Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
ID | PMID | Title | PublicationDate | abstract |
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25810923 | Adherence to methotrexate in rheumatoid arthritis: a danish nationwide cohort study. | 2015 | Objectives. To study adherence to methotrexate (MTX) and factors of importance thereof in patients with rheumatoid arthritis (RA). Methods. Patients with a hospital diagnosis of RA (ICD10 codes M05.X or M06.X) after January 1, 1997, and aged ≥18 years at the date of first diagnosis/contact, with at least one prescription of MTX (L04AX03), were included. Results. A total of 18,703 (47.6%) patients had ever used MTX among 39,286 with a diagnosis of RA; among the MTX users, 16,503 (88.2%) had filed more than one MTX prescription. The median time from diagnosis to first MTX prescription was 0.66 (IQR 0.26-1.80) years. In those who filed more than one MTX prescription, the mean adherence time for ≥7.5 mg MTX per week was 1,925 (IQR 467-3,056) days for patients treated in private practice versus 1,892 (IQR 452-3,316) days for patients treated in hospital. The main determinants of nonadherence were female gender, younger age, and time from diagnosis to initiation of MTX. Conclusions. Treatment at hospital or in private practice did not influence the adherence to MTX. Nonmodifiable factors of importance were gender and age, while adherence to MTX therapy decreased with time lapse between diagnosis and prescription. | |
27476421 | Discovery and SAR of pyrrolo[2,1-f][1,2,4]triazin-4-amines as potent and selective PI3Kδ | 2016 Sep 1 | Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models. | |
27659403 | Alarmins firing arthritis: Helpful diagnostic tools and promising therapeutic targets. | 2017 Jul | Alarmins are endogenous molecules with homeostatic roles that have reached the focus of research in inflammatory arthritis in the last two decades, mostly due to their ability to indicate tissue related damage after active or passive release from injured cells. From HMGB1, S100A8/A9 and S100A12 proteins, over heat-shock proteins (HSPs) and purine metabolites (e.g. uric acid, ATP) to altered matrix proteins and interleukin-33 (IL-33), a number of alarmins have been determined until now as having a role in rheumatoid arthritis, psoriatic and juvenile idiopathic arthritis, as well as spondyloarthritis and gout. Although formerly being linked to initiation and chronification of inflammatory arthritis, driving auto- and paracrine inflammatory loops, more recent research has also unraveled the alarmins' role in the crosstalk between innate and adaptive immunity and in resolution of inflammation. Providing a state-of-the-art overview of known alarmins, this review lists the known modes of action and pathologic contribution of alarmins to inflammatory arthritis, as well as biomarker potential of alarmins in the clinical setting for tracking disease severity. Based upon research on animal experimental models (CIA, AIA) and clinical trials, a look is made into potentially viable strategies for modifying alarmin secretion and their target receptor (e.g. TLR, RAGE) interaction with the purpose of attenuating arthritic disease. | |
27271903 | Studying Neutrophil Migration In Vivo Using Adoptive Cell Transfer. | 2016 | Adoptive cell transfer experiments can be used to study the roles of cell trafficking molecules on the migratory behavior of specific immune cell populations in vivo. Chemoattractants and their G protein-coupled seven-transmembrane-spanning receptors regulate migration of cells in vivo, and dysregulated expression of chemoattractants and their receptors is implicated in autoimmune and inflammatory diseases. Inflammatory arthritides, such as rheumatoid arthritis (RA), are characterized by the recruitment of inflammatory cells into joints. The K/BxN serum transfer mouse model of inflammatory arthritis shares many similar features with RA. In this autoantibody-induced model of arthritis, neutrophils are the critical immune cells necessary for the development of joint inflammation and damage. We have used adoptive neutrophil transfer to define the contributions of chemoattractant receptors, cytokines, and activation receptors expressed on neutrophils that critically regulate their entry into the inflamed joint. In this review, we describe the procedure of neutrophil adoptive transfer to study the influence of neutrophil-specific receptors or mediators upon the their recruitment into the joint using the K/BxN model of inflammatory arthritis as a model of how adoptive cell transfer studies can be used to study immune cell migration in vivo. | |
