Pii: s0002-9270(01)02234-

PRACTICE GUIDELINES
Management of Crohn’s Disease in AdultsStephen B. Hanauer, M.D., William Sandborn, M.D., andThe Practice Parameters Committee of the American College of Gastroenterology University of Chicago Pritzker School of Medicine, Chicago, Illinois; and Mayo Medical School,Rochester, Minnesota PREAMBLE
symptomatic control, improve quality of life, and minimizeshort- and long-term toxicity and complications (4). Despite Guidelines for clinical practice are intended to suggest pref- the therapeutic burden, the majority of patients do maintain erable approaches to particular medical problems as estab- long-term well-being interspersed with short intervals of lished by interpretation and collation of scientifically valid morbidity (5). Despite the relatively low incidence and research, derived from extensive review of published liter- prevalence compared to more common GI disorders, the ature. When data are not available that will withstand ob- cost of medical and surgical therapy for Crohn’s disease is jective scrutiny, a recommendation may be made based on estimated at up to 2 billion dollars annually in the United a consensus of experts. Guidelines are intended to apply to States (6, 7) and is increasing with the advent of newer the clinical situation for all physicians without regard to biological approaches (8). Since the previous edition of specialty. Guidelines are intended to be flexible, not neces- these guidelines (9), significant advances have arisen re- sarily indicating the only acceptable approach, and should garding therapeutic alternatives although the volume of an be distinguished from standards of care that are inflexible appropriately derived evidence base that accounts for the and rarely violated. Given the wide range of choices in any disease heterogeneity and potential for site-specific therapy health care problem, the physician should select the course (10) remains relatively thin. This update follows a similar best suited to the individual patient and the clinical situation organization for therapy according to disease severity, mod- presented. These guidelines are developed under the aus- ified where applicable to disease location.
pices of the American College of Gastroenterology and itsPractice Parameters Committee. Expert opinion is solicitedfrom the outset for the document. The Committee reviews CLINICAL FEATURES
guidelines in depth, with participation from experiencedclinicians and others in related fields. The final recommen- The heterogeneity of manifestations, a potentially insidious dations are based on the data available at the time of the onset, overlapping features with other inflammatory bowel production of the document and may be updated with per- diseases, and/or presentation without GI symptoms (i.e., tinent scientific developments at a later time. (Am J Gas- extraintestinal symptoms), can make the diagnosis of troenterol 2001;96:635– 643. 2001 by Am. Coll. of Gas- Crohn’s disease difficult. Characteristic symptoms of chronic or nocturnal diarrhea and abdominal pain, weightloss, fever, and rectal bleeding reflect the underlying inflam-matory process (1). Clinical signs include pallor, cachexia, INTRODUCTION
an abdominal mass or tenderness, or perianal fissures, fis-tulae, or abscess. Associated extraintestinal features can Crohn’s disease encompasses a spectrum of clinical and include inflammation of the eyes, skin, or joints and, in pathological patterns manifested by focal, asymmetric, children, the failure of growth or retarded development of transmural, and, occasionally, granulomatous inflammation secondary sex characteristics (11, 12). Although the onset is affecting the gastrointestinal (GI) tract with the potential for typically insidious, occasionally, Crohn’s disease can systemic and extraintestinal complications (1). The inci- present with a fulminate onset or toxic megacolon (13).
dence and prevalence in the United States remain similar to Despite the potential heterogeneity, individual manifesta- other “Westernized” countries, estimated at 5/100,000 and tions and complications, there are definable patterns accord- 50/100,000, respectively (2, 3). The disease can affect any ing to disease location (14) and type (inflammatory, fibro- age group, but the onset (diagnosis) is most common in the stenotic, or fistulizing) (15), which are important in second and third decade (teenagers and young adults).
