Granulomatosis With Polyangiitis With And Without Antineutrophil Cytoplasmic Antibodies: A Case-Control Study.

BACKGROUND: ANCA-negative GPA remains a diagnosis of exclusion. Clinical differences between patients with ANCA-negative vs ANCA-positive GPA have not been analyzed in sizable case-control studies, and the effects of ANCA-seroconversion from negative to positive are not well documented. METHODS: A single-center, sex, and age matched case-control study evaluated ANCA-negative vs ANCA-positive GPA from January 1, 1996, to December 31, 2015. Patients who experienced seroconversion were the subject of a case crossover study. Clinical data and outcomes were retrieved from electronic medical records. RESULTS: ANCA-negative GPA was identified in 110 patients; 65% were female; median age was 55 (IQR 39-65) years at time of diagnosis. Disease severity was milder in ANCA-negative GPA (BVAS/WG = 2 vs 6, p< 0.001). Mucous membranous/eye manifestations were more frequent in ANCA-negative GPA. General symptoms, pulmonary, and renal involvement were more frequent in ANCA-positive GPA. Patients with ANCA-positive GPA relapsed more over 60 months (21.8% vs.9.1%, p= 0.009) compared with ANCA-negative GPA and had shorter time to event (p= 0.043). Patients with general manifestations, BMI > 30kg/m2 and necrotizing granulomatous inflammation were more likely to relapse. The 16 patients who seroconverted into ANCA-positive during follow-up had higher mean BVAS/WG at time of diagnosis (p< 0.001) and increased incidence of relapses (p= 0.004) after seroconversion. Necrotizing granulomatous inflammation on biopsy in ANCA-negative GPA patients was identified as a risk factor for subsequent seroconversion to ANCA-positivity. CONCLUSION: Patients with ANCA-negative GPA have milder disease and a lower frequency of relapse than those with ANCA-positive GPA. ANCA appearance portended higher disease severity and an increased frequency of relapses.

Autoreactive Plasmablasts After B Cell Depletion With Rituximab and Relapses in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: Autoreactive B cells are responsible for antineutrophil cytoplasmic antibody (ANCA) production in ANCA-associated vasculitis (AAV). Rituximab (RTX) depletes circulating B cells, including autoreactive B cells. We aimed to evaluate changes and associations with relapse of the circulating autoreactive B cell pool following therapeutic B cell depletion in AAV. METHODS: Sequential flow cytometry was performed on 148 samples of peripheral blood mononuclear cells from 23 patients with proteinase 3 (PR3)-ANCA-positive AAV who were treated with RTX for remission induction and monitored after stopping therapy during long-term follow-up in a prospective clinical trial. PR3 was used as a ligand to target autoreactive PR3-specific (PR3+) B cells. B cell recurrence was considered as the first blood sample with ≥10 B cells/µl after RTX treatment. RESULTS: At B cell recurrence, PR3+ B cell frequency among B cells was higher than baseline (P < 0.01). Within both PR3+ and total B cells, frequencies of transitional and naive subsets were higher at B cell recurrence than at baseline, while memory subsets were lower (P < 0.001 for all comparisons). At B cell recurrence, frequencies of B cells and subsets did not differ between patients who experienced relapse and patients who remained in remission. In contrast, the plasmablast frequency within the PR3+ B cell pool was higher in patients who experienced relapse and associated with a shorter time to relapse. Frequencies of PR3+ plasmablasts higher than baseline were more likely to be found in patients who experienced relapse within the following 12 months compared to those in sustained remission (P < 0.05). CONCLUSION: The composition of the autoreactive B cell pool varies significantly following RTX treatment in AAV, and early plasmablast enrichment within the autoreactive pool is associated with future relapses.

A Target Antigen-Based Approach to the Classification of Membranous Nephropathy.

OBJECTIVE: To describe the clinical and pathological phenotype of membranous nephropathy (MN) associated with M-type-phospholipase-A2-receptor (PLA2R), thrombospondin-type-1-domain-containing-7A (THSD7A), semaphorin 3B (SEMA3B), neural-epidermal-growth-factor-like-1-protein (NELL-1), protocadherin 7 (PCDH7), exostosin 1/exostosin 2 (EXT1/EXT2) and neural cell adhesion molecule 1 (NCAM-1) as target antigens. METHODS: A retrospective cohort of 270 adult patients with biopsy-proven MN diagnosed between January 2015 and April 2020 was classified as PLA2R-, THSD7A-, SEMA3B-, NELL-1-, PCDH7-, EXT1/EXT2-, NCAM-1-associated or septuple-negative MN using serologic tests, immunostaining, and/or mass spectrometry. Clinical, biochemical, pathologic, and follow-up data were systematically abstracted from the medical records, including disease activity of conditions traditionally associated with MN and occurring within 5 years of MN diagnosis. RESULTS: Patients with PLA2R-associated MN were predominantly middle-aged white men without associated disease. The presence of associated disease did not affect the clinical and pathologic characteristics of PLA2R-associated MN, suggesting that they were coincidental rather than causally linked. THSD7A-, NELL-1-, PCDH7-, and NCAM-1-associated MN were rare and SEMA3B-associated MN was not discovered in our cohort. EXT1/EXT2-associated MN was primarily diagnosed in younger women with active systemic autoimmunity. A significant proportion of septuple-negative patients had associated malignancy or systemic autoimmunity. CONCLUSION: The widely used distinction between primary and secondary MN has limitations. We propose a refined terminology that combines the target antigen and associated disease to better classify MN and guide clinical decision making.

