Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — A subset of patients with ulcerative colitis requires glucocorticoids to control symptoms while others continue to have symptoms despite glucocorticoid treatment. Glucocorticoids are intended for short-term use only, and patients should be transitioned to safer, effective medical therapies or referred to surgery if their disease cannot be well controlled when glucocorticoids are discontinued.
This topic review will discuss the approach to managing adults with steroid-refractory and steroid-dependent ulcerative colitis. A general overview of the management of mild to moderate and severe or fulminant ulcerative colitis and the management of left-sided colitis are presented separately. (See "Management of severe ulcerative colitis in adults" and "Management of mild to moderate ulcerative colitis in adults".)
DEFINITIONS — The following definitions of ulcerative colitis have been proposed [1-5]:
●Steroid-responsive disease – Clinical response to high-dose glucocorticoids (prednisone 40 to 60 mg/day or equivalent) within 30 days for oral therapy or 7 to 10 days for intravenous therapy.
●Steroid-dependent disease – Ulcerative colitis is defined as steroid-dependent if glucocorticoids cannot be tapered to less than 10 mg/day within three months of starting steroids, without recurrent disease, or if relapse occurs within three months of stopping glucocorticoids.
●Steroid-refractory disease – Lack of a meaningful clinical response to glucocorticoids up to doses of prednisone 40 to 60 mg/day (or equivalent) within 30 days for oral therapy or 7 to 10 days for intravenous therapy.
EVALUATION OF A PATIENT WITH STEROID-DEPENDENT OR STEROID-REFRACTORY ULCERATIVE COLITIS — It is important to assess disease severity, rule out an underlying infection, and alternate diagnoses (eg, Crohn disease) in patients with steroid-refractory or steroid-dependent ulcerative colitis.
Laboratory testing — Blood counts, measurement of C-reactive protein (CRP), and erythrocyte sedimentation (ESR) rate can help determine the severity of the underlying inflammation. In addition, CRP levels may have a role in distinguishing between active ulcerative colitis and Crohn disease from those with symptoms caused by functional disorders [6-10]. Normal CRP, ESR, white blood cell count, hematocrit, and platelet count are more consistent with irritable bowel syndrome (IBS) rather than active IBD.
Positive serology for antineutrophil cytoplasmic antibodies (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) are not diagnostic for ulcerative colitis or Crohn, respectively, given the limited sensitivity and specificity of the tests. However, when they are performed in combination, the results may help differentiate between ulcerative colitis, Crohn disease, and indeterminate colitis. (See "Irritable bowel syndrome in patients with inflammatory bowel disease", section on 'Laboratory testing' and "Clinical manifestations, diagnosis and prognosis of Crohn disease in adults", section on 'Serologic markers'.)
Stool studies — Stool evaluation is necessary in patients with steroid-dependent or steroid-refractory ulcerative colitis in order to exclude a superimposed infection.
Stool studies should include stool Clostridium difficile toxin, routine stool cultures, and specific testing for E. coli O157:H7. Microscopy for ova and parasites (three samples) and a Giardia stool antigen test and Cryptosporidium testing by immunofluorescence or other antigen-detection assays should also be performed, particularly if the patient is in an endemic area or has risk factors such as travel. In addition, specific testing for sexually transmitted diseases including Neisseria gonorrhea, herpes simplex virus, and Treponema pallidum should be considered, particularly in patients with severe rectal symptoms. Elevated levels of fecal calprotectin and fecal lactoferrin suggest the presence of underlying inflammation rather than a functional disorder [10,11]. (See "Irritable bowel syndrome in patients with inflammatory bowel disease", section on 'Stool studies' and "Clostridium difficile infection in adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.)
Endoscopy — Endoscopic evaluation may be required to confirm the presence, severity, and/or extent of inflammation and can exclude the presence of an infection such as cytomegalovirus (CMV). In patients with CMV colitis, conventional hematoxylin and eosin stains reveal enlarged (cytomegalic) cells that are often two- to fourfold larger than surrounding cells, usually with large eosinophilic intranuclear inclusions, sometimes surrounded by a clear halo, and smaller cytoplasmic inclusions . Immunoperoxidase-staining can aid in the detection and should be done to confirm suspected CMV. A full colonoscopy with adequate evaluation of the terminal ileum (with biopsies of the ileum and throughout the colon in separate jars) may be helpful in excluding Crohn disease, which would have direct implications upon surgical options. (See "Surgical management of ulcerative colitis" and "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults".)
Full colonoscopy should be avoided in hospitalized patients with severe colitis because of the potential to precipitate toxic megacolon. In such patients, a sigmoidoscopy limited to the rectum and distal sigmoid should be performed with biopsies to assist in confirming the diagnosis and excluding CMV.
The symptoms in patients with ulcerative colitis may be caused by other pathologies in the absence of active colitis. Upper endoscopy with biopsies of the stomach and duodenum (even if endoscopically normal) may be helpful in confirming a diagnosis of Crohn disease or excluding other malabsorptive processes, such as celiac disease.
Imaging studies — If there is no active colitis or ileitis on colonoscopy, yet the patient still has symptoms, small bowel imaging with computed tomography (CT) enterography, magnetic resonance (MR) enterography, or a dedicated small bowel series should be performed to rule out Crohn disease of the small bowel. CT and MR enterography have high sensitivities for detecting active small bowel inflammation . CT enterography has the advantage of better temporal resolution, mesenteric imaging, and shorter length of examination. It is preferred when there is a suspicion of an intra-abdominal abscess. MR enterography is gradually replacing CT enterography. MR enterography has the advantage of avoiding radiation exposure and better characterization of stenotic lesions . MR enterography is preferred when there is a suspicion of intestinal fistulae. A dedicated small bowel series by an experienced gastrointestinal radiologist may be helpful when analyzing patients with previous small bowel stricturoplasty, or to clarify whether an obstruction is from a stricture versus an adhesion. (See "Clinical manifestations, diagnosis and prognosis of Crohn disease in adults", section on 'Imaging studies'.)
A CT scan or MR imaging of the abdomen and pelvis should also be considered in patients in whom there is a concern for an abscess, diverticulitis, fistula formation, perforation, megacolon, or potentially unrelated abdominal process (eg, a kidney stone). (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults" and "Clinical manifestations, diagnosis and prognosis of Crohn disease in adults".)
STEROID-DEPENDENT ULCERATIVE COLITIS — Ulcerative colitis is defined as steroid-dependent if glucocorticoids cannot be tapered to less than 10 mg/day within three months of starting steroids without recurrent disease, or if relapse occurs within three months of stopping glucocorticoids . An approach to the treatment of steroid-dependent ulcerative colitis is presented in the algorithm (algorithm 1).
