Definitions for level of evidence (1-3) and strength of recommendation (A-D) are given at the end of the "Major Recommendations" field.
The diagnosis of Crohn's disease (CD) is based on a composite of endoscopic, radiographic, and pathological findings documenting focal, asymmetric, transmural, or granulomatous features. The sequence of diagnostic maneuvers is based on presenting symptoms, physical findings, and basic laboratory abnormalities (grade C). Currently, the measurement of genetic mutations in patients with CD remains a research tool that is not yet proven to be of clinical benefit for the general assessment of diagnosis, guidance of patient care, or prediction of response to specific medical therapies. The use of genetic testing is currently not recommended in the caring of patients with CD (level C). Additionally, serological studies evaluating antibodies against Saccharomyces cerevisiae, antineutrophil cytoplasmic antibodies, antibodies directed against CBir1, OmpC are evolving to provide adjunctive support for the diagnosis of CD but are not sufficiently sensitive or specific to be recommended for use as a screening tools.
CD should be considered in the differential diagnosis for patients presenting with chronic or nocturnal diarrhea, abdominal pain, bowel obstruction, weight loss, fever, night sweats, or symptoms retching underlying intestinal inflammation, fibrosis, or fistula. Alternative inflammatory bowel diseases (infectious, ischemic, radiation-induced, medication-induced, particularly related to the use of non-steroidal anti-inflammatory drugs), or idiopathic intestinal disorders (ulcerative colitis, celiac disease, or microscopic colitis), and irritable bowel syndrome comprise the major differential diagnoses. The presence of fecal leukocytes (or more recently abnormal fecal concentrations of calprotectin or lactoferrin) is an excellent way to confirm intestinal inflammation or inflammation in general; sometimes the presence of intestinal inflammation is also reflected in serum acute-phase reactants (e.g., elevated erythrocyte sedimentation rate, and elevated orosomucoid, and elevated C-reactive protein). In the presence of diarrhea at presentation or relapse, stools should be examined for enteric pathogens, ova, and parasites, and Clostridium difficile toxin.
Upper or lower gastrointestinal endoscopy is used to confirm the diagnosis of CD, assess disease location, or obtain tissue for pathological evaluation. Endoscopy can also serve a therapeutic role in the dilation of strictures, particularly those at a surgical anastomosis, although double-blind, sham-controlled trials are lacking.
Colonoscopic evaluation of surgical anastomoses can be used to predict the likelihood of clinical relapse and assess response to postoperative therapy. Endoscopic biopsy can establish the diagnosis, differentiate between ulcerative colitis and CD, exclude the presence of acute self-limited colitis, or identify dysplasia or cancer.
Recently, the use of video capsule endoscopy (VCE) has been assessed, and in a prospective blinded evaluation, it was demonstrated to be superior in its ability to detect small bowel pathology missed on small bowel radiographic studies and computerized tomography (CT) radiographic examinations. However, there is a risk of capsule retention within strictures that may require surgical intervention and the role of VCE in CD remains to be defined as a validated instrument to determine whether ulceration(s) discovered at the time of VCE are specific for CD. Retention of the VCE has been reported to occur in up to 13% of patients with CD. It is currently recommended that radiographic studies (small bowel follow through, CT enterography, or magnetic resonance enterography) be performed prior to VCE in patients with CD to assess for the presence of unsuspected small intestinal strictures. Small bowel strictures, which occur frequently in patients with known CD, are considered to be a contraindication to VCE for fear of capsule retention. A patency capsule, which can be administered prior to the use of a VCE to assess for the presence of significant strictures, has recently become available. The "patency capsule" is a self-dissolving capsule that is of the same size as the video capsule. It contains a radiofrequency identification tag that permits it to be detected by a scanning device placed on the abdominal wall. When its passage is blocked by a stenosis, the patency capsule dissolves in 40–80 h after ingestion.
Diagnosis of CD can be accomplished by contrast radiography (air contrast barium enema, small bowel follow through, or enteroclysis) to confirm disease location and intestinal complications. Transabdominal ultrasound or endoscopic ultrasonography, CT, or magnetic resonance imaging (MRI) can delineate and discriminate intra-abdominal masses/abscesses or perianal complications. Recently, CT and MRI enterography have been used and early evaluation suggests efficacy in the evaluation of small bowel pathology in patients with CD. These modalities offer the potential to differentiate inflammatory from non-inflammatory disease. Their roles are evolving and have not been conclusively established. For patients requiring serial imaging, MRI may be preferred over CT to minimize cumulative risks of radiation.
