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ID PMID Title PublicationDate abstract
29435630 CT assessment of axillary lymphadenopathy in patients with rheumatoid arthritis: associati 2018 Jun BACKGROUND: Axillary lymph nodes (ALNs) are often seen on chest computed tomography (CT) in rheumatoid arthritis (RA) patients. Early reports described lymphadenopathy as one of the systemic manifestations rather than regional lymphadenopathy secondary to drainage from the affected joints. Subsequently, the importance of the immunological events occurring in draining lymph nodes in the development of arthritis was documented. OBJECTIVE: To identify the relationships of local disease activity and background characteristics, including systemic disease activity, systemic disease activity, with axillary lymphadenopathy (AL) in RA using CT. METHODS: RA patients who had undergone chest CT were retrospectively analyzed. The maximum short axis of the ALNs was measured, and the number of positive ALNs ≥ 5 mm was counted. Tender and swollen joints in the upper limbs were counted as indicators of local disease activity. Background characteristics and systemic disease activity were assessed based on the selected RA indicators. Correlations between AL and both local disease activity and background characteristics including systemic disease activity were analyzed. RESULTS: Of 135 patients, 58 had positive ALNs (average size 7.97 mm, range up to 15 mm). The presence of positive unilateral ALNs was correlated with the severity of ipsilateral upper limb arthritis. Multivariate analysis showed correlations between AL and both local disease activity and serological findings such as serum C-reactive protein (CRP) and immunoglobulin (Ig) G. CONCLUSION: AL in patients with RA was correlated with local arthritis activity, as well as background characteristics and systemic disease activity.
29303709 Cost-effectiveness of early treatment of ACPA-positive rheumatoid arthritis patients with 2018 May OBJECTIVES: Studies have reported that the presence of elevated anti-citrullinated protein antibodies (ACPA)/RF levels, together with joint erosions, is associated with higher disease burden in terms of disability and mortality in rheumatoid arthritis (RA). Abatacept has been shown to be effective in this patient population with favourable comparative data against adalimumab. However, few studies have investigated the cost-effectiveness of abatacept in this population to similar treatments such as TNFs. The objective of the study was to compare the cost-effectiveness of abatacept to adalimumab as a first bDMARD in ACPA-positive RA patients who failed treatment with methotrexate (MTX) in Germany. METHODS: A decision tree model was used to estimate the cost-effectiveness, from a payer's perspective, of different treatment sequences in RA over a two year time frame. The effectiveness criteria were defined as achieving the treatment target measured by the Disease Activity Score 28 (DAS28(CRP)<2.6; "remission"). A treatment switch to a different biologic as 2nd line and 3rd line bDMARD was allowed - in case of not achieving remission with therapy - every 6 months over a two year time period. Effectiveness data was based on randomised controlled trials (RCT) identified by an updated previous systematic literature search by the Institute for Quality and Efficiency in Health Care (IQWiG). Costs of medication and other direct medical costs were considered. Cost-effectiveness of RA treatment was investigated in ACPA-positive patients and presented as overall costs per day in remission. RESULTS: For ACPA-positive patients, treatment strategies including early treatment with abatacept had lower total costs per clinical outcome compared to later use. Treatment sequences starting with abatacept resulted in lower costs per day in remission (mean 330 €/day, range 328-333 €/day) compared to sequences starting with adalimumab (mean 384 €/day, range 378-390 €/day). Choice of the second or third biologic in the treatment sequences appears to have little impact on the costs per outcome. CONCLUSIONS: The results of this analysis suggest that in ACPA-positive RA patients treatment with abatacept appears to have lower costs per response (remission) compared to treatment with adalimumab as a first bDMARD.