Avoidance of contributing factors and assessment of compliance — Lactose intolerance is frequently noted in patients with ulcerative colitis. Calcium supplementation should be maintained in patients with limited lactose intake to minimize the risk of bone loss. Patients with active colitis should avoid foods that can mimic symptoms of active colitis, such as high fiber, nuts, seeds, corn, popcorn, and fatty foods. Patients with active distal colitis may develop severe constipation. In these patients, high fiber foods are beneficial . (See "Nutrition and dietary interventions in adults with inflammatory bowel disease", section on 'Dietary interventions' and "Lactose intolerance: Clinical manifestations, diagnosis, and management", section on 'Diagnosis'.)
Stress may have a role in the exacerbation of symptoms of inflammatory bowel disease (IBD) [16-19], possibly via activation of the enteric nervous system and the elaboration of proinflammatory cytokines. Appropriate pharmacologic and/or behavioral interventions may be useful in the management of their disease or improving symptoms. (See "Definition, epidemiology, and risk factors in inflammatory bowel disease", section on 'Psychosocial factors'.)
An assessment of medication compliance is also necessary in patients with steroid-dependent ulcerative colitis. Only 40 percent of colitis patients with IBD are adherent to their medication regimens . Simplifying prescribed therapies to fewer medications with fewer daily applications can be helpful in improving compliance. (See "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease".)
Medications — Several adjunctive therapies exist that, when used alone or in combination with systemic steroids, can reduce or eliminate the need for systemic glucocorticoids and limit systemic steroid use (algorithm 1) . The choice among options depends in part upon the decision to use glucocorticoids as induction therapy while new therapies are started. Whenever reasonable, multimatrix release budesonide should be used in lieu of traditional glucocorticoids, because this formulation greatly decreases the systemic glucocorticoid exposure and resultant side effects [21,22]. Budesonide delivered as a rectal foam may also be used in patients with distal disease .
Adding a slow-acting second medication — The main options for patients who are well on glucocorticoids, and able (and/or willing) to remain on glucocorticoids while a second slow-acting maintenance medication is introduced, are 6-mercaptopurine (6-MP) or azathioprine (AZA). The therapeutic effect of 6-MP or AZA can take three to six months during which attempts can be made to taper glucocorticoids. The administration, safety, and monitoring of AZA and 6-MP are discussed in detail separately (See "Azathioprine and 6-mercaptopurine in inflammatory bowel disease".)
AZA or 6-MP are not good options for patients who are unlikely to comply with regular monitoring, are unwilling to accept the risk of toxicity, or have dysplasia or other indications for colectomy. (See "Colorectal cancer surveillance in inflammatory bowel disease" and "Azathioprine and 6-mercaptopurine in inflammatory bowel disease" and "Azathioprine and 6-mercaptopurine in inflammatory bowel disease", section on 'Adverse effects'.)
Available evidence suggests that 6-MP and AZA improve the likelihood that remission will be maintained in patients with ulcerative colitis that is refractory to steroids and 5-ASA from approximately 40 to 70 percent in patients, and that these drugs will decrease glucocorticoid requirements in approximately 70 percent of patients with glucocorticoid-dependent disease. A number of small controlled trials and two meta-analyses have demonstrated that AZA is superior to placebo in maintenance of remission [24-30]. A 2011 meta-analysis found that AZA was superior to placebo for preventing relapse (RR of relapse 0.60, 95% CI 0.37-0.95) and estimated that approximately four patients would need to be treated to prevent one relapse in patients with ulcerative colitis . A 2008 meta-analysis of 286 patients in four randomized trials that had at least 12 months of follow-up concluded that AZA was superior to placebo for maintenance of remission (OR for failure to maintain remission 0.41, 95% CI 0.24-0.70) .
AZA has also been demonstrated to be superior to 5-aminosalicylate (ASA) medications in the maintenance of remission in glucocorticoid-dependent ulcerative colitis . In a randomized trial in which glucocorticoid-dependent patients with active ulcerative colitis were randomized to receive AZA 2 mg/kg/day or oral 5-ASA 3.2 g/day, for a six-month follow-up period, the proportion of patients with glucocorticoid-free remission was significantly higher with AZA as compared with 5-ASA medications (53 versus 21 percent).
There is no evidence that addition of 5-ASA medications reduces relapses in patients on AZA. A systemic review identified two small controlled trials that compared AZA alone to AZA combined with 5-ASA . There was no evidence of benefit from combined therapy, but both trials had methodologic limitations [34,35].
Adding a fast-acting second medication — If glucocorticoids are ineffective or not desired to be used (either by the patients or their physicians), there are nonsteroid options that are effective for induction of remission (cyclosporine, tacrolimus) or for both induction of remission and for maintenance therapy (infliximab, adalimumab, golimumab, vedolizumab).
Anti-tumor necrosis factor therapy — Anti-tumor necrosis factor (anti-TNF) therapy with infliximab and adalimumab has been shown to induce and maintain remission in patients with moderate to severe ulcerative colitis [36,37]. Anti-TNF medication (eg, infliximab, adalimumab, golimumab) can be used both for induction of remission and for maintenance and should be considered in patients who have failed or have an allergy to azathioprine or 6-mercaptopurine, or who cannot wait the anticipated three to six months for full therapeutic effect. Combination therapy with a purine analogue and anti-TNF agent has the highest efficacy rates, and lowest anti-drug antibody rates to the anti-TNF agent . The safety, efficacy, and administration of these agents are discussed separately. (See "Anti-tumor necrosis factor therapy in ulcerative colitis".)
Vedolizumab — Vedolizumab is a recombinant humanized, anti-alpha-4-beta-7 integrin monoclonal antibody. Integrins are proteins involved in regulating cellular movement including migration of leukocytes to the gut. Vedolizumab has been shown to be effective in the induction and maintenance of remission in patients with moderately to severely active ulcerative colitis [39,40]. It is available in Europe and was approved for use in patients with moderate to severe ulcerative colitis by the US Food and Drug Administration in May 2014 . The timing of use is similar to that described for the anti-TNF agents.
In a randomized trial, 374 patients with active ulcerative colitis were assigned to vedolizumab or placebo for the induction of remission . A significantly greater proportion of vedolizumab-treated patients achieved clinical response (47 versus 26 percent), remission (17 versus 5 percent), and mucosal healing (41 versus 25 percent) at six weeks compared with placebo . In a trial of vedolizumab for the maintenance of remission, 373 patients with a clinical response to vedolizumab at six weeks, in either the induction trial or following open label treatment, were assigned to continue to receive vedolizumab every eight weeks, four weeks, or switch to placebo for up to 52 weeks. At week 52, remission rates were significantly higher in patients who received vedolizumab compared with placebo (42, 45, and 16 percent, respectively).
