- ACRONYMS AND DEFINITIONS
- ACG - American College of Gastroenterology
- AGA - American Gastroenterological Association
- CRP - C-reactive protein
- ESR - Erythrocyte sedimentation rate
- FC - Fecal calprotectin
- IBD - Inflammatory bowel disease
- RCT - Randomized controlled trial
- TNF - Tumor necrosis factor
- UC - Ulcerative colitis
- UCEIS - Ulcerative colitis endoscopic index of severity
- 5-ASA - also called mesalamine and 5-aminosalicylate
- EPIDEMIOLOGY
- UC prevalence is highest in Northern Europe (0.5%) and North America and lowest in Asia. In the U.S., around 0.3% of the population is affected. Men and women are equally susceptible, and the peak age of incidence is between 15 and 30, with a second smaller peak occurring between 50 and 70. [1,22]
- RISK FACTORS
- Known risk factors
- Family history/genetics - most important risk factor
- Affected first-degree relative - risk is 5 - 16%
- Monozygotic twins concordance rate is 6 - 13%
- Age - UC has a bimodal peak incidence, with the main peak occurring between 15 and 30 years and a second smaller peak occurring between 50 and 70
- Ashkenazi Jews
- Possible risk factors
- Geography - North > South; urban > rural
- GI infections - e.g. Salmonella, Shigella
- NSAIDs
- Oral contraceptives
- Isotretinoin
- Possible protective factors
- Smoking - smoking appears to protect against the disease and smokers tend to have a milder course
- Appendicitis - appendectomy before age 20 years or a genetic/environmental predisposition to appendicitis may be protective against UC [1,15,18]
- SYMPTOMS
- Rectal bleeding
- Diarrhea
- Tenesmus - continuous urge to evacuate bowels
- Abdominal pain
- Fever (if severe) [1,6]
- PATHOLOGY
- Overview
- The exact pathology of UC is not entirely understood
- UC is believed to occur when defects in the epithelial barrier of the colon allow commensal bacteria in the lumen to come in contact with underlying tissue
- Defects in the epithelial barrier may occur secondary to faulty tight junctions and/or impaired mucin secretion
- In the underlying tissue, immune cells are activated, and they release inflammatory mediators. Other immune cells are recruited and the inflammatory process propagates.
- T-cell activity also appears to be altered in UC. Natural killer T-cells have been shown to secrete abnormally large amounts of interleukin 13 in patients with UC. Interleukin 13 promotes further inflammation and epithelial cell damage.
- Inflammatory lesions in UC only involve the mucosal surface of the colon. This distinguishes UC from Crohn's disease where the entire wall (transmural) of the colon is affected.
- UC lesions typically start at the anorectal verge and extend proximally in a continuous fashion. UC may involve the entire colon or only a small section. In some patients, a small patch of inflammation can be found in the cecum. UC differs from Crohn's disease in that it mostly affects the colon, and the lesions are continuous as opposed to the "skip lesions" seen in Crohn's disease.
- Intestinal involvement at diagnosis:
- Disease confined to the rectum or sigmoid colon - 30 - 50%
- Left-sided colitis (up to splenic flexure) - 20 - 30%
- Pancolitis - 20% [1]
- DIAGNOSIS
- Overview
- The diagnosis of UC is established by a combination of clinical symptoms, findings on colonoscopy, and histological features seen in colon biopsies
- Colonoscopy
- Colonoscopy is the gold standard for establishing the diagnosis of UC
- Findings on colonoscopy include a granular, erythematous mucosa with friability and loss of vascular patterns. In more severe disease, erosions and ulcers are found along with spontaneous bleeding.
- Inflammation typically begins in the rectum (> 95% of adult patients) and extends proximally in a continuous fashion to involve part or all of the colon.
