Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
28958056 Genetic Risks for Chronic Conditions: Implications for Long-term Wellbeing. 2018 Mar 14 BACKGROUND: Relationships between genetic risks for chronic diseases and long-run wellbeing are largely unexplored. We examined the associations between genetic predispositions to several chronic conditions and long-term functional health and socioeconomic status (SES). METHODS: We used data on a nationally representative sample of 9,317 adults aged 65 years or older from the 1992 to 2012 Health and Retirement Survey (HRS) in the US. Survey data were linked to genetic data on nearly 2 million single-nucleotide polymorphisms (SNPs). We measured individual-level genetic predispositions for coronary-artery disease, type 2 diabetes (T2D), obesity, rheumatoid arthritis (RA), Alzheimer's disease, and major depressive disorder (MDD) by polygenic risk scores (PRS) derived from genome-wide association studies (GWAS). The outcomes were self-rated health, depressive symptoms, cognitive ability, activities of everyday life, educational attainment, and wealth. We employed regression analyses for the outcomes including all polygenic scores and adjusting for gender, birth period, and genetic ancestry. RESULTS: The polygenic scores had important associations with functional health and SES. An increase in genetic risk for all conditions except T2D was significantly (p < .01) associated with reduced functional health and socioeconomic outcomes. The magnitudes of functional health declines were meaningful and in many cases equivalent in magnitude to several years of aging. These associations were robust to several sensitivity checks for ancestry and adjustment for parental educational attainment and age at death or the last interview if alive. CONCLUSION: Stronger genetic predispositions for leading chronic conditions are related to worse long-run health and SES outcomes, likely reflecting the adverse effects of the onset of these conditions on one's wellbeing.
30417696 Periodontal sources of citrullinated antigens and TLR agonists related to RA. 2018 Sep Anti-citrullinated protein autoantibodies (ACPA) precede the onset of clinical and subclinical rheumatoid arthritis (RA). ACPA are frequently generated in further chronic inflammatory diseases, e.g. chronic obstructive pulmonary disease, lupus, periodontitis (PD), characterized by citrullination and mucosal as well as systemic autoimmunity against citrullinated proteins. PD is of particular interest, as it exhibits two sources of citrullination, namely peptidylarginine deiminase 4 (PAD4) of periodontal neutrophils and neutrophil extracellular traps (NETs) as well as the PAD of Porphyromonas gingivalis (PPAD). Whereas the PAD4-citrullinated host peptides and/or proteins occur physiologically, PPAD-citrullinated ones appear under pathological conditions as neo-antigens. Frequently, the oral pathogens P. gingivalis and A. actinomycetemcomitans directly and indirectly participate in synovitis in RA, providing topical citrullination: P. gingivalis via PPAD and A. actinomycetemcomitans via leukotoxin A-mediated ROS-independent NET formation. In addition, transient bacteraemia due to tooth brushing indicates the possibility that citrullinated peptides and/or proteins from periodontium regularly enter the blood circulation. In this way, the mucosal firewall is evaded and the systemic immune response against citrullinated peptides and/or proteins is facilitated. However, the role of swallowed PD-derived sludge for the induction of oral tolerance remains to be established. We hypothesize (I) PD-driven endotoxemia may increase the host responsiveness to autoantigens via TLR4 activation and (II) this participates in development and propagation of RA (III) circulating PD-derived bacterial DNA is taken up by phagocytes, activates TLR9, and thus increases the responsiveness to autoantigens.