Factors recognized to exacerbate CD include intercurrent infections (both upper respiratory tract and enteric infections, including C. difficile), cigarette smoking, and non-steroidal anti-inflammatory drugs. These issue of stress initiating or exacerbating CD remains controversial.
Determining Disease Activity
Therapeutic options are determined by an assessment of the disease location, severity, and extraintestinal complications. In the absence of a "gold standard" for the measurement of disease activity, severity is established on clinical parameters, systemic manifestations, and the global impact of the disease on the individual's quality of life. Additional factors that impact on therapy include the assessment of growth and nutrition, extraintestinal complications, therapy-induced complications, functional ability, social and emotional support and resources, and education about the disease.
Defining CD activity is complicated by the heterogeneous patterns of disease, location, and complications, and the potential for coexistent symptoms of irritable bowel syndrome. No single "gold standard" indicator of clinical disease has been established.
In general, the goal of therapy for CD is to eliminate all disease-related symptoms, normalize the patients' quality of life, and maintain the general "well-being" of patients with as few side effects and long-term sequelae as possible.
Since the previous editions of these Practice Guidelines, the working definitions of CD activity have not changed substantially and are now presented and are consistent with the European Crohn's and Colitis Organization's (ECCO) grading of disease activity. Although the majority of clinical trials have utilized the Crohn's Disease Activity Index (CDAI) to assess therapeutic outcomes, a more "clinical," working definition, for CD activity is valuable for the practicing physician. This enables clinicians to guide therapy in an appropriate manner. It should be stressed that there may be various end points to consider when defining remission. An individual may be in endoscopic remission, clinical remission, or surgical remission. An individual is in symptomatic remission (usually corresponding to a CDAI <150) when that patient is asymptomatic or without any symptomatic inflammatory sequelae. Individuals included in this category may have responded to medical therapy or surgical therapy (such as ileocolonic resection) and have no residual active disease. Individuals who require the use of conventional corticosteroids to achieve clinical well-being are said to be "steroid dependent" and are not considered to be in remission. This statement is based on the potential for adverse events to accrue in patients on conventional corticosteroids. Individuals with mild–moderate disease (usually corresponding to a CDAI 150–220) are ambulatory and able to tolerate oral alimentation without manifestations of dehydration, systemic toxicity (high fevers, rigors, and prostration), abdominal tenderness, painful mass, intestinal obstruction, or >10 % weight loss. Individuals who are considered to have moderate–severe disease (usually corresponding to a CDAI 220–450) are considered to have failed to respond to treatment for mild–moderate disease, or those with more prominent symptoms of fever, significant weight loss, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings), or significant anemia. Finally, those individuals who are considered to have severe/fulminant disease (usually corresponding to a CDAI >450) are patients with persistent symptoms despite the introduction of conventional corticosteroids or biologic agents (infliximab, adalimumab, certolizumab pegol, or natalizumab) as outpatients, or individuals presenting with high fevers, persistent vomiting, evidence of intestinal obstruction, significant peritoneal signs such as involuntary guarding or rebound tenderness, cachexia, or evidence of an abscess.
Individual patients with other conditions may have symptoms indistinguishable from those of patients with active luminal CD. A search for other etiologies should be attempted as a general rule to ascertain whether a patient has symptoms from their CD or other conditions, such as bile salt diarrhea, intestinal infection (e.g., Salmonella, Shigella, Campylobacter, and C. difficile), bacterial overgrowth (especially if these have had an ileocolonic resection or have known intestinal strictures), bypass from a fistula (such as a gastrocolic fistula), lactose intolerance, irritable bowel syndrome, anorectal sphincter dysfunction, food intolerance, intestinal obstruction or a stricture, accentuated gastrocolic reflex, a medication-related adverse event (such as diarrhea from an aminosalicylates), or other conditions. Although also not specific for CD activity, determination of C-reactive protein has become a useful laboratory correlate with disease activity assessed by the CDAI. In individuals without any observable mucosal inflammation or ulceration, consideration should be given to the aforementioned potential differential diagnostic possibilities. However, it is not necessary to have the complete absence of mucosal inflammation to entertain alternative explanations for specific symptoms or signs; there may be several coexisting conditions.