25129058 | Pemetrexed ameliorates experimental arthritis in rats. | 2015 Feb | Pemetrexed (PMTX) is an anti-folate drug as methotrexate. The purpose of this study was to assess the efficacy of PMTX on collagen-induced arthritis (CIA). Forty Wistar albino rats were randomized into four groups. Arthritis was induced by intradermal injection of chicken type II collagen combined with incomplete Freund's adjuvant. Animals were sacrificed at the 15th day after the onset of arthritis. Tumor necrosis factor alpha (TNF-α), interleukin (IL)-17, and malondialdehyde (MDA) levels were increased, and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities and the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were decreased in the arthritis group. In the PMTX-treated (0.2 and 1 mg/kg/week i.p.) groups, the levels of TNF-α, IL-17, and MDA were decreased; the activities of SOD, CAT, and GPx and the expressions of Nrf2 and HO-1 were restored, and perisynovial inflammation and cartilage-bone destruction were decreased. PMTX has anti-arthritic potential in the CIA model and may be a therapeutic agent for rheumatoid arthritis. | |
25510234 | Mast cell promotion of T cell-driven antigen-induced arthritis despite being dispensable f | 2015 Apr | OBJECTIVE: The function of mast cells (MCs) in autoimmune disorders has been a subject of controversy recently. MC-deficient Kit(W/W-v) mice were found to be resistant to K/BxN serum-transfer arthritis, whereas Kit(W-sh/W-sh) mice and a genetic model of MC deficiency independent of the Kit mutation were found to be fully susceptible. This debate might lead to the assumption that MCs are dispensable in autoimmunity in general. Thus, the purpose of this study was to examine the relevance of MCs to arthritis using a genetic model of inducible MC deficiency without compromised Kit signaling. METHODS: We compared MC functions in K/BxN serum-induced arthritis and in collagen-induced arthritis (CIA) in a mouse model of inducible MC deficiency by analyzing joint inflammation, parameters of cartilage degradation and bone erosion, and the autoreactive adaptive immune response. RESULTS: We observed a redundant role of MCs in K/BxN serum-induced arthritis, where joint inflammation is triggered by cartilage-bound immune complexes independently of T cells. In contrast, we found MCs to be critically relevant in CIA, which is provoked by two arms of autoimmune attack: autoreactive antibodies and effector T cells. In addition to diminished joint inflammation in the absence of MCs, we found a dramatic loss of T cell expansion upon immunization, accompanied by reduced T cell cytokine responses. CONCLUSION: In this analysis of an arthritis model in which the cellular arm of adaptive immunity was not bypassed, we identified MCs as important promoters of T cell-conditioned autoimmune disorders and, consequently, as potential therapeutic targets in rheumatoid arthritis. | |
27039208 | Sulforaphane regulates phenotypic and functional switching of both induced and spontaneous | 2016 Jun | At the site of inflammation, switching default on polarization of monocyte differentiation into classically activated macrophages (M1 type) is one of the pathogenic outcomes in several inflammatory autoimmune diseases, such as rheumatoid arthritis and osteoarthritis. In rheumatoid and osteoarthritis, a soluble collagen known as self-antigen is considered as a biomarker and acts as an important inflammatory mediator. In the present study, we investigated the effects of sulforaphane (SFN) on phenotypic changes and functional switching during in vitro induced and spontaneous differentiation of monocytes/macrophages, whose conditions were established with THP1 induced by PMA, and human peripheral blood