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ID PMID Title PublicationDate abstract
30653667 Tocilizumab-Associated Reversible Cerebral Vasoconstriction: A Case Report. 2019 Feb OBJECTIVES: To report a case of reversible cerebral vasoconstriction syndrome (RCVS) possibly precipitated by tocilizumab. BACKGROUND: Immunosuppressant drugs are a rare cause of reversible cerebral vasoconstriction, a syndrome characterized by segmental vasospasm. However, although it is considered a reversible process that resolves within 3 months, the cerebral vasoconstriction over time may lead to severe complications such as strokes. RESULTS: We describe a 53-year-old woman who presented with a reversible vasoconstriction syndrome possibly associated with tocilizumab, an inhibitor of IL-6 receptor used in inflammatory diseases such as rheumatoid arthritis. The patient developed a cerebellar infarction as the major complication of the vasoconstriction syndrome. CONCLUSION: Tocilizumab could be a trigger of RCVS. It is important to bear in mind the role of tocilizumab as a possible precipitating factor in order to remove it and reduce complications such as strokes. It is, to our knowledge, the first reversible vasoconstriction syndrome possibly precipitated by tocilizumab published to date.
31693324 2019 Apr 17 INFLAMMATORY BOWEL DISEASE: Inflammatory bowel disease (IBD) is a disease involving inflammation conditions located in colon and small intestines. Ulcerative colitis (UC) and Crohn’s disease (CD) are two primary types of IBD with different characteristics. UC is a mucosal disease that often affects the rectum and all or part of the colon. Sometimes it is difficult to distinguish UC and CD clinically. The symptoms commonly seen in the patients with UC include diarrhea, rectal bleeding, tenesmus, passage of mucus, and crampy abdominal pain. The inflammation may cause major consequences, particularly a fibrostenotic obstructing pattern or a penetrating fistulous pattern. Depending on disease severity, the options of conventional treatment for IBD include 5-aminosalicylic acid agents, glucocorticoids, antibiotics, and immunomodulators. Immunomodulators include azathioprine, 6-mercaptopurine, methotrexate, and cyclosporine, and modify the activities of the immune system. The use of immunomodulators are associated with minor or severe adverse events, such as headache, infection, and certain cancers. Due to such risks, the use of immunomodulators needs to be closely monitored. Conventionally, a “step-up” treatment strategy usually include a sequential use of aminosalicylates, steroids, immunomodulators, and finally biologics. Medications such as 5-aminosalicylic acids or prednisolone are tried first. Biologics or pharmacological immunomodulators are particularly useful when patients are not responsive to steroids for induction or relapse prevention. BIOLOGICS: Recent advances in IBD treatment include biologics (also called biologic agents or biologic therapies), particularly for patients unresponsive to conventional therapy. Biologics are protein-based molecules that can block inflammation in several immune-related diseases.(,) The first biologic approved for IBD is infliximab, a chimeric immunoglobulin (IgG)1 antibody against tumor necrosis factor (TNF)-α. The usual dose of infliximab is to repeat infusion 5mg/kg every eight weeks. Infliximab was approved by Health Canada to treat rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, CD, fistulizing Crohn disease (FCD), and UC. Currently, three types of biologics are approved for the treatment of one or both primary types of IBD: anti-TNF agents (infliximab, adalimumab, and golimumab), anti-integrin agents (vedolizumab) and anti-interleukin (IL) 12/23 IgG1 kappa agents (ustekinumab).(,) PLACE IN THERAPY: Health Canada has approved several biologics or biosimilars for the treatment of ulcerative colitis in patients without adequate response to conventional therapy, including infliximab and vedolizumab. Although, infliximab and other biologics are often reserved for patients unresponsive to conventional therapy,(,) some practitioners argue that early adoption of biologics or immunomodulators may be beneficial to patients with IBD. The benefits of early adoption may include avoiding toxic effects of immunomodulators and fewer adverse effects related to conventional therapy. It is uncertain whether early adoption of biologics or immunomodulators may be beneficial to patients with UC. This study aims to review the literature and understand the effectiveness and cost-effectiveness of biologics and immunomodulators among UC patients naïve to both types of drugs.
