Disease Management Based on Clinical Severity

Introduction

The primary goal of treatment is to induce and maintain remission, with the long-term goals of improving patient quality of life and preventing disability, colectomy and colorectal cancer. Treatment selection for patients with ulcerative colitis (UC) is guided by disease severity (mild, moderate, or severe), extent of disease (proctitis, left-sided, or extensive colitis) and assessment of disease prognosis. In the past treatment of UC has tended to follow a step-up approach; however, recent practice guidelines for the treatment of UC highlight the importance of selecting treatments based not only on inflammatory activity but also on disease prognosis. For example, a patient who satisfies criteria for mildly active disease but currently has steroid dependency and a previous UC-related hospitalization should be evaluated for treatments typically recommended for patients with moderately to severely active UC. As their disease prognosis follows a more virulent course of disease and thus mandates appropriately aggressive medical therapy. Use of biologic therapy or small molecules such as tofacitinib or upadacitinib in this patient would therefore be merited. Although the current FDA-approved indications for JAK inhibitors are after a patient has used anti-TNF therapy.

The adoption of the treat-to-target approach, which consists of routine monitoring and therapy adjustment to achieve remission targets (Figure 7-1) has revolutionized UC treatment. Remission targets include resolution of clinical symptoms (e.g., rectal bleeding and diarrhea) and endoscopic healing, defined as an endoscopic Mayo score of 0 or 1. Steroid-free endoscopic remission is the ideal outcome since endoscopic healing improves long-term clinical remission, decreases the risk of future disease flare and colectomy, reduces corticosteroid use and may also reduce the risk for colorectal cancer. Although histologic remission – microscopic normalization of the colonic mucosa – is predictive of steroid-free remission, clinical relapse, hospitalization and steroid use rates, it has not yet been validated as a treatment endpoint and is therefore not currently recommended as a treatment target. Importantly, a successful application of the treat-to-target approach requires collaboration between the patient and physician to set and achieve the treatment targets.

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Patient Assessment and Compliance

Patient symptoms and physician assessments may not correspond with underlying endoscopic activity, so it is important to directly assess inflammation by colonoscopy or flexible sigmoidoscopy depending upon the patient’s condition and disease severity. Colonoscopy should be performed 3 to 6 months following the initiation of new treatments to assess response. Noninvasive markers can be used to help monitor disease activity once the patient has achieved remission. Fecal calprotectin, with a cutoff of 150 mg/kg, has the highest sensitivity and specificity for endoscopic remission (0.79 and 0.75, respectively).

In the event of a flare, infection should be excluded (especially C difficile and enteric pathogens), and objective assessments performed (e.g., sigmoidoscopy, complete blood complete (CBC), C-reactive protein (CRP), Comprehensive metabolic panel (CMP) (including serum albumin), fecal calprotectin, or stool lactoferrin). If objective evidence of inflammation is confirmed, medications should be optimized by reviewing dosage, administration and adherence. Patient compliance is critical to the successful management of UC, with a significant number of flare-ups being caused by lack of adherence, especially when the treatment regimen is complex or uncomfortable, as can be the case with topically administered medications. Including patients in the treatment decision-making process and emphasizing the importance of continuing treatments even during remission are simple ways to improve patient adherence.

Mild to Moderate Disease

The 5-aminosalicylates (5-ASAs) are the treatment of choice for mild to moderate UC. 5-ASAs can be administered as suppositories, enemas, or as oral formulations. Several 5-ASA agents are available, including mesalamine, sulfasalazine, olsalazine and balsalazide. There does not appear to be any difference in efficacy between the different formulations; however, sulfasalazine, the first 5-ASA agent, may be associated with more tolerability issues. Refer to Aminosalicylate Therapy for additional information on 5-ASA therapy.