monocytes, respectively. SFN at non-cytotoxic concentration (10μM) blocked soluble collagen induced inflammatory responses specific to M1 macrophages, COX-2, iNOS, surface CD14, CD197 expressions and production of IL12p70, suggesting that signals induced by SFN eventually shifted macrophage polarization to a direction specific to M2 macrophages (CD36high CD197extremely low). Results obtained with the induction of inflammatory conditions specific to M1 macrophages followed by SFN treatment showed that MAPKs were involved in the M1 to M2 phenotype switching. This immune-modulatory nature of SFN provides a clear indication for its ability to alleviate chronic inflammatory diseases by targeting monocytes/macrophages. | |
27133489 | Patient-Reported Outcomes in Psoriatic Arthritis. | 2016 May | Patient-reported outcome (PRO) measures are an important component to assessing disease impact and therapy response in patients with psoriatic arthritis (PsA). Overall, there are few PsA-specific PROs. Most PROs used in PsA are borrowed from other diseases (eg, rheumatoid arthritis and ankylosing spondylitis) or general population PROs. PROs are used in PsA clinical trials and in the clinical management of PsA. In this review, we discuss the most commonly used PRO in PsA, including their inclusion in composite measures. Future studies may be helpful to determine the best performing PROs in patients with PsA. | |
24467766 | Comparison of plasma vitamin D levels in patients with Sjögren's syndrome and healthy sub | 2015 Jan | AIM: Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of the salivary and lacrimal glands. There is increasing evidence indicating that vitamin D is important in the initiation and propogation of a range of autoimmune diseases which may include SS. The aim of the present study was to evaluate plasma vitamin D (vit D) levels in patients with SS and to compare this with a control group. METHOD: One hundred and seven SS patients (97 [90.7%] female and 10 [9.3%] male) and 74 healthy controls (64 [86.5%] female and 10 [13.5%] male) were included into the study. Plasma baseline 25-hydroxy-vit D levels were measured by high-powered liquid chromatography method using an Agilent 1100 liquid chromatograph. RESULTS: Plasma vit D levels in SS patients (20.5 ± 10.5 μg/L) were significantly lower than in the control group (28.4 ± 15.2 μg/L) (P < 0.001). Female SS patients had significanly lower vit D levels (19.3 ± 9.3 μg/L) than controls (28.3 ± 15.8 μg/L) (P < 0.001) but this difference was not present among the male patients and controls. There was no correlation between plasma vit D levels and erythrocyte sedimentation rate and C-reactive protein in SS patients. CONCLUSION: Vit D deficiency was frequent in patients with SS. In particular, female SS patients had the risk of vit D deficiency. It may be convenient to look for vit D deficiency and to correct vit D nutritional status in SS patients. | |
27455357 | Primary Sjögren's syndrome is associated with significant cognitive dysfunction. | 2016 Oct | AIM: Cognitive dysfunction is a neurologic manifestation in primary Sjögren syndrome (PSS). On the other hand, several antibodies are related to cognitive dysfunction. The aim of this study is to assess the cognitive dysfunction of PSS patients via detailed neurologic tests. Moreover, its associations with antibodies were also evaluated. METHOD: Twenty-eight female patients with PSS and 17 healthy controls comprised the study groups. Short-term memory, long-term memory, verbal learning, visual memory, visual spatial perception, attention, verbal frequency function, executive functions and information processing speed were evaluated with neurologic tests in both of the study groups. Furthermore, anti-N-methyl-D-aspartate (NMDA) type anti-glutamate-receptor antibody, anti-ribosomal-p and antiganglioside antibodies were assessed in the study groups. RESULTS: The attention, data processing speed, verbal learning, short-term verbal memory and visuo-spatial perception performances were lower in the patients with PSS when compared to the healthy controls. The difference reached statistical significance in Paced Auditory Serial Addition Test (P < 0.01), Serial Digit Learning Test (P < 0.01), clock drawing (P = 0.03), Auditory Verbal Learning Test immediate verbal memory (P = 0.01) and Benton Judgement of Line Orientation Test (P = 0.03). Even if antiganglioside antibodies were more likely to be present in the PSS group when compared to the healthy controls, no relationship was found between its positivity and cognitive dysfunction. CONCLUSION: Results of this study suggest that cognitive dysfunction is quite prevalent in PSS patients without being associated with studied antibodies. | |
