Endoscopic Ultrasound With Fine Needle Biopsy Confirming a Diagnosis of Immune Checkpoint Inhibitor-Related Type 3 Autoimmune Pancreatitis

Can histopathology be the “Gold Standard” for diagnosing autoimmune pancreatitis?

Introduction: Autoimmune pancreatitis (AIP), types 1 and 2, are well described. While type 1 AIP is a pancreatic manifestation of immunoglobulin G4-related disease (IgG4-RD) and type 2 AIP is a duct-centric pancreatic injury sometimes associated with inflammatory bowel disease. A third form of AIP (type 3) is caused by increased immune activity by immune checkpoint inhibitor therapy (ICI-℞) for advanced malignancies. We describe the clinico-radiological spectrum and short-term natural history of type 3 AIP. Methods: We performed a detailed clinical record review of the 248/11,165 (2.2%) adult patients receiving ICI-℞ who developed type 3 AIP (>3-fold serum lipase elevation + pain, absent other etiologies). A radiologist reviewed 379 abdominal computerized tomography scans (CT) and measured pancreas volume in a subset of CTs done before, during and after pancreatitis. Results: At onset, type 3 AIP was painful in 96 (38%) and asymptomatic in 154 (62%); none had jaundice or local/systemic complications. CT showed normal pancreas (43%), peri-pancreatic edema (27%), loss of feathery pattern (21%) or diffuse/focal pancreatic enlargement (10%). A minority achieved complete and persistent biochemical resolution, more often when ICI-℞ was held (32/89) vs no intervention (13/84, P = 0.003) or vs steroid treatment alone (2/23, P = 0.01). Early or late relapses occurred equally frequently regardless of intervention. Compared to pancreas volume before ICI-℞, >20% volume loss occurred in 55% 1 year post-pancreatitis, more so with dual ICI-Rx, regardless of pain or steroid therapy at presentation. 18% had new diabetes within 2 years of pancreatitis. No patient developed calcifications or duct dilation. Conclusion: Type 3 AIP is a novel drug-induced chronic inflammatory disease of the pancreas. Predominantly asymptomatic and mild in severity, it causes rapid pancreatic atrophy and functional endocrine failure despite steroid therapy or ICI-℞ withdrawal. Table 1. - Clinical profile of all type 3 and subjects in imaging cohorts Type 3 AIP* (n=248) Imaging cohort (n=93) Symptomatic (n=94) Asymptomatic (n=154) ≥3x lipase elevation cohort (n=48) 2x lipase elevation cohort (n=24) Normal lipase cohort (n=21) Median Age in years (IQR) 61 (50-68) 62 (54-69) 58 (49-67) 63 (54-69) 59 (55-67) Male N (%) 37 (39%) 72 (47%) 17 (35%) 18 (75%) 13 (62%) Cancer type (%) Genitourinary 27 (29%) 63 (41%) 20 (42%) 14 (58%) 10 (48%) Melanoma 26 (28%) 28 (18%) 16 (33%) 3 (13%) 5 (24%) Other 41 (44%) 63 (41%) 12 (25%) 7 (29%) 6 (29%) ICI Agent (%) CTLA-4 8 (9%) 10 (6%) 5 (10%) 2 (8%) 4 (19%) PD-1 62 (66%) 95 (62%) 28 (58%) 14 (58%) 10 (48%) Combined 24 (26%) 49 (32%) 15 (31%) 8 (33%) 7 (33%) ICI doses prior to elevated lipase (IQR) 4 (2-6) 3 (2-8) 5.5 (3-10) 4.5 (3-13) 3 (2-5, to normal lipase) Median days from ICI to pancreatitis (IQR) 114 (69-264) 113 (52-230) 124 (83-261) 175 (63-348) 95 (47-167, to normal lipase) ICI discontinued (%) 67 (71%) 74 (48%) 28 (58%) 14 (58%) 11 (52%) Risk factors (%) Alcohol consumption 40 (43%) 69 (45%) 22 (46%) 13 (54%) 12 (57%) Smoking history 52 (55%) 77 (50%) 24 (50%) 17 (71%) 7 (33%) Diabetes prior to pancreatitis 16 (17%) 44 (29%) 15 (31%) 6 (25%) 4 (19%) Drug allergy 56 (60%) 81 (53%) 22 (46%) 10 (42%) 10 (48%) Prior history of pancreatitis 5 (5%) 6 (4%) 2 (4%) 1 (4%) 0 *Autoimmune pancreatitis, IQR= interquartile range, ICI= immune checkpoint inhibitor, CTLA-4 (cytotoxic T lymphocyte-associated protein 4), PD-1 (programmed cell death receptor-1) and PD-L1 (programmed cell death ligand-1) Figure 1.: a: Serial pancreatic volume in normal lipase, 2x and 3x groups (median, cm3), b: Serial Pancreatic Volume: Single Agent vs Combination in 3x group (median, cm3), c: Percentage of patients with >20% pancreas volume loss in each group.