Proctitis

In UC patients with proctitis, where inflammation is limited to the rectum, topical 5-ASA therapy (e.g., mesalamine suppositories) is the first-line choice. Suppositories directly target the site of inflammation and are more effective than oral 5-ASA in these patients. Topical steroids can be considered as second-line therapy or as an alternative in patients intolerant to or unresponsive to topical 5-ASA. Oral mesalamine has also been used to treat patients with active proctitis.

Left-Sided Colitis

In patients with left-sided colitis, combination oral/topical 5-ASA therapy can be used to induce remission since combination therapy demonstrates greater efficacy and leads to faster improvement in rectal bleeding compared to either route alone. Enemas can be used rather than suppositories to ensure it reaches up to the splenic flexure. Oral 5-ASA can be initiated at a daily dose of 2.0 g to 2.4 g and then increased up to 4.8 g daily, if required. A response is typically seen within 2 weeks, but symptomatic remission may take up to 8 weeks. 5-ASA agents are also effective at maintaining remission and patients who achieve remission should continue the same regimen. Factors associated with poor patient adherence include older age, greater dosing frequency and busy lifestyle. If adherence is an issue, once-daily dosing should be considered, since there is no significant difference in efficacy or safety between once daily and conventionally dosed 5-ASA.

If symptoms persist despite combination 5-ASA therapy, a step-up to corticosteroids may be required to induce remission. Rectal steroids can first be tried as second-line add-on therapy. Topical 5-ASA agents are superior to topical corticosteroids at inducing remission (OR 2.01), but clinical and endoscopic improvement may be higher when both are used. Foam formulations of rectal steroids (e.g., budesonide rectal foam) are more viscous and have a lower volume per application, which improve patient tolerability and retention.

Oral corticosteroids are often utilized to induce remission in patients who see no benefit from the previous lines of therapy or can be used as initial therapy when a patient has disease with moderate or severe activity. Oral corticosteroids with minimal systemic activity (e.g., budesonide tablets) can be considered as a first-line alternative to prednisone, given its lower risk for systemic adverse events and its demonstrated effectiveness at inducing remission. The recommended starting dose is 40 mg to 60 mg prednisone or equivalent (such as budesonide MMX 9 mg) daily.

A response should be observed within 4 to 8 weeks, after which steroids should be tapered. Corticosteroids are not suitable for maintenance of remission, given their lack of long-term efficacy and risk for adverse reactions. 5-ASA agents (oral with or without topical) can be considered as maintenance therapy if the patient demonstrates a partial initial response; thiopurines (least favored), sphingosine 1-phosphate (S1P) receptor modulators, Janus kinase (JAK) inhibitors, or biologics are other maintenance options. Patients who do not respond to or are unable to taper off oral corticosteroids should step up to treatment for moderate to severe UC, which often may require immune modulatory and/or biologic therapies.

Extensive Colitis

The medical therapeutic recommendations for patients with extensive mild to moderate colitis are similar to those with left-sided colitis; however, systemic corticosteroids should be considered earlier in those with extensive disease.

Moderate to Severe Disease

Patients who present with moderate to severe symptoms can initially be treated with oral corticosteroids (40 mg to 60 mg prednisone per day or budesonide MMX 9 mg per day) to induce remission. Patients who respond should be transitioned to optimized 5-ASA therapy (oral alone or in combination with topical), optimized thiopurine therapy, an S1P receptor modulator, a JAK inhibitor, or biological treatment. Those who achieve remission after 3 to 6 months should continue therapy with their current treatment and be reassessed every 6 to 12 months; those who do not achieve remission should be managed with thiopurines (least currently favored approach), tofacitinib, upadacitinib and/or biological drugs (infliximab, adalimumab, golimumab, ustekinumab, vedolizumab, or mirikizumab) or an S1P receptor modulator (ozanimod or etrasimod), with dose intensification or a switch to a different biologic or other agent in patients who were already treated with a biologic. The SUCCESS trial demonstrated that azathioprine in combination with infliximab is more effective than azathioprine or infliximab alone, in terms of endoscopic healing.

