Cigarette smoking is associated with immune-mediated disorders. We explored the contribution of smoking to polymyositis (PM) and dermatomyositis (DM) phenotypes and attempted to determine whether ...cigarette smoking effects differ by race and genotype.
Associations of tobacco smoking with disease features, autoantibodies, HLA types, and race were evaluated using multiple logistic regressions in 465 patients.
Caucasian ever-smokers (n = 140) were more likely to have PM (adjusted OR = 2.24, 95% CI: 1.41\x963.57), anti-synthetase (adjusted OR = 1.93, 95% CI: 1.12\x963.34) and anti-Jo-1 autoantibodies (adjusted OR = 1.94, 95% CI: 1.08\x963.46) and less likely to have anti-p155/140 autoantibodies (adjusted OR = 0.36, 95% CI: 0.14\x960.92). In Caucasians, ever-smokers had a greater interstitial lung disease (ILD) frequency than never-smokers, while in African-Americans this relationship was inverted, but neither trend reached statistical significance. Pack-years of cigarette smoking showed significant positive associations with PM (adjusted OR = 1.02, 95% CI: 1.002\x961.04) and ILD (adjusted OR = 1.02, 95% CI: 1.001\x961.03) and was inversely associated with anti-p155/140 autoantibodies (adjusted OR = 0.93, 95% CI: 0.87\x960.99) in Caucasians. Caucasian heavy smokers (=20 pack-years) were more likely to have PM (adjusted OR = 2.52, 95% CI: 1.25\x965.09), ILD (adjusted OR = 2.48, 95% CI: 1.23\x965.00) and anti-Jo-1 autoantibodies (adjusted OR = 2.65, 95% CI: 1.16\x966.08) than never-smokers.
In Caucasians, compared to never-smokers without HLA-DRB1*03:01 allele, ever-smokers with HLA-DRB1*03:01 allele had the highest odds of PM, ILD, ASA, and anti-Jo-1 autoantibodies. Risks for those with only one of these two factors were intermediate. An inverse pattern was observed regarding anti-p155/140 autoantibodies.
Tobacco smoking was associated with clinical and autoantibody phenotypes in Caucasians. Our findings also suggest possible interactions among HLA-DRB1*03:01 and smoking on the risk of PM and ILD, as well as, anti-synthetase, anti-Jo-1, and anti-p155/140 autoantibodies in Caucasians.
To assess the utility of the vascular physical examination to detect arteriographic lesions in patients with established large vessel vasculitis (LVV), including Takayasu's arteritis (TAK) and giant ...cell arteritis (GCA).
In total, 100 patients (TAK = 68, GCA = 32) underwent standardized physical examination and angiography of the carotid, subclavian, and axillary arteries. Sensitivity and specificity were calculated for the association between findings on physical examination focusing on the vascular system (absent pulse, bruit, and blood pressure difference) and arteriographic lesions defined as stenosis, occlusion, or aneurysm.
We found 67% of patients had at least 1 abnormality on physical examination (74% TAK, 53% GCA). Arteriographic lesions were seen in 76% of patients (82% TAK, 63% GCA). Individual physical examination findings had poor sensitivity (range 14%-50%) and good-excellent specificity (range 71%-98%) to detect arteriographic lesions. Even when considering physical examination findings in combination, at least 30% of arteriographic lesions were missed. Specificity improved (range 88%-100%) if individual physical examination findings were compared to a broader region of vessels rather than specific anatomically correlated vessels and if ≥ 1 physical examination findings were combined.
In patients with established LVV, physical examination alone is worthwhile to detect arterial disease but does not always localize or reveal the full extent of arteriographic lesions. Abnormal vascular system findings on physical examination are highly associated with the presence of arterial lesions, but normal findings on physical examination do not exclude the possibility of arterial disease. Serial angiographic assessment is advisable to monitor arterial disease in patients with established LVV.
Objective
Takayasu arteritis is a rare large vessel vasculitis with incompletely understood etiology. This study was undertaken to perform the first unbiased genome‐wide association analysis of ...Takayasu arteritis.
Methods
Two independent cohorts of patients with Takayasu arteritis from Turkey and North America were included in our study. The Turkish cohort consisted of 559 patients and 489 controls, and the North American cohort consisted of 134 patients and 1,047 controls of European ancestry. Genotyping was performed using the Omni1‐Quad and Omni2.5 genotyping arrays. Genotyping data were subjected to rigorous quality control measures and subsequently analyzed to discover genetic susceptibility loci for Takayasu arteritis.
