Refractory Ulcerative Colitis Treatment

Abstract

Treatment of refractory ulcerative colitis (UC) is a common clinical challenge. In either acute or chronic refractory UC, the disease may continue to remain active, even though the patient is on appropriate therapy. It is important to reassess and characterize the patient's disease before adding new medications to the current medical regimen. After determining the current extent and severity of the UC—ruling out other causes of bloody diarrhea and determining what complications are present—new treatment approaches can then be started. It is critical to first optimize oral 5-aminosalicylic acid (5-ASA) therapy combined with rectal 5-ASA or corticosteroid suppositories, plus corticosteroid or 5-ASA enemas or foam preparations. Oral or intravenous corticosteroids are appropriate to use if needed, but alternative approaches must be used for long-term maintenance. 6-Mercaptopurine (6-MP) or azathioprine can be very helpful for severe chronic refractory UC. In those patients who do not respond to 5-ASA medications, corticosteroids, and 6-MP or azathioprine, infliximab offers an important approach for induction and maintenance of remission for refractory chronic ulcerative colitis as well as for select cases of refractory acute UC. Cyclosporine use is an alternative medical approach for the refractory acute UC patient. Colectomy with ileal pouch-anal anastomosis remains a valuable option for the refractory chronic or acute UC patient, because it can provide both a “cure” for the disease, as well as eliminate ineffective medications with their associated side effects.

A common problem we face is what to do when a patient with ulcerative colitis (UC) is refractory to initial medical therapy. Before beginning new therapies, it is important to address several issues (Table 1). First, does the patient have acute or chronic disease? Although the individual with chronic moderate-to-severe disease can continue to be treated as an outpatient, the patient with acute-severe (fulminant) UC needs to be immediately hospitalized. Second, what is the clinical activity of the disease process? Is the disease activity mild-to-moderate, is it moderate-to-severe, or is it acute severe (fulminant)? Third, have there been significant changes in blood work or abnormalities on abdominal imaging studies suggestive of severe UC that might require emergent care? Fourth, have other possible causes of bloody diarrhea been excluded? Having a diagnosis of UC does not preclude a patient from contracting an infectious agent, such as Clostridium difficile, which might be causing the bloody diarrhea. Likewise, a patient with UC might develop other well-known causes of colitis, such as ischemic colitis. A cautious unprepped flexible sigmoidoscopic examination (performed only in the absence of contraindications) with biopsies and samples for culture can provide critically important information on whether or not the patient has either C. difficile, hemorrhagic Escherichia coli O157:H7, salmonella, shigella, cytomegalovirus (CMV), amebiasis, Crohn's colitis, ischemic colitis, nonsteroidal anti-inflammatory drug-induced colitis, or radiation colitis. CMV is often overlooked in cases of refractory UC, and it is therefore of particular importance to have mucosal biopsies examined carefully by an expert pathologist for evidence of this pathogen.¹

Table 1.

Ten Questions to Answer Before Treating a Patient with Refractory Ulcerative Colitis

Does the patient have acute-severe (fulminant) or chronic refractory ulcerative colitis (UC)? If the patient has chronic refractory UC, is the disease activity mild-to-moderate or moderate-to-severe? Are there blood work and/or radiologic abnormalities suggestive of severe UC? Have all other possible causes of bloody diarrhea been excluded? What is the current extent and severity of the UC? Has the patient been compliant with the previously prescribed medical therapy? Is the patient malnourished and in need of enteral hyperalimentation or total parenteral nutrition? Are there extraintestinal manifestations of UC that might influence the choice of therapeutic regimens? Does the patient need to work with social workers, psychologists, and/or psychiatrists to develop better coping strategies? Does the patient understand the clinical aspects and treatment of UC?

Fifth, what is the current extent and severity of the UC? This is often another reason for an initial flexible sigmoidoscopic examination with biopsies, followed by a complete colonoscopic examination with biopsies after the patient has stabilized. Sixth, has the patient been compliant with therapy? One of the most common causes of refractory UC is that the patient is not taking the prescribed medications appropriately. Seventh, is the patient malnourished and in need of enteral hyperalimentation or total parenteral nutrition? Eighth, are there extraintestinal manifestations that might influence the choice of therapeutic regimens? For example, the presence of pyoderma gangrenosum, ankylosing spondylitis, or sacroiliitis would be reasons to consider early use of infliximab, whereas iritis or scleritis requires immediate evaluation by an ophthalmologist. Ninth, does the patient need to work with social workers, psychologists, and/or psychiatrists to develop better coping strategies? Finally, does the patient understand the clinical aspects and treatment of UC? The Crohn's and Colitis Foundation of America's website (www.CCFA.org) can be a very helpful resource for patients with UC, who have many complex issues that they must deal with.