Tofacitinib, a Janus kinase (JAK) inhibitor, has gained Food and Drug Administration (FDA) approved for the treatment of adult patients with moderately to severely active UC who have had an inadequate response or intolerance to one or more tumor necrosis factor (TNF) blockers. Tofacitinib may be used for both induction therapy and maintenance treatment. However, the combination use of tofacitinib with biological therapies or with potent immunosuppressants (e.g., azathioprine and cyclosporine) is not recommended.

Similar to tofacitinib, upadacitinib is also a JAK inhibitor. This agent, selective for JAK1 inhibition, has been approved by the FDA for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response or intolerance to one or more TNF blockers.

Ozanimod and etrasimod are S1P receptor modulators that are FDA approved for moderately to severely active UC in adults. Refer to Immunomodulators for additional information on tofacitinib, upadacitinib, ozanimod, and etrasimod.

Patients who do not respond to the above treatments should consider the use of IV steroids.

The introduction of biologics and small molecules into the treatment landscape was a paradigm shift in the management of moderate to severe UC. Current biologic options include three FDA-approved tumor necrosis factor (TNF) blockers (infliximab, adalimumab and golimumab), one interleukin-12 and -23 antagonist (ustekinumab) one interleukin-23 antagonist (mirikizumab), and one integrin blocker (vedolizumab). The indications of these agents are as follows:

• Adalimumab: Treatment of moderately to severely active UC in adults and pediatric patients 5 years of age and older.
• Golimumab: Indicated in adult patients with moderately to severely active UC who have demonstrated corticosteroid dependence or who have had an inadequate response to or failed to tolerate oral aminosalicylates, oral corticosteroids, azathioprine, or 6-MP for:
• Inducing and maintaining clinical response
• Improving endoscopic appearance of the mucosa during induction
• Inducing clinical remission
• Achieving and sustaining clinical remission in induction responders.
• Infliximab (adult patients): Reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing and eliminating corticosteroid use in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy
• Infliximab (pediatric patients): Reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active disease who have had an inadequate response to conventional therapy
• Ustekinumab: Adult patients with moderately to severely active UC.
• Vedolizumab: Adult patients with moderately to severely active UC.
• Mirikizumab: Adult patients with moderately to severely active UC

Refer to Biologics for more information about these agents.

Acute Severe Disease

Hospital admission and treatment with intravenous (IV) steroids are usually required in patients with acute severe colitis and in those who continue to have moderate to severe symptoms despite optimized treatment. Approximately two thirds of patients will respond to IV steroids; in those who do not respond within 3 to 5 days, treatment options include vedolizumab, TNF blockers, cyclosporine, or surgery. Recent data has suggested that tofacitinib or upadacitinib may be effective in this patient population. Once remission is induced, medications can be modified to maintain remission. Delays in surgery may be associated with increased postoperative complications and mortality, so if rescue therapy fails, surgical evaluation for colectomy should be initiated.

Supportive therapy is an important component of patient care in the severe acute UC setting and should be addressed in all patients admitted to hospital. Additional treatments that can help reduce complications include adjusting electrolyte levels, prophylactic heparin, iron therapy, blood transfusions, nutritional support and exclusion of certain medications (e.g., N nonsteroidal anti-inflammatory drugs (NSAIDs,) opioids). Antibiotics do not impact outcomes unless there is evidence of bacterial infection and should not be used routinely unless merited.

Surgery

Total proctocolectomy with ileal-pouch anal anastomosis (IPAA) is the most common operation for UC. Indications for surgery include:

• Acute, severe UC refractory to IV steroids with failed response to rescue therapy
• Toxic megacolon
• Life-threatening complications, such as severe uncontrolled hemorrhage, perforation, or multiple organ dysfunction syndrome (MODS)
• Refractory disease, where optimal medical therapy fails to control disease symptoms or extraintestinal manifestations, when adverse reactions from medications negatively affect quality of life or compliance, or when prolonged medication use results in unacceptable risks
• Colorectal carcinoma or dysplastic lesions not amenable to endoscopic removal
• Stricture formation

See Surgery for additional information on surgery in UC patients.

