Colitis, Ulcerative


Article Author:
Whitney Lynch


Article Editor:
Ronald Hsu


Editors In Chief:
Jeff Thompson


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
11/18/2018 1:48:24 PM

Introduction

Ulcerative colitis is an idiopathic inflammatory condition of the colon which results in diffuse friability and superficial erosions on the colonic wall associated with bleeding. It is the most common form of inflammatory bowel disease worldwide. It characteristically involves inflammation restricted to the mucosa and submucosa of the colon. Typically, the disease starts in the rectum and extends proximally in a continuous manner. In the United States, the disease accounts for a quarter million physician visits annually and medical costs directly related to the disease are estimated to exceed four billion dollars annually.[1][2][3]

Etiology

The specific cause of inflammatory bowel disease is not known. There seems to be a primary genetic component since the most important independent risk factor is a family history of the disease (8% to 14% of patients). A first-degree relative of a patient with ulcerative colitis has four times higher risk of developing the disease. Additionally, ulcerative colitis has a higher incidence in Jewish populations than other ethnicities.

Although there is little evidence to support this, it has been postulated that alterations in the composition of the gut microbiota and defects in mucosal immunity could lead to ulcerative colitis. Autoimmunity may also play an important role in the etiology of ulcerative colitis.[4][5]

Epidemiology

Worldwide, the highest incidence and prevalence of inflammatory bowel diseases are seen in Northern Europe and North America. Inflammatory bowel disease is closely linked to a westernized environment and lifestyle. Ulcerative colitis has an incidence of 9 to 20 cases per 100,000 persons per year. Its prevalence is 156 to 291 cases per 100,000 persons per year. Compared to Crohn disease, ulcerative colitis has a greater prevalence in adults. When considering the pediatric population; however, ulcerative colitis is less prevalent that Crohn disease. 

Ulcerative colitis has a bimodal pattern of incidence. The main onset peaks between the ages of 15 and 30 years. A second, and smaller, the peak of incidence occurs between the ages of 50 and 70 years. Though some studies show a slight predilection for men, most studies note no preference regarding sex. There is an increased prevalence of ulcerative colitis in nonsmokers or those who recently quit smoking. Additionally, smokers diagnosed with ulcerative colitis tend to have milder disease, fewer hospitalizations, and need less medication. There is evidence, though weak, that non-steroidal anti-inflammatory drug use is associated with onset or relapse of ulcerative colitis.

There is also an association of inflammatory bowel disease with the removal of an inflamed appendix. Appendectomy before the age of twenty is associated with a decreased incidence of ulcerative colitis; whereas the opposite is true for Crohn disease. In fact, appendectomy has been shown to reduce the risk of developing ulcerative colitis by 69%.[6][7]

Pathophysiology

The pathophysiology of ulcerative colitis involves defects in the epithelial barrier, immune response, leukocyte recruitment, and microflora of the colon.[8][9]

The epithelial barrier has a defect in colonic mucin, and possibly tight junctions, leading to increased uptake of luminal antigens. The lamina propria of the mucosa also has increased number of activated and mature dendritic cells which include a large number of Toll-like receptors (TLR), specifically TLR2 and TLR4. There also seems to be an atypical T-helper (Th) cell response in patients with ulcerative colitis, specifically Th2, which exerts a cytotoxic response against epithelial cells. Other immune-related factors that play a role in the pathophysiology of ulcerative colitis include tumor necrosis factor alpha (TNF-alpha), Interleukin 13, and natural killer T-cells. Levels of IgM, IgA, and IgG are elevated in inflammatory bowel disease; however, a disproportionate increase in IgG1 antibodies is found in patients diagnosed with ulcerative colitis.

Leukocyte recruitment is affected on two fronts. There is an upregulated release of the chemoattractant CXCL8 in ulcerative colitis so that Leukocytes are recruited to the mucosa from systemic circulation. Additionally, there is an upregulation of mucosal addressin cellular adhesion molecule-1 (Mad-CAM1) on the endothelium of mucosal blood vessels which promotes leukocyte adhesion and extravasation into mucosal tissue.

Studies have shown that enteric microflora is important in the pathogenesis and severity of inflammation and disease phenotype. Ulcerative colitis seems to also result, in part, from a homeostatic imbalance between enteric microflora and the host's mucosal immunity. This results in an aberrant response to non-pathogenic bacteria.

Histopathology

Histologically, the mucosal layer of the colon in a patient with ulcerative colitis includes infiltrates of varying density and composition, depending on the stage of the disease. These infiltrates primarily consist of lymphocytes, plasma cells, and granulocytes, with the latter being more prominent during acute flares of the disease. Additionally, goblet cell depletion, ulcerations, and alterations in mucosal crypts are sometimes apparent. These findings might also be present on histological evaluation of the distal ileum, even though ulcerative colitis is a disease confined to the colon. This is backwash ileitis.