- Laboratory
- ESR and C-reactive protein - nonspecific inflammatory markers (e.g. erythrocyte sedimentation rate, C-reactive protein) are often elevated in UC
- Fecal calprotectin - calprotectin is an antimicrobial substance released by polymorphonuclear granulocytes (PMNs). Fecal calprotectin concentrations are directly proportional to the number of PMNs migrating to the intestinal lumen. In patients with active inflammatory bowel disease, fecal calprotectin levels are typically very high. In studies involving adults with suspected inflammatory bowel disease (IBD) based on symptoms, the sensitivity and specificity of fecal calprotectin in detecting IBD (verified by endoscopy and histology) was 93% and 96%, respectively. In studies involving children and teenagers, the sensitivity was 92% and the specificity was 76%. The cutoff value typically used in the studies was > 50 mcg/g. [2,3]
- Fecal lactoferrin - lactoferrin is an iron-binding protein that has antimicrobial activity. Lactoferrin is found in neutrophil granules. During intestinal inflammation, neutrophils migrate to the intestinal mucosa and secrete lactoferrin into the lumen. Because of this, fecal lactoferrin levels are often elevated in patients with active inflammatory bowel disease (IBD). In studies involving adults with suspected IBD, the sensitivity and specificity of fecal lactoferrin in detecting IBD (verified by endoscopy and histology) was 78% and 94%, respectively. The cutoff value used in most studies was 7.25 mcg/ml. [4]
- Clostridioides difficile (C. diff) - The ACG guidelines recommend stool testing to rule out C. diff in patients suspected of having UC
- CLINICAL COURSE
- Overview
- UC typically follows an undulating course of disease flares followed by periods of remission
- At diagnosis, most patients have mild-to-moderate disease, and only about 10% of patients have severe disease
- For patients with disease confined to the rectum at diagnosis, approximately 14% will progress to extensive colitis over 10 years
- For patients with left-sided colitis at diagnosis, approximately 28% will progress to extensive colitis over 10 years
- Patients diagnosed at a younger age (< 30 years) are at greater risk for disease progression [5]
- Colectomy rates among patients with UC vary depending on the population studied and the treatment options available. In general, patients with UC have a 10-year colectomy rate that ranges from 4% - 30%. The risk of colectomy is highest during the first 2 years after diagnosis. Patients who are treated with biologic therapies appear to be at lower risk. [1,6,7.21]
- Factors associated with an increased risk of colectomy
- Age < 40 years at diagnosis
- Extensive colitis
- Severe endoscopic disease (Mayo endoscopic subscore 3, UCEIS ≥ 7)
- Hospitalization for colitis
- Elevated CRP
- Low serum albumin
- Clostridium difficile infection [18,21]
- SEQUELAE
- Rectal bleeding - common; may become severe in 10% of patients; can lead to iron-deficiency anemia [6]
- Bowel strictures - uncommon; if present, patient may be at increased risk of colon cancer [1,6]
- Toxic megacolon - a syndrome of severe colonic distension (≥ 6 cm); seen in patients with severe/fulminant disease; perforation may occur; is an indication for colectomy [6,8]
- Colon cancer - patients with UC are at an increased risk for colon cancer. The risk appears to be higher in patients who are diagnosed in childhood or adolescence and in those with primary sclerosing cholangitis. Recent studies suggest that the risk is decreasing. This is likely due to newer therapies (e.g. TNF inhibitors) and better disease control. [PMID 22522090, PMID 31929014] See colon cancer screening for recommendations on screening in UC [9]
- Cytomegalovirus (CMV) - CMV superinfection of the colon may occur in patients with severe, fulminant disease; immunosuppression (e.g. steroids, cyclosporine) also increases the risk; CMV colitis is diagnosed with viral cultures performed on colon biopsies; CMV colitis is treated with ganciclovir [8]
- Clostridium difficile (C. diff) - C. diff infections may occur in patients with severe disease; oral vancomycin may be more effective than metronidazole for treating C. diff in UC patients [8]
- Pouchitis - in patients who have had a total colectomy, an ileal pouch–anal anastomosis is typically formed; a syndrome called pouchitis where the ileal pouch becomes inflamed occurs in up to 40% of patients; pouchitis may be chronic in up to 20% of patients; symptoms include incontinence, tenesmus, urgency, bleeding, and increased stool frequency; pouchitis is treated with a short course of antibiotics (metronidazole 250 TID, or ciprofloxacin 500 mg BID); the diagnosis should be confirmed by endoscopy and histology [6,8]
- EXTRAINTESTINAL DISEASE
- Overview
- Extraintestinal disease occurs in 10 - 30% of patients with UC [6]
- Extraintestinal disease in UC includes the following:
- Arthritis - occurs in 5 - 10% of patients
- Pauciarticular (affecting < 5 large joints) - knee is commonly involved; typically associated with intestinal disease activity; improves with treatment of bowel disease
- Polyarticular (affecting ≥ 5 small joints) - MCP joints are commonly involved; typically not associated with intestinal disease activity; may be treated with steroids and COX-2 inhibitors
- See features of different arthritis syndromes for a comparison of different types of arthritis including IBD-associated arthritis
- Erythema nodosum - occurs in up to 10% of patients; typically coincides with acute flares; improves with disease treatment
- Primary sclerosing cholangitis - occurs in up to 7.5% of patients; associated with a higher risk of colon cancer; disease course appears to be independent of UC
- Eye disease - episcleritis, scleritis, and uveitis; occurs in 2 - 5% of patients
- Pyoderma gangrenosum - rare; associated with severe disease; typically affects the shin; more common in women and blacks [10]
- DISEASE CATEGORIES
- Overview
- There is no consensus method for quantifying disease activity in UC patients. The ACG 2019 guidelines present criteria for categorizing patients into four disease activity groups (remission, mild, moderate-severe, fulminant). These groups are then used to make treatment recommendations.