31398661 Inhibitory effect of α-amyrin acetate isolated from Fraxinus rhynchophylla on Th17 polari 2019 Oct BACKGROUND: T helper 17 (Th17) cells, which are differentiated from CD4(+) T cells, drive inflammation, leading to autoimmune diseases such as psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Therefore, inhibiting Th17 polarization could be a therapeutic target for inflammatory diseases. PURPOSE: We investigated the inhibitory effect of Fraxinus rhynchophylla (Oleaceae) on Th17 differentiation and found its active component. STUDY DESIGN: The activity of F. rhynchophylla and its active constituent was verified using CD4(+) cells extracted from C57BL/6 mice. METHODS: Micro-environment for Th17 polarization was provided to CD4(+) cells and the effect of treatment with samples was measured by enzyme linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), and Western blot. RESULTS: The extract of F. rhynchophylla Hance and its chemical constituent, α-amyrin acetate, which was isolated via bioassay-guided isolation, significantly inhibited Th17 polarization as revealed when interleukin (IL)-17, a characteristic cytokine produced by Th17 cells, was measured. Furthermore, the inhibitory effect of α-amyrin acetate was compared to the amyrin derivatives, α-amyrin and β-amyrin. All displayed a suppressive effect on Th17 polarization and all reduced the expression of single transducer and activator of transcription 3 (STAT3) and retinoic acid receptor-related orphan receptor γt (RORγt), which are crucial transcription factors regulating Th17 differentiation. α-Amyrin acetate, however, exhibited the most prominent effects, which indicates that the functional group, acetate, might strengthen the inhibitory effect on Th17 differentiation. CONCLUSION: Taken together, these results suggest that the extract of F. rhynchophylla and its active constituent, α-amyrin acetate, could be applied as a potential therapeutic agent for autoimmune disorders such as rheumatoid arthritis.
31124343 Upregulation of miR-27b Facilitates Apoptosis of TNF-α-Stimulated Fibroblast-Like Synovio 2019 Jun PURPOSE: The aim of this study was to explore the function of microRNA-27b (miR-27b) in fibroblast-like synoviocytes (FLSs) stimulated by tumor necrosis factor α (TNF-α). MATERIALS AND METHODS: mRNA expression of miR-27b in FLS cells (MH7A) treated with or without TNF-α was determined by q-PCR. MiR-27b mimics was transfected into MH7A cells to upregulate miR-27b expression. MTT assay and flow cytometry analysis were performed to investigate the effect of miR-27b on MH7A cell viability and apoptosis. The targets of miR-27b were predicted by TargetScan. The direct regulation of miR-27b on IL-1β expression was verified by luciferase assay. The protein expression levels of apoptosis-related proteins, IL-1β, and NF-κB signaling-related proteins were detected by Western blot. RESULTS: We discovered that miR-27b expression was decreased in MH7A cells stimulated by TNF-α. Upregulation of miR-27b by miR-27b mimics significantly inhibited the proliferation and promoted the apoptosis of TNF-α-stimulated MH7A cells. Consistently, upregulation of miR-27 decreased the level of Bcl-2 and increased Bax and caspase-3 expression in MH7A cells stimulated by TNF-α. Luciferase assay revealed that IL-1β was indeed a target of miR-27b. By quantitative real-time PCR and Western blot, we found that the expression of IL-1β is negatively regulated by miR-27b. Moreover, the NF-κB signaling pathway was significantly inhibited by miR-27b. CONCLUSION: Taken together, our results illustrated that enhanced miR-27b expression results in the suppression of proliferation and the promotion of apoptosis in FLSs stimulated by TNF-α, partially by regulating IL-1β expression and NF-κB signaling.
30844679 The impact of rheumatological disorders on lymphomas and myeloma: a report on risk and sur 2019 Apr BACKGROUND: Autoimmune inflammatory disease increases the risk of diffuse large B-cell lymphoma (DLBCL) and marginal zone lymphoma (MZL), but findings for other mature B-cell malignancies are equivocal. Furthermore, it has been suggested that the increase in DLBCL is due to the activated B-cell (ABC) subtype; but data on this, and the impact of inflammatory co-morbidities on survival, are sparse and contradictory. METHODS: Data are from an established UK population-based cohort. Patients (n = 6834) diagnosed between 01/2009 and 08/2015 are included; DLBCL (n = 1771), myeloma (n = 1760), chronic lymphocytic leukaemia (CLL, n = 1580), MZL (n = 936), and follicular lymphoma (FL, n = 787). Information on rheumatological disorders and deaths was obtained by record-linkage to nationally compiled Hospital Episode Statistics, with age-and sex-matched individuals (n = 68,340) from the same catchment population (˜4 million people) providing the comparator. RESULTS: Significantly increased risks for DLBCL (OR = 2.3, 95% CI 1.8-2.8) and MZL (OR = 2.0, 95% CI 1.5-2.7) were found for those with rheumatological disorders; the site distribution of those with/without rheumatological conditions differing for DLBCL (p = 0.007) and MZL (p = 0.002). No increases in risk were observed for the remaining mature B-cell malignancies, and no associations with survival were detected for DLBCL (age-adjusted HR = 1.2, 95% CI 0.9-1.6) or MZL (age-adjusted HR = 1.0, 95% CI 0.6-1.9). Furthermore, whilst our findings provide evidence for an association with rheumatological disease severity for DLBCL, they offer little support for the notion that the association is driven by an increase in the incidence of the ABC subtype. CONCLUSION: Our findings support the hypothesis that the chronic activation and proliferation of specific B-cell populations which characterize autoimmune disease increase the potential for the lymphomagenic events that lead to DLBCL and MZL in both males and females; but have no impact on the development of CLL, FL or MM, or on survival.
