Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that includes an annual national meeting, regional satellites in both official languages, www.mentoringinibd.com, an educational newsletter series, and regular electronic communications answering key clinical questions with new research. This issue is based on the presentation made by the contributing editor, Dr. Neeraj Narula, at the annual national meeting, Mentoring in IBD XIX: The Master Class, held November 2, 2018 in Toronto, Ontario.
Episodes of acute, severe ulcerative colitis (ASUC) requiring hospitalization are quite common. Up to one-quarter of patients will experience this during their lifetime.(1,2) Of those patients who experience an episode of ASUC, 20-30% will undergo colectomy,(3) and mortality from severe UC is estimated to be approximately 1%.(2)
Severity is a relative term that has never been conclusively defined. However, the most widely used classification (Truelove and Witts) defines “severe” as a bloody stool frequency ≥6/day, with tachycardia (>90 bpm), temperature >37.8 °C, anemia (haemoglobin <10.5 g/dL), or an elevated ESR (>30 mm/h).(4,5) This classification remains the most widely used due in part to ease of use in the clinical setting.
This review will provide a summary of current knowledge about best practices for patients presenting with ASUC, including: general considerations and nutritional issues; treatment with systemic corticosteroids; and rescue therapy with cyclosporine or infliximab.
When a patient presents with ASUC, it is critical that the initial assessment include a stool sample for C. difficile. Hospitalized IBD patients with C.difficile have been shown to have a dramatically increased risk of mortality compared to those without C. difficile infection (4-fold risk).(6) Also, among patients with C. difficile infection, there is a 6.6-fold increase in risk of colectomy among those with IBD compared to those without IBD.(6) Often, the clinical symptoms of C. difficile may be indistinguishable from severe UC flare.(7) Importantly, the endoscopic appearance of C. difficile in UC may also be atypical and without classic pseudomembranes.(7)
Regardless of severity score, hospitalized UC patients with C. difficile should be treated with vancomycin. Research has shown reduction in short term readmissions with this intervention compared to metronidazole,(8) leading to the inclusion of vancomycin as preferred therapy in clinical practice guidelines.(9) Immunosuppression medications can be maintained in patients with C. difficile; however, escalation of immunosuppression medications should be avoided in the setting of untreated infection.(9)
While C. difficile testing is critical, it is not considered necessary to test for ova and parasites due to very low yield, unless the patient with a flare has had recent travel to an endemic area.(10)
Patients should have an early flexible sigmoidoscopy to assess endoscopic severity and predict outcomes.(11) Intubation to 30 cm should be sufficient and proceeding further is unlikely to impact immediate medical management. To help to exclude Crohn’s disease, MR or CT enterography may be considered.
Those individuals with severe endoscopic lesions at baseline are more likely to go on to require colectomy. In a study evaluating 85 patients with ASUC in a single centre, 43 of 45 individuals with severe endoscopic lesions went on to have colectomy, while only 9/40 with moderate endoscopic lesions required had colectomy.(11)
Infection with cytomegalovirus (CMV) is also a consideration. The prevalence estimates of CMV infection in resected colonic specimens from UC patients range from 0–22%.(12) Infection is more likely to occur in immunosuppressed patients.(12) If a patient has steroid refractory UC, one should take biopsies for tissue immunohistochemistry for CMV.(13) If a patient is responding to infliximab, cyclosporine, or other treatment and is CMV positive, there is no need to treat the CMV as it may just be an innocent bystander.(13) However, if the patient is not responding and is CMV-positive, treatment of the CMV is indicated.(13) Typical treatment is two to three days of IV ganciclovir, then two to three weeks of oral ganciclovir or valcyclovir.(13). Immunosuppressive therapy should be stopped in the presence of severe systemic CMV.(13)
Generally speaking, patients should be offered a normal diet or enteral nutrition unless oral intake is not tolerated.(14) A small (n=27) prospective trial showed no difference in clinical outcomes between patients on total parenteral nutrition vs. oral diet.(14)
IBD patients are at increased risk of venous thromboembolism (relative risks of deep vein thrombosis and pulmonary embolism are 2.8 and 3.6, respectively, for ulcerative colitis patients vs. controls).(15) Prophylaxis for thromboembolism is recommended. Unfractionated or low-molecular-weight heparin is recommended in acutely ill medical patients.(16) A meta-analysis of eight RCTs assessing heparin as adjunctive therapy in UC found no increased bleeding vs. controls.(16)
Routine use of antibiotics is not recommended. Small studies have found no differences in outcome between UC patients that received metronidazole, ciprofloxacin, or tobramycin in addition to steroids vs. steroids alone.(17–19)
Most patients with ASUC should be treated initially with intravenous corticosteroids.(3) However, indications for early surgery include: massive hemorrhage; toxic megacolon with impending or frank perforation; co-existent colorectal cancer or dysplasia; longstanding colitis with “intractability”; and medical noncompliance (especially for cyclosporine).(20)
A systematic review of corticosteroids in severe UC showed a response rate of 67%.(3) The colectomy rate, which was reported as stable over three decades, was 27%, and the mortality rate was 1%.(3) There were no differences in response reported between the different steroids included in the review.(3) There was no dose-colectomy response seen with doses >60 mg/day of methylprednisolone, so this dose is recommended for use in inpatients with UC.(3) If the patient appears to be a steroid responder, intravenous steroids can be continued up to five days, at which point the patient should transition to oral prednisone 40 mg/d. It may be beneficial to observe patients in the hospital while transitioning to oral steroids since some may regress. There should be a steroid-sparing maintenance strategy ready to start either as inpatient or outpatient.
