Crohn Disease Treatment & Management

Surgery plays an integral role in controlling symptoms and treating complications of Crohn disease. Because of the high rate of disease recurrence after segmental bowel resection, the guiding principle of surgery is preservation of intestinal length and function.^[2] Recommended indications for surgery include the following:^[2]

• Persistent symptoms despite high-dose corticosteroids
• Treatment-related complications, including intra-abdominal abscesses
• Medically intractable fistulae
• Fibrotic strictures with obstructive symptoms
• Toxic megacolon
• Intractable hemorrhage
• Perforation
• Cancer

Most patients with Crohn disease require surgical intervention during their lifetime. Unlike ulcerative colitis, Crohn disease has no surgical cure. Within 20 years of the onset of symptoms, 75-80% of patients with Crohn disease require surgery, and many require multiple procedures. Twenty to 30% of patients experience a recurrence of disease within the first postoperative year. Hence, every attempt at conserving the small bowel should be made in the surgical approach to Crohn disease. Despite this approach, repeated intestinal resection for Crohn disease is a major cause of short bowel syndrome.^{[37, 38, 39, 40, 41]}

The most common complication of Crohn disease is small bowel obstruction, occurring in 30%-50% of patients. Typically, the obstruction is due to intestinal strictures from repeated bouts of inflammation and subsequent fibrosis. In the case of a complete obstruction or a partial obstruction refractory to nonsurgical management, surgical intervention is required. Surgical options for intestinal strictures include resection of the strictured bowel or stricturoplasty. In cases of long strictures (>12 cm) or multiple strictures in close proximity, surgical resection with primary anastomosis is often required.

Stricturoplasty for multiple shorter strictures has the benefit of bowel conservation. A Foley catheter (inflated to 25 mm) can be passed through the lumen to detect additional distal strictures. The strictured bowel is incised longitudinally to a point 1-2 cm beyond the narrowing and then closed transversely without resection. For long or multiple confluent strictures, a stricturoplasty that resembles a Finney side-to-side pyloroplasty can be used to conserve bowel length. Hydrostatic balloon dilatation of ileocolic strictures has been performed, but its effects may not be long lasting. Bypass procedures are usually reserved for duodenal obstructions.^{[42, 43]}

Other complications of Crohn disease that may require operative intervention include free perforation, abscesses, fistulae, toxic megacolon, and massive hemorrhage. More than 10% of patients with Crohn disease have an intra-abdominal or pelvic abscess during their lifetime. Unfortunately, many patients at risk for perforation or abscess will be on corticosteroids, which are known to suppress peritoneal signs and fever and mask the presenting signs of infection. A CT scan helps confirm the diagnosis. Abscesses must be drained, either surgically or percutaneously, and treated with broad-spectrum antibiotics. Although surgical drainage is more often successful, an attempt at percutaneous drainage may spare some patients an operation.^[44]

Enteroenteric, enterocutaneous, enterovesical, and rectovaginal fistulae are often treated initially using the principles of fistula healing and medical therapy. If medical therapy is unsuccessful, resection of the involved bowel is required in symptomatic patients.

Toxic megacolon and massive hemorrhage are much less common complications of Crohn disease. However, they may require urgent bowel resection. Total abdominal colectomy with a Hartmann pouch has been advocated for fulminant toxic megacolon. This allows future restoration of bowel continuity with a sphincter-preserving ileorectal anastomosis. However, a permanent ileostomy may ultimately be required to treat recurrent rectal disease.^[45]

A study by Kiran et al using a strictly defined cohort of patients was not able to identify segmental bowel resection as an independent risk factor for recurrence or stoma formation; no reduction in quality of life scores to suggest an adverse effect of recurrence was observed.^[46] Nevertheless, segmental colectomy provides good function, and the data support practice of a conservative approach with anastomosis in anatomically-linked Crohn disease.

