Increased prevalence of malignancies in patients with IgG4-related disease: implications for clinical care.

OBJECTIVES: The association between cancer and IgG4-related disease (IgG4-RD) is evolving. The primary aim of this study was to investigate the prevalence of malignancies in IgG4-RD. The secondary aim was to describe the epidemiological and clinical characteristics of IgG4-RD patients with a history of cancer. METHODS: Two hundred and ten patients with IgG4-RD were included in this retrospective study. IgG4-RD phenotypes, clinical and serological variables were analyzed. The prevalence of cancer in IgG4-RD was compared with that in the Italian population using the registry of the Global Cancer Observatory (GCO) of the World Health Organization. The Standardized Incidence Ratio (SIR) for cancer in IgG4-RD was obtained based on the 5-years Limited Duration Prevalence (2015-2020) of tumors in the Italian population. RESULTS: Thirty-seven/210 patients (18%) developed cancer before or after the diagnosis of IgG4-RD. Solid and hematologic tumors were more frequently observed in pancreato-biliary IgG4-RD. The SIR for malignancy in IgG4-RD patients was 2.54 higher than the general Italian population (p= 0.007). The SIR was 2.78 higher for males (p= 0.005) and 1.15 higher for females (p> 0.05). Thirty-two malignancies were diagnosed before and 16 after IgG4-RD diagnosis. Interval "from IgG4-RD to cancer" was shorter than that "from cancer to IgG4-RD". Most tumors occurring after IgG4-RD developed within 36 months from diagnosis of IgG4-RD. CONCLUSIONS: The prevalence of cancer in patients with IgG4-RD is increased compared with the Italian population and mechanistically suggests a possible paraneoplastic association. Close surveillance is warranted for the first 36 months after IgG4-RD diagnosis.

Fibrotic phenotype of IgG4-related disease.

A prompt response to glucocorticoids is a clinical hallmark of IgG4-related disease. However, manifestations characterised by prominent tissue fibrosis on histological examination can be less responsive to glucocorticoid therapy than other types of IgG4-related disease. These manifestations include retroperitoneal fibrosis, fibrosing mediastinitis, Riedel thyroiditis, orbital pseudotumor, and hypertrophic pachymeningitis, among others. To explain this discrepancy, a preliminary distinction into proliferative and fibrotic phenotypes of IgG4-related disease has been proposed on the basis of clinical presentation, pathological features, and response to immunosuppressive therapy. Implications of this classification for patient management remain an important area of investigation. In this Series paper, we aim to dissect the pathophysiology of tissue fibrosis in IgG4-related disease and discuss how clinicians should approach the management of fibrotic manifestations of IgG4-related disease based on the most recent diagnostic and therapeutic developments.

Association of autoimmune pancreatitis and intraductal papillary mucinous neoplasm. A retrospective analysis from a tertiary care referral center.

BACKGROUND: Autoimmune Pancreatitis (AIP) is a rare chronic inflammatory disease affecting the pancreas. Chronic pancreatic inflammation represents a risk factor for pre-neoplastic conditions such as Intraductal Papillary Mucinous Neoplasia (IPMN). Due to the rarity of AIP, the incidence, and clinical features of IPMN occurring in AIP patients remains unknown. AIMS: In the present study we aimed to explore the relationship between AIP and IPMN and to characterize the clinical features and outcomes of IPMN occurring in the context of AIP. METHODS: We retrospectively (2008-2020) analyzed the clinical and radiological records of a large single center cohort of patients with AIP and investigated the prevalence of IPMN. We then compared the clinical, laboratory and radiological characteristics of patients with IPMN and AIP with a cohort of patients with isolated IPMN. RESULTS: Five hundred and nineteen patients were included in this retrospective study. Sixteen patients had concomitant IPMN and AIP(3%); 61 patients had isolated AIP (12%); 442 patients had isolated IPMN (85%). The prevalence of IPMN in patients with AIP was higher than that observed in the general population (21%vs8-10%). Worrisome Features and High-Risk Stigmata were more frequently observed in IPMN occurring together with AIP compared to isolated IPMN(p < 0.05). Based on radiological features IPMN in the context of AIP was more frequently of main-duct type compared to isolated IPMN(p < 0.05). CONCLUSION: Our data suggest that AIP represents a chronic inflammatory condition that might favor IPMN development with high-risk features. Prolonged surveillance of these patients and longitudinal studies are required to further test the association with AIP and malignant and pre-malignant conditions.

