Recessive NLRC4-Autoinflammatory Disease Reveals an Ulcerative Colitis Locus

Abstract Purpose NLRC4-associated autoinflammatory disease (NLRC4-AID) is an autosomal dominant condition presenting with a range of clinical manifestations which can include macrophage activation syndrome (MAS) and severe enterocolitis. We now report the first homozygous mutation in NLRC4 (c.478G > A, p.A160T) causing autoinflammatory disease with immune dysregulation and find that heterozygous carriers in the general population are at increased risk of developing ulcerative colitis. Methods Circulating immune cells and inflammatory markers were profiled and historical clinical data interrogated. DNA was extracted and sequenced using standard procedures. Inflammasome activation assays for ASC speck formation, pyroptosis, and IL-1β/IL-18 secretion confirmed pathogenicity of the mutation in vitro. Genome-wide association of NLRC4 (A160T) with ulcerative colitis was examined using data from the IBD exomes portal. Results A 60-year-old Brazilian female patient was evaluated for recurrent episodes of systemic inflammation from six months of age. Episodes were characterized by recurrent low-grade fever, chills, oral ulceration, uveitis, arthralgia, and abdominal pain, followed by diarrhea with mucus and variable skin rash. High doses of corticosteroids were somewhat effective in controlling disease and anti-IL-1β therapy partially controlled symptoms. While on treatment, serum IL-1β and IL-18 levels remained elevated. Genetic investigations identified a homozygous mutation in NLRC4 (A160T), inherited in a recessive fashion. Increased ASC speck formation and IL-1β/IL-18 secretion confirmed pathogenicity when NLRC4 (A160T) was analyzed in human cell lines. This allele is significantly enriched in patients with ulcerative colitis: OR 2.546 (95% 1.778–3.644), P = 0.01305. Conclusion NLRC4 (A160T) can either cause recessively inherited autoinflammation and immune dysregulation, or function as a heterozygous risk factor for the development of ulcerative colitis.

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P397 Surveillance in ulcerative colitis: Can we predict the risk for intraepithelial neoplasia?

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.526 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S368-S369

Author(s):

J Estorninho ◽

P Freire ◽

S Lopes ◽

M Ferreira ◽

...

Keyword(s):

Ulcerative Colitis ◽

Disease Duration ◽

Intraepithelial Neoplasia ◽

Screening Colonoscopy ◽

Low Grade ◽

Surveillance Colonoscopy ◽

High Quality ◽

Increased Risk ◽

History Of ◽

Low Grade Dysplasia

Abstract Background Ulcerative colitis (UC) has been associated with an increased risk of colorectal cancer (CRC). Although dye spray chromoendoscopy showed superiority to standard colonoscopy in surveillance studies, with the availability of higher-resolution colonoscopes, the utility of chromoendoscopy (CE) has been questioned. We aimed to evaluate the risk of intraepithelial neoplasia (IN) after a high-quality screening colonoscopy (making use of CE or random biopsies (RB) and removing all detected lesions) in a population with longstanding UC and to identify potential risk factors for dysplasia incidence. Methods In a previous study, 145 patients with clinically and endoscopic longstanding (≥8 yr) distal/extensive UC without primary sclerosing cholangitis and/or history of IN were prospectively randomised to undergo CE or RB. In this study, after a median follow-up of 5 additional years, we evaluated subsequent IN incidence in these patients, submitted to surveillance colonoscopy. Patients without high-quality surveillance colonoscopy (with good bowel preparation and cecum intubation) using high-definition were excluded. Results One hundred and twenty-one patients were included. Nine had removed adenomas with low-grade dysplasia in the index colonoscopy. Now, in surveillance colonoscopy, we detected 9 (7.4%) IN: low-grade dysplasia was found in 8 (6.6%) patients and a colorectal adenocarcinoma in 1 (0.008%) patient. After multivariate analysis, IN was significantly associated with older age (68 vs. 52 years, p < 0.05) and higher disease duration (26 vs. 20 years, p < 0.05). No association was found between IN and previous detection of IN in screening colonoscopy sex, the CE or RB use in index colonoscopy, extent of disease, The presence of pseudopolyps, smoking habits, familial history of CRC or maintenance therapy for UC. Conclusion In this study, older patients and higher disease duration were associated with a higher risk of IN in surveillance colonoscopy.