29291895 Evidence of reduced parasympathetic autonomic regulation in inflammatory joint disease: A 2018 Aug BACKGROUND: Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are inflammatory joint disorders (IJD) with increased risk of cardiovascular disease (CVD). Autonomic dysfunction (AD) is a risk factor for CVD, and parasympathetic AD is linked to key features of IJD such as inflammation, physical inactivity and pain. Heart-rate variability (HRV) is a marker of cardiac AD. The study objective was to compare parasympathetic cardiac AD, measured by HRV, between patients with IJD and healthy controls, using meta-analysis methodology, and to examine the impact of inflammation, physical inactivity and pain on HRV in IJD. METHODS: Medline, Embase and Amed were searched. Inclusion criteria were adult case-control studies published in English or a Scandinavian language, presenting HRV data in IJD. Two measures of HRV and 3 from the Ewing protocol were selected: square root of mean squared difference of successive R-R intervals (RMSSD), high frequency (HF), Ewing protocol; standing (E-S), breathing (E-B) and Valsalva (E-V). Patients with RA, SpA and healthy controls were compared separately using random-effects meta-analyses of standardized mean differences (SMD). RESULTS: In all, 35 papers were eligible for inclusion. For RMSSD the pooled SMD (95% CI) RA vs. controls was -0.90 (-1.35 to -0.44), for SpA vs. controls; -0.34 (-0.73 to 0.06). For HF pooled SMD RA vs. controls was -0.78 (-0.99 to -0.57), for SpA vs. controls; -0.04 (-0.22 to 0.13). All Ewing parameters were significantly lower in cases, except for E-V which was comparable between cases and controls in patients with RA. CONCLUSION: Patients with IJD have cardiac parasympathetic AD which is related to inflammation.
29698950 The Influence of Reactive Oxygen Species and Glucocorticoids on Dry Skin in a Mouse Model 2018 BACKGROUND: Dry skin induced by rheumatoid arthritis (RA) causes itching, which negatively influences a patient's quality of life. We previously reported that mast cells are related to dry skin in arthritic mice. However, the mechanism of mast cell activation is unclear. In this study, we examined the mechanism underlying the formation of dry skin induced by mast cells in arthritis that involves thymic stromal lymphopoietin (TSLP), neutrophils, reactive oxygen species (ROS), and glucocorticoids. METHODS: Mice with DBA/1JJmsSlc collagen-induced arthritis were treated with inhibitors or neutralizing antibodies. We measured transepidermal water loss (TEWL) to examine the modulating signal of mast cells. RESULTS: TEWL, the number of mast cells, and the plasma levels of TSLP, ROS, and corticosterone in the arthritic mice were increased when compared with the control mice. However, the mice treated with TSLP- and neutrophil-neutralizing antibodies and ROS and glucocorticoid receptor inhibitors (N-acetyl-L-cysteine [NAC] and RU-486, respectively) experienced an improvement. The ameliorating effect was most remarkable following treatment with NAC + RU-486. CONCLUSION: This study suggested that inhibiting ROS and glucocorticoids is important to ameliorate dry skin in arthritis, which may provide a novel treatment option for dry skin in RA patients.
28065486 Biologic Disease-modifying antirheumatic drug attributes in the first lines of treatment o 2018 Mar OBJECTIVE: To date, between 17% and 35% of patients with rheumatoid arthritis (RA) do not respond as expected to the initial biological therapy. The objective of this project is to recognize and weigh the attributes of biologic DMARD (bDMARD) to identify the most appropriate for each case, in the first lines of treatment of RA (after inadequate response to at least one synthetic DMARD or previous bDMARD). METHODS: To recognize the possible attributes that could define the bDMARD, we performed a systematic search of the literature that recognized the possible attributes involving general aspects, pharmacology, efficacy, safety, management, and cost. Then a Delphi process was conducted with two rounds among a group of selected expert rheumatologists in the management of RA indicating the degree of agreement with the attributes identified in the literature. The project was completed between February and September 2015, indicating the degree of importance that was ascribed to each attribute. Two criteria were applied to determine the consistency of results: 1) based on the median and interquartile range; and 2) on the simultaneous compliance with mean, median, standard deviation, interquartile range and coefficient of variation. The agreement and final ratification of the expert panel were also determined. RESULTS: Eighty-three Spanish rheumatologists participated and completed both rounds of the Delphi process. In no case was the importance of the 77 attributes identified considered to be low; 75 of 77 (97.4%) were considered highly important and 76 of 77 (98.7%) were ratified. Fifteen attributes had the support of 100% of the working group. CONCLUSIONS: There was a high degree of agreement concerning the selected attributes. Fifteen of them had the support of 100% of the working group and could be considered the definition of the ideal bDMARD in the first lines of RA treatment.