Results
We identified genetic susceptibility loci for Takayasu arteritis with a genome‐wide level of significance in IL6 (rs2069837) (odds ratio OR 2.07, P = 6.70 × 10−9), RPS9/LILRB3 (rs11666543) (OR 1.65, P = 2.34 × 10−8), and an intergenic locus on chromosome 21q22 (rs2836878) (OR 1.79, P = 3.62 × 10−10). The genetic susceptibility locus in RPS9/LILRB3 lies within the leukocyte receptor complex gene cluster on chromosome 19q13.4, and the disease risk variant in this locus correlates with reduced expression of multiple genes including the inhibitory leukocyte immunoglobulin‐like receptor gene LILRB3 (P = 2.29 × 10−8). In addition, we identified candidate susceptibility genes with suggestive levels of association (P < 1 × 10−5) with Takayasu arteritis, including PCSK5, LILRA3, PPM1G/NRBP1, and PTK2B.
Conclusion
Our findings indicate novel genetic susceptibility loci for Takayasu arteritis and uncover potentially important aspects of the pathophysiology of this form of vasculitis.
Glomerulonephritis (GN) is common in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but tools for early detection of renal involvement are imperfect. We investigated 4 ...urinary proteins as markers of active renal AAV: alpha-1 acid glycoprotein (AGP), kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein-1 (MCP-1), and neutrophil gelatinase-associated lipocalin (NGAL).
Patients with active renal AAV (n = 20), active nonrenal AAV (n = 16), and AAV in longterm remission (n = 14) were identified within a longitudinal cohort. Urinary biomarker concentrations (by ELISA) were normalized for urine creatinine. Marker levels during active AAV were compared to baseline remission levels (from 1-4 visits) for each patient. Areas under receiver-operating characteristic curves (AUC), sensitivities, specificities, and likelihood ratios (LR) comparing disease states were calculated.
Baseline biomarker levels varied among patients. All 4 markers increased during renal flares (p < 0.05). MCP-1 discriminated best between active renal disease and remission: a 1.3-fold increase in MCP-1 had 94% sensitivity and 89% specificity for active renal disease (AUC = 0.93, positive LR 8.5, negative LR 0.07). Increased MCP-1 also characterized 50% of apparently nonrenal flares. Change in AGP, KIM-1, or NGAL showed more modest ability to distinguish active renal disease from remission (AUC 0.71-0.75). Hematuria was noted in 83% of active renal episodes, but also 43% of nonrenal flares and 25% of remission samples.
Either urinary MCP-1 is not specific for GN in AAV, or it identifies early GN not detected by standard assessment and thus has potential to improve care. A followup study with kidney biopsy as the gold standard is needed.
Granulomatosis with polyangiitis (Wegener's) is a rare autoimmune neutrophil-mediated vasculitis that can cause renal disease and mucosal manifestations. Antineutrophil cytoplasmic antibodies (ANCA) ...are present in many patients, vary in level over time, and induce neutrophil activation through engagement with Fc receptors (FcRs). Given roles for FcRs in ANCA-mediated neutrophil activation and IgA antibodies in mucosal immunity, we hypothesized that FcR genetics and previously unappreciated IgA ANCA affect clinical presentation. We assembled a total of 673 patients and 413 controls from two multicenter cohorts, performed ELISA and immunofluorescence assays to determine IgA and IgG ANCA positivity, and used Illumina, TaqMan, or Pyrosequencing to genotype eight haplotype-tagging SNPs in the IgA FcR (FCAR) and to determine NA1/NA2 genotype of FCGR3B, the most prevalent neutrophil IgG FcR. We evaluated neutrophil activation by measuring degranulation marker CD11b with flow cytometry or neutrophil extracellcular trap formation with confocal microscopy. Functional polymorphisms in FCGR3B and FCAR differed between patient groups stratified by renal involvement. IgA ANCA were found in ~30% of patients and were less common in patients with severe renal disease. Neutrophil stimulation by IgA or IgG ANCA led to degranulation and neutrophil extracellcular trap formation in a FcR allele-specific manner (IgA:FCAR P = 0.008; IgG: FCGR3B P = 0.003). When stimulated with IgA and IgG ANCA together, IgG ANCA induced neutrophil activation was reduced (P = 0.0001). FcR genotypes, IgA ANCA, and IgG ANCA are potential prognostic and therapeutic targets for understanding the pathogenesis and presentation of granulomatosis with polyangiitis (Wegener's).