- The ACG criteria incorporate two measures of endoscopic disease (the UCEIS and the Mayo endoscopic subscore) which are presented below
- In practice, most patients will not have information available for every criteria. The ACG index should be used as a general guideline for quantifying disease activity so that patients do not have to meet every criteria to be considered for a specific category.
Ulcerative Colitis Endoscopic Index of Severity (UCEIS) | ||
---|---|---|
Category | Scoring | Description |
Vascular pattern | 0 = normal | Normal vascular pattern with arborizations of capillaries clearly defined |
1 = patchy obliteration | Patchy obliteration of vascular pattern | |
2 = obliterated | Complete loss of vascular pattern | |
Bleeding | 0 = none | No visible blood |
1 = mucosal | Spots or streaks of coagulated blood on the mucosa surface, which can be washed off | |
2 = luminal mild | Some free liquid blood in the lumen | |
3 = luminal moderate or severe | Frank blood in the lumen or visible oozing from the mucosa after washing or visible oozing from a hemorrhagic mucosa | |
Erosions and ulcers | 0 = none | Normal mucosa, no visible ulcers or erosions |
1 = erosions | Small defects in the mucosa #= mm, white or yellow, flat edge | |
2 = superficial ulcer | Larger defects in the mucosa .= mm, discrete fibrin covered, remain superficial | |
3 = deep ulcer | Deeper excavated defects in the mucosa, with a slightly raised edge |
Mayo endoscopic subscore | |
---|---|
Findings on endoscopy | Score |
Normal or inactive disease | 0 |
Mild disease (erythema, decreased vascular pattern, and mild friability) | 1 |
Moderate disease (marked erythema, lack of vascular pattern, friability, and erosions) | 2 |
Severe disease (spontaneous bleeding and ulcerations) | 3 |
American College of Gastroenterology Ulcerative Colitis Activity Index | ||||
---|---|---|---|---|
Remission | Mild | Moderate-severe | Fulminant | |
Stools (#/day) | Formed stools | <4 | >6 | >10 |
Blood in stools | None | Intermittent | Frequent | Continuous |
Urgency | None | Mild, occasional | Often | Continuous |
Hemoglobin | Normal | Normal | <75% of normal | Transfusion required |
ESR | <30 | <30 | >30 | >30 |
CRP (mg/L) | Normal | Elevated | Elevated | Elevated |
FC (mcg/g) | <150–200 | >150–200 | >150–200 | >150–200 |
Endoscopy (Mayo subscore) | 0–1 | 1 | 2–3 | 3 |
UCEIS | 0–1 | 2–4 | 5–8 | 7–8 |
- TREATMENT
Ulcerative colitis drugs | |
---|---|
Biologicals
|
Immunosuppressants
|
- Overview
- The ACG and AGA issue guidelines on the treatment of UC. Both guidelines are based on categorizing the patient's disease into mild, moderate, or severe categories. The ACG guidelines use the classification system detailed above (see ACG categories), and the AGA guidelines use different criteria (see respective guidelines below).
- The AGA has also published an algorithm for making treatment decisions - AGA UC treatment algorithm.