Type 1 Autoimmune Pancreatitis in Europe: Clinical Profile and Response to Treatment.

BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) is an immune-mediated disease of the pancreas with distinct pathophysiology and manifestations. Our aims were to characterize type 1 AIP in a large pan-European cohort and study the effectiveness of current treatment regimens. METHODS: We retrospectively analyzed adults diagnosed since 2005 with type 1 or not-otherwise-specified AIP in 42 European university hospitals. Type 1 AIP was uniformly diagnosed using specific diagnostic criteria. Patients with type 2 AIP and those who had undergone pancreatic surgery were excluded. The primary end point was complete remission, defined as the absence of clinical symptoms and resolution of the index radiologic pancreatic abnormalities attributed to AIP. RESULTS: We included 735 individuals with AIP (69% male; median age, 57 years; 85% White). Steroid treatment was started in 634 patients, of whom 9 (1%) were lost to follow-up. The remaining 625 had a 79% (496/625) complete, 18% (111/625) partial, and 97% (607/625) cumulative remission rate, whereas 3% (18/625) did not achieve remission. No treatment was given in 95 patients, who had a 61% complete (58/95), 19% partial (18/95), and 80% cumulative (76/95) spontaneous remission rate. Higher (≥0.4 mg/kg/day) corticosteroid doses were no more effective than lower (<0.4 mg/kg/day) doses (odds ratio, 0.428; 95% confidence interval, 0.054-3.387) and neither was a starting dose duration >2 weeks (odds ratio, 0.908; 95% confidence interval, 0.818-1.009). Elevated IgG4 levels were independently associated with a decreased chance of complete remission (odds ratio, 0.639; 95% confidence interval, 0.427-0.955). Relapse occurred in 30% of patients. Relapses within 6 months of remission induction were independent of the steroid-tapering duration, induction treatment duration, and total cumulative dose. CONCLUSIONS: Patients with type 1 AIP and elevated IgG4 level may need closer monitoring. For remission induction, a starting dose of 0.4 mg/kg/day for 2 weeks followed by a short taper period seems effective. This study provides no evidence to support more aggressive regimens.

Safety of Janus Kinase Inhibitors: A Real-World Multicenter Retrospective Cohort Study.

OBJECTIVE: Oral Janus kinase inhibitors (JAKis) represent an effective strategy for rheumatoid arthritis (RA) treatment. A previous study supported that tofacitinib (TOF) is associated with higher incidence of cardiovascular (CV) and neoplastic events compared to tumor necrosis factor inhibitors. Given the apparent discrepancy between these data and real-world experience, we aimed to investigate the safety and efficacy of the available JAKis in a multicenter cohort. METHODS: We retrospectively evaluated patients with RA who ever received 1 JAKi (TOF, baricitinib [BAR], upadactinib [UPA], filgotinib [FIL]) from 4 tertiary care centers in Milan, Italy. Outcomes related to JAKi safety were recorded, particularly major CV events as well as adverse events of special interest (AESIs), which included serious infections, opportunistic infections, venous thromboembolism, herpes zoster infections, liver injury, malignancies, and deaths; retention rates were also calculated. Further analyses included patients fulfilling the risk factors suggested to influence TOF safety. RESULTS: Six hundred eighty-five patients were included and received BAR (48%), TOF (31%), UPA (14%), or FIL (7%) as first-line innovative treatment prior to a biologic. Of a total of 1137 patient-years of observation, we recorded 1 stroke and 123 (18%) AESIs, including 3 deaths, all a result of severe infections. Among patients with a higher CV risk, we observed a higher frequency of AESIs (23%). CONCLUSION: Our real-world data confirm that JAKis are effective and carry a low risk of AESIs, especially in patients who do not display CV risk factors at baseline. Our study could not identify differences between JAKis. Different safety profiles should be defined in larger prospective cohorts.

Role of systemic immunosuppression on subglottic stenosis in granulomatosis with polyangiitis: Analysis of a single-centre cohort.