Beyond Giant Cell Arteritis and Takayasu's Arteritis: Secondary Large Vessel Vasculitis and Vasculitis Mimickers.

PURPOSE OF REVIEW: To provide an overview of mimickers of large vessel vasculitis (LVV), by the main presenting manifestation, i.e., systemic, vascular, and cranial manifestations. RECENT FINDINGS: The main differential diagnoses in patients with giant cell arteritis (GCA) and Takayasu arteritis (TAK) presenting with systemic manifestations (i.e., fever, anorexia, weight loss, night sweats, arthralgia/myalgia, and/or increased inflammatory indexes) are neoplastic, infectious, or other inflammatory conditions. In patients with vascular manifestations (such as peripheral ischemia, vascular stenoses, or aneurysms), atherosclerosis and non-inflammatory vascular diseases should be excluded. In those presenting with predominant cranial symptoms (i.e., temporal headache, jaw claudication, scalp tenderness, transient or permanent vision loss), other causes of headache, cerebrovascular accidents, optic neuropathy, and neuromuscular syndromes need to be considered. The diagnosis of LVV maybe challenging, especially when patients present with atypical or incomplete clinical forms. In these cases, a multidisciplinary approach is strongly recommended.

Thoracic Involvement in IgG4-Related Disease.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder that has been recognized to involve virtually any organ in the body and typically manifests mass-like lesions (tumefactive). Although initial reports of this disease (autoimmune pancreatitis [AIP]) were described in the Japanese population, it has since been reported worldwide. It is most commonly seen in adults of middle age or older, more often men than women. The pathogenesis of IgG4-RD is largely unknown, but genetic factors, microorganisms, and autoimmunity are thought to play important roles. Serum IgG4 concentration is elevated in the majority of patients with IgG4-RD but is a nonspecific finding. Characteristic histopathologic features include dense lymphoplasmacytic infiltrate, fibrosis (often in storiform pattern), and obliterative phlebitis. Lung involvement in IgG4-RD was first reported in 2004 in two patients with AIP and coexisting interstitial lung disease. Since then, a wide spectrum of intrathoracic involvement has been reported and includes not only parenchymal lung diseases but also pleural, airway, vascular, and mediastinal lesions. Thoracic involvement in IgG4-RD is often found incidentally during the workup of extrathoracic lesions but can sometimes be the presenting abnormality. The diagnosis of IgG4-RD requires correlation of clinical, laboratory, imaging, and histopathologic features. Glucocorticoids are the first-line therapy but other options including B cell depletion are being investigated. IgG4-RD is generally associated with an indolent clinical course and most patients improve with glucocorticoid therapy.

Liver cytolysis in acute heart failure: What does it mean? Clinical profile and outcomes of a prospective hospital cohort.

UNLABELLED: Abnormal liver function tests (LFTs) are a common manifestation of heart failure (HF). Our purpose was to characterize patients hospitalized for acute HF (AHF) with liver cytolysis, analyze cytolysis predictors and explore its prognostic implications. METHODS: In a prospective cohort study, we enrolled patients with AHF consecutively admitted to the Internal Medicine Department of University Hospital between January 2009 and December 2010, and recorded demographic, clinical, laboratory and echocardiogram parameters. A logistic regression was done to identify cytolysis predictors. In survival analysis primary endpoints were all-cause death, readmission due to AHF, and the combined event of all-cause death and readmission for AHF at 90days of follow-up. RESULTS: Fifty-eight patients had cytolysis at admission. AHF attributed to atrial fibrillation (OR 3.235), higher heart rate at admission (OR 1.028), cold/wet profile at admission (OR 7.12) and ejection fraction <30% (OR 2.316) were independent predictors of cytolysis. Death occurred more frequently during follow-up in the cytolysis group (27.6 vs. 15.1%, p=0.014, respectively). On survival analysis, cytolysis remained an independent predictor of death at 90days when adjusted to age (HR 1.066), male gender (HR 1.884), valvular etiology (HR 2.365), neurologic status at admission (sleepy HR 3.854; confusion HR 3.176) and cardiac output (HR 0.762). CONCLUSION: Cytolysis may be a marker of systemic hypoperfusion, so strategies to improve hemodynamic profile should be considered, especially in the presence of cold/wet clinical profile, AHF attributed to AF, tachycardia, and EF<30%. Cytolysis is associated with higher mortality at 90days in patients with AHF.