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Fertility Impact of Initial Operation Type for Female Ulcerative Colitis Patients

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz307 ◽

2019 ◽

Vol 26 (9) ◽

pp. 1368-1376

Author(s):

Adam S Faye ◽

Aaron Oh ◽

Lindsay D Kumble ◽

Ravi P Kiran ◽

Timothy Wen ◽

...

Keyword(s):

Ulcerative Colitis ◽

Childbearing Age ◽

End Points ◽

Vitro Fertilization ◽

Life Years ◽

Increased Risk ◽

Individualized Approach ◽

Surgical Options ◽

The Impact

Abstract Background Ileal pouch–anal anastomosis (IPAA) is the mainstay of surgical treatment for patients with ulcerative colitis (UC) but is associated with an increased risk of infertility. We developed a simulation model examining the impact of initial surgical procedure on quality-adjusted life-years (QALYs) and fertility end points. Methods A patient-level state transition model was used to analyze outcomes by surgical approach strategy for females of childbearing age. Initial surgical options included IPAA, rectal-sparing colectomy with end ileostomy (RCEI), and ileorectal anastomosis (IRA). The primary outcome examined was QALYs, whereas secondary outcomes included UC and fertility-associated end points. Results IPAA resulted in higher QALYs for patients aged 20–30 years, as compared with RCEI. For patients aged 35 years, RCEI resulted in higher QALYs (7.54 RCEI vs 7.53 IPAA) and was associated with a 28% higher rate of childbirth, a 14-month decrease in time to childbirth, and a 77% reduction in in vitro fertilization utilization. When accounting for the decreased infertility risk associated with laparoscopic IPAA, IPAA resulted in higher QALYs (7.57) even for patients aged 35 years. Conclusions Despite an increased risk of infertility, our model results suggest that IPAA may be the optimal surgical strategy for female UC patients aged 20–30 years who desire children. For patients aged 35 years, RCEI should additionally be considered, as QALYs for RCEI and IPAA were similar. These quantitative data can be used by patients and providers to help develop an individualized approach to surgical management choice.

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Treatment of Homozygous Type II Antithrombin Heparin-Binding Site Deficiency in Pregnancy

Case Reports in Obstetrics and Gynecology ◽

10.1155/2021/4393821 ◽

2021 ◽

Vol 2021 ◽

pp. 1-3

Author(s):

Hilde Fiskvik ◽

Anne F. Jacobsen ◽

Nina Iversen ◽

Carola E. Henriksson ◽

Eva-Marie Jacobsen

Keyword(s):

Binding Site ◽

Clinical Manifestations ◽

Late Pregnancy ◽

Individual Risk ◽

Homozygous Mutation ◽

Heparin Binding ◽

Heparin Binding Site ◽

Increased Risk ◽

At Deficiency ◽

In Pregnancy

Pregnancy is associated with an increased risk of venous thromboembolism (VTE). Previous VTE and severe thrombophilia are important risk factors. Our case was a 36-year-old woman, gravida 6, para 0, with antithrombin (AT) deficiency caused by a homozygous mutation in the heparin-binding site (HBS). Her history included seven prior VTEs, three early and two late pregnancy losses. She was prophylactically treated with both human plasma-derived AT concentrate (hpATC) and low molecular weight heparin (LMWH), resulting in a successful 6th pregnancy and a healthy live born baby. There is limited evidence and guidance on the management of AT deficiency in pregnancy. Dosing and monitoring of anticoagulants, alone or together with hpATC, must be based on individual risk assessment. The severity of clinical manifestations varies with the type of AT deficiency. Characterization of the AT mutation may aid in the decision-making process and optimize pregnancy outcomes.

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Motion - Colonoscopic Surveillance is More Cost Effective than Colectomy in Patients with Ulcerative Colitis: Arguments for the Motion

Canadian Journal of Gastroenterology ◽

10.1155/2003/759457 ◽

2003 ◽

Vol 17 (2) ◽

pp. 119-121 ◽

Cited By ~ 1

Author(s):

Bret A Lashner

Keyword(s):

