ULCERATIVE COLITIS (UC)



























  • Patients receive one score for each category and the 3 scores are added for the index value
  • Reference [18]
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

  • Reference [18]
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

  • The above factors are general guides for disease activity. With the exception of remission, a patient does not need to have all the factors to be considered in a specific category.
  • Reference [18]
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


Ulcerative colitis drugs
Biologicals
  • IL-12 / IL-23 inhibitor
    • Ustekinumab (Stelara®)

  • TNF inhibitors
    • Adalimumab (Humira®)
    • Golimumab (Simponi®)
    • Infliximab (Remicade®)

  • T-cell agents
    • Vedolizumab (Entyvio®)
Immunosuppressants
  • Aminosalicylates
    • Balsalazide (Colazal®, Giazo®)
    • Mesalamine (Asacol®, etc.)
    • Olsalazine (Dipentum®)
    • Sulfasalazine (Azulfidine®)

  • Calcineurin inhibitors
    • Cyclosporine (Neoral®)

  • Janus kinase inhibitors
    • Tofacitinib (Xeljanz®)
    • Upadacitinib (Rinvoq®)

  • Thiopurines
    • Azathioprine (Imuran®)
    • Mercaptopurine (6-MP)

  • Corticosteroids
    • Oral/IV corticosteroids (e.g. prednisone)
    • Budesonide tablet/foam (Uceris®)
    • Hydrocortisone foam/enema (Colocort®, etc.)

  • Sphingosine 1-phosphate modulator
    • Ozanimod (Zeposia®)


  • Reference [18]
ACG 2019 Mild UC Treatment Recommendations
Mild disease defined as:
Induction of remission
  • Proctitis (within 18 cm of the anal verge, distal to the rectosigmoid junction)
    • Initial: Rectal 5-aminosalicylate therapies at a dose of 1 g/d
    • If suboptimal response: Consider adding oral 5-aminosalicylate at a dose of at least 2 g/d +/- oral budesonide ER tablet 9 mg/d. Oral corticosteroids may be necessary in refractory cases.
  • Left-sided (extending from the sigmoid to the splenic flexure)
    • Initial (preferred): Rectal 5-aminosalicylate enemas at a dose of at least 1 g/d
    • Initial (other): Rectal 5-aminosalicylate enemas at a dose of at least 1 g/d combined with oral 5-aminosalicylate at a dose of at least 2 g/d
    • If suboptimal response: Oral budesonide ER table 9 mg/d
    • Resistant cases: Oral corticosteroids
  • Extensive (extending beyond the splenic flexure)
    • Initial: Oral 5-aminosalicylate at a dose of at least 2 g/d
    • If suboptimal response: Consider adding oral budesonide ER table 9 mg/d. Oral corticosteroids may be necessary in refractory cases.
  • Other recommendations
    • Patients with mildly active UC should be reassessed to determine response to induction therapy within 6 weeks
    • Low dose oral 5-aminosalicylate therapy (2–2.4 g/d) is preferred over higher dose therapy (4.8 g/d) because there is no difference in remission rates
    • For patients who have a suboptimal response on appropriately dosed 5-aminosalicylate therapies (2 g/d oral and 1 g/d rectal), changing to alternative 5-aminosalicylate therapy is not recommended. Alternative therapeutic classes should be considered.
Maintenance of remission
  • Proctitis (within 18 cm of the anal verge, distal to the rectosigmoid junction)
    • Rectal 5-aminosalicylate therapies at a dose of 1 g/d
  • Left-sided (to the splenic flexure) or extensive disease (beyond the splenic flexure)
    • Oral 5-aminosalicylate at a dose of at least 2 g/d [18]

  • Reference [19]
AGA 2019 Mild-to-Moderate UC Treatment Recommendations
Mild-to-moderate disease defined as all of the following:
  • < 4 – 6 bowel movements per day
  • Mild–moderate rectal bleeding
  • Absence of constitutional symptoms (e.g. fever, anemia, tachycardia)
  • Low overall inflammatory burden
  • Absence of features suggestive of high inflammatory activity based upon Truelove and Witts criteria and the Mayo Clinic score. (AGA does not specifically define this, but an ESR < 30 and a Mayo score < 6 is considered milder disease. See Mayo Score calculator.)