Perianal Crohn disease presents a particularly difficult management challenge. Fissures, fistulae, and abscess may be multiple and recurrent, and repeat operations may lead to sphincter damage and incontinence. True abscess requires drainage. When a fistula tract can be identified, a silastic seton can be used to prevent premature skin closure and recurrent abscesses. These indwelling setons should be left in place for at least 12 months to allow complete epithelialization of the tract. This approach leads to a chronically draining fistula tract. In patients in whom severe perianal disease has destroyed the sphincter, proctectomy with permanent ileostomy may be necessary.^{[47, 48, 49, 50]}

Laparoscopic versus open resection

The laparoscopic approach to Crohn disease has been shown to be feasible as well as safe.^{[51, 52]} Complications of Crohn disease such as abscesses, phlegmons, and recurrent disease have been safely treated laparoscopically and are not contraindications to laparoscopy in these patients.

Although open resection is still used by many surgeons and should be considered the criterion standard, the laparoscopic approach is being used with increasing frequency. In children, laparoscopic intestinal resections have been used for proctectomy and pull-through procedures in Hirschsprung disease for more than a decade.^[53] Segmental intestinal resections in Crohn disease can easily be accomplished as well. No difference in recurrence rates has been found in adults undergoing laparoscopic versus open ileocolic resection, and the laparoscopic approach has been found to significantly reduce the duration of postoperative ileus.^{[54, 55]} Adult patients who undergo laparoscopic ileocecectomy tend to experience a better quality of life than those who undergo the open approach. In addition, patients undergoing the laparoscopic approach report that they are more satisfied with the physical appearance of their surgical scar.^[56]

A study comparing laparoscopic ileocolic resection versus infliximab in the treatment of distal ileitis is currently enrolling participants in the Netherlands. The primary outcomes of the study are quality of life and costs, with recurrence being a secondary outcome.^[57] To date, no data have been published on recurrence rates in children undergoing open versus laparoscopic resection.

Preoperative details

Preoperatively, a recent evaluation of the extent of intestinal disease with appropriate radiologic and endoscopic studies is essential. Steroids are tapered as much as is tolerable, and the patient’s nutritional status is optimized.

In patients who may receive stomas, preoperative counseling better prepares the patients and their families. A stomal therapist should be involved with patient care prior to surgery. Patients should also be counseled about the expectations of surgery because future recurrences are likely.

Intraoperative details

Most patients will have received corticosteroids recently. Therefore, perioperative steroid dosing will likely be required.

Perianal, rectal, and sigmoidoscopic examinations are often performed while the patient is under anesthesia in order to determine the presence and extent of perianal disease.

The goal of surgical resection is to remove the grossly involved bowel; microscopic disease at resection margins is acceptable. Primary anastomosis of bowel can usually be achieved. Occasionally, a proximal functioning stoma or Brooke ileostomy is required in patients in whom an anastomosis would be unsafe.

Operative steps: Laparoscopic resection

After the patient is placed under general endotracheal anesthesia and after a urinary catheter is introduced, the abdomen is prepared and draped widely. A 12-mm incision is made in the umbilicus through which a 12-mm cannula is introduced for future insertion of the endoscopic stapling device. Two 5-mm incisions are made, one in the left mid abdomen and one in the left suprapubic region; through these, grasping forceps are inserted for retraction.

The final port (if necessary) is initially 5 or 10 mm in length and is placed in the right lower abdomen in a location similar to an open appendectomy incision. This incision is subsequently enlarged to approximately 2 cm, and the specimen is extracted from the abdominal cavity through this incision (see image below). In addition, the 2 ends of the intestine to be anastomosed are exteriorized through this incision and a 2-layer extracorporeal anastomosis is created.

The first step in the operation is ligation and division of the proximal ileum with the endoscopic stapler. Next, with either an UltraCision Harmonic Scalpel (Ethicon Endosurgery, Cincinnati, Ohio) or LigaSure device (Valley Lab, Boulder, Colo), the mesentery of the proximal right colon is coagulated and transected (see image below). Then, the right lower abdominal incision is enlarged to 2 cm and the specimen is exteriorized. Alternatively, the umbilical incision may be enlarged to allow for exteriorization of the specimen. With this technique, the distal margin of resection is more precisely determined, and the distal resection margin can be divided with the surgical stapler. This procedure may also be performed intracorporeally with an endoscopic stapler.

