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ID PMID Title PublicationDate abstract
27813878 Antimalarial Drugs as Immune Modulators: New Mechanisms for Old Drugs. 2017 Jan 14 The best known of the naturally occurring antimalarial compounds are quinine, extracted from cinchona bark, and artemisinin (qinghao), extracted from Artemisia annua in China. These and other derivatives are now chemically synthesized and remain the mainstay of therapy to treat malaria. The beneficial effects of several of the antimalarial drugs (AMDs) on clinical features of autoimmune disorders were discovered by chance during World War II. In this review, we discuss the chemistry of AMDs and their mechanisms of action, emphasizing how they may impact multiple pathways of innate immunity. These pathways include Toll-like receptors and the recently described cGAS-STING pathway. Finally, we discuss the current and future impact of AMDs on systemic lupus erythematosus, rheumatoid arthritis, and devastating monogenic disorders (interferonopathies) characterized by expression of type I interferon in the brain.
26815016 Identification of IRX1 as a Risk Locus for Rheumatoid Factor Positivity in Rheumatoid Arth 2016 Jun OBJECTIVE: Rheumatoid factor (RF) is a well-established diagnostic and prognostic biomarker in rheumatoid arthritis (RA). However, ∼20% of RA patients are negative for this anti-IgG antibody. To date, only variation at the HLA-DRB1 gene has been associated with the presence of RF. This study was undertaken to identify additional genetic variants associated with RF positivity. METHODS: A genome-wide association study (GWAS) for RF positivity was performed using an Illumina Quad610 genotyping platform. A total of 937 RF-positive and 323 RF-negative RA patients were genotyped for >550,000 single-nucleotide polymorphisms (SNPs). Association testing was performed using an allelic chi-square test implemented in Plink software. An independent cohort of 472 RF-positive and 190 RF-negative RA patients was used to validate the most significant findings. RESULTS: In the discovery stage, a SNP in the IRX1 locus on chromosome 5p15.3 (SNP rs1502644) showed a genome-wide significant association with RF positivity (P = 4.13 × 10(-8) , odds ratio [OR] 0.37 [95% confidence interval (95% CI) 0.26-0.53]). In the validation stage, the association of IRX1 with RF was replicated in an independent group of RA patients (P = 0.034, OR 0.58 [95% CI 0.35-0.97] and combined P = 1.14 × 10(-8) , OR 0.43 [95% CI 0.32-0.58]). CONCLUSION: To our knowledge, this is the first GWAS of RF positivity in RA. Variation at the IRX1 locus on chromosome 5p15.3 is associated with the presence of RF. Our findings indicate that IRX1 and HLA-DRB1 are the strongest genetic factors for RF production in RA.
26265263 Association between anti-Porphyromonas gingivalis or anti-α-enolase antibody and severity 2015 Aug 12 BACKGROUND: Periodontitis (PD) has been reported to be associated with rheumatoid arthritis (RA). Porphyromonas gingivalis (P. gingivalis) is a gram-negative anaerobic bacterium that is recognized as one of the major pathogenic organisms in PD and is the only bacterium known to express peptidylarginine deiminase (PAD). Antibody against human α-enolase (ENO1) is one of the autoantibodies in RA. ENO1 is a highly conserved protein, and could be a candidate molecule for molecular mimicry between bacterial and human proteins. In the present study, we measured serum antibody against P. gingivalis and human ENO1 in patients with RA and investigated their association with the severity of PD or disease activity of RA. METHODS: Two hundred, forty-eight patients with RA and 85 age- and sex-matched healthy controls were evaluated by rheumatologic and periodontal examinations. The serum levels of anti-P. gingivalis and anti-ENO1 antibodies were measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS: Patients with RA had significantly higher levels of anti-P. gingivalis and anti-ENO1 antibody titers than the controls (p = 0.002 and 0.0001, respectively). Anti-P. gingivalis antibody titers significantly correlated with anti-ENO1 antibody titers in RA patients (r = 0.30, p < 0.0001). There were significant correlations between anti-P. gingivalis antibody titers and the gingival index (GI), probing pocket depth (PPD), bleeding on probing (BOP) and clinical attachment level (CAL) (p = 0.038, 0.004, 0.004 and 0.002, respectively) in RA. Anti-P. gingivalis antibody titers were not correlated with disease activity score 28 (DAS28) or anti-CCP titer. However, anti-ENO1 antibody titers were significantly correlated not only with the periodontal indices, such as PPD, BOP, and CAL (p = 0.013, 0.023 and 0.017, respectively), but also RA clinical characteristics, such as DAS28, anti-CCP titer, and ESR (p = 0.009, 0.015 and 0.001, respectively). CONCLUSION: Anti-P. gingivalis and anti-ENO1 antibody titers were correlated with the severity of PD in RA. Anti-ENO1 antibody titers, but not anti-P. gingivalis antibody titers, were further associated with RA disease activity.
