Chowla, Navreet

ABSTRACT Background Chimeric antigen receptor T‐cell (CAR‐T) therapy has revolutionised the treatment of hematologic malignancies, and its use is expanding rapidly into numerous other disease states including autoimmune diseases. However, CAR‐T therapy is associated with a spectrum of immune‐related toxicities. In addition to the already well characterized cytokine release syndrome and immune effector cell‐associated neurotoxicity syndrome, it has become apparent that rarely, CAR‐T can cause gastrointestinal mucosal inflammation, termed immune effector cell‐mediated enterocolitis (IEC‐EC). Aims This state‐of‐the‐art review highlights the CAR‐T mechanism and details the epidemiology, pathophysiology, clinical manifestations, endoscopic and histopathologic features, and management of IEC‐EC. Methods This review presents the current state of knowledge through a comperhensive and detailed synthesis of all case series reported in the literature to date. Results Occurring in up to approximately 6% of patients typically following B cell maturation antigen‐targeted CAR‐T therapy, IEC‐EC presents with severe diarrhoea and malabsorption, responds poorly to treatment, and portends a dire prognosis. Multi‐disciplinary management should centre on early diagnosis, supportive cares, assessment and treatment of infections, and step‐up pharmacotherapy, often featuring biologics and small molecules drawn from the inflammatory bowel disease pharmacologic armamentarium. Conclusions Clinicians should maintain a high degree of vigilance for IEC‐EC in patients presenting with gastrointestinal symptoms following CAR‐T treatment. Early recognition and multi‐disciplinary treatment may improve patient outcomes.

Abstract Immune effector cell–associated enterocolitis (IEC-EC) has been observed after ciltacabtagene autoleucel (cilta-cel [Carvykti]) chimeric antigen receptor T-cell (CAR-T) therapy. It is associated with dismal outcomes and is poorly characterized. Here, we examined its clinical features, risk factors, and proposed management strategies. Among the 229 consecutive patients who received cilta-cel at Mayo Clinic, 9 (3.9%) presented with a nonresolving, nonbloody, grade 3 diarrhea, often requiring prolonged total parenteral nutrition. Gastrointestinal coinfections were seen in most patients. Median time from CAR-T infusion to symptom onset was 85 days (range, 35-166), and there appeared to be a latency from symptom onset to endoscopic evaluation. Histopathology findings resembling a graft-versus-host disease pattern of mucosal injury were most seen on duodenal biopsies, whereas 2 cases had patterns akin to a T-cell lymphoproliferative disorder (1 CD4+ and 1 CD8+). Independent associated factors for IEC-EC included high-risk disease as defined by the International Myeloma Society and International Myeloma Working Group, prolonged cytokine release syndrome, and antecedent delayed neurotoxicity. Response to first-line therapy comprising IV or oral corticosteroids, bile acid sequestrants, IV immunoglobulin, and antimicrobial-directed therapy was poor, with no durable responses. Biologic therapy appeared to induce durable responses in 3 of the 5 patients (2/2 vedolizumab; 1/3 infliximab); none of the responders had gastrointestinal coinfection. Early gastroenterology input for endoscopic evaluation with the inclusion of duodenal biopsy is a key component for diagnosis. Early institution of biologic therapy after failure of a short course of corticosteroids should be considered.

