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IgG4-related disease (IgG4-RD) has only existed as a unique disease entity since 2003, yet remarkable progress has already been achieved in describing the essential features of the disease. A framework for systematic clinical studies has been created by the development of a quantitative disease activity tool (the IgG4-RD Responder Index) and the validation of classification criteria, both of which were the products of international, multi-centre investigations. In addition, substantial strides have been made in understanding the pathophysiology of IgG4-RD. In particular, the central role of B cells in the disease has been demonstrated by both the robust clinical responsiveness of IgG4-RD to B cell depletion and by the identification of multiple self-antigens that promote B cell expansion. CD4+ T cells have also been investigated in detail; CD4+ cytotoxic T lymphocytes (suspected of promoting disease) and a specific T follicular helper cell subset that contributes to IgG4 isotype switching have both been defined by multiple groups. The mechanisms by which these immune cells converge on target tissues, interact with fibroblasts and promote tissue remodelling are beginning to be understood and will be an important research focus in the coming years.Over the past few years, considerable advances have been made in understanding the pathogenesis of IgG4-related disease. Our increased knowledge of the important roles of B cells and T cells is now starting to make its way into the clinic.

Sjögren’s syndrome is a chronic autoimmune disorder whose pathogenesis is poorly understood and that lacks effective therapies. Detailed quantitative and spatial analyses of tissues affected by Sjögren’s syndrome were undertaken, including the quantitation of the frequency of selected cell–cell interactions in the disease milieu. Quantitative analyses of CD4 + T cell subsets and of CD8 + T cells in the labial salivary glands from untreated patients with primary Sjögren’s syndrome revealed that activated CD8 + cytotoxic T cells (CD8 + CTLs) were the most prominent T cells in these infiltrates. An accumulation of apoptotic glandular epithelial cells, mainly ductal and acinar cells, was observed, consistent with the impaired salivary secretion often observed in patients with this disease. FasL expressing activated CD8 + T cells were seen to accumulate around Fas expressing apoptotic epithelial cells. Quantitative analyses of apoptotic cell types and of conjugates between cytotoxic T cells and epithelial cells undergoing apoptosis suggest that Sjögren’s syndrome is primarily driven by CD8 + CTL mediated execution of epithelial cells mainly represented by ductal and acinar cells.

Background Immunoglobulin G4-related disease (IgG4-RD) and systemic sclerosis (SSc) are rare autoimmune diseases characterized by the presence of CD4+ cytotoxic T cells in the blood as well as inflammation and fibrosis in various organs, but they have no established etiologies. Similar to other autoimmune diseases, the gut microbiome might encode disease-triggering or disease-sustaining factors. Methods The gut microbiomes from IgG4-RD and SSc patients as well as healthy individuals with no recent antibiotic treatment were studied by metagenomic sequencing of stool DNA. De novo assembly-based taxonomic and functional characterization, followed by association and accessory gene set enrichment analysis, were applied to describe microbiome changes associated with both diseases. Results Microbiomes of IgG4-RD and SSc patients distinctly separated from those of healthy controls: numerous opportunistic pathogenic Clostridium and typically oral Streptococcus species were significantly overabundant, while Alistipes , Bacteroides , and butyrate-producing species were depleted in the two diseases compared to healthy controls. Accessory gene content analysis in these species revealed an enrichment of Th17-activating Eggerthella lenta strains in IgG4-RD and SSc and a preferential colonization of a homocysteine-producing strain of Clostridium bolteae in SSc. Overabundance of the classical mevalonate pathway, hydroxyproline dehydratase, and fibronectin-binding protein in disease microbiomes reflects potential functional differences in host immune recognition and extracellular matrix utilization associated with fibrosis. Strikingly, the majority of species that were differentially abundant in IgG4-RD and SSc compared to controls showed the same directionality in both diseases. Compared with multiple sclerosis and rheumatoid arthritis, the gut microbiomes of IgG4-RD and SSc showed similar signatures; in contrast, the most differentially abundant taxa were not the facultative anaerobes consistently identified in inflammatory bowel diseases, suggesting the microbial signatures of IgG4-RD and SSc do not result from mucosal inflammation and decreased anaerobism. Conclusions These results provide an initial characterization of gut microbiome ecology in fibrosis-prone IgG4-RD and SSc and reveal microbial functions that offer insights into the pathophysiology of these rare diseases.