Therapeutic recommendations depend on the disease location, disease severity, and disease-associated complications. Therapeutic approaches are individualized according to the symptomatic response and tolerance to medical intervention. Present therapeutic approaches should be considered sequential to treat "acute disease" or "induce clinical remission," and then to "maintain response/remission." Surgery is advocated for neoplastic/preneoplastic lesions, obstructing stenoses, suppurative complications, or medically intractable disease. Narcotic analgesia should be avoided except for the perioperative setting because of the potential for tolerance and abuse in the setting of chronic disease.
The patients' response to initial therapy should be evaluated within several weeks, whereas adverse events should be monitored closely throughout the period of therapy. Treatment for active disease should be continued to the point of symptomatic remission or failure to continue improvement. In general, clinical evidence of improvement should be evident within 2–4 weeks and the maximal improvement should occur with 12–16 weeks. Patients achieving remission should be considered for maintenance therapy. Those with continued symptoms should be treated with an alternative therapy for mild to moderate disease or advanced to treatment for moderate to severe disease according to their clinical status.
The following sections review the specific data and recommendations for the treatment of luminal inflammatory CD. The anatomic distribution and disease activity are the factors to be considered when determining appropriate medical therapy for individual patients. The anatomic distribution of disease is important only for medications with targeted delivery systems, such as sulfasalazine, mesalamine, and enteric-coated budesonide, or where the target for the mechanism of action may be localized such as greater luminal bacterial concentrations in the colon for antibiotics. For all other agents (parenteral or oral corticosteroids, mercaptopurine, azathioprine, methotrexate, infliximab, adalimumab, certolizumab pegol, natalizumab, cyclosporine A, or tacrolimus), therapeutic activity against CD is believed to occur throughout the entire gastrointestinal tract.
Mild to Moderate Active Disease
Ileal, ileocolonic, or colonic disease has commonly been treated in clinical practice with oral mesalamine 3.2–4 g daily (grade C) or sulfasalazine for ileocolonic or colonic disease as 3–6 g daily (grade A) in divided doses. Despite the use of oral mesalamine treatment in the past, new evidence suggests that this approach is minimally effective as compared with placebo (grade A) and less effective than budesonide or conventional corticosteroids (grade A). Alternatively, metronidazole at a dose of 10–20 mg/kg/day has been used in a proportion of patients not responding to sulfasalazine (grade C). Controlled ileal release budesonide (9 mg/day) is effective when active disease is confined to the ileum and/or right colon (grade A). Anti-tuberculous therapy has not been effective for either induction of remission or maintenance of remission in patients with CD (grade A).
Budesonide is recommended for use as the preferred primary therapy for patients with mild to moderately active CD who have disease localized to the ileum and/or right colon.
Owing to the relative infrequent occurrence of CD isolated to the esophagus, stomach, duodenum, or jejunum, there is a paucity of controlled clinical trials to determine evidence-based therapeutic recommendations. Rotating antibiotics can be effective in the treatment of small bowel bacterial overgrowth, and supportive nutritional therapies (see below) are frequently required.
Moderate to Severe Disease
Patients with moderate to severe disease are treated with prednisone 40 – 60 mg daily until resolution of symptoms and resumption of weight gain (generally 7–28 days) (grade A). Infection or abscess requires appropriate antibiotic therapy or drainage (percutaneous or surgical) (grade C). Elemental diets are less effective than corticosteroids (grade A), but can avoid corticosteroid-induced toxicities. Azathioprine and 6-mercaptopurine are effective for maintaining a steroid-induced remission (grade A), and parenteral methotrexate at a dose of 25 mg/week is effective for steroid-dependent and steroid-refractory CD (grade B). The anti-tumor necrosis factor (TNF) monoclonal antibodies, infliximab, adalimumab, and certolizumab pegol, are effective in the treatment of moderate to severely active CD in patients who have not responded despite complete and adequate therapy with a corticosteroid or an immunosuppressive agent (grade A). Infliximab monotherapy and infliximab combined with azathioprine are more effective than azathioprine in the treatment of patients with moderate to severe CD who have failed to respond to first-line therapy with mesalamine and/or corticosteroids (grade A). Infliximab, adalimumab, and certolizumab pegol may be used as alternatives to steroid therapy in selected patients in whom corticosteroids are contraindicated or not desired (grade B). The anti-alpha 4 integrin antibody, natalizumab, is effective in the treatment of patients with moderate to severely active CD who have had an inadequate response or are unable to tolerate conventional CD therapies and anti-TNF monoclonal antibody therapy (grade A).
