Prior History Of Ulcerative Colitis Research Articles

P584 Efficacy, safety, and tolerability of AMT-101, a gut selective oral IL-10 fusion, in the Phase 2 FILLMORE trial of patients with chronic pouchitis

Abstract Background Chronic pouchitis can occur in up to half of patients within 10 years of ileal pouch-anal anastomosis (IPAA) after proctocolectomy for ulcerative colitis (UC). There is a large unmet need for medical treatments. Methods This was a phase 2, randomized double-blind, parallel-group, 2 active-arm trial of the combined phase 2/3 trial in adults (18-75 years) with a prior history of UC with proctocolectomy and subsequent IPAA, who presented with chronic or recurrent pouchitis. The trial was conducted in US, Canada, and Western Europe. Approximately 20 patients were planned to be randomized 1:1 to either 3 mg or 10 mg AMT-101 doses administered once daily, orally, for 12 weeks. The key efficacy endpoints were: 1) the proportion of patients with symptomatic improvement, as measured by stool frequency response, and 2) the proportion of patients with histologic healing, as measured by Geboes scores. Histology and endoscopy were centrally read. Results 22 patients were randomized to receive AMT-101 3 mg (n=10) or 10 mg (n=12). The mean (SD) baseline absolute stool frequency was 13.4 (4.5). Overall, 36.4% (8/22) of patients achieved stool frequency response, defined as either a reduction of ≥ 3 stools and a ≥ 30% reduction in number of stools from baseline, or a return to post-IPAA number of stools or lower, at Week 12. 40% (4/10) and 33% (4/12) of patients dosed with 3 mg or 10 mg, respectively, achieved stool frequency response at Week 12. Rapidity of stool frequency response was demonstrated as early as Week 2 in both arms and was substantially maintained through Week 12. Patients had a median (IQR) baseline Geboes score of 5.1 (3.2 to 5.2), representing severe pouchitis with ulceration and tissue destruction. Across both arms, 22.7% (5/22) [20.0% (3 mg) and 25.0% (10 mg)] of patients met the histologic healing response of Geboes score ≤ 3.1, an objective assessment of disease improvement. Endoscopic assessments (SES-CD, ≥50% reduction) were also performed, with modest improvements [10% (3 mg) and 8.3% (10 mg)] at Week 12. There was no systemic AMT-101 PK (by design) nor anti-drug antibodies detected. Translational analysis revealed IL-10 biological responses in both arms. In tissue, IHC results showed increases in anti-inflammatory FOXP3+ (Tregs) and CD163+ (M2-macrophages) cells in the lamina propria. Treatment emergent adverse events were mostly mild to moderate, with only one treatment-unrelated serious adverse event. Conclusion AMT-101 3 mg and 10 mg both appeared to be safe and generally well tolerated. PK and translational data confirmed AMT-101’s gut-restricted profile over the 12-week treatment with tissue-level PD effects and no systemic exposure. The AMT-101 3 mg dose is advancing into a Phase 3 trial for chronic pouchitis.

Response of Severe Osteomalacia to High Dose Vitamin D3 Replacement in a Patient With Ulcerative Colitis and Liver Transplantation on Immunosuppressive Therapy