ObjectiveIgG4-related disease (IgG4-RD) is a heterogeneous, multiorgan condition of unclear aetiology that can cause organ failure. Difficulty recognising IgG4-RD contributes to diagnostic delays. We sought to identify key IgG4-RD phenotypes.MethodsWe used two cross-sectional studies assembled by an international, multispecialty network of IgG4-RD specialists who submitted 765 cases to derive and replicate phenotypic groups. Phenotype groups of disease manifestations and key covariate distributions across the identified groups were measured using latent class analysis.ResultsIn the derivation cohort (n=493), we identified four groups with distinct manifestations: Group 1 (31%), Pancreato-Hepato-Biliary disease; Group 2 (24%), Retroperitoneal Fibrosis and/or Aortitis; Group 3 (24%), Head and Neck-Limited disease and Group 4 (22%), classic Mikulicz syndrome with systemic involvement. We replicated the identification of four phenotype groups in the replication cohort. Compared with cases in Groups 1, 2 and 4, respectively, cases in Group 3 were more likely to be female (OR 11.60 (95% CI 5.39 to 24.98), 10.35 (95% CI 4.63 to 23.15) and 9.24 (95% CI 3.53 to 24.20)) and Asian (OR 6.68 (95% CI 2.82 to 15.79), 7.43 (95% CI 2.97 to 18.56) and 6.27 (95% CI 2.27 to 17.29)). Cases in Group 4 had a higher median serum IgG4 concentration (1170 mg/dL) compared with groups 1–3 (316, 178 and 445 mg/dL, respectively, p<0.001).ConclusionWe identified four distinctive IgG4-RD phenotypes according to organ involvement. Being Asian or female may predispose individuals to head and neck-limited disease. These phenotypes serve as a framework for identifying IgG4-RD and studying its aetiology and optimal treatment.

IgG4-related disease is a multiorgan, relapsing, fibroinflammatory, immune-mediated disorder with no approved therapy. Inebilizumab targets and depletes CD19+ B cells and may be effective for treating patients with IgG4-related disease. In this phase 3, multicenter, double-blind, randomized, placebo-controlled trial, adults with active IgG4-related disease underwent randomization in a 1:1 ratio to receive inebilizumab (300-mg intravenous infusions on days 1 and 15 and week 26) or placebo for a 52-week treatment period. Participants in both groups received identical glucocorticoid tapers. Glucocorticoids were allowed to treat disease flares, but background immunosuppressants were not permitted. The primary end point was the first treated, adjudicated disease flare during the treatment period, assessed in a time-to-event analysis. Key secondary end points were the annualized flare rate and treatment-free and glucocorticoid-free complete remission. A total of 135 participants with IgG4-related disease underwent randomization: 68 participants were assigned to receive inebilizumab and 67 were assigned to receive placebo. Treatment with inebilizumab reduced flare risk; 7 participants (10%) in the inebilizumab group had at least one flare, as compared with 40 participants (60%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.06 to 0.28; P<0.001). The annualized flare rate was lower with inebilizumab than with placebo (rate ratio, 0.14; 95% CI, 0.06 to 0.31; P<0.001). More participants in the inebilizumab group than in the placebo group had flare-free, treatment-free complete remission (odds ratio, 4.68; 95% CI, 2.21 to 9.91; P<0.001) and flare-free, glucocorticoid-free complete remission (odds ratio, 4.96; 95% CI, 2.34 to 10.52; P<0.001). Serious adverse events occurred during the treatment period in 12 of the participants (18%) who received inebilizumab and 6 of the participants (9%) who received placebo. Inebilizumab reduced the risk of flares of IgG4-related disease and increased the likelihood of flare-free complete remission at 1 year, confirming the role of CD19-targeted B-cell depletion as a potential treatment for IgG4-related disease. (Funded by Amgen; MITIGATE ClinicalTrials.gov number, NCT04540497.).

Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of 35 untreated patients with early diffuse SSc and here show that CD4+ cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR-expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in patients with systemic sclerosis. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction.