Once the resected specimen is removed, the proximal small intestine is delivered through the right lower abdominal incision (or enlarged umbilical incision), and a 2-layer extracorporeal anastomosis is created between the proximal and distal margins. The bowel is then returned to the abdominal cavity and all incisions are closed.

In the experience at Children’s Mercy Hospital (20 patients), all patients have been discharged on either the fourth or fifth postoperative day. Nasogastric tubes were not placed in these patients, allowing for a more comfortable postoperative convalescence. Two patients developed postoperative pelvic abscesses; both were being treated with steroids for high-grade stricture at the time of surgery. One patient had a secondary stricture that required a repeat operation during the same hospital stay.

Postoperative details

Postoperatively, steroids are tapered appropriately. Patients who were receiving low-dose or short-term steroids preoperatively may be treated with a more rapid taper. Parenteral nutrition is often continued until bowel function returns.

Complications of surgery

The most common complication of surgery for Crohn disease is the development of intraperitoneal adhesions. Patients with Crohn disease undergoing abdominal surgery are also at an increased risk for developing enterocutaneous fistulae as a result of their surgery.

Crohn disease is a chronic disease that needs to be treated by a team of experts consisting of primary care providers, gastroenterologists, psychologists, nutritionists, social workers, and nurses. A critical factor in successful management of this disease is the willingness of the patient to participate and cooperate with the team. Patients and parents must be educated and receive support to treat this disorder effectively.

The general goals of treatment for Crohn disease are to achieve the best possible clinical, laboratory, and histologic control of the inflammatory disease with the least adverse effects from medication; to permit the patient to function as normally as possible; and, in children, to promote growth with adequate nutrition. Treatment has changed over the past few years, reflecting the development of new agents that can target specific locations in the GI tract and specific cytokines.

Therapy is typically administered in a step-up approach. Patients with mild disease are treated with preparations of 5-aminosalicylic acid (5-ASA), antibiotics, and nutritional therapy. If no response occurs or if disease is more severe than initially thought, corticosteroids and inhibitors of DNA synthesis with 6-mercaptopurine (6-MP)/azathioprine (Imuran) or methotrexate (Folex PFS, Rheumatrex) are administered. Finally, biologic and surgical therapies can be useful. More recently, adult data have supported the use of biologic therapy earlier in the course of disease (a top-down approach) as a more effective treatment method.^[5]

Diarrhea may also develop because of bacterial overgrowth, short bowel syndrome, and lactase deficiency. Chronic diarrhea in Crohn disease responds well to antidiarrheal agents such as loperamide, diphenoxylate with atropine, and tincture of opium. Such agents should not be given to patients with active colitis because of the risk of developing toxic megacolon.

Patients with terminal ileal disease may not absorb bile acids normally, which can lead to secretory diarrhea in the colon. These patients may benefit from bile acid sequestrants (eg, cholestyramine, colestipol). Those who have extensive ileal disease or resection of more than 100 cm of the ileum have defective bile salt absorption and develop steatorrhea. These patients benefit from a low-fat diet and medium-chain triglyceride preparations. Bile sequestrants exacerbate this type of diarrhea.

Abdominal cramps may be reduced with propantheline, dicyclomine, or hyoscyamine. These drugs should not be used if there is the possibility of a bowel obstruction.^{[3, 23]}

For colon and small bowel inflammation, anti-inflammatory drugs or antibiotics are helpful. Sulfasalazine (Azulfidine) is useful mainly in colonic disease, because the active compound, 5- ASA, is released in the large bowel by bacterial degradation of the parent compound. Sulfasalazine does not alleviate small bowel disease. Sulfasalazine provides a modest benefit for the treatment of mild to moderately active Crohn disease compared with placebo and is inferior to corticosteroids for treatment of active Crohn disease.^[24]

A systemic review of the efficacy of biological therapies in IBD confirmed placebo is inferior to anti-TNF-alpha antibodies and natalizumab in inducing remission of active Crohn disease.^[25]

Products such as mesalamine (Asacol, Rowasa, Canasa) that release 5-ASA in the distal small bowel triggered by pH changes are more useful in patients with small intestinal Crohn disease. Long-term maintenance with mesalamine may delay clinical relapse. 5-ASA provides only modest benefit in preventing relapse of Crohn disease in remission after surgery. It should be considered when immunosuppressive therapy is either not warranted or contraindicated.