PURPOSE: Subglottic stenosis (SGS) is a potentially life-threatening manifestation of granulomatosis with polyangiitis (GPA). Endoscopic dilation is effective, but relapses are frequent and the benefit of systemic immunosuppression in this setting is still controversial. We aimed to investigate the role of immunosuppressive treatment on SGS relapse risk. METHODS: This is a retrospective observational study based on review of medical charts among our cohort of patients with GPA. RESULTS: Twenty-one patients with SGS-GPA were identified, with a prevalence of 20% among our entire GPA cohort (n = 105). Compared to patients without SGS, patients with SGS-GPA had an earlier disease onset (mean age 30.2 vs. 47.3 years, p<0.001), and lower BVAS (mean 10.5 vs 13.5; p = 0.018). Five patients didn't receive systemic immunosuppression for SGS and they all (100%) relapsed after the first procedure, while among medical treatment group relapse rate was 44% (p = 0.045). When single treatment regimens are considered, rituximab (RTX) and cyclophosphamide (CYC) yielded a protective role towards the need of subsequent dilation procedure after the first if compared with absence of medical treatment. Patients with SGS and generalized disease, who initially received either a RTX- or a CYC-based induction treatment, and higher cumulative doses of glucocorticoids, showed a delayed median time to SGS relapse (36 vs. 12 months, p = 0.024). CONCLUSIONS: Subglottic stenosis is highly prevalent in patients with GPA and may define a milder systemic disease subset occurring more frequently in younger patients. Systemic immunosuppression provides benefit in preventing recurrence of SGS in GPA patients and regimens based on cyclophosphamide or rituximab might have a non-redundant role in this setting.

Association of IgG4-related disease and systemic rheumatic disorders.

PURPOSE: Autoimmune disorders can occur together especially in genetically predisposed individuals. We here aimed to assess the occurrence of IgG4-related disease (IgG4-RD) in association with other systemic immune-mediated conditions. METHODS: We retrospectively analyzed the clinical records of patients with IgG4-RD followed at the IgG4-RD Clinic of San Raffaele Hospital (Milan, Italy) for pre-existing or concomitant immune-mediated disorders. IgG4-RD was diagnosed based on histological findings and on the 2011 Comprehensive Diagnostic criteria. Associated immune-mediated disorders were diagnosed based on available classification and/or diagnostic criteria. RESULTS: Two-hundred and thirty-four patients with a definitive diagnosis of IgG4-RD were included in this study. A pre-existing immune-mediated connective tissue disease was reported in 6/234 patients (3%): one case each of sarcoidosis, Takayasu arteritis (TA), eosinophilic granulomatosis with polyangitis (EGPA), and rheumatoid arthritis; and two cases of granulomatosis with polyangitis (GPA). Organs involved by IgG4-RD included the lungs, the pancreas, the peritoneum, lacrimal glands, meninges and orbits. Sarcoidosis, EGPA, and TA preceded the onset of IgG4-RD. GPA preceded IgG4-RD onset in one case and occurred simultaneously in the other case. Rheumatoid arthritis occurred together with IgG4-RD in one case. CONCLUSION: Our observation suggests that "secondary" IgG4-RD can present in the context of pre-existing systemic immune-mediated disorders and complicate systemic autoimmune diseases as well as chronic granulomatous conditions. Further studies are needed to define whether this peculiar clinical scenario is associated with different genetic backgrounds, pathological bases, and long-term outcomes.

Development of an algorithm for IgG4-related disease management.

OBJECTIVES: IgG4-related disease (IgG4-RD) is a rare fibro-inflammatory condition affecting multiple organs lacking standardized management. In this article, we review the evidence available to provide European expert-based statements on the management of IgG4-RD which were integrated in a final algorithm. METHODS: A panel of nine European experts in IgG4-RD from different specialties was asked to elaborate a set of consensus statements through a Delphi exercise. Three rounds of survey were taken. Consensus was reached when ≥75% of the responders agreed with a statement. RESULTS: Thirty-one statements on induction treatment, maintenance treatment, non-pharmacological treatment, and general considerations were assessed. Patients should be treated promptly in situations when there is an immediate organ threatened, or when organ damage is anticipated. Glucocorticoids (GC) are considered the first line of treatment and should be progressively tapered. Maintenance treatment is recommended for patients with high disease activity or with risk factors for relapse. Rituximab is effective for induction and maintenance of remission, but its use can be limited by economics. Low dose GC with or without GC-sparing agents can be used for maintenance therapy. Stenting or surgery should be ancillary to pharmacological treatment. Follow up should be based on physical examination, blood works, and imaging studies. Furthermore, it should be tailored on individual patient clinical history. 18-fluorodeoxyglucose positron emission tomography/computerized tomography may provide additional information over other imaging modalities. CONCLUSIONS: These new statements and algorithm reached a high degree of agreement and may help guiding the clinical management of IgG4-RD.