29316383 Effectiveness of a Web-Based Personalized Rheumatoid Arthritis Risk Tool With or Without a 2018 Oct OBJECTIVE: To assess knowledge of rheumatoid arthritis (RA) risk factors among unaffected first-degree relatives (FDRs) and to study whether a personalized RA education tool increases risk factor knowledge. METHODS: We performed a randomized controlled trial assessing RA educational interventions among 238 FDRs. The web-based Personalized Risk Estimator for RA (PRE-RA) tool displayed personalized RA risk results (genetics, autoantibodies, demographics, and behaviors) and educated about risk factors. Subjects were randomly assigned to a Comparison arm (standard RA education; n = 80), a PRE-RA arm (PRE-RA alone; n = 78), or a PRE-RA Plus arm (PRE-RA and a one-on-one session with a trained health educator; n = 80). The RA Knowledge Score (RAKS), the number of 8 established RA risk factors identified as related to RA, was calculated at baseline and post-education (immediate/6 weeks/6 months/12 months). We compared RAKS and its components at each post-education point by randomization arm. RESULTS: At baseline before education, few FDRs identified behavioral RA risk factors (15.6% for dental health, 31.9% for smoking, 47.5% for overweight/obesity, and 54.2% for diet). After education, RAKS increased in all arms, higher in PRE-RA and PRE-RA Plus than Comparison at all post-education points (P < 0.05). PRE-RA subjects were more likely to identify risk factors than those who received standard education (proportion agreeing that smoking is a risk factor at 6 weeks: 83.1% in the PRE-RA Plus arm, 71.8% in the PRE-RA arm, and 43.1% in the Comparison arm; P < 0.05 for PRE-RA versus Comparison). CONCLUSION: Despite being both familiar with RA and at increased risk, FDRs had low knowledge about RA risk factors. A web-based personalized RA education tool successfully increased RA risk factor knowledge.
29425105 IL8 and IL16 levels indicate serum and plasma quality. 2018 Jun 27 BACKGROUND: Longer pre-centrifugation times alter the quality of serum and plasma samples. Markers for such delays in sample processing and hence for the sample quality, have been identified. METHODS: Twenty cytokines in serum, EDTA plasma and citrate plasma samples were screened for changes in concentration induced by extended blood pre-centrifugation delays at room temperature. The two cytokines that showed the largest changes were further validated for their "diagnostic performance" in identifying serum or plasma samples with extended pre-centrifugation times. RESULTS: In this study, using R&D Systems ELISA kits, EDTA plasma samples and serum samples with a pre-centrifugation delay longer than 24 h had an IL16 concentration higher than 313 pg/mL, and an IL8 concentration higher than 125 pg/mL, respectively. EDTA plasma samples with a pre-centrifugation delay longer than 48 h had an IL16 concentration higher than 897 pg/mL, citrate plasma samples had an IL8 concentration higher than 21.5 pg/mL and serum samples had an IL8 concentration higher than 528 pg/mL. CONCLUSIONS: These robust and accurate tools, based on simple and commercially available ELISA assays can greatly facilitate qualification of serum and plasma legacy collections with undocumented pre-analytics.
28681650 Safety, pharmacokinetics, and efficacy of E6011, an antifractalkine monoclonal antibody, i 2018 Jan OBJECTIVE: Fractalkine (CX3CL1/FKN) is a chemokine that regulates chemotaxis and adhesion of CX3C chemokine receptor 1 (CX3CR1)-expressing inflammatory cells. We conducted the first phase 1/2, open-label, multiple ascending dose study of E6011, a humanized anti-FKN monoclonal antibody, in Japanese rheumatoid arthritis (RA) patients (clinicaltrial.gov identifier: NCT02196558). METHODS: Active RA patients with an inadequate response or intolerance to methotrexate or tumor necrosis factor (TNF) inhibitor received E6011 at week 0, 1, 2, and thereafter every 2 weeks for 12 weeks. RESULTS: Twelve, 15, and 10 subjects were enrolled in the 100, 200, and 400 mg cohorts, respectively. No severe adverse events (AEs) or deaths occurred, and no major differences were observed in the incidence or severity of AEs across the cohorts. Serum E6011 concentrations increased dose dependently. American College of Rheumatology (ACR) 20, 50, and 70 responses at week 12 were 75.0%, 33.3%, and 8.3% in the 100 mg cohort; 66.7%, 20.0%, and 13.3% in the 200 mg cohort; and 60.0%, 30.0%, and 20.0% in the 400 mg cohort, respectively. CONCLUSIONS: E6011 appeared to be safe and well tolerated in RA patients during this 12-week treatment period, suggesting that E6011 has an effective clinical response in active RA patients.