Sulfasalazine does not have an additive effect or a steroid-sparing effect when used in conjunction with corticosteroids. In contrast to its action in ulcerative colitis, sulfasalazine does not seem to maintain remission in Crohn disease.

A short course of corticosteroid therapy is indicated in patients with severe systemic symptoms (eg, fever, nausea, weight loss) and in those whose condition does not respond to anti-inflammatory agents. Prednisone (Deltasone, Orasone) is generally helpful in acute inflammation. In patients with a tender, palpable mass, the possibility of an underlying abscess should be excluded before steroids are started. Adding antibiotics is always beneficial if coexisting infection is considered likely.

Steroids are not indicated for maintenance therapy because of serious complications, such as aseptic necrosis of the hip, osteoporosis, cataract, diabetes, and hypertension. Accordingly, once remission is achieved, the agent is slowly tapered. It should be noted that steroids are not disease modifying and do not induce sustained mucosal healing. Enteric-coated ileal-release preparations with decreased systemic effects have been developed for the treatment of ileal and cecal Crohn disease. In patients who relapse after the withdrawal of steroids, other treatment options are required.

If steroid withdrawal proves difficult, immunosuppressants such as azathioprine (Imuran) or its active metabolite, 6-MP, may be considered. Response is usually observed within 3-6 months. Careful supervision is needed because of the risk of bone marrow suppression. Thiopurine methyltransferase (TPMT) activity should be measured prior to initiation of therapy to identify patients predisposed to altered drug metabolism, increasing the risk of leukopenia. Measurement of 6-thioguanine nucleotide (6-TG) metabolites is helpful in assessing compliance and adjusting therapy.

Methotrexate is effective in inducing and maintaining remission in chronic Crohn disease in adults and has been shown to be effective and well tolerated for maintenance of remission in children.^[26] The onset of action is shorter for methotrexate than for 6-MP, and the once-weekly dosing is sometimes preferred. Whether oral therapy is as effective as parenteral administration is unclear.

If medical therapy fails, surgical resection of the inflamed bowel, with restoration of continuity, is indicated. Urgent surgery may be required in rare cases of sustained or recurrent hemorrhage and toxic megacolon. Partial small bowel obstruction may sometimes be treated conservatively with intravenous hydration, nasogastric suction, and parenteral nutrition if there is no evidence of adhesion or strangulation.^{[3, 23]}

Fistulae between bowel loops (eg, ileoileal, ileocecal, ileosigmoid) are usually benign and may not produce any major problems. Enterovesicular, enterocutaneous, cologastric, and coloduodenal fistulae are more serious. Surgical intervention is rarely required, unless fistulae are complicated by progressive obstruction or abscess formation or a large segment of bowel is bypassed, leading to severe diarrhea and malabsorption. Otherwise, medical management is used to treat underlying infections and symptoms with oral metronidazole (Flagyl) for at least 1-2 months. Ciprofloxacin (Cipro) confers additional benefit if no improvement occurs. One study demonstrated that the combination of ciprofloxacin and metronidazole in 14 patients with perianal fistulae healed the fistulae in 3 patients and improved 85% of them.

Inhibitors of DNA synthesis and antimetabolites are beneficial in reducing drainage and closing fistulae in 30-40% of patients. Total parenteral nutrition (TPN) and bowel rest may promote fistulae healing during medical therapy.^{[3, 23]}

Biologic therapy

Tumor necrosis factor, a key inflammatory cytokine and mediator of intestinal inflammation, is expressed prominently in IBD. Infliximab (Remicade) is a chimeric mouse-human monoclonal antibody against TNF-alpha that shows promise in Crohn disease treatment; it blocks TNF-alpha in the serum and at the cell surface, leading to the lysis of TNF-producing macrophages and T cells. Infliximab has been approved for the treatment of pediatric Crohn disease.