  • Patients who have more frequent bowel movements, more prominent rectal bleeding, or greater overall inflammatory burden should be considered to have moderate disease
Treatment recommendations
  • In patients with extensive disease, the AGA recommends using either standard-dose mesalamine (2–3 g/d) or diazo-bonded 5-ASA rather than low-dose mesalamine, sulfasalazine, or no treatment
    • Comment: Patients already on sulfasalazine in remission or patients with prominent arthritic symptoms may reasonably choose sulfasalazine 2–4 g/d if alternatives are cost prohibitive, albeit with higher rate of intolerance
  • In patients with extensive or left-sided disease, the AGA suggests adding rectal mesalamine to oral 5-ASA
  • In patients with suboptimal response to standard-dose mesalamine or diazo-bonded 5-ASA or with moderate disease activity, the AGA suggests using high-dose mesalamine (> 3 g/d) with rectal mesalamine
  • In patients being treated with oral mesalamine, the AGA suggests using once-daily dosing rather than multiple times per day dosing
  • The AGA suggests using standard-dose oral mesalamine or diazo-bonded 5-ASA, rather than budesonide MMX or controlled ileal release budesonide for induction of remission
  • In patients with left-sided ulcerative proctosigmoiditis or proctitis, the AGA suggests using mesalamine enemas (or suppositories) rather than oral mesalamine
    • Comment: patients who place a higher value on convenience of oral medication administration and a lower value on effectiveness could reasonably choose oral mesalamine.
  • In patients with ulcerative proctosigmoiditis who choose rectal therapy over oral therapy, the AGA suggests using mesalamine enemas rather than rectal corticosteroids
    • Comment: Patients who place a higher value on avoiding difficulties associated with mesalamine enemas and a lower value on effectiveness may reasonably select rectal corticosteroid foam preparations.
  • In patients with ulcerative proctitis who choose rectal therapy over oral therapy, the AGA recommends using mesalamine suppositories
  • In patients with ulcerative proctosigmoiditis or proctitis being treated with rectal therapy who are intolerant of or refractory to mesalamine suppositories, the AGA suggests using rectal corticosteroid therapy rather than no therapy for induction of remission
  • In patients with disease refractory to optimized oral and rectal 5-ASA, regardless of disease extent, the AGA suggests adding either oral prednisone or budesonide MMX
  • The AGA makes no recommendation for use of probiotics
  • In patients with disease despite 5-ASA therapy, the AGA makes no recommendation for use of curcumin
  • In patients without Clostridium difficile infection, the AGA recommends fecal microbiota transplantation be performed only in the context of a clinical trial

  • Reference [18]
ACG 2019 Moderate-to-severe UC Treatment Recommendations
Moderate-to-severe disease defined as:
Induction of remission
  • Moderately active: Oral budesonide ER table 9 mg/day
  • Moderately to severely active
    • One of the following:
      • Oral corticosteroids
      • TNF inhibitor (adalimumab, golimumab, or infliximab)
      • Vedolizumab
      • Tofacitinib 10 mg orally twice daily for 8 weeks
  • Other recommendations
    • 5-aminosalicylate therapy could be used as monotherapy for induction of moderately but not severely active UC
    • In patients with moderately active UC, consider nonsystemic corticosteroids such as budesonide ER table before the use of systemic therapy
    • In patients with severely active UC, consider systemic corticosteroids rather than topical corticosteroids
    • Robust data on combination TNF inhibitor and immunomodulator therapy in moderately to severely active UC exist only for infliximab and thiopurines
    • Patients who do not initially respond to a TNF inhibitor should be tried on a different drug class and not switched to another TNF inhibitor. Patients who initially respond to a TNF inhibitor but lose response may be tried on another TNF inhibitor.
    • Patients who do not respond or lose response to a TNF inhibitor should have therapeutic drug monitoring performed. See treatment failure below.
    • Patients who have failed previous 5-aminosalicylate therapy who are using TNF inhibitors should not take 5-aminosalicylates with the TNF inhibitor
    • When infliximab is used as induction therapy for patients with moderately to severely active UC, combination therapy with a thiopurine is recommended
    • Patients who have previously failed TNF inhibitor therapy should be treated with vedolizumab or tofacitinib
Maintenance of remission
  • For patients who achieve remission with corticosteroids, thiopurines should be used for maintenance of remission
  • Patients who achieve remission with a TNF inhibitor, vedolizumab, or tofacitinib should continue their respective medication for maintenance of remission
  • Corticosteroids, budesonide ER table, and methotrexate are not recommended for maintenance of remission
  • Patients who have failed previous 5-aminosalicylate therapy who are using TNF inhibitors should not take 5-aminosalicylates with the TNF inhibitor [18]