31626646 Birth outcomes in women who have taken adalimumab in pregnancy: A prospective cohort study 2019 BACKGROUND: Information is needed on the safety of adalimumab when used in pregnancy for the treatment of certain autoimmune diseases. METHODS AND FINDINGS: Between 2004 and 2016, the Organization of Teratology Information Specialists Research Center at the University of California San Diego conducted a prospective controlled observational cohort study in 602 pregnant women who had or had not taken adalimumab. Women in the adalimumab-exposed cohort had received at least one dose of the drug in the first trimester for the treatment of rheumatoid arthritis or Crohn's Disease (N = 257). Women in the disease comparison cohort had not used adalimumab in pregnancy (N = 120). Women in the healthy comparison cohort had no rheumatic or inflammatory bowel diseases (N = 225). Women and their infants were followed to one year postpartum with maternal interviews, medical records abstraction, and physical examinations. Study outcomes were major structural birth defects, minor defects, spontaneous abortion, preterm delivery, pre and post-natal growth deficiency, serious or opportunistic infections and malignancies. 42/602 (7.0%) of pregnancies were lost-to-follow-up. 22/221 (10.0%) in the adalimumab-exposed cohort had a live born infant with a major birth defect compared to 8/106 (7.5%) in the diseased unexposed cohort (adjusted odds ratio 1.10, 95% confidence interval [CI] 0.45 to 2.73). Women in the adalimumab-exposed cohort were more likely to deliver preterm compared to the healthy cohort (adjusted hazard ratio [aHR] 2.59, 95% CI 1.22 to 5.50), but not compared to the diseased unexposed cohort (aHR 0.82, 95% CI 0.66 to 7.20). No significant increased risks were noted with adalimumab exposure for any other study outcomes. CONCLUSIONS: Adalimumab exposure in pregnancy compared to diseased unexposed pregnancies was not associated with an increased risk for any of the adverse outcomes examined. Women with rheumatoid arthritis or Crohn's Disease were at increased risk of preterm delivery, irrespective of adalimumab exposure.
31821152 Detecting Lifestyle Risk Factors for Chronic Kidney Disease With Comorbidities: Associatio 2019 Dec 10 BACKGROUND: The rise in the number of patients with chronic kidney disease (CKD) and consequent end-stage renal disease necessitating renal replacement therapy has placed a significant strain on health care. The rate of progression of CKD is influenced by both modifiable and unmodifiable risk factors. Identification of modifiable risk factors, such as lifestyle choices, is vital in informing strategies toward renoprotection. Modification of unhealthy lifestyle choices lessens the risk of CKD progression and associated comorbidities, although the lifestyle risk factors and modification strategies may vary with different comorbidities (eg, diabetes, hypertension). However, there are limited studies on suitable lifestyle interventions for CKD patients with comorbidities. OBJECTIVE: The objectives of our study are to (1) identify the lifestyle risk factors for CKD with common comorbid chronic conditions using a US nationwide survey in combination with literature mining, and (2) demonstrate the potential effectiveness of association rule mining (ARM) analysis for the aforementioned task, which can be generalized for similar tasks associated with noncommunicable diseases (NCDs). METHODS: We applied ARM to identify lifestyle risk factors for CKD progression with comorbidities (cardiovascular disease, chronic pulmonary disease, rheumatoid arthritis, diabetes, and cancer) using questionnaire data for 450,000 participants collected from the Behavioral Risk Factor Surveillance System (BRFSS) 2017. The BRFSS is a Web-based resource, which includes demographic information, chronic health conditions, fruit and vegetable consumption, and sugar- or salt-related behavior. To enrich the BRFSS questionnaire, the Semantic MEDLINE Database was also mined to identify lifestyle risk factors. RESULTS: The results suggest that lifestyle modification for CKD varies among different comorbidities. For example, the lifestyle modification of CKD with cardiovascular disease needs to focus on increasing aerobic capacity by improving muscle strength or functional ability. For CKD patients with chronic pulmonary disease or rheumatoid arthritis, lifestyle modification should be high dietary fiber intake and participation in moderate-intensity exercise. Meanwhile, the management of CKD patients with diabetes focuses on exercise and weight loss predominantly. CONCLUSIONS: We have demonstrated the use of ARM to identify lifestyle risk factors for CKD with common comorbid chronic conditions using data from BRFSS 2017. Our methods can be generalized to advance chronic disease management with more focused and optimized lifestyle modification of NCDs.
