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[Display omitted] IgG4-related disease (IgG4-RD), an example of a type I immune disease, is an immune-mediated fibrotic disorder characterized by dysregulated resolution of severe inflammation and wound healing. However, truly dominant or pathognomonic autoantibodies related to IgG4-RD are not identified. We sought to perform single-cell RNA sequencing and T-cell receptor and B-cell receptor sequencing to obtain a comprehensive, unbiased view of tissue-infiltrating T and B cells. We performed unbiased single-cell RNA-sequencing analysis for the transcriptome and T-cell receptor sequencing and B-cell receptor sequencing on sorted CD3+ T or CD19+ B cells from affected tissues of patients with IgG4-RD. We also conducted quantitative analyses of CD3+ T-cell and CD19+ B-cell subsets in 68 patients with IgG4-RD and 30 patients with Sjögren syndrome. Almost all clonally expanded T cells in these lesions were either Granzyme K (GZMK)-expressing CD4+ cytotoxic T cells or GZMK+CD8+ T cells. These GZMK-expressing cytotoxic T cells also expressed amphiregulin and TGF-β but did not express immune checkpoints, and the tissue-infiltrating CD8+ T cells were phenotypically heterogeneous. MKI67+ B cells and IgD−CD27−CD11c−CXCR5− double-negative 3 B cells were clonally expanded and infiltrated affected tissue lesions. GZMK+CD4+ cytotoxic T cells colocalized with MKI67+ B cells in the extrafollicular area from affected tissue sites. The above-mentioned cells likely participate in T-B collaborative events, suggesting possible avenues for targeted therapies. Our findings were validated using orthogonal approaches, including multicolor immunofluorescence and the use of comparator disease groups, to support the central role of cytotoxic CD4+ and CD8+ T cells expressing GZMK, amphiregulin, and TGF-β in the pathogenesis of inflammatory fibrotic disorders. [ABSTRACT FROM AUTHOR]

IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti–IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti–IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti–IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti–IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti–IL-1RA autoantibodies compared with those of the controls. A subset of patients with IgG4-RD have anti–IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti–IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases. [ABSTRACT FROM AUTHOR]

Myocardial infarction and ischemic stroke are leading causes of cardiovascular (CV) morbidity and mortality in ANCA-associated vasculitis (AAV), especially for the 20% with end-stage renal disease (ESRD). We assessed the impact of renal transplantation on the risk of myocardial infarction and stroke among patients with ESRD due to AAV. We identified patients from the United States Renal Data System with ESRD due to AAV between 2000 and 2016. We examined the association between renal transplantation and the risk of non-fatal and fatal myocardial infarction or ischemic stroke among waitlisted patients using Medicare claims and death data through 2017. We used time-varying Cox proportional hazards models with age as the time scale to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for myocardial infarction and ischemic stroke events among patients who received a renal transplant compared to those who remained on the waitlist. Of 1029 waitlisted patients, 593 (58%) were transplanted over a mean of 5.7 years. There were 17 events (4.6/1,000 person-years) in the transplanted group and 40 events (13.7/1,000 person-years) in the group that remained waitlisted. A renal transplant was associated with a 78% lower risk of myocardial infarction or ischemic stroke (HR=0.22, 95% CI 0.11 to 0.47). These findings persisted across sex and age groups and when censoring patients after living donor transplantation. Among AAV patients with ESRD, renal transplantation can substantially reduce the risk of myocardial infarction and ischemic stroke. Improving access to transplantation for this population may further improve outcomes. [ABSTRACT FROM AUTHOR]

The randomized, placebo (PBO)-controlled GiACTA trial demonstrated the efficacy and safety of tocilizumab (TCZ) in patients with giant cell arteritis (GCA). The present study evaluated the efficacy of TCZ in patients with GCA presenting with polymyalgia rheumatica (PMR) symptoms only, cranial symptoms only or both PMR and cranial symptoms in the GiACTA trial. In GiACTA, 250 patients with GCA received either TCZ weekly or every other week plus a 26-week prednisone taper or PBO plus a 26- or 52-week prednisone taper. This post hoc analysis assessed baseline characteristics, sustained remission rate, number of flares, annualized flare rate, time to flare, cumulative prednisone dose, methotrexate use and safety in patients with PMR symptoms only, cranial symptoms only or both at baseline. Overall, 52 patients had PMR symptoms only, 94 had cranial symptoms only and 104 had both symptoms at baseline. At Week 52, rates of sustained remission were significantly higher with TCZ vs PBO in all 3 groups (PMR only, 45.2% vs 19.0%, P = 0.0446; cranial only, 60.3% vs 19.4%, P = 0.0001; PMR and cranial, 55.0% vs 11.4%, P < 0.0001). Smaller proportions of TCZ-treated patients experienced disease flare than PBO-treated patients across all groups (PMR only, 41.9% vs 57.1%; cranial only, 20.7% vs 47.2%; PMR and cranial, 31.7% vs 81.8%). Annualized flare rate and risk of flare were significantly lower with TCZ vs PBO for patients with cranial symptoms only and both symptoms; they were numerically lower, but did not reach statistical significance, in the smaller group of patients with PMR symptoms only. TCZ improved clinical outcomes in patients who presented with PMR symptoms only, cranial symptoms only or both at baseline, suggesting that TCZ is effective in patients with GCA regardless of the presenting clinical phenotype. [ABSTRACT FROM AUTHOR]