25541410 Outcomes of coronary artery bypass grafting in patients with inflammatory rheumatic diseas 2015 Mar OBJECTIVE: Patients with inflammatory rheumatic diseases have an increased risk of developing coronary atherosclerosis. However, outcomes of surgical revascularization in these patients have been rarely studied. We aimed to determine whether, or which, inflammatory rheumatic diseases may pose effects on mortality and adverse cardiac outcomes after coronary artery bypass grafting. METHODS: By using the National Health Insurance Research Database of Taiwan, we identified 40,639 adult patients who underwent first-time coronary artery bypass grafting between 2000 and 2010. Among these patients, 101 had rheumatoid arthritis, 56 had systemic lupus erythematosus, and 73 had ankylosing spondylitis. The odds ratios (ORs) of operative mortality and hazard ratios (HRs) of overall mortality and adverse cardiac outcomes after coronary artery bypass grafting (ie, myocardial infarction and repeat revascularization) in relation to rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis were estimated. RESULTS: With adjustment for potential confounders including patient characteristics, hospital levels, and combined surgery, systemic lupus erythematosus was an independent predictor for operative mortality (adjusted OR, 2.63; 95% confidence interval [CI], 1.04-6.65; P = .04) and ankylosing spondylitis was marginally associated with operative mortality (adjusted OR, 2.41; 95% CI, 0.99-5.88; P = .054). Systemic lupus erythematosus was a significantly independent predictor for overall mortality during the follow-up period (adjusted HR, 2.23; 95% CI, 1.51-3.31; P < .0001) and might increase the risk of repeat revascularization (adjusted HR, 1.89; 95% CI, 0.97-3.68; P = .06). Neither rheumatoid arthritis nor ankylosing spondylitis was significantly associated with overall mortality and adverse cardiac outcomes. CONCLUSIONS: Our study may help surgeons and physicians recognize the potential risks inherent to systemic lupus erythematosus and ankylosing spondylitis when conducting coronary artery bypass grafting and providing follow-up care.
26621482 How comparable are rates of malignancies in patients with rheumatoid arthritis across the 2016 Oct BACKGROUND: The overall incidence of cancer in patients with rheumatoid arthritis (RA) is modestly elevated. The extent to which cancer rates in RA vary across clinical cohorts and patient subsets, as defined by disease activity or treatment is less known but critical for understanding the safety of existing and new antirheumatic therapies. We investigated comparability of, and means to harmonise, malignancy rates in five RA registries from four continents. METHODS: Participating RA registries were Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (several countries) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan). Within each registry, we analysed a main cohort of all patients with RA from January 2000 to last available data, and sensitivity analyses of sub-cohorts defined by disease activity, treatment change, prior comorbidities and restricted by calendar time or follow-up, respectively. Malignancy rates with 95% CIs were estimated, and standardised for age and sex, based on the distributions from a typical RA clinical trial programme population (fostamatinib). RESULTS: There was a high consistency in rates for overall malignancy excluding non-melanoma skin cancer (NMSC), for malignant lymphomas, but not for all skin cancers, across registries, in particular following age/sex standardisation. Standardised rates of overall malignancy excluding NMSC varied from 0.56 to 0.87 per 100 person-years. Within each registry, rates were generally consistent across sensitivity analyses, which differed little from the main analysis. CONCLUSION: In real-world RA populations, rates of both overall malignancy and of lymphomas are consistent.
25782042 Increased risk of revision for infection in rheumatoid arthritis patients with total hip r 2015 BACKGROUND AND PURPOSE: Medical treatment of rheumatoid arthritis (RA) has changed dramatically over the last 15 years, including immune modulation. We investigated the risk of revision for infection after primary total hip replacement (THR) in patients with rheumatoid arthritis over a 16-year period, and compared it with that in THR patients with osteoarthritis (OA). PATIENTS AND METHODS: We identified 13,384 THRs in RA patients and 377,287 THRs in OA patients from 1995 through 2010 in a dataset from the Nordic Arthroplasty Register Association (NARA). Kaplan-Meier survival curves, with revision for infection as the endpoint, were constructed. Cox regression analyses were performed to calculate the relative risk (RR) of revision for infection adjusted for age, sex, fixation technique, and year of primary surgery. RESULTS: RA patients had a 1.3 times (95% CI 1.0-1.6) higher risk of revision for infection. After 2001, this risk increased more for RA patients than for OA patients. During the first 3 months and from 8 years postoperatively, the risk of revision for infection was higher in RA patients with THRs fixated with antibiotic-loaded cement than in corresponding OA patients. INTERPRETATION: We found a slightly higher overall risk of revision for infection in RA patients than in OA patients, but this difference was only present after 2001. In THRs with antibiotic-loaded cement, the risk of very early and late infections leading to revision was higher in RA patients than in OA patients.
