Manifestations

Both UC and Crohn’s disease are marked by a variety of extraintestinal manifestations, the severity of which generally parallels the severity of colonic inflammation. Population-based studies report the overall incidence of extraintestinal disease at up to 40%, with 10% of patients having extraintestinal manifestations at the time of IBD diagnosis (▶ Table 25.2). ^{94 , 95 , 96} These numbers likely underestimate the true incidence, as patients may or may not link their extraintestinal symptoms with their disease, and as such may not report them.

Plain Film X-Rays

X-rays still play a role when considering the patient who presents acutely with abdominal pain. Upright abdominal films will reveal the presence of free air or “toxic megacolon,” a term that has all but fallen out of favor due to the fact that patients can be “toxic” without having “megacolon.” Nevertheless, colonic dilatation ≥ 6 cm or cecal diameter greater than 9 cm in the setting of fever, tachycardia, and abdominal pain is a grave concern that mandates urgent surgical intervention. ^{141 , 142} More subtle findings on plain films include nodularity of the mucosa suggesting the presence of pseudopolyps, mucosal edema (“thumbprinting”), and an ahaustral, “lead-pipe” colon, which is suggestive of chronic disease.

Contrast Enema

Double-contrast barium enema is not required for the diagnosis of CD; however, it is useful to help exclude CD when there is any question of small bowel involvement. The specific benefit of rectal contrast over small bowel follow-through is that it more clearly delineates the terminal ileum as there is less interference from proximal intestinal loops.

Enteroclysis

Enteroclysis is preferred over small bowel follow-through for detailed assessment of the small intestine. In fact, this technique is more sensitive than computed tomography (CT) for the detection of small bowel fistulas and early mucosal abnormalities. ¹⁴³ Nevertheless, this study is not widely utilized as it is labor intensive and requires nasointestinal tube placement, which is never desirable for the patient. The study entails placement of a postpyloric nasal tube, followed by repetitive small boluses of barium contrast, which will coat the bowel wall. Each bolus is followed by insufflation of air to distend the small bowel, and a spot film is taken. The additional detail offered by this technique is not generally worth the added time and labor. As such, if a contrast study is obtained to evaluate the small bowel, it is generally either standard small bowel follow-through or CT.

Computed Tomography

CT of the abdomen and pelvis is the most commonly obtained radiographic study in the acute evaluation of IBD. As with plain films, the role of CT in UC is negligible when the diagnosis of UC is secure. The benefit of CT is twofold: first, it has the ability to evaluate all intra-abdominal organs simultaneously and, second, it can evaluate the thickness of the entire intestinal wall. It must be emphasized here that a CT scan to evaluate the bowel wall specifically is severely limited if intraluminal contrast is not used. We therefore recommend a full oral contrast load with consideration of rectal contrast if a CT scan is to be performed for any diagnostic study in IBD. In UC specifically, signs that may be identified on CT include increased perirectal and presacral fat, heterogeneous colonic thickening, target or “double-halo” sign of the colon, and strictures. ¹⁴⁴

Magnetic Resonance

The role of magnetic resonance imaging (MRI) in IBD is still evolving. While less efficient and more costly than CT for an abdominal survey, ¹⁴³ its ability to objectively quantify severity of inflammation in the bowel and mesentery may hold promise for monitoring response to medical therapy. ^{145 , 146} It may also have a unique role in characterizing perianal fistulas in CD, although this technology would have limited use in UC unless the diagnosis is in question. In addition, the lack of radiation exposure is appealing.

Ultrasound

Ultrasonography may be used as an adjunctive measure to assess response to therapy in IBD patients. A transabdominal wall ultrasound (TABS) can assess for strictures or other bowel wall thickening. Some functional data can be obtained as well, as peristalsis can be observed. ¹⁴⁷ The technique is obviously operator dependent, and the data obtained are nonspecific, which may account for the lack of enthusiasm for TABS in the United States.