A follow up observational study examined 32 patients who initially responded to vedolizumab induction but then flared while receiving maintenance therapy every eight weeks. After increasing the vedolizumab maintenance dosing frequency to every four weeks, clinical response and remission rates were higher compared with baseline (41 versus 19 percent and 28 versus 5 percent, respectively) . In some countries, including the US and Canada, dosing of vedolizumab every four weeks is not approved and further long term data are needed.
Cyclosporine — Cyclosporine has a role in induction of remission in patients with refractory colitis but is not effective and/or safe for long-term use. Cyclosporine is used as a short-term "bridge" to therapy with the slower onset, longer acting medications (AZA or 6-MP) or to a biologic (vedolizumab) (See 'Adding a slow-acting second medication' above.)
Cyclosporine is not an option in patients who were intolerant to AZA or 6-MP, and in patients who have previously failed AZA or 6-MP [44,45]. In addition, using cyclosporine after recent treatment with another immunosuppressant such as infliximab has not been shown to be effective or safe . (See "Anti-tumor necrosis factor therapy in ulcerative colitis".)
In a controlled trial, for example, 20 steroid-resistant patients with severe colitis were randomly assigned to placebo or cyclosporine given at a dose of 4 mg/kg per day as a continuous infusion . Response within a mean of seven days occurred in 9 of 11 patients given cyclosporine versus none of those given placebo. Furthermore, all five placebo-treated patients who were then given cyclosporine had a response.
●In one report, cyclosporine permitted the avoidance of colectomy for up to 5.5 years in 62 percent of 42 patients who initially had severe steroid-refractory ulcerative colitis; patients who also received treatment with 6-MP or AZA were more likely to retain their colons (80 versus 55 percent) . The benefit of cyclosporine was further underscored in another study, in which the quality of life of patients who were treated with cyclosporine was superior to those who had undergone colectomy .
●In a retrospective cohort study of 142 patients treated with cyclosporine, 118 (83 percent) had an initial response and avoided colectomy . However, 41 (35 percent) of these patients ultimately required a colectomy. The rate of colectomy was significantly higher in patients already taking AZA when cyclosporine was started compared with those who started AZA concurrently with cyclosporine (59 versus 31 percent). Life table analysis suggested that 88 percent of responding patients will require a colectomy by seven years.
Most studies of intravenous cyclosporine administered it as a continuous infusion at a dose of 4 mg/kg per 24 hours . Lower doses (2 mg/kg) may have similar efficacy and less toxicity [51,52] (see "Pharmacology of cyclosporine and tacrolimus"). We initially dose in the 2 mg/kg to 4 mg/kg range, using the lower dose in patients who have low serum cholesterol. Intravenous glucocorticoids are maintained, and nightly hydrocortisone enemas encouraged. We recommend prophylaxis against Pneumocystis pneumonia (PCP). (See "Treatment and prevention of Pneumocystis pneumonia in HIV-uninfected patients", section on 'Prophylaxis'.)
Blood levels of cyclosporine should be checked every one to two days after each dose change, and every two to three days when on stable doses. Goal levels for a dose of 4 mg/kg are 300 to 400 ng/mL. Patients dosed at 2 mg/kg should have levels no less than 200 ng/mL. Dose adjustments are based upon efficacy, side effects, and blood levels of cyclosporine. Doses should be rounded to the nearest 25 mg, to aid in subsequent conversion to oral cyclosporine.
Patients should show an initial response to cyclosporin within 48 to 72 hours; the goal is a complete resolution of symptoms, along with normalization of blood tests. Specifically, patients should have a reasonable number of formed stools, without associated blood, no abdominal pain, and should be able to eat, prior to converting IV to oral cyclosporine microemulsion. Patients who relapse or fail to improve within 72 hours should undergo stool tests to exclude an infection with C. difficile, and proceed to surgery. (See 'Surgery' below.).
Conversion to oral cyclosporine is calculated by doubling the intravenous dose that had led to adequate levels, administered in divided doses 12 hours apart. For example, patients who had good response at levels of 4 mg/kg/day of intravenous cyclosporine would be converted to 8 mg/kg/day of oral cyclosporine microemulsion, delivered as 4 mg/kg every 12 hours. Steady state is achieved after the third dose; trough levels are checked immediately prior to fourth dose, with a goal level of 200 ng/mL to 300 ng/mL. Levels below 200 ng/mL have been associated with loss of response .
Patients should be discharged on oral cyclosporine microemulsion, oral glucocorticoids, hydrocortisone enemas, and PCP prophylaxis. Azathioprine or 6-mercaptopurine is started and the doses optimized over the ensuing weeks. We often first taper off the glucocorticoids over the first four to six weeks, and then taper off the oral cyclosporine microemulsion over the next six to eight weeks. Some patients may require shorter or longer durations of therapy. Patients who cannot stay well or get off of glucocorticoids should be evaluated for surgery. (See "Azathioprine and 6-mercaptopurine in inflammatory bowel disease", section on 'Dose' and "Surgical management of ulcerative colitis", section on 'Surgical options'.)
Side effects and drug interactions with cyclosporine are common, and some may be life-threatening. Thus, patients receiving therapy must be carefully monitored for electrolyte abnormalities, nephrotoxicity, hypertension, neurotoxicity, and infections. Prophylaxis against PCP during therapy is required. The side effects of cyclosporine, drug interactions, and strategies to minimize toxicity are discussed in detail separately. (See "Pharmacology of cyclosporine and tacrolimus" and "Treatment and prevention of Pneumocystis pneumonia in HIV-uninfected patients".)
Tacrolimus — Oral tacrolimus has been used in patients with refractory ulcerative colitis, but its role has not yet been determined, especially when compared with alternative approaches such as infliximab. In one randomized trial, tacrolimus use was examined in 62 hospitalized patients with steroid-refractory ulcerative colitis . Patients were assigned to either tacrolimus or placebo for two weeks. Patients treated with tacrolimus had a higher clinical response rate (50 versus 13 percent), mucosal healing rate (44 versus 13 percent), and clinical remission rate (9 versus 0 percent). Most experience with tacrolimus has been as a bridging agent to the purine analogues, similar to that of cyclosporine [54-57]. However, a least one study suggests that it may be effective for the maintenance of remission . (See "Pharmacology of cyclosporine and tacrolimus".)
Surgery — Surgery is indicated in patients with steroid-dependent ulcerative colitis who fail medical therapy, have intolerable side effects, or for colorectal dysplasia or cancer . (See "Surgical management of ulcerative colitis".)
STEROID-REFRACTORY ULCERATIVE COLITIS — Patients who do not have a meaningful clinical response to glucocorticoids up to doses of prednisone 40 to 60 mg/day (or equivalent) within 30 days for oral therapy or 7 to 10 days for IV therapy are considered to have steroid-refractory ulcerative colitis. Such patients should undergo careful re-evaluation to rule out the presence of an underlying infection, an alternate diagnosis including Crohn disease and complications of ulcerative colitis. (See 'Evaluation of a patient with steroid-dependent or steroid-refractory ulcerative colitis' above.)