Consider second-line medical therapy or surgery in patients who fail to improve on intravenous steroids within 72 hours.(21,22) Improvement should be assessed by clinical, radiological, and laboratory parameters. There are numerous scoring systems to predict failure to steroids; the best validated is the Oxford criteria.(21) Poor outcomes are predicted when there are >8 stools/day on day 3, or when there are 3–8 stools/day and CRP >45 mg/L.(21)
The timing of decision-making at day 3 is supported by a study that evaluated outcomes in those who underwent colectomy after steroid failure, and found that post-operative morbidity and mortality is higher in those who were on steroids for a longer period of time before having surgery (Figure 1).(22)
If patients fail intravenous steroids, there are essentially two medical options for the hospitalized ASUC patient: cyclosporine and infliximab. Other therapies used in IBD (e.g., other biologics, fecal microbiota transplantation) have not been studied in this population and are not recommended.
The key goals of rescue therapy are to induce remission and to preserve the colon. However, we need to remember that saving lives is even more important than saving colons. A surgical consult is recommended for anyone considering rescue therapy. In certain cases, colectomy is not avoidable, but rescue therapy can allow prevention of urgent colectomy and serve as a bridge to elective colectomy, allowing more ileal pouch-anal anastomosis interventions to be completed successfully. Rescue therapy with cyclosporine or infliximab may also help to maximize nutritional status and minimize steroid doses, which can improve outcomes of surgery.
Because of the need for careful monitoring, the use of cyclosporine has generally been reserved for expert centres. However, there is renewed interest in its use since the introduction of vedolizumab as a potential maintenance option. For those interested in detailed “how-to” guidance on cyclosporine in this setting, two key resources are a review article by Kornbluth et al (23) and an online severe UC protocol published by the University of Michigan.(24)
The typical regimen for cyclosporine in this setting is intravenous 2 mg/kg/day for seven days, followed by oral cyclosporine for 3 months.(23–26) While hospitalized, serum cyclosporine level should be monitored daily or every other day, with a goal level of 150–400 ng/mL during intravenous therapy. If the patient is a responder to intravenous cyclosporine, the maintenance oral dose target is 4 mg/kg, targeting blood levels of 100–250 ng/mL. Current practice is to initiate azathioprine or vedolizumab within two weeks of hospital discharge and wean off cyclosporine at three months.(24)
Other key points to keep in mind with cyclosporine are to avoid use in those with active infection or detectable anti-TNF levels; to maintain cholesterol >3.0 mmol/L and normal magnesium to minimize seizure risk; to dose adjust if serum creatinine rises by >30%; and to use prophylaxis for pneumocystis pneumonia.(23,24)
Short-term adverse events associated with cyclosporine include hypertension, paresthesias, hypokalemia, hypomagnesemia and risk of opportunistic infections.(26) Longer-term adverse events include nephrotoxicity, dyslipidemia and gingival hyperplasia.(26)
There are now real-world data available supporting a transition from cyclosporine to vedolizumab maintenance.(27) Investigators at the University of Chicago showed that among 11 patients with UC, seven (64%) were able to have a long-term clinical response with vedolizumab and five (45%) were able to achieve steroid-free clinical remission.(27) More data are needed.