Abstract Background We aimed to describe the real-world durability of clinical and endoscopic outcomes of upadacitinib (UPA) in ulcerative colitis (UC). Methods We retrospectively analyzed an ongoing multi-center cohort of UC patients(pts) in the United States who were started on UPA for active disease. Primary outcome was clinical remission at 1yr assessed by partial Mayo score(pMS)(resolution of all UC related symptoms and physician global assessment). Secondary outcomes assessed at various timepoints, including after re-escalation, included clinical response(>50%reduction in symptoms utilizing the pMS), endoscopic response (Mayo endoscopic score≤1or absence of erosions/ulcerations) and histological remission(defined as normal or chronic inactive). Durable secondary outcomes achieved at both 6months and at 1yr and beyond were also assessed. Descriptive statistics were performed. Adverse events(AEs) investigated included cardiovascular events and herpes zoster (HZ). Results 416pts were included(Table 1) with median values for age at initiation of36.00yrs(range27-48), disease duration7.00yrs(range3-14)and follow-up 993days(IQR,672-1103), with206(49.52%)with follow-up at 1yr or beyond. Of these, 66.1%had extensive colitis. Induction duration was8wks in 86.5%and16wks in 4.8 %(20/416). Most received an induction dose of45mg(97.1%)and maintenance dose of30mg(85.8%). Among the evaluable population at1yr and beyond, 62.5%(45/80)were in clinical remission, 75.9%(22/29)in endoscopic response with58.6%(17/29) in remission and66.6%(20/30)in histological remission. At 6months, clinical remission was51.6%(42/93), endoscopic response was 75%(24/32) of which43.75%(14/32)were in remission and histologic remission was seen in 40.8%(20/49).Durable secondary outcomes of clinical remission were seen in 71.4%(30/42), endoscopic improvement in 45.8%(11/24), and histologic remission in35%(7/20). Re-escalation to 45mg occurred in 35pts, of which48.6%(17/35)were re-escalated due to incomplete induction clinical response with all achieving response(11 in remission). The rest(18/35)were re-escalated for clinical relapse after initial remission where72.2%(13/18)were able to recapture remission. After re-escalation,54.3%(19/35)continued on 45mg daily. AEs were reported in12.7%with HZ in 7pts(2.1%). One pt aged53yrs had an episode of TIA after 1yr on UPA at 15mg, without pre-existing cardiovascular risk factors and UPA use is ongoing at the same dose. There were no reported episodes of worsening of pre-existing cardiovascular disease or DVT/PE. Conclusion UPA is durably effective and safe in a real-world clinical setting with re-escalation to 45mg capturing response in a majority of the pts. Ongoing recruitment will provide further evidence on long term effectiveness and safety. Conflict of interest: Ms. Huang, Katherine: No conflict of interest Chandnani, Arun: No conflict of interest Samaan, Sami: None Tan, Tingyi: I have no conflict of interests to declare. Ramesh, Prajith Raj: None Conlon, Caroline: No conflict of interest Klein, Jeremy: None Reddy, Nikhil: No conflict of interest Ayoub, Malek: None Cervantes Limon, Gabriela: none Myers, Melissa: None Bucaram, Martha: No conflict of interest Lieto, Stephen: No conflict of interest Scalzo, Nicholas: No conflict of interest Cohen, Benjamin: Abbvie - consulting and speaking ALPCO - consulting J & J Innovative Medicine - consulting Takeda - consulting and speaking Emmes Biopharma Services LLC - DSMB Pfizer - consulting Mohamed, Islam: nothing to declare Ciorba, Matthew: Advisory Board: Janssen, AbbVie, Pfizer, Geneoscopy Consulting: Janssen, AbbVie, Pfizer, Geneoscopy Grant contracts: Janssen, Pfizer, Incyte Shukla, Richa: Speakers bureau - Abbvie and Lilly Wright, Michael: None Xu, An Tao: No conflict of interest Chowla, Navreet: No conflict of interest Ogholikhan, Sina: Abbvie Medical Director Kujawski, Michelle: Abbvie Scientific Director Dulaney, David: Speaker bureau - Regeneron Speaker bureau - Sanofi Speaker bureau - Takeda Speaker bureau - Eli Lilly Fenster, Marc: none Benson, Caroline: No conflict of interest Alhobayb, Tamara: No conflict of interest Berinstein, Jeffrey: No conflict of interest Shivashankar, Raina: Abbvie and BMS - speaker bureau Janssen and Celltrion - grant for IBD fellowship funding Pfizer - consultant Bishu, Shrinivas: None Patel, Anish: speaker: abbvie, J & J, Lilly, BMS, Pfizer, Phathom, Takeda consultant: abbvie Ungaro, Ryan: Personal Fees: AbbVie, Bristol Myers Squibb, Genentech, Lilly, Pfizer, Janssen, Takeda Johnson, Amanda: Research grant: Abbvie, Spyre Therapeutics Pekow, Joel R.: CVS Health - Consulting Abbvie, Eli Lilly, Pfizer, Johnson and Johnson - Stocks Yarur, Andres: Personal Fees: Consultant for Takeda, Pfizer, Roche, Merck, Abbvie, Eli Lilly. Bristol Myers Squibb, Celltrion, Johnson and Johnson. Deepak, Parakkal: Parakkal Deepak has received research support under a sponsored research agreement unrelated to the data in the abstract from AbbVie, Johnson and Johnson, Sanofi, Merck, Teva, Direct Biologics, Tr1x, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Prometheus Biosciences, Takeda Pharmaceuticals, Roche Genentech, Eli Lilly, AstraZeneca, Spyre and Agomab, has received consulting fees from Johnson and Johnson, Abbvie, Merck, Sobi, Celltrion, Fresenius Kabi, Asahi Kasei Pharma, Sandoz and CorEvitas, LLC and has served on the board of the Srategic Alliance for Intercultural Advocacy in GI.