A subset of patients with steroid refractory ulcerative colitis who are on oral glucocorticoids can achieve a clinical response when switching to intravenous glucocorticoids (typically given as methylprednisolone 40 to 60 mg daily in single or divided doses, or equivalent) (algorithm 2) [3,59-61].
Patients who do not respond to IV glucocorticoids after three to seven days should be treated with cyclosporine or infliximab . Cyclosporine and infliximab have similar safety and efficacy in patients with acute severe colitis refractory to IV steroids . (See "Anti-tumor necrosis factor therapy in ulcerative colitis".)
The decision to choose infliximab versus cyclosporine in hospitalized patients with steroid refractory ulcerative colitis depends upon several factors. We use cyclosporine in those who are refractory to IV glucocorticoids as a short-term "bridge" to therapy with the slower onset, longer acting medications (azathioprine or 6-mercaptopurine). We use standard dosing of infliximab (5 mg/kg at 0, 2, and 6 weeks, and every 8 weeks thereafter) in patients who respond to glucocorticoids but who cannot transition to oral steroids or stay well on oral steroids (relapses within 12 weeks after steroid tapering), patients who cannot tolerate azathioprine/6-mercaptopurine or who have failed azathioprine/6-mercaptopurine (fails a taper in glucocorticoids after 12 to 24 weeks of full dose azathioprine/6-mercaptopurine). We also use infliximab in patients with hypertension, renal disease, seizure disorders, or other major comorbidities who are poor candidates for cyclosporine and in patients who are not able or willing to comply with strict dosing and monitoring requirements while on cyclosporine. Studies are needed to identify the optimal dosing regimen for anti-tumor necrosis factor therapy in severe ulcerative colitis. A retrospective study of 50 hospitalized patients with steroid-refractory acute severe ulcerative colitis compared colectomy rates in patients who received standard infliximab dosing with an accelerated dosing regimen consisting of three induction doses of infliximab within a median period of 24 days . Although colectomy rates during induction therapy were significantly lower with the accelerated regimen as compared with the standard regimen (7 versus 40 percent), there were no significant differences between the two groups in the two-year follow-up period.
If a response is not seen in 7 to 10 days, we recommend surgery. Composite indices also appear to be reliable in predicting which patients will respond poorly to intensive medical treatment and will require colectomy [65-68]. For example, using the Oxford index, colectomy is likely to be necessary in a patient with ulcerative colitis if the C-reactive protein level is above 45 mg/mL and a stool frequency of three to eight stools per day, or stool frequency greater than eight stools per day on day 3 after the initiation of treatment with intravenous glucocorticoids or cyclosporine [67,69]. The use of infliximab blood levels may be helpful in determining the reasons for lack or loss of efficacy. Infliximab has been identified in the stool of patients with severe colitis, suggesting possible dumping of the protein-based therapy into the gastrointestinal lumen, as has been seen with other albumin and other proteins and low body weight [70,71]. (See 'Adding a fast-acting second medication' above and "Surgical management of ulcerative colitis".)
Of the patients who respond, many of these patients will eventually require surgery within a year, and thus it is important to discuss surgery as an option so that patients can undergo appropriate evaluation [72-74]. (See "Surgical management of ulcerative colitis".)
EXPERIMENTAL AGENTS — Multiple experimental approaches have been tried in patients with ulcerative colitis. Some of these agents may have a role in refractory colitis, although many have not been studied in this setting. None of these agents can be recommended for routine use based on available data but they may be an option in the setting of a clinical trial.
Methotrexate — The role of methotrexate in the treatment of ulcerative colitis is uncertain [76,77]. While observational studies have suggested a benefit of low-dose methotrexate in patients with ulcerative colitis [78-80], controlled studies have not demonstrated clear efficacy . In a trial of 111 patients with steroid-dependent ulcerative colitis, methotrexate 25 mg (IM or SC) per week was nonsignificantly superior to placebo for inducing steroid-free remission (32 versus 20 percent). Methotrexate was superior to placebo for the less stringent definition of clinical remission (42 versus 24 percent, absolute risk difference 18 percent, 95%CI 1.1-35.2) . A previous controlled trial in 21 patients found no benefit of oral methotrexate 12.5 mg per week over placebo for inducing clinical remission .
Anti-integrin antibodies — In addition to vedolizumab, other molecules have been developed to block the interaction between alpha-4 beta-7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM) and have demonstrated favorable short-term safety profiles and efficacy. These include monoclonal antibodies to block MAdCAM-1 and monoclonal antibodies against beta 7 [83-85].
In a randomized phase 2 trial that included 124 patients with moderate to severe ulcerative colitis that was refractory to conventional therapy, patients were assigned to 10 weeks of etrolizumab (100 mg at week 0, 4, and 5 or 420 mg loading dose followed by 300 mg at week 2, 4, and 8) or placebo . At 10 weeks, patients receiving etrolizumab were more likely to be in clinical remission as compared with placebo (21 and 10 versus 0 percent, respectively) . (See 'Vedolizumab' above.)
Phosphatidylcholine — Oral phosphatidylcholine (believed to have a mucosal protective effect in colonic mucus) was more effective than placebo in a small controlled trial of patients with steroid-refractory ulcerative colitis . Additional trials with long-term follow-up are needed.
Tofacitinib — The oral inhibitor of Janus kinase 1-3 is a promising agent to treat refractory ulcerative colitis (UC) [88,89]. In two phase 3 randomized trials (OCTAVE Induction 1 and 2 trials of 598 and 541 patients, respectively), patients with moderate to severe UC who received tofacitinib 10 mg twice daily experienced remission at eight weeks more frequently compared with those receiving placebo; for OCTAVE 1, 18.5 versus 8.2 percent (absolute difference 10.3, 95% CI: 4.3 to 16.3) and for OCTAVE 2: 16.6 versus 3.6 percent (absolute difference 13.0, 95% CI: 8.1 to 17.9) .
The OCTAVE Sustain trial included 593 patients who had initial clinical response to induction therapy . At 52 weeks, remission occurred more frequently in patients receiving tofacitinib 5 mg or 10 mg daily (34.5 and 40.6 percent, respectively) compared with placebo (11.1 percent); absolute percent difference for 5 mg dose was 23.2 (95% CI: 15.3 to 31.2) and for 10 mg, 29.5 (95% CI: 21.4 to 37.6). As compared with placebo, tofacitinib was associated with more overall infections and more cases of herpes zoster, although the absolute risk differences were low; this finding was also seen with the use of tofacitinib for rheumatoid arthritis. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tofacitinib'.)
Future trials can help determine the exact role of tofacitinib in the treatment of UC.