Objective Immunoglobulin‐G4‐related disease (IgG4‐RD) is a systemic autoimmune disease that can affect nearly any organ, but its epidemiology remains poorly understood. Validated algorithms to identify cases in claims data will enable studies to describe IgG4‐RD epidemiology in the general population. Methods Potential claims‐based algorithms were developed by IgG4‐RD experts using a combination of International Classification of Diseases, Ninth Revision (ICD‐9) and International Classification of Diseases, 10th Revision (ICD‐10) codes, dispensed medications, and procedure codes for immunoglobulin G (IgG) subclass testing. Algorithms were tested using Medicare Parts A, B, and D linked to medical records (2007‐2017). Classification of cases as IgG4‐RD was determined using the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) classification criteria for IgG4‐RD. We estimated the positive predictive value (PPV) of each algorithm; sensitivity was determined using a cohort of patients with IgG4‐RD also enrolled in Medicare Parts A, B, and D during the study period. Results We identified seven algorithms that used a combination of ICD‐9 and ICD‐10 codes, medication prescriptions, and/or IgG subclass tests to identify patients with IgG4‐RD. The PPV of algorithms in the derivation cohort ranged from 57% to 100%, and sensitivity ranged from 0% to 58%. The best performing algorithm in the validation cohort had a PPV of 81% and a sensitivity of 58%. Typical IgG4‐RD manifestations were observed in the cohort (n = 36) assembled by this algorithm, including 50% with sialadenitis, 64% with pancreatic disease, 31% with renal disease, and 59% with an elevated IgG4 concentration. Conclusion We derived and validated a well‐performing algorithm to identify IgG4‐RD cases with typical manifestations of the disease. The claims‐based algorithm can be used in research studies of IgG4‐RD.

A Woman with Dyspnea and TachypneaA 19-year-old woman presented with respiratory failure. Examination was notable for a diastolic heart murmur and multiple bruits. A diagnosis and management decisions were made.

A 70-year-old man presented with a recurrent left pleural effusion. He had a history of polymyalgia rheumatica, relapsing polychondritis, scleritis, macrocytic anemia, and intermittent neutropenia, all of which had been refractory to multiple immunosuppressive agents. A diagnostic test was performed, and management decisions were made.

Purpose of Review Autoimmune pancreatitis (AIP) refers to a group of diseases characterized by chronic immune-mediated inflammation of the pancreas. In the past decade, there has been tremendous progress in the understanding of these forms of AIP, and as a result, the landscape of treatment and monitoring of AIP has evolved rapidly. Here, we summarize the pathophysiology and clinical presentation of Types 1 and 2 AIP and review the management of AIP based on recent literature.  Recent Findings Type 1 (lymphoplasmacytic) AIP is the pancreatic manifestation of IgG4-related disease (IgG4-RD), a systemic disease that most often presents with multiorgan involvement. Type 2 (idiopathic duct centric) AIP typically presents in younger individuals and is strongly associated with inflammatory bowel disease (IBD). Both may present with symptoms of pancreatitis or radiologic findings such as pancreatic enlargement or mass lesions. AIP frequently leads to pancreatic damage, including atrophy, exocrine insufficiency, or endocrine insufficiency (pancreatogenic diabetes mellitus), and all patients should be monitored longitudinally for the development of these complications. In contrast to Type 1 AIP, which typically has a chronic, relapsing course, the vast majority of cases of Type 2 AIP do not relapse. Glucocorticoids are universally effective in both, but the chronic and relapsing nature of Type 1 AIP necessitates the use glucocorticoid-sparing therapies. While observational data have supported the historical use of conventional immunosuppressive agents such as azathioprine, mycophenolate mofetil, and leflunomide in Type 2 AIP, recent studies including the phase 3 MITIGATE trial of inebilizumab in IgG4-RD have confirmed that B cell depletion is profoundly effective in the disease. Accordingly, B cell depletion should now be used as the first line treatment in most patients with Type 1 AIP/IgG4-RD. Multiple ongoing clinical trials are investigating the efficacy of other treatment targets in Type 1 AIP/IgG4-RD. As Type 2 AIP is most often monophasic, most patients do not require glucocorticoid-sparing medications; however, in relapsing cases associated with IBD, IBD-targeted medications may improve pancreatic inflammation as well. Summary In recent years, our understanding of the clinical presentation, pathophysiology, and treatment of AIP has grown immensely. While effective treatments exist, further research is needed to identify additional effective treatment options and clarify the optimal manner by which B cell depletion should be used to balance disease control and risk of immunosuppression.