  • Reference [20]
AGA 2020 Moderate-to-Severe UC Treatment Recommendations
Moderate-to-severe disease defined as any of the following:
  • Dependent on or refractory to corticosteroids
  • Severe endoscopic disease activity (presence of ulcers) or at high risk of colectomy
  • Mayo Clinic scores of 6 - 12 with an endoscopic subscore of 2 or 3 (see Mayo Score calculator and Mayo endoscopic subscore)
General recommendations
  • In adult outpatients, the AGA recommends using infliximab, adalimumab, golimumab, vedolizumab, tofacitinib or ustekinumab over no treatment
  • In adult outpatients who are naïve to biologic agents, the AGA recommends that tofacitinib be only be used in biologic-naïve patients in the setting of a clinical or registry study
  • In adult outpatients, the AGA suggests combining TNF inhibitors, vedolizumab or ustekinumab with thiopurines or methotrexate, rather than biologic monotherapy
    • Comment: Patients, particularly those with less severe disease, who place higher value on the safety of biologic monotherapy, and lower value on the efficacy of combination therapy, may reasonably chose biologic monotherapy
  • In adult outpatients, the AGA suggests combining TNF inhibitors, vedolizumab or ustekinumab with thiopurines or methotrexate rather than thiopurine monotherapy
  • In adult outpatients, the AGA suggests early use of biologic agents with or without immunomodulator therapy, rather than gradual step up after failure of 5-aminosalicylates
    • Comment: Patients, particularly those with less severe disease, who place higher value on the safety of 5-ASA therapy, and lower value on the efficacy of biologic agents or tofacitinib, may reasonably choose gradual step therapy with 5-ASA therapy
  • In adult outpatients who have achieved remission with biologic agents and/or immunomodulators or tofacitinib, the AGA suggests against continuing 5-aminosalicylates for induction and maintenance of remission
Induction of remission
  • In adult outpatients who are naïve to biologic agents, the AGA suggests using infliximab or vedolizumab rather than adalimumab, for induction of remission
    • Comment: Patients, particularly those with less severe disease, who place higher value on the convenience of self-administered subcutaneous injection, and a lower value on the relative efficacy of medications, may reasonably chose adalimumab as an alternative
  • In adult outpatients who have previously been exposed to infliximab, particularly those with primary non-response, the AGA suggests using ustekinumab or tofacitinib, rather than vedolizumab or adalimumab for induction of remission
  • In adult outpatients with active moderate-severe ulcerative colitis, the AGA suggests against using thiopurine monotherapy for induction of remission
  • In adult outpatients, the AGA suggests against using methotrexate monotherapy for induction or maintenance of remission
  • In adult outpatients, the AGA suggests using biologic monotherapy (TNF inhibitors, vedolizumab or ustekinumab) or tofacitinib rather than thiopurine monotherapy for induction of remission
Maintenance of remission
  • In adult outpatients in remission, the AGA suggests using thiopurine monotherapy, rather than no treatment, for maintenance of remission
  • In adult outpatients, the AGA suggests against using methotrexate monotherapy for induction or maintenance of remission
  • In adult outpatients in remission, the AGA makes no recommendation in favor of, or against, using biologic monotherapy or tofacitinib, rather than thiopurine monotherapy for maintenance of remission.