No appropriate dose-ranging studies have been performed to evaluate conventional steroid dosing or dose schedules for CD.
There are no standards for corticosteroid tapering. When a clinical response has been achieved, doses are tapered according to the rapidity and completeness of response. Generally, doses are tapered by 5–10 mg per week until 20 mg and then by 2.5–5 mg weekly from 20 mg until discontinuation of therapy.
Owing to a significantly increased risk of osteoporosis in the setting of CD when conventional glucocorticosteroid therapy is used, a baseline dual-energy X-ray absorptiometry (DEXA) scan, supplementation of calcium and vitamin D, and consideration of a bisphosphonate are warranted once corticosteroid therapy is initiated.
More than 50% of patients treated acutely with corticosteroids will become "steroid dependent" or "steroid resistant," particularly smokers, or those with colonic disease. There are no short- or long-term benefits from the addition of aminosalicylates to corticosteroids. Azathioprine and 6-mercaptopurine have had demonstrable adjunctive benefits to steroids in adults. Dose–response studies have not been performed with azathioprine or 6-mercaptopurine. Methotrexate, 25 mg intramuscular or subcutaneously, has also been effective in the treatment of steroid-refractory or steroid-dependent patients.
Genetic polymorphisms for thiopurine methyltransferase (TPMT), the primary enzyme-metabolizing azathioprine/6-mercaptopurine, have been identified that afford the potential to regulate therapy according to the measurement of azathioprine/6-mercaptopurine metabolites (6-thioguanine nucleotides). No prospective controlled trial has compared whether dose escalation or initiation of therapy at the target dose is most advantageous with either 6-mercaptopurine or azathioprine. Current recommendations from the Food and Drug Administration (FDA) include determination of TPMT (either enzyme activity or genotype) prior to initiating treatment with azathioprine or 6-mercaptopurine.
Determination of 6-thioguanine nucleotide and 6-methylmercaptopurine levels can be helpful to assess lack of response, elevations in liver enzymes (usually associated with high TPMT levels and increased metabolism to 6-methylmercaptopurine), leukopenia, or to assess patient adherence. Routine monitoring of complete blood counts, initially every 1–2 weeks, then, at least every 3 months is recommended to avoid the risk of acute or delayed bone marrow suppression.
Parenteral methotrexate, 25 mg subcutaneous or intramuscular on a once weekly basis, is also effective at inducing remission and in allowing steroid tapering for steroid-refractory or steroid-dependent patients with CD. Lower doses have not been effective. Potential adverse events generally associated with the use of methotrexate include bone marrow suppression, including leukopenia, nausea, vomiting, hepatic fibrosis, and, uncommonly, hypersensitivity pneumonitis. A baseline chest X-ray along with monitoring of complete blood counts and liver chemistries is advocated. Hepatic fibrosis is one of the most consequential sequelae of long-term treatment with methotrexate. Risk factors for methotrexate hepatotoxicity include obesity, presence of diabetes mellitus, a prior history of excessive or long-term ethanol use, elevated baseline hepatocellular laboratory chemistries, a cumulative dose of methotrexate exceeding 1.5 g total drug dose, and daily dosing of methotrexate. The risk of methotrexate liver toxicity in patients with CD who do not have one or more of these risk factors is low. Prior to initiation of therapy with methotrexate, a liver biopsy is appropriate for patients with abnormal baseline liver chemistries, patients with one or more risk factors for hepatotoxicity, and patients who are suspected of having baseline chronic liver disease. The need to perform a repeat liver biopsy once a cumulative dose in excess of 1.5 g is reached has not been formally assessed in controlled clinical trials in patients with inflammatory bowel disease, as the risk of methotrexate-induced hepatotoxicity in patients without known risk factors is low. In the absence of adequate biopsy data from patients with CD, it is recommended that the American Rheumatology Association guidelines regarding surveillance for hepatic toxicity be followed. These guidelines recommend that a liver biopsy be performed during therapy if a majority of aspartate aminotransferase values over 1 year (performed every 4–8 weeks) are elevated or if the serum albumin value is decreased. Furthermore, reduction in methotrexate dose is recommended in response to an elevated aspartate aminotransferase level. If moderate to severe fibrosis or cirrhosis is found, treatment with methotrexate should be discontinued.