30613275 Delivery of miR-146a to Ly6C(high) Monocytes Inhibits Pathogenic Bone Erosion in Inflammat 2018 Rationale: Monocytes play critical roles in the pathogenesis of arthritis by contributing to the inflammatory response and bone erosion. Among genes involved in regulating monocyte functions, miR-146a negatively regulates the inflammatory response and osteoclast differentiation of monocytes. It is also the only miRNA reported to differentially regulate the cytokine response of the two classical Ly6C(high) and non-classical Ly6C(low) monocyte subsets upon bacterial challenge. Although miR-146a is overexpressed in many tissues of arthritic patients, its specific role in monocyte subsets under arthritic conditions remains to be explored. Methods: We analyzed the monocyte subsets during collagen-induced arthritis (CIA) development by flow cytometry. We quantified the expression of miR-146a in classical and non-classical monocytes sorted from healthy and CIA mice, as well as patients with rheumatoid arthritis (RA). We monitored arthritis features in miR-146a(-/-) mice and assessed in vivo the therapeutic potential of miR-146a mimics delivery to Ly6C(high) monocytes. We performed transcriptomic and pathway enrichment analyses on both monocyte subsets sorted from wild type and miR-146a(-/-) mice. Results: We showed that the expression of miR-146a is reduced in the Ly6C(high) subset of CIA mice and in the analogous monocyte subset (CD14(+)CD16(-)) in humans with RA as compared with healthy controls. The ablation of miR-146a in mice worsened arthritis severity, increased osteoclast differentiation in vitro and bone erosion in vivo. In vivo delivery of miR-146a to Ly6C(high) monocytes, and not to Ly6C(low) monocytes, rescues bone erosion in miR-146a(-/-) arthritic mice and reduces osteoclast differentiation and pathogenic bone erosion in CIA joints of miR-146a(+/+) mice, with no effect on inflammation. Silencing of the non-canonical NF-κB family member RelB in miR-146a(-/-) Ly6C(high) monocytes uncovers a role for miR-146a as a key regulator of the differentiation of Ly6C(high), and not Ly6C(low), monocytes into osteoclasts under arthritic conditions. Conclusion: Our results show that classical monocytes play a critical role in arthritis bone erosion. They demonstrate the theranostics potential of manipulating miR-146a expression in Ly6C(high) monocytes to prevent joint destruction while sparing inflammation in arthritis.
29600626 [Effects of Jinwu Jiangu recipe on IL-17/STAT3 signals in rheumatoid arthritis synoviocyte 2018 Feb This paper aimed to investigate the effects of Jinwu Jiangu recipe total extract on the IL-17/STAT3 signals in rheumatoid arthritis synovial fibroblasts(RASF). The primary RASFs were cultured by tissue piece method in vitro， and divided into blank control group， Jinwu Jiangu recipe low dose group， Jinwu Jiangu recipe middle dose group， Jinwu Jiangu recipe high dose group， and tripterygium glycosides control group. They were then treated with corresponding serum free medium， different doses of Jinwu Jiangu recipe total extract(0.06， 0.6， 6.0 g·L⁻¹)， and tripterygium glycosides(0.03 g·L⁻¹) respectively for 24 hours. The gene expression levels of RORα， RORγt， and STAT3 mRNA were detected by polymerase chain reaction(PCR)， and the protein activity of IL-17R and pSTAT3 were measured by Western blot assay. The results showed that as compared with blank control group， the expression levels of RORα， RORγt， IL-17R and STAT3 mRNA in RASF were significantly declined(P<0.01). As compared with tripterygium glycosides control group， Jinwu Jiangu recipe total extract middle dose group and high dose group can down-regulate the expression levels of RORα， RORγt， IL-17R and STAT3 mRNA(P<0.05)， and the effect was more obvious in high dose group(P<0.01). As compared with blank control group， the protein expression levels of IL-17R and pSTAT3 in each treatment group were obviously decreased(P<0.01). As compared with tripterygium glycosides control group， Jinwu Jiangu recipe high dose group had more obvious effect in down-regulating the protein expression of pSTAT3(P<0.01). Therefore， Miao medicine Jinwu Jiangu recipe total extract can down-regulate the expressions of RORα， RORγt， and STAT3 mRNA， and inhibit the protein activity of IL-17R and pSTAT3 in RASF.
