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Objectives: To evaluate relapses in giant cell arteritis (GCA), investigate the utility of vascular ultrasound to detect relapses, and develop and assess a composite score for GCA disease activity (GCAS) based on clinical symptoms, ultrasound imaging activity, and C-reactive protein (CRP). Methods: Patients with GCA were prospectively followed with scheduled visits, including assessment for clinical relapse, protocol ultrasound examination, and CRP. At each visit, patients were defined as having ultrasound remission or relapse. GCAS was calculated at every visit. Results: The study included 132 patients, with a median follow-up time of 25 months [interquartile range (IR) 21]. The clinical relapse rate was 60.6%. There were no differences in relapse rates between GCA subtypes (cranial-GCA, large vessel (LV)-GCA, and mixed-GCA) (p = 0.83). Ultrasound yielded a sensitivity of 61.2% and a specificity of 72.3% for diagnosing GCA- relapse in our cohort. In 7.7% of follow-up visits with clinical relapses, neither high CRP nor findings of ultrasound relapse were registered. In comparison, in 10.3% of follow-up visits without symptoms of clinical relapse, there were both a high CRP and findings of ultrasound relapse. Conclusion: We found moderate sensitivity and specificity for ultrasound as a monitoring tool for relapse in this prospective cohort of GCA patients. The extent or subtype of vasculitis at the diagnosis did not influence the number of relapses. Based on a combination of clinical symptoms, elevated CRP, and ultrasound findings, a composite score for GCA activity is proposed.
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OBJECTIVES: To compare the sensitivity of 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) classification criteria against 1997 ACR criteria for systemic lupus erythematosus (SLE), for incident SLE cases in the presumably complete population-based Nor-SLE cohort from Southeast Norway (2.9 million inhabitants). METHODS: All cases International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) coded as SLE during 2000-2017 were individually reviewed. Those with a confirmed SLE diagnosis by expert clinical assessment were included in the Nor-SLE cohort. Core clinical data were recorded, and the cases were classified according to 2019 EULAR/ACR and 1997 ACR criteria. Juvenile SLE was defined as <16 years at diagnosis and adult SLE was defined as ≥16 years at diagnosis. RESULTS: We included 737 incident SLE cases (701 adults, 36 juveniles). At diagnosis, 2019 EULAR/ACR criteria were more sensitive than 1997 ACR criteria for adults (91.6% vs 77.3%; p<0.001), but not for juveniles (97.2% vs 88.9%). The 2019 EULAR/ACR counts at diagnosis differed by age group and ethnicity, being higher in young cases and those originating from Asia. From time of diagnosis to study end the fulfilment rate of 2019 EULAR/ACR criteria for the adult cohort increased from 92.5% and 86.5% to 94.6% and 91.0%, respectively, for females and males (mean disease duration of 7.5 years). CONCLUSION: Showing 92% criteria fulfilment already at time of SLE diagnosis by 2019 EULAR/ACR criteria versus 77% by 1997 ACR criteria, the results from this population-based study suggest that the 2019 EULAR/ACR criteria will achieve its goal of capturing more early-SLE cases for clinical trials.
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Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/epidemiologia , Noruega/epidemiologia , Masculino , Feminino , Adulto , Adolescente , Incidência , Pessoa de Meia-Idade , Adulto Jovem , Estudos de Coortes , Criança , Classificação Internacional de Doenças , Vigilância da População , Sensibilidade e EspecificidadeRESUMO
Genome-wide association studies (GWASs) have been successful at finding associations between genetic variants and human traits, including the immune-mediated diseases (IMDs). However, the requirement of large sample sizes for discovery poses a challenge for learning about less common diseases, where increasing volunteer numbers might not be feasible. An example of this is myositis (or idiopathic inflammatory myopathies [IIM]s), a group of rare, heterogeneous autoimmune diseases affecting skeletal muscle and other organs, severely impairing life quality. Here, we applied a feature engineering method to borrow information from larger IMD GWASs to find new genetic associations with IIM and its subgroups. Combining this approach with two clustering methods, we found 17 IMDs genetically close to IIM, including some common comorbid conditions, such as systemic sclerosis and Sjögren's syndrome, as well as hypo- and hyperthyroidism. All IIM subtypes were genetically similar within this framework. Next, we colocalized IIM signals that overlapped IMD signals, and found seven potentially novel myositis associations mapped to immune-related genes, including BLK, IRF5/TNPO3, and ITK/HAVCR2, implicating a role for both B and T cells in IIM. This work proposes a new paradigm of genetic discovery in rarer diseases by leveraging information from more common IMD, and can be expanded to other conditions and traits beyond IMD.