Crohn’s disease must be differentiated from other inflam- The ileum and colon are the most commonly affected matory bowel diseases that mimic or complicate the clinical sites, usually complicated by intestinal obstruction, inflam- course. Crohn’s disease is neither medically nor surgically matory mass, or abscess (14, 16). The acute presentation of “curable” requiring therapeutic approaches to maintain ileitis may mimic appendicitis and, rarely, Crohn’s disease Hanauer et al.
may be limited to the appendix. Perianal manifestations are and intestinal complications (29, 30). Radiolabeled leuko- common and may precede the onset of bowel symptoms cyte scans can discriminate between inflammatory and non- (17). Patients with Crohn’s disease limited to the colon inflammatory features and may be used occasionally in commonly present with rectal bleeding, perianal complica- clinical practice when there is a discrepancy between clin- tions, and extraintestinal complications involving the skin or ical symptoms and structural or anatomic studies (31). Ab- joints (18). Crohn’s disease limited to the colon can be dominal or endoscopic ultrasonography, computerized to- difficult to distinguish from ulcerative colitis (19). Diffuse mography, or magnetic resonance imaging can delineate and jejunoileitis is a less common variant often complicated by discriminate intra-abdominal masses/abscesses or perianal multifocal stenoses, bacterial overgrowth, and protein-los- ing enteropathy (20). Gastric and duodenal manifestationsinclude epigastric pain, nausea and vomiting, or gastric Endoscopy
Upper or lower GI endoscopy is used to confirm the diag- Extraintestinal symptoms of Crohn’s disease related to nosis of Crohn’s disease, assess disease location, or obtain intestinal inflammation include spondylarthritis (ankylosing tissue for pathological evaluation (31, 33). Endoscopic ap- spondylitis and sacroiliitis), peripheral arthritis, cutaneous pearance has not correlated with clinical disease activity manifestations (erythema nodosum and pyoderma gangre- after steroid therapy (34), but there is a closer correlation nosum), ocular inflammation (uveitis or sclero-conjunctivi- between therapeutic effects and mucosal healing with chi- tis), primary sclerosing cholangitis, and hypercoagulability meric anti–tumor necrosis factor (anti-TNF) monoclonal (22). In addition, Crohn’s disease also may be complicated antibodies (35). Upper GI endoscopic findings of focal by sequelae related to malabsorption (e.g., anemia, choleli- gastritis have recently been described that are indicative of thiasis, nephrolithiasis, or metabolic bone disease). Also, Crohn’s disease and separate from the findings related to there has been an increased awareness that Crohn’s disease Helicobacter pylori (36, 37). Colonoscopic evaluation of of long duration can be complicated by adenocarcinomas of surgical anastomoses can be used to predict the likelihood of the GI tract and, rarely, lymphoma (23).
clinical relapse and assess response to postoperative therapy(38). Endoscopic biopsy can establish the diagnosis, differ-entiate between ulcerative colitis and Crohn’s disease, rule DIAGNOSIS
out acute self-limited colitis, or identify dysplasia or cancer The diagnosis of Crohn’s disease is based upon a composite of endoscopic, radiographic, and pathological findings doc-umenting focal, asymmetric, transmural, or granulomatous EXACERBATING FACTORS
features. The sequence of diagnostic maneuvers is basedupon presenting symptoms, physical findings, and basic Factors recognized to exacerbate Crohn’s disease include: intercurrent infections (both upper respiratory tract and en-teric infections, including Clostridium difficile), cigarette General
smoking (39), and nonsteroidal anti-inflammatory drugs Crohn’s disease should be considered for patients presenting (25). The issue of stress initiating or exacerbating Crohn’s with chronic or nocturnal diarrhea, abdominal pain, bowel disease remains controversial (40). Although many patients obstruction, weight loss, fever, night sweats, or symptoms (and family members) are convinced that stress in an im- reflecting underlying intestinal inflammation, fibrosis, or portant factor in the onset or course of illness, it has not been fistula. Alternative inflammatory bowel diseases (infectious, possible to correlate the development of disease with any ischemic, radiation-induced, medication-induced, particu- psychological predisposition or exacerbations to stressful larly nonsteroidal anti-inflammatory drugs), or idiopathic (ulcerative colitis, celiac disease, or microscopic colitis),and irritable bowel syndrome comprise the major differen-tial diagnoses. The presence of fecal leukocytes confirms DETERMINING DISEASE ACTIVITY
intestinal inflammation. In the presence of diarrhea at pre- Therapeutic options are determined by an assessment of the sentation or relapse, stools should be examined for enteric disease location, severity, and extraintestinal complications.