History and Physical

Ulcerative colitis's main symptom is bloody diarrhea, with or without mucus. Associated symptoms also include urgency or tenesmus, abdominal pain, malaise, weight loss, and fever, depending on the extent and severity of the disease. The onset of the disease is typically gradual, and patients will likely experience periods of spontaneous remission and subsequent relapses. Factors that typically exacerbate ulcerative colitis include smoking cessation and nonsteroidal anti-inflammatory drug use. 

There are some extraintestinal manifestations (EIMs) that are also present in 10% to 30% of patients with ulcerative colitis. Extraintestinal manifestations associated with disease activity include episcleritis, scleritis, and uveitis, peripheral arthropathies, erythema nodosum, and pyoderma gangrenosum. Extraintestinal manifestations independent of colitis activity include axial arthropathies, sacroiliitis, and ankylosing spondylitis. A significant hepatic extraintestinal manifestation of ulcerative colitis includes primary sclerosing cholangitis and is associated with a greater risk of colorectal cancer.

Evaluation

Diagnosis of ulcerative colitis is made clinically with supportive findings on endoscopy, biopsy, and by negative stool examination for infectious causes. Because colonic infection can produce clinical findings indistinguishable from idiopathic ulcerative colitis, microbiologic studies for bacterial infection and parasitic infestation should be included in the initial evaluation.[10][11]

Radiologic examinations are not critical for the diagnosis but may be useful. Patient's with longstanding ulcerative colitis may show "stovepipe" sign on double contrast barium enema (DCBE).

Colonoscopy or proctosigmoidoscopy might reveal loss of typical vascular pattern, granularity, friability, and ulceration which involve the distal rectum and proceed proximally in a symmetric, continuous, and circumferential pattern. The disease can range from disease isolated to the rectum and sigmoid colon (proctitis) to disease of the entire colon (pancolitis). Population-based studies show that, upon presentation, proctitis is found 30% to 60% of patients, left-sided colitis is found in 16% to 45%, and pancolitis is found in 14% to 35%.

Laboratory evaluation will usually reveal an increase in inflammatory factors (ESR, CRP, leukocytosis), especially during an acute flare. Regardless of disease stage, 60% to 70% of ulcerative colitis patients are positive for perinuclear antineutrophil cytoplasmic antibodies (P-ANCA). P-ANCA is also found in a small number of patients with Crohn's disease. In addition to P-ANCA, anti-saccharomyces cerevisiae antibodies (ASCA) are found in both Crohn disease and ulcerative colitis but are more prevalent in Crohn disease, therefore testing for both P-ANCA and ASCA has some utility in distinguishing types. Testing for carcinoembryonic antigen (CEA) can also be helpful in ulcerative colitis as higher levels can indicate a flare.

Testing for fecal calprotectin also has some utility in the diagnosis of ulcerative colitis, though it is nonspecific. Fecal calprotectin correlates with increased neutrophils in the intestine and therefore can be helpful in ruling out inflammatory bowel disease. Studies show that less than 1% of patients with low fecal calprotectin are likely to suffer from inflammatory bowel disease.

When a diagnosis of ulcerative colitis is made, the most common classification system used to determine extent and severity of the disease is the Montreal classification system. Extent (E) is determined by endoscopic evaluation and includes E1 (Proctitis), E2 (left-sided or distal colitis), and E3 (pancolitis). Symptoms and systemic findings determine severity (S). It ranges from S0 (remission) to S3 (severe).

Treatment / Management

Treatment choice for patients with ulcerative colitis is based on both the extent of the disease and the severity. The prognosis during the first decade after diagnosis is often generally good, and most patients go into remission. Rectal application of medical therapy, via suppository or enema, is usually appropriate for isolated distal disease (proctitis); however, a rectal application is usually used in combination with systemic therapy to help target the distal colon and therefore decrease tenesmus. [6][12][13]

First line treatment is sulfasalazine and 5-aminosalicylates, given orally or rectally, which have a remission rate of about 50%. Glucocorticoids, orally or rectally, can be added for those who fail to achieve remission within two weeks. Except for glucocorticoids, all of these medications can be used in the maintenance of remission. Additionally, there is some evidence that probiotics are helpful in attaining remission. Fecal microbiota transplantation also shows promise in the treatment of ulcerative colitis to help establish healthy gut microbiota.