Alicaforsen — Alicaforsen is an inhibitor of intracellular adhesion molecule-1. Alicaforsen enemas showed efficacy in the treatment of distal ulcerative colitis and pouchitis [91-95].
Sphingosine-1-phosphate receptor agonist — Ozanimod is an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 that decreases circulating activated lymphocytes. In a randomized trial, 197 patients with moderate to severe ulcerative colitis were assigned to ozanimod (1 mg or 0.5 mg daily) or placebo for 32 weeks . At eight weeks, patients treated with the higher dose of ozanimod had a slightly higher rate of clinical remission as compared with placebo (16 versus 6 percent). There were no significant differences in adverse effects between the groups. Larger trials with extended treatment are needed to establish the clinical efficacy and safety of ozanimod.
Anti-matrix metalloproteinase 9 (MMP) inhibitor — GS-5745 is an IgG4 monoclonal antibody that inhibits matrix metalloproteinase 9. This collagenase enzyme is a mediator of various inflammatory pathways and thought to be one mechanism whereby neutrophils and macrophages cause tissue destruction in ulcerative colitis . Early phase Ib results showed higher rates of response (43 versus 13 percent), remission, and mucosal healing when compared with placebo .
Phosphodiesterase 4 inhibitor — Apremilast (CC-10004) is an oral inhibitor of phosphodiesterase 4 (PDE4), leading to downregulation of TNF-α, nitric oxide synthase, and interleukin -23 while upregulation of interleukin-10 . It is currently FDA approved for the treatment of psoriasis and psoriatic arthritis [100,101]. Animal models of colitis have shown this compound to significantly reduce the production of TNF-α and matrix metalloproteinase (MMP)-3 by the gut lamina propria mononuclear cells .
Anti-SMAD7 therapy — Mongerson is an oral SMAD7 antisense oligonucleotide with notable phase II results in the treatment of Crohn disease . In both Crohn disease and ulcerative colitis, elevated SMAD7 levels are thought to result in defective TGF-beta 1 activity, preventing the suppression of inflammatory pathways . The current formulation has been designed to be released in the terminal ileum and the right colon, and therefore aims to treat Crohn disease. Manipulation of the pH release capsule and/or suspending the active agent in a rectal enema has been proposed for the treatment of ulcerative colitis. Clinical trials with the oral version are also underway.
Fecal microbiota transplantation — Although available evidence is limited and studies have demonstrated variable results, data suggest that fecal microbiota transplantation (FMT) has the potential to be an effective and safe treatment for ulcerative colitis when standard treatments have failed [105-108]. In two trials in which patients with mild-to-moderate ulcerative colitis were randomly assigned to FMT or placebo, FMT demonstrated an increase in microbial diversity [109,110]. However, both studies were terminated early due to futility in reaching the primary endpoint.
Patients in whom a single FMT failed to induce remission may benefit from repeat infusion or prolonged therapy. In a pilot study of 14 patients with steroid-dependent ulcerative colitis in which patients were treated with repeat FMT, eight (57 percent) had clinical improvement, of whom four (28 percent) had durable steroid-free remission of at least three months . The efficacy of intensive-dosing, multidonor FMT in patients with ulcerative colitis was studied in a randomized, placebo controlled trial of 81 patients. FMT or placebo was delivered by colonoscopy into the cecum or terminal ileum followed by enemas five times per week for eight weeks. The intensive FMT group was more likely to achieve the primary outcome, defined as a combined steroid-free clinical remission with endoscopic remission or response, compared with the placebo group (27 versus 8 percent; RR 3.6, 95% CI 1.1-11.9) .
Probiotics — A pathogenic role for enteric flora has been suggested in patients with ulcerative colitis, since colitis does not develop in animal models raised in a germ-free environment. (See "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease".)
This observation provided the rationale for controlled trials of probiotic therapy in patients with ulcerative colitis. However, probiotics have demonstrated variable efficacy in the treatment of ulcerative colitis and more studies are required before they can be recommended. (See "Probiotics for gastrointestinal diseases".)
Curcumin — Curcumin may have a protective role in ulcerative colitis through modulation of the release of tumor necrosis factor (TNF)-alpha and nitric oxide . However, there are limited data to support the use of curcumin in the induction or maintenance of remission in patients with ulcerative colitis [113,114]. In a randomized trial, 50 patients with active mild to moderate ulcerative colitis who did not respond to two weeks of maximum-dose oral and topical mesalamine therapy were assigned to additional treatment with curcumin (3 grams daily) or placebo for one month. At four weeks, patients in the curcumin group had significantly higher rates of clinical and endoscopic remission as compared with the placebo group (54 versus 0 percent and 38 versus 0 percent, respectively) . However, the exceptionally low placebo response rates raise concern as to how well study subjects were blinded . In another randomized trial, 89 patients with quiescent ulcerative colitis on sulfasalazine or mesalamine were treated with curcumin (2 grams daily) or placebo for six months for maintenance of remission [113,117]. Patients treated with curcumin had lower relapse rates at six months (4 versus 18 percent), but not at 12 months, as compared with placebo.
SUMMARY AND RECOMMENDATIONS
Steroid-dependent ulcerative colitis
●Ulcerative colitis is defined as steroid-dependent if glucocorticoids cannot be tapered to less than 10 mg/day within three months of starting steroids without recurrent disease, or if relapse occurs within three months of stopping glucocorticoids.
●In patients with steroid-dependent ulcerative colitis, it is important to rule out the presence of an underlying infection (eg, cytomegalovirus [CMV]), alternative diagnosis (eg, Crohn disease), concomitant conditions (irritable bowel syndrome, lactose intolerance, or stress), and assess medication compliance. (See 'Evaluation of a patient with steroid-dependent or steroid-refractory ulcerative colitis' above and 'Avoidance of contributing factors and assessment of compliance' above.)
For patients with steroid-dependent ulcerative colitis, who are well on glucocorticoids, and able (and/or willing) to remain on glucocorticoids while a second slow-acting maintenance medication is introduced, we recommend treatment with 6-mercaptopurine or azathioprine (Grade 1B). The therapeutic effect of 6-mercaptopurine or azathioprine can take three to six months during which periodic attempts can be made to taper glucocorticoids. (algorithm 1). (See 'Steroid-dependent ulcerative colitis' above.) Glucocorticoid side effects may be minimized with the preferential use of multimatrix budesonide rather than traditional glucocorticoids.
●If glucocorticoids are ineffective or not desired to be used (by either the patients or their physicians), we recommend treatment with cyclosporine, an anti-tumor necrosis factor (anti-TNF) agent, or vedolizumab (Grade 1A). Cyclosporine is effective for induction of remission and can be used as a short-term "bridge" to therapy with the slower onset medications (azathioprine or 6-mercaptopurine). Anti-TNF medication (eg, infliximab, adalimumab, golimumab) or vedolizumab can be used both for induction of remission and for maintenance. Combination therapy with a purine analogue and a biological agent has the highest efficacy rates, and lowest anti-drug antibody rates to the biological agents. (See 'Adding a fast-acting second medication' above.)
