHAQ) score. RESULTS: The 264 pairs of propensity score-matched ABA and TCZ initiators were well matched with no substantial differences in the baseline characteristics, defined as standardized differences >0.1 in the stratification. Both treatment groups had similar mean change in CDAI at 6 months (-11.3 in ABA vs -9.9 in TCZ; mean difference -1.27, 95% CI -3.65, 1.11). Similar proportions of both treatment groups achieved low disease activity/remission (adjusted odds ratio for ABA vs TCZ 0.99, 95% CI 0.69, 1.43). Mean change in mHAQ was -0.12 in ABA initiators vs -0.11 in TCZ initiations (mean difference -0.01, 95% CI -0.09, 0.06). CONCLUSIONS: Patients receiving either ABA or TCZ had substantial improvement in clinical disease activity. In this propensity score-matched sample, similar outcomes were observed for both treatment cohorts.
27858553 Cross-Sectional Evaluation of Periodontal Status and Microbiologic and Rheumatoid Paramete 2017 Apr BACKGROUND: This study evaluates periodontal conditions and microbiologic findings and their influence on rheumatologic disease parameters in patients with rheumatoid arthritis (RA). METHODS: One hundred and sixty-eight patients with RA were included. A healthy control group (HC, n = 168) was composed according to age, sex, and smoking habits. Rheumatologic data (duration of illness, Disease Activity Score 28, rheumatic factor [RF], anti-cyclic citrullinated peptide [aCCP], medications) were extracted from patients' records. Dental examination included: 1) dental findings (decayed, missing, and/or filled adult teeth [DMF-T] index); 2) gingival inflammation (papillary bleeding index [PBI]); and 3) periodontal status (probing depth [PD], attachment loss [AL]). Periodontal condition was classified as healthy/mild, moderate, or severe periodontitis. Subgingival biofilm was analyzed regarding 11 periodontopathogenic bacteria. Statistical analyses included: 1) Kolmogorov-Smirnov test; 2) Mann-Whitney U test; 3) Pearson χ(2) test; 4) Kruskal-Wallis test; and 5) regression analysis; level of significance α = 5%. RESULTS: Mean DMF-T was significantly higher in patients with RA (19.3 ± 4.8) than in HC group (16.9 ± 5.8), especially owing to number of missing teeth (RA = 6.0 ± 5.4, HC = 3.1 ± 3.3; P <0.01). Patients with RA had a significantly higher proportion of increased PD (P <0.01) and AL compared with HC group (P <0.01). Moderate to severe periodontitis was noted in 98% of patients with RA and 82% of the HC group (P <0.01). RF-positive patients with RA suffered from worse periodontal conditions than RF-negative patients (P = 0.01). Age, PBI, and presence of Treponema denticola (P <0.03) are related to periodontal condition in patients with RA. Although not statistically significant, Porphyromonas gingivalis and Fusobacterium nucleatum occur in higher concentrations more often in aCCP-positive patients with RA (P = 0.06). CONCLUSIONS: Patients with RA had worse periodontal conditions than HC participants. Although a trend for higher F. nucleatum and P. gingivalis concentrations in aCCP-positive patients with RA was found, importance of periodontal pathogenic bacteria and rheumatoid parameters in the interrelationship between periodontitis and RA remains unclear.
26401963 Real-world evaluation of TNF-inhibitor utilization in rheumatoid arthritis. 2016 OBJECTIVES: To evaluate 12-month treatment patterns, healthcare resource use (HCRU), and costs for patients with rheumatoid arthritis (RA), following initiation of index TNF inhibitors (TNFi) and subsequent biologic DMARDs (bDMARDs). METHODS: This was a retrospective cohort analysis of adults with RA newly initiating TNFi in the Truven Marketscan Commercial Claims and Encounters and Medicare Supplemental Databases during 2010-2013. A sub-group of patients who switched to a bDMARD within 12 months post-index and within 180 days of last index TNFi were subsequently evaluated over 12 months. TNFi/bDMARD treatment patterns were characterized as: continuers, no gap >180 days in prescription/administration of index TNFi; discontinuers, gap >180 days; switchers, initiated new bDMARD. Concomitant conventional synthetic DMARD use, co-morbid chronic illnesses, and RA severity were assessed. All-cause/RA-related HCRU and costs were evaluated 12 months post-index. RESULTS: Of 9567 identified patients, 67.2%, 17.3%, and 15.4% were continuers, discontinuers, and switchers, respectively. Switchers had the highest 12-month unadjusted mean all-cause costs of $34,585 vs $33,051 for continuers (p = 0.1158) and $24,915 for discontinuers (p < 0.0001; discontinuers vs continuers, p < 0.0001). RA-related costs comprised 82.8%, 31.4%, and 85.7% of total costs for continuers, discontinuers, and switchers, respectively. Of 764 switchers, 68.2% switched to alternative TNFi (cyclers), the rest to non-TNFi bDMARDs; 36.7% of patients who switched to TNFi switched again (to third-line bDMARD) vs 27.6% (p = 0.0313) of those who switched to non-TNFi bDMARDs. Switchers to non-TNFi bDMARDs had higher mean 12-month all-cause costs of $76,580 compared with $50,689 for switchers to alternative TNFi (p < 0.0001); biologic-administration visits comprised 78.8% of the greater total RA-related costs of switchers to non-TNFi bDMARDs. CONCLUSIONS: Real-world TNFi discontinuation/switching rates correspond to randomized controlled trial non-response rates. TNFi cycling is common and associated with an increased likelihood of switching to third-line bDMARD. Switching to non-TNFi bDMARDs was associated with higher costs, mostly attributed to in-office administrations.