26275591 Anti-citrullinated protein antibodies promote apoptosis of mature human Saos-2 osteoblasts 2016 Jan We hypothesized that anti-citrullinated protein antibodies (ACPAs) react with osteoblast surface citrullinated proteins and affect cell function, leading to joint damage in patients with rheumatoid arthritis (RA). First, we purified ACPAs by cyclic citrullinated peptide (CCP)-conjugated affinity column chromatography. The cognate antigens of ACPAs on Saos-2 cells, a sarcoma osteogenic cell line generated from human osteoblasts, were probed by ACPAs, and the reactive bands were analyzed using proteomic analyses. We found that ACPAs bind to Saos-2 cell membrane, and several protein candidates, including HSP60, were identified. We then cloned and purified recombinant heat shock protein 60 (HSP60) and citrullinated HSP60 (citHSP60) and investigated the effect of ACPAs on Saos-2 cell. We confirmed that HSP60 obtained from Saos-2 cell membrane were citrullinated and reacted with ACPAs, which induces Saos-2 cells apoptosis via binding to surface-expressed citHSP60 through Toll-like receptor 4 signaling. ACPAs promoted interleukin (IL)-6 and IL-8 expression in Saos-2 cells. Finally, sera from patients with RA and healthy controls were examined for their titers of anti-HSP60 and anti-citHSP60 antibodies using an enzyme-linked immunosorbent assay. The radiographic change in patients with RA was evaluated using the Genant-modified Sharp scoring system. Patients with RA showed higher sera titers of anti-citHSP60, but not anti-HSP60, antibodies when compared with controls. In addition, the anti-citHSP60 level was positively associated with increased joint damage in patients with RA. In conclusion, Saos-2 cell apoptosis was mediated by ACPAs via binding to cell surface-expressed citHSP60 and the titer of anti-citHSP60 in patients with RA positively associated with joint damage.
27114561 Effect of adalimumab on the work-related outcomes scores in patients with early rheumatoid 2016 Aug OBJECTIVES: To evaluate the effects of adalimumab plus MTX (ADA + MTX) vs MTX monotherapy on work-related outcomes in early RA patients with elevated risk of employment loss. METHODS: A post hoc analysis at weeks 26 and 24 from the Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab (OPTIMA) and PRevention Of Work Disability (PROWD) trials, respectively, was conducted in MTX-naïve RA patients randomized to ADA + MTX or placebo (PBO) + MTX. Work instability was assessed using the RA-Work Instability Scale (RA-WIS) and work productivity was measured with the Work Productivity and Activity Impairment Questionnaire. Employed patients with a baseline RA-WIS score ⩾10, indicating medium to high risk for job loss, were included (OPTIMA, n = 320; PROWD, n = 124). RESULTS: Patients receiving ADA + MTX in OPTIMA had significantly greater improvements in RA-WIS compared with PBO + MTX (mean change -7.22 vs -5.23, respectively). Significantly higher percentages of patients in the ADA + MTX group experienced improvements in one or more risk category (58 vs 47%) and ⩾5 (55 vs 43%), ⩾7 (47 vs 35%) and ⩾9 (42% vs 26%) points in their RA-WIS score. These trends were seen in PROWD but were not significant. In OPTIMA, patients receiving ADA + MTX showed significant changes in percentage points from baseline vs PBO + MTX in activity impairment, presenteeism and overall work impairment (-32.0 vs -23.7, -24.6 vs -17.1, -27.3 vs -18.3, respectively). CONCLUSIONS: Among early RA patients with elevated risk of employment loss, ADA + MTX therapy was associated with a significant reduction in work instability vs PBO + MTX. Significantly greater percentages of patients receiving ADA + MTX therapy achieved clinically meaningful improvements in their RA-WIS scores.