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BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.
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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Arterite de Células Gigantes , Arterite de Células Gigantes/genética , Arterite de Células Gigantes/patologia , Humanos , Loci Gênicos/genética , Feminino , Masculino , Idoso , Polimorfismo de Nucleotídeo Único , Pessoa de Meia-Idade , Estudos de Casos e ControlesRESUMO
OBJECTIVE: The goal of this study was to provide complete, robust data on annual systemic lupus erythematosus (SLE) incidence rates over nearly two decades from the Southeast Norway area (2.9 million inhabitants) and assess accuracy of SLE-specific International Classification of Diseases (ICD) codes for SLE diagnosis. METHODS: From administrative databases, we identified all cases International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) coded as SLE during 1999 through 2017 in Southeast Norway. We manually reviewed the chart of every case ICD-10 coded as SLE to either confirm or reject SLE diagnosis. Using SLE classification criteria, we classified all cases with confirmed SLE. We estimated annual incidence rates of classified SLE, and subsets, defined by age at diagnosis, sex, and parental country of birth. The chi-square test was applied for linear time-trend analyses of incidence. RESULTS: Among the 3,488 cases ICD-10 coded as SLE, chart reviews confirmed SLE diagnosis in 1,558 (45%), of which 797 had new-onset disease during 1999 through 2017. Annual SLE incidence rates fell during 1999 to 2017. The fall was most pronounced in female persons 50 to 59 years old at diagnosis, in whom incidence fell from 3.4 to 1.1 per 100,000 persons (P trend < 0.001). Concurrent ecological data from the study area showed a 74% reduction in prescriptions of menopausal hormone treatment. Accuracy of ICD-10 codes for incident SLE diagnosis was acceptable in juveniles and young adults (up to 20 years) but otherwise low. CONCLUSION: In a presumably complete population-based cohort, we identified decreasing incidence of SLE, especially among female persons 50 to 59 years old. Although reasons for declining incidence are not clear, ecological data indicate a possible role of environmental factors, for example, menopausal hormone treatments.
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Classificação Internacional de Doenças , Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Noruega/epidemiologia , Incidência , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Adolescente , Idoso , Estudos de Coortes , CriançaRESUMO
OBJECTIVE: B cell function and autoantibodies are important in SLE pathogenesis. In this work, we aimed to investigate the impact of cumulative SLE B cell genetics on SLE subphenotype and autoantibody profile. METHODS: Female patients with SLE (n=1248) and healthy controls (n=400) were genotyped using Illumina's Global Screening Array. Two polygenic risk scores (PRSs), one representing B cell genes and the other B cell activation genes, were calculated for each individual using risk loci for SLE in genes assigned to B cell-related pathways according to the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Reactome Databases. RESULTS: Double-stranded DNA (dsDNA) antibodies were more prevalent among patients with a high compared with a low SLE B cell PRS (OR 1.47 (1.07 to 2.01), p=0.018), and effect sizes were augmented in patients with human leucocyte antigen (HLA) risk haplotypes HLA-DRB1*03:01 and HLA-DRB1*15:01 (DRB1*03/15 -/- (OR 0.99 (0.56 to 1.77), p=0.98; DRB1*03/15 +/- or -/+ (OR 1.64 (1.06 to 2.54), p=0.028; and DRB1*03/15 +/+ (OR 4.47 (1.21 to 16.47), p=0.024). Further, a high compared with a low B cell PRS was associated with low complement levels in DRB1*03/15 +/+ patients (OR 3.92 (1.22 to 12.64), p=0.022). The prevalence of lupus nephritis (LN) was higher in patients with a B cell activation PRS above the third quartile compared with patients below (OR 1.32 (1.00 to 1.74), p=0.048). CONCLUSIONS: High genetic burden related to B cell function is associated with dsDNA antibody development and LN. Assessing B cell PRSs may be important in order to determine immunological pathways influencing SLE and to predict clinical phenotype.