29266879 Differences in Safety of Nonsteroidal Antiinflammatory Drugs in Patients With Osteoarthrit 2018 Apr OBJECTIVE: To determine the relative risks of cardiovascular (CV), gastrointestinal (GI), and renal adverse events during long-term treatment with celecoxib, compared with ibuprofen and naproxen, in patients with osteoarthritis (OA) and patients with rheumatoid arthritis (RA). METHODS: A total of 24,081 patients with OA or RA who had a moderate or high risk for CV disease were enrolled internationally into a double-blind randomized controlled trial. Interventions included celecoxib at a dosage of 100-200 mg twice daily, ibuprofen at a dosage of 600-800 mg 3 times daily, or naproxen at a dosage of 375-500 mg twice daily. The main outcomes were the first occurrence of a major adverse CV event, GI event, or renal event, and mortality. RESULTS: In the subgroup of patients with OA, the risk of a major adverse CV event was significantly reduced when celecoxib was compared with ibuprofen (hazard ratio [HR] 0.84, 95% confidence interval [95% CI] 0.72-0.99), but no significant difference was observed when celecoxib was compared with naproxen. In the RA subgroup, comparisons of celecoxib versus ibuprofen and celecoxib versus naproxen for the risk of major adverse CV events revealed HRs of 1.06 (95% CI 0.69-1.63) and 1.22 (95% CI 0.78-1.92), respectively. In the OA subgroup, comparisons of celecoxib versus ibuprofen for the risk of GI events showed an HR of 0.68 (95% CI 0.51-0.91), and a comparison of celecoxib versus naproxen showed an HR of 0.73 (95% CI 0.55-0.98). Duplicate comparisons in patients with RA revealed HRs of 0.48 (95% CI 0.22-1.07) and 0.54 (95% CI 0.24-1.24), respectively. In patients with OA, a comparison of celecoxib versus ibuprofen for the risk of renal events showed an HR of 0.58 (95% CI 0.40-0.82). In patients with RA, celecoxib treatment was associated with significantly lower mortality compared with naproxen treatment (HR 0.47, 95% CI 0.25-0.88). CONCLUSION: Treatment with celecoxib at approved dosages conferred a similar or lower risk of CV, GI, and renal adverse events compared with treatment with ibuprofen or naproxen in patients with OA and patients with RA.
29367090 Inhibition of NF-κB pathway in fibroblast-like synoviocytes by α-mangostin implicated in 2018 Mar α-Mangostin (MG) is a bioactive compound isolated from mangosteen. This study was aimed to investigate effects of MG on adjuvant-induced arthritis (AA) in rats and decipher the underlying mechanisms. Clinical severity of AA was evaluated by paw oedema, arthritis score, and hematological parameters. Digital radiography (DR) and histological examinations were employed to assess joints destructions. Immune functions were evaluated by T cell subsets distribution. Effects on NF-κB pathway were investigated by immunohistochemical, western-blot and immunofluorescence methods both in vivo and vitro. It was found MG possessed superior anti-inflammatory effects in vivo, suggested by attenuated paw swelling, reduced inflammatory cells infiltration and decreased the secretion of TNF-α and IL-1β in serum. Meanwhile MG inhibited fibrous hyperplasia, synovial angiogenesis, cartilage and bone degradation in AA rats. Although MG exerted little effects on CD4(+) population, it greatly decreased IFN-γ positive cells and promoted expression of FOXP3 in immune organs, indicating restoration of Th1/Treg cells ratio and recovery of immune homeostasis in vivo. Inhibition of NF-κB induced by MG was indicated by reduced the expression of p-p65 and VEGF in synovium. In vitro experiments found MG at 10 μg/ml significantly suppressed the expression and phosphorylation of key proteins implicated in NF-κB pathway and inhibited nucleus translocation of p65. These changes led to increased apoptosis and proliferation inhibition of HFLS-RA cells. The results demonstrated regulation of immune functions was deeply involved in the therapeutic actions of MG on AA, and it's inhibition on NF-κB in fibroblast-like synoviocytes was associated to the protective effects on joints.