Steroid-refractory ulcerative colitis
●Steroid-refractory ulcerative colitis is defined as ulcerative colitis that lacks of a meaningful clinical response to glucocorticoids up to doses of prednisone 40 to 60 mg/day (or equivalent) within 30 days for oral therapy or 7 to 10 days for intravenous therapy. (See 'Definitions' above.)
●Patients with steroid-refractory ulcerative colitis should undergo careful re-evaluation to rule out the presence of an underlying infection (eg, CMV) and alternative diagnosis (eg, Crohn disease). (See 'Evaluation of a patient with steroid-dependent or steroid-refractory ulcerative colitis' above.)
●We recommend switching from oral to intravenous glucocorticoids as the first step in managing patients with steroid-refractory ulcerative colitis (algorithm 2) (Grade 1C). In patients who do not respond to intravenous glucocorticoids after three to seven days, we recommend treatment with cyclosporine or infliximab (Grade 1A). Patients who continue to be refractory to treatment will require surgery. (See 'Evaluation of a patient with steroid-dependent or steroid-refractory ulcerative colitis' above and 'Steroid-refractory ulcerative colitis' above.)
- Stange EF, Travis SP, Vermeire S, et al. European evidence-based Consensus on the diagnosis and management of ulcerative colitis: Definitions and diagnosis. J Crohns Colitis 2008; 2:1.
- Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and dependency in Crohn's disease. Gut 1994; 35:360.
- Truelove SC, Jewell DP. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet 1974; 1:1067.
- Cohen JL, Strong SA, Hyman NH, et al. Practice parameters for the surgical treatment of ulcerative colitis. Dis Colon Rectum 2005; 48:1997.
- Bianchi Porro G, Cassinotti A, Ferrara E, et al. Review article: the management of steroid dependency in ulcerative colitis. Aliment Pharmacol Ther 2007; 26:779.
- Beattie RM, Walker-Smith JA, Murch SH. Indications for investigation of chronic gastrointestinal symptoms. Arch Dis Child 1995; 73:354.
- Shine B, Berghouse L, Jones JE, Landon J. C-reactive protein as an aid in the differentiation of functional and inflammatory bowel disorders. Clin Chim Acta 1985; 148:105.
- Poullis AP, Zar S, Sundaram KK, et al. A new, highly sensitive assay for C-reactive protein can aid the differentiation of inflammatory bowel disorders from constipation- and diarrhoea-predominant functional bowel disorders. Eur J Gastroenterol Hepatol 2002; 14:409.
- Vermeire S, Van Assche G, Rutgeerts P. C-reactive protein as a marker for inflammatory bowel disease. Inflamm Bowel Dis 2004; 10:661.
- Schoepfer AM, Trummler M, Seeholzer P, et al. Discriminating IBD from IBS: comparison of the test performance of fecal markers, blood leukocytes, CRP, and IBD antibodies. Inflamm Bowel Dis 2008; 14:32.
- Otten CM, Kok L, Witteman BJ, et al. Diagnostic performance of rapid tests for detection of fecal calprotectin and lactoferrin and their ability to discriminate inflammatory from irritable bowel syndrome. Clin Chem Lab Med 2008; 46:1275.
- Kandiel A, Lashner B. Cytomegalovirus colitis complicating inflammatory bowel disease. Am J Gastroenterol 2006; 101:2857.
- Siddiki HA, Fidler JL, Fletcher JG, et al. Prospective comparison of state-of-the-art MR enterography and CT enterography in small-bowel Crohn's disease. AJR Am J Roentgenol 2009; 193:113.
- Fletcher JG, Huprich J, Loftus EV Jr, et al. Computerized tomography enterography and its role in small-bowel imaging. Clin Gastroenterol Hepatol 2008; 6:283.
- Fernández-Bañares F, Hinojosa J, Sánchez-Lombraña JL, et al. Randomized clinical trial of Plantago ovata seeds (dietary fiber) as compared with mesalamine in maintaining remission in ulcerative colitis. Spanish Group for the Study of Crohn's Disease and Ulcerative Colitis (GETECCU). Am J Gastroenterol 1999; 94:427.
- Levenstein S, Prantera C, Varvo V, et al. Psychological stress and disease activity in ulcerative colitis: a multidimensional cross-sectional study. Am J Gastroenterol 1994; 89:1219.
- Levenstein S, Prantera C, Varvo V, et al. Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission. Am J Gastroenterol 2000; 95:1213.
- Lerebours E, Gower-Rousseau C, Merle V, et al. Stressful life events as a risk factor for inflammatory bowel disease onset: A population-based case-control study. Am J Gastroenterol 2007; 102:122.
- Singh S, Graff LA, Bernstein CN. Do NSAIDs, antibiotics, infections, or stress trigger flares in IBD? Am J Gastroenterol 2009; 104:1298.
- Kane SV, Cohen RD, Aikens JE, Hanauer SB. Prevalence of nonadherence with maintenance mesalamine in quiescent ulcerative colitis. Am J Gastroenterol 2001; 96:2929.
- Sandborn WJ, Travis S, Moro L, et al. Once-daily budesonide MMX® extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study. Gastroenterology 2012; 143:1218.
- Travis SP, Danese S, Kupcinskas L, et al. Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut 2014; 63:433.
- Gross V, Bar-Meir S, Lavy A, et al. Budesonide foam versus budesonide enema in active ulcerative proctitis and proctosigmoiditis. Aliment Pharmacol Ther 2006; 23:303.
- Rosenberg JL, Wall AJ, Levin B, et al. A controlled trial of azathioprine in the management of chronic ulcerative colitis. Gastroenterology 1975; 69:96.
- Hawthorne AB, Logan RF, Hawkey CJ, et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992; 305:20.
- Sood A, Midha V, Sood N, Kaushal V. Role of azathioprine in severe ulcerative colitis: one-year, placebo-controlled, randomized trial. Indian J Gastroenterol 2000; 19:14.
- Sood A, Kaushal V, Midha V, et al. The beneficial effect of azathioprine on maintenance of remission in severe ulcerative colitis. J Gastroenterol 2002; 37:270.
- Kirk AP, Lennard-Jones JE. Controlled trial of azathioprine in chronic ulcerative colitis. Br Med J (Clin Res Ed) 1982; 284:1291.
- Ardizzone S, Maconi G, Russo A, et al. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut 2006; 55:47.
- Jewell DP, Truelove SC. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. Br Med J 1974; 4:627.