30690793 Accuracy of FRAX(®) in People With Multiple Sclerosis. 2019 Jun People with multiple sclerosis (MS) have a higher risk of low bone mineral density (BMD), osteoporosis, and osteoporotic fractures than healthy adults. The Fracture Risk Assessment tool (FRAX(®) ) has been reported to underestimate fracture risk in people with MS when BMD is unknown. We tested FRAX performance for people with MS when BMD is known, and determined if MS is a risk factor for fracture independent of FRAX score. Using population-based databases in Manitoba, Canada, we identified people with MS who underwent BMD screening after MS diagnosis (n = 744) and controls matched on age, sex, and first BMD screening date (n = 3721). We calculated FRAX 10-year probabilities at the BMD screening date, and ascertained incident major osteoporotic fractures (MOF). Using Cox proportional hazards modeling we assessed the effect of MS on the hazard of MOF, adjusting for FRAX 10-year probabilities. MS cases had a higher mean FRAX 10-year probability of MOF calculated with BMD (8.32 ± 7.53) than controls (6.98 ± 5.18; p < 0.01). MS increased the risk for MOF after controlling for FRAX 10-year probability without BMD (HR 1.67; 95% confidence interval [CI], 1.29 to 2.16), and after controlling for FRAX individual risk factors (HR 1.45; 95% CI, 1.12 to 1.89). MS remained a risk factor for MOF even when controlling for FRAX 10-year probability of MOF with BMD (HR 1.48; 95% CI, 1.14 to 1.92). The FRAX 10-year probability with and without BMD underestimated the observed 10-year MOF risk in MS cases by 3% to 5%. Calibration improved when secondary osteoporosis was used to calculate FRAX without BMD. Calibration was best when the rheumatoid arthritis input was used to calculate FRAX probability along with BMD. Using secondary osteoporosis or rheumatoid arthritis as proxies for MS improves performance of FRAX and accurately predicts MOF outcomes in those with MS. This provides clinicians with a readily available approach to improve the accuracy of fracture prediction in MS. © 2019 American Society for Bone and Mineral Research.
31387327 IL-38: A New Player in Inflammatory Autoimmune Disorders. 2019 Aug 5 Interleukin (IL)-38, a newly discovered IL-1 family cytokine, is expressed in several tissues and secreted by various cells. IL-38 has recently been reported to exert an anti-inflammatory function by binding to several receptors, including interleukin-36 receptor (IL-36R), interleukin-1 receptor accessory protein-like 1 (IL-1RAPL1), and interleukin-1 receptor 1 (IL-1R1) to block binding with other pro-inflammatory cytokines and inhibit subsequent signaling pathways; thereby regulating the differentiation and function of T cells, peripheral blood mononuclear cells, macrophages, and dendritic cells. Inflammatory autoimmune diseases, which are common immune-mediated inflammatory syndromes, are characterized by an imbalance between T helper cells (Ths), especially Th1s and Th17s, and regulatory T cells (Tregs). Recent findings have shown that abnormal expression of IL-38 in inflammatory autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, primary Sjogren's syndrome, psoriasis, inflammatory bowel disease, hidradenitis suppurativa, ankylosing spondylitis, and glaucoma, involves Th1s, Th17s, and Tregs. In this review, the expression, regulation, and biological function of IL-38 are discussed, as are the roles of IL-38 in various inflammatory autoimmune disorders. Current data support that the IL-38/IL-36R and/or IL-38/IL-1RAPL1 axis primarily play an anti-inflammatory role in the development and resolution of inflammatory autoimmune diseases and indicate a possible therapeutic benefit of IL-38 in these diseases.