29803913 Combination of 4-hydroperoxy cyclophosphamide and methotrexate inhibits IL-6/sIL-6R-induce 2018 Aug Although conventional combination therapy is effective for most patients with rheumatoid arthritis (RA), many still do not respond to current therapies. Therefore, novel combination regimens that better target cellular processes involved in RA pathogenesis are required. Preliminary studies have demonstrated the beneficial effects of a combination of cyclophosphamide (CTX) and methotrexate (MTX) in models of RA. Using western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assays, and immunofluorescent staining, we demonstrated that the combination of 4-hydroperoxy CTX (4-H-CTX) and MTX inhibited the expression of receptor activator of nuclear factor-κB ligand (RANKL) in fibroblast-like synoviocytes (FLS) treated with the interleukin (IL)-6/soluble IL-6 receptor (sIL-6R) complex. To elucidate the mechanisms underlying this effect, we treated RA-FLS with the JAK2/STAT3 inhibitor AG490 or p38MAPK inhibitor SB203580. The results showed that IL-6/sIL-6R-induced RANKL upregulation required phosphorylation-mediated activation of STAT3 and p38 signaling, and that 4-H-CTX and/or MTX inhibited RANKL expression in IL-6/sIL-6R-stimulated FLS by suppressing JAK2/STAT3 and p38MAPK signaling. This study demonstrated for the first time the inhibitory effects of 4-H-CTX and MTX on RANKL expression in IL-6/sIL-6R-stimulated FLS via suppression of STAT3 and p38MAPK phosphorylation. These results identify promising therapeutic agents that might have clinical applications in patients with RA who are at high risk of bone erosion or do not respond well to conventional therapy.
29093151 Effect of Anticitrullinated Protein Antibody Status on Response to Abatacept or Antitumor 2018 Jan OBJECTIVE: Assess whether baseline anticyclic citrullinated peptide antibodies (anti-CCP) status is associated with treatment response in patients with rheumatoid arthritis (RA) initiating abatacept (ABA) or a tumor necrosis factor-α inhibitor (TNFi). METHODS: Using the Corrona RA registry, patients were identified who initiated ABA or a TNFi (June 2004-January 2015), had a followup visit 6 months (± 3 mos) after initiation, and anti-CCP measured at or prior to initiation. Primary outcome was mean change in Clinical Disease Activity Index (CDAI) from initiation to 6 months. Treatment response was evaluated based on a typical patient profile (female, aged 57 yrs, body mass index of 30 kg/m(2), baseline CDAI of 20, 1 prior biologic, and no comorbidities other than RA). Secondary outcomes included remission and low disease activity. RESULTS: There were 566 ABA initiators [anti-CCP+ (≥ 20 units/ml): n = 362; anti-CCP- (< 20 units/ml): n = 204] and 1715 TNFi initiators (anti-CCP+: n = 1113; anti-CCP-: n = 602). Differences between treatment groups included baseline disease duration, CDAI, and prior biologic use. At 6 months, anti-CCP+ ABA initiators were associated with significantly greater CDAI response versus anti-CCP- ABA initiators; no significant difference was observed for TNFi initiators. When considering a typical RA patient profile, CDAI response was greater in anti-CCP+ versus anti-CCP- ABA initiators; anti-CCP+ versus anti-CCP- TNFi initiators were similar. Secondary outcome responses were also greater in anti-CCP+ versus anti-CCP- ABA initiators; TNFi initiators did not differ by anti-CCP status. CONCLUSION: In a US-based clinical practice setting, anti-CCP status was associated with a differential treatment response to ABA, but not TNFi.
29083085 CDK7 inhibition suppresses rheumatoid arthritis inflammation via blockage of NF-κB activa 2018 Feb Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint swelling, joint tenderness and destruction of synovial joints, leading to severe disability. Anti-inflammatory drugs and disease-modifying anti-rheumatic drugs (DMARDs) may improve RA process. However, in most patients the treatment effect is still not satisfactory. Cyclin-dependent kinase 7 (CDK7) plays a well-established role in the regulation of the eukaryotic cell division cycle, and recent studies indicated that it exerted anti-inflammatory effect. In our previous research, we found that inhibition of CDK7 by highly selective inhibitor BS-181 significantly impeded the development of collagen-induced arthritis (CIA) mice. However, the underlying mechanism of CDK7 in RA remains to be explored. We elucidated the molecular mechanism of CDK7 inhibition in RA inflammation by administration of CDK7 highly selective inhibitor BS-181 and siRNA-CDK7. We found that both IL-1β, IL-6, IL-8 and RANKL transcript levels and IL-1β/IL-6 secretion were effectively suppressed by BS-181 treatment as well as CDK7 knockdown. Furthermore, CDK7 inhibition prevented NF-κB signalling pathway activation and restrained p65 nuclear translocation. Moreover, CDK7 selective inhibitor BS-181 also blocked phosphorylation of p65 in MH7A cells. These results strongly indicate that CDK7 inhibition by BS-181 and siRNA-CDK7 significantly suppresses rheumatoid arthritis inflammation, which may be via blockage of NF-κB signalling pathway and IL-1β/IL-6 secretion.