ABSTRACT Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder causing hypogammaglobulinemia. Although rare, nodular regenerative hyperplasia is the most common liver complication in CVID, which can progress to noncirrhotic portal hypertension. We report a case of a young male with CVID presenting with recurrent parastomal bleeding secondary to noncirrhotic portal hypertension from CVID-associated nodular regenerative hyperplasia.

Abstract Background There is limited data on the clinical effectiveness of upadacitinib (UPA), an oral selective inhibitor of Janus kinase 1 (JAKi), in patients with perianal Crohn's disease (pCD). The objective of this study was to evaluate the real-world effectiveness of UPA in pCD. Methods This retrospective analysis utilized data on adults (>17 years) who initiated UPA at 45 mg/day for active pCD across 10 centers in the United States and Canada. Standardized data extraction and entry protocols were followed. The primary outcome was clinical response, defined as a ≥3-point reduction in Perianal Disease Activity Index (PDAI) between baseline and follow-up. Secondary outcomes included normalization of CRP (<5 mg/L) or hsCRP (<1 mg/L), clinical remission (PDAI ≤4), and rates of hospitalization, antibiotic use, corticosteroid initiation, and new pCD-related surgeries. Fistula healing on MRI pelvis fistula protocol was defined as an absence of T2-weighted hyperintensity and post-contrast enhancement on T1-weighted images. Predictive analyses used Cox proportional hazards models to evaluate baseline factors influencing time to PDAI remission, including BMI, CRP, albumin, PDAI, pCD disease duration, Montreal location and prior biologic exposure (<2 vs 2+). Results A total of 81 patients were treated with UPA for pCD (median age 35 years and 54.3% male). Most had ileocolonic disease (65.4%), with 54% presenting with complex fistulas. Of these, 92.6% had prior anti-TNF exposure, and 91 (88.9%) had prior exposure to 2+ biologics (Table 1). During a median follow-up of 4 months, clinical response (PDAI) was achieved in 17.3%. Improvement was observed in pain and restriction of activities (27.2%), restriction of sexual activity (13.6%), reduction in number of fistulas (11.1%), degree of induration (11.1%), and discharge (35.8%). Median CRP reduction was 21.05% [IQR: 0.00–74.53], and 21.0% achieved a ≥50% reduction in CRP. MRI healing was limited to 17.7% (6/34). Proctitis decreased from 23.5% at baseline to 7.4% at follow-up. During follow-up, hospitalizations occurred in 9.9%, 14.8% required antibiotics, 8.6% underwent examination under anesthesia in 8.6%, seton placement in 6.2%, and abscess drainage in 6.2%. Patients with ileocolonic disease showed the highest remission (54%) and response (15%) rates, while MRI healing was limited across all Montreal locations (7.4%). Lower baseline CRP (p < 0.05) and PDAI scores (p < 0.01) predicted shorter time to remission. Number of prior biologic exposures (p =0.2) and Montreal location (p = 0.7) were not predictive of time to PDAI remission (Figure 1). Conclusion UPA in a real-world cohort is effective in the management of treatment-refractory pCD. Randomized trials are needed to confirm these observations.