The first published study investigating infliximab for rescue therapy in UC was a randomized, placebo-controlled study involving 45 patients with severe to moderately severe ulcerative colitis not responding to conventional treatment.(28) For the primary end point of colectomy or death three months after randomization, the risk was significantly higher for those randomized to placebo (seven patients in the infliximab group and 14 in the placebo group had a colectomy; Odds ratio 4.9; 95% CI 1.4–17, P=0.017). No patients died. Longer-term follow-up showed that the benefit of rescue therapy with infliximab in steroid-refractory acute ulcerative colitis remained after 3 years.(29)
Infliximab has been directly compared with cyclosporine in this setting, including three randomized, controlled trials.(30–32) In each individual study and in a meta-analysis, there were no significant differences in response to treatment or three-month colectomy rates between the active treatment arms.(30–33) For twelve-month colectomy rates, the odds ratio begins to favor infliximab, but this was not statistically significant in the meta-analysis (Table 1).(33)
It may be possible to further improve infliximab outcomes for patients with ASUC. In the RCTs mentioned above, there was close therapeutic drug monitoring of cyclosporine, but the infliximab dose was not maximized in any of the studies. One might speculate that aggressive dosing based on drug level monitoring may result in improved outcomes with infliximab.(34) The theory to why response to infliximab in severe UC may be decreased is that more drug may be needed to neutralize the high inflammatory burden with severe UC.(35) Infliximab is rapidly cleared from the system, and drug may also be excreted through protein-losing colopathy. An interesting study published in Gastroenterology in 2015 showed high fecal levels of infliximab in the stool of nonresponders soon after the first dose.(36)
Another study demonstrated significantly decreased infliximab levels at the time of the planned second dose in severe UC patients as compared to moderate UC patients.(37) A population pharmacokinetic model has been developed using data from 51 patients at Mount Sinai Hospital in Toronto. It showed that patients who failed infliximab therapy and required colectomy had significantly increased drug clearance compared to those who did not require colectomy.(38)
An additional consideration is that none of the infliximab-cyclosporine comparative studies included used combination therapy with thiopurines for induction.(33) Research in the non-severe acute induction setting also suggests that combination therapy can be more effective than infliximab alone.(39,40)
Some investigators have studied the impact of an accelerated infliximab dosing protocol (10 mg/kg initial induction) among patients with ASUC.(41,42) Although there was a suggestion of early benefit in terms of short-term colectomy rates with accelerated dosing in one study,(41) the opposite finding was reported in another, where 30-day colectomy rates were higher in those who received accelerated dosing.(42) This may reflect selection bias, as patients who received accelerated dosing had features suggestive of increased severity compared to those who did not. Dosing in the real world has been shown to be highly variable. A survey study was performed among members of the International Organization for the Study of IBD (IOIBD), to find out their general approaches to dosing infliximab in severe UC.(43) The survey showed that no single strategy was agreed upon by more than a quarter of respondents, although the majority used some sort of accelerated dosing strategy, usually based on clinical severity. This highlights the need for prospective studies in this patient group as well as clinical pathways to standardize care.
In the meantime, some considerations to keep in mind are that patients with low albumin, high CRP, and/or deep ulcers may need high dose or accelerated infliximab dosing. One should also not assume response: do not discharge patients early after initial infliximab dose in severe UC. Inflammatory markers should be monitored closely and, if response plateaus or clinical symptoms worsen after initial response, consider early re-dosing (day 3/4). One should exhibit caution with regards to accelerated dosing in older patients, those on extended course of high dose steroids, or those with significant comorbidities.
Case reports of adverse events (including death) initially raised concerns about using infliximab and cyclosporine sequentially in severe UC patients.(44) However, a systematic review examining outcomes of sequential therapy with calcineurin inhibitors (cyclosporine or tacrolimus) and infliximab have shown treatment response in 62% of patients, remission in 39%, serious infections in 6% and mortality in 1%. The sequential strategy is feasible, but should be considered only at centres familiar with cyclosporine use.
Longer periods of uncontrolled inflammation are more likely to lead to adverse outcomes, including toxic megacolon, perforation, severe hemorrhage, thromboembolism, infection and mortality. If a patient is not improving or is deteriorating on rescue therapy with cyclosporine or infliximab, he or she should be referred for colectomy.