25874584 Should we search Chinese biomedical databases when performing systematic reviews? 2015 Mar 6 BACKGROUND: Chinese biomedical databases contain a large number of publications available to systematic reviewers, but it is unclear whether they are used for synthesizing the available evidence. METHODS: We report a case of two systematic reviews on the accuracy of anti-cyclic citrullinated peptide for diagnosing rheumatoid arthritis. In one of these, the authors did not search Chinese databases; in the other, they did. We additionally assessed the extent to which Cochrane reviewers have searched Chinese databases in a systematic overview of the Cochrane Library (inception to 2014). RESULTS: The two diagnostic reviews included a total of 269 unique studies, but only 4 studies were included in both reviews. The first review included five studies published in the Chinese language (out of 151) while the second included 114 (out of 118). The summary accuracy estimates from the two reviews were comparable. Only 243 of the published 8,680 Cochrane reviews (less than 3%) searched one or more of the five major Chinese databases. These Chinese databases index about 2,500 journals, of which less than 6% are also indexed in MEDLINE. All 243 Cochrane reviews evaluated an intervention, 179 (74%) had at least one author with a Chinese affiliation; 118 (49%) addressed a topic in complementary or alternative medicine. DISCUSSION AND CONCLUSIONS: Although searching Chinese databases may lead to the identification of a large amount of additional clinical evidence, Cochrane reviewers have rarely included them in their search strategy. We encourage future initiatives to evaluate more systematically the relevance of searching Chinese databases, as well as collaborative efforts to allow better incorporation of Chinese resources in systematic reviews.
25917104 A New Approach for the Treatment of Arthritis in Mice with a Novel Conjugate of an Anti-C5 2015 Jun 1 Rheumatoid arthritis (RA) is an inflammatory autoimmune joint disease in which the complement system plays an important role. Of the several components of complement, current evidence points to C5 as the most important inducer of inflammation. Several groups generated Abs or small interfering RNAs (siRNAs) or small molecule inhibitors against C5 and C5aR1 (CD88) that have showed some efficacy in RA in animal models. However, none of these candidate therapeutics has moved from bench to bedside. In this study, we test in collagen Ab-induced arthritis (CAIA) a new therapeutic strategy using a novel anti-C5ab-C5 siRNA conjugate. We first demonstrate that although C5aR2 or C5L2 (GPR77) plays no role in CAIA, C5aR1 contributes to pathogenesis. We demonstrate that injection of siRNAs blocking C5, C5aR1, or the combination decreased clinical disease activity in mice with CAIA by 45%, 51%, and 58%, respectively. Anti-C5 Ab (BB5.1) has only limited efficacy, but significantly reduced arthritis up to 66%. We then generated a novel anti-C5aR1 Ab-protamine-C5 siRNA conjugate. To our knowledge, we show for the first time that whereas unconjugated Ab plus siRNAs reduce arthritis by 19%, our anti-C5aR1 Ab-protamine-C5 siRNA conjugate was effective in reducing arthritis by 83% along with a parallel decrease in histopathology, C3 deposition, neutrophils, and macrophages in the joints of mice with CAIA. These data suggest that by targeting anti-C5 siRNAs to the receptor for its C5a activation fragment (C5aR1), a striking clinical effect can be realized.
27165179 Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naïve patient 2017 Jan OBJECTIVES: To assess the efficacy and safety of certolizumab pegol (CZP)+dose-optimised methotrexate (MTX) versus placebo (PBO)+dose-optimised MTX in inducing and sustaining clinical remission in DMARD-naïve patients with moderate-to-severe, active, progressive rheumatoid arthritis (RA), with poor prognostic factors over 52 weeks. METHODS: DMARD-naïve patients with ≤1 year of active RA were randomised (3:1) in a double-blind manner to CZP (400 mg Weeks 0, 2, 4, then 200 mg Q2W to Week 52)+MTX or PBO+MTX (the mean optimised-MTX dose=21 and 22 mg/week, respectively). Sustained remission (sREM) and sustained low disease activity (sLDA; DAS28(ESR)<2.6 and DAS28(ESR)≤3.2, respectively, at both Weeks 40 and 52) were the primary and secondary endpoints. RESULTS: Patients were randomised to CZP+MTX (n=660) and PBO+MTX (n=219). At Week 52, significantly more patients assigned to CZP+MTX compared with PBO+MTX achieved sREM (28.9% vs 15.0%, p<0.001) and sLDA (43.8% vs 28.6%, p<0.001). Inhibition of radiographic progression and improvements in physical functioning were significantly greater for CZP+MTX versus PBO+MTX (van der Heijde modified total Sharp score (mTSS) mean absolute change from baseline (CFB): 0.2 vs 1.8, p<0.001, rate of mTSS non-progressors: 70.3% vs 49.7%, p<0.001; least squares (LS) mean CFB in Health Assessment Questionnaire-Disability Index (HAQ-DI): -1.00 vs -0.82, p<0.001). Incidence of adverse events (AEs) and serious AEs was similar between treatment groups. Infection was the most frequent AE, with higher incidence for CZP+MTX (71.8/100 patient-years (PY)) versus PBO+MTX (52.7/100 PY); the rate of serious infection was similar between CZP+MTX (3.3/100 PY) and PBO+MTX (3.7/100 PY). CONCLUSIONS: CZP+dose-optimised MTX treatment of DMARD-naïve early RA resulted in significantly more patients achieving sREM and sLDA, improved physical function and inhibited structural damage compared with PBO+dose-optimised MTX. TRIAL REGISTRATION NUMBER: NCT01519791.