29269163 Non-traditional risk factors for atherosclerotic disease: A review for emergency physician 2018 Mar INTRODUCTION: Acute coronary syndrome (ACS) is a life-threatening disease frequently managed in the Emergency Department (ED). Risk factors such as age, hypertension, diabetes mellitus, obesity, and smoking are classically associated with atherosclerosis and ACS. OBJECTIVE: This review evaluates non-traditional risk factors for atherosclerotic disease and seeks to inform physicians of their potential danger, particularly in vulnerable patient populations. DISCUSSION: Traditional risk factors are commonly utilized in the evaluation of patients with concern for ACS and acute myocardial infarction (AMI), though these may not be as useful for individual patient assessment. Heart disease accounts for a significant number of deaths in the U.S. Awareness of disease presentation and risk factors is important; however, several non-traditional risk factors are associated with atherosclerosis. Vasculitides, as well as immunologic medications used to treat these patients, increase atherosclerosis. Specific types of cancer and some therapies used to treat cancer are associated with atherosclerosis development and cardiovascular disease (CVD). Heavy alcohol use increases atherosclerosis and risk of AMI. Pregnancy also increases risk of AMI. Patients with HIV develop atherosclerosis at higher rates, and antiretroviral therapy predisposes patients to early development of coronary disease. Infections such as pneumonia and sepsis, associated with elevated inflammation, increase rate of ACS events during illness and throughout the one-year period after diagnosis of infection. CONCLUSIONS: Several non-traditional factors are associated with increased risk of atherosclerosis and ACS. Knowledge of these risk factors is important in the ED to minimize the potential of missing ACS.
30471243 Detection of anti-adalimumab antibodies in a RA responsive cohort of patients using three 2019 Feb 1 Reliable monitoring of clinical relevant anti-drug antibodies is fundamental in the follow-up of patients under adalimumab treatment. The aim of this study is to compare anti-adalimumab antibodies by using three methods based on different technologies. A cross-sectional study was performed in 50 patients with rheumatoid arthritis (RA) treated with adalimumab. Anti-adalimumab antibodies were detected in patients' sera by different techniques: bridging ELISA, reporter gene assay (RGA), and surface plasmon resonance (SPR). Results showed that all methods recognized anti-adalimumab antibodies and the percentage of positives fluctuated among the assays. Five (10%) of the 50 patients were positive in ELISA, 4 (8%) in RGA, and 6 (12%) in SPR. Among positive patients, 4 were positive in the three assays, one patient uniquely in ELISA, and two in SPR. Spearman correlation between ELISA and RGA showed good agreement (Spearman r = 0.800). No correlation between RGA and SPR was observed (Spearman r = 0.108). Similar results were obtained between ELISA and SPR (Spearman r = - 0.241). Summarizing, ELISA, RGA and SPR recognized anti-adalimumab antibodies in few RA patients, showing good agreement among the methodology employed. On the other hand, differences observed between SPR and ELISA or RGA highlight the relevance of the employed technologies in anti-drug antibody identification.
30573655 Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic disea 2019 Mar OBJECTIVE: Immune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies. METHODS: We meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases. RESULTS: Our analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study. CONCLUSIONS: We have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.