Atypical Antiglomerular Basement Membrane Nephritis Following Immune Checkpoint Inhibitor

Autoimmune Dorsal Pancreatitis: Involvement of the Pancreatic and Bile Ducts in Autoimmune Pancreatitis

<h3>Background</h3> Immune-related adverse events (irAEs) induced by immune checkpoint inhibitor (ICI) therapy can involve multiple organ systems, of which cutaneous irAEs (c-irAEs) are the most common.^1–5 Understanding co-occurrence patterns and...

Type 3 auto-immune pancreatitis (AIP) is a rare immune-related adverse event (irAE) because of immune checkpoint inhibitor (ICI) therapy employed in the management of advanced malignancies. The evaluation and management of this disease entity is not well documented in the literature. We summarize the available information on the clinical profile, diagnosis, and treatment of this disorder. ICI-pancreatic injury (ICI-PI) is a form of AIP, recently termed type 3 AIP, which may present as an asymptomatic lipase elevation or clinical pancreatitis, that is, abdominal pain and elevated lipase. CT findings of pancreatitis may be absent in some cases. Diagnosis is based on a temporal relationship to ICI exposure and the absence of other cause of pancreatitis. Combination ICIs increase the risk of type 3 AIP compared with ICI monotherapy. Though corticosteroids are used for ICIP, their role and benefit remain unclear to date. Holding immunotherapy carries the risk of progression of underlying cancer. ICI-PI is a unique form of AIP (type 3) with a distinct disease profile. The majority of patients with ICIPI are asymptomatic and steroid therapy has unclear benefits.

EUS-guided FNA for diagnosing autoimmune pancreatitis: Doesit enhance existing consensus criteria?

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized cancer therapy over the last decade. Despite the efficacy of ICIs, immune-related adverse events (irAEs) occur in over a third of treated patients and...

2584 Background: Cancer immune checkpoint inhibitor (ICI) therapy may be associated with kidney immune-related adverse events (IRAEs) and other causes of acute kidney injury (AKI). In clinical trials, the frequency of AKI events was uncommon, however, further real-world study is warranted. Methods: We evaluated the proportion of AKI events among patients with advanced cancer (bladder, head and neck, lung, kidney and malignant melanoma) treated with ICI therapy in Ontario, Canada from 2012 - 2018. AKI was defined by a rise in the concentration of serum creatinine as per Kidney Disease: Improving Global Outcomes (KDIGO) criteria. A multivariable regression model was used to identify predictors of AKI while accounting for the competing risk of death. Results: A total of 4,380 patients received ICI therapy. In follow-up, 1,283 (29%) had recorded AKI event (any stage AKI) and 289 (7%) had a severe AKI event (≥ stage 2). Median time to AKI was 6 months (Interquartile Range 2-16 months) and ≤ 1 % of patients received dialysis therapy. Within 30 days of any observed AKI event, 853 (58%) discontinued ICI therapy, 372 (29%) were hospitalized and 266 (21%) died. Mortality was significantly higher among patients who experiencing a severe AKI event (≥ stage 2) as compared to patients with a less severe AKI event (stage 1) or no observed AKI event. Among patients alive at 30 days following an AKI event, 14% received an outpatient corticosteroid or immunosuppressive therapy prescription, 7% had a visit with a nephrologist. Characteristics associated with a higher risk of AKI included female sex, bladder or kidney cancer (reference malignant melanoma), history of hypertension or diabetes, higher Charlson comorbidity score, a baseline estimated glomerular filtration rate less than 30 mL/min/1.73 m2, or outpatient prescription for either a proton pump inhibitor or non-steroidal anti-inflammatory drug. Among patients with an AKI event and treatment discontinuation, re-challenge of ICI therapy was infrequent (16%) with a significant risk of a recurrent AKI event (57%). Conclusions: In a population-based study among patients with cancer receiving ICI therapy, the rate of AKI was common (29%) but severe AKI was less frequent (7%). Rates of ICI discontinuation, hospitalization and death are substantial following an AKI event. Kidney function should be monitored carefully among patients undergoing ICI therapy who have common risk factors for developing renal disease. Nephrology consultation may be optimized among patients who develop a severe AKI event, especially among individuals who are considered for ICI therapy re-challenge.