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Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Humanos , Feminino , Lúpus Eritematoso Sistêmico/complicações , Anticorpos Antinucleares , Nefrite Lúpica/diagnóstico , Autoanticorpos , DNA , Cadeias HLA-DRB1 , Fatores de RiscoRESUMO
BACKGROUND: We investigated sensitivity of the 2020 Revised Comprehensive Diagnostic Criteria (RCD) and the 2019 ACR/EULAR classification criteria across the four identified IgG4-related disease (IgG4-RD) phenotypes: "Pancreato-Hepato-Biliary", "Retroperitoneum and Aorta", "Head and Neck-limited" and "Mikulicz' and Systemic" in a well-characterized patient cohort. METHODS: We included adult patients diagnosed with IgG4-RD after comprehensive clinical assessment at Oslo University Hospital in Norway. We assigned patients to IgG4-RD phenotypes based on pattern of organ involvement and assessed fulfillment of RCD and 2019 ACR/EULAR classification criteria. Differences between phenotype groups were analyzed using one-way ANOVA for continuous variables, and contingency tables for categorical variables. RESULTS: The study cohort included 79 IgG4-RD patients assigned to the "Pancreato-Hepato-Biliary" (22.8%), Retroperitoneum and Aorta" (22.8%) "Head and Neck-limited" (29.1%), and "Mikulicz' and Systemic" (25.3%) phenotype groups, respectively. While 72/79 (91.1%) patients in total fulfilled the RCD, proportion differed across phenotype groups and was lowest in the "Retroperitoneum and Aorta" group (66.7%, p < 0.001). Among the 57 (72.2%) patients meeting the 2019 ACR/EULAR classification criteria, proportion was again lowest in the "Retroperitoneum and Aorta" group (27.8%, p < 0.001). CONCLUSION: The results from this study indicate that IgG4-RD patients having the "Retroperitoneum and Aorta" phenotype less often fulfill diagnostic criteria and classification criteria than patients with other IgG4-RD phenotypes. Accordingly, this phenotype is at risk of being systematically selected against in observational studies and randomized clinical trials, with potential implications for patients, caregivers and future definitions of IgG4-RD.
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Doença Relacionada a Imunoglobulina G4 , Humanos , Noruega , FenótipoRESUMO
OBJECTIVE: To estimate mortality and survival rates of systemic lupus erythematosus (SLE) in a contemporary, population-based setting and assess potential influences by time, sex, ethnicity, classification criteria and age at diagnosis. METHODS: We assessed mortality and survival in the Nor-SLE cohort, which includes all chart-review confirmed SLE cases resident in Southeast Norway (population 2.9 million) 1999-2017. Study end was at death, emigration, or 1 October 2022. We defined juvenile SLE by age <16 years at diagnosis. For standardized mortality rate (SMR) estimates, we applied 15 population controls per case, all matched for age, sex, residency, and ethnicity. We analyzed survival by Kaplan-Meier and risk factors by cox regression. RESULTS: The Nor-SLE cohort included 1558 SLE cases, of whom 749 were incident and met the 2019 European Alliance of Associations for Rheumatology and American College of Rheumatology (2019-EA) classification criteria. SMR was increased to 1.8 (95% CI 1.6-2.2) in incident adult-onset SLE but did not differ between females and males. Survival rates at 5-, 10-, 15 and 20-years were lower in incident adult-onset SLE than in matched controls. In multivariable analysis, lupus nephritis associated with decreased survival, while sex did not. Separate, long-term mortality analyses in the total Nor-SLE cohort showed that SMR peaked at 7.2 (95% CI 3.3-14) in juvenile-onset SLE (n = 93) and fell gradually by increasing age at SLE diagnosis. CONCLUSION: This study shows persistence of a mortality gap between adult-onset SLE and controls at population level and provides indications of worryingly high mortality in juvenile-onset SLE.