Nuclear Medicine

Nuclear imaging techniques have shown some promise in distinguishing CD from UC, and may be utilized to assess response to therapy as well. These studies rely on injection of the patient’s own radionuclide-labeled white blood cells, and have been shown to accurately delineate the anatomic extent of inflammation. Newer techniques use Technetium-99 m haxamethyl-propylamine-oxime (HMPAO), which has improved sensitivity over older, Indium-111 labeling. While the specificity is inadequate to differentiate infectious versus idiopathic or autoimmune inflammation, studies have shown 93 to 98% accuracy in differentiating CD from UC. ^{89 , 148 , 149} These findings are based on the differential anatomic patterns of inflammation between CD and UC, so it may be that nuclear imaging provides little if any information that is not readily obtained by more traditional techniques. Given its high sensitivity for identifying inflammation, nuclear medicine may have a future role in assessing response to therapy. Whether this methodology offers any benefit beyond standard MRI has yet to be determined.

Proctitis

Mild to moderate UC confined to the rectum is generally treated by topical therapy alone, although oral adjuncts may be used as well. Mesalamine (5-ASA) and steroids are the mainstays of therapy; both indications are available in a variety of formulations. Suppositories are the preferred method of delivery for isolated proctitis as they are easier to administer, leak less, and have been shown to target the site of inflammation more effectively than liquid or foam enemas. ^{154 , 155} Randomized controlled trials suggest that topical mesalamine is more effective than monotherapy with topical steroids, oral mesalamine, or placebo at inducing remission, with 63 to 94% of patients experiencing a clinical response within 4 to 6 weeks. ^{102 , 156 , 157 , 158 , 159 , 160} The dosage administered should be 1 to 2 g daily, although there is no increased dose response above 1 g. Divided daily doses are no more effective than once daily. ^{161 , 162}

Topical steroids are four to five times more likely to induce remission than placebo, ¹⁶³ although they are considered second-line therapy due to randomized controlled trials showing inferiority to topical mesalamine. ^{156 , 157 , 158 , 159 , 160} Nevertheless, topical steroids continue to play a role in those who do not tolerate mesalamine or in patients who are refractory to topical mesalamine monotherapy. Formulations and dosing are variable in the studies, which may account for the wide-ranging response rate of 35 to 70% at 4 weeks. ^{156 , 157 , 158}

If patients are not responsive to topical monotherapy, combination therapy with topical mesalamine and budesonide may be more efficacious than either therapy alone. A randomized controlled trial comparing topical mesalamine (2 g/d) plus topical budesonide (3 g/d) to either therapy alone noted clinical, endoscopic, and histologic improvement at 4 weeks in 100, 76, and 71% for combination therapy, mesalamine, and budesonide, respectively. Endoscopic remission followed a similar trend favoring combination therapy, with 37, 30, and 10% of patients showing complete endoscopic healing at 4 weeks. ¹⁵⁶

While not as effective as topical mesalamine, oral mesalamine may be utilized as monotherapy or in combination with other agents for distal UC. When used as monotherapy, a 4-g daily dose of pH-dependent release oral mesalamine is more effective than placebo or lower doses. ^{154 , 164 , 165 , 166} The combination of oral (2.4 g/d) and topical mesalamine, however, was found to be more efficacious than either application alone in patients with disease progression halting within 50 cm of the anal verge. ^{167 , 168}

Ultimately, patients with mild to moderate ulcerative proctitis should be started on mesalamine suppositories. Combination therapies with topical steroid and/or oral mesalamine should be considered in refractory patients. If inflammation is ongoing, systemic therapy with oral steroids is indicated in order to induce remission. It is this final group of patients that may go on to require immune modulation, biologic therapy, or surgery if the rectal inflammation cannot be controlled. ¹⁰²

Left-Sided Colitis

The treatment algorithm for mild to moderate left-sided UC is similar to that for ulcerative proctitis, with several minor distinctions. First-line therapy consists of combination therapy with oral (2–4 g/d) and topical mesalamine, which was found to have improved disease activity indices (–5.2 for combination therapy; −4.4 for topical mesalamine; −3.9 for oral mesalamine) and clinical improvement at 8 weeks (86% for combination therapy vs. 68% for monotherapy) for left-sided disease. ^{102 , 168 , 169} Remission rates at 8 weeks were similarly improved by combination therapy, with 64% remission in those on combination therapy versus 43% of those on oral mesalamine only. ¹⁶⁹ The argument for this combination is strengthened when data from the treatment of more extensive UC are extrapolated to left-sided UC. ¹⁷⁰