Autoimmune pancreatitis (AIP) has traditionally been classified into two subtypes: type 1, associated with immunoglobulin G4-related disease and type 2, characterized by idiopathic duct-centric pancreatitis. The emergence of immune checkpoint inhibitors (ICIs) in cancer treatment has introduced a new entity, type 3 AIP, representing ICI-induced pancreatic autoimmunity. This review examines the pathophysiology, clinical features, diagnosis, treatment, and outcomes of type 3 AIP. The condition affects 0.6-4% of patients receiving ICI therapy, with higher incidence in combination therapy compared to monotherapy. Pathophysiologically, activated CD8+ T-cells appear to be the primary mediators of pancreatic injury. Two-thirds of patients are asymptomatic with only elevated pancreatic enzymes, while symptomatic cases typically present with epigastric pain radiating to the back. Diagnosis requires establishing temporal association with ICI therapy, elevated pancreatic enzymes, characteristic imaging findings, and exclusion of other etiologies. Management depends on disease severity, ranging from monitoring with continued ICI therapy in asymptomatic patients to temporary or permanent discontinuation in more severe cases. The efficacy of steroid therapy remains controversial, with limited evidence supporting its role in preventing long-term complications. Over 50% of patients develop pancreatic atrophy within 1 year, leading to potential endocrine and exocrine insufficiency requiring long-term pancreatic enzyme supplementation and diabetic management. As ICI use expands across oncology, greater awareness of type 3 AIP among clinicians and the development of evidence-based management protocols are essential to improve patient outcomes and quality of life.

Differential diagnosis of autoimmune pancreatitis apart from everything else is based on specifi cs of immunoglobulin G4 involvement into the pathogenesis. Aims: to analyze two forms of autoimmune pancreatitis and their relation to the level of IgG4-positive plasma cells. Methods and results. The present study was conducted on 54 patients with chronic pancreatitis, from which 15 cases with autoimmune pancreatitis were selected by using morphological and immunohistochemical methods. Conclusion. It has been established that for autoimmune pancreatitis type I dense lymphocytic periductal infi ltrate, multilevel fi brosis, obliterating venulitis and high IgG4-positive plasma cells in the pancreas (≥ 30 per high power fi eld) were typical. In the cases of autoimmune pancreatitis type II, besides the specifi c histopathological signs of AIP, signifi cantly epithelial damage of pancreatic ducts by leukocytes, low levels of IgG4-PPC in the pancreas and focal lesions on stages I-III of disease (80%) were observed.