pathogens, ova and parasites, and Clostridium difficile (24, In the absence of a “gold standard” measure of disease 25). Serological studies such as antibodies against Saccha- activity, severity is established on clinical parameters, sys- romyces cerevisiae are evolving to support the diagnosis of temic manifestations, and the global impact of the disease Crohn’s disease (26) but may not be sufficiently sensitive or on the individual’s quality of life (4). Additional factors that specific to be practical as screening tools (27, 28).
impact on therapy include the assessment of growth and Radiological Features
nutrition, extraintestinal complications, therapy-induced Diagnosis of Crohn’s disease can be accomplished by con- complications, functional ability, social and emotional sup- trast radiography (air contrast barium enema, small bowel port and resources, and education about the disease (41).
follow through, or enteroclysis) to confirm disease location Defining Crohn’s disease activity is complicated by the Management of Crohn’s Disease in Adults
heterogeneous patterns of disease location and complica- tients who have responded to acute medical intervention or tions, and the potential for co-existent symptoms of irritable have undergone surgical resection without gross evidence of bowel syndrome (10). No single “gold standard” indicator residual disease. Patients requiring steroids to maintain of clinical disease has been established. Composite indices well-being are considered to be “steroid-dependent” and are of disease activity have been used in controlled clinical trials usually not considered to be “in remission.” to provide reliable and reproducible correlates to clinicians’and patients’ “global assessment of well-being” (10), but MANAGEMENT
these have not been commonly employed in clinical prac-tice. Regulatory authorities have not yet established recom- General
mendations for a single measurement of disease activity Therapeutic recommendations depend upon the disease lo- (42). However, the most recent approval for Crohn’s disease cation, severity, and complications. Therapeutic ap- therapy in the United States was based upon definitions of proaches are individualized according to the symptomatic “clinical improvement” and “clinical remission” supported response and tolerance to medical intervention. Therapy is by the Crohn’s Disease Activity Index (4) and “fistula sequential to treat “acute disease” then to “maintain re- closure.” Other investigators have used individual therapeu- mission.” Surgery is advocated for obstructing stenoses, tic goals such as “steroid withdrawal or sparing,” or “avoid- suppurative complications, or medically intractable disease. ance of surgery,” which, although in accord with clinical Narcotic analgesia should be avoided except for the peri- decision making, suffer from patient and physician subjec- operative setting because of the potential for tolerance and tivity (10). Endoscopic indices have been developed to abuse in the setting of chronic disease (46). quantify ileal and colonic lesions (43) as well as the pres-ence of recurrent disease at surgical anastomoses (38). In- Mild–Moderate Active Disease
struments have also been developed to assess perianal dis- Ileal, ileocolonic, or colonic disease is treated with an oral ease (44) and quality of life (45). In general, the goal of aminosalicylate (mesalamine 3.2– 4 g or sulfasalazine 3– 6 therapy for Crohn’s disease is to eliminate symptoms and to g daily in divided doses). Alternatively, metronidazole maintain the general “well-being” of patients with as few 10 –20 mg/kg/day may be effective in a proportion of pa- side effects and long-term sequelae as possible. Cost con- tients not responding to sulfasalazine. Ciprofloxacin 1 g straints are becoming increasingly important with the de- daily is equally effective to mesalamine, and controlled ileal velopment of novel biological agents (7, 8) but have not yet release budesonide may become an available alternative in entered into therapeutic decision making.