29928274 Sialylated Autoantigen-Reactive IgG Antibodies Attenuate Disease Development in Autoimmune 2018 Pro- and anti-inflammatory effector functions of IgG antibodies (Abs) depend on their subclass and Fc glycosylation pattern. Accumulation of non-galactosylated (agalactosylated; G0) IgG Abs in the serum of rheumatoid arthritis and systemic lupus erythematosus (SLE) patients reflects severity of the diseases. In contrast, sialylated IgG Abs are responsible for anti-inflammatory effects of the intravenous immunoglobulin (pooled human serum IgG from healthy donors), administered in high doses (2 g/kg) to treat autoimmune patients. However, whether low amounts of sialylated autoantigen-reactive IgG Abs can also inhibit autoimmune diseases is hardly investigated. Here, we explore whether sialylated autoantigen-reactive IgG Abs can inhibit autoimmune pathology in different mouse models. We found that sialylated IgG auto-Abs fail to induce inflammation and lupus nephritis in a B cell receptor (BCR) transgenic lupus model, but instead are associated with lower frequencies of pathogenic Th1, Th17 and B cell responses. In accordance, the transfer of small amounts of immune complexes containing sialylated IgG Abs was sufficient to attenuate the development of nephritis. We further showed that administration of sialylated collagen type II (Col II)-specific IgG Abs attenuated the disease symptoms in a model of Col II-induced arthritis and reduced pathogenic Th17 cell and autoantigen-specific IgG Ab responses. We conclude that sialylated autoantigen-specific IgG Abs may represent a promising tool for treating pathogenic T and B cell immune responses in autoimmune diseases.
28082032 Recommendations for the use of parenteral methotrexate in rheumatic diseases. 2018 May OBJECTIVE: To develop recommendations for the use of parenteral methotrexate (MTX) in rheumatic diseases, mainly rheumatoid arthritis, based on best evidence and experience. METHODS: A group of 21 experts on parenteral MTX use was selected. The coordinator formulated 13 questions about parenteral MTX (indications, efficacy, safety and cost-effectiveness). A systematic review was conducted to answer the questions. Using this information, inclusion and exclusion criteria were established, as were the search strategies (involving Medline, EMBASE and the Cochrane Library). Three different reviewers selected the articles. Evidence tables were created. Abstracts from the European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) were evaluated. Based on this evidence, the coordinator proposed preliminary recommendations that the experts discussed and voted in a nominal group meeting. The level of evidence and grade of recommendation were established using the Oxford Center for Evidence-Based Medicine and the level of agreement with the Delphi technique (2 rounds). Agreement was established if at least 80% of the experts voted yes (yes/no). RESULTS: Most of the evidence involved rheumatoid arthritis. A total of 13 preliminary recommendations on the use of parenteral MTX were proposed; 11 of them were accepted. Two of the 13 were not voted and are commented on in the main text. CONCLUSIONS: The manuscript aims to solve frequent questions and help in decision-making strategies when treating patients with parenteral MTX.
28941039 A Randomized Phase IIb Study of Mavrilimumab and Golimumab in Rheumatoid Arthritis. 2018 Jan OBJECTIVE: This 24-week, phase IIb, double-blind study was undertaken to evaluate the efficacy and safety of mavrilimumab (a monoclonal antibody to granulocyte-macrophage colony-stimulating factor receptor α) and golimumab (a monoclonal antibody to tumor necrosis factor [anti-TNF]) in patients with rheumatoid arthritis (RA) who have had an inadequate response to disease-modifying antirheumatic drugs (DMARDs) (referred to as DMARD-IR) and/or inadequate response to other anti-TNF agents (referred to as anti-TNF-IR). METHODS: Patients with active RA and a history of DMARD-IR (≥1 failed regimen) or DMARD-IR (≥1 failed regimen) and anti-TNF-IR (1-2 failed regimens) were randomized 1:1 to receive either mavrilimumab 100 mg subcutaneously every other week or golimumab 50 mg subcutaneously every 4 weeks alternating with placebo every 4 weeks, administered concomitantly with methotrexate. The primary end points were the American College of Rheumatology 20% improvement (ACR20), 50% improvement, and 70% improvement response rates at week 24, percentage of patients achieving a Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) of <2.6 at week 24, percentage of patients with a score improvement of >0.22 on the Health Assessment Questionnaire (HAQ) disability index (DI) at week 24, and safety/tolerability measures. This study was not powered to formally compare the 2 treatments. RESULTS: At week 24, differences in the ACR20, ACR50, and ACR70 response rates between the mavrilimumab treatment group (n = 70) and golimumab treatment group (n = 68) were as follows: in all patients, -3.5% (90% confidence interval [90% CI] -16.8, 9.8), -8.6% (90% CI -22.0, 4.8), and -9.8% (90% CI -21.1, 1.4), respectively; in the anti-TNF-IR group, 11.1% (90% CI -7.8, 29.9), -8.7% (90% CI -28.1, 10.7), and -0.7% (90% CI -18.0, 16.7), respectively. Differences in the percentage of patients achieving a DAS28-CRP of <2.6 at week 24 between the mavrilimumab and golimumab groups were -11.6% (90% CI -23.2, 0.0) in all patients, and -4.0% (90% CI -20.9, 12.9) in the anti-TNF-IR group. The percentage of patients achieving a >0.22 improvement in the HAQ DI score at week 24 was similar between the treatment groups. Treatment-emergent adverse events were reported in 51.4% of mavrilimumab-treated patients and 42.6% of golimumab-treated patients. No deaths were reported, and no specific safety signals were identified. CONCLUSION: The findings of this study demonstrate the clinical efficacy of both treatments, mavrilimumab at a dosage of 100 mg every other week and golimumab at a dosage of 50 mg every 4 weeks, in patients with RA. Both regimens were well-tolerated in patients who had shown an inadequate response to DMARDs and/or other anti-TNF agents.