29510818 Ultrasonography for diagnosis, monitoring and treatment of tenosynovitis in patients with 2018 Mar Rheumatod arthritis is a chronic systemic autoimmune disease, characterized by inflammation in joints and tendon sheaths, which frequently leads to permanent and serious disability due to joint destruction, but also tendon and ligament ruptures. Clinical management of rheumatoid arthritis has traditionally been supported by biochemical and radiographic findings. However, imaging modalities like ultrasound and magnetic resonance imaging (MRI) have improved the possibility for better management of rheumatoid arthritis patients, due to higher sensitivity and specificity for detecting ongoing inflammation, this thesis is focusing on tenosynovitis as recent studies have shown that inflammation in tendon sheaths, i.e. tenosynovitis, is a very common manifestation of rheumatoid arthritis and may often be mistaken for synovitis. Furthermore, presence of ultrasonographic tenosynovitis may predict clinical flare and erosive progression. 
The main aim of this PhD thesis was to further develop and validate ultrasound as a tool for diagnosis, monitoring and treatment of tenosynovitis. This was investigated in four studies: 
Study I: 3D Doppler Ultrasound findings in healthy wrist and finger tendon sheaths - Can feeding vessels lead to misinterpretation in Doppler-detected tenosynovitis? 
Study II: Image fusion of Ultrasound and MRI and B-flow evaluation of tenosynovitis - A pilot study on new imaging techniques in rheumatoid arthritis patients. 
Study III: Validity and sensitivity to change of the semi-quantitative Outcome Measures in Rheumatology Clinical Trials (OMERACT) ultrasound scoring system for tenosynovitis in patients with rheumatoid arthritis and for the quantitative scoring system, pixel index. 
Study IV: Intramuscular versus ultrasound guided intratenosynovial glucocorticoid injection for tenosynovitis in patients with rheumatoid arthritis - A randomised, double-blind, controlled study with ultrasound and clinical follow up at 4 and 12 weeks. 
From the studies presented in the PhD thesis the following was concluded:
 Doppler findings in or in close proximity to the tendon sheaths were common in wrists and fingers in healthy participants. These feeding vessels may be a source of misinterpretation, i.e .wrong diagnosis of a low degree of tenosynovitis, not only due to their presence but also because they may be interpreted as being inside the tendon sheath due to blooming and reverberations artefacts.
 Ultrasound and MRI had high agreement using image fusion for assessment of tenosynovitis when MRI partial volume artefacts were taken into account. In contrast, the agreement between B-flow and ultrasound was poor, since the quality of the b-flow images and the flow sensitivity were low.
 The OMERACT ultrasound scoring system for tenosynovitis had an excellent intra- and interreader agreement between trained investigators and a high ability to detect change over time, similarly, the quantitative tenosynovitis assessment by pixel index had a very good intrareader agreement and moderate to good interreader agreement, but only a moderate ability to detect change over time. The ultrasound scores had a high responsiveness, indicating that the OMERACT ultrasound scoring system was useful for diagnosing and monitoring tenosynovitis in rheumatoid arthritis patients in clinical trials and practice. For treatment of tenosynovitis in rheumatoid arthritis patients, remission (ultrasound tenosynovitis grey scale score ≤1 and Doppler score = 0) was achieved significantly more frequently in the ultrasound guided intratenosynovial glucocorticoid injection group than in the intramuscular glucocorticoid injection group, both at 4 and 12 week follow-ups. Furthermore, tenosynovitis responded significantly better clinically and by ultrasound assessment when treated with ultrasound guided intratenosynovial glucocorticoid injection com-pared to intramuscular glucocorticoid injection, both at 4 and 12 week follow-ups.
30028343 Use of Dipeptidyl Peptidase-4 Inhibitors and New-onset Rheumatoid Arthritis in Patients wi 2018 Nov BACKGROUND: Case reports have suggested a link between dipeptidyl peptidase-4 (DPP-4) inhibitors, antidiabetic drugs used as second- to third-line treatments, and incidence of rheumatoid arthritis. Because the DPP-4 enzyme is involved in several immunologic processes and possibly in the pathophysiology of rheumatoid arthritis, further research is warranted. This population-based study aimed to determine whether use of DPP-4 inhibitors is associated with incidence of rheumatoid arthritis. METHODS: Using the United Kingdom Clinical Practice Research Datalink, we conducted a cohort study among 144,603 patients with type 2 diabetes initiating antidiabetic drugs between 2007 and 2016. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for incident rheumatoid arthritis using time-dependent Cox proportional hazards models, comparing use of DPP-4 inhibitors with use of other antidiabetic drugs. We imposed a 6-month exposure lag period for latency and diagnostic delays. Secondary analyses included assessment of the duration-response relation and comparison with other second-line antidiabetic drugs, among others. RESULTS: During 567,169 person-years of follow-up, 464 patients were newly diagnosed with rheumatoid arthritis (crude incidence rate: 82 per 100,000/year). Compared with use of other antidiabetic drugs, use of DPP-4 inhibitors was not associated with an increased risk of rheumatoid arthritis (82 vs. 79 per 100,000/year; HR = 1.0; 95% CI = 0.8, 1.3), with no evidence of duration-response relation. The results did not change after using second-line antidiabetic drugs as the comparator group. CONCLUSIONS: In this large population-based study, use of DPP-4 inhibitors was not associated with an increased risk of incident rheumatoid arthritis.