The five main considerations to keep in mind for managing ASUC are:
Jim is a 32-year-old male with a longstanding history of left-sided UC that you have been following for many years. His disease has been in remission for more than five years on oral 5-ASA and azathioprine. His last surveillance colonoscopy eight months prior was normal, with biopsies showing no histologic activity or dysplasia. He now presents to the emergency department with a four-week history of bloody diarrhea and abdominal cramps, which have significantly worsened in the last week.
The physical exam reveals:
In an acute presentation like this, it is important to investigate for potential triggers and rule out infections (e.g., C. difficile, CMV).(45) Patients should have an early flexible sigmoidoscopy with biopsies to assess endoscopic severity, C. difficile infection or CMV colitis.(45) Endoscopic severity (i.e., ulceration) may also be a predictor of steroid failure.(46)
Plain abdominal radiographs should be obtained at baseline as part of the initial assessment of patients with severe UC. Changes that can be identified on radiographs include megacolon, thumbprinting, pneumatosis intestinalis, and perforation.(45)
While CT scanning increases exposure to radiation, in situations where perforation, or abdominal sepsis is suspected, a CT scan would be the imaging modality of choice.(45)
Patients should be offered a normal diet or enteral nutrition unless such a diet is not tolerated.(45) There is no role for TPN as primary therapy in ASUC. If the patient’s symptoms worsen (e.g., increased abdominal pain and bloody diarrhea),oral intake should be withheld and an alternative nutritional source, such as TPN, should be instituted.(45)
Patients should receive prophylaxis for thromboembolic complications. There is strong evidence to support the use of un-fractionated or low molecular weight heparins as prophylaxis for venous thromboembolic complications in medical inpatients.(47,48)
Patients should be assessed for risk of tuberculosis (TB) including a careful history, chest X-ray, and TB testing at onset of hospitalization in preparation for possible medical rescue therapy.(45)
A flexible sigmoidoscopy to 45 cm shows diffuse friability with ulceration extending beyond the scope: Mayo 3. Biopsies are done. Abdominal CT reveals a pancolitis. You initiate IV corticosteroids.
Intravenous corticosteroids are established as the most effective first-line treatment for acute severe UC.(45)
A number of parenteral corticosteroids, including hydrocortisone, prednisolone, methylprednisolone, betamethasone, and adrenocorticotropic hormone, have been tested in the treatment of severe UC, and a systematic review found no obvious differences in treatment response between the various steroids used in the studies included.(3,45)
Similarly, no dose-ranging studies of the various intravenous corticosteroids have been carried out. In the meta-analysis, no correlation was found between corticosteroid dose and colectomy rate and there was no evidence to support increasing the corticosteroid dose beyond 60 mg/day of methylprednisolone or equivalent.(3)
Based on the very limited data that show no obvious differences in terms of efficacy or safety, the selection of a parenteral steroid and the dosing regimen in the hospitalized UC patient will most often be based on physician and centre experience.
Clinical parameters that should be monitored during acute intravenous steroid treatment include stool frequency, hemoglobin and CRP.
Predictors of steroid failure at 72 hours include the Oxford index (positive predictive value [PPV] 85%) and the Swedish Index (PPV 70%).(21,49)
Should patients fail to respond to steroids within 72 hours, they should be considered for intravenous infliximab or cyclosporine therapy.(45)
Over the next 72 hours, he reports partial improvement. Bloody bowel movements have decreased from 12 per day to eight per day with persistent nocturnal bowel movements. He continues to have abdominal cramps with eating.
Both infliximab and cyclosporine have quality evidence showing efficacy in the acute, severe UC setting.(45)
In a parallel, open-label, randomised controlled trial, intravenous ciclosporin (2 mg/kg per day for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg on days 0, 14, and 42) were initiated among 115 patients with an acute, severe flare of UC.(30)
The primary efficacy outcome, treatment failure, occurred in 35 (60%) patients given cyclosporine and 31 (54%) given infliximab (P=0·52).
Nine (16%) patients in the cyclosporine group and 14 (25%) in the infliximab group had severe adverse events (SAEs).
An analysis of 270 patients in the UK also found no significant difference between the two drugs in clinical effectiveness, colectomy rates, incidence of SAEs or reactions, or mortality, when measured 1–3 years post treatment.(32)
Currently in Canada there are two infliximab biosimilars available—Inflectra® and RenflexisTM—in addition to the originator biologic Remicade®. The infliximab biosimilars have not been studied in ASUC.