Ulcerative Colitis ◽

Cost Effective ◽

Low Grade ◽

Surveillance Colonoscopy ◽

Case Control Studies ◽

Colonoscopic Surveillance ◽

Prophylactic Colectomy ◽

Increased Risk ◽

Surveillance Programs ◽

Related Mortality

Patients with ulcerative colitis (UC) are at increased risk for colorectal cancer (CRC), especially those with longstanding disease, pancolitis or primary sclerosing cholangitis. The incidence of colitis- associated cancer is increasing, and the mortality rates from CRC are higher in UC patients than in the general population. Case control studies have demonstrated that surveillance colonoscopy reduces the risk of dying from CRC. A well conducted decision analysis found that surveillance colonoscopy decreases cancer-related mortality and increases life expectancy. The results with surveillance programs were almost as good as with prophylactic colectomy. A subsequent cost effectiveness analysis using the same model found that, compared with a policy of no surveillance, colonoscopic surveillance was more effective at preventing death from CRC and was less costly. The best strategy appears to be to perform colonoscopies every three years. The analysis also showed that colectomy should be recommended in patients with low-grade dysplasia. Patients at very high risk for CRC should undergo yearly colonoscopy, and patients who are concerned about the limitations of this technique should be offered prophylactic colectomy.

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Immunodeficiency: Innate, Primary, and Secondary

Asthma ◽

10.1093/med/9780199918065.003.0004 ◽

2014 ◽

pp. 32-46

Author(s):

Jean M. Brown ◽

John W. Sleasman

Keyword(s):

Adaptive Immunity ◽

Primary Immunodeficiency ◽

Clinical Manifestations ◽

Immune Dysregulation ◽

Recurrent Infections ◽

Immunodeficiency Diseases ◽

Normal Individuals ◽

Increased Risk ◽

Pulmonary Manifestations ◽

Immune Deficiencies

Clinical manifestations of immunodeficiency diseases are recurrent infections with sinopulmonary conditions as the predominant manifestation. Immune deficiencies also result in immune dysregulation, with asthma as a common feature. Many immune deficiencies can lead to chronic pulmonary infections that mimic asthma and remain unrecognized. Immunodeficiency disorders, based on their etiology, are classified as primary or secondary. Primary immunodeficiency diseases are usually due to heritable defects in innate or adaptive immunity resulting in distinct susceptibility to certain types of infections, immune dysregulation, or increased risk for malignancy. Secondary immunodeficiencies are acquired conditions, which occur in otherwise normal individuals and can lead to similar clinical manifestations, that is, chronic sinopulmonary infection. Immune deficiencies are often underdiagnosed and misdiagnosed, especially if pulmonary manifestations are involved.

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Epstein-Barr Virus associated gastric carcinoma in a patient with germline STAT3 gain-of-function mutation

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqab191.134 ◽

2021 ◽

Vol 156 (Supplement_1) ◽

pp. S65-S65

Author(s):

J Mahadik ◽

K Patel ◽

N Cortes-Santiago

Keyword(s):

Poor Response ◽

Posterior Wall ◽

Immune Dysregulation ◽

The Body ◽

Low Grade ◽

Solid Organ ◽

Muscularis Mucosa ◽

Gain Of Function ◽

First Case ◽

Increased Risk

Abstract Introduction/Objective Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in inflammation, proliferation, differentiation and survival. STAT3 gain-of-function (GoF) disorders are characterized by immune dysregulation and present with polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)- or autoimmune lymphoproliferative syndrome (ALPS)-like features. While patients with STAT-3 GoF are known to have an increased risk for hematologic malignancies, neither solid tumors nor an increased risk for EBV-associated disorders have been described. We report the first case of an EBV-associated solid organ tumor in a patient with STAT-3 GoF. Methods/Case Report A 21-year-old male with germline mutation in STAT3 (variant p. M329K) presented with early satiety, abdominal pain and worsening of chronic anemia. Serology showed high EBV DNA PCR levels. Endoscopy showed multiple nodular lesions in the stomach, which were biopsied to reveal EBV-associated high-grade dysplasia and intramucosal adenocarcinoma. Initiation of chemotherapy with a poor response led to a total gastrectomy. Gross examination of the specimen showed a 7.9 x 6.5 x 1.8 cm tan-brown, exophytic mass in the posterior wall of the body and antrum, involving the greater curvature. Histology revealed an adenocarcinoma with tubulovillous morphology extending into the lamina propria, without invasion into the muscularis mucosa or submucosa. EBER in-situ hybridization was diffusely positive in the tumor cells. The background mucosa showed severe chronic active and atrophic gastritis with intestinal metaplasia and low-grade dysplasia. All the seventy examined lymph nodes were negative for metastasis. Helicobacter-like organisms were not seen. Results (if a Case Study enter NA) NA Conclusion This is the first report of a solid tumor in a patient with STAT3 GoF mutation. The role of the patient’s underlying immune dysregulation disorder in the development of EBV-associated gastric adenocarcinoma is unclear and warrants further investigation. The case also highlights the importance of a close clinical follow-up in this patient population, as unexpected malignancies can develop at younger ages.