The bulk of the literature suggests the superiority of topical 5-ASA over topical steroids for left-sided UC, although the data are not as strong as they are for isolated proctitis. ^{163 , 171 , 172} Topical steroids are therefore a reasonable second line, especially in the case of 5-ASA hypersensitivity (bleeding and urgency 3–5 days after starting therapy; resolves in 72 hours with discontinuation of 5-ASA). Additionally, combining steroid and mesalamine topical therapy with oral mesalamine in cases refractory to oral and topical mesalamine alone may result in clinical improvement. While no comparative studies of this triple therapy exist, there is evidence to suggest that dual topical therapy results in improved remission rates when compared to either therapy alone. ¹⁵⁶ Regardless of whether mesalamine or steroids are being used, topical agents should be delivered via enema (foam or liquid) as opposed to suppository form. ¹⁰² Neither foam nor liquid enemas have shown superiority over the other. ¹⁷³ Low- and high-volume doses also show equivalent efficacy, although the low-volume dose is better tolerated. ¹⁷⁴

Although oral mesalamine alone is better tolerated than is oral sulfasalazine, it is no more effective. ¹⁷⁵ As described earlier, a single daily 2- to 4-g dose of pH-dependent release oral mesalamine is more effective than placebo when used as monotherapy for left-sided colitis. ^{164 , 166} While the literature is somewhat mixed, most agree that any dose-dependent effect is negligible at doses over 2 g/d. ^{154 , 165 , 166} Combined analysis of the studies limited to pH-dependent release oral mesalamine has shown 8-week remission rates of approximately 40%, which marks a 100% increase in efficacy over earlier formulations. ¹⁶⁶ Once daily dosing with 3-g oral mesalamine has been associated with improved remission rates when compared to 3-g divided daily dosing (86 vs. 73%). ¹⁷⁶ Once-daily oral mesalamine dosing has not been comparatively evaluated as part of combined modality therapy.

While most patients with left-sided UC will experience symptomatic improvement within 2 weeks, it may take up to 16 weeks for mesalamine responders to achieve remission. ^{177 , 178 , 179 , 180 , 181 , 182} Within this time frame, the patient will have ongoing symptoms to some degree, and may not respond at all. As such, a discussion regarding the timing for escalation of therapy often takes place prior to declaration of failure of first-line treatments. Oral steroids are the next line of therapy, and induce remission in the majority of patients. ^{102 , 183 , 184} Unfortunately they are not without complications, and an extensive discussion should be undertaken in which the patient is thoroughly counseled regarding the desired time-to-response versus steroid-induced side effects. Regardless, oral corticosteroids are likely needed in cases of clinical deterioration, continued rectal bleeding beyond 14 days, and inability to achieve remission after 40 days of appropriate mesalamine and/or topical steroid therapy. ¹⁰²

Extensive Ulcerative Colitis

Extensive UC, also referred to as pancolitis, refers to inflammation extending proximal to the splenic flexure. This disease pattern requires oral therapy as the proximal extent of the inflammation cannot effectively be reached by topical agents. It should be noted that the data driving the treatment of both left-sided colitis and extensive colitis are largely drawn from the same studies, which include a heterogeneous patient population. As such, much of the treatment of mild-to-moderate extensive colitis has already been reviewed.

First-line therapy is a single daily dose of 2- to 4-g oral mesalamine in addition to a 1-g mesalamine enema. This combined therapy effectively targets both the proximal and distal extents of the disease, and results in an 8-week remission rate of 63%. ^{102 , 168 , 169 , 175 , 180 , 185} Topical steroids are therefore a reasonable alternative to topical mesalamine, especially in the case of 5-ASA hypersensitivity.

Patients who do not respond to first-line therapy, or who have a relapse of disease while on maintenance therapy, require oral steroids. Truelove and Witts initially reported the benefit of cortisone for the treatment of UC in 1954. ¹¹² A follow-up study used a regimen of a 20-mg divided daily dose of prednisolone in addition to topical hydrocortisone. The remission rate in this group of patients was 76%, which represented a significant improvement over the 52% seen with sulfasalazine alone. ¹⁸⁴ The oral steroid regimen for induction of remission is 40 to 60 mg of prednisone or prednisolone daily. These dosages are based largely on a 1962 study by Baron et al, which showed a 50% revision rate for patients with pancolitis regardless of whether they received 60- or 40-mg daily prednisone doses. ¹⁸⁶ Most prefer a 40-mg dose, as the side-effect profile worsens with little or no additional therapeutic benefit above this dose. ¹⁸⁶