In terms of infliximab pharmacokinetics, evidence suggests that some patients with acute severe UC have increased infliximab clearance, resulting in low serum infliximab concentrations and suboptimal clinical response.(50)
A systematic review concluded that infliximab dose intensification is beneficial to at least 50% of acute severe UC patients, and that an intensified infliximab dosing regimen with 1–2 additional infusions in the first 3 weeks of treatment could reduce the early (3-month) colectomy rate by up to 80%.(51)
Therapeutic drug monitoring is a consideration to ensure adequate drug levels in this setting.
For cyclosporine, higher doses (e.g., 4 mg/kg) have been associated with a higher risk of serious adverse events (e.g., nephrotoxicity, hypertension, hypomagnesemia, seizure if low cholesterol).(45)
Review of the evidence suggests the optimal cyclosporine dose in this setting is 2 mg / kg / day IV followed by dose adjustment according to whole blood levels.(45,51)
Guidelines recommend bridging from cyclosporine to a thiopurine agent (azathioprine or 6-MP), and not sequencing cyclosporine and anti-TNF therapy due to safety concerns.(45) Others have suggested that the benefits of sequencing may outweigh the risks.(44)
There is insufficient evidence on bridging to other advanced therapies (e.g., vedolizumab or tofacitinib) following acute therapy.
The PPD test is negative and the chest X-ray is normal. You discuss the options of infliximab and surgery, including risks and benefits. You have no experience with cyclosporine and your centre cannot measure drug levels of cyclosporine. You prescribe infliximab 10 mg/kg IV.
Four days after the infliximab infusion there is no improvement. He still has eight to 10 bloody bowel movements daily. His CRP is now 82 mg/L and his hemoglobin is now 85 g/L.
As mentioned above, infliximab pharmacokinetics in acute, severe UC are such that some patients have increased infliximab clearance, resulting in low serum infliximab concentrations and suboptimal clinical response.(50)
Therapeutic drug monitoring in a situation like this with poor response to infliximab could be considered.
Guidelines have recommended against sequencing cyclosporine and anti-TNF therapy.(45)
This is largely based on initial reports of unacceptably high rates of serious infection and death after sequential therapy with cyclosporine and infliximab.(52,53)
A more recent systematic review, however, concluded that “The risk of sequential therapy in steroid-refractory UC seems lower than initially reported. . . In contrast to recent guidelines, the current analysis does not support a decision for or against use of sequential rescue therapy, which should only be performed at specialized referral centres familiar with the use of calcineurin inhibition.”(44)
Adalimumab and vedolizumab are theoretically options for patients who have failed either infliximab or cyclosporine, but there are no data available for either of these agents in ASUC.
Jim absolutely refuses colectomy. He says that he was well for so long and doesn’t understand why he flared and he cannot accept surgery. After discussion of therapeutic options, you treat him with a second dose of infliximab 10 mg/kg IV. After five days, there is no clinical response. He is seen by you and the surgeon and he remains opposed to surgery. You explain and he understands the risk of morbidity and mortality with ongoing acute severe ulcerative colitis (ASUC) but this does not impact his decision to refuse surgery.
The options at this point are to try to convince Jim to have surgery, with a frank discussion of benefits and risks,(54) to consider a third dose of infliximab, or to treat with cyclosporine.
Many sites do not have access to cyclosporine, so this decision may have to take into account an assessment of feasibility of a transfer the patient to a specialized centre.
You decide to refer him to a specialized centre for cyclosporine treatment. However, after a long discussion with his family and evaluating his condition, he decides to opt for surgery.
John K. Marshall, MD MSc FRCPC AGAF
Director, Division of Gastroenterology
Professor, Department of Medicine, McMaster University
Neeraj Narula,MD MPH FRCPC
Director of the IBD Clinic
Assistant Professor of Medicine
Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Brian Bressler, MD MS FRCPC, University of British Columbia, Vancouver, BC
Anne M. Griffiths, MC FRCPC, University of Toronto, Toronto, ON
Steven E. Gruchy, MD MSc FRCPC, Dalhousie University, Halifax, NS
Remo Panaccione, MD FRCPC, University of Calgary, Calgary, AB
Hillary Steinhart, MD MSc FRCPC, University of Toronto, Toronto, ON
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON
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