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Purinergic Signaling and Inflammasome Activation in Psoriasis Pathogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms22179449 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9449

Author(s):

Davide Ferrari ◽

Fabio Casciano ◽

Paola Secchiero ◽

Eva Reali

Keyword(s):

T Cell Activation ◽

Cell Activation ◽

Purinergic Signaling ◽

Critical Role ◽

Clinical Manifestations ◽

Skin Lesions ◽

Psoriatic Skin ◽

Inflammasome Activation ◽

Increased Risk

Psoriasis is a chronic inflammatory disease of the skin associated with systemic and joint manifestations and accompanied by comorbidities, such as metabolic syndrome and increased risk of cardiovascular disease. Psoriasis has a strong genetic basis, but exacerbation requires additional signals that are still largely unknown. The clinical manifestations involve the interplay between dendritic and T cells in the dermis to generate a self-sustaining inflammatory loop around the TNFα/IL-23/IL-17 axis that forms the psoriatic plaque. In addition, in recent years, a critical role of keratinocytes in establishing the interplay that leads to psoriatic plaques’ formation has re-emerged. In this review, we analyze the most recent evidence of the role of keratinocytes and danger associates molecular patterns, such as extracellular ATP in the generation of psoriatic skin lesions. Particular attention will be given to purinergic signaling in inflammasome activation and in the initiation of psoriasis. In this phase, keratinocytes’ inflammasome may trigger early inflammatory pathways involving IL-1β production, to elicit the subsequent cascade of events that leads to dendritic and T cell activation. Since psoriasis is likely triggered by skin-damaging events and trauma, we can envisage that intracellular ATP, released by damaged cells, may play a role in triggering the inflammatory response underlying the pathogenesis of the disease by activating the inflammasome. Therefore, purinergic signaling in the skin could represent a new and early step of psoriasis; thus, opening the possibility to target single molecular actors of the purinome to develop new psoriasis treatments.

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Negotiating the complexities of exocrine and endocrine dysfunction in chronic pancreatitis

Proceedings of The Nutrition Society ◽

10.1017/s0029665117001045 ◽

2017 ◽

Vol 76 (4) ◽

pp. 484-494 ◽

Cited By ~ 17

Author(s):

Sinead N. Duggan

Keyword(s):

Abdominal Pain ◽

Chronic Pancreatitis ◽

Dietary Intake ◽

Pancreatic Enzyme ◽

Clinical Manifestations ◽

Disease Process ◽

Endocrine Function ◽

Low Grade ◽

Heavy Smoking ◽

Increased Risk

Chronic pancreatitis is a chronic inflammatory disease of the pancreas characterised by irreversible morphological change and typically causing pain and/or permanent loss of function. This progressive, irreversible disease results in destruction of healthy pancreatic tissue and the development of fibrous scar tissue. Gradual loss of exocrine and endocrine function follows, along with clinical manifestations such as steatorrhoea, abdominal pain and diabetes. Nutrition in chronic pancreatitis has been described as a problem area and, until recently, there was little research on the topic. It is often asserted that >90 % of the pancreas must be damaged before exocrine insufficiency occurs; however, an exploration of the original studies from the 1970s found that the data do not support this assertion. The management of steatorrhoea with pancreatic enzyme replacement therapy is the mainstay of nutritional management, and early identification and treatment is a key. The presence of steatorrhoea, coupled with poor dietary intake (due to intractable abdominal pain, gastrointestinal side effects and often alcoholism) renders the chronic pancreatitis patients at considerable risk for undernutrition, muscle depletion and fat-soluble vitamin deficiency. Premature osteoporosis/osteopenia afflicts two-thirds of patients as a consequence of poor dietary intake of calcium and vitamin D, low physical activity, low sunlight exposure, heavy smoking, as well as chronic low-grade inflammation. Bone metabolism studies show increased bone formation as well as bone resorption in chronic pancreatitis, indicating that bone turnover is abnormally high. Loss of the pancreatic islet cells occurs later in the disease process as the endocrine cells are diffusely distributed throughout the pancreatic parenchyma. Patients may develop type 3c (pancreatogenic) diabetes, which is complicated by concurrent decreased glucagon secretion, and hence an increased risk of hypoglycaemia. Diabetes control is further complicated by poor diet, malabsorption and (for some) alcoholism, and therefore those with type 3c diabetes have clinical characteristics and therapeutic goals that are different from that of type 1 and type 2 diabetes patients. This review describes emerging research and clinical guidelines for nutrition in chronic pancreatitis.