Treatment of Refractory Mild-to-Moderate Ulcerative Proctitis and Left-Sided UC

The most important approach in working with the patient with refractory UC is to make certain that each type of therapy is optimized before proceeding to the next treatment option (Figure 1). Topical rectal therapies have the lowest potential side effect profile of all of the therapies we use for UC.^2–7 Direct application of topical rectal therapies to involved distal colonic mucosa, which is commonly difficult to treat, provides optimal drug delivery, similar to the use of topical agents for dermatologic conditions.

Figure 1.

Treatment algorithm for outpatients with refractory chronic mild-to-moderate ulcerative proctitis, ulcerative proctosigmoiditis, or left-sided ulcerative colitis (UC). It is important to optimize high dose oral 5-aminosalicylic acid (5-ASA) medications combined with 5-ASA or corticosteroid suppositories plus corticosteroid or 5-ASA enema or foam preparations. Maintenance of remission can usually be achieved using 5-ASA or corticosteroid suppositories once or twice a day in combination with oral 5-ASA medications.

For refractory mild-to-moderate UC involving the rectum (ulcerative proctitis), 5-aminosolicylic acid (5-ASA) or corticosteroid suppositories are used 2–3 times a day to maximize delivery when the proctitis is active.^2–5 Because patients with refractory ulcerative proctitis often have difficulty retaining suppositories, using them 2 or 3 times per day can be very helpful for inducing a response. For maintenance of remission for ulcerative proctitis, use of 5-ASA or corticosteroid suppositories once or twice a day is usually effective.^2–5 Thus, topical therapies alone are our treatments of choice for mild-to-moderate ulcerative proctitis, with the refractory patient often requiring more frequent dosing intervals.

5-ASA or corticosteroid enemas, and/or corticosteroid foam in combination with 5-ASA or corticosteroid suppositories, constitute the topical therapies of choice for the treatment of refractory mild-to-moderate UC involving the rectum and sigmoid colon (ulcerative proctosigmoiditis) or involving the left colon to the splenic flexure (left-sided colitis).^2–5 One common problem seen in refractory ulcerative proctosigmoiditis or left-sided colitis is that enema and foam preparations can bypass and not treat the rectum because they are inserted and released proximally to the distal rectum into the sigmoid and left colon, followed by the patient lying on his or her left side. Therefore, suppositories are usually needed in combination with enemas and/or foam preparations to ensure optimal delivery of topical medications to both the distal colon and the rectum. For refractory mild-to-moderate proctosigmoiditis or left-sided colitis, 5-ASA enemas in combination with 5-ASA suppositories should be used 2–3 times a day.^2–5 Alternatively, corticosteroid enemas or foam in combination with corticosteroid suppositories can be used 2–3 times a day.

There are a number of different formulations of 5-ASA that permit targeted delivery of high concentrations of drug to the colon.⁷ The efficacy of 5-ASA for UC is dose-dependent and the newer 5-ASA medications deliver the 4 to 6.4 g/day necessary to achieve remission. Oral 5-ASA therapy is particularly effective for maintenance of remission in patients with refractory mild-to-moderate proctosigmoiditis or left-sided colitis when combined with 5-ASA or steroid enemas and suppositories.^2–7 The increased response with optimal oral and rectal combined therapy may be due to both enhanced topical delivery of medications to all parts of the diseased rectum and colon as well as the additive effects of oral plus rectal therapy.^2–7 For maintenance of remission for ulcerative proctosigmoiditis or left-sided colitis, the use of 5-ASA or corticosteroid suppositories once or twice a day in combination with oral 5-ASA medications is often effective.

Corticosteroids for Refractory Moderate-to-Severe UC

For refractory moderate-to-severe UC in the outpatient setting (Figure 2), oral corticosteroids successfully induce remission in 60–70% of patients.^8,9 The onset of action in responders is rapid, usually within 48 hours.^8,9 Prednisone is begun at a dose of 40 mg once daily in the morning and tapered very gradually over a 2–4 month period. However, corticosteroids are ineffective at maintenance of remission and can lead to potentially severe side effects.^2–5 Therefore, the appropriate use of corticosteroids is to induce remission, prior to seeking alternative therapies.^2–5 Furthermore, those patients who either fail to respond or are refractory to steroids pose a clinical challenge in which the risks and benefits of the available medical options (immunomodulators and biologics) and surgical options (colectomy with ileal pouch-anal anastomosis, IPAA) must be carefully weighed and considered by both patient and physician.

Figure 2.