26555431 Incidence and complications of interstitial lung disease in users of tocilizumab, rituxima 2015 Nov 11 INTRODUCTION: Interstitial lung disease (ILD) is a common extra-articular condition in rheumatoid arthritis (RA), but few studies have systematically investigated its incidence and risk factors in patients receiving anti-tumor necrosis factor-alpha (anti-TNFα) agents or alternate mechanisms of action (MOAs) (e.g., T-cell, B-cell, and interleukin-6 inhibitors). METHODS: RA patients at least 18 years old were selected from the MarketScan databases (2010-2012) if they had at least one prescription/administration of abatacept, rituximab, tocilizumab, or anti-TNF after having discontinued a different biologic agent and meeting enrollment criteria. Cox models estimated the risk of incident ILD and ILD-related hospitalization. Sensitivity analyses used an alternate ILD case definition. RESULTS: We identified 13,795 episodes of biologic exposure in 11,219 patients. Mean (standard deviation) follow-up was 0.7 (0.5) years. Patients receiving alternate MOA agents were more likely to have had recent exposure to steroids, prior exposure to a greater number of biologics, and history of ILD, anemia, chronic obstructive pulmonary disease, and other pulmonary conditions. When the sensitive definition was used, unadjusted ILD incidence rates (95% confidence interval, or CI) ranged from 4.0 (1.6-8.2, abatacept) to 12.2 (5.6-23.2, infliximab) per 1000 person-years. Being older (hazard ratio (HR) 3.5; 95% CI 2.1-6.0), being male (HR 3.1; 95% CI 1.2-8.4), and having another pulmonary condition (HR 4.8; 95% CI 1.7-13.7) were associated with increased ILD incidence in either sensitive and/or specific models. There were no significant differences by biologic class. Hospitalization rates (95% CI) when the sensitive definition was used ranged from 55.6 (6.7-200.7, tocilizumab) to 262.5 (71.5-672.2, infliximab). In Cox models, recent methotrexate exposure was associated with reduced ILD hospitalization (HR 0.16; 95% CI 0.06-0.46), whereas being male (HR 2.5; 95% CI 1.3-4.8) and having had a hospitalization for asthma (HR 3.4; 95% CI 1.2-9.8) or ILD/pneumonia (HR 2.3; 95% CI 1.1-4.7) in the 12 months prior to index were associated with increased hospitalization risk. CONCLUSIONS: There were no significant differences in the risk of ILD and its related complications between RA patients receiving anti-TNFα agents and those receiving alternate MOA agents. Further studies are needed that account for differences in baseline characteristics in order to fully evaluate the risk of ILD and its complications.
25667208 What are the effects of medication adherence interventions in rheumatic diseases: a system 2016 Apr OBJECTIVES: Consistent reports of suboptimal treatment adherence among patients with inflammatory arthritis underscore the importance of understanding how adherence can be promoted and supported. Our objectives were to identify and classify adherence interventions; and assess the evidence on the effects of adherence interventions on outcomes of patients with rheumatic diseases. METHODS: We conducted a mapped search of Medline, Embase and International Pharmaceutical Abstract databases to identify studies meeting inclusion criteria of: (1) patient population with inflammatory arthritis; (2) evaluation of an intervention or programme targeting medication adherence directly or indirectly; (3) reporting of one or more measures of medication adherence and disease outcome; (4) publication in English, French or Spanish. For our first objective, we applied a structured framework to classify interventions according target (patient vs provider), focus (educational vs behavioural vs affective), implementation (generalised vs tailored), complexity (single vs multifaceted) and provider. For the second objective, we appraised the evidence of effects of interventions on adherence and disease outcomes. RESULTS: We identified 23 studies reporting adherence interventions that directly or indirectly addressed treatment adherence in rheumatic diseases and further appraised included RCTs. Interventions that were shown to impact adherence outcomes were generally interventions directed at adherence, tailored to patients and delivered by a healthcare provider. For interventions that were not shown to have impacts, reasons may be those related to the intervention itself, patient characteristics or study methodology. CONCLUSIONS: Our systematic review shows limited research on adherence interventions in rheumatic diseases with inconsistent impacts on adherence or disease outcome.