27838788 Does addition of glucocorticoids to the initial therapy influence the later course of the 2017 Jan The main goal of this study was to analyse whether initial addition of glucocorticoid to DMARD therapy influences the long-term course of the disease in patients with early rheumatoid arthritis. All patients from the Swiss RA cohort SCQM with recent-onset arthritis (disease duration ≤1 year) were analysed. The exposure of interest was the use of glucocorticoids (GCs) at baseline. As primary outcome, we considered clinical and radiographic disease progression, assessed by the disease activity (disease activity score, DAS-28), function (health assessment questionnaire disability index, HAQ-DI) and structural joint damage (Ratingen erosion score). The baseline disease characteristics were compared using standard descriptive statistics. The effects of initial GC use on disease progression during follow-up were estimated using linear mixed models with random slope and random intercept, adjusted for potential confounders. In total, 592 patients with early disease were available, with 4.3 years of follow-up (average). Of these, 363 were initially treated with glucocorticoids (GC patients) and 228 were not (no-GC patients). DAS-28 (4.6 vs. 4.3, p = 0.01) and the HAQ-DI (0.94 vs. 0.82, p = 0.01) were higher at baseline in GC patients, while other prognostic factors were balanced at baseline. Neither the change of DAS-28, of HAQ-DI nor of the development of joint erosions differed between the two groups during follow-up. Escalation of treatment employing biologics was documented in 18.0% of the no-GC patients and 27.3% of the GC patients (p < 0.01). In this cohort, patients with early RA initially treated with GCs had higher measures of disease activity at baseline in comparison to no-GC patients. Despite a similar course of the disease in GC versus non-GC patients, the higher escalation rate to biologic agents in GC patients may reflect a disease less responsive to therapy in these patients. These data suggest that GC use as part of the initial therapeutic strategy in early RA may prevent a more severe course of the disease in patients with higher clinical disease measures at the start of therapy.
25678083 Increased frequency of JC-polyomavirus detection in rheumatoid arthritis patients treated 2015 Oct Progressive multifocal leukoencephalopathy (PML) represents a rare but potentially fatal reactivation of JC-polyomavirus (JCPyV) recently also reported in patients with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis (RA) treated with rituximab. The aim of the present study was to analyse the pattern of JCPyV infections in patients with RA undergoing treatment with biologic agents. Urine and blood samples were analysed from 80 patients for antibody levels and/or the presence of JCPyV DNA. Genotyping of the control region and VP1 was performed for all JCPyV DNA-positive specimens. Viremia of JCPyV was only temporarily detected in two patients, and these viruses did not carry any mutations associated with the occurrence of PML. JCPyV DNA was prevalent in initial urine samples of 33% of all patients. RA patients who have consecutively been treated with two or more biologic agents revealed significantly higher prevalence of JCPyV DNA in the urine compared to RA patients treated with their first biologic agent. The presence of JCPyV DNA in the urine closely correlated to JCPyV antibody positivity, and therefore, antibody titres were higher in RA patients who had consecutively received two or more biologic agents over time. Therefore, the overall number of biologic agents had an impact on the pattern of JCPyV detection in this study. Hence, JCPyV antibody screening might be useful as part of the PML risk stratification for RA patients in the future.