  • Reference [18]
ACG 2019 Acute Severe UC Treatment Recommendations
Acute severe UC defined as:
  • Presence of 6 or more bowel movements daily accompanied by at least 1 systemic sign of toxicity including tachycardia, fever, anemia (hemoglobin , 10.5 g/dL), or elevated inflammatory markers (ESR > 30 mm/hr)
Induction of remission
  • Initial therapy: Methylprednisolone 60 mg/d or hydrocortisone 100 mg 3 or 4 times per day
  • If inadequate response after 3 - 5 days: Infliximab or cyclosporine
  • Surgery: In patients failing to adequately respond to medical therapy by 3 – 5 days or with suspected toxicity, surgical consultation should be obtained. Toxic megacolon, colonic perforation, severe refractory hemorrhage, and refractoriness to medical therapy are indications for surgery.
  • Other recommendations
    • Stool testing for C diff should be performed and all patients should have flexible sigmoidoscopy within 72 hours, and preferably within 24 hours of admission. Biopsies to evaluate for cytomegalovirus (CMV) colitis should be obtained.
    • C diff infection should be treated with vancomycin
Maintenance of remission
  • Patients who achieve remission with infliximab should continue infliximab for maintenance of remission
  • Patients who achieve remission with cyclosporine should use a thiopurine or vedolizumab for maintenance of remission

  • Reference [20]
AGA 2020 Acute Severe UC Treatment Recommendations
Acute severe UC defined as:
  • Presence of ≥ 6 bloody bowel movements/day with at least one of the following markers of systemic toxicity: heart rate > 90 beats/minute, temperature > 37.8°C, hemoglobin < 10.5 g/dl, erythrocyte sedimentation rate > 30 mm/h
Recommendations
  • In hospitalized adult patients, the AGA suggests using intravenous methylprednisolone dose equivalent of 40 to 60 mg/d rather than higher dose intravenous corticosteroids
  • In hospitalized adult patients without infections, the AGA suggests against adjunctive antibiotics
  • In hospitalized adult patients who are refractory to intravenous corticosteroids, the AGA suggests using infliximab or cyclosporine
  • In hospitalized adult patients being treated with infliximab, the AGA makes no recommendation on routine use of intensive vs. standard infliximab dosing


Step 1 - Check trough TNF inhibitor levels
  • Target trough levels for TNF inhibitors:
    • Adalimumab (Humira®): ≥ 7.5 mcg/ml
    • Certolizumab Pegol (Cimzia®): ≥ 20 mcg/ml
    • Golimumab (Simponi®): unknown
    • Infliximab (Remicade®): ≥ 5 mcg/ml
Step 2
  • If trough levels are adequate, suspect drug failure and consider switching to another drug class
  • If trough levels are low, check for anti-drug antibodies
    • Low/absent trough with no anti-drug antibodies
      • Possible pharmacokinetic failure
      • Shorten dosing interval, and/or increase dose, and/or add immunosuppressant
    • Absent trough with high-titer anti-drug antibodies
      • Possible immune-mediated failure
      • Change to another TNF inhibitor or use a different class
    • Low trough with low- or high-titer anti-drug antibodies
      • Indeterminate. Consider one of the above approaches. [17]


