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Fulltext Human TGF-β1 deficiency causes severe inflammatory bowel disease and encephalopathy

Kotlarz D, Marquardt B, Barøy T, Lee WS, Konnikova L, Hollizeck S, et al.

Nat Genet, 2018 Mar;50(3):344-348.
PMID: 29483653 DOI: 10.1038/s41588-018-0063-6

Transforming growth factor (TGF)-β1 (encoded by TGFB1) is the prototypic member of the TGF-β family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis1,2. Following its discovery 3 , enormous interest and numerous controversies have emerged about the role of TGF-β in coordinating the balance of pro- and anti-oncogenic properties4,5, pro- and anti-inflammatory effects 6 , or pro- and anti-fibrinogenic characteristics 7 . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-β1-LAP complex, which is suggestive of perturbed bioavailability of TGF-β1. Our study shows that TGF-β1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.

Matched MeSH terms: Inflammatory Bowel Diseases/pathology
Multivariate Prediction of Intraoperative Abandonment of Ileal Pouch Anal Anastomosis

Poh KS, Qureshi S, Hong YK, Moreno T, Stocchi L, Hull T, et al.

Dis Colon Rectum, 2020 05;63(5):639-645.
PMID: 32032200 DOI: 10.1097/DCR.0000000000001617

BACKGROUND: Restorative total proctocolectomy with IPAA may not be feasible in some patients because of technical intraoperative limitations.
OBJECTIVE: This study aimed to assess preoperative predictors for intraoperative IPAA and review management.
DESIGN: This is a retrospective review.
SETTING: This study was conducted at Cleveland Clinic between January 2010 and May 2018.
PATIENTS: Patients ≥18 years of age who underwent ileoanal pouch surgery were included. Patients with successful pouch creation as planned were grouped as "successful IPAA creation." Operative reports of patients who underwent alternative procedures were reviewed to identify cases when the pouch was preoperatively planned but intraoperatively abandoned (IPAA-abandoned group). Multivariate logistic regression models were developed to determine predictors of intraoperative pouch abandonment. We also reviewed the management of patients in whom the initial pouch creation failed.
MAIN OUTCOME MEASURES: The primary outcomes measured were preoperative predictors for intraoperative ileoanal pouch abandonment.
RESULTS: A total of 1438 patients were offered an ileoanal pouch; 21 (1.5%) experienced pouch abandonment due to inadequate reach (n = 17) and other technical reasons (n = 4). These patients underwent alternative procedures such as end or loop ileostomy with/without proctectomy. Multivariate logistic regression analysis indicated male sex (OR, 6.021; 95% CI, 1.540-23.534), BMI (OR, 1.217; 95% CI, 1.114-1.329), and a 2-stage procedure (OR, 14.510; 95% CI, 4.123-51.064) as independent factors associated with intraoperative abandonment of pouch creation. Alternative procedures were total proctocolectomy with end ileostomy (n = 14) and total abdominal colectomy with end ileostomy without proctectomy (n = 7). Ultimately, pouch creation was achieved in 6 of 21 patients after a median interval of 8.8 (range, 4.1-34.8) months. All patients had intentional weight loss before a reattempt and total abdominal colectomy with end ileostomy without proctectomy as their initial procedure.
LIMITATIONS: This study was limited by its retrospective nature.
CONCLUSIONS: Ileoanal pouch abandonment is rare and can be mitigated by initial total abdominal colectomy and weight loss. Male, obese patients are at a higher risk of failure. Intraoperative assessment of ileoanal pouch feasibility should occur before rectal dissection. See Video Abstract at http://links.lww.com/DCR/B156. PREDICCIÓN MULTIVARIANTE DEL ABANDONO INTRAOPERATORIO DE LA ANASTOMOSIS ANAL CON BOLSA ILEAL: La proctocolectomía total restaurativa con anastomosis de bolsa ileoanal puede no ser posible en algunos pacientes debido a limitaciones técnicas intraoperatorias.Evaluar los predictores preoperatorios para el abandono intraoperatorio de la bolsa ileoanal y revisar el manejo.Revisión retrospectiva.Cleveland Clinic entre Enero de 2010 y mayo de 2018.Pacientes > 18 años que se sometieron a cirugía de bolsa ileoanal. Los pacientes con una creación exitosa de la bolsa según lo planeado se agruparon como "creación exitosa de anastomosis de bolsa ileoanal". Se revisaron los informes operativos de los pacientes que se sometieron a procedimientos alternativos para identificar los casos en que la bolsa se planificó preoperatoriamente pero se abandonó intraoperatoriamente (grupo de "anastomosis anal de bolsa ileoanal abandonada"). Se desarrollaron modelos de regresión logística multivariante para determinar los predictores del abandono intraoperatorio de la bolsa. También revisamos el manejo de pacientes que fallaron en la creación inicial de la bolsa.Predictores preoperatorios para el abandono intraoperatorio de la bolsa ileoanal.A un total de 1438 pacientes se les ofreció una bolsa ileoanal; 21 (1.5%) experimentaron abandono de la bolsa debido a un alcance inadecuado (n = 17) y otras razones técnicas (n = 4). Estos pacientes se sometieron a procedimientos alternativos como ileostomía final o de asa con / sin proctectomía. El análisis de regresión logística multivariante indicó género masculino (OR, 6.021; IC 95%, 1.540-23.534), índice de masa corporal (OR, 1.217; IC 95%, 1.114-1.329) y procedimiento en 2 etapas (OR, 14.510; IC 95%, 4.123-51.064) como factores independientes asociados con el abandono intraoperatorio de la creación de la bolsa. Los procedimientos alternativos fueron la proctocolectomía total con ileostomía final (n = 14) y la colectomía abdominal total con ileostomía final sin proctectomía (n = 7). Finalmente, la creación de la bolsa se logró en 6/21 pacientes después de un intervalo medio de 8.8 (rango, 4.1-34.8) meses. Todos los pacientes tuvieron pérdida de peso intencional antes de la reintenta y colectomía abdominal total con ileostomía final sin proctectomía como procedimiento inicial.Naturaleza retrospectiva.El abandono de la bolsa ileoanal es raro y puede mitigarse mediante la colectomía abdominal total inicial y la pérdida de peso. Los pacientes masculinos y obesos tienen un mayor riesgo de fracaso. La evaluación intraoperatoria de la viabilidad de la bolsa ileoanal debe ocurrir antes de la disección rectal. Consulte Video Resumen en http://links.lww.com/DCR/B156. (Traducción-Dr. Yesenia Rojas-Kahlil).