29790108 The impact of dietary habits on the pathogenesis of rheumatoid arthritis: a case-control s 2018 Oct It has not been clear what kinds and how much nutrients could be harmful, preventive, or healthful for development of rheumatoid arthritis. This study aimed to determine the impact of dietary habits on the pathogenesis of rheumatoid arthritis. This case-control study was conducted on a total of 500 rheumatoid arthritis patients and 500 healthy controls refereed to three clinics of Shiraz University of Medical Sciences in 2015-2016. Convenience sampling was used for data collection in both case and control groups. An approved valid and reliable questionnaire including information about the intake of different kinds of beverages, and nutritious and non-nutritious diet was used. Data were analyzed by SPSS, version 20, using t test, chi-square and Multiple Logistic Regression model. The associations between rheumatoid arthritis development and variables including drinking 1-7 cups of coffee (OR = .44, CI .25-.76), ≥ 8 cups of coffee (OR = .50, CI .28-.90), full-fat milk (OR = 1.01, CI 1.003-1.03) per month, and intake of green tea (OR = .65, CI .45-.93) and solid oils (OR = 2.29, CI:1.57-3.34) were significant. Based on the findings, coffee consumption more than one cup per month and green tea might have preventive effects on developing rheumatoid arthritis. On the other hand, patients who consumed more full-fat milk per month and solid oil might be at risk of development of rheumatoid arthritis. Therefore, modification of diet based on these findings is suggested. Performing a cohort study to determine the causality effect of dietary habits and development and prevention of rheumatoid arthritis is recommended.
29101015 DNA damage, metabolism and aging in pro-inflammatory T cells: Rheumatoid arthritis as a mo 2018 May The aging process is the major driver of morbidity and mortality, steeply increasing the risk to succumb to cancer, cardiovascular disease, infection and neurodegeneration. Inflammation is a common denominator in age-related pathologies, identifying the immune system as a gatekeeper in aging overall. Among immune cells, T cells are long-lived and exposed to intense replication pressure, making them sensitive to aging-related abnormalities. In successful T cell aging, numbers of naïve cells, repertoire diversity and activation thresholds are preserved as long as possible; in maladaptive T cell aging, protective T cell functions decline and pro-inflammatory effector cells are enriched. Here, we review in the model system of rheumatoid arthritis (RA) how maladaptive T cell aging renders the host susceptible to chronic, tissue-damaging inflammation. In T cells from RA patients, known to be about 20years pre-aged, three interconnected functional domains are altered: DNA damage repair, metabolic activity generating energy and biosynthetic precursor molecules, and shaping of plasma membranes to promote T cell motility. In each of these domains, key molecules and pathways have now been identified, including the glycolytic enzymes PFKFB3 and G6PD; the DNA repair molecules ATM, DNA-PKcs and MRE11A; and the podosome marker protein TKS5. Some of these molecules may help in defining targetable pathways to slow the T cell aging process.
29734516 Dermal capillary rarefaction as a marker of microvascular damage in patients with rheumato 2018 Jul OBJECTIVE: Capillary rarefaction is observed in various cardiovascular diseases, yet it remains understudied in RA, a chronic inflammatory disease accompanied by excess cardiovascular risk. We quantified capillary density in RA patients and explored potential associations with macrocirculatory disorders, inflammation, and cardiovascular risk. METHODS: Dermal capillary density was assessed with nailfold capillaroscopy in RA and non-RA individuals, using specifically designed semiautomated software. Macrocirculation assessments included large artery stiffening, evaluated with PWV, and myocardial blood flow, calculated as cardiac index from impedance cardiography. Cardiovascular risk score was estimated from the Framingham Heart Study. RESULTS: The number of capillaries per visual field was lower in patients (n = 99) compared to controls (n = 35) (132.6 ± 30.3 vs 152.9 ± 25.2, P = .001). In the RA group, capillary density negatively correlated with CRP and PWV, and positively with HDL and cardiac index. In the multivariate analysis, CRP independently predicted capillary rarefaction (P = .044). Capillary density significantly correlated with cardiovascular risk, even after adjustment for inflammation (P = .030). CONCLUSION: Capillary rarefaction appears pronounced in RA and correlates with lower cardiac output, increased arterial stiffness, and cardiovascular risk. However, the associations with macrocirculatory disorders may be obscured by inflammation, which appears as the major contributor to capillary rarefaction in RA.
