Association of Pulmonary Hemorrhage, Positive Proteinase 3, and Urinary Red Blood Cell Casts With Venous Thromboembolism in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Objective To assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (RAVE) trial and identify novel potential risk factors. Methods VTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA-associated vasculitis (AAV). Results VTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0-2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247-134.842]; P = 0.006), positive proteinase 3 (PR3)-ANCA (HR 7.731 [95% CI 1.021-58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448-10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491-69.854]; P <0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566-185.805]; P = 0.005), PR3-ANCA (HR 9.12 [95% CI 1.158-71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453-10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607-75.075]; P <0.001) remained. Conclusion Patients diagnosed as having AAV with pulmonary hemorrhage, positive PR3-ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention

Context-dependent associations between heterozygosity and immune variation in a wild carnivore

Background: A multitude of correlations between heterozygosity and fitness proxies associated with disease have been reported from wild populations, but the genetic basis of these associations is unresolved. We used a longitudinal dataset on wild Galapagos sea lions (Zalophus wollebaeki) to develop a relatively new perspective on this problem, by testing for associations between heterozygosity and immune variation across age classes and between ecological contexts. Results: Homozygosity by locus was negatively correlated with serum immunoglobulin G production in pups (0-3 months of age), suggesting that reduced genetic diversity has a detrimental influence on the early development of immune defence in the Galapagos sea lion. In addition, homozygosity by locus was positively correlated with total circulating leukocyte concentration in juveniles (6-24 months of age), but only in a colony subject to the anthropogenic environmental impacts of development, pollution and introduced species, which suggests that reduced genetic diversity influences mature immune system activity in circumstances of high antigen exposure. Conclusions: These findings demonstrate the environmental context-dependency of the phenotypic expression of immune variation, which is implicit in the theory of ecoimmunology, but which has been rarely demonstrated in the wild. They also indicate that heterozygosity may be linked to the maintenance of heterogeneity in mammalian immune system development and response to infection, adding to the body of evidence on the nature of the mechanistic link between heterozygosity and fitness

Rituximab for Refractory Wegener's Granulomatosis: Report of a Prospective, Open-Label Pilot Trial

Rationale: Standard therapy for Wegener's granulomatosis is fraught with substantial toxicity and not always effective. B lymphocytes have been implicated in the pathogenesis of Wegener's granulomatosis. Their depletion has been proposed as salvage therapy for refractory disease. Earlier encouraging reports are confounded by concomitant immunosuppressive medications and include only limited available biomarker data

Treatment of interstitial lung disease associated cough CHEST guideline and expert panel report

BACKGROUND: Chronic cough in interstitial lung disease (ILD) causes significant impairment in quality of life. Effective treatment approaches are needed for cough associated with ILD.METHODS: This systematic review asked: Is there evidence of clinically relevant treatment effects for therapies for cough in ILD? Studies of adults aged > 18 years with a chronic cough >= 8 weeks' duration were included and assessed for relevance and quality. Based on the systematic review, guideline suggestions were developed and voted on by using CHEST guideline methodology.RESULTS: Eight randomized controlled trials and two case series (>= 10 patients) were included that reported data on patients with idiopathic pulmonary fibrosis, sarcoidosis, and scleroderma-related ILD who received a variety of interventions. Study quality was high in all eight randomized controlled trials. Inhaled corticosteroids were not supported for cough associated with sarcoidosis. Cyclophosphamide and mycophenolate were not supported for solely treating cough associated with scleroderma-associated ILD. A recommendation for thalidomide to treat cough associated with idiopathic pulmonary fibrosis did not pass the panel vote. In view of the paucity of antitussive treatment options for refractory cough in ILD, the guideline panel suggested that the CHEST unexplained chronic cough guideline be followed by considering options such as the neuromodulator gabapentin and speech pathology management. Opiates were also suggested for patients with cough refractory to alternative therapies.CONCLUSIONS: The evidence supporting the management of chronic cough in ILD is limited. This guideline presents suggestions for managing and treating cough on the best available evidence, but future research is clearly needed

ANCA-associated vasculitis

The majority of patients with Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA) have antineu-trophil cytoplasmic antibodies (ANCA) in their serum. This is particularly true of patients with "disseminated" disease, the great majority of whom are ANCA positive. WG and MPA are often termed "ANCA-associated vasculitides" (AAV), even though not all patients with these conditions have ANCA. The Churg-Strauss syndrome, another disorder classified as an AAV, is discussed in Chap. 23. Multiple antibodies may lead to positive immunofluores-cence testing for ANCA in either perinuclear (P-ANCA) or cytoplasmic (C-ANCA) patterns. However, only antibodies to myeloperoxidase (MPO) and proteinase-3 (PR3) are associated with the A AV. Antibodies directed against PR3 and MPO are termed PR3-ANCA and MPO-ANCA, respectively. WG may be associated with destructive upper respiratory tract disease, including saddle-nose deformity, erosive sinusitis, and subglottic stenosis. A host of ocular lesions may occur in the A AV, including episcleritis, scleritis, peripheral ulcerative keratitis, and orbital pseudotumor. Most of these lesions are more common in WG than in MPA. Lung disease in the AAV ranges from nodular lesions with a tendency to cavitate (in WG), to interstitial lung disease (MPA), and to alveolar hemorrhage (both WG and MPA). Segmental, necrotizing glomerulonephritis commonly accompanies the AAV. Because of the paucity of immunoreactants such as immunoglobulins and complement components in kidney biopsies relative to the biopsies from patients with immune complex-mediated glomerulonephritis, the glomerulonephritis of the A AV is termed "pauci-immune".</p