28718578 | Atypical Cutaneous Presentation Of Adult Onset Still Disease. | 2016 Apr | Adult onset still disease is a rare systemic inflammatory disease which presents with cardinal symptoms of spiking fever, arthralgia, and characteristic non pruritic evanescent salmon pink rash and neutrophilic leukocytosis. However it can have accompanied atypical cutaneous manifestations of pruritic plaques and papules. Clinicians need to be aware of this condition so that they can correctly diagnose it and prevent its serious complications. | |
26779996 | Induction of tolerance against the arthritogenic antigen with type-II collagen peptide-lin | 2016 Jun | In murine collagen-induced arthritis (CIA), self-reactive T cells can recognize peptide antigens derived from type-II collagen (CII). Activation of T cells is an important mediator of autoimmune diseases. Thus, T cells have become a focal point of study to treat autoimmune diseases. In this study, we evaluated the efficacy of recombinant MHC class II molecules in the regulation of antigen-specific T cells by using a self peptide derived from CII (CII260-274; IAGFKGEQGPKGEPG) linked to mouse I-A(q) in a murine CIA model. We found that recombinant I-A(q)/CII260-274 molecules could be recognized by CII-specific T cells and inhibit the same T cells in vitro. Furthermore, the development of CIA in mice was successfully prevented by in vivo injection of recombinant I-A(q)/CII260-274 molecules. Thus, treatment with recombinant soluble MHC class II molecules in complex with an immunodominant self-peptide might offer a potential therapeutic for chronic inflammation in autoimmune disease such as rheumatoid arthritis. [BMB Reports 2016; 49(6): 331-336]. | |
25545152 | Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates | 2015 Apr | OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that have the ability to suppress T cell responses. The aim of this study was to evaluate the effects of the JAK inhibitor tofacitinib on MDSCs in a mouse model of rheumatoid arthritis. METHODS: Arthritis was induced in SKG mice by zymosan A (ZyA) injection. MDSCs isolated from the bone marrow (BM) of donor SKG mice with arthritis were adoptively transferred to recipient mice with arthritis. In a separate experiment, tofacitinib was administered to arthritic SKG mice subcutaneously via osmotic pump, in some cases followed by injection of an anti-Gr-1 monoclonal antibody (mAb). BM cells from untreated mice were cultured for 5 days with granulocyte-macrophage colony-stimulating factor, with or without tofacitinib, and then analyzed by flow cytometry. RESULTS: The numbers of MDSCs and polymorphonuclear MDSCs (PMN-MDSCs) were significantly increased in the spleens of SKG mice following ZyA injection. Adoptive transfer of MDSCs to recipient arthritic mice reduced the severity of arthritis compared to that in untreated control mice. Treatment with tofacitinib also ameliorated the progression of arthritis in SKG mice and induced significantly higher numbers of MDSCs and PMN-MDSCs in the BM of these animals. Furthermore, administration of an anti-Gr-1 mAb reduced the antiarthritic effect of tofacitinib in SKG mice. In vitro, tofacitinib facilitated the differentiation of BM cells to MDSCs, and inhibited their differentiation to dendritic cells. CONCLUSION: Tofacitinib facilitates the expansion of MDSCs and ameliorates arthritis in SKG mice. | |