This study aimed to characterise the presenting features and outcomes of patients with vasculitis and gastrointestinal perforation.
Using a retrospective cohort design, this study included 20 cases ...with verified vasculitis and gastrointestinal perforation at Mayo Clinic, Rochester, USA, between 1998 and 2017.
Four of the twenty cases experienced vasculitis-induced perforation. Cases with perforations due to vasculitic involvement had more small bowel involvement, longer duration of abdominal pain prior to perforation (41 days vs. 0 days, p=0.005), and a higher proportion of active tobacco use (75% vs. 7%, p=0.01) compared to the cases with non-vasculitis perforation. A majority (88%) of the non-vasculitis perforations were associated with glucocorticoid use. The median cumulative glucocorticoid dose prior to perforation in patients with additional, non-vasculitic risk factors for perforation was 4,320 mg prednisone and was 22,170 mg for those without additional risk factors. Mortality rates for the whole cohort were higher than the general population (standardised mortality ratio: 2.19, 95% confidence interval 1.05 to 4.02). The cases with vasculitis-induced perforation tended to have increased number of surgeries and length of stay compared to the non-vasculitis cases; however, those differences failed to reach statistical significance.
Small bowel location and longer abdominal pain duration may help distinguish vasculitis-induced bowel perforation from other etiologies. Overall mortality in patients with vasculitis and bowel perforation is increased, highlighting the importance of prompt diagnosis and management.
Recent studies have shown increased expression of interferon (IFN)-regulated genes in the peripheral blood cells of patients with systemic lupus erythematosus. A similar interferon signature has been ...observed in affected muscle tissue from patients with dermatomyositis (DM), but it has not yet been determined if this signature extends to the peripheral blood in DM. We performed global gene expression profiling of peripheral blood cells from adult and juvenile DM patients and healthy controls. Several interesting groups of genes were differentially expressed in DM, including genes with immune function, and others that function in muscle or are involved in mitochondrial/oxidative phosphorylation. Investigation of type I IFN-regulated transcripts revealed a striking interferon signature present in most DM patients studied. Levels of type I IFN-regulated proteins were also elevated in DM serum samples. Furthermore, both the transcript and serum protein IFN signatures were associated with disease activity. These data suggest that the IFN signature may be a useful marker for DM disease activity, and that sampling peripheral blood may be a more practical alternative to muscle biopsy for measuring this signature.
Objective
To describe the clinical presentation, laboratory findings, and outcome of patients with Pneumocystis jiroveci pneumonia (PCP) and biopsy‐proven giant cell arteritis (GCA) seen at a ...tertiary referral center.
Methods
Using International Classification of Diseases, Ninth Revision codes, all patients with GCA and PCP between January 1, 1976 and December 31, 2008 were identified. Medical records were reviewed. PCP was defined by the identification of Pneumocystis jiroveci organisms in the clinical setting of pneumonia.
Results
We identified 7 patients with GCA (5 women and 2 men) who developed PCP (the mean ± SD age at diagnosis was 71.6 ± 6.1 years). The median time from GCA diagnosis to PCP diagnosis was 3 months (range 1–18 months). All patients were taking prednisone (the median dosage 50 mg/day range 30–80) when diagnosed as having PCP. No patients were receiving PCP prophylaxis. PCP was diagnosed by positive smear on bronchoalveolar lavage fluid in 6 patients (86%) and by positive sputum polymerase chain reaction in 1 patient. All the patients were hospitalized (median duration 17 days range 12–39 days). Four patients (57%) were admitted to the intensive care unit. Three patients (43%) required mechanical ventilation. Two patients (29%) died; both were on mechanical ventilation.
Conclusion
Although PCP is rare among patients with GCA, this preventable infection is associated with significant morbidity and mortality.
To determine the incidence and prevalence of sporadic inclusion body myositis (sIBM) and polymyositis (PM) in a population-based study.
Charts of patients with myositis in Olmsted County, Minnesota, ...USA, from 1981 to 2000 were reviewed.
For sIBM, the age- and sex-adjusted incidence rates per 100,000 were 0.79 (95% confidence interval = 0.24-1.35), and for PM, 0.41 (95% CI 0.08-0.73). The age- and sex-adjusted prevalence rates per 100,000 were 7.06 (95% CI 0.87-13.24) for sIBM and 3.45 (95% CI 0.00-7.35) for PM.
The incidence and prevalence rates for sIBM are higher than previously reported.
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