Oral mesalamine (as delayed-release tablets or extended-release capsules) is used for the management of mildly to moderately active ulcerative colitis. In addition, mesalamine 400-mg delayed-release tablets (Asacol) are used to maintain clinical remission in patients with ulcerative colitis, while mesalamine extended-release capsules (Pentasa) and mesalamine 1.2-g delayed-release tablets (Lialda) are used to induce clinical remission in patients with mildly to moderately active ulcerative colitis. Mesalamine rectal suspension is used in the management of mildly to moderately active distal ulcerative colitis, including ulcerative proctosigmoiditis and ulcerative proctitis. Mesalamine rectal suppositories are used in the management of active ulcerative proctitis. The drug is used in the management of these conditions in conjunction with usual supportive and dietary measures. Oral preparations of the drug may be preferable to rectal preparations in patients with extensive inflammatory bowel disease, since efficacy of rectal preparations may be limited to disease distal to the splenic flexure.
Mildly to Moderately Active Ulcerative Colitis
Delayed- or extended-release oral preparations of mesalamine have been effective in patients with mildly to moderately active ulcerative colitis, including those with proctitis. When used in the management of mildly to moderately active ulcerative colitis, oral mesalamine has reduced disease activity, including improvement in sigmoidoscopic appearance of the bowel, rectal bleeding, abdominal/rectal pain, and stool consistency, frequency, and urgency.
Efficacy of mesalamine 400-mg delayed-release tablets (Asacol) for the management of mildly to moderately active ulcerative colitis has been established in 2 placebo-controlled studies. In one randomized, double-blind, multicenter, dose-ranging (1.6 or 2.4 g daily) study, reduction of disease activity (measured by improvement in sigmoidoscopic appearance) was reported in 49 or 27% of patients receiving mesalamine (2.4 g daily) or placebo, respectively, while no consistent evidence of efficacy was observed with the 1.6-g daily dosage. In addition, substantially more patients receiving mesalamine (2.4 g daily) showed improvement in rectal bleeding and stool frequency than those receiving placebo.
In the other randomized, double-blind, 6-week study, sigmoidoscopic improvement occurred in 74 or 26% of patients receiving mesalamine delayed-release tablets (4.8 g daily) or placebo, respectively. More patients receiving mesalamine have shown improvement in overall symptoms than those receiving placebo.
Efficacy of mesalamine extended-release capsules for the management of mildly to moderately active ulcerative colitis has been established in 2 randomized, double-blind, placebo-controlled, dose-ranging studies. Primary efficacy parameters in these studies were measured by clinical improvement assessed by clinician global assessment (proportion of patients with complete or marked improvement), sigmoidoscopic index (objective measure of disease activity rated by mucosal vascular pattern, erythema, friability, granularity/ulcerations, improvement from baseline in mucopus), and treatment failure (proportion of patients developing severe or fulminant ulcerative colitis requiring corticosteroid therapy, hospitalization, or worsening of the disease within 7 days of therapy or lack of substantial improvement by 14 days of therapy). Secondary efficacy parameters were assessed by clinical symptoms (e.g., stool consistency/frequency/urgency, rectal bleeding, abdominal/rectal pain). Patients received 2 g (1 g twice daily) or 4 g (1 g 4 times daily) of mesalamine extended-release capsules daily. In one of these studies, clinician global index of treatment success was reported in 59, 57, or 36% of patients receiving a daily 4-g dosage of mesalamine, 2-g dosage of mesalamine, or placebo, respectively, while reductions in sigmoidoscopic index (rated by a standard 15-point scale) were 5, 4.3, or 2.5, respectively. Treatment failure was reported in 9, 18, or 22% of patients receiving a daily 4-g dosage of mesalamine, 2-g dosage of mesalamine, or placebo, respectively. Similar efficacy was observed in the other placebo-controlled study; clinician global index of treatment success was reported in 55, 41, or 31% of patients receiving a daily 4-g dosage of mesalamine, 2-g dosage of mesalamine, or placebo, respectively, while reductions in sigmoidoscopic index were 3.8, 2.6, or 1.6, respectively, and treatment failure was reported in 9, 17, or 31% of patients, respectively. While the 4-g daily dosages of mesalamine produced consistent improvement in primary parameters in these studies, the 2-g daily dosage was associated with inconsistent results. Consistent improvement in secondary parameters and induction of remission (assessed by endoscopic and symptomatic endpoints) also were observed with the 4-g daily dosages.
Induction of Remission of Ulcerative Colitis
Safety and efficacy of oral mesalamine 1.2-g delayed-release tablets (Lialda) for induction of remission in patients with active, mild to moderate ulcerative colitis were evaluated in two 8-week randomized, double-blind, placebo-controlled trials that included 517 patients. Patients were randomized to receive a 2.4- or 4.8-g daily dosage of mesalamine or placebo. The primary efficacy end point at week 8 of treatment was the percentage of patients achieving remission (defined as an Ulcerative Colitis Disease Activity Index [UC-DAI] of 1 or less, with scores of zero for rectal bleeding and stool frequency, and a sigmoidoscopy score reduction of 1 point or more from baseline). The incidence of remission at 8 weeks was about 34-41, 29-41, or 13-22% in patients receiving mesalamine 2.4 g daily, mesalamine 4.8 g daily, or placebo, respectively. Patients receiving mesalamine 2.4 or 4.8 g daily also experienced greater benefit in secondary efficacy parameters (e.g., clinical improvement, treatment failure, clinical remission, sigmoidoscopic appearance) compared with patients receiving placebo.