Background: Bone disease is common in inflammatory bowel disease (IBD), more frequently in Crohn’s disease than ulcerative colitis (UC). We present the case of a patient with prior history of ulcerative colitis with severe 25 OH vitamin D deficiency and metabolic bone disease. Case: 67 year old male with h/o ulcerative colitis, colon cancer s/p proctocolectomy and ileostomy, chemo-radiation, h/o primary sclerosing cholangitis (PSC) and orthotopic liver transplantation (OLT) 20 years prior presented with presented with severe muscle aches, severe limitation in mobility and severe vitamin D deficiency. He had been on chronic prednisone and tacrolimus, mycophenolate. Three years after OLT, he had fragility fractures at different times in both hips requiring hip arthroplasty. Labs were significant for persistently elevated alkaline phosphatase (ALP) up to 1569 U/L for last 10 years, bone specific ALP at 423.6 mcg/L, Calcium 9 mg/dl, phosphorus 2 mg/dl, 25 OH vitamin D was 4 ng/ml, 1, 25-hydroxy vitamin D (25-OHD) was 34 ng/ml, PTH was 189 pg/ml, urine calcium/creatinine ratio was 50 mg/g and urine NTX at 223 nM BCE/mM. Celiac screen was negative and tacrolimus levels were within normal range. Patient had extensive workup by gastroenterology for elevated ALP including three liver biopsies which were unrevealing. A bone scan showed increased uptake in thoracic region and metaphyses of large joints. A diagnosis of osteomalacia and secondary hyperparathyroidism was made and he was started on high dose vitamin D gradually increased to 8000 units thrice a day. Within few weeks, he noted marked improvement in mobility, bone pain and need for pain medications. In few months, BSAP decreased to 144.9 mcg/l, NTX and PTH also improved. 25 OH has also increased slightly to 13. He continues on high dose vitamin D and 1200mg of calcium daily. Discussion: Our patient likely had severe osteomalacia due to prolonged vitamin D deficiency, caused by multiple etiologies. Firstly, poor absorption in UC might lower 25-OHD levels. Secondly CYP3A enzymes are involved in the metabolism of calcineurin inhibitor tacrolimus as well as vitamin D, this could result in enhanced vitamin D metabolism, which would explain persistently low vitamin D level despite replacement with such high doses. The significant improvement in his symptoms with supplementation resulting in increased mobility despite not having a normal vitamin D level suggest other pleiotropic effects of vitamin D on muscle and bone as well. Additionally effects of liver transplantation on vitamin D metabolism need to be explored further.

Up-Regulation of Annexin-A1 and Lipoxin A4 in Individuals with Ulcerative Colitis May Promote Mucosal Homeostasis

BackgroundOne of the characteristics of an active episode of ulcerative colitis (UC) is the intense mucosal infiltration of leukocytes. The pro-resolution mediators Annexin-A1 (AnxA1) and lipoxin A4 (LXA4) exert counter-regulatory effects on leukocyte recruitment, however to date, the dual/cumulative effects of these formyl peptide receptor-2 (FPR2/ALX) agonists in the context of human intestinal diseases are unclear. To define the contribution of these mediators, we measured their expression in biopsies from individuals with UC.MethodsColonic mucosal biopsies were collected from two broad patient groups: healthy volunteers without (‘Ctrl’ n = 20) or with a prior history of UC (‘hx of UC’ n = 5); individuals with UC experiencing active disease (‘active’ n = 8), or in medically-induced remission (‘remission’ n = 16). We assessed the mucosal expression of LXA4, AnxA1, and the FPR2/ALX receptor in each patient group using a combination of fluorescence microscopy, biochemical and molecular analyses.ResultsMucosal expression of LXA4 was elevated exclusively in biopsies from individuals in remission (3-fold, P<0.05 vs. Ctrl). Moreover, in this same group we observed an upregulation of AnxA1 protein expression (2.5-fold increase vs. Ctrl, P<.01), concurrent with an increased level of macrophage infiltration, and an elevation in FPR2/ALX mRNA (7-fold increase vs. Ctrl, P<.05). Importantly, AnxA1 expression was not limited to cells infiltrating the lamina propria but was also detected in epithelial cells lining the intestinal crypts.ConclusionsOur results demonstrate a specific up-regulation of this pro-resolution circuit in individuals in remission from UC, and suggest a significant role for LXA4 and AnxA1 in promoting mucosal homeostasis.

Oral contraceptives, reproductive factors and risk of inflammatory bowel disease

BackgroundOral contraceptive use has been associated with risk of Crohn's disease (CD) and ulcerative colitis (UC).ObjectiveTo determine whether this association is confounded or modified by other important lifestyle and reproductive...

A pro-resolution mediator, prostaglandin D 2 , is specifically up-regulated in individuals in long-term remission from ulcerative colitis

Patients with ulcerative colitis (UC) experience unpredictable bouts of active inflammation and ulceration. Relatively little attention has been paid to the role of antiinflammatory mediators in the pathogenesis of UC, although rodent studies suggest an important role of prostaglandin (PG) D(2) in the resolution of tissue injury and inflammation. The present study was performed to determine if colonic PGD(2) synthesis was altered in patients in remission from UC and if expression of the key enzymes and receptors related to PGD(2) was altered. During routine colon-cancer screening, colonic biopsies were obtained from healthy individuals, some of whom had been in remission from UC, without treatment, for >4 y. UC patients with active disease or in medically induced remission were also biopsied. Only patients with active UC exhibited elevated expression of several proinflammatory cytokines (TNFalpha and IFNgamma) and colonic PGE(2) synthesis. In contrast, colonic PGD(2) synthesis was only elevated ( approximately 3-fold) in the healthy individuals with a prior history of UC. This group also exhibited significantly elevated expression of DP1, the key receptor mediating the antiinflammatory actions of PGD(2). Expression of the synthetic enzymes cyclooxygenase-1, cyclooxygenase-2, and hematopoietic PGD synthase was not altered in the healthy individuals with a prior history of UC. These results show a marked up-regulation of synthesis of an antiinflammatory prostanoid and expression of its receptor, specifically in individuals in long-term remission from UC. This is consistent with animal studies showing the importance of PGD(2) in the induction and maintenance of remission from colitis.