Large controlled clinical trials completed in the 1970s Working Definitions
and 80s in the United States (47) and Europe (48) demon- Since the last edition of these Practice Guidelines, the work- strated benefits of sulfasalazine over placebo in trials lasting ing definitions of Crohn’s disease activity have not changed up to 16 wk enrolling patients with active ileocolonic and colonic Crohn’s disease. Although less effective than ste-roids, approximately one-half of patients achieved a “clin- MILD–MODERATE DISEASE. Mild–moderate Crohn’s ical remission.” Sulfasalazine has not been consistently ef- disease applies to ambulatory patients able to tolerate oral fective for patients with active disease limited to the small alimentation without manifestations of dehydration, toxicity intestine (47–50). Clinical trials have not been of sufficient (high fevers, rigors, prostration), abdominal tenderness, size to compare sulfasalazine to alternative aminosalicylates painful mass, obstruction, or Ͼ10% weight loss.
(51). Different formulations of mesalamine also have beeneffective for the acute treatment of mild–moderate Crohn’s MODERATE–SEVERE DISEASE. Moderate–severe dis- disease (52–54) at doses of 3.2– 4 g daily although all trials ease applies to patients who have failed to respond to with mesalamine have not been superior to placebo (51, 55).
treatment for mild–moderate disease or those with more Comparisons between mesalamine formulations have not prominent symptoms of fevers, significant weight loss, ab- been sufficient to discriminate between agents for ileal, dominal pain or tenderness, intermittent nausea or vomiting ileocolonic, or colonic disease. Although commonly em- (without obstructive findings), or significant anemia.
ployed in clinical practice, neither rectal mesalamine nor rectal corticosteroids have been adequately evaluated in disease refers to patients with persisting symptoms despite controlled trials to determine an ultimate role as topical the introduction of steroids as outpatients, or individuals presenting with high fever, persistent vomiting, evidence of Metronidazole, 10 or 20 mg/kg, was compared to placebo intestinal obstruction, rebound tenderness, cachexia, or ev- for mild–moderate disease and was more effective for ileo- colitis and colitis than for isolated ileal disease (56). Samplesizes were insufficient to determine a dose response. Met- REMISSION. Remission refers to patients who are asymp- ronidazole was also compared to sulfasalazine in a 16-wk, tomatic or without inflammatory sequelae and includes pa- crossover, Scandinavian trial (57). The initial response was Hanauer et al.
similar although more patients who failed sulfasalazine re- have been evaluated for treatment of active ileal and ileo- sponded to metronidazole than vice versa. There are no cecal Crohn’s disease with consistent benefits comparable to long-term data regarding metronidazole although peripheral prednisone or prednisolone, 40 mg daily (69 –71), and su- neuropathy has been well documented necessitating moni- perior to placebo (72). Steroid-related side effects are en- toring for symptoms or signs of paresthesias.
countered less often with short-term budesonide compared Ciprofloxacin 1 g daily has been evaluated in a short, 6-wk to prednisolone, but some degree of adrenal suppression can controlled trial and compared to mesalamine 4 g daily (58).
Approximately 50% of patients in each group achieved a Over 50% of patients treated acutely with corticosteroids clinical remission. In uncontrolled trials, combinations of cip- will become “steroid dependent” or “steroid resistant” (73), rofloxacin and metronidazole have been reported to provide particularly smokers, or those with colonic disease (74).
superior results to either agent alone (59, 60). In contrast, There are no short- or long-term benefits from the addition controlled trials using combinations of antimycobacterial of an aminosalicylate to corticosteroids (48, 75, 76). Aza- agents have not demonstrated short- or long-term efficacy (61).