30550295 F8-IL10: A New Potential Antirheumatic Drug Evaluated by a PET-Guided Translational Approa 2019 Jan 7 Antibody fragment F8-mediated interleukin 10 (IL10) delivery is a novel treatment for rheumatoid arthritis (RA). F8 binds to the extra-domain-A of fibronectin (ED-A). In this study, in vivo biodistribution and arthritis targeting of radiolabeled F8-IL10 were investigated in RA patients, followed by further animal studies. Therefore, three RA patients (DAS28 > 3.2) received 0.4 mg of 30-74 megabecquerel [(124)I]I-F8-IL10 for PET-CT and blood sampling. In visually identified PET-positive joints, target-to-background was calculated. Healthy mice, rats, and arthritic rats were injected with iodinated F8-IL10 or KSF-IL10 control antibody. Various organs were excised, weighed, and counted for radioactivity. Tissue sections were stained for fibronectin ED-A. In RA patients, [(124)I]I-F8-IL10 was cleared rapidly from the circulation with less than 1% present in blood after 5 min. PET-CT showed targeting in 38 joints (11-15 per patient) and high uptake in the liver and spleen. Mean target-to-background ratios of PET-positive joints were 2.5 ± 1.2, 1.5 times higher for clinically active than clinically silent joints. Biodistribution of radioiodinated F8-IL10 in healthy mice showed no effect of the radioiodination method. [(124)I]I-F8-IL10 joint uptake was also demonstrated in arthritic rats, ∼14-fold higher than that of the control antibody [(124)I]I-KSF-IL10 ( p < 0.001). Interestingly, liver and spleen uptake were twice as high in arthritic than in healthy rats and were related to increased (∼7×) fibronectin ED-A expression in these tissues. In conclusion, [(124)I]I-F8-IL10 uptake was observed in arthritic joints in RA patients holding promise for visualization of inflamed joints by PET-CT imaging and therapeutic targeting. Patient observations and, subsequently, arthritic animal studies pointed to awareness of increased [(124)I]I-F8-IL10 uptake in the liver and spleen associated with moderate systemic inflammation. This translational study demonstrated the value of in vivo biodistribution and PET-CT-guided imaging in development of new and potential antirheumatic drugs'.
30638975 Safety of combination therapy with two bDMARDs in patients with rheumatoid arthritis: A sy 2019 Aug OBJECTIVES: We performed a systematic review and meta-analysis of the current literature to assess the safety of combining two biologic disease-modifying antirheumatic drugs (bDMARDs) in the treatment of rheumatoid arthritis (RA). METHODS: We systematically searched for controlled studies evaluating safety in patients with RA treated with two bDMARDs independently of dose-regimen. Databases used were MEDLINE (via Pubmed), EMBase, Cochrane Library, Scopus, ClinicalTrials.gov, and the WHO International Clinical Trials Registry platform. A meta-analysis was performed between groups on combination therapy and patients on single therapy using random effects model calculating odds ratio (OR) as well as 95% confidence interval (CI). The primary outcome was the rate of serious adverse events (SAEs). RESULTS: Six studies with a total of 623 patients (410 on combination therapy and 213 on single therapy) were included. Median follow-up was 9.5 months (range 6-12 months). There was a significant increase in SAEs in the combination group (14.9 vs 6.0%, OR 2.51, 95% CI 1.29-4.89, I(2) 0%) as well as in total adverse events (94.6 vs 89.1%, OR 2.07, 95% CI 1.11-3.86, I(2) 0%). When performing subgroup analysis in patients receiving only full-dose of both bDMARDs there was a significant increase in serious infections (6.7 vs 0.6%, OR 5.58, 95% CI 1.25-24.90, I(2) 0%) and the risk of SAEs remained significantly higher (17.1 vs 6.2%, OR 2.72, 95% CI 1.30-5.69, I(2) 0%). CONCLUSION: Our findings suggest that combination therapy with two bDMARDs in RA appears to increase the risk of SAEs during the first twelve months of treatment.