26528618 Endoscopic endonasal removal of the invaginated odontoid process of the C2 vertebra. 2015 Pathological processes in the craniovertebral region (clivus, C1 anterior arch, odontoid process and body of the C2 vertebra, i.e. C0-C1-C2 segments) are very difficult to diagnose and treat. The craniovertebral junction instability may develop in the case of a significant lesion of C1-C2 segments. Among diseases causing destruction of the clivus structures and C1-C2 vertebrae and compression of the spinal cord, the following ones are most common: chordoma, giant cell tumor, osteoblastoma, rheumatoid lesion, metastases, platybasia, and basilar impression. These diseases can cause the initial instability of the craniovertebral junction and be accompanied by gross neurological disorders, which complicates the diagnosis and surgical treatment of these patients. MATERIAL AND METHODS: We operated on two patients diagnosed with invagination of the odontoid process of the C2 vertebra. In both cases, one-stage operation was performed that included occipitospondylodesis and endoscopic endonasal removal of the C2 odontoid process. RESULTS: In the postoperative period, partial regression of the neurological symptoms was observed that included an increase in the strength and range of motions in the arms and distal legs, regressed spasticity in the arms and significantly reduced spasticity in the legs, and a significant improvement in all kinds of sensitivity in the arms, legs, and torso. Postoperative liquorrhea was observed in 1 case (patient 2); re-operation to close a CSF fistula was conducted. Later, no signs of liquorrhea were noted. In both cases, control MRI and spiral CT revealed a postoperative bone defect of the C2 odontoid process and clivus, complete decompression of the medulla oblongata and upper cervical spine segments, and no evidence of spinal canal stenosis; the stabilizing system was competent and properly placed. CONCLUSION: The endoscopic endonasal approach, compared to the standard transoral approach, has significant advantages in that the soft palate remains intact, the oropharynx area is less damaged, and the hospitalization and rehabilitation duration is reduced. Also, there are no problems and complications such as possible failure of sutures in the oral cavity and a large wound surface in the oropharynx area. The patient can eat on his own immediately after the operation without the use of a stomach tube (it does not cause any inflammatory complications of the oral cavity). However, the surgical technique of the endoscopic endonasal approach to the C1-C2 segment is more complex than that of transoral surgery and requires the surgeon to be skilled and experienced.
26369816 The Roles of Vitamin D and Its Analogs in Inflammatory Diseases. 2016 The discovery of nonclassical actions, other than mineral homeostasis, of 1α,25- dihydroxyvitamin D3 (1,25D3) has expanded its applications. Among these, its anti-inflammation activity has drawn more and more attention of researchers to investigate its role in regulating the progression of inflammatory diseases. The expression of many inflammation-related genes is regulated by 1,25D3 through vitamin D receptor (VDR) in a large variety of cells including immune cells such as, but not limited to, macrophages, dendritic cells, T helper cells, and B cells. Studies of 1,25D3 in these immune cells have shown both direct and indirect immunomodulatory activities affecting innate and adaptive immune responses. Moreover, 1,25D3 can also exert its anti-inflammation effects through regulating the biosynthesis of pro-inflammatory molecules in the prostaglandin pathway or through nuclear factor kappa light-chain-enhancer of activated B cells (NFκB) by affecting cytokine production and inflammatory responses. These actions of 1,25D3 may explain the associations between vitamin D levels and inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, asthma, type 1 diabetes, and systemic lupus erythematosus. Although several analogs of 1,25D3 have shown potent immunomodulatory or anti-inflammatory activity on immune cell cultures or in animal models, no vitamin D analog has been used in clinical research to treat inflammatory diseases. Here, we review the relationship between vitamin D analogs and inflammation based on observations of immune cells, prostaglandin and NFκB pathways, as well as common inflammatory diseases.