IgG4-related disease (IgG4-RD), a multi-organ autoimmune disease, causes diverse manifestations that can lead to symptoms and distress. We developed and validated the Symptom Severity Index (SSI) to assess symptom burden. A pilot SSI was tested in n = 5; several gaps were identified. Twenty semi-structured qualitative interviews were performed to expand the item set and identify missing symptoms. Subsequent changes resulted in the current SSI; it was administered with quality of life (QOL) measures to n = 136. We assessed symptom burden and the construct validity of the SSI. A distress score for each symptom is calculated by multiplying symptom frequency ("Never" [0 points] to "Every Day" [3 points]) by associated distress ("None" [0 points] to "Very Much" [4 points]). Each distress score is summed to calculate a total SSI score. The SSI assesses the frequency and distress of 24 symptoms. Among n = 136 with ≥ 1 SSI, 90% experienced ≥ 1 symptom and 88% had distress. The median SSI score was 6.5 (IQR 3.0, 18.0). Fear of more severe disease was observed in 49%. The SSI inversely correlated with the SF-36 (r = - 0.51, p <0.001), the feeling thermometer (r = - 0.28, p <0.001), and the EQ-5D (r = - 0.28, p <0.001). The median SSI score was higher during active vs non-active disease among n = 52 who completed >1 SSI (15 [6, 26] vs. 3 [2, 14], p = 0.008). Symptoms and distress are common in IgG4-RD and associated with worse health-related QOL. The SSI has face, content, and construct validity; it corresponds with QOL measures. [ABSTRACT FROM AUTHOR]

Clinical notes from electronic health records (EHR) are important to characterize the natural history, comorbidities, and complications of ANCA-associated vasculitis (AAV) because these details may not be captured by claims and structured data. However, labor-intensive chart review is often required to extract information from notes. We hypothesized that machine learning can automatically discover clinically-relevant themes across longitudinal notes to study AAV. This retrospective study included prevalent PR3- or MPO-ANCA+ AAV cases managed within the Mass General Brigham integrated health care system with providers' notes available between March 1, 1990 and August 23, 2018. We generated clinically-relevant topics mentioned in notes using latent Dirichlet allocation-based topic modeling and conducted trend analyses of those topics over the 2 years prior to and 5 years after the initiation of AAV-specific treatment. The study cohort included 660 patients with AAV. We generated 90 topics using 113,048 available notes. Topics were related to the AAV diagnosis, treatment, symptoms and manifestations (e.g., glomerulonephritis), and complications (e.g., end-stage renal disease, infection). AAV-related symptoms and psychiatric symptoms were mentioned months before treatment initiation. Topics related to pulmonary and renal diseases, diabetes, and infections were common during the disease course but followed distinct temporal patterns. Automated topic modeling can be used to discover clinically-relevant themes and temporal patterns related to the diagnosis, treatment, comorbidities, and complications of AAV from EHR notes. Future research might compare the temporal patterns in a non-AAV cohort and leverage clinical notes to identify possible AAV cases prospectively. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Prostate involvement by IgG4-related disease (IgG4-RD) is a rarely described organ manifestation and knowledge regarding its frequency and clinical features is limited. From a single-center cohort, 168 male patients were examined who satisfied the 2019 ACR/EULAR classification criteria or 2012 consensus histopathologic criteria for IgG4-RD. Prostate involvement were identified in 25 (15%) of these cases. The majority of patients with IgG4-RD involving the prostate gland (80%) were symptomatic at presentation with incomplete voiding (64%), urinary frequency (52%), and urinary hesitancy (48%) being the most common complaints. The radiologic presentation of prostate disease is most often a focal abnormality suggesting inflammation rather than a mass lesion. While most patients with IgG4-related prostate disease (89%) experienced recurrence after or during glucocorticoid tapering, patients treated with B cell targeted therapy in this series experienced clinical improvement and were tapered off of glucocorticoids. Additionally, patients with IgG4-RD involving the pancreas (p = < 0.001) were more likely to have prostate involvement than were those with other types of organ involvement. This report provides the first comprehensive clinical description of IgG4-RD involving the prostate gland and links this manifestation with pancreatic involvement. [ABSTRACT FROM AUTHOR]