- Khan KJ, Dubinsky MC, Ford AC, et al. Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 2011; 106:630.
- Timmer A, McDonald JW, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2007; :CD000478.
- Andrews JM, Travis SP, Gibson PR, Gasche C. Systematic review: does concurrent therapy with 5-ASA and immunomodulators in inflammatory bowel disease improve outcomes? Aliment Pharmacol Ther 2009; 29:459.
- Campbell S, Ghosh S. Effective maintenance of inflammatory bowel disease remission by azathioprine does not require concurrent 5-aminosalicylate therapy. Eur J Gastroenterol Hepatol 2001; 13:1297.
- Mantzaris GJ, Sfakianakis M, Archavlis E, et al. A prospective randomized observer-blind 2-year trial of azathioprine monotherapy versus azathioprine and olsalazine for the maintenance of remission of steroid-dependent ulcerative colitis. Am J Gastroenterol 2004; 99:1122.
- Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012; 142:257.
- Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut 2011; 60:780.
- Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 2014; 146:392.
- Feagan BG, Greenberg GR, Wild G, et al. Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin. N Engl J Med 2005; 352:2499.
- Bickston SJ, Behm BW, Tsoulis DJ, et al. Vedolizumab for induction and maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2014; :CD007571.
- http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm398065.htm (Accessed on May 21, 2014).
- Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369:699.
- Loftus EV Jr, Colombel JF, Feagan BG, et al. Long-term Efficacy of Vedolizumab for Ulcerative Colitis. J Crohns Colitis 2017; 11:400.
- Moskovitz DN, Van Assche G, Maenhout B, et al. Incidence of colectomy during long-term follow-up after cyclosporine-induced remission of severe ulcerative colitis. Clin Gastroenterol Hepatol 2006; 4:760.
- Cohen RD. How should we treat severe acute steroid-refractory ulcerative colitis? Inflamm Bowel Dis 2009; 15:150.
- Maser EA, Deconda D, Lichtiger S, et al. Cyclosporine and infliximab as rescue therapy for each other in patients with steroid-refractory ulcerative colitis. Clin Gastroenterol Hepatol 2008; 6:1112.
- Arts J, D'Haens G, Zeegers M, et al. Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis. Inflamm Bowel Dis 2004; 10:73.
- Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol 1999; 94:1587.
- Cohen RD, Brodsky AL, Hanauer SB. A comparison of the quality of life in patients with severe ulcerative colitis after total colectomy versus medical treatment with intravenous cyclosporin. Inflamm Bowel Dis 1999; 5:1.
- Kornbluth A, Present DH, Lichtiger S, Hanauer S. Cyclosporin for severe ulcerative colitis: a user's guide. Am J Gastroenterol 1997; 92:1424.
- Van Assche G, D'Haens G, Noman M, et al. Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis. Gastroenterology 2003; 125:1025.
- Rayner CK, McCormack G, Emmanuel AV, Kamm MA. Long-term results of low-dose intravenous ciclosporin for acute severe ulcerative colitis. Aliment Pharmacol Ther 2003; 18:303.
- Ogata H, Kato J, Hirai F, et al. Double-blind, placebo-controlled trial of oral tacrolimus (FK506) in the management of hospitalized patients with steroid-refractory ulcerative colitis. Inflamm Bowel Dis 2012; 18:803.
- Ogata H, Matsui T, Nakamura M, et al. A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis. Gut 2006; 55:1255.
- Gonzalez-Lama Y, Gisbert JP, Mate J. The role of tacrolimus in inflammatory bowel disease: a systematic review. Dig Dis Sci 2006; 51:1833.
- Baumgart DC, Macdonald JK, Feagan B. Tacrolimus (FK506) for induction of remission in refractory ulcerative colitis. Cochrane Database Syst Rev 2008; :CD007216.
- Baumgart DC, Pintoffl JP, Sturm A, et al. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease--a long-term follow-up. Am J Gastroenterol 2006; 101:1048.
- Yamamoto S, Nakase H, Matsuura M, et al. Tacrolimus therapy as an alternative to thiopurines for maintaining remission in patients with refractory ulcerative colitis. J Clin Gastroenterol 2011; 45:526.
- Kornbluth A, Sachar DB, Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2004; 99:1371.
- Truelove SC, Willoughby CP, Lee EG, Kettlewell MG. Further experience in the treatment of severe attacks of ulcerative colitis. Lancet 1978; 2:1086.
- Järnerot G, Rolny P, Sandberg-Gertzén H. Intensive intravenous treatment of ulcerative colitis. Gastroenterology 1985; 89:1005.
- Järnerot G, Hertervig E, Friis-Liby I, et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005; 128:1805.
- Laharie D, Bourreille A, Branche J, et al. Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet 2012; 380:1909.
- Gibson DJ, Heetun ZS, Redmond CE, et al. An accelerated infliximab induction regimen reduces the need for early colectomy in patients with acute severe ulcerative colitis. Clin Gastroenterol Hepatol 2015; 13:330.
- Lindgren SC, Flood LM, Kilander AF, et al. Early predictors of glucocorticosteroid treatment failure in severe and moderately severe attacks of ulcerative colitis. Eur J Gastroenterol Hepatol 1998; 10:831.
- Seo M, Okada M, Yao T, et al. Evaluation of the clinical course of acute attacks in patients with ulcerative colitis through the use of an activity index. J Gastroenterol 2002; 37:29.
- Travis SP, Farrant JM, Ricketts C, et al. Predicting outcome in severe ulcerative colitis. Gut 1996; 38:905.
- Saito K, Katsuno T, Nakagawa T, et al. Predictive factors of response to intravenous ciclosporin in severe ulcerative colitis: the development of a novel prediction formula. Aliment Pharmacol Ther 2012; 36:744.
- Travis S, Satsangi J, Lémann M. Predicting the need for colectomy in severe ulcerative colitis: a critical appraisal of clinical parameters and currently available biomarkers. Gut 2011; 60:3.
- Brandse JF, Wildenberg ME, Wolbink G, et al. Fecal loss of infliximab as a cause of lack of response in severe inflammatory bowel disease (poster P500). The 8th Congress of the European Crohn's and Colitis Organisation, February 14-16, 2013, Vienna, Austria.
- Dotan I, Ron Y, Yanai H, et al. Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: a population pharmacokinetic study. Inflamm Bowel Dis 2014; 20:2247.
- Faubion WA Jr, Loftus EV Jr, Harmsen WS, et al. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001; 121:255.
- Baudet A, Rahmi G, Bretagne AL, et al. Severe ulcerative colitis: present medical treatment strategies. Expert Opin Pharmacother 2008; 9:447.
- Gustavsson A, Järnerot G, Hertervig E, et al. Clinical trial: colectomy after rescue therapy in ulcerative colitis - 3-year follow-up of the Swedish-Danish controlled infliximab study. Aliment Pharmacol Ther 2010; 32:984.