The chimeric monoclonal antibody directed against tumor necrosis factor-alpha (TNF-α), infliximab, is effective in the treatment of moderate to severe CD in patients who have not responded to aminosalicylates, antibiotics, corticosteroids, or immunomodulators. Although a single infusion of infliximab at a dose of 5 mg/kg is effective at reducing signs and symptoms of CD over 4 weeks, an induction regimen of 5 mg/kg infusions at weeks 0, 2, and 6 followed by maintenance therapy (see below) has had significant advantages over episodic treatment strategies. Infliximab monotherapy and infliximab combined with azathioprine are more effective than azathioprine in the treatment of patients with moderate to severe CD who have failed to respond to first-line therapy with mesalamine and/or corticosteroids and are naïve to immunosuppressive and biologic agents. Assessment of prior tuberculosis exposure, current purified protein derivative status, and a chest X-ray prior to treatment with infliximab are important as infliximab use has been associated with reactivation of latent tuberculosis. Infectious complications with other organisms, particularly intracellular pathogens are also increased with anti-TNF therapy. A substantial proportion of patients with CD will be anergic, thus a vigilant approach to symptoms of active tuberculosis or other infections should be maintained.
Treatment with infliximab is generally well tolerated; however, infliximab infusions have been associated with both acute and delayed hypersensitivity (serum sickness-like) infusion reactions. Other adverse events include the development of antibodies to infliximab (ATI; previously termed human anti-chimeric antibody) and anti-double-stranded DNA antibodies. The development of ATIs correlates with an increased risk of infusion reactions and a shorter duration of response. Acute infusion reactions typically occur during or 1–2 h after a patient receives infliximab and can include headaches, dizziness, nausea, erythema at the injection site, flushing, fever, chills, chest pain, cough, dyspnea, and pruritis. Acute infusion reactions can be controlled by slowing or temporarily stopping the infusion and by giving acetaminophen 1,000 mg orally and diphenhydramine 50 mg orally or intravenously. Some clinicians routinely pretreat patients with acetaminophen, corticosteroids, and/or diphenhydramine, although these are of unproven benefit for patients who have not had a prior infusion reaction. Delayed infusion reactions characteristically occur 3–14 days after infliximab infusions presenting with symptoms similar to serum sickness (myalgias, arthralgias, fever, rash, pruritis, dysphagia, urticaria, and headaches). These symptoms generally abate spontaneously, or occasionally require a brief course of corticosteroids. The primary risk for both acute and delayed reactions to infliximab is a hiatus between infliximab treatments. An induction schedule of infliximab at weeks 0, 2, and 6, as well as maintenance therapy, reduces the likelihood of ATI (and infusion reactions) as does concomitant immunosuppressive therapy or pretreatment with corticosteroids. A significant percentage of patients treated with anti-TNF therapy develop positive anti-nuclear antibodies and a smaller proportion develop antibodies to double-stranded DNA. The development of symptomatic disease (i.e., drug-induced lupus) is distinctly unusual and no patient has developed renal or central nervous system involvement.
Alternative biologic formulations targeting TNF have also been reported to induce benefits in CD. Adalimumab, a human anti-TNF monoclonal antibody administered subcutaneously, has been approved by the FDA for the treatment of moderate to severe CD and has been demonstrated to be effective both in patients who are naïve to biologic therapy and in patients who have lost response to infliximab. The most effective induction dosing of adalimumab is 160 mg followed by 80 mg after 2 weeks. Subsequent maintenance dosing of 40 mg every other week in patients who respond to the initial induction doses prolongs responses and remissions. Dose escalation to 40 mg weekly may be necessary to maintain responses in some patients. Certolizumab pegol, 400 mg subcutaneously, has also been effective at inducing and maintaining clinical response and remissions. Adalimumab and certolizumab pegol share similar risks as infliximab, in particular infectious complications. However, due to subcutaneous administration infusion reactions and delayed hypersensitivity reactions have not been reported. Injection site reactions have been described with both adalimumab and certolizumab pegol. Similarly, concomitant immunomodulator use reduces immunogenicity, but has not impacted on 6–12 month efficacy. Although the combination of an immunomodulator with anti-TNF monoclonal antibodies reduces immunogenicity (anti-drug antibody formation) and increases serum concentrations, the risk–benefit of combination therapy in lieu of the recent reports of hepatosplenic T-cell lymphomas in young males receiving combination therapy has led to a re-evaluation of recommendations for concurrent immunomodulatory therapy with anti-TNF biologics (see maintenance section for further discussion).