ACG 2019 Mild UC Treatment Recommendations |
---|
Mild disease defined as:
|
Induction of remission
|
Maintenance of remission
|
AGA 2019 Mild-to-Moderate UC Treatment Recommendations |
---|
Mild-to-moderate disease defined as all of the following:
|
Treatment recommendations
|
ACG 2019 Moderate-to-severe UC Treatment Recommendations |
---|
Moderate-to-severe disease defined as:
|
Induction of remission
|
Maintenance of remission
|
AGA 2020 Moderate-to-Severe UC Treatment Recommendations |
---|
Moderate-to-severe disease defined as any of the following:
|
General recommendations
|
Induction of remission
|
Maintenance of remission
|
AGA 2020 Acute Severe UC Treatment Recommendations |
---|
Acute severe UC defined as:
|
Recommendations
|
- Treatment failure with TNF inhibitors
- In 2017, the AGA issued recommendations for evaluating treatment failure in patients with IBD who are being treated with TNF inhibitors (infliximab, adalimumab, certolizumab, golimumab)
- The guidelines recommend checking for the presence of anti-drug antibodies and trough levels of TNF inhibitors
- The steps below outline their recommendations
Step 1 - Check trough TNF inhibitor levels
|
Step 2
|
- MEDICATION DOSING
Topical aminosalicylate | 5-aminosalicylate | 5-ASA | Mesalamine |
---|
Mesalamine suppository (Canasa®)
|
Mesalamine enema (Rowasa®)
|
Oral aminosalicylates | 5-aminosalicylates | 5-ASA | Mesalamine |
Balsalazide (Colazal®, Giazo®)
|
Mesalamine (Apriso®, Asacol® HD, Delzicol®, Pentasa®, Lialda®)
|
Olsalazine (Dipentum®)
|
Sulfasalazine (Azulfidine®, Azulfidine EN®)
|
Topical steroids |
Budesonide foam (Uceris®)
|
Budesonide tablet (Uceris®)
|
Hydrocortisone enema (Colocort®, Cortenema®)
|
Hydrocortisone foam (Cortifoam®)
|
Oral steroids |
Prednisone
|
Thiopurines |
Azathioprine (Imuran®)
|
Mercaptopurine (6-MP)
|
TNF inhibitors |
Infliximab (Remicade®)
|
Adalimumab (Humira®)
|
Golimumab (Simponi®)
|
Vedolizumab (Entyvio®) |
Dosing
|
Tofacitinib (Xeljanz®) |
Dosing
|
Cyclosporine |
Active disease dosing
|
- STUDIES
- The CONSTRUCT trial enrolled 270 patients with steroid-resistant, acute, severe UC
Main inclusion criteria
- Age ≥ 18
- Unscheduled admission for severe UC that had failed to respond to 2 - 5 days of IV hydrocortisone
Main exclusion criteria
- Enteric infection
- Histological diagnosis inconsistent with UC
- Treatment with infliximab or cyclosporine within 3 months
Baseline characteristics
- Average age 35 years
- Female sex - 37%
- Montreal score: E3 - 46%, E2 - 47%
- Median duration of symptoms - 24 days
- Median duration of IV hydrocortisone - 5 days
Randomized treatment groups
- Group 1 (135 patients) - Infliximab 5 mg/kg IV at baseline, Week 2, and Week 6
- Group 2 (135 patients) - Cyclosporine 2 mg/kg/day by continuous infusion for up to 7 days, then 5.5 mg/kg/day by mouth in divided doses for 12 weeks
- Treatment was open-label
- Oral cyclosporine dosing was adjusted to achieve a trough level of 100 - 200 ng/ml
- Other therapies were left at the discretion of the patient's provider. Stopping steroids by Week 12 was encouraged in patients who were doing well.
Primary outcome: Average quality-adjusted survival over the course of the study defined as the total area under the curve (AUC) of scores
from the Crohn’s and Ulcerative Colitis Questionnaire (CUCQ) measured at 3 and 6 months, and then every 6 months from 1 year to 3 years. By convention lower CUCQ scores
indicate better health on disease-specific patient-reported outcome measures. For the purposes of presenting the area under the curve, the CUCQ scores were transformed
so that lower scores indicated worse health.
Results
Duration: Median of 2.1 years | |||
Outcome | Infliximab | Cyclosporine | Comparisons |
---|---|---|---|
Primary outcome | 564 | 587 | p=0.603 |
Colectomy rates at 3 months | 29% | 30% | p>0.05 |
Colectomy rates at 12 months | 35% | 45% | p>0.05 |
Colectomy rates overall | 41% | 48% | p=0.223 |
Average time to colectomy | 811 days | 744 days | p=0.251 |
Median duration of study drug therapy | 43 days | 60 days | N/A |
|
Findings: There was no significant difference between cyclosporine and infliximab in clinical effectiveness
StraightHealthcare analysis:
- The CONSTRUCT trial found that cyclosporine was as effective as infliximab in patients with severe UC flare for both quality of life outcomes and colectomy rates. Also of note, there was no significant difference in adverse events between the two treatments.