Given the considerable side-effect profile, steroids are not intended as maintenance therapy. As such, a reasonable taper must be implemented such that steroid dependence is recognized early, but not at the cost of early relapse. Steroid courses less than 3 weeks in duration have been associated with early relapses. As such, an 8-week course starting with 40-mg prednisolone per day for 1 week and reducing by 5 mg/d every week is recommended by the most recent European consensus. ¹⁰²

Budesonide is an alternative oral steroid with limited systemic effects due to first pass metabolism. While attractive in concept due to the lack of side effects, numerous studies have failed to identify any benefit of budesonide over mesalamine. A newer formulation with a colonic release mechanism (budesonide multimatrix [MMX]) has improved remission rates over placebo (15 vs. 7%), and is most effective in left-sided patients who are mesalamine responsive. Nevertheless, a recent Cochrane review found no definitive data to suggest a benefit of budesonide MMX over standard budesonide, much less over mesalamine. ¹⁸⁷

Severe Ulcerative Colitis

Severe UC is defined as at least six bloody stools daily, abdominal tenderness with signs of systemic toxicity including fever (> 37.5 °C), tachycardia (> 90 bpm), anemia (hgb < 75% normal), and increased ESR (> 30 mm/h). ¹⁸⁸ Historically, these cases carried a high mortality burden, with up to 75% of patients dying within the first year of a severe flare. The era of corticosteroid salvage was ushered in by the landmark study of Truelove and Witts in 1954; outcomes have improved dramatically since that time. Nevertheless, a significant number of severely inflamed patients progress to fulminant, life-threatening colitis.

While the clinical urgency of a toxic patient with presumed fulminant UC must be acknowledged, uninformed decision making can be potentially catastrophic. In the moment, it is of dire importance that intestinal infection be ruled out or at least treated empirically before starting immune suppression. Patients with inflammatory bowel disease (IBD) are at increased risk for C. difficile and CMV infections for a variety of reasons, and failure to address these as potential confounders, if not primary etiologies, could mean the difference between life and death. ^{92 , 93 , 189 , 190 , 191 , 192 , 193 , 194} Clostridial infection may easily be determined by stool studies, which should be performed on admission for any UC flare. Biopsies are needed to effectively rule out CMV colitis. As such, an unprepared, limited flexible sigmoidoscopy with biopsies should be undertaken in truly refractory cases that do not require urgent surgical intervention. While the decision to perform endoscopy in the face of acute inflammation is never taken lightly, the information obtained could be of vital importance. Infected patients should be treated with appropriate antimicrobials, and consideration should be given to withholding immunosuppression (when able). ^{194 , 195} In addition to excluding or treating infection, a number of other measures should be undertaken to ensure the patient is medically “optimized” ¹⁰² :

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  Liberal fluid resuscitation and correction of electrolytes should be undertaken, as hypokalemia and hypomagnesemia can promote toxic colonic dilation. ⁹¹

  
  
• 
  

  DVT chemoprophylaxis should be administered, as patients with IBD are at increased risk for venous thromboembolism compared to controls. The risk further increases during an acute flare independent of other risk factors. ^{196 , 197}

  
  
• 
  

  Nutritional support should be undertaken, particularly in patients who suffer from malnutrition at baseline. Enteral feeding is preferable to parenteral, as bowel rest with intravenous (IV) nutrition has not shown any benefit and is associated with significantly more complications (35 vs. 9%). ^{198 , 199}

  
  
• 
  

  Narcotics, anticholinergics, antidiarrheals, and nonsteroidal anti-inflammatories should be limited as they may increase the risk of progression to toxic colonic dilatation. ^{91 , 200 , 201}

  
  
• 
  

  Topical mesalamine or corticosteroids may be given if tolerated; however, there are no comparative studies to suggest a benefit in this setting. ^{184 , 202}

  
  
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  Appropriate antibiotics should be given empirically if infection is suspected. There is no therapeutic advantage to antibiotics in the absence of infection. ^{203 , 204 , 205}