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We aimed to identify cardiac function in patients with established mixed connective tissue disease (MCTD). This was a cross-sectional case-control study of well-characterised MCTD patients who had previously been included in a nationwide cohort. Assessments comprised protocol transthoracic echocardiography, electrocardiogram and blood samples. In patients only, we evaluated the findings of high-resolution pulmonary computed tomography and disease activity. We assessed 77 MCTD patients (mean age 50.5 ± 12.3 years) with a mean disease duration of 16.4 years, and 59 age- and sex-matched healthy controls (49.9 ± 11.7 years). By echocardiography, measures of left ventricular function, i.e. fractional shortening (38.1 ± 6.4% vs. 42.3 ± 6.6%, p < 0.001), mitral annulus plane systolic excursion (MAPSE) (13.7 ± 2.1 mm vs. 15.3 ± 2.3 mm, p < 0.001) and early diastolic velocity of the mitral annulus (e') (0.09 ± 0.02 m/s vs. 0.11 ± 0.03 m/s, p = 0.002) were subclinical and lower in patients than controls. Right ventricular dysfunction was found in patients assessed by tricuspid annular plane systolic excursion (TAPSE) (22.7 ± 4.0 mm vs. 25.5 ± 4.0 mm, p < 0.001). While cardiac dysfunction was not associated with pulmonary disease, e' and TAPSE were found to correlate with disease activity at baseline. In this cohort of MCTD patients, echocardiographic examinations demonstrated a higher frequency of cardiac dysfunction than in matched controls. Cardiac dysfunction was associated with disease activity at baseline, but was independent of cardiovascular risk factors and pulmonary disease. Our study indicates that cardiac dysfunction is part of the multi-organ affliction seen in MCTD.
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Pneumopatias , Doença Mista do Tecido Conjuntivo , Humanos , Adulto , Pessoa de Meia-Idade , Estudos de Casos e Controles , Estudos Transversais , EcocardiografiaRESUMO
OBJECTIVES: In long-term juvenile dermatomyositis (JDM), altered adipose tissue distribution and subclinical cardiac dysfunction have been described. Our aims were to compare adipokine levels in patients with JDM after long-term disease with controls, and explore associations between adipokines and (1) adipose tissue distribution and (2) cardiac function. METHODS: The study cohort included 59 patients with JDM (60% female, mean age 25.2 years, mean disease duration 16.9 years), and 59 age/sex-matched controls. Updated Pediatric Rheumatology International Trials Organization criteria for clinically inactive JDM were used to stratify patients into active (JDM-active) or inactive (JDM-inactive) disease groups. Lipodystrophy was clinically assessed in all patients. In all study participants, we measured adipose tissue distribution by dual-energy X-ray absorptiometry and cardiac function by echocardiography. Serum adipokines (adiponectin, apelin-12, lipocalin-2, leptin, visfatin and resistin) were analysed using ELISA. RESULTS: Patients with JDM had higher leptin levels compared with controls (p≤0.01). In JDM-active, apelin-12 and visfatin were higher compared with JDM-inactive (p≤0.05). In JDM-total and JDM-active, lower adiponectin correlated with lipodystrophy and total fat mass. Also, systolic dysfunction correlated with: lower adiponectin in JDM-total, JDM-inactive and JDM-active, and with lower apelin-12 in JDM-total and JDM-active and resistin in JDM-active (all p≤0.05). Lower adiponectin correlated with diastolic dysfunction in JDM-total and JDM-active. CONCLUSION: After long-term disease, leptin levels were unfavourably regulated in patients with JDM compared with controls, and apelin-12 and visfatin in JDM-active versus JDM-inactive. We found associations between adipokines and both adipose tissue distribution and cardiac systolic function in all patients with JDM, which was most prominent in patients with active disease.