thioprine and mercaptopurine have had demonstrable ad- In some countries, controlled-release budesonide formu- junctive benefits to steroids in adults but may require up to lations (currently not FDA approved) are used to treat mild– 4 months to demonstrate a beneficial effect (77). Dose- moderate active Crohn’s disease involving the distal ileum response studies have not been performed with azathioprine or mercaptopurine. Genetic polymorphisms for thiopurine The evidence base for treatment of upper intestinal methyltransferase, the primary enzyme metabolizing mer- (esophageal, gastroduodenal, and jejunoileal) Crohn’s dis- captopurine, have been identified which may afford the ease is inadequate. Symptoms of upper GI Crohn’s disease potential to regulate therapy according to measurement of have been reported (uncontrolled) to respond to acid-reduc- tion therapy with proton pump inhibitors (63– 66). Jejuno- present, the optimal dose and mode of therapeutic monitor- ileitis is often complicated by small bowel bacterial over- ing remain to be established although clinical trials have growth (21, 67), which responds to rotating antibiotics.
demonstrated efficacy for oral azathioprine at 2.5 mg/kg Response to initial therapy should be evaluated within (77). Intravenous loading of azathioprine does not offer a several weeks. Treatment for active disease should be con- therapeutic advantage over 2 mg/kg daily dosing (79). Par- tinued to the point of symptomatic remission or failure to enteral methotrexate, 25 mg subcutaneous or intramuscular continue improvement. Patients achieving remission should on a weekly basis, also is effective in allowing steroid be considered for maintenance therapy. Those with contin- tapering for steroid-dependent patients (80).
ued symptoms should be treated with an alternative therapy Chimeric anti-TNF monoclonal antibody therapy with for mild–moderate disease or advanced to treatment for infliximab is effective for treatment of Crohn’s disease patients moderate–severe disease according to their clinical status.
who have not responded to aminosalicylates, antibiotics, cor-ticosteroids, or immunomodulators (81). Improvement at 4 wk Moderate–Severe Disease
was observed in over 80% of patients treated with 5 mg/kg, and Patients with moderate–severe disease are treated with over 50% achieved a clinical remission. Retreatment is likely prednisone 40 – 60 mg daily or budesonide 9 mg daily (cur- to be necessary on an ongoing basis to prevent relapse (82).
rently not FDA approved), until resolution of symptoms and Infliximab infusions have been associated with both acute and resumption of weight gain (generally 7–28 days). Infection delayed infusion reactions including delayed hypersensitivity or abscess requires appropriate antibiotic therapy or drain- (serum sickness-like) reactions, particularly after prolonged age (percutaneuous or surgical). Infusions of infliximab are intervals (Ͼ12 wk) subsequent to an initial treatment. Other an effective adjunct and may be an alternative to steroid adverse events include the development of antichimeric therapy in selected patients in whom corticosteroids are (HACA) and anti-DNA antibodies (83). It remains to be determined whether concurrent immunomodulation will im- No appropriate dose-ranging studies have been performed prove the clinical response or reduce immunogenicity to the to evaluate conventional steroid dosing or dose schedules for Crohn’s disease (68). Comparable clinical effects have Although elemental diets and possibly liquid polymeric been reported from placebo-controlled and active-compari- diets have demonstrable clinical benefits and reduce inflam- tor trials with approximately 50 –70% receiving the equiv- matory features of active Crohn’s disease, the long-term alent of prednisone, 0.5– 0.75 mg/kg (or 40 mg) daily, course of disease is not altered, compliance is difficult in achieving a clinical remission over 8 –12 wk (47, 48, 69 – adults, and the cost is considerable (84). Elimination diets 71). When a clinical response has been achieved, doses are are not effective at preventing relapse after elemental diets.