If patients are refractory to glucocorticoids, thiopurines or biological drugs can be added to therapy. Thiopurines are immunosuppressants such as azathioprine or 6-mercaptopurine. Biological drugs include anti-TNF-alpha drugs, such as infliximab, adalimumab, and golimumab. Infliximab is the most widely used for ulcerative colitis and can be used in severe cases during hospital admissions. The newest class of biological drugs are anti-adhesion molecule inhibitors, such as vedolizumab, which blocks alpha-4-beta-7 integrin.

Since patients with ulcerative colitis have reduced expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) in their colonocytes, future treatment may include (PPAR-gamma) agonistic activity. PPAR-gamma is a negative regulator of NF-KB-dependent inflammation. Novel 5-aminosalicylic acid (5-ASA) analogues are being developed that have greater PPAR-gamma activity. Cardiotoxicity and metabolic toxicity restrict the use of existing PPAR-gamma agonists.

Colectomy is curative in patients with ulcerative colitis since the disease is restricted to the colon. Indications for surgery are a failure of medical therapy, intractable fulminant colitis, toxic megacolon, perforation, uncontrollable bleeding, intolerable side effects of medications, strictures, unresectable high-grade or multifocal dysplasia, cancer, or growth retardation in children. The procedure of choice is proctocolectomy with ileal pouch-anal anastomosis (IPAA); however, in patients who are ineligible for IPAA proctocolectomy with ileostomy is a viable alternative.

Differential Diagnosis

  • Crohn disease
  • Parasitic colitis
  • Tuberculosis
  • Radiation colitis
  • Colon cancer
  • Toxic megacolon
  • Bacterial/viral gastroenteritis

Staging

The severity of ulcerative colitis:

  • Mild: Fewer than 4 rectal bleeding episodes per day
  • Moderate: More than 4 rectal bleeding episodes per day
  • Severe: More than 4 rectal bleeding episodes  per day and patient has systemic features of an illness combined with hypoalbuminemia

Complications

  • Leak from anastomosis
  • Pelvic abscess
  • Enterocutaneous fistulas
  • Pouch prolapse, pouchitis
  • Incontinence
  • Sexual dysfunction
  • Toxic  megacolon
  • Colon/rectal cancer

Pearls and Other Issues

There is an increased risk of colorectal cancer in patients with ulcerative colitis. The risk is cumulative, with a 2% chance of colorectal cancer after ten years of diagnosis, 8% after 20 years, and 20% to 30% after 30 years. Two factors associated with increased risk of colorectal cancer are the duration and extent of the disease.

Enhancing Healthcare Team Outcomes

Ulcerative colitis is a systemic disorder with no cure. All patients with the disorder need lifelong monitoring. Because of the risk colorectal cancer, surveillance colonoscopy should occur every 1-2 years. Further, since patients are often treated with biological agents, they need to undergo screening for melanoma and nonmelanoma skin cancer. Patients with risk factors for osteoporosis need screening for bone mineral density periodically. Patients should be encouraged to undergo annual vaccination against influenza and the pneumococcus. Finally, many patients with ulcerative colitis develop depression and anxiety and should be referred to a mental health counselor.[14][15]

Outcomes

Ulcerative colitis has no cure and despite treatment, many continue to have increased bouts of stool frequency. An increase in mortality is usually seen in elderly patients, those with complications like infection, shock, anemia and those who require repeated surgical interventions. Data show that when the disease involves the muscularis propria, it can lead to bowel dysmotility, necrosis and gangrene. A certain number of patients also develop toxic megacolon with poor outcomes. It is estimated that about 5% of patients will develop colorectal cancer over time. The risk of colon cancer is higher in patients with pancolitis and in patients whose disease started before the age of 15. Overall, the quality of life in patients with ulcerative colitis is poor. [16][17](Level V)


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Colitis, Ulcerative - Questions

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Which of the following is false about ulcerative colitis?



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Which is not true regarding microscopic features of ulcerative colitis?



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A female presents with complaints of abdominal pain and rectal bleeding. She says she has lost weight over the past 2 years and has a lack of appetite. A colonoscopy revealed crypt abscesses limited to the mucosa and submucosa. What is the major long-term risk for this patient?



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Which of the following factors are associated with an increased risk of colorectal cancer in patients with ulcerative colitis?



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What surgical procedure, when done early in life, has been associated with a reduced risk of developing ulcerative colitis?



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What is the classic and most common presentation of ulcerative colitis?



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Colonoscopy is not indicated for which of the following?



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Which if the following is false regarding ulcerative colitis?



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Backwash ileitis is most likely seen in patients with which of the following?



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In which of the following disorders are carcinoembryonic antigen levels (CEA) elevated?