27160609 | Juvenile arthritis: current concepts in terminology, etiopathogenesis, diagnosis, and mana | 2016 Jul | The latest change in terminology from juvenile rheumatoid arthritis (JRA) to juvenile idiopathic arthritis (JIA), established by the International League of Associations for Rheumatology (ILAR), has resulted in some confusion for OMFS and other treating clinicians. JIA comprises a group of systemic inflammatory diseases that result in the destruction of hard and soft tissues in a single or multiple joints. In a significant number of patients, one or both temporomandibular joints (TMJ) are also involved. TMJ disease may be accompanied by pain, swelling, and limitation of motion, as well as mandibular retrognathism, open bite, and asymmetry. The purpose of this article is to provide a review, for the oral and maxillofacial surgeon, of the terminology, etiopathogenesis, diagnosis, and management of children with JIA. | |
25530283 | Overview review: Comparative efficacy of oral ibuprofen and paracetamol (acetaminophen) ac | 2015 Oct | BACKGROUND: Ibuprofen and paracetamol have long been used as analgesics in a range of acute, intermittent and chronic pain conditions. Paracetamol is often the first line analgesic recommended, without consensus about which is the better analgesic. METHODS: An overview review of systematic reviews and meta-analyses directly compares ibuprofen and paracetamol at standard doses in particular painful conditions, or uses indirect comparisons against placebo. Electronic searches for systematic reviews were sought published since 1995 using outcomes approximating to ≥50% pain intensity reduction. Painful conditions were acute post-operative pain, dysmenorrhoea, tension-type headache (TTH), migraine, osteoarthritis and rheumatoid arthritis, back pain, cancer and paediatric pain. There was no systematic assessment of harm. RESULTS: Sixteen systematic reviews and four individual patient data meta-analyses were included. Ibuprofen was consistently superior to paracetamol at conventional doses in a range of painful conditions. Two direct comparisons favoured ibuprofen (acute pain, osteoarthritis). Three of four indirect comparisons favoured ibuprofen (acute pain, migraine, osteoarthritis); one showed no difference (TTH), although there were methodological problems. In five pain conditions (dysmenorrhoea, paediatric pain, cancer pain, back pain and rheumatoid arthritis), there were limited data on paracetamol and ibuprofen. CONCLUSIONS: At standard doses in different painful conditions, ibuprofen was usually superior producing more patients with the degree of pain relief that patients feel worthwhile. Neither of the drugs will be effective for everyone, and both are needed. This overview questions the practice of routinely using paracetamol as a first line analgesic because there is no good evidence for efficacy of paracetamol in many pain conditions. | |
27925370 | The role of enjoyment in exercise for people with arthritis: Four different viewpoints fro | 2017 Dec | PURPOSE: There is limited research on the role of enjoyment of exercise among people with arthritis. The aim of the present study was to determine distinct viewpoints on exercise held by people with arthritis, and how enjoyment features in these viewpoints. METHODS: A Q-methodology study was conducted, which involved two interviews with people with rheumatoid arthritis, osteoarthritis or ankylosing spondylitis (aged 20-85Â years). In the first interviews, 11 participants helped to create the Q-set, a set of statements reflecting a range of existing views on exercising. In the second interviews, 12 participants (nine of the 11 from the first interviews and three others) ranked the Q-set on a forced quasi-normal distribution of agreement. A Q-method factor analysis was carried out to determine groupings of participants with similar views on exercise. RESULTS: Four groupings were discovered, and defined in terms of rankings of statements and illustrative quotes from the ranking procedure. The first grouping had all changed their exercise habits after diagnosis with arthritis. The second grouping had a shared enjoyment for walking to stay healthy. The third grouping's viewpoints focused on knowledge about how much exercise they should carry out. The fourth grouping shared a sense of importance of being responsible for their health by exercising. CONCLUSION: These findings provide information about the role that enjoyment plays in motivating people with arthritis to exercise, although enjoyment of exercise was not expressed by all participants. People with arthritis who share these viewpoints on exercise enjoyment may require different forms of advice regarding feasible and enjoyable exercise. | |