30401463 [Life-threatening hypercalcemia and acute kidney injury induced by etanercept]. 2018 Nov Drug-induced sarcoidosis-like disease is a rare, but not exceptional, side effect of anti-tumor necrosis factor (anti-TNF) agents. The organs most commonly involved are lungs, skin and lymph nodes. Kidney involvement is exceptional. Histology usually reveals non-caseating granulomas. Some of the biological features usually described in sarcoidosis are very infrequent in drug-induced granulomatosis. We report a case of sarcoid-like granulomatosis manifesting as life-threatening hypercalcemia and acute kidney injury in a woman treated with etanercept for a rheumatoid arthritis. Seven days after admission, she developed hypoxemic interstitial pneumonia with negative mycobacterial and fungal analysis. This picture suggested sarcoid-like disease induced by tumor necrosis factor blockers and prompted etanercept cessation. Kidney biopsy performed 30 days after admission revealed significant acute interstitial nephritis and intratubular calcium crystals. Staining for acid-fast bacilli and fungi was negative. Clinical picture improved gradually after etanercept withdrawal and cortisone treatment. Three weeks after admission, serum creatinine and calcium levels were normal. Clinical presentation of sarcoidosis-like disease induced by anti-tumor necrosis factor agents may be extremely variable. Our observation shows that severe, life-threatening hypercalcemia may occur. Renal involvement is very unusual. This case highlights this diagnostic difficulty and the importance of a close clinical monitoring in patients treated with these drugs. Cessation of the anti-tumor necrosis factor agent leads to resolution of this condition in most cases.
28654766 Methotrexate-Related Lymphoproliferative Disorder in Patients With Osteonecrosis of the Ja 2018 Jan Patients with immunodeficiency or immunosuppression are at risk of developing a lymphoproliferative disorder (LPD). Methotrexate (MTX) is an iatrogenic cause of LPD, which in up to 50% cases occurs in extranodal sites. The occurrence of MTX-related LPD with osteonecrosis of the jaw (ONJ) has rarely been reported. Moreover, there are no clear diagnostic criteria and treatment strategies for management of these lesions. In the present cases, discontinuing MTX and debridement of the necrotic bone were effective. This report describes 3 cases of MTX-related LPD in patients with longstanding rheumatoid arthritis (RA) who presented with ONJ. The first patient was a 74-year-old man with RA who had received treatment with MTX for 7 years before presenting with ONJ and submental lymphadenopathy. The second patient was a 79-year-old woman who had been treated for 21 years with MTX and who presented with ONJ. The third patient was a 67-year-old man who had been treated with MTX for more than 15 years. In all 3 cases, biopsy, histology, and immunohistochemistry using a panel of lymphoid markers (Epstein-Barr virus [EBV], CD79a, CD20, PAX-5, CD3, and CD30) resulted in the diagnosis of EBV-driven T-cell, B-cell, and Hodgkin-like LPD. All 3 patients recovered after cessation of MTX and surgical debridement. Biopsy examination, diagnostic immunohistochemistry using lymphoid immune markers, and imaging studies using computed tomography, magnetic resonance imaging, and positron-emission tomographic computed tomography were useful for the correct diagnosis of this condition.