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Dermatomiosite , Lipodistrofia , Criança , Humanos , Feminino , Adulto , Masculino , Adipocinas , Dermatomiosite/complicações , Leptina , Resistina , Estudos Transversais , Nicotinamida Fosforribosiltransferase , Adiponectina , Distribuição Tecidual , Lipodistrofia/complicaçõesRESUMO
OBJECTIVES: In SSc, gastrointestinal tract (GIT) involvement is a major concern, with no disease-modifying and limited symptomatic therapies available. Faecal microbiota transplantation (FMT) represents a new therapeutic option for GIT-affliction in SSc, showing clinical promise in a recent controlled pilot trial. Here, we aim to investigate effects of FMT on duodenal biopsies collected from SSc patients by immunohistochemistry and transcriptome profiling. METHODS: We analysed duodenal biopsies obtained pre-intervention (week 0) and post-intervention (weeks 2 and 16) from nine SSc patients receiving an intestinal infusion of FMT (n = 5) or placebo (n = 4). The analysis included immunohistochemistry (IHC) with a selected immune function and fibrosis markers, and whole biopsy transcriptome profiling. RESULTS: In patients receiving FMT, the number of podoplanin- and CD64-expressing cells in the mucosa were lower at week 2 compared with baseline. This decline in podoplanin- (r = 0.94) and CD64-positive (r = 0.89) cells correlated with improved patient-reported lower GIT symptoms. Whole biopsy transcriptome profiling from week 2 showed significant enrichment of pathways critical for cellular and endoplasmic reticulum stress responses, microvillus and secretory vesicles, vascular and sodium-dependent transport, and circadian rhythm. At week 16, we found enrichment of pathways mandatory for binding activity of immunoglobulin receptors, T cell receptor complexes, and chemokine receptors, as well as response to zinc-ions. We found that 25 genes, including Matrix metalloproteinase-1 were upregulated at both week 2 and week 16. CONCLUSION: Combining selective IHC and unbiased gene expression analyses, this exploratory study highlights the potential for disease-relevant organ effects of FMT in SSc patients with GIT involvement. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT03444220.
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Transplante de Microbiota Fecal , Escleroderma Sistêmico , Humanos , Transplante de Microbiota Fecal/efeitos adversos , Método Duplo-Cego , Intestinos , Mucosa Intestinal , Escleroderma Sistêmico/terapia , Escleroderma Sistêmico/etiologia , Resultado do TratamentoRESUMO
OBJECTIVES: To compare limited with a more extended ultrasound examination (anteromedial ultrasound, A2-ultrasound) to detect large vessel (LV) involvement in patients with newly diagnosed GCA. METHODS: Patients with new-onset GCA were included at the time of diagnosis. All patients were examined using limited ultrasound (ultrasound of the axillary artery as visualized in the axilla) and an extended A2-ultrasound method (which also includes the carotid, vertebral, subclavian and proximal axillary arteries), in addition to temporal artery ultrasound. RESULTS: One hundred and thirty-three patients were included in the study. All patients fulfilled the criteria according to a proposed extension of the 1990 ACR classification criteria for GCA and had a positive ultrasound examination at diagnosis. Ninety-three of the 133 GCA patients (69.9%) had LV involvement when examined by extended A2-ultrasound, compared with only 56 patients (42.1%) by limited ultrasound (P < 0.001). Twelve patients (9.0%) had vasculitis of the vertebral arteries as the only LVs involved. Five patients (3.8%) would have been missed as having GCA if only limited ultrasound was performed. Forty patients (30.0%) had isolated cranial GCA, 21 patients (15.8%) had isolated large vessel GCA and 72 patients (54.1%) had mixed-GCA. CONCLUSION: Extended A2-ultrasound examination identified more patients with LV involvement than the limited ultrasound method. However, extended A2-ultrasound requires high expertise and high-end equipment and should be performed by ultrasonographers with adequate training.
