Provide an update of the developments in IgG4 related disease within the last year in terms of nomenclature, diagnostic criteria and clinical features.
The number of diseases associated with IgG4 ...related disease continues to grow. The entities of idiopathic orbital inflammation, idiopathic cervical fibrosis, eosinophilic angiocentric fibrosis, reactive nodular fibrous pseudotumor, sclerosing mesenteritis, and membranous glomerulonephritis should all be added to the list of diseases associated with the IgG4 related disease spectrum. The issues of nomenclature and diagnostic criteria for IgG4 related disease have important recent developments as well.
The diagnosis of IgG4 related disease continues to be challenging. Increasing recognition of IgG4 related disease has led to a large body of literature on organ sites of involvement. Understanding how the disease manifests itself is critical to diagnosis and ultimately treatment.
Abstract IgG4-related disease (IgG4-RD) is an under recognized, protean, multiorgan fibro-inflammatory condition of unknown aetiology that is defined by its unique histopathological features, that ...are fairly similar regardless of the affected organ. Patients with IgG4-RD also share certain clinical features: a tendency for formation of mass lesion(s), frequent elevations in their serum IgG4 concentration, as well as an excellent response to glucocorticoid treatment. The 3 key histologic features of IgG4-RD are: 1) dense lymphoplasmacytic infiltrate, 2) fibrosis, arranged at least focally in a storiform pattern, and 3) obliterative phlebitis. The diagnosis of IgG4-RD requires both these characteristic histologic features as well as elevated numbers of IgG4 positive plasma cells. Neither elevations in serum IgG4 concentrations nor increased tissue IgG4-plasma cells are in themselves sufficient for the diagnosis, and histopathology remains the key to the accurate diagnosis of IgG4-RD.
Social determinants of health (SDoH) likely contribute to outcome disparities in lupus nephritis (LN). Understanding the overall burden and contribution of each domain could guide future ...health-equity focused interventions to improve outcomes and reduce disparities in LN. Objectives of this meta-analysis were to: 1) determine the association of overall SDoH and specific SDoH domains on LN outcomes, and 2) develop a framework for the multidimensional impact of SDoH on LN outcomes.
We performed a comprehensive search of studies measuring associations between SDoH and LN outcomes. We examined pooled odds of poor LN outcomes including mortality, end-stage kidney disease, or cardiovascular disease in patients with and without adverse SDoH. Additionally, we calculated the pooled odds ratios of outcomes by four SDoH domains: individual (e.g., insurance), healthcare (e.g., fragmented care), community (e.g., neighborhood socioeconomic status), and health behaviors (e.g., smoking).
Among 531 screened studies, 31 met inclusion and 13 studies with raw data were included in meta-analysis. Pooled odds of poor outcomes, were 1.47-fold higher in patients with any adverse SDoH. Patients with adverse SDoH in individual and healthcare domains had 1.64-fold and 1.77-fold higher odds of poor outcomes. We found a multiplicative impact of having ≥2 adverse SDoH on LN outcomes. Patients of Black Race with public insurance and fragmented care had 12-fold higher odds of poor LN outcomes.
Adverse SDoH is associated with poor LN outcomes. Having ≥2 adverse SDoH, specifically in different SDoH domains, had a multiplicative impact leading to worse LN outcomes, widening disparities.
Objective
Obexelimab is an investigational, bifunctional, noncytolytic monoclonal antibody that binds CD19 and FcyRIIb to inhibit B cells, plasmablasts, and plasma cells. This trial evaluated the ...efficacy and safety of obexelimab in the treatment of patients with systemic lupus erythematosus (SLE).
Methods
During screening, patients with active, non–organ‐threatening SLE received corticosteroid injections to ameliorate symptoms while immunosuppressants were withdrawn (≤10 mg/day prednisone equivalent and ≤400 mg/day hydroxychloroquine allowed). Patients with improved disease activity were randomized 1:1 to obexelimab 5 mg/kg intravenously or placebo once every 2 weeks until week 32 or loss of improvement (LOI).