tapered according to the rapidity and completeness of re-sponse. Generally, doses are tapered by 5–10 mg weekly Severe–Fulminant Disease
until 20 mg, and by 2.5–5 mg weekly from 20 mg until Patients with persisting symptoms despite introduction of oral steroids or infliximab, or those presenting with high Enteric coated formulations of budesonide, 9 mg daily, fever, frequent vomiting, evidence of intestinal obstruction, Management of Crohn’s Disease in Adults
rebound tenderness, cachexia, or evidence of an abscess chronic fistulization, or perianal fissuring is treated medi- should be hospitalized. Surgical consultation is warranted cally with antibiotics, immunosuppressives, or infliximab. for patients with obstruction or tender abdominal mass. An Perianal/perirectal abscesses require surgical drainage.
abdominal mass should be evaluated via ultrasound or Nonsuppurative perianal complications of Crohn’s disease computerized tomography to exclude an abscess. Abscesses typically respond to metronidazole alone (93) or in combi- require percutaneous or surgical drainage. Once an abscess nation with ciprofloxacin (94). In the absence of controlled, has been excluded or if the patient has been receiving oral maintenance trials, it appears that continuous therapy is steroids, parenteral corticosteroids equivalent to 40 – 60 mg necessary to prevent recurrent drainage (95). The safety of of prednisone are administered in divided doses or as a long-term antibiotic therapy has not been established, and continuous infusion. There is no specific role for total par- patients treated with metronidazole should be monitored for enteral nutrition in addition to steroids. Nutritional support evidence of peripheral neuropathy. There are no controlled via elemental feeding or parenteral hyperalimentation is data regarding immunosuppressives although several series indicated, after 5–7 days, for patients unable to maintain have reported benefits from short-term treatment with cy- closoporine (89, 96, 97) or tacrolimus (90, 91). Long-term Supportive or resuscitative therapy with fluid and elec- data are lacking, and most patients require chronic therapy trolytes is indicated for dehydrated patients. Transfusions with azathioprine or mercaptopurine (96, 97). The latter are necessary in the setting of anemia and active hemor- have not been assessed in controlled trials for perianal rhage. Oral feedings may be continued, as tolerated, for complications of Crohn’s disease although several reports patients without obstructive manifestations or severe ab- describe long-term improvement in perianal disease (98, dominal pain. More severely ill patients or those with evi- A placebo-controlled trial has demonstrated benefits from dence of obstruction should be treated with bowel rest and a series of infliximab, 5 mg/kg, infusions at 0, 2, and 6 wk parenteral nutritional support (85). Obstruction may be sec- in the closure of Crohn’s disease fistulae that had not re- ondary to inflammatory narrowing, fibrotic stricturing or an sponded to prior therapy with antibiotics, corticosteroids, or adhesive process. Differentiation is based on evaluation of immunomodulatory agents (100). A total of 68% and 55% the clinical course (presence or absence of inflammatory of patients achieved closure of at least one, or all fistulae for features) and prior radiographic studies. Adhesive obstruc- at least 4 wk. Duration of closure averaged 12 wk. Long- tions typically respond to nasogastric suction and, in the term strategies for re-infusion or transitioning to oral, im- absence of fever or rebound tenderness, do not commonly munomodulatory agents need to be evaluated.
require emergent surgery. Fibrostenotic disease may re-spond, initially, to bowel rest and corticosteroids but ob- Maintenance Therapy
structive symptoms often recur with steroid tapering. In the Corticosteroids should not be used as long-term agents to presence of an inflammatory mass, broad-spectrum antibi- prevent relapse of Crohn’s disease. Azathioprine/mercap- otics should be instituted along with parenteral corticoste- topurine have demonstrable maintenance benefits after in- ductive therapy with corticosteroids. Mesalamine or aza- Parenteral corticosteroids are indicated for patients with severe–fulminant Crohn’s disease (87). Dose-ranging stud- ileocolonic resections to reduce the likelihood of symptom- ies have not been performed to define an optimal dose or schedule of administration although most clinicians admin- Evidence continues to accumulate regarding the benefits ister parenteral corticosteroids equivalent to 40 – 60 mg of of long-term, maintenance therapy for Crohn’s disease.
prednisone in divided doses or as a continuous infusion.