Treatment algorithm for outpatients with refractory chronic moderate-to-severe ulcerative colitis (UC). Initial therapy includes oral corticosteroids plus high dose oral 5-aminosalicylic acid (5-ASA) medications combined with 5-ASA or corticosteroid suppositories plus corticosteroid or 5-ASA enema or foam preparations. For nonresponsive patients, 6-mercaptopurine (6-MP) or azathioprine and then infliximab are used. For outpatients with refractory chronic moderate-to-severe UC who have not responded or only partially responded to the above medications, colectomy with ileal pouch-anal anastomosis is important to consider, because the disease is removed and also ineffective medications with their potential side effects can be discontinued.

6-MP and Azathioprine for Refractory Moderate-to-Severe UC

6-MP and azathioprine can be very helpful in patients with refractory moderate-to-severe UC (Figure 2).^10–16 Controlled trials in patients with refractory moderate-to-severe UC have demonstrated that 6-MP and azathioprine improve overall symptoms, allow steroids to be discontinued, induce remission, and maintain remission in patients who have had their remission induced by 6-MP or azathioprine.^10–16 Induction of a clinical response or remission with 6-MP or azathioprine occurs in 30–50% of patients with refractory chronic UC, although it may take as long as 4–6 months to achieve;^{2–5,10–13} it has been demonstrated that 70% of patients maintain remission.^2–5,15,16 Most importantly, when patients maintained in remission on azathioprine or 6-MP discontinue their medications, a very high relapse rate of 70–87% occurs.^14–16

Reversible short-term side effects such as fever, rash, nausea, and headaches occur in up to 10% of patients on 6-MP or azathioprine¹⁷ and pancreatitis and very high fevers occur in 2–4% of patients. Opportunistic infections can develop in patients on these immunomodulators plus corticosteroids, because both medications are immunosuppressive. When working with chronic severe refractory UC patients on 6-MP or azathioprine therapy, monitoring of 6-thioguanine levels can guide dose adjustments in order to optimize the likelihood of a therapeutic response and minimize adverse effects.^18,19 In refractory UC patients in whom noncompliance is suspected, low or absent metabolite concentrations can help determine if the patients are medication noncompliant or are 6-MP or azathioprine nonresponders.^18,19 Bone marrow suppression and mild hepatitis (transaminitis) can be reversed by lowering the 6-MP or azathioprine dosage. Therefore, 6-MP and azathioprine are very appropriate for refractory UC patients who have failed to respond to or are dependent on corticosteroids. However, because 6-MP and azathioprine often take 4–6 months to be effective, patients with acute severe (fulminant) UC are not candidates for 6-MP or azathioprine.

Infliximab for Refractory Moderate-to-Severe UC

Infliximab was initially demonstrated to be effective for UC in preliminary studies.^20–22 In the definitive multicenter clinical Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and 2), patients who received infliximab at Weeks 0, 2, and 6 had a 61–69% clinical response rate after 8 weeks compared with a placebo clinical response rate of 29–37%.²³ At Week 54, the clinical response rates were 44–45% with infliximab compared to a 20% pla cebo response, whereas at Week 54 the infliximab clinical remission rates were 34–35% compared to a 17% placebo response.²³ Infliximab was also found to decrease steroid use and induce mucosal healing.²³ For maintenance of remission, infliximab is continued long-term, using progressive decreases in infusion intervals and increases in dose as needed. Thus, infliximab is an appropriate therapeutic approach for moderate-to-severe UC patients who are refractory to other therapies (Figure 2).^20–23

Serious infections have been observed in patients treated with infliximab, including pneumonia, bacterial sepsis, urinary tract infections, abscess formation, and peritonitis.^24,25 Systemic infections that have been described in patients treated with infliximab include primary and disseminated tuberculosis, coccidioidomycosis, aspergillosis, histoplasmosis, candidiasis, and Pneumocystis carinii pneumonia (PCP).^24,25 It has also been demonstrated that corticosteroids, either alone or in combination with immunomodulators and/or infliximab, markedly increase the risk of infectious complications. Therefore, in UC patients treated with infliximab, corticosteroids should be discontinued as rapidly as possible in order to decrease the risk of acquiring an opportunistic infection.²⁶

Steroids for Refractory Acute Severe UC

Patients with refractory acute severe (fulminant) UC require hospitalization for treatment with intravenous (IV) steroids and antibiotics. IV steroids (hydrocortisone 400 mg/day or methylprednisolone 60 mg/day given in divided doses 2 or 3 times a day) will lead to a partial or complete response in 50–75% of patients with refractory fulminant UC within one week.^2,3,27,28 Broad-spectrum IV antibiotics are used with the assumption that intestinal bacteria can be prevented from perpetuating the UC and from crossing the ulcerated colon and causing bacteremia and sepsis (Figure 3).