Results
In this study, 104 patients were randomized. Analysis of the primary endpoint, proportion of patients reaching week 32 without LOI, used an efficacy‐evaluable (EE) population defined as patients who completed the study or withdrew for flare or treatment‐related toxicity. This endpoint did not reach statistical significance: 21 of 50 obexelimab‐treated patients (42.0%) versus 12 of 42 patients (28.6%) treated with a placebo (P = 0.183). Time to LOI was increased in obexelimab‐treated patients versus patients treated with a placebo in the EE (hazard ratio HR 0.53, P = 0.025) and intention‐to‐treat (HR 0.59, P = 0.062) populations. In obexelimab‐treated patients, B cells decreased approximately 50%, and trough concentration and inclusion in baseline gene expression clusters with high B cell pathway modules were associated with increased time to LOI. Obexelimab was associated with infusion reactions but was generally safe and well‐tolerated.
Conclusion
Although the primary endpoint was not reached, secondary analysis showed time to LOI was significantly increased in obexelimab‐treated patients, and analysis of patient subsets defined by gene expression patterns at baseline suggests a responding subpopulation.
Objective
A retrospective cohort study was undertaken in a predominantly Black population undergoing standard treatment for lupus nephritis (LN) to estimate the incidence of, and risk factors for, ...complete response (CR) according to modified Aspreva Lupus Management Study (mALMS) and modified Belimumab International Study in Lupus Nephritis (mBLISS) criteria by 12 months.
Methods
Patients with biopsy‐proven LN class III or IV ± V, urine protein‐to‐creatinine ratio of ≥1gm/gm and estimated glomerular filtration rate of >50 ml/minute/1.73 m2 at the time of the incident LN flare were included. The clinical, treatment, and laboratory factors associated with CR were identified using multivariable Cox regression.
Results
Of 173 patients, 86.1% were women, 77.5% were Black, and over half (59.5%) had non‐commercial insurance. By 12 months, 20.6% (95% confidence interval (95% CI) 14.6–28.6%) achieved mALMS CR and 33.7% (95% CI 26.4–42.4%) achieved mBLISS CR. Factors associated with mBLISS CR were commercial insurance (adjusted CR ratio = 3.5 95% CI 1.9–6.7; P < 0.001), albumin (adjusted CR ratio = 1.8 per 1 gm/dl increase in albumin; P = 0.02), and low C4 (adjusted CR ratio = 2.6; P = 0.03). Cumulative incidence of end‐stage renal disease (ESRD) at 3 years was 23.1% (95% CI 15.7–31.3%) and 6.1% (95% CI 2.8–11.1%) for death. Patients with non‐commercial insurance were more likely to develop ESRD, with cumulative incidence of 30.4% (95% CI 19.6–41.9%) compared to 12.7% (95% CI 5.0–24.2%) for patients with commercial insurance (P = 0.024).
Conclusion
In a primarily Black, uninsured LN population, despite achieving similar CR rates at 12 months, the incidence of ESRD and death exceeded those observed in controlled clinical trials with placebo arms.
While immunologic correlates of COVID-19 have been widely reported, their associations with post-acute sequelae of COVID-19 (PASC) remain less clear. Due to the wide array of PASC presentations, ...understanding if specific disease features associate with discrete immune processes and therapeutic opportunities is important. Here we profile patients in the recovery phase of COVID-19 via proteomics screening and machine learning to find signatures of ongoing antiviral B cell development, immune-mediated fibrosis, and markers of cell death in PASC patients but not in controls with uncomplicated recovery. Plasma and immune cell profiling further allow the stratification of PASC into inflammatory and non-inflammatory types. Inflammatory PASC, identifiable through a refined set of 12 blood markers, displays evidence of ongoing neutrophil activity, B cell memory alterations, and building autoreactivity more than a year post COVID-19. Our work thus helps refine PASC categorization to aid in both therapeutic targeting and epidemiological investigation of PASC.