Maintenance of Remission of Ulcerative Colitis
Safety and efficacy of oral mesalamine 400-mg delayed-release tablets (Asacol) for maintenance therapy in patients with ulcerative colitis were evaluated in a 6-month randomized, double-blind, placebo-controlled study that included 264 patients. Patients were randomized to receive a daily 0.8-g dosage of mesalamine (90 patients), 1.6-g dosage of mesalamine (87 patients), or placebo (87 patients). Treatment success or failure was defined as maintenance of remission after 6 months or relapse during the study, respectively. Treatment success in patients receiving a daily 0.8-g mesalamine dosage was not statistically different from patients receiving placebo. Endoscopic remission of ulcerative colitis (based on intention-to-treat analysis) in all 174 patients receiving either 1.6 g of mesalamine daily or placebo, was reported in 61 out of 87 patients (70.1%) receiving mesalamine or 42 out of 87 patients (48.3%) in those receiving placebo. Pooled analysis of data from 4 comparator-drug (sulfasalazine) controlled maintenance trials indicate that treatment success occurred in 59 or 69% of patients receiving mesalamine extended-release capsules (0.8-2.8 g daily) or sulfasalazine (2-4 g daily), respectively; however, the difference in response was not statistically significant.
Mildly to Moderately Active Distal Ulcerative Colitis
When used in the management of active distal ulcerative colitis, including proctosigmoiditis or proctitis, mesalamine rectal suspension has reduced stool frequency, rectal bleeding, mucosal inflammation, and abdominal pain. When used in the management of active ulcerative proctitis, mesalamine rectal suppositories have reduced stool frequency, rectal bleeding, and mucosal inflammation. Patients most likely to respond to rectal mesalamine are those with disease confined to the distal 20-40 cm of the colon. Clinical remission has occurred in 30-90% of patients with these conditions receiving rectal mesalamine; however, relapse usually has occurred following discontinuance and, rarely, during continued use of the drug. In responsive disease, improvement usually is evident within 1 week to 3 months of initiation of therapy, and some patients may need prolonged periods of rectal mesalamine therapy to achieve improvement. However, some clinicians have suggested that if clinical remission is not achieved within 2-4 months of initiation of rectal mesalamine therapy, it is unlikely that further improvement would be achieved with more prolonged therapy. There is limited evidence that the efficacy of rectal mesalamine can be sustained during chronic therapy, but additional study and experience are needed.
The optimum role of rectal mesalamine in the management of active ulcerative colitis remains to be elucidated, particularly relative to other therapies (e.g., oral sulfasalazine) and in patients with severe and/or refractory disease. Clinical studies have shown that rectal mesalamine is more effective than placebo and at least as effective as oral sulfasalazine in reducing signs and symptoms (e.g., stool frequency, rectal bleeding, mucosal inflammation) of these conditions. However, many patients who were already receiving oral sulfasalazine therapy continued to receive the drug when rectal mesalamine was initiated, and combined therapy may be necessary for optimal response in many such patients. In addition, some clinicians state that sulfasalazine therapy should be continued to minimize the risk of an exacerbated flare developing secondary to withdrawal of the drug and the delayed onset of mesalamine. Rectal mesalamine also was at least as effective as rectal hydrocortisone in patients with sigmoidoscopically or radiographically confirmed mild to moderate distal ulcerative colitis.
In patients with ulcerative colitis whose symptoms progress despite a recommended regimen of oral sulfasalazine and/or rectal or oral corticosteroids, therapy with rectal mesalamine may be beneficial. Combined therapy with rectal mesalamine and oral sulfasalazine and/or rectal or oral corticosteroids may produce additive effects in reducing signs and symptoms of refractory ulcerative colitis, although combined rectal mesalamine and oral corticosteroid therapy may be no more effective than an oral corticosteroid alone in severe disease. In addition, although efficacy of rectal mesalamine may be limited in patients with severe ulcerative colitis, the drug has been effective in some patients refractory to, or intolerant of, oral sulfasalazine and/or rectal or oral corticosteroids.
Clinical studies have shown that mesalamine rectal suppositories are more effective than placebo in reducing signs and symptoms (e.g., stool frequency, rectal bleeding, mucosal inflammation) of active ulcerative proctitis. Efficacy of mesalamine rectal suppositories appears to be independent of patients' gender, duration and extent of disease, or duration of current episode.
Mesalamine has been used for the management of active Crohn's disease.