31064410 Abatacept induced granulomatous hepatitis with a sarcoidosis- like reaction: a blinded tri 2019 May 7 BACKGROUND: Abatacept is increasingly used for rheumatoid arthritis (RA) and juvenile idiophathic arthritis (JIA) treatment. However little is known about the risk of hepatotoxicity. The aim of this study was to determine whether the inhibition of the T cell CD28 receptor by abatacept results in acute hepatitis in BALB/c mice. METHODS: Twenty BALB/c mice were studied. Ten mice received subcutaneous (SC) injection of abatacept (0.25mg per 25g body weight per 0.03 ml normal saline) at 0, 2, 4 and 8 weeks. For the control group, 10 mice received a SC injection of normal saline (NS) (0.03 ml). At the 10th week post injection, the mice were sacrificed, and histopathological studies were conducted. RESULTS: Of the abatacept-treated group, 3/10 mice died. Liver histology for the abatacept-treated group showed that 6/7 displayed histopathological changes in the lobular cellular infiltrates of eosinophils, lymphocytes and histiocytes, in addition to granuloma formation. In contrast, only minimal inflammation was observed in 3/10 mice in the control group (p=0.036). CONCLUSION: Abatacept may play a role in inducing granulomatous hepatitis with a sarcoidosis-like reaction. Additional data including transaminases, antinuclear antibodies (ANA), Antimitochondrial antibodies (AMA) and other auto antibodies should be tested.
31800917 Rheumatological Manifestations Associated with Viral Hepatitis B or C. 2019 INTRODUCTION: Rheumatological findings and rheumatic diseases may be associated with hepatitis virus infection. This study assessed the frequency of these manifestations in a reference unit in Acre, Brazil. METHODS: This was a cross-sectional study with a convenience sample of patients having their first consultation at the rheumatology outpatient clinics of a referral unit in Rio Branco, Acre, from March to November 2017. Sociodemographic, clinical, laboratory, and imaging data registereds using a standardized questionnaire form. RESULTS: Among the 600 patients with rheumatic complaints, 3.0% were newly diagnosed with hepatitis B virus (HBV) or hepatitis C virus (HCV), and 8.7% were previously diagnosed with hepatitis. Among the 70 patients with hepatitis, 54.3% were carriers of HBV and 45.7% of HCV. For patients infected with HBV and HCV, arthralgia was the most prevalent rheumatic manifestation in 97.4% and 90.6%, followed by myalgia in 81.6% and 65.6%, and arthritis in 26.3% and 40.6% of patients, respectively, according to the descriptive analysis performed using the Statistical Package for the Social Sciences software. In comparative analyses using the chi-squared test, despite the fact that fibromyalgia was the most prevalent rheumatic disease only the Rheumatoid Arthritis there were differences in distribution between the carriers of HCV (18.8%) and HBV (2.6%). According to the Fisher's exact test, hypothyroidism was the most frequent comorbidity in patients with HCV (21.9%). CONCLUSIONS: An increased frequency of musculoskeletal manifestations, better than those reported in the medical literature, in patients infected with HBV and HCV was observed.
31351784 Changing epidemiology of immune-mediated inflammatory diseases in immigrants: A systematic 2019 Dec BACKGROUND: Immune-mediated inflammatory diseases (IMIDs) are systemic diseases of multifactorial etiology that share aberrant immune responses as the common final pathway. With rising globalization, their incidence is increasing in developing countries and among immigrants. Our primary objective was to systematically review the epidemiology of IMIDs in immigrants and conduct a meta-analysis to estimate the risk of IMIDs in immigrant populations according to their origin and destination countries. METHODS: We systematically searched five biomedical databases and reviewed population-based studies, from inception through August 2018, that reported incidence or prevalence data of inflammatory bowel disease (IBD), multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS) or psoriasis and psoriatic arthritis (PPA) among immigrants and the host population. RESULTS: The incidence and prevalence of IMIDs among immigrants differ from host populations, and evolve over subsequent generations. The risk of IBD among immigrants approximates that in hosts, especially among South Asians, with ulcerative colitis incidence changing prior to Crohn's disease incidence. MS risk is highest in Iranian immigrants, T1D in African immigrants and SLE in African and Iraqi immigrants. Data on other IMIDs are sparse. Significant heterogeneity between the studies precluded meta-analysis. CONCLUSION: Based on our systematic review, the epidemiology of IMIDs among immigrants varies according to native and host countries, immigrant generation, and IMID type. The rapid evolution suggests a role for non-genetic factors and gene-environment interactions. Future studies should focus on these pattern shifts, given implications of rising global burden of IMIDs and immigration.