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Which of the following is used to treat ulcerative colitis?



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A 17-year-old female presents with a long history of abdominal pain, intermittent diarrhea, constipation, rectal bleeding, and weight loss. She has been to many physicians and nothing has ever been found. She undergoes a colonoscopy that reveals that the rectum is involved. A biopsy of the specimen reveals an inflammatory reaction to the entire colon without intervening areas of normal mucosa. The pathology is limited to the mucosa and submucosa. She may have which of the following conditions?



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Which of the following is used in the treatment of ulcerative colitis?



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A drug of choice in ulcerative colitis is which of the following?



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Which of the following drugs would be most effective for treating ulcerative colitis?



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Which of the following is true of ulcerative colitis?



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What personality disorder is most likely to be present in a patient with ulcerative colitis?



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A 26-year-old female presents with a several month history of diarrhea, rectal bleeding, and mucus per rectum. Stool culture for ova and parasites is negative. Colonoscopy shows inflammation of the rectum only. Relatives of this patient are at risk for which of the following diseases?



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Which of the following is the best initial management for ulcerative colitis?



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Which of the following would be least likely for a patient newly diagnosed with ulcerative colitis?



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In which of the following is anti-neutrophil cytoplasmic antibodies most commonly positive?



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Which of the following diseases significantly increases the risk of developing colorectal cancer?



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Pancolitis is a feature of which of the following disease?



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Which of the following liver diseases commonly is associated with ulcerative colitis?



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Which type of kidney stone is common in patients with ulcerative colitis?



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Which of the following races/ethnicities are at highest risk for developing ulcerative colitis?



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What does the "stovepipe sign" seen on double-contrast barium enema examination indicate?



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Which case is curative with surgical intervention for refractory inflammatory bowel disease?



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What autoimmune disease is associated with chronic inflammatory lesions confined to the colon and rectum?



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A 16-year-old male is admitted with a 4-month history of intermittent abdominal pain, fever, and bloody diarrhea. He has lost 5 kg over this period. Stool cultures were negative, but C-reactive protein is elevated. Anti-neutrophil cytoplasm antibodies (p-ANCA) are positive, and anti-saccharomyces cerevisiae antibodies (ASCA) are negative. The perianal and oral exams are normal. Colonoscopy provides the diagnosis. What is the incorrect statement about his condition?



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A 26 year old female complains of increasing low abdominal pain with cramping and bloody diarrhea. She has been ill for 4 days and denies any travel or undercooked food. Her temperature is 38.2°C, heart rate 110, and blood pressure 110/60 mmHg. There is leukocytosis and elevated erythrocyte sedimentation rate. Flexible sigmoidoscopy shows continuous rectal and sigmoid edema and hyperemia to the splenic flexure. There are multiple small mucosal hemorrhages with suppuration at the center and superficial ulcerations. What is the most likely diagnosis?



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Which stool test does not suggest active inflammation in ulcerative colitis?



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A 22-year-old woman presents with a long history of abdominal pain, intermittent diarrhea, constipation, rectal bleeding, and loss of weight. She has been to many physicians without a diagnosis. She undergoes a colonoscopy which reveals that the rectum is inflamed with mucus in the lumen. Biopsy of the specimen reveals an inflammatory reaction that is limited to the mucosa and submucosa. Numerous neutrophils and cryptic abscesses are visible. What treatment will you start this patient on?



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A 22-year-old female presents with a long history of abdominal pain, intermittent diarrhea, constipation, rectal bleeding and loss of weight. She has been to many physicians, and nothing has ever been diagnosed. She undergoes a colonoscopy, which reveals that the rectum is inflamed with mucus in the lumen. The rest of colon is normal Biopsy of the specimen reveals an inflammatory reaction that is limited to the mucosa and submucosa. Numerous neutrophils and cryptic abscesses are visible. In this patient, regular surveillance colonoscopy is recommended after how many years of colitis?



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You have just admitted a patient with an inflammatory bowel disorder. She has been having abdominal pain and vomiting for the past 12 hours. She also complains of bloody diarrhea. She has a fever and blood work reveals leukocytosis and marked anemia. Physical exam reveals hypotension, tachycardia, and absent bowel sounds. Plain x-ray reveals a dilated loop of bowel and thumb printing. The patient fails to respond to medical therapy and worsens over the next 48 hours. It is decided to take the patient for a colectomy. What will you tell the patient when obtaining the consent?



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Which of the following receptors are decreased in the colonocytes of patient's with ulcerative colitis?



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Which of the following is not seen on histologic examination of biopsies in ulcerative colitis?



