Interleukin 21 Drives a Hypermetabolic State and CD4+ T-Cell-Associated Pathogenicity in Chronic Intestinal Inflammation.

BACKGROUND & AIMS: Incapacitated regulatory T cells (Tregs) contribute to immune-mediated diseases. Inflammatory Tregs are evident during human inflammatory bowel disease; however, mechanisms driving the development of these cells and their function are not well understood. Therefore, we investigated the role of cellular metabolism in Tregs relevant to gut homeostasis. METHODS: Using human Tregs, we performed mitochondrial ultrastructural studies via electron microscopy and confocal imaging, biochemical and protein analyses using proximity ligation assay, immunoblotting, mass cytometry and fluorescence-activated cell sorting, metabolomics, gene expression analysis, and real-time metabolic profiling utilizing the Seahorse XF analyzer. We used a Crohn's disease single-cell RNA sequencing dataset to infer the therapeutic relevance of targeting metabolic pathways in inflammatory Tregs. We examined the superior functionality of genetically modified Tregs in CD4+ T-cell-induced murine colitis models. RESULTS: Mitochondria-endoplasmic reticulum appositions, known to mediate pyruvate entry into mitochondria via voltage-dependent anion channel 1 (VDAC1), are abundant in Tregs. VDAC1 inhibition perturbed pyruvate metabolism, eliciting sensitization to other inflammatory signals reversible by membrane-permeable methyl pyruvate supplementation. Notably, interleukin (IL) 21 diminished mitochondria-endoplasmic reticulum appositions, resulting in enhanced enzymatic function of glycogen synthase kinase 3 ß, a putative negative regulator of VDAC1, and a hypermetabolic state that amplified Treg inflammatory response. Methyl pyruvate and glycogen synthase kinase 3 ß pharmacologic inhibitor (LY2090314) reversed IL21-induced metabolic rewiring and inflammatory state. Moreover, IL21-induced metabolic genes in Tregs in vitro were enriched in human Crohn's disease intestinal Tregs. Adoptively transferred Il21r-/- Tregs efficiently rescued murine colitis in contrast to wild-type Tregs. CONCLUSIONS: IL21 triggers metabolic dysfunction associated with Treg inflammatory response. Inhibiting IL21-induced metabolism in Tregs may mitigate CD4+ T-cell-driven chronic intestinal inflammation.

Alcohol Use in Patients With Inflammatory Bowel Disease.

Alcohol consumption is common in patients with inflammatory bowel disease (IBD), but alcohol has been reported to be the most-avoided diet item by this patient population. This article explores the available evidence for the impact that alcohol use has on IBD development, relapse, symptom control, and medication interactions. Although evidence linking the consumption of alcoholic beverages and the development of new-onset IBD is controversial, prospective research has reported that alcohol use is associated with a higher risk of relapse. Moreover, patients with IBD report worse gastrointestinal symptoms following alcohol consumption. On the other hand, alcoholic beverages such as red wine may have anti-inflammatory properties capable of assisting in disease control, although they may also have a negative effect on disease monitoring, namely fecal calprotectin levels. Importantly, the use of alcohol can interfere with the metabolism of several medications, leading to increased adverse events or even loss of efficacy. In the available literature, alcohol use in patients with IBD trends toward harmful effects; however, more research is needed to provide confident recommendations.

Outcomes of repeat balloon assisted enteroscopy in small-bowel bleeding.

BACKGROUND/AIMS: The rate of recurrent small-bowel bleeding (SBB) remains high despite the advent of balloon assisted enteroscopy (BAE). The study aims were to determine: (1) the diagnostic and therapeutic yields, and adverse event rate of repeat BAE in SBB, and (2) the predictors of a positive repeat BAE. METHODS: A retrospective review of a BAE database was conducted. Patients who had > 1 BAE for SBB were included. Primary outcomes were diagnostic yield, therapeutic yield, and adverse events of repeat BAE. Secondary outcomes were predictors of a positive repeat BAE. RESULTS: A total of 175 patients (55 % men; mean age 64.1 ±â€Š16.3 years) were included. The diagnostic and therapeutic yields of repeat BAE were 55 % and 42 %, respectively. Repeat BAE adverse events occurred in 5 % with self-limited abdominal pain being most common. Patients with a positive repeat BAE were significantly older than the negative group (68.6 ±â€Š13.9 vs. 60.9 ±â€Š17.1; P  = 0.001) and were more likely to have cardiac comorbidities (OR 2.4, 95 %CI: 1.3 - 4.6; P  = 0.01), chronic kidney disease (OR 2.3, 95 %CI: 1.1 - 4.9; P  = 0.04), chronic obstructive pulmonary disease (OR 3.3, 95 %CI: 1.3 - 8.1; P  = 0.01), positive initial BAE (OR 3.6, 95 %CI: 1.9 - 6.8; P  < 0.001), and antegrade procedure (OR 3.3, 95 %CI: 1.7 - 6.1; P  < 0.001). On multivariate analysis, a positive initial BAE and antegrade route were the only significant predictive factors. CONCLUSIONS: Performing a repeat BAE for SBB appears safe and provided modest yields. A positive initial BAE and antegrade route were predictive of a positive repeat BAE.