Unraveling the relationship between autoimmune pancreatitis type 2 and inflammatory bowel disease: Results from two centers and systematic review of the literature.

INTRODUCTION: The relationship between autoimmune pancreatitis (AIP) type 2 and inflammatory bowel disease (IBD) has been established and previously described within International Consensus Diagnostic Criteria. However, it is unknown if the presence of IBD changes the natural disease course of AIP type 2. Our aim was to investigate the association between AIP type 2 and IBD as well as to systematically summarize all the existing evidence in the literature. METHODS: Electronic medical record analysis was conducted in two centers (in Stockholm, Sweden, and Milan, Italy; records dated between January 2001 and June 2021). Additionally, we conducted a systematic review of the literature. RESULTS: A total of 35 patients (18 females, 51.4%) fulfilled the diagnostic criteria of AIP type 2 and were included in the study. A diagnosis of IBD was established in 29 patients (82.8%), ulcerative colitis in 17 (58.6%) and Crohn's disease in 11 (37.9%). Median follow-up was 54 months. AIP patients with IBD commonly presented with abdominal pain and/or acute pancreatitis at diagnosis, the latter was prevailing in concomitant and later IBD onset. These patients more frequently used steroids, but there were no differences in relapse rates. Concomitant onset of IBD was associated with the development of diabetes mellitus. There were no cases of colon or pancreatic malignancy during follow-up. In our systematic analysis, a total of 693 AIP type 2 patients were included from 24 single-center retrospective studies and 8 multicenter retrospective studies. A diagnosis of IBD was reported in 330 (47.8%) patients. Relapse rate was 20.0%. CONCLUSIONS: Clinical and radiological remission of AIP type 2 was high, while the cumulative incidence of relapse is around 20%. Our results show that concomitance of IBD imposes no obvious risk of a different disease course for AIP type 2.

Blood biomarkers recommended for diagnosing and monitoring IgG4-related disease. Considerations from the ERN ReCONNET and collaborating partners.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a chronic, clinically heterogenous fibroinflammatory condition, characterised by an accumulation of IgG4 secreting plasma cells in affected tissues and associated with increased serum IgG4 concentrations. Despite a growing recognition of the disease among clinicians from different specialties worldwide, its indolent nature, lack of a single diagnostic test and ability to mimic other malignant, infective and inflammatory conditions, makes the diagnosis challenging. As treatment options evolve, biomarkers correlating with disease activity, predicting prognosis and response to treatment are deemed required. A multidisciplinary panel of experts from the European Reference Network for Rare and Complex Connective tissue diseases (ERN ReCONNET) and affiliated international partners have performed a narrative literature search and reviewed the current evidence of biomarkers in IgG4-RD, including immunoglobulins, cytokines, chemokines and other soluble immune mediators, and cellular components of the immune system. The aim of this paper is to provide useful information for clinicians as to the utility of biomarkers for diagnosing and monitoring IgG4-RD in clinical routine and sets out recommendations for clinical decision making.

Differential EUS findings in focal type 1 autoimmune pancreatitis and pancreatic cancer: A proof-of-concept study.