Matched MeSH terms: Inflammatory Bowel Diseases/pathology
Coatless alginate pellets as sustained-release drug carrier for inflammatory bowel disease treatment

Md Ramli SH, Wong TW, Naharudin I, Bose A

Carbohydr Polym, 2016 Nov 05;152:370-381.
PMID: 27516284 DOI: 10.1016/j.carbpol.2016.07.021

Conventional alginate pellets underwent rapid drug dissolution and failed to exert colon targeting unless subjected to complex coating. This study designed coatless delayed-release oral colon-specific alginate pellets for ulcerative colitis treatment. Alginate pellets, formulated with water-insoluble ethylcellulose and various calcium salts, were prepared using solvent-free melt pelletization technique which prevented reaction between processing materials during agglomeration and allowed reaction to initiate only in dissolution. Combination of acid-soluble calcium carbonate and highly water-soluble calcium acetate did not impart colon-specific characteristics to pellets due to pore formation in fragmented matrices. Combination of moderately water-soluble calcium phosphate and calcium acetate delayed drug release due to rapid alginate crosslinking by soluble calcium from acetate salt followed by sustaining alginate crosslinking by calcium phosphate. The use of 1:3 ethylcellulose-to-alginate enhanced the sustained drug release attribute. The ethylcellulose was able to maintain the pellet integrity without calcium acetate. Using hydrophobic prednisolone as therapeutic, hydrophilic alginate pellets formulated with hydrophobic ethylcellulose and moderately polar calcium phosphate exhibited colon-specific in vitro drug release and in vivo anti-inflammatory action. Coatless oral colon-specific alginate pellets can be designed through optimal formulation with melt pelletization as the processing technology.

Matched MeSH terms: Inflammatory Bowel Diseases/pathology
Fulltext Anti-TNF Treatment for Extraintestinal Manifestations of Inflammatory Bowel Disease in the Swiss IBD Cohort Study

Vavricka SR, Gubler M, Gantenbein C, Spoerri M, Froehlich F, Seibold F, et al.

Inflamm Bowel Dis, 2017 07;23(7):1174-1181.
PMID: 28452862 DOI: 10.1097/MIB.0000000000001109

BACKGROUND: Extraintestinal manifestations (EIMs) in patients with inflammatory bowel disease (IBD) are frequently observed. Little is known about the efficacy of anti-tumor necrosis factor (TNF) in EIM management. We assessed the effect of 3 anti-TNF agents (infliximab, adalimumab, and certolizumab pegol) on EIM evolution.
METHODS: Data on 1249 patients from the Swiss IBD Cohort Study (SIBDCS) were analyzed. All EIMs were diagnosed by relevant specialists. Response was classified into improvement, stable disease, and clinical worsening based on the physician's interpretation.
RESULTS: Of the 366 patients with at least 1 EIM, 213 (58.2%) were ever treated with an anti-TNF. A total of 299 treatments were started for 355 EIMs. Patients with EIM were significantly more often treated with anti-TNF compared with those without EIM (58.2% versus 21.0%, P < 0.001). Infliximab was the most frequently used drug (63.2%). In more than 71.8%, a clinical response of the underlying EIM to anti-TNF therapy was observed. In 92 patients (43.2%), anti-TNF treatments were started for the purpose of treating EIM rather than IBD. Response rates to anti-TNF were generally good and best for psoriasis, aphthous stomatitis, uveitis, and peripheral arthritis. In 11 patients, 14 EIM occurred under anti-TNF treatment.
CONCLUSIONS: Anti-TNF was frequently used among patients with EIM. In more than 40%, anti-TNF treatments are started to treat EIM rather than IBD. Given the good response rates, anti-TNF seems to be a valuable option in the treatment of EIM, whereas appearance of EIM under anti-TNF does not seem to be a source of considerable concern.

Matched MeSH terms: Inflammatory Bowel Diseases/pathology