The humanized monoclonal antibody to alpha-4 integrin, natalizumab, is effective in the treatment of patients with moderate to severe CD and evidence of active inflammation (e.g., elevated C-reactive protein) who have not responded to aminosalicylates, antibiotics, corticosteroids, immunomodulators, and TNF inhibitors. An induction regimen of 300 mg infusions at weeks 0, 4, and 8 is recommended. Natalizumab is associated with an increased risk of reactivation of a latent virus, the human JC polyoma virus, which can lead to infection of the central nervous system called progressive multifocal leukoencephalopathy (PML). PML is typically fatal. To minimize the risk of PML, natalizumab must be administered as a monotherapy (without concomitant immunosuppressive therapy) and patients must enroll in a mandatory safety follow-up program called the TOUCH program. Infectious complications with other organisms may also be increased with natalizumab therapy. Treatment with natalizumab is generally well tolerated; however, natalizumab infusions have been associated with acute hypersensitivity infusion reactions. Other adverse events include the development of anti-natalizumab antibodies and hepatotoxicity.
At present time, the only appropriate use of enteral diets is as an adjunctive therapy to support a patients' nutrition.
As a consequence of the acuteness and diversity of presentation of patients with severe CD and the potential for development of complications, the management decisions for these patients are based more on practicality than controlled trial evidence. Patients with persistence of Crohn's related symptoms despite introduction of conventional oral steroids or an anti-TNF (infliximab or adalimumab), or those presenting with high fever, frequent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess should be hospitalized. Surgical evaluation is warranted for patients with intestinal obstruction or who have a tender abdominal mass. An abdominal mass should be evaluated through transabdominal ultrasound, MRI scan, or CT to exclude the presence of an abscess. Abscesses require percutaneous or open surgical drainage. Once the presence of an abscess has been excluded or if the patient has been receiving oral corticosteroids, parenteral corticosteroids equivalent to 40–60 mg of prednisone daily or its equivalent are administered in divided doses or as a continuous infusion (grade C). There is no specific role for total parenteral nutrition in addition to steroids. Nutritional support through elemental feeding or parenteral hyperalimentation is indicated, after 5–7 days, for patients who are unable to maintain adequate nutritional requirements (grade C).
Supportive or resuscitative therapy with fluid and electrolytes is indicated for dehydrated patients. Transfusions are necessary in the setting of anemia and active hemorrhage. Oral feedings may be continued, as tolerated, for patients without obstructive manifestations or severe abdominal pain. More severely ill patients or those with evidence of intestinal obstruction should be treated with bowel rest and parenteral nutritional support. Obstruction may be secondary to inflammatory narrowing, fibrotic strictures, or an adhesive process. Differentiation is based on evaluation of the clinical course (presence or absence of inflammatory features) and prior radiographic studies. Adhesive obstructions typically respond to nasogastric suction and, in the absence of fever or rebound tenderness, do not commonly require emergent surgery. Fibrostenotic disease may respond, initially, to bowel rest and corticosteroids but obstructive symptoms often recur with steroid tapering.
In the presence of an inflammatory mass, broad-spectrum antibiotics should be instituted along with parenteral corticosteroids.
Parenteral corticosteroids are indicated for patients with severe/fulminant CD.
Patients who respond to parenteral corticosteroids, cyclosporine, or tacrolimus are gradually transitioned to an equivalent oral regimen and discharged. Most will require maintenance therapy with an alternative immunomodulator such as 6-mercaptopurine or azathioprine. Failure to respond or worsening symptoms are indications for acute surgical intervention.
Perianal and Fistulizing Disease
Acute suppuration is an indication for surgical drainage with or without placement of non-cutting setons (grade C). Nonsuppurative, chronic fistulization, or perianal fissuring is treated medically with antibiotics (grade C), immunosuppressives (grade C), or infliximab (grade A).