31205675 Effectiveness of the golimumab educational program in ensuring healthcare professionals' a 2019 BACKGROUND: The golimumab safety awareness study commenced in 2010 to measure, periodically, the awareness of golimumab prescriber healthcare professionals (HCPs) of specific risks associated with golimumab as well as awareness of the requirement to provide a patient alert card to each patient treated with golimumab, as described in the European golimumab educational program. The aim of this study was to measure the awareness of HCPs who prescribe or who intend to prescribe SIMPONI(®) (golimumab) of the risks potentially related to golimumab and of the requirements for distributing the patient alert card, as described in the golimumab educational program. METHODS: A structured, quantitative Web-based survey was conducted in 2010, 2012, 2014, and 2016 in eight European countries among HCPs who were at that time current or future prescribers of golimumab for patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, nonradiographic axial spondyloarthritis, or ulcerative colitis. RESULTS: The overall golimumab risk awareness was high for golimumab prescriber HCPs across the risk statement categories (median awareness in 2016 across categories: 91%). The awareness of the golimumab risks was generally slightly higher among rheumatologists (75-98%) and gastroenterologists (73-97%) than among dermatologists (67-94%). Overall, the awareness of the requirements for handing out the patient alert card to golimumab-treated patients remained steady or increased slightly in 2016 relative to the other surveys. CONCLUSIONS: The results of this study show that the awareness of risks associated with golimumab by golimumab prescriber HCPs is high. The information made available to golimumab prescriber HCPs appears to have been sufficient with respect to golimumab risk awareness education.
31464632 Risk of immune-mediated inflammatory diseases in newly diagnosed ankylosing spondylitis pa 2019 Aug 29 OBJECTIVE: To investigate the risk of immune-mediated inflammatory diseases (IMIDs) in patients with ankylosing spondylitis (AS). METHODS: Using 2003-2012 claims data from the Taiwanese National Health Insurance Research Database, we identified 30,911 newly diagnosed AS patients requiring medical therapy from 2006 to 2012. In addition, we randomly selected 309,110 non-AS individuals matching (1:10) the AS patients with regard to age, sex and the year of the index date. After excluding subjects with the corresponding prior IMIDs, we calculated the incidence rates (IRs) of various IMIDs in the AS and non-AS cohorts and estimated the hazard ratios (HRs) with 95% confidence intervals after adjusting for age, sex, the Charlson comorbidity index, the frequency of ambulatory visits during the follow-up period and medications. We conducted sensitivity analyses by excluding those who developed IMIDs within 3 months after the index date. RESULTS: In the follow-up period, we found that newly diagnosed AS patients had significantly increased risks of acute anterior uveitis, psoriasis, Sjögren's syndrome, thromboangiitis obliterans, Behcet's disease and sarcoidosis. However, the risk of Sjögren's syndrome did not increase in AS patients in the sensitivity analysis. In the same period, this study found no significant differences in the risks of Crohn's disease, ulcerative colitis, systemic lupus erythematosus, systemic sclerosis, dermatomyositis, polymyositis, pemphigus and vitiligo between newly diagnosed AS patients and non-AS individuals. AS patients had a significantly reduced risk of rheumatoid arthritis. CONCLUSION: Newly diagnosed Taiwanese AS patients had increased risks of acute anterior uveitis, psoriasis, thromboangiitis obliterans, Behcet's disease and sarcoidosis, but a reduced risk of rheumatoid arthritis.
31720749 Can antineutrophil cytoplasmic antibody positivity at diagnosis predict the poor outcomes 2020 Jul We investigated the clinical implication of ANCA positivity at diagnosis on the poor outcomes in patients with Sjögren's syndrome. The medical records of 606 Korean patients with Sjögren's syndrome were retrospectively reviewed. The results of perinuclear (P)-ANCA, myeloperoxidase (MPO)-ANCA, cytoplasmic (C)-ANCA, and proteinase 3 (PR3)-ANCA were collected and the frequencies of all-cause mortality, interstitial lung disease (ILD), end-stage renal disease (ESRD), and lymphoma were assessed as the poor outcomes of Sjögren's syndrome. Comparison of the cumulative patient survivals between the two groups was analysed by the Kaplan-Meier survival analysis. Of the 606 patients, ANCA was detected in 10.2% of Sjögren's syndrome patients without AAV. Twenty-one patients (3.5%) died, 99 patients (16.3%) suffered from ILD, and 8 patients had ESRD. Lymphoma occurred in 5 patients (0.8%) during 37.5 months. Sjögren's syndrome patients with ANCA positivity exhibited a lower cumulative ILD-free survival rate than those with ANCA negativity (P = 0.001). Sjögren's syndrome patients with P-ANCA positivity and those with MPO-ANCA (or P-ANCA) positivity showed a lower cumulative ILD-free survival rate than those without (P = 0.012 and P < 0.001). Also, Sjögren's syndrome patients with P-ANCA positivity exhibited a lower cumulative ESRD-free survival rate than those without (P = 0.043). ANCA positivity was associated with neither all-cause mortality nor lymphoma in Sjögren's syndrome patients. ANCA positivity and MPO-ANCA (or P-ANCA) positivity at diagnosis was associated with the development of ILD during follow-up in patients with Sjögren's syndrome.