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Which of the following is not an indication for non-elective surgical resection in patients with ulcerative colitis?



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Which of the following is not involved in the pathophysiology of ulcerative colitis?



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Colitis, Ulcerative - References

References

Gisbert JP,Chaparro M, Clinical usefulness of proteomics in inflammatory bowel disease: A comprehensive review. Journal of Crohn's     [PubMed]
Jackson B,De Cruz P, Algorithms to facilitate shared decision making for the management of mild-to-moderate ulcerative colitis. Expert review of gastroenterology     [PubMed]
Spiceland CM,Lodhia N, Endoscopy in inflammatory bowel disease: Role in diagnosis, management, and treatment. World journal of gastroenterology. 2018 Sep 21     [PubMed]
Ashton JJ,Ennis S,Beattie RM, Early-onset paediatric inflammatory bowel disease. The Lancet. Child     [PubMed]
Liu CY,Polk DB, Microbiomes through the Looking Glass: What Do UC? Cell host     [PubMed]
Danese S,Banerjee R,Cummings JF,Dotan I,Kotze PG,Leong RW,Paridaens K,Peyrin-Biroulet L,Scott G,Assche GV,Wehkamp J,Yamamoto-Furusho JK, Consensus recommendations for patient-centered therapy in mild-to-moderate ulcerative colitis: the i Support Therapy-Access to Rapid Treatment (iSTART) approach. Intestinal research. 2018 Oct 16     [PubMed]
Pai RK,Jairath V,Vande Casteele N,Rieder F,Parker CE,Lauwers GY, The emerging role of histologic disease activity assessment in ulcerative colitis. Gastrointestinal endoscopy. 2018 Aug 22     [PubMed]
Terry R,Chintanaboina J,Patel D,Lippert B,Haner M,Price K,Tracy A,Lalos A,Wakeley M,Gutierrez LS, Expression of WIF-1 in inflammatory bowel disease. Histology and histopathology. 2018 Jul 27     [PubMed]
Yamamoto-Furusho JK,Fonseca-Camarillo G,Furuzawa-Carballeda J,Sarmiento-Aguilar A,Barreto-Zuñiga R,Martínez-Benitez B,Lara-Velazquez MA, Caspase recruitment domain (CARD) family (CARD9, CARD10, CARD11, CARD14 and CARD15) are increased during active inflammation in patients with inflammatory bowel disease. Journal of inflammation (London, England). 2018     [PubMed]
Guardiola J,Lobatón T,Cerrillo E,Ferreiro-Iglesias R,Gisbert JP,Domènech E,Chaparro M,Esteve M,Rodríguez-Moranta F, Recommendations of the Spanish Working Group on Crohn's Disease and Ulcerative Colitis (GETECCU) on the utility of the determination of faecal calprotectin in inflammatory bowel disease. Gastroenterologia y hepatologia. 2018 Oct     [PubMed]
Lee JS,Kim ES,Moon W, Chronological Review of Endoscopic Indices in Inflammatory Bowel Disease. Clinical endoscopy. 2018 Aug 21     [PubMed]
Rodríguez-Lago I,Ferreiro-Iglesias R,Nos P,Gisbert JP, Management of acute severe ulcerative colitis in Spain: A nationwide clinical practice survey. Gastroenterologia y hepatologia. 2018 Oct 4     [PubMed]
Borman ZA,Côté-Daigneault J,Colombel JF, The risk for opportunistic infections in inflammatory bowel disease with biologics: an update. Expert review of gastroenterology     [PubMed]
Dreesen E,Gils A, Pharmacodynamic monitoring of biological therapies in chronic inflammatory diseases. Therapeutic drug monitoring. 2018 Oct 3     [PubMed]
McKenna NP,Bews KA,Behm KT,Mathis KL,Lightner AL,Habermann EB, Do Patients With Inflammatory Bowel Disease Have a Higher Postoperative Risk of Venous Thromboembolism or Do They Undergo More High-risk Operations? Annals of surgery. 2018 Aug 30     [PubMed]
Willian MK,D'Haens G,Yarlas A,Joshi AV, Changes in health-related quality of life and work-related outcomes for patients with mild-to-moderate ulcerative colitis receiving short-term and long-term treatment with multimatrix mesalamine: a prospective, open-label study. Journal of patient-reported outcomes. 2018 Dec     [PubMed]
Drews JD,Onwuka EA,Fisher JG,Huntington JT,Dutkiewicz M,Nogalska A,Nwomeh BC, Complications after proctocolectomy and ileal pouch-anal anastomosis in pediatric patients: A systematic review. Journal of pediatric surgery. 2018 Sep 19     [PubMed]

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