Background and Objectives: Autoimmune pancreatitis (AIP) often mimics pancreatic cancer (PC), particularly if presenting as a focal lesion. EUS may orient the differential diagnosis between them. This study aims to identify EUS findings that might be useful to differentiate type 1 focal autoimmune pancreatitis (f-AIP1) and PC. Materials and Methods: F-AIP1 and PC patients were retrospectively collected, matched, and compared. EUS findings considered were: focal mass echogenicity, loss of lobularity, distal atrophy, peripancreatic hypoechoic margins (PHM), pancreatic duct dilation, duct-penetrating sign (DPS), pancreatic/common bile duct thickened walls (PD/CBD-TW), and vessel infiltration (VI). Elastography findings were also recorded. Variables with a P < 0.05 at univariate analysis were included in logistic multiple regression. Results: Fifteen patients with f-AIP and 60 with PC were studied. FE was hypoechoic in all patients from both groups. PHM was observed in 40% of f-AIP1 cases but not in PC ones (P < 0.001). DPS was found in 10/15 (66.7%) f-AIP1 and in 7/60 (11.7%) PC patients (P < 0.001). PD-TW and CBD-TW were observed in 66.7%/60% f-AIP1 cases and in 6.7%/13.6% PC patients, respectively (P < 0.001 for both comparisons). Pancreatic masses were significantly different at EUS elastography (elastic respectively in 71.4% f-AIP1 and 3.8% PC, P < 0.001). VI was suspected in 20% of f-AIPs and 85% of PCs (P < 0.001). At multiple regression, PD-TW, CBD-TW, elastic pattern, and the absence of VI independently supported a diagnosis of f-AIP1. Conclusions: Our results suggest that EUS findings deserve consideration in the diagnostic workup of AIP to improve the differential diagnosis with PC.

Respiratory Impairment Predicts Response to IL-1 and IL-6 Blockade in COVID-19 Patients With Severe Pneumonia and Hyper-Inflammation.

BACKGROUND: Restraining maladaptive inflammation is considered a rationale strategy to treat severe coronavirus disease-19 (COVID-19) but available studies with selective inhibitors of pro-inflammatory cytokines have not provided unequivocal evidence of survival advantage. Late administration is commonly regarded as a major cause of treatment failure but the optimal timing for anti-cytokine therapy initiation in COVID-19 patients has never been clearly established. OBJECTIVES: To identify a window of therapeutic opportunity for maximizing the efficacy of interleukin (IL)-1 and IL-6 blockade in COVID-19. METHODS: Survival at the longest available follow-up was assessed in severe hyper-inflamed COVID-19 patients treated with anakinra, tocilizumab, sarilumab, or standard of care, stratified according to respiratory impairment at the time of treatment initiation. RESULTS: 107 patients treated with biologics and 103 contemporary patients treated with standard of care were studied. After a median of 106 days of follow-up (range 3-186), treatment with biologics was associated with a significantly higher survival rate compared to standard therapy when initiated in patients with a PaO2/FiO2 ≥ 100 mmHg (p < 0.001). Anakinra reduced mortality also in patients with PaO2/FiO2 < 100 mmHg (p = 0.04). CONCLUSIONS: IL-1 and IL-6 blocking therapies are more likely to provide survival advantage in hyper-inflamed COVID-19 patients when initiated before the establishment of severe respiratory failure.

Mer tyrosine kinase as a possible link between resolution of inflammation and tissue fibrosis in IgG4-related disease.

OBJECTIVES: IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disorder characterized by a dysregulated resolution of inflammation and wound healing response that might develop after an apoptotic insult induced by cytotoxic T lymphocytes (CTLs). Mer receptor tyrosine kinase (MerTK) and its ligand, protein S (ProS1), have a pivotal role in the resolution of inflammation, being implicated in the clearance of apoptotic cells, quenching of the immune response and development of tissue fibrosis. In the present work we aimed to investigate a possible involvement of the MerTK signalling pathway in the pathogenesis of IgG4-RD and development of tissue fibrosis. METHODS: MerTK and ProS1 expression patterns in IgG4-RD lesions were evaluated by immunohistochemistry and immunofluorescence studies. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were measured in the peripheral blood of IgG4-RD patients and healthy controls by flow cytometry and ELISA, respectively. RESULTS: MerTK was highly expressed by macrophages infiltrating IgG4-RD lesions. MerTK+ macrophages were more abundant in IgG4-RD than in Sjögren's syndrome and interacted with apoptotic cells and ProS1-expressing T and B lymphocytes. Moreover, they expressed the pro-fibrotic cytokine TGF-ß and their numbers declined following rituximab-induced disease remission. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were not increased in the peripheral blood of patients with IgG4-RD. CONCLUSIONS: The MerTK-ProS1 axis is activated in IgG4-RD lesions, possibly leading to persistent stimulation of processes involved in the resolution of inflammation and tissue fibrosis.