Patients admitted for severe UC should be given IV steroids; both methylprednisolone 60 mg/24 h and hydrocortisone 100 mg every 4 hours are effective. Higher dosages, continuous infusions, and prolonged courses beyond 7 to 10 days do not confer added benefit. ^{102 , 117 , 206 , 207} Approximately 67% of patients will respond to IV steroids, although 29% of patients will ultimately stall or deteriorate, necessitating a colectomy. ¹¹⁷

Cyclosporine may be an alternative to IV steroids in this setting, although it is less studied. A small, randomized controlled trial comparing cyclosporine 4 mg/kg/d to methylprednisolone 40 mg/d in 30 patients with severe acute UC resulted in equivalent (if not improved) efficacy in obtaining a clinical response in the cyclosporine group (67% for cyclosporine vs. 53% for methylprednisolone). It should be emphasized here that this is not the standard of care, and should only be considered in patients in whom steroids should be avoided (history of steroid psychosis, osteoporosis, poorly controlled diabetes).

Clinical response should be continuously assessed, and decision making should be undertaken in a multidisciplinary setting with a surgeon and a gastroenterologist, with input from the patient. Steroid-refractory patients must be identified early and projected to either rescue therapy or surgery, as delayed colectomy is associated with high morbidity. ^{208 , 209}

Intravenous Steroid Refractory Ulcerative Colitis

If declaration of success or failure has not already been made, the third day of treatment marks a critical junction in decision making. Continued administration of ineffective high-dose IV steroids in this setting risks progression of disease, delayed colectomy, and increased morbidity. ^{208 , 209} Any discussion regarding salvage attempts using cyclosporine, infliximab, or tacrolimus should be framed such that expectations are appropriately managed. Ideally, the patient has already met with the surgical team and enterostomal therapist, as it is important to have already established a foundation of trust should the patient deteriorate. Certainly if significant clinical improvement is not seen by day 3, a surgical consultation must be sought even as salvage therapy is undertaken. Colectomy is indicated if improvement is not seen after 4 to 7 days of salvage therapy. ¹⁰²

A number of clinical, biochemical, and radiologic/endoscopic markers have been used to predict the likelihood of steroid failure and progression to urgent colectomy. Fever, tachycardia, and elevation of inflammatory markers such as ESR and CRP are all associated with increased colectomy rates despite aggressive steroids. ESR greater than 75 mm/h and fever greater than 38 °C at the time of admission confers a 4.6- and 8.8-fold increased risk of colectomy on that admission. ²¹⁰ Days 2 to 5 are critical for repeat assessment of risk for steroid nonresponse. Greater than 12 bowel movements in 24 hours on day 2 of steroids is associated with colectomy in 55% of patients. ²¹¹ Greater than eight bowel movements, three to eight bowel movements in addition to a CRP > 45 mg/L, or the product of number of stools multiplied by 0.14 CRP equaling ≥ 8 on day 3 of steroids is suggestive of a 75 to 85% chance of acute progression to colectomy. ^{212 , 213} If the result is less than a 40% reduction in the bowel movements on day 5, the conclusion is that the patient did not respond to steroids. ²¹⁰ Colonic dilatation greater than 5.5 cm, mucosal islands, and/or small bowel ileus noted on radiography each predict a 73 to 75% chance of same-admission colectomy. ^{211 , 214} The presence of severe ulceration noted on endoscopy predicts progression to colectomy in 93% of patients. ²¹⁵ These dire numbers should be used to set the stage for the patient’s decision regarding salvage therapy versus procession directly to surgery.

Refractory Proctitis and Distal Colitis

A category of disease that warrants separate discussion is refractory proctitis and distal colitis. By definition, these patients have failed topical mesalamine and/or topical steroids as well as oral mesalamine and steroids. These patients suffer from the most distressing symptoms (urgency, tenesmus, incontinence), but may not progress to fulminant disease or even develop the dangerous signs of fevers and abdominal pain and distention. ¹⁰² As such, the decision to proceed with surgery is never forced and the patient is left in limbo, suffering from disease, medication side effects, and the tormenting decision regarding whether or not to proceed with “elective” surgery.

In these situations, it is important to exclude medication noncompliance, alternative diagnoses, and proximal constipation/dysmotility (which may decrease the concentration of medication delivered to the site of inflammation). If these alternative explanations are not identified, additional treatments may be considered. Remaining therapeutic options include oral and/or rectal calcineurin inhibitors and biologics. ^{216 , 217 , 218 , 219} The overall efficacy of these salvage therapies specifically for isolated distal disease has not been established; however, they are not likely any more efficacious than in more extensive colitis. A considerable number of these patients will therefore fail salvage therapy.