26629363 | A new classification of HLA-DRB1 alleles based on acid-base properties of the amino acids | 2015 | OBJECTIVE: To group HLA-DRB1 alleles based on acid-base properties of amino acids at positions 13, 70 and 71 and analyse their association with the presence of anticitrullinated peptide antibodies (ACPA) and structural progression in 2 cohorts of early rheumatoid arthritis (RA). METHODS: Patients with RA (N=612) from ESPOIR cohort and from EAC cohort (n=624) were genotyped for HLA-DRB1 alleles. The alleles containing the RAA sequence at positions 72-74 were classified into 3 groups according to the amino acid at positions 13, 70 and 71: BB encoding basic amino acids at positions 13, 70 and 71; A encoding acidic amino acids at positions 70 and 71; and BN encoding either neutral amino acids at position 13 and basic amino acids at positions 70 and 71, or basic amino acid at position 13 and neutral amino acids at positions 70 and 71. The associations between the different alleles and (1) the ACPA presence, and (2) the structural progression were assessed by χ(2) test; a meta-analysis was performed on the 2 cohorts using the Mantel-Haenszel method. RESULTS: After meta-analysis, BB alleles were significantly associated with ACPA presence (OR (95% CI) 4.08 (3.14 to 5.31)) and structural progression (OR (95% CI) 2.33 (1.76 to 3.09)). The alleles protected significantly against ACPA presence (OR (95% CI) 0.37 (0.28 to 0.50)) and structural progression (OR (95% CI) 0.34 (0.23 to 0.50)). This acid-base classification allowed to separate another group BN with an intermediate risk of ACPA production (OR (95% CI) 1.14 (0.91 to 1.44)) and structural progression (OR (95% CI) 1.01 (0.77 to 1.33)). CONCLUSIONS: This new classification permitted to make a hierarchy of HLA-DRB1 alleles in terms of association with ACPA presence or structural progression in early RA. | |
27041992 | Correlations between immunogenicity, drug levels, and disease activity in an Italian cohor | 2016 | The aim of this study was to evaluate the real-life immunogenicity of anti-drug antibodies, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab (TCZ). We evaluated 126 TCZ-treated patients with rheumatoid arthritis (16 males and 110 females; mean age 59±12 years, range 26-83; mean disease duration 11±5 years) with inadequate 12-week response to any synthetic and biological disease-modifying anti-rheumatic drugs, in a retrospective analysis. One-hundred and seven patients were treated with methotrexate mean dose 12.6±1.3 mg/week in combination with TCZ, 13 received TCZ monotherapy, and six received leflunomide 20 mg/day plus TCZ; all patients were treated with prednisone mean dose 6.4±1.2 mg/day. They had a 28-joint Disease Activity Score (DAS28) of >3.2, an erythrocyte sedimentation rate (ESR) of >30 mm/hour, and CRP levels of >1.0 mg/dL. We evaluated at baseline and after 6 months of treatment: DAS28; rheumatoid factor (RF) IgM, IgA, and IgG; anti-citrullinated peptide antibody; ESR; CRP; TNF-α; and IL-6. TCZ and anti-TCZ antibodies were detected using LISA-TRACKER Duo TCZ. TCZ levels of <10 µg/mL were considered low and >10 µg/mL high. After 6 months of treatment only one patient was positive for anti-TCZ antibodies. There were correlations between DAS28, ESR, and CRP and IL-6 levels in all patients. Comparison of the 84 patients with TCZ levels of <10 µg/mL and the 42 with TCZ levels of >10 µg/mL showed the following differences: DAS28: 3.09±1.32 vs 2.78±1.32, P=0.0005; ESR: 27±14.8 vs 14±12 mm/hour, P=0.0001; CRP: 1.47±1.05 vs 0.65±0.80 mg/dL, P=0.0086; TNF-α: 10.2±1.2 vs 9.9±1.1 pg/mL, P=0.999; IL-6: 3.65±4.75 vs 3.62±4.41 pg/mL, P=0.97; anti-citrullinated peptide antibody: 85.2±93.7 vs 86.7±90.3 IU/mL, P=0.94; RF IgM: 72.4±62.7 vs 68.3±61.6 IU/mL, P=0.754; RF IgA: 41.7±36.4 vs 47.8±42.1 U/mL, P=0.449; and RF IgG: 46.4±46.1 vs 59.3±58.2 U/mL, P=0.212. These findings show that the occurrence of anti-drug antibodies against TCZ is very rare and that there are statistically significant correlations between TCZ levels of >10 µg/mL and ESR, CRP levels, and DAS28. | |