Clinical Management Guidelines

Since the advent of evidence-based medicine in the 1980s, clinical practice guidelines have gradually emerged as indispensable reference documents, collating and summarizing available data and promoting proven interventions. In the US, two professional societies publish guidelines for the management of UC: the American College of Gastroenterology (ACG) and the American Gastroenterological Association (AGA). The latest ACG guidelines on UC management were published in 2019, while the AGA released one set of guidelines for the management of mild to moderate UC in 2019, followed in 2020 by another set for the management of moderate to severe UC.

2019 ACG Guidelines for UC in Adults

The 2019 update to the ACG guidelines addresses the diagnosis, treatment and overall management of adult patients with UC. Since 2010, when the ACG last published these guidelines, the management of UC has become more complex, due to the introduction of new therapies and treatment approaches. For example, one of many important points from the updated guidelines is recognizing that treatment decisions should take into account patient prognosis in addition to disease severity and extent. Other important additions include recommendations concerning usage of golimumab, vedolizumab and tofacitinib – treatments approved for UC since the last set of guidelines were released. Upadacitinib was not yet approved at the time of the guidelines but is considered standard of practice for patients with moderate to severe UC. In total, the updated guidelines include 49 recommendations based on GRADE criteria (Table 7-1) and 54 summary statements. The updated guidelines aim to help practitioners incorporate these new therapies and treatment approaches, with the optimal goal of management being sustained and durable periods of steroid-free remission, accompanied by psychosocial support, normal health-related quality of life, prevention of morbidity and prevention of cancer.

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2019 AGA Guidelines for Mild to Moderate UC in Adults

The AGA released its clinical guidelines for the management of adult outpatients with mild to moderate UC. Because they cover only mild and moderate UC and are not concerned with diagnosis, these guidelines are narrower in scope than the 2019 ACG guidelines, focusing largely on oral and topical 5-ASA drugs, rectal corticosteroids and oral budesonide. Less conventional therapeutic approaches, including probiotics, curcumin and fecal microbiota transfer, are also addressed. Similar to the ACG guidelines, the AGA guidelines are developed using the GRADE methodology. A total of 13 recommendations are presented in the 2019 AGA guidelines, including specific recommendations for patients with proctosigmoiditis or isolated proctitis (Table 7-2).

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2020 AGA Guidelines for Moderate to Severe UC in Adults

In 2020, the AGA released its clinical guidelines for the management of adult outpatients with moderate to severe UC and hospitalized patients with acute severe UC. Similar to the 2019 AGA guidelines, these guidelines are narrower in scope than the 2019 ACG guidelines, focusing primarily on immunomodulators, biologics and small molecules. In its review of evidence, the 2020 AGA guidelines also included a network meta-analysis – a single analysis combining direct and indirect evidence across a network of three or more trials– comparing the efficacy and safety of infliximab, adalimumab, golimumab, vedolizumab, tofacitinib and ustekinumab. At the time of these guidelines, Upadacitinib, mirikizumab, and the S1P receptor modulators were not yet approved for the treatment of moderate to severe UC. While the 2020 AGA recommendations (Table 7-3) thus remain broadly concordant with those from the ACG guidelines, several discrepancies exist.

For example, based on the VARSITY trial and the above-mentioned network meta-analysis, the 2020 AGA guidelines recommend infliximab or vedolizumab over adalimumab for biologic-naïve patients, which the ACG guidelines do not. Furthermore, the 2020 AGA guidelines recommend tofacitinib or ustekinumab for TNF blocker-experienced patients, in contrast to the ACG guidelines which were published before the approval of ustekinumab in 2019 and which therefore recommend tofacitinib or vedolizumab for this patient group.

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