Abstract In 2015, a plebiscite was held on a new source of funding to support the expansion of the transit network in the Lower Mainland of Vancouver. Thus, in a region that has achieved admirable results over several decades through a strategic planning system based on a consensus model, civic leaders were forced to step outside this model to argue the case for a 0.5% increase to a local goods and service tax. This pitted a 'no new tax' grouping against a Better Transit and Transportation Coalition which brought supporters from across the community including from business, the unions, the environmental sector and students in support of the 'yes' case and the package of works crafted by consensus among municipal leaders. In this paper, we draw on in-depth key informant interviews with transportation and land use planners, municipal politicians and individuals involved in the 'yes' and 'no' campaigns built around the 2015 transport plebiscite. We show how the plebiscite was framed and how a critical component of Vancouver's planning ethos – consensus decision-making – catalysed the formation of the coalition of 'yes' campaign supporters. Despite its defeat, this coalition remained persistent and unified in their support for the development of a new funding stream and for the continued expansion of transit infrastructure across the Lower Mainland. The paper draws lessons from the transit plebiscite and how its outcome highlight the unique role that consensus planning can play in achieving progressive outcomes to politically vexing questions in transport planning in Vancouver and elsewhere. [ABSTRACT FROM AUTHOR]

Abstract Objective Therapeutic advances in ANCA-associated vasculitis (AAV) have improved patient survival, but mortality rates remain higher than the general population. Glucocorticoids contribute to AAV morbidity and mortality. We examined whether an 8-week glucocorticoid course in combination with rituximab (RTX) would induce disease remission in patients with AAV. Methods Patients with active AAV received an 8-week prednisone taper and RTX 375 mg/m2 weekly for 4 weeks. Patients with severe glomerulonephritis or diffuse alveolar hemorrhage requiring mechanical ventilation were excluded. In-person and telephone visits were scheduled for disease activity assessment. The primary endpoint was complete remission at 24 weeks (no disease activity while being off prednisone with no intercedent relapses). Secondary analysis included comparing study outcomes to historical controls from the Rituximab in AAV (RAVE) trial. Results Fourteen of 20 patients (70%) achieved the primary outcome. The patients in our trial achieved the primary outcome at a rate similar to that of controls from the RAVE trial (adjusted OR 1.31 [0.26–6.56]), had fewer median adverse events per patient (2 versus 8, p < 0.001) but were more likely to relapse (30% versus 7%, p = 0.03). Most relapses occurred in patients who had severe vasculitic manifestations at trial entry. Disease damage did not differ between the two trial populations. Conclusion An 8-week course of prednisone with RTX resulted in a similar rate of complete remission at 6 months as in the RAVE trial, with fewer adverse events but more frequent relapses. Further study of this protocol is warranted in selected patient populations. [ABSTRACT FROM AUTHOR]

IgG4-related disease (IgG4-RD) is a systemic autoimmune fibroinflammatory disease that can affect multiple organ systems. Although large-vessel vasculitis is a well-recognized manifestation of IgG4-RD, this condition is generally not regarded as a vasculitis. We aimed to describe coronary artery involvement (CAI), a vascular distribution about which little is known in IgG4-RD. Patients with IgG4-related CAI were identified from a large, prospective IgG4-RD cohort. CAI was confirmed by imaging evidence of arterial or periarterial inflammation in any coronary artery. We extracted details regarding demographics, features of IgG4-RD, and manifestations of CAI. Of 361 cases in the cohort, 13 (4%) patients had IgG4-related CAI. All were male and all had highly-elevated serum IgG4 concentrations, with a median value of 955 mg/dL (interquartile range [IQR]: 510–1568 mg/dL; reference: 4–86 mg/dL). Median disease duration at the time of CAI diagnosis was 11 years (IQR: 8.23–15.5 years). Extensive disease in the coronary arteries was the rule: all three major coronary arteries were involved in 11 patients (85%). The coronary artery manifestations included wall thickening or periarterial soft tissue encasement (85%), stenosis (69%), calcification (69%), and aneurysms or ectasia (62%). Five patients (38%) had myocardial infarctions, 2 (15%) required coronary artery bypass grafting, and 2 (15%) developed ischemic cardiomyopathy. Coronary arteritis and periarteritis are important manifestations of IgG4-RD, which should be regarded as a variable-vessel vasculitis that is among the most diverse forms of vasculitis known. Potential complications of CAI include coronary artery aneurysms, myocardial infarction, and ischemic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Summary Background Passenger leucocytes and inflammatory debris transferred from the donor limb to the recipient can induce allorecognition, which activates the host immune response. This is the first study to evaluate whether the transfer of this inflammatory burden can be reduced via post-preservation flush prior to revascularisation, and whether this is influenced by ischaemia. Methods Bilateral forelimbs from the same pig were procured and infused with preservation flush and stored on ice. Each limb from the same pig underwent a post-preservation intravascular flush with isotonic solution at either 2 or 6 h. Venous effluent underwent flow cytometry to phenotype leucocyte populations, with additional quantification of cytokines and cell-free DNA. Results We identified large populations of viable leucocytes in the flush effluent (8.65 × 10 8  ± 3.10 × 10 8 cells at 2 h and 1.02 × 10 9  ± 2.63 × 10 8 at 6 h). This comprised T cells, B cells, NK cells and monocytes. Post-preservation flush yielded significant concentrations of pro-inflammatory cytokines including IL-6, IL-18, GM-CSF, IL-1β, IL1α and CXCL-8 and mitochondrial DNA. The regulatory cytokine, IL-10 was undetectable. Conclusions This study supports the finding that a post-preservation flush removes leucocytes and inflammatory components that are responsible for direct presentation. This study also gives an indication of how ischaemia impacts on the inflammatory burden transferred to the recipient upon reperfusion. [ABSTRACT FROM AUTHOR]