Alternative therapies are not validated; however, small trials have suggested some conferred benefit with fatty acid enemas, lidocaine enemas, acetarsol suppositories, epidermal growth factor (EGF) enemas, and transdermal nicotine patches. ^{220 , 221 , 222 , 223 , 224 , 225} Cohort studies also suggest that up to 90% of patients with ulcerative proctitis may have significant improvement in disease activity after appendectomy, suggesting a possible etiologic link if not a potential therapeutic intervention. ²²⁶

Salvage Therapy

Cyclosporine has shown efficacy as salvage monotherapy in steroid-refractory severe acute UC, with 76 to 85% of patients avoiding colectomy on that admission. Median time to improvement in pooled series is approximately 4 days, which allows for timely colectomy in those who do not respond. ^{102 , 227 , 228 , 229 , 230 , 231} Response rates are no different between 2 and 4 mg/kg/d, ^{102 , 227 , 228 , 229 , 230 , 231} and considering the narrow therapeutic index, significant side effect profile, and 3 to 4% risk of death with cyclosporine, the 2 mg/kg/d dosing has become the most commonly used regimen. ¹⁰² Responders should be transitioned to oral cyclosporine at a dose of 5 mg/kg/d divided twice daily. This regimen is generally continued for 3 to 4 months, and is given in conjunction with a standard maintenance therapy for steroid-refractory patients such as azathioprine (see section on maintenance therapy). ²³²

While relatively effective for avoidance of colectomy in the short term, the long-term impact of cyclosporine on colon salvage is questionable. Follow-up data suggest that between 58 and 88% of patients who required cyclosporine rescue underwent a colectomy within 7 years. ^{230 , 233} Patients who were able to maintain some degree of remission on a thiopurine, or who were thiopurine naïve at baseline, were much more likely to avoid colectomy over the long term after cyclosporine salvage. ^{230 , 234 , 235}

Tacrolimus has a similar mechanism of action as cyclosporine (calcineurin inhibitor) but binds a different receptor. Both have multiple downstream immunologic effects, with inhibition of IL-2 likely the most significant. Several trials have shown a benefit in terms of induction of remission, symptomatic improvement, and decreased steroid requirements. Ogata et al performed a randomized controlled trial to identify dose efficacy of oral tacrolimus for salvage therapy. Results of treatment with high trough concentrations (10–15 ng/mL), low trough concentrations (5–10 ng/mL), and placebo were compared at 2 weeks. Sixty-eight percent of patients in the high-trough group experienced symptomatic improvement, with 20% entering clinical remission and 79% showing evidence of mucosal healing. These marked a substantial improvement over placebo (10% improvement) and low trough (18% improvement), although the study was underpowered to show a significant difference between the high- and low-trough strategies. An open label extension of that study showed the majority of patients who were improved at week 2 remained improved over an extended period, with 55% of patients demonstrating an improvement in disease activity index at week 10. Prednisolone doses were weaned from 19.7 mg/d at study entry to 7.8 mg/d at week 10. ²³⁶ A more recent prospective observational study showed clinical remission at 4 weeks in 76% of steroid refractory patients treated with tacrolimus. ²³⁷ The results of this latter study, while encouraging, are likely confounded by the inclusion of patients with moderate disease. Other case series have shown mixed outcomes, with clinical improvement rates ranging from 47 to 90%. ^{238 , 239 , 240} Long-term colectomy-free survival has been reported as 57% at 44 months; however, this included patients with both moderate and severe diseases. ²³⁸