Rituximab Maintenance Therapy Reduces Rate of Relapse of Pancreaticobiliary Immunoglobulin G4-related Disease.

BACKGROUND & AIMS: IgG4-related disease (IgG4-RD), a multi-organ fibroinflammatory syndrome, typically responds to steroids. However, some cases are steroid resistant, and pancreaticobiliary IgG4-RD commonly relapses after steroid withdrawal. Rituximab induces remission of IgG4-RD, but the need for and safety of maintenance rituximab treatment are unknown. We compared outcomes of patients with pancreaticobiliary IgG4-RD treated with or without maintenance rituximab therapy. METHODS: We performed a retrospective study of patients with pancreaticobiliary IgG4-RD treated with rituximab at the Mayo Clinic in Rochester, Minnesota, from January 2005 through December 2015. The cohort was divided into patients who received only rituximab induction therapy (group 1, n = 14) and patients who received rituximab induction followed by maintenance therapy (group 2, n = 29). We collected data on recurrence of IgG4-RD symptoms and findings, as well as information on evaluations, treatment, and adverse events. RESULTS: Median follow-up times were similar between group 1 (34 mo) and group 2 (27 mo) (P = .99). Thirty-seven patients (86%) were in steroid-free remission 6 months after rituximab initiation. A higher proportion of patients in group 1 had disease relapse (3-year event rate, 45%) than in group 2 (3-year event rate, 11%) (P = .034). Younger age, higher IgG4 responder index score after induction therapy, and increased serum levels of alkaline phosphatase at baseline or after rituximab induction were associated with relapse. Infections developed in 6 of 43 patients, all in group 2 (P = .067 vs group 1); all but 1 occurred during maintenance therapy. CONCLUSIONS: In a retrospective study of patients with pancreaticobiliary IgG4-RD, we found rituximab maintenance therapy prolongs remission. Relapses are uncommon among patients receiving maintenance therapy, but maintenance therapy may increase risk of infection. Patients with factors that predict relapse could be candidates for rituximab maintenance therapy.

Spontaneous intramural small bowel hematoma in a patient with acute myeloid leukaemia receiving chemotherapy and nilotinib.

Spontaneous intramural small bowel hematoma (SISBH) is a rare, acute abdominal condition, with increasing incidence in recent years. Excessive anticoagulation with vitamin K antagonists is the most common aetiology. We report the case of a large acute jejunal intramural hematoma in a patient with newly diagnosed acute myeloid leukaemia receiving chemotherapy and nilotinib. The patient presented with abdominal pain, haematochezia, acute anaemia and thrombocytopenia. CT of the abdomen and pelvis revealed SISBH. The patient was managed conservatively with supportive management and cessation of nilotinib therapy. The patient's symptoms improved, with subsequent CT imaging confirming resolution. This case highlights an uncommon cause of gastrointestinal bleed usually diagnosed only after radiological imaging. A correct diagnosis is important as SISBH usually responds to conservative measures, and may obviate the patient from unnecessary invasive investigations.

Targeted Approaches Applied to Uncommon Diseases: A Case of Salivary Duct Carcinoma Metastatic to the Brain Treated with the Multikinase Inhibitor Neratinib.

Salivary duct carcinoma is a rare malignancy associated with hormone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. Local surgical control is the cornerstone of therapy, but a subset of patients develops metastatic disease portending a poor prognosis and limited management options. Intracranial metastases are an uncommon manifestation and present a therapeutic challenge. We report the case of a 31-year-old male who presented with facial pain and swelling subsequently diagnosed with salivary duct carcinoma. Our patient underwent extensive locoregional resection and analysis of the tumor tissue demonstrated evidence of androgen receptor expression and HER2 overexpression. His course was complicated by metastatic extra- and intracranial recurrence despite combined modality treatment with radiation and chemotherapy followed by anti-HER2 monoclonal antibody therapy and androgen deprivation therapy. After exhausting standard treatment options, he received experimental therapy with a new small-molecule tyrosine kinase inhibitor, neratinib, with evidence of a transient clinical response and no significant adverse effects. This case exemplifies the potential and limitations of targeted therapy, particularly when applied to patients with rare diseases and presentations.

Initial presentation of CNS-restricted acute lymphoblastic B cell leukaemia as peripheral polyneuropathy.

We report a case of a 58-year-old woman who presented with a 1-month course of progressive lower and upper extremity weakness in addition to binocular diplopia. Diagnostic lumbar puncture revealed atypical lymphoid cells with 28% blasts. Immunophenotype was consistent with B cell acute lymphoblastic leukaemia (B-ALL). Further work up showed no systemic involvement but extensive thoracolumbar-sacral leptomeningeal disease. The patient was treated with several courses of intrathecal and systemic chemotherapy followed by craniospinal irradiation for consolidation. There was initial steady improvement in neurological symptoms and leptomeningeal disease, the latter being ascertained through radiological studies and cerebrospinal fluid examination. After 10 months of response, the patient relapsed with central nervous system (CNS) and systemic disease. B-ALL is a rare precursor lymphoid neoplasm that generally presents with systemic disease. While CNS involvement is not uncommon, isolated involvement of this compartment without systemic disease is exceedingly rare.