Figure 3.

Treatment algorithm for inpatients with refractory acute-severe ulcerative colitis (UC). If patients do not respond to intravenous (IV) steroids and IV antibiotics after 5 to 7 days, possible treatment choices include either IV cyclosporine or IV infliximab or colectomy. For inpatients with refractory acute severe UC, who do not respond or only partially respond to IV medications, colectomy with ileal pouch-anal anastomosis is important to consider, because the disease is removed and major complications from the severe acute UC can be avoided.

Cyclosporine for Refractory Acute Severe UC

Patients with fulminant UC who have not responded to high-dose IV steroids for 5–7 days may respond to IV cyclosporine.^2,3,29–33 IV cyclosporine (2–4 mg/kg daily) has been demonstrated to induce response or remission in 64–82% of patients;^2,3,29–33 however, up to 50% of patients ultimately undergo a colectomy. Because long-term cyclosporine is not effective for maintenance of remission, “bridge therapy” to 6-MP or azathioprine is necessary. Concurrent use of 6-MP or azathioprine as a bridge therapy with cyclosporine may decrease the release rate in those individuals who initially respond to cyclosporine to as low as 10%.³⁴ Potential side effects associated with cyclosporine include severe, opportunistic infections (such as PCP), nephrotoxicity, hypertension, seizures, peripheral neuropathy, and anaphylaxis.^2,3,29–33

Infliximab for Refractory Acute Severe UC

Hospitalized patients with refractory acute severe UC who did not respond to high-dose IV corticosteroids have been treated with infliximab.³⁵ Patients with signs of infection or abscesses were excluded and PCP prophylaxis was instituted. Sixty-seven percent of patients on placebo required colectomy, compared with 29% of patients treated with infliximab.³⁵ Patients with acute moderately severe UC had an outstanding response to infliximab, with none requiring colectomy compared with 62.5% of the patients receiving placebo.³⁵ Therefore, for hospitalized patients with acute severe or moderately severe UC, infliximab may be appropriate and also effective.³⁵ For maintenance of remission, infliximab is continued long-term using progressive decreases in infusion intervals and increases in dose as needed (Figure 3). Future studies will be needed to determine whether cyclosporine or infliximab should be used first for patients with acute-severe UC who have not responded to high-dose IV steroids. Because infliximab has been used extensively by gastroenterologists for Crohn's disease and UC, personal experience will likely make infliximab the most appropriate salvage therapy to use for acute severe UC patients refractory to IV steroids.

Colectomy for Refractory Severe UC Non-Responsive or Partially Responsive to Medications

For patients with severe refractory UC that does not respond or only partially responds to medications, colectomy must be considered and discussed (Figures 2 and 3). Colectomy offers a number of important benefits including removal of the diseased colon with its associated risks plus avoiding potent medications and their many potential side effects. Indications for colectomy for patients with refractory severe UC include: 1) toxic megacolon, 2) severe hemorrhage, 3) fulminant colitis unresponsive to therapy, 4) refractory acute or chronic severe UC, 5) dysplasia or carcinoma, and 6) colonic stricture.³⁶

Total proctocolectomy with or without recto-anal mucosal stripping and ileoanal anastomosis IPAA is the most common surgical procedure for UC.^37–39 An ileal reservoir (J pouch) is created in order to allow continence at the ileoanal anastomotic junction.^37–39 Although some complications can occur, most patients experience excellent pouch function and quality-of-life studies have revealed superb outcomes in the majority of patients who have undergone colectomy with IPAA.^37–40 Total proctocolectomy with IPAA or ileostomy are therefore important options to consider for patients with refractory severe UC who have failed medical therapy.^36–40

Conclusion

After using colonoscopy with biopsies to determine the extent and severity of disease and excluding other causes of colitis, a rational stepwise approach can be followed for patients with refractory UC. For patients with refractory mild-to-moderate ulcerative proctitis or left-sided UC, high-dose oral 5-ASA medications combined with 5-ASA or corticosteroid suppositories plus corticosteroid or 5-ASA enema or foam preparations can be effective. For the patient with refractory moderate-to-severe UC, oral corticosteroids plus high-dose oral 5-ASA medications combined with 5-ASA or corticosteroid suppositories plus corticosteroid or 5-ASA enema or foam preparations is the initial approach, followed by 6-MP or azathioprine, and infliximab if necessary. For the patient with refractory acute severe UC, after initially using IV steroids and IV antibiotics for 5–7 days, possible treatment choices include either IV cyclosporine or IV infliximab or colectomy. For refractory UC patients who have not responded or only partially responded to medications, colectomy with IPAA is important to consider because the disease is removed and ineffective medications with their potential side effects can be discontinued.