27338777 Improved survival in rheumatoid arthritis: a general population-based cohort study. 2017 Feb OBJECTIVE: Mortality trends of rheumatoid arthritis (RA) are largely unknown over the past decade when new drugs and management strategies have been adopted to effectively treat RA. METHODS: Using The Health Improvement Network, an electronic medical record database representative of the UK general population, we identified patients with incident RA and up to five individuals without RA matched for age, sex and year of diagnosis between 1999 and 2014. The RA cohort was divided in two sub-cohorts based on the year of RA diagnosis: the early cohort (1999-2006) and the late cohort (2007-2014). We compared mortality rates, HRs (using a Cox proportional hazard model) and rate differences (using an additive hazard model) between RA and non-RA cohorts adjusting for potential confounders. RESULTS: Patients with RA diagnosed between 1999 and 2006 had a considerably higher mortality rate than their comparison cohort (ie, 29.1 vs 18.0 deaths/1000 person-years), as compared with a moderate difference in patients with RA diagnosed between 2007 and 2014 and their comparison cohort (17.0 vs 12.9 deaths/1000 years). The corresponding absolute mortality rate differences were 9.5 deaths/1000 person-years (95% CIs 7.5 to 11.6) and 3.1 deaths/1000 person-years (95% CI 1.5 to 4.6) and the mortality HRs were 1.56 (95% CI 1.44 to 1.69) and 1.29 (95% CI 1.17 to 1.42), respectively (both p values for interaction <0.01). CONCLUSION: This general population-based cohort study indicates that the survival of patients with RA has improved over the past decade to a greater degree than in the general population. Improved management of RA and its associated comorbidities over recent years may be providing a survival benefit.
24924602 Prevalence of musculoskeletal disorders and rheumatic diseases in an urban community in Mo 2015 May The aim of the study was to determine the prevalence of musculoskeletal disorders and rheumatic diseases in an urban community in Venezuela. We conducted a cross-sectional, community-based study using the COPCORD (Community Oriented Program for Control of Rheumatic Diseases) methodology in subjects older than 18 years. Positive cases were evaluated by rheumatologists. We surveyed 3,973 individuals (1,606 males and 2,367 females), with a mean age of 43.7 years (standard deviation (SD) 17.6). Mean duration of education was 8.9 years (SD 3.7), 79.2 % had a monthly income of < US$569, and 46.4 % were working. Excluding trauma, the prevalence of pain in the 7 days prior to interview was 19.9 % (95 % confidence interval (CI) 18.7-21.2 %). Mean pain intensity on a visual analog scale was 6.3 (SD 2.2), and 30.1 % (95 % CI 28.7-31.6 %) had a history of pain. Respondents reported pain in the knees, back, hands, shoulders, and ankles in the last 7 days; 4.7 % described current functional limitation, with 16.5 % reporting limitations in the past. Regarding treatment, 23.9 % received medication, 6.4 % received physical therapy, and 2.6 % received alternative treatment. The main diagnoses were osteoarthritis in 15.0 % (95 % CI 13.9-16.1 %), rheumatic regional pain syndromes in 6.3 % (95 % CI 5.5-7.1 %), back pain in 2.8 % (95 % CI 2.3-3.4 %), rheumatoid arthritis in 0.4 % (95 % CI 0.2-0.6 %), crystal arthropathy in 0.3 % (95 % CI 0.1-0.5 %), fibromyalgia in 0.2 % (95 % CI 0.1-0.4 %), and systemic lupus erythematosus in 0.07 % (95 % CI 0.01-0.2 %). The prevalence of musculoskeletal disorders was 22.4 %, and the most prevalent disease was osteoarthritis. Pain, in which a patient is receiving treatment for musculoskeletal disorders, and physical disability were associated with the presence of a rheumatic disease.
25701499 Anti-TNFα treatment decreases the previously increased serum Indian Hedgehog levels in pa 2015 Jun OBJECTIVE: Indian Hedgehog (Ihh) is the ligand that activates the Hedgehog pathway (HH) in the skeleton-the main controller of endochondral ossification. We aimed at assessing serum levels of Ihh in patients with ankylosing spondylitis (AS) and the effect of serum from patients with AS on HH pathway activation. METHODS: Serum Ihh levels were measured in 59 patients with AS, 70 patients with rheumatoid arthritis (RA), and 53 healthy subjects. The effect of serum from patients with AS on HH pathway activation was evaluated using an osteoblast-like cell line model. RESULTS: Patients with AS not on anti-TNFα treatment had significantly higher Ihh levels compared to patients with RA not on anti-TNFα treatment (mean ± SEM of OD: 0.370 ± 0.025 vs. 0.279 ± 0.026 for patients with AS and RA, respectively, p = 0.027) and healthy subjects (p = 0.031). Patients with AS on anti-TNFα treatment had significantly lower Ihh levels compared to patients with AS not on such treatment (p = 0.028). Patients with RA on anti-TNF treatment had higher levels of Ihh compared to patients not on such treatment (p = 0.013). PTHrP levels were similar in patients with RA, AS, and healthy subjects and were not affected by anti-TNFα treatment. We next assessed HH pathway activation in Saos2 cells following incubation with serum from AS patients prior to and following anti-TNF treatment. The HH pathway was downregulated following treatment. CONCLUSIONS: Ihh levels are increased in patients with AS and decrease following anti-TNFα treatment; this finding may have pathogenic and clinical implications.