29340978 Methotrexate Aspasomes Against Rheumatoid Arthritis: Optimized Hydrogel Loaded Liposomal F 2018 Apr Aspasomes of methotrexate with antioxidant, ascorbyl palmitate, were developed and optimized using factorial design by varying parameters such as lipid molar ratio, drug to lipid molar ratio, and type of hydration buffer for transdermal delivery for disease modifying activity in rheumatoid arthritis (RA). Aspasomes were characterized by drug-excipients interaction, particle size analysis, determination of zeta potential, entrapment efficiency, and surface properties. The best formulation was loaded into hydrogel for evaluation of in vitro drug release and tested in vivo against adjuvant induced arthritis model in wistar rats, by assessing various physiological, biochemical, hematological, and histopathological parameters. Optimized aspasome formulation exhibited smooth surface with particle size 386.8 nm, high drug loading (19.41%), negative surface potential, and controlled drug release in vitro over 24 h with a steady permeation rate. Transdermal application of methotrexate-loaded aspasome hydrogel for 12 days reduced rat paw diameter (21.25%), SGOT (40.43%), SGPT (54.75%), TNFα (33.99%), IL β (34.79%), cartilage damage (84.41%), inflammation (82.37%), panus formation (84.38%), and bone resorption (80.52%) as compared to arthritic control rats. Free methotrexate-treated group showed intermediate effects. However, drug-free aspasome treatment did not show any effect. The experimental results indicate a positive outcome in development of drug-loaded therapeutically active carrier system which presents a non-invasive controlled release transdermal formulation with good drug loading, drug permeation rate, and having better disease modifications against RA than the free drug, thereby providing a more attractive therapeutic strategy for rheumatoid disease management.
29445863 Use of biological disease modifying antirheumatic drugs in rheumatoid arthritis in Austria 2018 Apr BACKGROUND: Rheumatoid arthritis (RA) is the most prevalent chronic inflammatory joint disease. On a national level in Austria, there are currently no data available on how often and which biological disease modifying antirheumatic drugs (bDMARDs) are prescribed in patients with RA. The aim of the present study was to explore prescription patterns of bDMARDs in RA in Austria with a focus on drug survival. METHODS: A retrospective data analysis of bDMARD courses of individual patients with RA that were extracted from the databases of nine Austrian health insurance funds covering 6.1 million (72%) insured people in a 4-year observation period from January 2008 to December 2011. Only patients with first prescriptions of bDMARDs were included. All patients with diagnoses other than RA were excluded. RESULTS: A total of 2906 first prescriptions of bDMARDs were included in the present analysis and 19.35% of RA patients were on bDMARDs in Austria taking into account a prevalence of RA of 0.5%. Tocilizumab showed the longest drug survival after 1 year (73.2%), followed by abatacept which had the longest drug survival after 2 (68.2%) and 3 years (65.2%). The most frequent second bDMARDs switched to were adalimumab (n = 109, 26%), tocilizumab (n = 83, 20%) and etanercept (n = 82, 20%) and 37% of biological DMARDs were prescribed as monotherapy (ranging from 33% with infliximab to 46% with tocilizumab). CONCLUSIONS: Our analysis is based on the largest health care database available in Austria. Tocilizumab and abatacept showed the longest drug survival. Adalimumab, tocilizumab and etanercept were the most frequent DMARDs switched to. Of interest was the high number of bDMARD monotherapies.