Perianal/perirectal abscesses require surgical drainage. Non-suppurative perianal complications of CD typically respond to metronidazole alone or in combination with ciprofloxacin. In the absence of controlled maintenance trials, it appears that continuous therapy is necessary to prevent recurrent drainage. The safety of long-term antibiotic therapy has not been established, and patients treated with metronidazole should be monitored for evidence of peripheral neuropathy and ciprofloxacin therapy can be complicated by tendonitis and tendon rupture. Other antibiotics have also been used in the treatment of perineal CD, including amoxicillin/clavulanate, trimethoprim sulfamethoxazole, levofloxacin, minocycline, and tetracycline.
Sulfasalazine and mesalamine have not had consistent maintenance benefits after medical inductive therapy (grade A). Conventional corticosteroids should not be used as long-term agents to prevent relapse of CD (grade A). Budesonide at a dose of 6 mg/day reduces the time to relapse in ileal and/or right colonic disease, but does not provide significant maintenance benefits after 6 months (grade A). Azathioprine/6-mercaptopurine (grade B) and methotrexate (grade B) have demonstrable maintenance benefits after inductive therapy with corticosteroids. Azathioprine can maintain remissions induced by infliximab in steroid-naïve patients (Grade B). Maintenance therapy with in infliximab, adalimumab, and certolizumab pegol is effective (grade A). Infliximab monotherapy and infliximab combined with azathioprine are more effective than azathioprine for maintenance of patients with moderate to severe CD who have failed to respond to first-line therapy with mesalamine and/or corticosteroids (grade B). Maintenance therapy with natalizumab is effective (grade A). Metronidazole (grade B), mesalamine (grade C), azathioprine/mercaptopurine (grade B), or infliximab (grade B) should be considered after ileocolonic resections to reduce the likelihood of symptomatic recurrence, whereas conventional corticosteroids (grade A) and budesonide at a dose of 6 mg/day (grade B) are not effective.
The majority of patients treated acutely with corticosteroids are unlikely to remain well over 1 year without specific effective maintenance therapy. Younger patients, those with colonic disease, and cigarette smokers are more likely to become steroid dependent. Budesonide, 6 mg/day, can allow withdrawal of systemic steroids for steroid-dependent patients with ileal and/or right colonic disease and delay clinical relapse rates for 3–6 months, but not at 1 year.
Azathioprine and 6-mercaptopurine have been effective in allowing reduction in steroid doses and maintaining remissions after steroid-inductive therapy. Complete blood counts must be monitored carefully early in the course of treatment and in the long term, at a minimum of every 3 months, because of the risk of delayed bone marrow suppression. (e.g., leukopenia and thrombocytopenia). Pancreatitis, typically presenting several weeks after initiating therapy, occurs in approximately 3–15% of patients and recurs with re-introduction of either azathioprine or mercaptopurine. The risk of lymphoma related to purine analogs has been widely debated. Aside from a potential risk of lymphoma, neoplasia has not been observed with the use of purine analogs for inflammatory bowel disease and it is accepted that the documented benefits are most likely to offset a small increased risk. Lymphomas that have occurred during thiopurine therapy have increasingly been recognized to be related to Epstein–Barr infections. A rare form of natural killer cell, hepatosplenic lymphoma has recently been described associated with azathioprine therapy for CD either alone or in combination with infliximab.
Scheduled infusions of infliximab have been effective at maintaining remissions in both luminal and fistulizing CD. Maintenance therapy, scheduled every 8 weeks, is more effective than episodic dosing and has been associated with prolonged mucosal healing, a novel end point in CD associated with improved pharmacoeconomic and quality-of-life outcomes. Regularly scheduled maintenance therapy is less immunogenic than episodic therapy. Infliximab monotherapy and infliximab combined with azathioprine are more effective than azathioprine for maintenance in patients with moderate to severe CD who have failed to respond to first-line therapy with mesalamine and/or corticosteroids and are naïve to immunosuppressive and biologic agents. Long-term monitoring for infectious complications while patients are receiving anti-TNF therapy is indicated and the benefits and risks are acceptable when indicated for patients who have failed to respond to optimal therapy with conventional agents.