25060517 Meta-analysis of the association between functional MICA-TM polymorphisms and systemic lup 2015 Mar OBJECTIVE: The aim of this study was to determine whether the major histocompatibility complex class I chain-related gene A transmembrane (MICA-TM) polymorphism is associated with susceptibility to systemic lupus erythematous (SLE), rheumatoid arthritis (RA) and ankylosing spondylitis (AS). METHODS: A meta-analysis was conducted to establish the association between MICA-TM polymorphisms and SLE, RA and AS in the overall study population, as well as in each ethnic group. RESULTS: A total of 13 comparison studies, including five SLE (1601 patients; 1846 controls), four RA (701 patients; 887 controls) and four AS (346 patients; 356 controls) studies were considered in the meta-analysis. An association between the MICA-TM A5.1 allele and SLE was demonstrated in Europeans but not in Asians: odds ratio (OR) = 1.699, 95 % confidence interval (CI) = 1.123-2.569, p = 0.012 and OR = 0.949, 95 % CI = 0.502-1.793, p = 0.871, respectively. However, no association was found in Europeans after Bonferroni correction (pcorrected = 0.060). An association was found between the MICA-TM A9 allele and RA in Asians (OR = 0.527, 95 % CI = 0.408-0.681, p = 8.9 × 10(-7)) but not in Europeans; the association in Asians remained significant after Bonferroni correction (pcorrected = 4.5 × 10(-6)). An association between the MICA-TM A4 phenotype and AS was observed in European and Asian populations (OR = 12.87, 95 % CI = 6.747-24.58, p < 1.0 × 10(-9) and OR = 9.461, 95 % CI = 5.754-15.55, p < 1.0 × 10(-9), respectively). Meta-analysis stratified by human leukocyte antigen (HLA)-B27 status revealed an association between the MICA-TM A4 phenotype and HLA-B27 positivity AS in Asians, but not in Europeans (OR = 0.318, 95 % CI = 0.102-0.995, p = 0.049 and OR = 2.080, 95 % CI = 0.422-10.25, p = 0.368, respectively). However, the association in Asians was not significant after Bonferroni correction (pcorrected = 0.245). CONCLUSION: This meta-analysis demonstrated that there was no association between MICA-TM polymorphisms and SLE susceptibility, but that the MICA-TM A9 allele was associated with an RA risk in Asians. Moreover, the association between the MICA-TM A4 phenotype and AS was HLA-B27-dependent.
26111149 Genetic variants within immune-modulating genes influence the risk of developing rheumatoi 2015 Sep BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that arises as a result of the interaction between genetic and environmental factors. A growing body of research suggests that genetic variants within immune-related genes can influence the risk of developing the disease and affect drug response. MATERIALS AND METHODS: To test this hypothesis, we carried out a comprehensive two-stage case-control study in a White population of 1239 White RA patients and 1229 healthy controls to investigate whether 49 single nucleotide polymorphisms within or near 17 immune-related genes modulate the risk of developing RA and antitumor necrosis factor (anti-TNF) drug response. RESULTS: Logistic regression analyses showed that carriers of the IL4rs2070874T and IL4rs2243250T and IL8RBrs1126580A alleles or the IL8RBrs2230054C/C genotype had a significantly increased risk of developing RA [odds ratio (OR)=1.37, 95% confidence interval (CI) 1.13-1.67, P=0.0016; OR=1.24, 95% CI 1.03-1.49, P=0.020; OR=1.23, 95% CI 1.08-1.41, P=0.002 and OR=1.19, 95% CI 1.04-1.36, P=0.01, respectively]. The association of the IL4 variants was further supported by a meta-analysis including 7150 individuals (P =0.0010), whereas the involvement of the IL8RB locus in determining the susceptibility to RA was also supported by gene-gene interaction analyses that identified significant two-locus and three-locus interaction models including IL8RB variants that act synergistically to increase the risk of the disease (P=0.014 and 0.018). Interestingly, we also found that patients harbouring the IFNGrs2069705C allele showed a significantly better response to anti-TNF drugs than those patients carrying the wild-type allele (P=0.0075). CONCLUSIONS: Our data suggest that IL4 and IL8RB loci may have a small-effect genetic impact on the risk of developing RA, whereas IFNG might be involved in modulating the response to anti-TNF drugs.