Infliximab has demonstrated efficacy for rescue therapy in patients with steroid-refractory severe acute UC. Case series report 20 to 75% colectomy rates in steroid refractory severe colitis treated with infliximab. ^{241 , 242 , 243 , 244 , 245} Järnerot et al ¹³⁶ performed a randomized controlled trial comparing colectomy rates in patients with steroid-refractory severe and moderately severe UC who received a 5 mg/kg dose of infliximab versus those who received placebo. Colectomy rates at 3 months and 3 years were significantly lower in those who received infliximab (29 vs. 67%; p = 0.017 and 50% vs. 76%; p = 0.02, respectively). ²⁴⁶ The Active Ulcerative Colitis Trial 1 (ACT-1) and ACT-2 randomized controlled trials evaluated infliximab induction and maintenance therapy in ambulatory patients with moderate to severe active UC. Clinical remission occurred significantly more in the infliximab group relative to placebo (≥ 30 vs. 15%). The studies also identified significantly decreased rates of colectomy at 54 weeks in the infliximab group (10 vs. 17%; p = 0.02). ¹³⁷ It should be noted that the ACT studies looked at ambulatory patients specifically and were not evaluating true salvage therapy per se, which likely explains the lower overall colectomy rate in its population when compared to inpatient studies.

The decision to proceed with a calcineurin inhibitor versus infliximab in acute, steroid refractory colitis is not straightforward. Pooling of available nonrandomized data suggests superiority of infliximab over cyclosporine, with therapeutic response rates of 75 and 55%, respectively. Similarly, nonrandomized 3- and 12-month colectomy rates were lower in patients treated with infliximab (24 vs. 43% and 21 vs. 37%, respectively), although the difference at 3 months was not statistically significant. ²⁴⁷ However, recent randomized controlled trials have refuted the superiority of infliximab, and meta-analysis of the three studies suggests similar clinical response rates of 43.8% for infliximab and 41.7% for cyclosporine. The 3- and 12-month colectomy rates of 26.5 versus 26.4 and 34 versus 43%, respectively, were also similar. ^{247 , 248 , 249 , 250}

In the absence of definitive data showing superiority of one rescue therapy over another, the treatment decided upon should be patient-centric. With the widespread use of infliximab for maintenance therapy, the decision regarding salvage therapy is often made by default, as the inflammation is already refractory to infliximab. Cyclosporine is therefore preferable in these patients if an attempt at rescue therapy is desired. Another theoretical benefit of cyclosporine over infliximab is the shorter half-life (8 hours vs. 8–10 days, respectively), which may be a factor for those who believe that infliximab imparts an increased risk for postoperative infections. Infliximab, however, has the desirable feature of being able to be continued for maintenance therapy in responders. In patients who are naïve to both therapies and do not have a contraindication to either, there is some evidence to suggest the safety of sequential therapy if one fails. ²⁵¹ Nevertheless, current recommendations discourage this strategy in favor of early colectomy based on prior studies suggesting an adverse risk-to-benefit ratio. ^{102 , 252 , 253}

An area of ongoing research is the ability to predict response to infliximab. Jürgens et al ²⁵⁴ correlated inflammatory markers and IBD-associated genetic variations to infliximab response in patients with moderate to severe UC. High CRP levels, ANCA seronegativity, and homozygosity for IBD-associated variants of the IL23R gene were associated with improved clinical responses. In the future, such predictive models will hopefully be able to guide our decision making as it pertains to escalation of medical care, timing of surgery, and even the recommendation for pouch reconstruction versus stoma.

Management in the Ambulatory Setting

Patients who respond to initial management may stratify into a number of disease courses. These categories include relapsing disease, steroid dependence, refractory, and long-term remission. The ultimate goal of medical management is long-term, steroid-free remission. Achievement of that goal depends on a symbiosis between disease phenotype, patient compliance, and selection of the appropriate therapeutic agent.

Biologic Therapy

The drive behind ongoing research on biologic therapies in autoimmunity is based on the inadequacy of disease control with the use of conventional therapies. Currently, there are six biologic agents used in UC: infliximab, adalimumab, golimumab, vedolizumab, etrolizumab, and tofacitinib, all of which are superior to placebo for both induction and maintenance of remission. ²⁵⁸ While no direct comparative studies have been performed, a recent meta-analysis including available randomized controlled data indirectly compared infliximab to adalimumab, and found that infliximab is more likely to induce a clinical response (OR, 2.36; 95% CI, 1.22–4.63) and mucosal healing (OR, 2.02; 95% CI, 1.13–3.59).

Related posts:

18 Rectal Prolapse 27 Diverticular Disease of the Colon 21 Colon Carcinoma: Epidemiology, Etiology, Pathology, and Diagnosis 29 Large Bowel Obstruction 33 Constipation 32 Intestinal Stomas

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