30385709 HLA-DRB1 Amino Acid Positions and Residues Associated with Antibody-positive Rheumatoid Ar 2019 Feb OBJECTIVE: To investigate the association of specific amino acid positions, residues, and haplotypes of HLA-DRB1 in black South Africans with autoantibody-positive rheumatoid arthritis (RA). METHODS: High-resolution HLA-DRB1 genotyping was performed in 266 black South Africans with autoantibody-positive RA and 362 ethnically and geographically matched controls. The alleles were converted to specific amino acid residues at polymorphic sites for downstream analyses. Logistic regression models were used to test whether variability at site, specific amino acid residues, and haplotypes (constructed from positions 11, 71, and 74) were associated with RA. RESULTS: Of the 29 amino acid positions examined, positions 11, 13, and 33 (permutation p = 3.4(e-26), 1.2(e-27), and 2.1(e-28), respectively) showed the strongest association with RA. Univariate analyses of individual amino acid residues showed valine at position 11 (OR 5.1, 95% CI 3.7-7.0) and histidine at position 13 (OR 6.1, 95% CI 4.2-8.6) conferred the highest risk. The valine containing haplotypes of position 11, 71, 74, V_K_A conferred the most risk (OR 4.52, 95% CI 2.68-7.61) and conversely the haplotype with serine at this position, S_K_R, conferred the most protection (OR 0.83, 95% CI 0.61-1.15). CONCLUSION: Autoantibody-positive RA in black South Africans is associated with histidine at position 13 and valine at position 11 of HLA-DRB1, and haplotypes with valine at position 11 conferred the highest risk; conversely, serine at position 11 conveyed protection.
29224375 Autoimmune rheumatic diseases and the risk of Parkinson disease: a nationwide population-b 2018 Feb BACKGROUNDS: In autoimmune rheumatic diseases (ARDs), the levels of inflammatory mediators are increased and microglia may be activated, resulting in an inflammatory state and the degeneration of dopaminergic neurons. We investigated the association between ARDs and Parkinson disease (PD). METHODS: We identified ARD patients through the Taiwan National Health Insurance Research Database from 2001 to 2012. From the general population, we randomly selected a comparison cohort that was frequency-matched by age (in 5-year increments), sex and index year. We analysed the risk of PD, stratified by sex, age and comorbidities, by using a Cox regression model. RESULTS: The risk of PD was 1.37 times greater in ARD patients than in controls after adjustment for age, sex, and comorbidities. ARD subgroups, such as the rheumatoid arthritis and Sjogren syndrome (SS) cohorts, were associated with a significantly higher risk of PD (adjusted hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.03-1.2 and adjusted HR, 1.56; 95% CI, 1.35-1.79, respectively). Furthermore, primary and secondary SS patients had significantly higher risks of PD (adjusted HR, 1.58; 95% CI, 1.32-1.88 and adjusted HR, 1.53, 95% CI, 1.23-1.90, respectively). CONCLUSIONS: The risk of PD was significantly higher in the ARD patients. Prospective studies are needed to confirm whether ARDs indeed increase the risk of PD.
30146566 Accelerated Progression of Hepatocellular Carcinoma during Immunosuppressive Therapy with 2019 Jan 1 Abatacept, a cytotoxic T lymphocyte antigen-4 immunoglobulin recombinant fusion protein, is an immunosuppressive agent indicated for rheumatoid arthritis. Although no significant increase in malignancy has been reported in abatacept-treated patients, whether or not abatacept accelerates tumor progression in specific cancer types remains unclear. We herein report a 66-year-old woman who showed unusually rapid progression of hepatocellular carcinoma following abatacept therapy for rheumatoid arthritis. Abatacept was speculated to have accelerated her hepatocellular carcinoma progression in the setting of her preexisting risk factors: autoimmune hepatitis and long-term methotrexate use. We propose close tumor surveillance be performed during abatacept therapy, especially for high-risk patients.
29959469 The beliefs of rheumatoid arthritis patients in their subcutaneous biological drug: streng 2018 Sep Patients' beliefs about their prescribed medication are an important factor influencing intentional non-adherence. This study describes rheumatoid arthritis (RA) patients' beliefs about their subcutaneous (SC) biological medication through the Beliefs about Medicines Questionnaire (BMQ), and potential associations. As part of the ARCO study (Study on Adherence of Rheumatoid arthritis patients to subCutaneous and Oral drugs), patients completed the BMQ specifically for their SC biological medication, encompassing a necessity and a concerns scale. The medication possession ratio (MPR) was calculated to assess adherence to the SC biological medication. The BMQ was completed by 321 patients. Between 71.0 and 89.7% of patients agreed/strongly agreed with necessity scale statements, and only 7.2% had low necessity scores. Between 20.0 and 49.8% of patients agreed/strongly agreed with four of five concern scale statements, and 72.3% agreed/strongly agreed with the concern statement regarding long-term medication effects. The percentage with high concerns was 58.9%, and was higher in patients not satisfied with, or with less fulfillment of, tolerability expectations. Non-adherence percentages were, respectively, 13.8 and 13.0% (p = 0.919) in those with high or low necessity, and 16.0 and 10.6% (p = 0.171) in those with high or low concerns. Most patients were categorized as 'ambivalent' (58.5%; high necessity/high concerns) or 'accepting' (36.1%; high necessity/low concerns) of their SC biological medication. The BMQ identified patients' concerns with their SC biological medication. Because patients' concerns could influence non-adherence to medication and future outcomes, physicians should address this issue in the clinic by informing patients and setting clear expectations.