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Exercise Inhibits NLRP3 Inflammasome Activation in Obese Mice via the Anti-Inflammatory Effect of Meteorin-like

Cells ◽

10.3390/cells10123480 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3480

Author(s):

Hafiz Muhammad Ahmad Javaid ◽

Namood E Sahar ◽

De-Li ZhuGe ◽

Joo Young Huh

Keyword(s):

Adipose Tissue ◽

Nlrp3 Inflammasome ◽

Exercise Intervention ◽

Inflammasome Activation ◽

Low Grade ◽

Obese Mice ◽

Nlrp3 Inflammasome Activation ◽

Anti Inflammatory ◽

Inflammatory Effect

Obesity is associated with chronic low-grade inflammation. The benefits of exercise are partly attributed to its anti-inflammatory effect, but whether exercise can regulate NLRP3 inflammasome activation in obese adipose tissue remains unknown. Meteorin-like (METRNL), a recently discovered myokine, has been implicated in mediating the effect of exercise on metabolism. Herein, we examined the effect of exercise and METRNL on NLRP3 inflammasome activation. High-fat diet (HFD)-induced obese mice were subjected to treadmill exercise for 8 weeks. A subgroup of HFD mice was switched to normal chow with the exercise intervention. Exercise and diet attenuated weight gain, fat accumulation, and insulin resistance in obese mice. In addition, exercise downregulated gene and protein levels of inflammasome markers, including NLRP3 and caspase-1, in adipose tissue. In isolated bone marrow-derived macrophages, activation of NLRP3 inflammasome was suppressed in the exercise group, as confirmed by the downregulation of IL-1β and IL-18. Exercise significantly enhanced the expression of METRNL in various muscle depots, and further in vitro analysis revealed that recombinant METRNL treatment inhibited IL-1β secretion in macrophages. In conclusion, exercise exerts its anti-inflammatory action by suppressing adipose tissue NLRP3 inflammasome, and this is, in part, associated with METRNL induction in muscle and its anti-inflammatory effects in macrophages.

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Multi-centre derivation and validation of a colitis-associated colorectal cancer risk prediction web-tool

10.1101/2020.04.10.20057869 ◽

2020 ◽

Author(s):

Kit Curtius ◽

Misha Kabir ◽

Ibrahim Al Bakir ◽

Chang-Ho Ryan Choi ◽

Juanda Hartono ◽

...

Keyword(s):

Colorectal Cancer ◽

Ulcerative Colitis ◽

Cancer Risk ◽

Risk Prediction ◽

Cox Regression ◽

Patient Specific ◽

Low Grade ◽

Web Tool ◽

Discovery Cohort ◽

Increased Risk

AbstractBackground and AimsUlcerative colitis (UC) patients diagnosed with low-grade dysplasia (LGD) have increased risk of developing advanced neoplasia (AN; high-grade dysplasia or colorectal cancer). We aimed to develop and validate a predictor of AN risk in UC patients with LGD and create a visual web-tool to effectively communicate the risk.MethodsIn our retrospective multi-centre validated cohort study, adult UC patients with an index diagnosis of LGD, identified from four UK centres between 2001-2019, were followed until progression to AN. In the discovery cohort (n=248), a multivariate risk prediction model was derived from clinicopathological features using Cox regression. Validation used data from 3 external centres (n=201). The validated model was embedded in a web-based tool to calculate and illustrate patient-specific risk.ResultsFour endoscopic variables were significantly associated with future AN progression in the discovery cohort: endoscopically visible LGD > 1 cm (HR = 2.8; 95% CI 1.3-6.0), incomplete endoscopic resection (HR = 2.9; 95% CI 1.3-6.5), moderate/severe histological inflammation within 5 years of LGD diagnosis (HR = 3.0; 95% CI 1.3- 6.7), and multifocality (HR = 2.8; 95% CI 1.3-6.1). In the validation cohort, this 4-variable model accurately predicted future AN cases with overall calibration Observed/Expected = 1 (95% CI 0.63-1.5), and achieved perfect specificity for the lowest predicted risk group over 13 years of follow-up.ConclusionMulti-cohort validation confirms that patients with large, unresected, and multifocal LGD and recent moderate/severe inflammation are at the highest risk of developing AN. Personalised risk prediction provided via the Ulcerative Colitis-Cancer Risk Estimator web-tool (www.UC-CaRE.uk) can be used to support treatment decision-making.

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