- Disadvantages of cyclosporine include frequent lab monitoring and an extensive list of drug interactions, but on the upside, it is considerably cheaper than infliximab
- The GEMINI 1 Study enrolled 374 patients with active UC
Main inclusion criteria
- ≥ 18 years old
- Active ulcerative colitis defined as Mayo score 6 - 12 with a sigmoidoscopy subscore of at least 2, and disease that extends ≥ 15 cm from the anal verge
- Previous unsuccessful treatment or unacceptable side effects with steroids, immunosuppressants, or TNF inhibitors
Main exclusion criteria
- TNF inhibitors within previous 60 days
- Cyclosporine or thalidomide within 30 days
- History of colectomy
- Increased risk of infection
Baseline characteristics
- Average age 40 years
- Average Mayo score - 8.6
- Treatment with steroids only - 37%
- Treatment with immunosuppressants only - 18%
- Treatment with steroids + immunosuppressants - 17%
- No steroids or immunosuppressants - 29%
- Prior TNF inhibitor - 48%
The study had 2 phases, an induction phase and a maintenance phase
- Induction phase
- Group 1 (149 patients) - Placebo infusion
- Group 2 (225 patients) - Vedolizumab 300 mg at Weeks 0 and 2
- Maintenance phase
- Group 1 (126 patients) - Placebo infusion
- Group 2 (122 patients) - Vedolizumab 300 mg every 8 weeks
- Group 3 (125 patients) - Vedolizumab 300 mg every 4 weeks
- Participants could continue to take mesalamine, up to 30 mg of prednisone (or the equivalent) per day, or immunosuppressive agents at stable doses
- The induction phase also had an open-label vedolizumab arm that included 521 patients
- Vedolizumab-responders from the induction phase (randomized and open-label) were re-randomized into the maintenance phase
Primary outcome:
- Induction phase - clinical response at week 6, defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of ≥ 3 points and a decrease of at least 30% from the baseline score, with a decrease of at least 1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1
- Maintenance phase - clinical remission at week 52 defined as Mayo Clinic score ≤ 2 and no subscore higher than 1, and mucosal healing, defined as an endoscopic subscore of 0 or 1
Results
Duration: Induction phase - 6 weeks | Maintenance phase - 52 weeks | ||||
Outcome | Placebo | Ved q 8 weeks | Ved q 4 weeks | Comparisons |
---|---|---|---|---|
Primary outcome (induction) | 25.5% | 47.1% | N/A | p<0.001 |
Primary outcome (maintenance) | 15.9% | 41.8% | 44.8% | 1 vs 2 p<0.001 | 1 vs 3 p<0.001 |
|
Findings: Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis
- The study enrolled 1139 patients with moderate-to-severe UC who had failed oral steroids, thiopurines, or a TNF inhibitor
Main inclusion criteria
- Documented UC (endoscopic or radiographic and histological) for ≥ 4 months
- Moderately to severely active UC as defined by a total Mayo score of ≥ 6
- Failed oral steroids, thiopurines, or TNF inhibitors (infliximab or adalimumab)
Main exclusion criteria
- Disease limited to distal 15 cm
- No previous treatment
- History of surgery for UC
Baseline characteristics
- Average age - 41 years
- Median duration of disease - 6.5 years
- Extensive colitis - 52%
- Previous treatment failure: TNF antagonist - 50%, Steroids - 76%, Immunosuppressants - 68%
- Average total Mayo score - 9
The study had 2 phases, an induction phase and a maintenance phase
- Induction phase
- Group 1 (234 patients): Placebo for 8 weeks
- Group 2 (905 patients): Tofacitinib 10 mg twice daily for 8 weeks
- Maintenance phase
- Group 1 (198 patients): Placebo for 52 weeks
- Group 2 (198 patients): Tofacitinib 5 mg twice daily for 52 weeks
- Group 3 (197 patients): Tofacitinib 10 mg twice daily for 52 weeks
- The induction phase was performed in 2 separate trials. The maintenance phase included responders from the induction phase.