26679631 CTLA-4 blockade in the treatment of rheumatoid arthritis: an update. 2016 Rheumatoid arthritis (RA) is characterized by chronic joint inflammation as well as by extra-articular involvement. The immunopathology of RA is polygenic and involves different cell populations. Patients with an inadequate response to non-biologic disease- modifying antirheumatic drugs (DMARDs) should integrate their therapy with biologic DMARDs. Biologic DMARDs can target several inflammatory cytokines, or CD20+ B cells, or can modulate T-cell co-stimulation and activation. The cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4-Ig: abatacept) that selectively modulates the CD28:CD80/86 co-stimulation signal appears a biologic DMARD interacting with T cells but also with other cell populations involved in RA pathophysiology. Activated B lymphocytes, macrophages, osteoclasts and endothelial cells express the costimulatory molecules (CD80/86) and are downregulated by CTLA-4 blockade. The relatively low frequency and severity of safety issues related to CTLA-4-Ig treatment seems further to confirm the targeted downregulatory action exerted by the fusion protein, which is mainly focussed on activated immune/inflammatory cells.
27729269 Analgesic and anti-edematogenic effects of oral trypsin were abolished after subdiaphragma 2016 Dec 1 AIMS: Rheumatoid arthritis brings great burdens to the patients. In addition to the highly expensive treatment, they are commonly associated with severe side effects. In such context, the research for safe and affordable treatments is needed. MAIN METHODS: Arthritis was induced by CFA (0.5mg/mL) in female wistar rats. Trypsin was given p.o. (2.95mg/kg; 2mL) 24h after the intra-articular CFA injection. Articular incapacitation was measured daily by counting the paw elevation time (PET; s) during 1-min periods of stimulated walk, throughout the 7-days after intra-articular CFA injection. Articular diameter (AD) was accessed just after each PET measurement, taken the difference between naïve and diseased knee-joint diameter (cm). KEY FINDINGS: The present study showed that orally administered trypsin was able to reduce nociception and edema, effects that could be observed throughout the evaluation period. These effect, however, were not observed in animals underwent subdiaphragmatic vagotomy, suggesting a vagal mediation for trypsin effects. Likewise, these effects were blocked in rats which received intrathecal injection of the neurotoxins 5,7-dihydroxytryptamine or 6-hydroxydopamine, suggesting the involvement of spinal amines from axon terminals. SIGNIFICANCE: The present study proposes that oral trypsin may cause vagal activation, followed by the activation of descending inhibitory pathways and such mechanism may lead to a novel approach for the treatment of arthritis.
25532946 Safety of disease-modifying antirheumatic drugs and biologic agents for rheumatoid arthrit 2015 Apr OBJECTIVE: The aim of this study was to describe the incidence rate (IR) of adverse drug reactions (ADRs) in daily clinical practice, related to disease-modifying antirheumatic drugs (DMARDs) and biologic agents (BA) in rheumatoid arthritis (RA) patients, and to analyze factors causing discontinuation due to ADRs. METHODS: This was a prospective observational study (October 2010 to October 2011). RA patients who were attended in our hospital taking DMARDs or BA during the study period were included. ADRs were injuries related to these drugs and registered with a software system in routine visits. ADRs could be mild (lowering dosage), moderate (drug discontinuation), or severe (hospital admission). The IR of ADR per 100 patient-years was estimated using survival techniques. Cox regression models (HR; 95% confidence interval) were used to explore factors associated with discontinuation due to ADRs. RESULTS: In total, 1202 patients were analyzed, with 158 ADRs (IR = 15.2). Of all ADRs, 80.4% required drug discontinuation (IR = 12.2). Age, less disease and therapy duration, taking corticoids, and combined therapy versus monotherapy (HR = 3; 95% CI: 2.0-4.4) were the factors independently associated to discontinuation due to ADRs. We did not find statistical differences between the different monotherapy regimens. Regarding combinations, Methotrexate + BA had the lowest risk of discontinuation compared to the rest (HR = 0.24; 95% CI: 0.09-0.6). CONCLUSIONS: We have estimated the incidence of ADRs related to DMARDs/BA in real-life conditions. We confirm the role of combined therapy in the development of discontinuations due to ADRs, except for BA + MTX, which did not show an increase of toxicity compared to monotherapy. This combination seems to be safer than others.