27812365 | Shared Genetic Etiology of Autoimmune Diseases in Patients from a Biorepository Linked to | 2016 | Autoimmune diseases represent a significant medical burden affecting up to 5-8% of the U.S. POPULATION: While genetics is known to play a role, studies of common autoimmune diseases are complicated by phenotype heterogeneity, limited sample sizes, and a single disease approach. Here we performed a targeted genetic association study for cases of multiple sclerosis (MS), rheumatoid arthritis (RA), and Crohn's disease (CD) to assess which common genetic variants contribute individually and pleiotropically to disease risk. Joint modeling and pathway analysis combining the three phenotypes were performed to identify common underlying mechanisms of risk of autoimmune conditions. European American cases of MS, RA, and CD, (n = 119, 53, and 129, respectively) and 1924 controls were identified using de-identified electronic health records (EHRs) through a combination of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) billing codes, Current Procedural Terminology (CPT) codes, medication lists, and text matching. As expected, hallmark SNPs in MS, such as DQA1 rs9271366 (OR = 1.91; p = 0.008), replicated in the present study. Both MS and CD were associated with TIMMDC1 rs2293370 (OR = 0.27, p = 0.01; OR = 0.25, p = 0.02; respectively). Additionally, PDE2A rs3781913 was significantly associated with both CD and RA (OR = 0.46, p = 0.02; OR = 0.32, p = 0.02; respectively). Joint modeling and pathway analysis identified variants within the KEGG NOD-like receptor signaling pathway and Shigellosis pathway as being correlated with the combined autoimmune phenotype. Our study replicated previously-reported genetic associations for MS and CD in a population derived from de-identified EHRs. We found evidence to support a shared genetic etiology between CD/MS and CD/RA outside of the major histocompatibility complex region and identified KEGG pathways indicative of a bacterial pathogenesis risk for autoimmunity in a joint model. Future work to elucidate this shared etiology will be key in the development of risk models as envisioned in the era of precision medicine. | |
27903507 | Hydroxychloroquine inhibits proinflammatory signalling pathways by targeting endosomal NAD | 2017 May | OBJECTIVES: Hydroxychloroquine (HCQ) has been used for decades to treat patients with rheumatic diseases, for example, systemic lupus erythematosus (SLE), rheumatoid arthritis or the antiphospholipid syndrome (APS). We hypothesise that HCQ might target endosomal NADPH oxidase (NOX), which is involved in the signal transduction of cytokines as well as antiphospholipid antibodies (aPL). METHODS: For in vitro experiments, monocytic cells were stimulated with tumour necrosis factor α (TNFα), interleukin-1β (IL-1β) or a human monoclonal aPL and the activity of NOX was determined by flow cytometry. The expression of genes known to be induced by these stimuli was quantified by quantitative reverse transcription PCR. Live cell imaging was performed by confocal laser scanning microscopy. Finally, the effects of HCQ on NOX-induced signal transduction were analysed in an in vivo model of venous thrombosis. RESULTS: HCQ strongly reduces or completely prevents the induction of endosomal NOX by TNFα, IL-1β and aPL in human monocytes and MonoMac1 cells. As a consequence, induction of downstream genes by these stimuli is reduced or abrogated. This effect of HCQ is not mediated by direct interference with the agonists but by inhibiting the translocation of the catalytic subunit of NOX2 (gp91phox) into the endosome. In vivo, HCQ protects mice from aPL-induced and NOX2-mediated thrombus formation. CONCLUSIONS: We describe here a novel mechanism of action of HCQ, that is, interference with the assembly of endosomal NOX2. Since endosomal NOX2 is involved in many inflammatory and prothrombotic signalling pathways, this activity of HCQ might explain many of its beneficial effects in rheumatic diseases including the APS. |