In one study, nearly 65% of refractory cases of Crohn disease responded well to treatment with infliximab (5 mg/kg), and one third went into complete remission. Patients who relapsed after the initial response responded again to further infusions. Infliximab is also effective in patients who have refractory perianal and enterocutaneous fistulae. Current clinical practice is to use it as an intravenous (IV) infusion of 5 mg/kg at 0 weeks, 2 weeks, and 6 weeks, followed by maintenance IV infusions every 8 weeks. On average, the effect lasts for 12 weeks. Important adverse effects include the development of a lupus like syndrome and an increased incidence of tuberculosis. Anti–double-stranded DNA is not always associated with clinical lupus. An added benefit of infliximab treatment is the ability to possibly taper steroids, which will decrease further adverse effects.^{[27, 28]}

Unfortunately, infliximab is immunogenic, and repeated administration may result in the development of antibodies to infliximab that lead to infusion reactions, loss of efficacy, and delayed hypersensitivity reactions.^[29]

Two other anti-TNF-alpha agents, adalimumab (Humira) and certolizumab pegol (Cimzia), may be less immunogenic than infliximab and have shown efficacy in the treatment of Crohn disease that is refractory to the standard medical treatment of corticosteroids and inhibitors of DNA synthesis.^[29]

Adalimumab is a recombinant human immunoglobulin (Ig) G1 monoclonal antibody that binds with high affinity and specificity to human soluble TNF-alpha but not to lymphotoxin (TNF-beta). Results have shown that the immunogenicity of adalimumab is low compared with the chimeric infliximab.^[29] Two placebo-controlled trials, CLASSIC I and CLASSIC II, showed that adalimumab was effective for both induction and maintenance of remission in patients who were previously naive to anti-TNF therapy. The CHARM trial demonstrated the same effect in a mixed population of patients who were either naive to infliximab therapy or who had previously been on infliximab therapy. In patients who had lost response or become intolerant of infliximab, the GAIN trial results showed a benefit from adalimumab therapy induction with remission at 4 weeks. Furthermore, an open-label study conducted in France that assessed the long-term efficacy and safety of adalimumab maintenance therapy in this population showedthatitwaswelltolerated and effective in maintaining clinical remission in patients who had Crohn disease with a lost response or intolerance to infliximab.^{[7, 30, 31]}

Certolizumab pegol, a humanized Fab' antibody fragment conjugated to polyethylene glycol, has also demonstrated efficacy in maintaining remission in patients with moderately to severely active Crohn disease whose condition previously responded to induction therapy with the same agent (PRECISE trial). However, the data covered only a 6-month period.^[7]

One area of concern with the use of these anti-TNF-alpha medications is that several patients have been reported to develop a rare hepatosplenic T-cell lymphoma when treated with dual therapy of 6-MP or azathioprine as well as a TNF-alpha inhibitor. Although this has been a rare complication, all reported cases have been in adolescents and young adults.

Tacrolimus (Prograf, Advagraf) may be effective in treating Crohn disease.

Mycophenolate mofetil (CellCept) acts by inhibiting a de novo pathway of purine synthesis in lymphocytes, leading to intracellular depletion of guanosine monophosphate. This results in the suppression of cytotoxic T cells and the formation of antibodies by activated B cells. A dose of 500 mg twice a day in 2 divided doses is well tolerated by patients and can be used to reduce the steroid dose.^{[3, 23]}

The use of the anti-inflammatory cytokine IL-10 (Ilodecakin) resulted in a trend toward clinical improvement, but not remission in chronic active Crohn disease, and IL-11 (Oprelvekin) was found to be effective in inducing remission in a preliminary study in patients with mild-to-moderate Crohn disease. However, more trials are needed.^[3]

Monoclonal antibody to IL-6 receptor, tocilizumab (Actemra), has been suggested to have a beneficial clinical effect in Crohn disease, as has antibody to IL-12, which has been found to decrease the Th1-mediated inflammatory cytokines at the site of disease.^[3]

Natalizumab (Tysabri) is a monoclonal antibody against the alpha4 integrin subunit that inhibits leukocyte adhesion and migration to areas of inflammation. Pooled clinical data indicate that this drug may be effective for inducing clinical response and remission, although trials were suspended because of 3 reported cases of progressive multifocal leukoencephalopathy (PML) in 2 patients with multiple sclerosis receiving this agent in combination with IFN beta-1A.^[3]