Cancer immunotherapy has firmly established itself as a pillar of cancer care due to its advantages over traditional anti-tumor therapy but also carries limitations due to potential for severe adverse reactions. This review highlights the current understanding and management of patients with autoimmune and viral hepatitis immune in the setting of immune checkpoint inhibitor (ICI) therapy. A literature search was conducted on PubMed, Scopus, Google Scholar SEER*Stat databases (from inception to December 2022) using search terms: "immune checkpoint inhibitor", "autoimmune hepatitis", "viral hepatitis", "HBV pathogenesis", "HCV pathogenesis", "HBV reactivation", "HCV reactivation", "cancer immunotherapy", "immune related adverse events", "immune related hepatitis". Pre-existing autoimmune disease (AD), whether active or inactive, can predispose patients receiving ICI therapy to develop autoimmune disease flares or immune-related adverse events (irAEs). Thus, patients with AD have routinely been excluded from clinical trials and data on safety of ICI therapy are limited. Hepatic irAE can be seen in ICI therapy and is a distinct entity from autoimmune hepatitis (AIH). ICI therapy alters the immune environment in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Patients who had prior exposure to HBV are at risk for viral reactivation. However, the prevalence of viral hepatitis in patients receiving immunotherapy is underrecognized and can lead to increases in liver biochemical tests as well as deterioration of liver function ultimately limiting treatment. The high morbidity and mortality associated with immune-related hepatitis emphasizes the need for screening of underlying diseases, including autoimmune and viral hepatitis, prior to initiation of ICI. Presence of AIH or chronic viral hepatitis is the most important risk factor for hepatic adverse events in ICI therapy. Screening for AIH, HBV and HCV is paramount in patients who will undergo ICI therapy.

The occurrence of a diffusely swollen pancreas raises the possibility of several diseases in the differential diagnosis, including autoimmune pancreatitis (AIP), pancreatic lymphoma and whole pancreatic cancer (PC). Diffuse-type AIP, in particular, is characterized by a capsule-like rim, without dilation of the main pancreatic duct (MPD). In this article we report a case of PC that mimicked diffuse-type AIP on ultrasonography (US) and computed tomography (CT) images, which was successfully diagnosed by a cytology of pancreatic juice obtained using endoscopic naso-pancreatic drainage (ENPD).

INTRODUCTION: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of malignancies, but are limited by immune-related adverse events (iRAE). Pancreatic iRAEs, broadly defined by asymptomatic lipase elevation to complicated pancreatitis, lack clear management. We seek to report rates of varying definitions, evaluations, and management of pancreatic iRAEs, classified as immune-checkpoint inhibitor pancreatic injury (ICIPI) and ICI pancreatitis. METHODS: From a database of 1672 patients treated with ICI, data was collected on those with possible pancreatic injury. They were classified into four groups: ICIPI, as defined by either lipase elevation or imaging of pancreatitis due to ICI; ICI pancreatitis, as defined by fulfilling Atlanta criteria; non-ICI asymptomatic lipase elevation; non-ICI pancreatitis. Data on rates of diagnosed pancreatitis, lipase elevations, imaging evidence, symptomatology, treatment, management of ICI, and patient outcome after cessation of ICI were collected. RESULTS: Of 31/1672 (2%) patients with pancreatic injury, 7 had ICI pancreatitis, 14 had ICIPI, 6 had non-ICI pancreatitis, and 4 had non-ICI asymptomatic lipase elevations. In the 7 ICI pancreatitis patients meeting Atlanta criteria, 5/7 (71%) had follow up evaluation to rule out other etiologies of pancreatitis. In contrast, only 1/13 (8%) ICIPI patients had a follow up evaluation to meet Atlanta criteria or rule out other etiologies. Of the ICIPI patients, 6/14 (43%) were diagnosed as pancreatitis, 8/14 (57%) were asymptomatic, 9/14 (64%) had lipase &gt;3x upper limit of normal (ULN), and only 1/14 (7%) ICIPI was due to imaging alone (Table 1). Most ICI pancreatitis, 5/7 (71%), and ICIPI, 10/14 (71%) patients received corticosteroids (CS). While 4/7 (57%) ICI pancreatitis patients received intravenous fluids (IVF), only 2/14 (14%) of ICIPI patients did. Of 6/7 (86%) of ICI pancreatitis patients that stopped ICI, 3/6 (50%) reinitiated them. In contrast, 7/14 (50%) of ICIPI patients stopped ICI and 5/7 (71%) reinitiated them (Table 2). CONCLUSION: Pancreatic injury is known to be associated with ICI. Efforts to identify and treat those with pancreatic iRAE are critical to avoid delay in ICI therapy. In our study, most patients with ICIPI and ICI pancreatitis received CS. Almost all ICI pancreatitis patients stopped ICI with half reinitiating them, while only half of ICIPI patients stopped ICI with most reinitiating them. Further characterizing outcomes to develop a diagnostic algorithm will enhance care.