Topical aminosalicylate | 5-aminosalicylate | 5-ASA | Mesalamine
Mesalamine suppository (Canasa®)
  • Active disease dosing
    • 1000 mg once daily at bedtime [12]
  • Maintenance dosing
    • 1000 mg once daily at bedtime [12]
  • Other
    • In active treatment, benefit is seen within 3 - 21 days
    • Suppository effects been shown to reach ∼ 10 cm into the colon [8]
    • See mesalamine for full prescribing information
Mesalamine enema (Rowasa®)
  • Active disease dosing
    • 4 grams once daily at bedtime [12]
  • Maintenance dosing
    • 2 - 4 grams once daily, every other day, or less frequently in some regimens [8]
  • Other
    • In active treatment, benefit is seen within 3 - 21 days
    • Enema effects have been shown to reach as far as the splenic flexure in some patients [8]
    • See mesalamine for full prescribing information
Oral aminosalicylates | 5-aminosalicylates | 5-ASA | Mesalamine
Balsalazide (Colazal®, Giazo®)
  • Active disease dosing
    • Colazal capsule: 2250 mg three times a day
    • Giazo tablet: 3300 mg two times a day [12]
  • Maintenance dosing
    • 2000 - 6750 mg a day given in divided doses [8]
  • Other
Mesalamine (Apriso®, Asacol® HD, Delzicol®, Pentasa®, Lialda®)
  • Active disease dosing
    • Asacol HD: 1600 mg three times a day
    • Delzicol: 800 mg three times a day for 6 weeks
    • Pentasa: 1000 mg four times a day for 8 weeks
    • Lialda: 2400 - 4800 mg once daily [12]
  • Maintenance dosing
    • Apriso: 1500 mg (4 capsules) once daily
    • Delzicol: 1600 mg per day given in divided doses
    • Lialda: 2400 mg once daily [12]
  • Other
Olsalazine (Dipentum®)
  • Active disease dosing
    • 1500 - 3000 mg a day given in 2 divided doses [8]
  • Maintenance dosing
    • 500 mg two times a day [12]
  • Other
    • Efficacy of olsalazine in active UC has not been conclusively established [8]
    • See osalazine for full prescribing information
Sulfasalazine (Azulfidine®, Azulfidine EN®)
  • Active disease dosing
    • 4000 - 6000 mg a day given in 4 divided doses [8]
  • Maintenance dosing
    • 2000 - 4000 mg a day given in divided doses [8]
  • Other
    • Dosing intervals should not exceed 8 hours
    • Maintenance therapy with 4000 mg/day is most effective, but up to 25% of patients will not tolerate this dose [8]
    • See sulfasalazine for full prescribing information
Topical steroids
Budesonide foam (Uceris®)
  • Active disease dosing
    • 2 mg twice a day for 2 weeks, then 2 mg once daily for 4 weeks [12]
  • Maintenance dosing
    • Not recommended
  • Other
    • Foam is approved to treat disease that extends up to 40 cm from the anal verge [12]
    • See budesonide foam for full prescribing information
Budesonide tablet (Uceris®)
  • Active disease dosing
    • 9 mg once daily for up to 8 weeks [12]
  • Maintenance dosing
    • Not recommended
  • Other
    • Budesonide tablets are enteric coated and do not dissolve until they reach the intestine
    • The therapeutic effect is thought to occur largely through local effects in the colon
    • Budesonide undergoes extensive first-pass metabolism and systemic effects are minimized [12]
    • See budesonide tablets for full prescribing information
Hydrocortisone enema (Colocort®, Cortenema®)
  • Active disease dosing
    • 100 mg once daily for 21 days or longer if necessary [12]
  • Maintenance dosing
    • Not recommended
  • Other
    • Clinical response typically seen within 3 - 5 days
    • Enema effects reach the splenic flexure, and have been shown to be beneficial in some patients with transverse and ascending disease [12]
    • See hydrocortisone enema for full prescribing information
Hydrocortisone foam (Cortifoam®)
  • Active disease dosing
    • One applicatorful 1 - 2 times a day for 2 - 3 weeks, and every second day thereafter [12]
  • Maintenance dosing
    • Not recommended
  • Other
    • Clinical response typically seen within 5- 7 days [12]
    • Foam effects have been shown to reach ∼ 15 - 20 cm into the colon [8]
    • See hydrocortisone foam for full prescribing information
Oral steroids
Prednisone
  • Active disease dosing
    • 40 - 60 mg a day until significant improvement
    • Then taper dose by 5 - 10 mg/week until dose of 20 mg is reached