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Arterite de Células Gigantes , Humanos , Arterite de Células Gigantes/diagnóstico , Artérias Temporais , Artéria Axilar , Artérias Carótidas , Artéria SubcláviaRESUMO
OBJECTIVE: The idiopathic inflammatory myopathies (IIMs) are heterogeneous diseases thought to be initiated by immune activation in genetically predisposed individuals. We imputed variants from the ImmunoChip array using a large reference panel to fine-map associations and identify novel associations in IIM. METHODS: We analyzed 2,565 Caucasian IIM patient samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically matched control samples. We imputed 1,648,116 variants from the ImmunoChip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM and clinical and serologic subgroups. RESULTS: The HLA locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, SDK2 and LINC00924 (both novel) and STAT4 in the whole IIM cohort, with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and for CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. CONCLUSION: We found novel and strong associations in IIM and PM and localized signals to single genes and immune cell types.
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Doenças Autoimunes , Miosite , Polimiosite , Humanos , Miosite/genética , Doenças Autoimunes/genética , Predisposição Genética para Doença , HaplótiposRESUMO
OBJECTIVE: To compare the effectiveness of tumor necrosis factor inhibitors (TNFi) ± comedication and methotrexate (MTX) monotherapy between patients with adult juvenile idiopathic arthritis (JIA) and patients with rheumatoid arthritis (RA). METHODS: Adult patients with JIA and RA were identified from the Norwegian Antirheumatic Drug Register (NOR-DMARD) register. Disease activity measurements at baseline, 3, 6, and 12 months were compared between patients with JIA and RA starting (1) TNFi and (2) MTX monotherapy, using age- and gender-weighted analyses. We calculated differences between JIA and RA in mean changes in Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI), among other disease activity measures. DAS28, CDAI, SDAI, and American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) remission rates at 3, 6, and 12 months, as well as 6- and 12-month Lund Efficacy Index (LUNDEX)-corrected rates, were calculated. RESULTS: We identified 478 patients with JIA (TNFi/MTX monotherapy, n = 358/120) and 4637 patients with RA (TNFi/MTX monotherapy, n = 2292/2345). Patients with JIA had lower baseline disease activity compared to patients with RA across treatment groups. After baseline disease activity adjustment, there were no significant differences in disease activity change from baseline to 3, 6, and 12-months of follow-up between patients with JIA and RA for either treatment group. Twelve-month remission rates were similar between groups based on DAS28 (TNFi: JIA 55.2%, RA 49.5%; MTX monotherapy: JIA 45.3%, RA 41.2%) and ACR/EULAR remission criteria (TNFi: JIA 20.4%, RA 20%; MTX monotherapy: JIA 17%, RA 12.7%). Median drug survival (yrs) was similar for JIA and RA in both treatment groups (TNFi: JIA 1.2, RA 1.4; MTX monotherapy: JIA 1.3, RA 1.6). CONCLUSION: TNFi and MTX monotherapy are effective in adult JIA, with similar effectiveness to that shown in RA.