There continues to be confusion regarding the issues of Intravenous ACTH can be used instead of intravenous cor- “steroid maintenance” versus “steroid dependence.” The ticosteroids but is potentially complicated by adrenal hem- former applies to (clinical trial) evidence of a therapy that orrhage (88). Patients who do not respond to parenteral prevents relapse in a population of patients. The latter is a steroids may respond to intravenous cyclosporine (89) or clinical observation pertaining to individual patients unable tacrolimus (90, 91) although there are no controlled or to taper steroids below a certain dose without developing dose-response data. There are no data on the utility of infliximab for treatment of severe Crohn’s disease.
Patients treated acutely with corticosteroids are unlikely Patients who respond to parenteral corticosteroids or cy- to remain well over 1 yr without some maintenance therapy closporine are gradually transitioned to an equivalent oral (47, 73). Younger patients, those with colonic disease, and regimen and discharged (92). Failure to respond or worsen- cigarette smokers are more likely to become steroid depen- ing symptoms are indications for surgical intervention.
dent (74). Yet, there is a preponderance of evidence thatsteroids are ineffective for maintaining remissions in Perianal Disease
Crohn’s disease. This applies to conventional corticoste- Acute suppuration is an indication for surgical drainage roids (101) as well as controlled-release budesonide (102– with or without placement of setons. Nonsuppurative, Hanauer et al.
Neither early trials using sulfasalazine (47, 48) nor sub- 7–10 days of intensive inpatient management should be sequent trials with mesalamine (107) have demonstrated significant maintenance benefits for Crohn’s disease after The ability to reduce the risk of postoperative recurrence medically induced clinical remissions. In particular, me- after surgical resection no longer justifies prolongation of salamine has not been efficacious in preventing relapse after ineffective medical management to “avoid surgery.” The corticosteroid-induced remissions (76). In contrast, azathio- primary objective of therapy for Crohn’s disease is to restore prine and mercaptopurine have been effective in allowing the patient to health and well-being. Quality of life typically reduction in steroid doses and maintaining remissions after can be restored after surgical resection or stricturoplasty for steroid-inductive therapy (108). It remains to be determined how to “optimize” dose and whether induction of leukope- Therefore, medical therapies are acceptable only if they nia or therapeutic monitoring 6-thioguanine metabolites of- achieve their inductive or maintenance goals safely and fer improved means of assuring a long-term response (78).
effectively with a satisfactory quality of life. Neither pa- Azathioprine at 2.5 mg/kg and mercaptopurine at 1.5 mg/kg tients nor physicians should view surgery as a “failure” have been effective after 3 to 6 months, but the duration of when it can be the swiftest, safest, and most effective route clinical benefits beyond 4 yr has yet to be defined (109).
to physical and psychosocial rehabilitation (6).
Complete blood counts must be monitored carefully early inthe course of treatment and long term, at a minimum of CONTROVERSIAL ISSUES
every 3 months because of the risk of delayed neutropenia(110, 111). Pancreatitis, typically presenting several weeks Many unresolved questions remain regarding practice after initiating therapy (112), occurs in approximately guidelines for Crohn’s disease because of insufficient data 3–15% of patients and recurs with re-introduction of either and experience to make recommendations.
azathioprine or mercaptopurine. An increase risk of neopla-sia has not been observed with the use of purine analogues 1. Despite expanding evidence of the carcinogenic poten- for inflammatory bowel disease (113–115). Maintenance tial of long-standing Crohn’s disease, surveillance data are not yet available for methotrexate (116) whereas cyclosporine is not indicated for maintenance therapy of 2. Evidence regarding the safety of Crohn’s disease ther- apy during pregnancy and lactation is needed.