Objective Giant cell arteritis (GCA) is an inflammatory vasculitis preferentially affecting large and medium-sized arteries. High-dose oral glucocorticoids (GCs) are the mainstay of GCA therapy. Using data from the UK Clinical Practice Research Datalink (CPRD), we examined the risk of oral GC-related serious adverse events (SAEs) in a UK population of patients with giant cell arteritis (GCA). Methods We conducted a series of nested case–control analyses in GCA patients to examine the effect of increasing dose of prednisolone on the risk of developing diabetes, glaucoma, osteoporosis, fractures, serious infection requiring hospitalization, and death. We used conditional logistic regression to calculate the unadjusted and multivariate odds ratios (ORs) with 95% CIs for the associations between prednisolone use and the risks of all outcomes of interest. We stratified the analyses by increasing cumulative prednisolone use and average daily dose. Results In the multivariate analyses, we observed a trend of increasing risk of diabetes and osteoporosis with increasing cumulative dose of oral prednisolone ( p trend < 0.05). GCA patients in the highest daily dose category (30 mg/d) had an increased risk of diabetes (adjusted OR, 95% CI) (4.7, 2.8–7.8), osteoporosis (1.9, 1.2–2.9), fractures (2.6, 1.6–4.3), glaucoma (3.5, 2.0–6.1), serious infection (3.3, 2.2–5.2), and death (2.1, 1.3–3.5) compared to those with lower average daily prednisolone doses (5 mg/d). Conclusion Compared to lower average daily prednisolone doses, high average daily doses were associated with an increased risk of serious adverse effects. [ABSTRACT FROM AUTHOR]

Objective To report entry criteria and clinical features of patients with newly diagnosed and relapsing giant cell arteritis (GCA) enrolled in a randomized trial of tocilizumab, an interleukin-6 receptor-alpha inhibitor. Methods Newly diagnosed GCA was defined as diagnosis ≤6 weeks before baseline. Relapsing GCA was defined as diagnosis >6 weeks before baseline with ≥2 consecutive weeks of prednisone ≥40 mg/day. All patients had active GCA within 6 weeks of baseline. All statistical results are exploratory. Results Of 251 patients, 119 (47%) had newly diagnosed and 132 (53%) had relapsing GCA. Mean age was 69 years in both subsets; 75% were women. Relapsing patients were heavier [difference in means (95% CI): women, 4.18 kg (0.49–7.87, P = 0.027); men, 8.25 kg (1.42–15.09, P = 0.019)] and had higher mean body mass index [difference in means (95% CI): women, 1.72 kg/m 2 (0.44–2.99, P = 0.009); men, 2.85 kg/m 2 (0.3 2 –5.37, P = 0.028)]. Relapsers had higher baseline prevalence of depression (16% vs. 4%) and osteopenia/osteoporosis (33% vs. 23%, P = 0.002 and P = 0.062, respectively). At diagnosis, 67% had new-onset headaches; 34% had mouth pain/jaw claudication. One-fifth had polymyalgia rheumatica symptoms but no cranial manifestations; 62% had positive temporal artery biopsy findings; 37% were enrolled on the basis of cross-sectional imaging study findings. Conclusions Demographics of the GiACTA population reflect the epidemiologic profile of GCA. Baseline comorbidities associated with glucocorticoids were more prevalent among relapsing patients than among those with newly diagnosed disease, highlighting the need for new GCA treatment options. More than one-third of patients were enrolled based on large-vessel imaging. [ABSTRACT FROM AUTHOR]