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Antirreumáticos , Artrite Juvenil , Artrite Reumatoide , Humanos , Adulto , Metotrexato/uso terapêutico , Antirreumáticos/efeitos adversos , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/induzido quimicamente , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Resultado do Tratamento , Fator de Necrose Tumoral alfa , Artrite Reumatoide/tratamento farmacológico , Quimioterapia CombinadaRESUMO
Introduction: Systemic sclerosis (SSc) is a heterogenous disorder that appears to result from interplay between vascular pathologies, tissue fibrosis and immune processes, with evidence for deregulation of chemokines, which normally control immune trafficking. We recently identified altered levels of chemokine CCL21 in SSc associated pulmonary arterial hypertension (PAH). Here, we aimed to define target organ expression and biomarker characteristics of CCL21. Materials and methods: To investigate target organ expression of CCL21, we performed immunohistochemistry (IHC) on explanted lung tissues from SSc-PAH patients. We assessed serum levels of CCL21 by ELISA and Luminex in two well-characterized SSc cohorts from Oslo (OUH, n=552) and Zurich (n=93) University hospitals and in 168 healthy controls. For detection of anti-CCl21 antibodies, we performed protein array analysis applying serum samples from SSc patients (n=300) and healthy controls. To characterize circulating CCL21 in SSc, we applied immunoprecipitation (IP) with antibodies detecting both full length and tailless and a custom-made antibody detecting only the C-terminal of CCL21. IP products were analyzed by SDS-PAGE/western blot and Mass spectrometry (MS). Results: By IHC, we found that CCL21 was mainly expressed in the airway epithelial cells of SSc patients with PAH. In the analysis of serum levels of CCL21 we found weak correlation between Luminex and ELISA (r=0.515, p<0.001). Serum levels of anti-CCL21 antibodies were higher in SSc patients than in healthy controls (p<0.001), but only 5% of the SSc population were positive for anti-CCL21 antibodies in SSc, and we found no correlation between anti-CCl21 and serum levels of CCL21. By MS, we only identified peptides located within amino acid (aa) 23-102 of CCL21, indicating that CCL21 in SSc circulate as a truncated protein without the C-terminal tail. Conclusion: This study demonstrates expression of CCL21 in epithelial lung tissue from SSc patients with PAH, and indicate that CCL21 in SSc circulates as a truncated protein. We extend previous observations indicating biomarker potential of CCL21, but find that Luminex is not suitable as platform for biomarker analyses. Finally, in vivo generated anti-CCL21 antibodies exist in SSc, but do not appear to modify serum CCL21 levels in patients with SSc-PAH.
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Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Escleroderma Sistêmico , Aminoácidos , Biomarcadores , Quimiocina CCL21 , Hipertensão Pulmonar Primária Familiar , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologiaRESUMO
Primary cardiac involvement is one of the leading causes of mortality in systemic sclerosis (SSc), but little is known regarding circulating biomarkers for cardiac SSc. Here, we aimed to investigate potential associations between cardiac SSc and candidate serum markers. Serum samples from patients of the Oslo University SSc cohort and 100 healthy controls were screened against two custom-made candidate marker panels containing molecules deemed relevant for cardiopulmonary and/or fibrotic diseases. Left (LV) and right ventricular (RV) dysfunction was assessed by protocol echocardiography, performed within three years from serum sampling. Patients suspected of pulmonary hypertension underwent right heart catheterization. Vital status at study end was available for all patients. Descriptive analyses, logistic and Cox regressions were conducted to assess associations between cardiac SSc and candidate serum markers. The 371 patients presented an average age of 57.2 (± 13.9) years. Female sex (84%) and limited cutaneous SSc (73%) were predominant. Association between LV diastolic dysfunction and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (OR 0.41, 95% CI 0.21-0.78, p = 0.007) was identified. LV systolic dysfunction defined by global longitudinal strain was associated with angiopoietin 2 (ANGPT2) (OR 3.42, 95% CI 1.52-7.71, p = 0.003) and osteopontin (OPN) (OR 1.95, 95% CI 1.08-3.52, p = 0.026). RV systolic dysfunction, measured by tricuspid annular plane systolic excursion, was associated to markers of LV dysfunction (ANGPT2, OPN, and TRAIL) (OR 1.67, 95% CI 1.11-2.50, p = 0.014, OR 1.86, 95% CI 1.25-2.77, p = 0.002, OR 0.32, 95% CI 0.15-0.66, p = 0.002, respectively) and endostatin (OR 1.86, 95% CI 1.22-2.84, p = 0.004). In conclusion, ANGPT2, OPN and TRAIL seem to be circulating biomarkers associated with both LV and RV dysfunction in SSc.