IgG4-Related Disease of the Oral Cavity. Case Series from a Large Single-Center Cohort of Italian Patients.

A series of destructive and tumefactive lesions of the oral cavity are increasingly recognized as part of the IgG4-related disease (IgG4-RD) spectrum. We herein examined the clinical, serological, radiological, and histological features of a series of patients referred to our clinic because of oral cavity lesions ultimately attributed to IgG4-RD. In particular, we studied 6 consecutive patients out of 200 patients referred to the immunology outpatient unit who presented with erosive and/or tumefactive lesions of the oral cavity. All patients underwent serum IgG4 measurement, nasal endoscopy, radiological studies, and histological evaluation of tissue specimens. The histological studies included immunostaining studies to assess the number of IgG4+ plasma cells/High-Power Field (HPF) for calculation of the IgG4+/IgG+ plasma cell ratio. Six patients (3% of the entire cohort) were diagnosed with IgG4-RD of the oral cavity based on histological evaluation. A major complaint at presentation was oral discomfort due to bulging mass. A mild to no increase in serum IgG4 was observed. Different patterns of organ involvement were associated with oral lesions. Five patients were treated with immunosuppressive therapy and two patients promptly responded to B-cell depletion with rituximab. Watchful waiting was decided in one patient with no major clinical symptoms. Involvement of the oral cavity is an infrequent manifestation of IgG4-RD but should be taken into consideration as a possible differential diagnosis of tumefactive or erosive lesions once neoplastic conditions are excluded. A histological examination of biopsy samples from the oral cavity represents the mainstay for diagnosis of IgG4-RD.

B lymphocytes contribute to stromal reaction in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent stromal reaction that has been variably implicated in both tumor growth and tumor suppression. B-lymphocytes have been recently implicated in PDAC progression but their contribution to the characteristic stromal desmoplasia has never been assessed before. In the present work, we aimed to verify whether B-lymphocytes contribute to stromal cell activation in PDAC. CD19+ B-lymphocytes purified from peripheral blood of patients with PDAC were cultivated in the presence of human pancreatic fibroblasts and cancer-associated fibroblasts. Released pro-fibrotic soluble factors and collagen production were assessed by ELISA and Luminex assays. Quantitative RT-PCR was used to assess fibroblast activation in the presence of B cells. The expression of selected pro-fibrotic and inflammatory molecules was confirmed on PDAC tissue sections by multi-color immunofluorescence studies. We herein demonstrate that B-cells from PDAC patients (i) produce the pro-fibrotic molecule PDGF-B and stimulate collagen production by fibroblasts; (ii) express enzymes implicated in extracellular matrix remodeling including LOXL2; and (iii) produce the chemotactic factors CCL-4, CCL-5, and CCL-11. In addition we demonstrate that circulating plasmablasts are expanded in the peripheral blood of patients with PDAC, stimulate collagen production by fibroblasts, and infiltrate pancreatic lesions. Our results indicate that PDAC is characterized by perturbations of the B-cell compartment with expansion of B-lymphocyte subsets that directly contribute to the stromal reaction observed at disease site. These findings provide an additional rationale for modulating B-cell activity in patients with pancreatic cancer.

PrescrAIP: A Pan-European Study on Current Treatment Regimens of Auto-Immune Pancreatitis.