Adalimumab, when given at doses of either 40 mg subcutaneously every other week or 40 mg subcutaneously every week is effective for maintaining remission in patients who respond to induction therapy with adalimumab. Certolizumab pegol, 400 mg subcutaneously every 4 weeks, has also been effective at maintenance of response and remission. Natalizumab at doses of 300 mg every 4 weeks is effective for maintaining remission in patients who respond to induction therapy with natalizumab.
Indications for Surgery
Surgical resection, stricturoplasty, or drainage of abscesses is indicated to treat complications or medically refractory disease (grade C). Surgical resection, aside from total colectomy and ileostomy for CD limited to the colon, rarely "cures" CD. Nevertheless, surgical intervention is required in up to two-thirds of patients to treat intractable hemorrhage, perforation, persisting or recurrent obstruction, abscess (not amenable to percutaneous drainage), dysplasia or cancer, or unresponsive fulminant disease. The most common indications for surgical resection are refractory disease despite medical therapy or side effects of medication (steroid dependence). Recently, laparoscopic techniques in selected patients have been advantageous in terms of more rapid resolution of postoperative ileus and shortened hospital stay, without increased complications compared with open surgery. Patients who have active luminal CD and fail to improve within 7–10 days of intensive in-patient medical management should be considered to be potential surgical candidates.
The ability to reduce the risk of postoperative recurrence after surgical resection (although less than ideal) coupled with the potential substantial benefits of appropriate surgical therapy, no longer justifies the prolongation of ineffective medical management to "avoid surgery." The primary objective of therapy for CD is to restore the patient to health and well-being. Quality of life typically can be restored after surgical resection or stricturoplasty for CD. Therefore, medical therapies are acceptable only if they achieve their inductive or maintenance goals safely and effectively with a satisfactory quality of life. Neither patients nor physicians should view surgery as a "failure" when it can be the swiftest, safest, and most effective route to physical and psychosocial rehabilitation.
It is important to perform appropriate diagnostic tests, which may include colonoscopy, upper endoscopy, small bowel radiography, transabdominal imaging (such as CT, MRI), and VCE, to confirm the diagnosis, to confirm the presence or absence of active disease, to exclude dysplasia or cancer, and to identify the presence, extent, and severity of complications, such as strictures, fistulas, and abscesses. The perioperative use of azathioprine or 6-mercaptopurine, and/or infliximab has not been demonstrated to be a risk factor for postoperative infectious complications, in contrast to corticosteroids that do increase the risk of postoperative infectious complications.
At present, there is no surgical technique that reduces the risk of postoperative recurrence of CD. Histologic disease at the surgical resection margins does not predict a greater risk of recurrence of CD.
Stricturoplasty has been advocated as an important alternative to resection in the treatment of selected fibrotic strictures of the small bowel and should be attempted when possible to help avoid impaired nutrient absorption, bile salt diarrhea, steatorrhea, bacterial overgrowth, and short bowel syndrome. The rationale for the use of this technique is that it corrects obstructive strictures while preserving functional intestinal length. Where there are multiple strictures in a short segment and where bowel length is sufficient to avoid short bowel syndrome, resection may be preferable. The use of conventional stricturoplasties (Heineke–Mikulicz stricturoplasty form) is considered appropriate when small bowel stricture lengths are <10 cm in length. This is the most widely accepted form of stricturoplasty. Longer strictures, up to 25 cm, may be treated by side-to-side stricturoplasty. The bowel is arranged in a U-shape and the mesenteric edges of the bowel are approximated. This has been termed the Finney stricturoplasty. In general, stricturoplasty for colonic disease is not recommended.
Patients with CD may develop abdominal abscesses. The presence of active luminal CD with a concomitant abdominal abscess should preferably be managed with antibiotics, percutaneous or surgical drainage followed by delayed intestinal resection if necessary. There are no controlled data to indicate whether percutaneous or surgical drainage should always be followed by a delayed resection; however, most series favor a delayed resection.
Levels of Evidence and Grades of Recommendations
Grade A recommendations imply that there is consistent level 1 evidence (randomized controlled trials), grade B indicates that the evidence would be level 2 or 3, which are cohort studies or case-control studies. Grade C recommendations are based on level 4 studies, meaning case series or poor-quality cohort studies, and grade D recommendations are based on level 5 evidence, meaning expert opinion.