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Cardiomiopatias , Cardiopatias , Hipertensão Pulmonar , Escleroderma Sistêmico , Disfunção Ventricular Esquerda , Disfunção Ventricular Direita , Biomarcadores , Cardiomiopatias/complicações , Ecocardiografia/métodos , Feminino , Cardiopatias/complicações , Humanos , Hipertensão Pulmonar/complicações , Pessoa de Meia-Idade , Escleroderma Sistêmico/complicaçõesRESUMO
OBJECTIVE: Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjögren's syndrome (SS), or myositis. METHODS: Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls. RESULTS: A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2-33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7-5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals' capacity to deposit C4b on immune complexes. CONCLUSION: We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account.
Assuntos
Lúpus Eritematoso Sistêmico , Miosite , Autoanticorpos/genética , Complemento C4/genética , Complemento C4b/genética , Variações do Número de Cópias de DNA , Humanos , Lúpus Eritematoso Sistêmico/genética , Fatores de RiscoRESUMO
OBJECTIVES: To evaluate the severity and evolution of patient-reported gastrointestinal tract (GIT) symptoms in systemic sclerosis (SSc) patients, assess predictive factors for progression and determine the impact of standard of care treatment. METHODS: SSc patients from the Leiden and Oslo cohorts were included. We assessed clinical data and patient-reported GIT symptoms measured by the validated University of California, Los-Angeles Gastrointestinal-tract (UCLA-GIT) score at baseline and annually. GIT severity and progression was determined. Logistic regression was applied to identify risk factors associated with baseline GIT symptom severity. Linear mixed-effect models were applied to assess progression in GIT symptom burden and to identify predictive factors. We repeated all analysis in patients with early disease (inception cohort) to exclude the effect of longstanding disease and increase insights in development of GIT symptom burden early in the disease course. RESULTS: We included 834 SSc patients with baseline UCLA GIT scores, 454 from Leiden and 380 from Oslo. In the total cohort, 28% reported moderate-severe GIT symptoms at baseline, with increased risk for severity conferred by ACA, smoking and corticosteroid use, while use of calcium channel blockers appeared protective. In the inception cohort, 23% reported moderate-severe GIT symptoms at baseline, with increased risk for females and with smoking. Over time, symptom burden increased mainly for reflux/bloating. Female sex and ACA predicted GIT symptom progression. CONCLUSION: High GIT symptom burden is present early in SSc disease course. Both for prevalence and for progression of GIT symptom burden, female sex and smoking were identified as risk factors.
Assuntos
Gastroenteropatias , Escleroderma Sistêmico , Corticosteroides , Bloqueadores dos Canais de Cálcio , Feminino , Gastroenteropatias/etiologia , Humanos , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To compare body composition parameters in patients with long-standing JDM and controls and to explore associations between body composition and disease activity/inflammation, muscle strength, health-related quality of life (HRQoL) and cardiometabolic measures. METHODS: We included 59 patients (median disease duration 16.7 y; median age 21.5 y) and 59 age- and sex-matched controls in a cross-sectional study. Active and inactive disease were defined by the PRINTO criteria. Body composition was assessed by total body DXA, inflammation by high-sensitivity CRP (hs-CRP) and cytokines, muscle strength by the eight-muscle manual muscle test, HRQoL by the 36-item Short Form Health Survey physical component score and cardiometabolic function by echocardiography (systolic and diastolic function) and serum lipids. RESULTS: DXA analyses revealed lower appendicular lean mass index (ALMI; reflecting limb skeletal muscle mass), higher body fat percentage (BF%) and a higher android fat:gynoid fat (A:G) ratio (reflecting central fat distribution) in patients than controls, despite similar BMI. Patients with active disease had lower ALMI and higher BF% than those with inactive disease; lower ALMI and higher BF% were associated with inflammation (elevated monocyte attractant protein-1 and hs-CRP). Lower ALMI was associated with reduced muscle strength, while higher BF% was associated with impaired HRQoL. Central fat distribution (higher A:G ratio) was associated with impaired cardiac function and unfavourable serum lipids. CONCLUSION: Despite normal BMI, patients with JDM, especially those with active disease, had unfavourable body composition, which was associated with impaired HRQoL, muscle strength and cardiometabolic function. The association between central fat distribution and cardiometabolic alterations is a novel finding in JDM.