- Chaparro M, Burgueño P, Iglesias E, et al. Infliximab salvage therapy after failure of ciclosporin in corticosteroid-refractory ulcerative colitis: a multicentre study. Aliment Pharmacol Ther 2012; 35:275.
- Wang Y, MacDonald JK, Vandermeer B, et al. Methotrexate for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2015; :CD007560.
- Chande N, Wang Y, MacDonald JK, McDonald JW. Methotrexate for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2014; :CD006618.
- Cummings JR, Herrlinger KR, Travis SP, et al. Oral methotrexate in ulcerative colitis. Aliment Pharmacol Ther 2005; 21:385.
- Khan N, Abbas AM, Moehlen M, Balart L. Methotrexate in ulcerative colitis: a nationwide retrospective cohort from the Veterans Affairs Health Care System. Inflamm Bowel Dis 2013; 19:1379.
- Baron TH, Truss CD, Elson CO. Low-dose oral methotrexate in refractory inflammatory bowel disease. Dig Dis Sci 1993; 38:1851.
- Carbonnel F, Colombel JF, Filippi J, et al. Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis. Gastroenterology 2016; 150:380.
- Kozarek RA, Patterson DJ, Gelfand MD, et al. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989; 110:353.
- Vermeire S, Ghosh S, Panes J, et al. The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study. Gut 2011; 60:1068.
- Rutgeerts PJ, Fedorak RN, Hommes DW, et al. A randomised phase I study of etrolizumab (rhuMAb β7) in moderate to severe ulcerative colitis. Gut 2013; 62:1122.
- Vermeire S, O'Byrne S, Keir M, et al. Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 2014; 384:309.
- Rosenfeld G, Parker CE, MacDonald JK, Bressler B. Etrolizumab for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2015; :CD011661.
- Stremmel W, Ehehalt R, Autschbach F, Karner M. Phosphatidylcholine for steroid-refractory chronic ulcerative colitis: a randomized trial. Ann Intern Med 2007; 147:603.
- Sandborn W, Ghosh S, Panes J, et al. Phase 2 study of CP-690,550, an oral janus kinase inhibitor, in active ulcerative colitis. DDW abstract 594, Chicago, IL 2011.
- Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med 2012; 367:616.
- Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med 2017; 376:1723.
- Miner PB Jr, Geary RS, Matson J, et al. Bioavailability and therapeutic activity of alicaforsen (ISIS 2302) administered as a rectal retention enema to subjects with active ulcerative colitis. Aliment Pharmacol Ther 2006; 23:1427.
- Miner PB Jr, Wedel MK, Xia S, Baker BF. Safety and efficacy of two dose formulations of alicaforsen enema compared with mesalazine enema for treatment of mild to moderate left-sided ulcerative colitis: a randomized, double-blind, active-controlled trial. Aliment Pharmacol Ther 2006; 23:1403.
- van Deventer SJ, Tami JA, Wedel MK. A randomised, controlled, double blind, escalating dose study of alicaforsen enema in active ulcerative colitis. Gut 2004; 53:1646.
- van Deventer SJ, Wedel MK, Baker BF, et al. A phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided ulcerative colitis. Aliment Pharmacol Ther 2006; 23:1415.
- Vegter S, Tolley K, Wilson Waterworth T, et al. Meta-analysis using individual patient data: efficacy and durability of topical alicaforsen for the treatment of active ulcerative colitis. Aliment Pharmacol Ther 2013; 38:284.
- Sandborn WJ, Feagan BG, Wolf DC, et al. Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. N Engl J Med 2016; 374:1754.
- Marshall DC, Lyman SK, McCauley S, et al. Selective Allosteric Inhibition of MMP9 Is Efficacious in Preclinical Models of Ulcerative Colitis and Colorectal Cancer. PLoS One 2015; 10:e0127063.
- Sandborn WJ, Bhandari BR, Fogel R, et al. Randomised clinical trial: a phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis. Aliment Pharmacol Ther 2016; 44:157.
- Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol 2012; 83:1583.
- Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol 2015; 73:37.
- Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis 2014; 73:1020.
- Gordon JN, Prothero JD, Thornton CA, et al. CC-10004 but not thalidomide or lenalidomide inhibits lamina propria mononuclear cell TNF-α and MMP-3 production in patients with inflammatory bowel disease. J Crohns Colitis 2009; 3:175.
- Kennedy BW. Mongersen, an Oral SMAD7 Antisense Oligonucleotide, and Crohn's Disease. N Engl J Med 2015; 372:2461.
- Laudisi F, Dinallo V, Di Fusco D, Monteleone G. Smad7 and its Potential as Therapeutic Target in Inflammatory Bowel Diseases. Curr Drug Metab 2016; 17:303.
- Anderson JL, Edney RJ, Whelan K. Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease. Aliment Pharmacol Ther 2012; 36:503.
- Borody TJ, Warren EF, Leis S, et al. Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol 2003; 37:42.
- Cui B, Li P, Xu L, et al. Step-up fecal microbiota transplantation strategy: a pilot study for steroid-dependent ulcerative colitis. J Transl Med 2015; 13:298.
- Shi Y, Dong Y, Huang W, et al. Fecal Microbiota Transplantation for Ulcerative Colitis: A Systematic Review and Meta-Analysis. PLoS One 2016; 11:e0157259.
- Moayyedi P, Surette MG, Kim PT, et al. Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. Gastroenterology 2015; 149:102.
- Rossen NG, Fuentes S, van der Spek MJ, et al. Findings From a Randomized Controlled Trial of Fecal Transplantation for Patients With Ulcerative Colitis. Gastroenterology 2015; 149:110.
- Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 2017; 389:1218.
- Arafa HM, Hemeida RA, El-Bahrawy AI, Hamada FM. Prophylactic role of curcumin in dextran sulfate sodium (DSS)-induced ulcerative colitis murine model. Food Chem Toxicol 2009; 47:1311.
- Kumar S, Ahuja V, Sankar MJ, et al. Curcumin for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2012; 10:CD008424.
- Langhorst J, Wulfert H, Lauche R, et al. Systematic review of complementary and alternative medicine treatments in inflammatory bowel diseases. J Crohns Colitis 2015; 9:86.
- Lang A, Salomon N, Wu JC, et al. Curcumin in Combination With Mesalamine Induces Remission in Patients With Mild-to-Moderate Ulcerative Colitis in a Randomized Controlled Trial. Clin Gastroenterol Hepatol 2015; 13:1444.
- Bernstein CN. Spicing up the Treatment of Mild to Moderate Ulcerative Colitis. Clin Gastroenterol Hepatol 2015; 13:1450.
- Hanai H, Iida T, Takeuchi K, et al. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2006; 4:1502.