Epidermotropic Mucinous Adenocarcinoma Arising at Mucocutaneous Stomal Anastomosis Site

Polypoid lesions arising at ileostomy sites are uncommon and include inflammatory polyps related to prolapse and neoplastic polyps. Primary mucinous adenocarcinoma arising at an ileostomy site is rare and usually occurs in longstanding ulcerative colitis. An 82‐year‐old woman presented with an erythematous 1.5 cm polyp at the mucocutaneous junction of her ileostomy. Her history is significant for a cystectomy with ileal loop 23 years earlier for transitional cell carcinoma of the bladder. She had no prior history of ulcerative colitis. Histologically, a polypoid lesion was produced by variable‐sized cystic spaces filled with mucin and lined by columnar epithelium with goblet cells. The epithelial cells demonstrated cytological atypia and occasional mitotic figures were observed. Smaller neoplastic glands infiltrated the dermis and scattered, multiple epidermotropic foci were noted. We present an unusual case of a primary mucinous adenocarcinoma with multiple epidermotropic foci arising at an ileostomy site in a patient without a known history of ulcerative colitis. Primary mucinous adenocarcinoma arising at an ileostomy site is a rare occurrence described primarily in the gastrointestinal literature but could easily be unrecognized by a dermatopathologist. Knowledge of this phenomenon may prove helpful in arriving at the correct diagnosis.

Twenty cases of peristomal pyoderma gangrenosum: diagnostic implications and management.

Our experience with peristomal ulcers suggested that peristomal pyoderma gangrenosum (PPG) is an infrequent and usually unrecognized complication of inflammatory bowel disease. We hypothesized that a review of our experience with PPG would clarify the essentials of its diagnosis, evaluation, and treatment. A case series of 20 consecutive patients with PPG complicating inflammatory bowel disease were treated at our institution between 1986 and 1999. There were 15 women and 5 men. At the time of development of peristomal pyoderma, 10 of 20 patients had a diagnosis of Crohn disease (CD), while 9 had a diagnosis of ulcerative colitis (UC). One patient was diagnosed as having CD only after first developing PPG. Healing of PPG. All patients had failed local enterostomal care prior to referral. Debridements and/or stomal revisions were uniformly unsuccessful. Biopsies, when performed, did not provide clinically important information. Treatment was directed toward inflammatory bowel disease, with variable clinical responses to corticosteroids, metronidazole, cyclosporine, sulfasalazine, and infliximab. Ultimately, 13 patients had a diagnosis of CD. Of these patients, 12 (92%) of 13 developed PPG coincident with recurrent disease. Two patients had a remote history of proctocolectomy for UC and subsequent evaluation revealed CD. One patient developed PPG adjacent to a urinary Kock pouch after cystectomy; ultimately, a diagnosis of CD was made. No patients were lost to follow-up, but in 1 case of UC, no evaluation for latent CD was carried out. The final diagnosis was CD disease in 13 (65%) of 20 and UC in 7 (35%) of 20 patients. All PPG ulcers healed completely, within an average of 11.4 months (median, 8 months; range, 1-41 months). Ulcer resolution was achieved with medical therapy alone in 14 (70%) of 20 cases. Resection of active gastrointestinal CD resulted in healing in 5 (83%) of 6 cases. One case healed 2 months after conservative therapy only. This review of the largest reported series of PPG suggests the following: (1) PPG complicating inflammatory bowel disease is uncommon and often misdiagnosed by clinicians; (2) local wound care measures have little role in the healing of PPG; (3) PPG usually heralds active CD; (4) in patients with prior history of UC, PPG indicates CD until proven otherwise; (5) prolonged medical therapy (11 months), usually with immunosupression, is required for healing of PPG; and (6) if feasible, surgical resection of all active CD leads to the healing of PPG ulcers.