26107769 Preclinical Potency and Biodistribution Studies of an AAV 5 Vector Expressing Human Interf 2015 INTRODUCTION: Proof of concept for local gene therapy for the treatment of arthritis with immunomodulatory cytokine interferon beta (IFN-β) has shown promising results in animal models of rheumatoid arthritis (RA). For the treatment of RA patients, we engineered a recombinant adeno-associated serotype 5 vector (rAAV5) encoding human (h)IFN-β under control of a nuclear factor κB promoter (ART-I02). METHODS: The potency of ART-I02 in vitro as well as biodistribution in vivo in arthritic animals was evaluated to characterize the vector prior to clinical application. ART-I02 expression and bioactivity after transduction was evaluated in fibroblast-like synoviocytes (FLS) from different species. Biodistribution of the vector after local injection was assessed in a rat adjuvant arthritis model through qPCR analysis of vector DNA. In vivo imaging was used to investigate transgene expression and kinetics in a mouse collagen induced arthritis model. RESULTS: Transduction of RA FLS in vitro with ART-I02 resulted in high expression levels of bioactive hIFN-β. Transduction of FLS from rhesus monkeys, rodents and rabbits with ART-I02 showed high transgene expression, and hIFN-β proved bioactive in FLS from rhesus monkeys. Transgene expression and bioactivity in RA FLS were unaltered in the presence of methotrexate. In vivo, vector biodistribution analysis in rats after intra-articular injection of ART-I02 demonstrated that the majority of vector DNA remained in the joint (>93%). In vivo imaging in mice confirmed local expression of rAAV5 in the knee joint region and demonstrated rapid detectable and sustained expression up until 7 weeks. CONCLUSIONS: These data show that hIFN-β produced by RA FLS transduced with ART-I02 is bioactive and that intra-articular delivery of rAAV5 drives expression of a therapeutic transgene in the joint, with only limited biodistribution of vector DNA to other tissues, supporting progress towards a phase 1 clinical trial for the local treatment of arthritis in patients with RA.
26419001 [Progress of molecular genetics research on rheumatoid arthritis]. 2015 Oct Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disorder that principally attacks flexible joints and synovia. The precise pathogenesis of RA remains unclear, and genetic factors probably play an important role in its etiology. In addition to genes from human leukocyte antigen (HLA) region, such as HLA-DRB, genes from non-HLA region, such as TIM-3, PTPN22, TRAF1/C5, STAT4, CCR5, PADI4 and FCGR2A may also contribute to its susceptibility. The advance in molecular genetics research on RA is reviewed here.
26238146 Endometriosis and the risks of systemic lupus erythematosus and rheumatoid arthritis in th 2016 Jul OBJECTIVES: The aetiologies of endometriosis, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are all characterised by immune dysfunction. SLE and RA occur more often in women, and reproductive and hormonal factors have been shown to be related to increased risk. However, only one previous study has evaluated the temporal association between endometriosis and SLE or RA. We sought to investigate the association between laparoscopically confirmed endometriosis and subsequently diagnosed SLE and RA. METHODS: We analysed data from the Nurses' Health Study II (n=114 453 women) over a 22-year follow-up period. Multivariable, time-varying Cox proportional hazards models were used to calculate HRs and 95% CIs for the association between laparoscopically confirmed endometriosis and confirmed incident SLE or RA. RESULTS: From 1989 to 2011, 103 incident cases of SLE and 390 cases of RA were confirmed. Laparoscopically confirmed endometriosis was significantly associated with subsequent SLE diagnosis (HR=2.03; CI 1.17 to 3.51) and RA diagnosis (HR=1.41; CI 1.05 to 1.89). These associations were robust to adjustment for SLE or RA risk factors and for potential confounders; however, adjustment for hysterectomy and oophorectomy attenuated both relations such that they were no longer significant. No significant differences by infertility status or age (<45 years) were observed. CONCLUSIONS: Our findings suggest an association between endometriosis and risk of SLE and RA. It remains to be understood whether and how endometriosis itself, or hysterectomy or other factors associated with endometriosis, is related to risk of SLE or RA.
25344930 Automatic identification of methotrexate-induced liver toxicity in patients with rheumatoi 2015 Apr OBJECTIVES: To improve the accuracy of mining structured and unstructured components of the electronic medical record (EMR) by adding temporal features to automatically identify patients with rheumatoid arthritis (RA) with methotrexate-induced liver transaminase abnormalities. MATERIALS AND METHODS: Codified information and a string-matching algorithm were applied to a RA cohort of 5903 patients from Partners HealthCare to select 1130 patients with potential liver toxicity. Supervised machine learning was applied as our key method. For features, Apache clinical Text Analysis and Knowledge Extraction System (cTAKES) was used to extract standard vocabulary from relevant sections of the unstructured clinical narrative. Temporal features were further extracted to assess the temporal relevance of event mentions with regard to the date of transaminase abnormality. All features were encapsulated in a 3-month-long episode for classification. Results were summarized at patient level in a training set (N=480 patients) and evaluated against a test set (N=120 patients). RESULTS: The system achieved positive predictive value (PPV) 0.756, sensitivity 0.919, F1 score 0.829 on the test set, which was significantly better than the best baseline system (PPV 0.590, sensitivity 0.703, F1 score 0.642). Our innovations, which included framing the phenotype problem as an episode-level classification task, and adding temporal information, all proved highly effective. CONCLUSIONS: Automated methotrexate-induced liver toxicity phenotype discovery for patients with RA based on structured and unstructured information in the EMR shows accurate results. Our work demonstrates that adding temporal features significantly improved classification results.