31001245 Lysosomal pH Is Regulated in a Sex Dependent Manner in Immune Cells Expressing CXorf21. 2019 Background: CXorf21 and SLC15a4 both contain risk alleles for systemic lupus erythematosus (SLE) and Sjögren's syndrome (pSS). The former escapes X inactivation. Our group predicts specific endolysosomal-dependent immune responses are driven by the protein products of these genes, which form a complex at the endolysosomal surface. Our previous studies have shown that knocking out CXorf21 increases lysosomal pH in female monocytes, and the present study assesses whether the lysosomal pH in 46,XX women, who overexpress CXorf21 in monocytes, B cells, and dendritic cells (DCs), differs from 46,XY men. Methods: To determine endolysosome compartment pH we used both LysoSensor™ Yellow/Blue DND-160 and pHrodo® Red AM Intracellular pH Indicator in primary monocyte, B cells, DCs, NK cells, and T cells from healthy men and women volunteers. Results: Compared to male samples, female monocytes, B cells, and DCs had lower endolysosomal pH (female/male pH value: monocytes 4.9/5.6 p < 0.0001; DCs 4.9/5.7 p = 0.044; B cells 5.0/5.6 p < 0.05). Interestingly, T cells and NK cells, which both express low levels of CXorf21, showed no differential pH levels between men and women. Conclusion: We have previously shown that subjects with two or more X-chromosomes have increased CXorf21 expression in specific primary immune cells. Moreover, knockdown of CXorf21 increases lysosomal pH in female monocytes. The present data show that female monocytes, DC, B cells, where CXorf21 is robustly expressed, have lower lysosomal pH compared to the same immune cell populations from males. The lower pH levels observed in specific female immune cells provide a function to these SLE/SS-associated genes and a mechanism for the reported inflated endolysosomal-dependent immune response observed in women compared to men (i.e., TLR7/type I Interferon activity).
30764790 Bisphosphonate-induced orbital inflammation in a patient on chronic immunosuppressive ther 2019 Feb 14 BACKGROUND: To report a case of orbital inflammation after bisphosphonate infusion in a patient who was already receiving immunosuppressive therapy. CASE PRESENTATION: A 56-year-old woman presented to the ophthalmology clinic with acute onset of right eye pain 24 h after receiving her first Zolendronic acid infusion. She has a past medical history of chronic inflammatory demyelinating polyneuropathy, Sjogren's syndrome, and systemic lupus erythematosus that have been controlled with immunosuppressive therapy for three years. Clinical ophthalmic exam and MRI studies were significant for right orbital inflammation. The patient was started on oral prednisone with rapid resolution of symptoms. CONCLUSIONS: This is the first case report of a patient receiving chronic immunosuppressive therapy to develop orbital inflammation after Zoledronic acid infusion. In addition, it demonstrates that corticosteroids can be an effective first line therapy in treating orbital inflammation in similar patients. Physicians should be aware of this rare but serious potential side effect of bisphosphonates, and have bisphosphonate-related orbital inflammation on their differential for proper initiation of treatment.
31660791 Type I interferon gene signature test-low and -high patients with systemic lupus erythemat 2019 Nov OBJECTIVES: Type I interferon (IFN) is implicated in systemic lupus erythematosus (SLE) pathogenesis. We aimed to identify type I IFN signaling-dependent and -independent molecular pathways in a large population of patients with SLE. METHODS: Baseline blood samples from adult patients with moderate to severe SLE from two Phase IIb studies (NCT01438489, n = 265; NCT01283139, n = 416) were profiled using whole transcriptome array analyses. Type I IFN gene signature (IFNGS) test status (high or low) was determined using a validated qualitative polymerase chain reaction-based test. IFN-type-specific signatures were developed by stimulating healthy blood with IFN-β, IFN-γ, IFN-λ, IFN-ω, or pooled IFN-α. These, and multiple literature-derived cell type and cytokine pathway signatures, were evaluated in individual and pooled study populations. A Fisher's exact test was used for associations, adjusted for false discovery rate. RESULTS: Whole blood samples from IFNGS test-high patients were enriched versus IFNGS test-low patients for CD40L signaling (Q < 0.001), CXC cytokine (Q < 0.001), TLR8-mediated monocyte activation (Q < 0.001), IgG (Q < 0.001), major histocompatibility complex class I (Q < 0.001), and plasma cell (Q < 0.001) gene expression signatures. IFNGS test-low patients had significant enrichment of eosinophil (Q < 0.001), IFN-γ-specific (Q = 0.005), and T-cell or B-cell (Q < 0.001) signatures. Similar enrichment profiles were demonstrated in patients with primary Sjögren's syndrome, systemic sclerosis, and dermatomyositis. CONCLUSIONS: IFNGS test-high patients overexpressed many gene signatures associated with SLE pathogenesis compared with IFNGS test-low patients, reflecting broad immune activation. These results provide new insights into the molecular heterogeneity underlying SLE pathogenesis, highlighting shared mechanisms beyond type I IFN, across several autoimmune diseases. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01438489 and NCT01283139.