Filgrastim (Neupogen) or colony-stimulating factor (CSF) (granulocyte monocyte [GM]-CSF) has been shown to have a positive response to treatment in patients with fistulae.^[3]

Valentine et al examined whether use of sargramostim (Leukine), a recombinant GM-CSF and activator of innate immunity, provided steroid-sparing capabilities in patients with Crohn disease.^[32] Patients were randomized (2:1 ratio) to receive either sargramostim 6 mcg/kg SC qd (n = 87) or placebo (n = 42) for up to 22 weeks. During weeks 1-4, patients received sargramostim or placebo adjunctively to their corticosteroid therapy; during weeks 4-14 corticosteroids were titrated downward; and finally an observation phase of study drug plus prednisone less than or equal to 7.5 mg/d. Corticosteroid-free remission was obtained in 18.6% of the sargramostim group compared with 4.9% of the placebo group.^[32]

However, patients receiving sargramostim experienced more pain, injection site reactions, and dyspnea than those receiving placebo. Use of sargramostim may reduce the dose or duration of corticosteroids in patients with Crohn disease, thereby reducing steroid-induced adverse effects.

Fontolizumab (HuZAF) is an antibody to IFN-gamma that has provided significantly better clinical response rates and remission than placebo.^[3]

Nutritional therapy is another important modality for the treatment of disease, malnutrition, and growth failure observed in Crohn disease. Although ineffective as a primary therapy, nutritional manipulations that facilitate bowel rest can be effective adjuncts in the treatment of active Crohn disease. A dramatic reversal of malnutrition and a change in growth velocity can be expected in all children treated with adequate nutrition in conjunction with medical therapy to control symptoms of Crohn disease. Both parenteral and enteral nutrition are effective. Additionally, exclusive enteral nutrition has been shown to be as effective as corticosteroids for the induction of remission and might promote better GI tract mucosal healing.^[33] Consumption of at least 1200 kcal/d has been associated with lower rates of disease relapse, but patients frequently relapsed after initiation of a normal diet.^{[34, 35, 36]}

Because most patients have appetite suppression, overnight nasogastric feeds are often used. Nighttime supplemental enteral nutrition without daytime dietary restrictions has been shown to be beneficial in maintaining disease remission. Although the exact mechanism of action is unknown, beneficial effects could be due to alteration of the intestinal flora, decrease in the antigen load, and decrease in inflammatory cytokine levels.

The diet should be balanced in patients with Crohn disease. Fiber supplementation is said to be beneficial for patients with colonic disease because dietary fiber can be converted to short-chain fatty acids, which provide fuel for colonic mucosal healing, whereas a low-roughage diet is usually indicated for patients with obstructive symptoms.

Patients with Crohn disease of the small intestine often have lactose intolerance; therefore, avoidance of dairy products may be indicated. However, supplementation with calcium may be required. Osteoporosis is a common nutritional complication of Crohn disease because of the above reason, as well as the release of cytokines from inflammatory cells, which stimulate osteoclast activity and lead to increased bone breakdown. Corticosteroid use is another significant risk factor for the development of osteoporosis.^{[34, 35, 36]}

Patients who undergo extensive resection of the terminal portion of the ileum may benefit from a low-fat diet with the addition of medium-chain triglyceride preparations.

Selected patients may require total parenteral nutrition (TPN). Short-term use of TPN is appropriate for patients with active inflammation and severe malnutrition and those with fistulae (given preoperatively). Long-term use is suitable for patients who have had extensive intestinal resection, resulting in short bowel syndrome.^[23]

Patients with an exacerbation of Crohn disease can be treated on an outpatient basis. However, if a serious complication of Crohn disease (eg, obstruction, perforation, abscess, hemorrhage) is a concern or if the patient fails outpatient treatment, intravenous [IV] therapy (eg, corticosteroids, antibiotics, total parenteral nutrition) may be required and hospitalization is warranted.

Patients should be examined on a regular basis. The frequency depends on the severity and activity of their disease. Follow-up laboratory workup should be performed regularly to monitor the safety and success of therapy.