- Permitted concomitant medications for ulcerative colitis were oral aminosalicylates and oral glucocorticoids (at a maximum dose of 25 mg per day of prednisone or a prednisone equivalent), provided that the medications were administered at a stable dose throughout the induction trials; in the maintenance trial, tapering of glucocorticoids was mandatory
Primary outcome:
- Induction phase - remission at 8 weeks
- Maintenance phase - remission at 52 weeks
- Remission defined as a total Mayo score of ≤ 2, with no subscore > 1 and a rectal bleeding subscore of 0
Results
Duration: Induction phase - 8 weeks | Maintenance phase - 52 weeks | ||||
Outcome | Placebo | Tof 5 mg | Tof 10 mg | Comparisons |
---|---|---|---|---|
Remission (induction phase trial 1) | 8.2% | N/A | 18.5% | p=0.007 |
Remission (induction phase, trial 2) | 3.6% | N/A | 16.6% | p=<0.001 |
Remission (maintenance phase) | 11.1% | 34.3% | 40.6% | 2 or 3 vs 1 p<0.001 |
Findings: In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo
- Design: Randomized, placebo-controlled trial (N=86 | length=8 weeks)
- Treatment: Indigo Naturalis (IN) 0.5 g/day vs IN 1.0 g/day vs IN 2 g/day vs Placebo
- Primary outcome: Rate of clinical response at week 8, defined as a 3-point decrease in the Mayo score and a decrease of at least 30% from baseline, with a decrease of at least 1 point for the rectal bleeding subscore or absolute rectal bleeding score of 0-1
- Results:
- Primary outcome: IN 0.5g/day - 70%, IN 1g/day - 75%, IN 2 g/day - 81%, Placebo - 13.6%
- Findings: In a randomized, placebo-controlled trial, we found 8 weeks of IN (0.5-2.0 g per day) to be effective in inducing a clinical response in patients with UC. However, IN should not yet be used because of the potential for adverse effects, including pulmonary arterial hypertension.
- Design: Randomized controlled trial (N=73 | length = 8 weeks) in patients with mild to moderately active UC
- Treatment: Anaerobically prepared pooled donor fecal transplant vs Autologous fecal transplant via colonoscopy
- Primary outcome: Steroid-free remission of UC, defined as a total Mayo score of ≤2 with an endoscopic Mayo score of 1 or less at week 8
- Results:
- Primary outcome: Donor transplant - 32%, Autologous transplant - 9% (p=0.03)
- Findings: In this preliminary study of adults with mild to moderate UC, 1-week treatment with anaerobically prepared donor FMT compared with autologous FMT resulted in a higher likelihood of remission at 8 weeks. Further research is needed to assess longer-term maintenance of remission and safety.
- BIBLIOGRAPHY
- 1 - PMID 22914296 - Lancet review
- 2 - PMID 20634346 - Calprotectin MA in BMJ
- 3 - LabCorp website
- 4 - PMID 25002150 - Lactoferrin MA
- 5 - PMID 24733679 - UC disease clinical course
- 6 - PMID 22047562 - NEJM review
- 7 - PMID 17258717 - Colectomy rates in Europe
- 8 - PMID 20068560 - ACG GL
- 9 - PMID 22522090 - Colon cancer risk
- 10 - PMID 26154136 - Extraintestinal disease
- 11 - AGA UC treatment algorithm
- 12 - Manufacturer's PI
- 13 - PMID 16530532 ADA GL for cyclosporine
- 14 - PMID 22835577 - Cyclosporine article
- 15 - PMID 27196591 - Appendicitis and UC risk
- 16 - PMID 27595142 - Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial, Lancet Gastroenterol Hepatol (2016)
- 17 - PMID 28780013 - Therapeutic Drug Monitoring in Inflammatory Bowel Disease, AGA Clinical Guidelines Committee (2017)
- 18 - PMID 30840605 - ACG Clinical Guideline: Ulcerative Colitis in Adults, Am J Gastroenterol (2019)
- 19 - PMID 30576644 - AGA Clinical Practice Guidelines on the Management of Mild-to-Moderate Ulcerative Colitis, Gastroenterology (2019)
- 20 - PMID 31945371 - AGA Clinical Practice Guidelines on the Management of Moderate to Severe Ulcerative Colitis, Gastroenterology (2020)
- 21 - PMID 33065311 - Rates of Intestinal Resection and Colectomy in Inflammatory Bowel Disease Patients after Initiation of Biologics: A Cohort Study, Clin Gastroenterol Hepatol (2020)
- 22 - PMID 29050646 - Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies, Lancet (2017)