30215233 Role of Salivary Immune Parameters in Patients With Primary Sjögren's Syndrome. 2019 Jan BACKGROUND: Several factors, including clinical manifestations and laboratory data, have been used to evaluate the disease activity of Sjögren's syndrome (SS). We investigated saliva indicators of disease activity in primary SS patients. METHODS: We enrolled 138 Taiwanese patients with primary SS and 100 Taiwanese normal controls. Interleukin (IL)-6, IL-17A, tumor necrosis factor-alpha (TNF-α), and rheumatoid factor (RF)-IgA levels in saliva samples were measured using ELISA or fluorescent enzyme-linked immunoassay. Serum IgG, IgA, and IgM levels were measured by nephelometry. Erythrocyte sedimentation rate (ESR) was measured with an automatic ESR analyzer. The t-test and Pearson correlation test were used. RESULTS: IL-6 level was higher in primary SS patients than in normal controls (14.23±14.77 vs 9.87±7.32, P=0.012), but there were no significant differences in IL-17A, TNF-α, and RF-IgA levels. In primary SS patients, IL-6 level correlated weakly with ESR and IgG levels (r=0.252, P=0.015, and r=0.248, P=0.017, respectively), and TNF-α level correlated weakly with IgG level (r=0.231, P=0.024). CONCLUSIONS: IL-6 may play a role in SS pathogenesis. Saliva IL-6 might be an indicator of disease activity in primary SS patients.
30835086 Persistence, Discontinuation, and Switching Patterns of Newly Initiated TNF Inhibitor Ther 2019 Jun INTRODUCTION: The primary goals of treating ankylosing spondylitis (AS) patients are to maximize long-term health-related quality of life through control of symptoms and inflammation, prevention of progressive structural damage, and preservation of function. The objective of this study was to describe treatment patterns (persistence, discontinuations, and switch) in the 2 years following the initiation of tumor necrosis factor inhibitors (TNFi) therapy in AS patients. METHODS: Adult patients with ≥ 2 AS diagnostic codes (ICD-9: 720.0 and/or ICD-10:M45.x) by a healthcare provider were included in this retrospective analysis of data from the IBM MarketScan Commercial Claims database. Patients who newly initiated a TNFi from 01/01/2009 to 12/31/2013 were indexed on their first TNFi. Patients were required to have a 1-year pre-index period free of TNFi and continuous enrollment 1-year pre-index and 2-year post-index. Patients were excluded if they had ≥ 2 diagnostic codes for any of the following conditions: rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, or uveitis. Demographic, clinical, and treatment patterns were analyzed. Treatment patterns included switching to a new TNFi, discontinuation (≥ 90-day gap in therapy without starting a new TNFi), or persistence (no gaps in therapy ≥ 90 days) during the 2-year follow-up period. Logistic regression analyses predicting persistent vs. non-persistent and switching vs. discontinuation were conducted. RESULTS: A total of 1372 AS patients (846 males/526 females) met the inclusion criteria for this study. Males had a mean age of 44.3 years, while females had a mean age of 42.3 years. Adalimumab was the first biologic for the majority of patients (44.6% males/43.3% females), followed by etanercept (40.4% males/41.6% females), infliximab (10.4% males/10.8% females), golimumab (4.6% males/3.8% females), and certolizumab pegol (0.0% males/0.4% females). During the follow-up period, 33.1% of patients (n = 454) were persistent on their index TNFi, 40.7% (n = 559) discontinued their index TNFi and did not restart a TNFi, and 26.1% (n = 359) switched to a second TNFi. Patients prescribed cDMARDs were more likely to be persistent, while females and opioid users were less likely to be persistent on their first TNFi. Among those that discontinued their first TNFi, 32.8% (n = 187) of males and 43.6% (n = 177) of females switched to a second TNFi. CONCLUSIONS: This study suggests that approximately 67% of male AS patients and 77% of female AS patients newly initiating a TNFi do not remain on the index therapy 2 year post initiation. FUNDING: Eli Lilly and Company.