Autoimmune pancreatitis (AIP) is a chronic inflammatory disease of the pancreas. Examination of pancreatic resection specimens from patients with AIP has shown that there are 2 subclasses of this ...disease. However, there is no widely accepted pathologic classification scheme and the clinical significance of such a classification remains to be established. In this study, we revisited the subclassification of AIP and examine whether this provides clinically and prognostically meaningful information. We evaluated 29 pancreatic resection specimens from patients with AIP. Demographic, clinical, and imaging data were recorded, as was evidence of extrapancreatic manifestations. In addition to a detailed and semiquantitative histologic evaluation, immunohistochemistry for IgG4 was performed on pancreatic and extrapancreatic tissues. We also evaluated 48 consecutive cases of chronic pancreatitis, not otherwise specified. The resected specimens could readily be subclassified into 2 subtypes: type 1 (n=11) and type 2 (n=18). In comparison with patients with type 2 disease, patients with type 1 disease were significantly more likely to be males (P=0.09), older (P=0.02), and present with jaundice (P=0.01), and less likely to be associated with abdominal pain (P=0.04). On imaging, the pancreatic tail cut-off sign was exclusively seen in patients with type 2 disease (4 of 10 cases). Hypercellular inflamed interlobular stroma was unique to type 1 pattern (91%), whereas significant ductal injury in the form of microabscesses and ductal ulceration was almost exclusively seen in type 2 pattern (78%). Eight of 10 patients with a type 1 pattern had evidence of a systemic disease. Three patients with type 2 disease had recurrent episodes of pancreatitis after their pancreatic resection. In comparison with the cohort of chronic pancreatitis, not otherwise specified, type 2 AIP cases were less likely to be associated with a history of alcohol abuse, and showed significantly more foci of periductal inflammation and neutrophilic microabscesses. Our review of pancreatic resection specimens shows 2 histologically distinct forms of AIP. Our data support the concept that type 1 AIP is a systemic disease and is the pancreatic manifestation of IgG4-related systemic disease. Type 2 disease is confined to the pancreas. The intensity of the periductal inflammatory infiltrate and the presence of ductal neutrophilic abscesses are features that assist in distinguishing type 2 AIP from chronic pancreatitis, not otherwise specified. Although imperfect, clinical and imaging features may help distinguish the 2 subtypes of AIP. On the basis of these significant differences between the 2 types of AIP, we advocate the position that all subsequent studies attempt to substratify their patients into these 2 groups.
To estimate the risk of malignancy in autoimmune pancreatitis (AIP).
We examined resected pancreata to compare the prevalence of pancreatic intraepithelial neoplasia (PanIN) in 28 cases of AIP and 30 ...cases of chronic pancreatitis not otherwise specified (CP-NOS). We also reviewed a cohort of 84 AIP cases.
The mean age of the AIP cohort (57 years) was significantly higher than that of the cohort of CP-NOS (47 years) (P = 0.01). Twenty-three cases (82%) of AIP showed PanIN, and 7 cases (25%) showed grade 2 PanIN. Grade 3 PanIN was identified in one case of AIP. There was no statistically significant difference in the number of cases with high-grade PanIN lesions between the cases of type 1 as opposed to type 2 AIP. In comparison to CP-NOS, a comparable percentage of patients with AIP had PanIN (82% of AIP cases vs 63% of CP-NOS cases) (P = NS) and PanIN 2 (25% AIP vs 20% CP-NOS) (P = NS). Of the 84 AIP cases at our institution (mean follow-up, 49 months), 2 cases of pancreatic carcinoma were identified 6 and 10 years after the diagnoses of AIP.
These findings raise concern that AIP is associated with an elevated risk of malignancy and should prompt additional studies.