    • From 20 mg, taper dose by 2.5 mg/week [8]
  • Maintenance dosing
    • Not recommended
  • Other
Thiopurines
Azathioprine (Imuran®)
  • Dosing
    • 2.5 mg/kg/day given once daily or in divided doses [1,8]
  • Other
    • Primary benefit is in maintenance therapy because of the slow onset of action (up to 3 - 6 months) [8]
    • See azathioprine for full prescribing information
Mercaptopurine (6-MP)
  • Dosing
    • 1.0 - 1.5 mg/kg/day given once daily [1]
  • Other
    • Primary benefit is in maintenance therapy because of the slow onset of action (up to 3 - 6 months) [8]
    • See mercaptopurine for full prescribing information
TNF inhibitors
Infliximab (Remicade®)
  • Dosing
    • Starting; 5 mg/kg at Weeks 0, 2, and 6
    • Maintenance: 5 mg/kg every 8 weeks [12]
  • Other
Adalimumab (Humira®)
  • Dosing
    • Day 1: 160 mg
    • Day 15: 80 mg
    • Day 29 and on: 40 mg every other week [12]
  • Other
    • Tumor necrosis factor inhibitor
    • See adalimumab for full prescribing information
Golimumab (Simponi®)
  • Dosing
    • Starting: 200 mg at Week 0, followed by 100 mg at Week 2
    • Maintenance: 100 mg every 4 weeks [12]
  • Other
    • Tumor necrosis factor inhibitor
    • See golimumab for full prescribing information
Vedolizumab (Entyvio®)
Dosing
  • Starting: 300 mg IV at Weeks 0, 2, and 6
  • Maintenance: 300 mg IV every 8 weeks [12]
Other
  • Anti-integrin antibody that inhibits T-cell migration
  • Approved for use in patients who do not respond to tumor necrosis factor inhibitors or immunosuppressants [12]
  • See vedolizumab vs placebo study below
  • See vedolizumab for full prescribing information
Tofacitinib (Xeljanz®)
Dosing
  • Dosing: 10 mg twice daily for at least 8 weeks, then 5 - 10 mg twice daily
Other
Cyclosporine
Active disease dosing
  • Starting: 2 - 4 mg/kg/day via IV infusion. May be given in doses or as a continuous infusion.
  • Target blood concentration is 200 - 250 ng/ml
  • After response is seen with IV therapy, patients are switched to oral therapy at a dose that is twice the daily IV dose
  • Oral cyclosporine (Neoral or Gengraf) is given in 2 divided doses. Target trough concentration for oral therapy is 200 - 250 ng/ml.
  • Oral cyclosporine should be overlapped with a thiopurine and continued for 2 - 3 months before tapering [13,14]
Maintenance dosing
  • Not recommended
Other
  • Most patients respond within 7 days
  • Patients who do not respond to IV cyclosporine should be considered for colectomy
  • Patients treated with cyclosporine and steroids should receive sulfamethoxazole/trimethoprim prophylaxis (1 DS tablet once daily) to prevent Pneumocystis jirovecii pneumonia
  • Cyclosporine microemulsion (Neoral and Gengraf) has greater bioavailability that standard cyclosporine (Sandimmune) [13,14]
  • See cyclosporine vs infliximab study below
  • See cyclosporine for full prescribing information


CONSTRUCT trial - Cyclosporine vs Infliximab in Severe UC, Lancet (2016) [PubMed abstract]
  • 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
  • There was no significant difference between the groups for adverse events
  • There was no significant difference between the groups in patients taking thiopurines or methotrexate (3 months, Infliximab - 43%, Cyclosporine - 49%; 24 months, Infliximab - 30%, Cyclosporine - 30%)
  • Nine patients assigned to the cyclosporine group were subsequently given infliximab and 1 patient assigned to infliximab was given cyclosporine

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

GEMINI 1 Study - Vedolizumab vs Placebo in Active UC, NEJM (2013) [PubMed abstract]
  • 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
  • There was no significant difference in adverse events between the vedolizumab groups and placebo groups

Findings: Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis

Tofacitinib vs Placebo for Treatment-resistant UC, NEJM (2017) [PubMed abstract]
  • 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

Indigo Naturalis vs Placebo in active UC, Gastroenterology (2018) [PubMed abstract]
  • 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.

Donor Fecal Transplant vs Autologous Fecal Transplant in UC, JAMA (2019) [PubMed abstract]
  • 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.