Introduction: Treatment of autoimmune pancreatitis (AIP) is based solely on consensus and has yet to become standardized. Consequently, therapeutic regimens vary greatly between countries and centers, and largely depend on the experience of the physician. At this moment, the optimal regimen for inducing disease remission and preventing relapse is unknown. Objectives: The primary objective of this study is to describe current treatment regimens used in Europe, and to compare their effectiveness in inducing remission and preventing and treating relapse. The secondary objectives are: to identify risk factors for relapse; to assess the diagnostic accuracy of the Unified-AIP criteria; to assess the performance of the M-ANNHEIM score for predicting relapse; and to assess long-term outcomes including pancreatic exocrine insufficiency and pancreatic cancer. Methods: This is an international, retrospective, observational cohort study, performed in over 40 centers from 16 European countries. Eligible are all patients diagnosed with AIP from 2005 onwards, regardless of the used diagnostic criteria. Data on study subjects will be retrieved from the hospital's electronic medical records and registered with a standardized, web-based, electronic case report form (eCRF). To compare the effectiveness of treatment regimens in inducing remission, preventing relapse, and treating relapse, subjects will be stratified in groups based on: type of therapy; initial therapy dose; cumulative therapy dose; therapy tapering speed and duration; and having received maintenance therapy or not. Ethics and Dissemination: Ethical and/or institutional review board approvals are obtained by all participating centers according to local regulations. The study complies with the General Data Protection Regulation (GDPR). All manuscripts resulting from the study will be submitted to peer-reviewed journals. Conclusion: This is the first pan-European retrospective registry for AIP. It will produce the first large-scale data on treatment of European patients with AIP, providing answers on the use and effectiveness of treatment regimens. In the future, this collaboration may provide a network for continuation into a prospective European registry.

Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study.

OBJECTIVES: To assess the safety and efficacy of interleukin (IL)-6 blockade with sarilumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation. METHODS: We conducted an open-label study of sarilumab in severe COVID-19 pneumonia (PaO2/FiO2 <300 mm Hg) with hyperinflammation (elevated inflammatory markers and serum IL-6 levels). Sarilumab 400 mg was administered intravenously in addition to standard of care and results were compared with contemporary matched patients treated with standard of care alone. Clinical improvement, mortality, safety and predictors of response were assessed at 28 days. RESULTS: Twenty-eight patients were treated with sarilumab and 28 contemporary patients receiving standard of care alone were used as controls. At day 28 of follow-up, 61% of patients treated with sarilumab experienced clinical improvement and 7% died. These findings were not significantly different from the comparison group (clinical improvement 64%, mortality 18%; p=NS). Baseline PaO2/FiO2 ratio >100 mm Hg and lung consolidation <17% at CT scan predicted clinical improvement in patients treated with sarilumab. Median time to clinical improvement in patients with lung consolidation <17% was shorter after sarilumab (10 days) than after standard treatment (24 days; p=0.01). The rate of infection and pulmonary thrombosis was similar between the two groups. CONCLUSIONS: At day 28, overall clinical improvement and mortality in patients with severe COVID-19 were not significantly different between sarilumab and standard of care. Sarilumab was associated with faster recovery in a subset of patients showing minor lung consolidation at baseline.

Clinical phenotypes of IgG4-related disease reflect different prognostic outcomes.

INTRODUCTION: Four clinical phenotypes of IgG4-related disease (IgG4-RD) have been recently identified by latent class analysis (LCA): pancreato-biliary (group 1); retroperitoneum/aortitis (group 2); head and neck limited (group 3); and Mikulicz/systemic (group 4). The reproducibility of this classification in clinical practice and its relevance for patient management, however, remain unknown. METHODS: The study included 179 patients. Four IgG4-RD experts were asked to classify a validation cohort of 40 patients according to published LCA-derived phenotypes based on clinical judgement. Agreement between LCA and clinical clustering was calculated. To assess differences among disease phenotypes, the following variables were recorded on an additional 139 patients: serum IgG4 and IgE; inflammatory markers; eosinophils; plasmablasts; IgG4-RD responder index (RI); history of atopy, diabetes, osteoporosis, relapses and malignancy; cumulative dose of glucocorticoids; and use of rituximab. RESULTS: Clinical judgement replicated LCA classification with strong agreement among IgG4-RD experts (κ = 0.841, P < 0.0005). At disease onset, group 1 showed the highest levels of serum IgG4 and IgE. Groups 2 and 4 had the lowest and highest IgG4-RD RI, respectively. At 2 years' follow-up, group 3 received the highest cumulative dose of glucocorticoids, but higher incidences of diabetes mellitus were observed in groups 1 and 4, consistent with the higher likelihood of pancreatic involvement in groups 1 and 4. No difference among the four groups was observed in terms of disease recurrence, time to relapse and frequency of rituximab infusion. CONCLUSION: Clinical phenotypes of IgG4-RD reflect differences in epidemiological features and prognostic outcomes.