There continues to be an expanding body of evidence in 3. Additional data are needed regarding optimal schedules favor of postoperative therapy to delay endoscopic and of infusions of infliximab, duration of response, safety clinical recurrence of Crohn’s disease (119, 120). Treatment of long-term use, and requisites for concurrent therapies with sulfasalazine at doses Ͼ3 g daily (121) and me- with aminosalicylates, antibiotics, steroids (or steroid salamine, Ն3 g daily (107), reduce the risk of postoperative recurrence for up to 3 yr in subgroups of patients. Short- 4. The optimal dose and formulation of mesalamine ther- term administration of high-dose metronidazole, 20 mg/kg, apy (including potential benefits of rectal mesalamine) also can reduce the likelihood of recurrence for up to 1yr, for acute and maintenance therapy of Crohn’s disease but longer duration trials at lower, more tolerable doses are necessary to evaluate antibiotic therapy (122). Cigarette 5. Optimal dosing, timing in relation to corticosteroid or smoking has a detrimental impact upon disease recurrence anti-TNF therapy, utility of therapeutic drug monitor- adding more rationale to encourage cessation (120).
ing, and duration of azathioprine and mercaptopurineremain to be established.
6. Dose-ranging and maintenance studies of methotrexate INDICATIONS FOR SURGERY
7. Comparative benefits of budesonide regarding long- Surgical resection, stricturoplasty, or drainage of abscesses term efficacy, safety, and cost need to be evaluated.
are indicated to treat complications or medically refractory 8. Additional studies of antibiotics as active and mainte- nance (including postoperative maintenance) therapies Surgical resection, aside from total colectomy and ileos- tomy for Crohn’s disease limited to the colon, rarely “cures” 9. Additional studies of probiotic therapies are needed.
Crohn’s disease (119, 123). Nevertheless, surgical interven- 10. Short- and long-term studies assessing efficacy and tion is required in up to two-thirds of patients to treat safety of cyclosporine, tacrolimus, and mycophenolate intractable hemorrhage, perforation, persisting or recurrent mofetil are needed as are exploratory studies of novel obstruction, abscess (not amenable to percutaneous drain- age), or unresponsive fulminant disease. The most common 11. Additional clinical data are required regarding novel indications for surgical resection are refractory disease de- biological agents targeting TNF, alternative cytokines spite medical therapy or medication side effects (steroid and their receptors, and NF␬ beta.
dependence) (124, 125). Patients who fail to improve within 12. Combination therapies incorporating “conventional” Management of Crohn’s Disease in Adults
and evolving therapeutic approaches require controlled 18. Platell C, Mackay J, Collopy B, et al. Anal pathology in patients with Crohn’s disease. Aust N Z J Surg 1996;66:5–9.
19. Lapidus A, Bernell O, Hellers G, et al. Clinical course of 13. Outcome studies comparing medical versus surgical colorectal Crohn’s disease: A 35-year follow-up study of 507 patients. Gastroenterology 1998;114:1151– 60.
14. Outcome studies assessing comparative cost– benefit 20. Ogorek CP, Fisher RS. Differentiation between Crohn’s dis- assessments of alternative strategies are needed.
ease and ulcerative colitis. Med Clin North Am 1994;78:1249 –58.
21. Touze I, et al. Diffuse jejuno-ileitis of Crohn’s disease: A Reprint requests and correspondence: Stephen B. Hanauer,
separate form of the disease? Gastroenterol Clin Biol 1999; M.D., University of Chicago, Section of Gastroenterology, MC 9028, 5841 South Maryland Avenue, Room 6601, Chicago, IL 22. Wagtmans MJ, et al. Clinical aspects of Crohn’s disease of the upper gastrointestinal tract: A comparison with distal Received Dec. 29, 2000; accepted Dec. 29, 2000. Crohn’s disease. Am J Gastroenterol 1997;92:1467–71.
23. Souto JC, et al. Prothrombotic state and signs of endothelial lesion in plasma of patients with inflammatory bowel disease.
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