30198906 Long noncoding RNA LERFS negatively regulates rheumatoid synovial aggression and prolifera 2018 Oct 1 Fibroblast-like synoviocytes (FLSs) are critical to synovial aggression and joint destruction in rheumatoid arthritis (RA). The role of long noncoding RNAs (lncRNAs) in RA is largely unknown. Here, we identified a lncRNA, LERFS (lowly expressed in rheumatoid fibroblast-like synoviocytes), that negatively regulates the migration, invasion, and proliferation of FLSs through interaction with heterogeneous nuclear ribonucleoprotein Q (hnRNP Q). Under healthy conditions, by binding to the mRNA of RhoA, Rac1, and CDC42 - the small GTPase proteins that control the motility and proliferation of FLSs - the LERFS-hnRNP Q complex decreased the stability or translation of target mRNAs and downregulated their protein levels. But in RA FLSs, decreased LERFS levels induced a reduction of the LERFS-hnRNP Q complex, which reduced the binding of hnRNP Q to target mRNA and therefore increased the stability or translation of target mRNA. These findings suggest that a decrease in synovial LERFS may contribute to synovial aggression and joint destruction in RA and that targeting the lncRNA LERFS may have therapeutic potential in patients with RA.
29423382 Polymorphisms in Protein Tyrosine Phosphatase Non-receptor Type 2 and 22 (PTPN2/22) Are Li 2018 A shared genetic pre-disposition, chronic inflammation, and treatment with similar biologics between Rheumatoid arthritis (RA) and Crohn's disease (CD) have intrigued us to investigate whether the two disorders share trigger association or possible causation. We hypothesized earlier that Single Nucleotide Polymorphisms (SNPs) in the negative regulators Protein Tyrosine Phosphatase Non-receptor type 2 and 22 (PTPN2/22) lead to a dysregulated immune response, susceptibility to environmental triggers, and continued apoptosis as seen in chronic inflammation in RA and CD. To test the hypothesis, peripheral leukocytes samples from 132 consented subjects were genotyped for 9 SNPs in PTPN2/22 using TaqMan™ genotyping. The effect of the SNPs on PTPN2/22 and IFN-γ expression was determined using real time PCR. T-cell proliferation and response to phytohematoagglutonin (PHA) mitogen and mycobacterial antigens were determined by BrdU proliferation assay. Blood samples were also analyzed for the Mycobacterium avium subspecies paratuberculosis (MAP) IS900 gene by nPCR. Out of 9 SNPs examined, heterozygous (TC) or minor (CC) alleles of PTPN2:rs478582 occurred in 79% RA compared to 60% healthy controls (p-values ≤ 0.05; OR = 2.28). Similarly, heterozygous (GA) or minor (AA) alleles of PTPN22:rs2476601 occurred in 29% RA compared to 6% healthy controls (p-values ≤ 0.05; OR = 5.90). PTPN2/22 expression in RA was decreased by 1.2-fold compared to healthy controls. PTPN2:rs478582 upregulated IFN-γ in RA by 1.5-fold. Combined PTPN2:rs478582 and PTPN22:rs2476601 increased T-cell proliferation by 2.7-fold when treated with PHA. Surprisingly, MAP DNA was detected in 34% of RA samples compared to 8% healthy controls, (p-values ≤ 0.05, OR = 5.74). RA samples with PTPN2:rs478582 and/or PTPN22:rs2476601 were more positive for MAP than samples without polymorphisms. Combined occurrence of PTPN2:rs478582 and PTPN22:rs2476601 in association with the presence of MAP has significantly increased T-cell response and elevated IFN-γ expression in RA samples. The data suggest that genetic polymorphisms may play vital role in T-cell regulation, susceptibility to mycobacteria and ultimately response to treatment. This is the first study to report the detection of MAP DNA in the blood of RA patients; further studies are needed using larger number of samples.