Crohn's disease, a chronic inflammatory bowel disease, is characterized by focal, asymmetric, transmural, and occasionally, granulomatous inflammation affecting the GI tract (most frequently the ileum and colon) with a potential for systemic and extraintestinal complications and recurrent flare-ups.The etiology and pathogenesis of Crohn's disease have not been elucidated, but they appear to be multifactorial. Many clinicians have suggested that environmental (e.g., smoking, intestinal bacterial flora), immunologic (increased mucosal IgG), and genetic factors may contribute to the development of the disease. The disease can develop in any age group, although disease onset is more frequent in adolescents and young adults. Diagnosis of Crohn's disease is difficult because of the heterogenicity of manifestations, overlapping features with other inflammatory bowel diseases, and/or presentation without GI symptoms (i.e., extraintestinal symptoms). Symptoms of chronic or nocturnal diarrhea, abdominal pain, weight loss, fever, and rectal bleeding may be indicative of underlying inflammatory processes. Clinical manifestations of the disease include pallor, cachexia, abdominal mass or tenderness, and perianal fissures, fistulae, or abscesses. In children, growth arrest or loss of height may be one of the initial manifestations of Crohn's disease. Diagnosis and consequent treatment of Crohn's disease is based on clinical, laboratory, and diagnostic evaluations, including radiologic examinations and/or endoscopy.
Crohn's disease is not medically or surgically curable and generally is managed by reducing inflammation, improving quality of life, and minimizing short- and long-term toxicity (associated with treatment) and complications. Choice of treatment depends on several factors, including the severity, location (stomach/duodenum, jejunum, ileum, colon, rectum, anus), extent (localized, diffused), and pattern/behavior (principally inflammatory, fistulizing, or fibrostenotic) of the disease. In addition, previous history of the disease (e.g., intestinal surgery, response to previous treatment), extraintestinal complications, certain patient characteristics (e.g., age, gender, lifestyle, nutrition, compliance, social and emotional status, resources, education, functional ability), and other factors (e.g., growth in children) should be considered when initiating therapy. Most currently available drugs for Crohn's disease including amino derivatives of salicylic acid (e.g., mesalamine, balsalazide, olsalazine, sulfasalazine), conventional corticosteroids (hydrocortisone, methylprednisolone, prednisolone, prednisone), more recently available corticosteroids (e.g., budesonide, having substantial topical anti-inflammatory activity and lower systemic availability than conventional corticosteroids), corticotropin, biologic response modifiers (e.g., adalimumab, infliximab, natalizumab), and immunosuppressive or immunomodulating agents (e.g., azathioprine, cyclosporine, mercaptopurine, methotrexate, mycophenolate mofetil, tacrolimus, thalidomide,) are used to manage chronic inflammation of the intestinal mucosa. In addition, since the intestinal bacterial flora may be associated with intestinal inflammation, anti-infective agents (metronidazole and/or ciprofloxacin) may be used in the management of mildly to moderately and moderately to severely active disease. Many clinicians currently state that therapy for inflammatory bowel disease (e.g., Crohn's disease) should be disease modifying rather than merely symptomatic whenever possible.
According to criteria established by the American College of Gastroenterology, severity of Crohn's disease may be classified as mildly to moderately active, moderately to severely active, or severely active to fulminant disease. Patients generally considered to be in remission are those who are asymptomatic, those without inflammatory sequelae, or those who have responded to acute medical intervention or have undergone surgical resection and have no gross evidence of residual disease.
Mildly to Moderately Active Crohn's Disease
Patients are considered to have mildly to moderately active Crohn's disease if they are ambulatory and can tolerate oral alimentation without experiencing more than 10% of body weight loss or presenting manifestations of dehydration, toxicity (e.g., high fever, rigor, prostration), or abdominal tenderness/painful mass/obstruction. For the initial management of ileal, ileocolonic, or colonic mildly to moderately active Crohn's disease, many clinicians recommend preparations containing or being metabolized to 5-aminosalicylic acid (e.g., mesalamine, sulfasalazine) or possibly, budesonide (a relatively new corticosteroid). In general, the choice of 5-aminosalicylic acid derivatives should be based on the location of the disease.
Oral formulations of mesalamine that are in a slow- or pH-dependent matrix can deliver therapeutic concentrations of the drug to the stomach, small bowel, or distal ileum and therefore are used in patients with gastroduodenal and/or ileal Crohn's disease. Results of placebo-controlled studies on the efficacy of oral mesalamine preparations in the management of mildly to moderately active Crohn's disease have been equivocal, since administration of the drug was not consistently more effective than placebo.
(See Active Crohn's Disease under Crohn's Disease: Use of Mesalamine in Crohn's Disease, in Uses.)
Sulfasalazine has not been consistently effective in patients with ileal disease and it is recommended that the drug be used in ileocolonic or colonic disease, preferably with left-sided condition, restricted to the colon. Budesonide, which appears to be more effective than mesalamine in the treatment of mildly to moderately active disease, generally is used in patients with Crohn's disease involving the ileum and/or ascending colon. Therefore, some clinicians recommend that for initial management of Crohn's disease involving the ileum and/or ascending colon, patients should receive 8-16 weeks of therapy with budesonide delayed-release capsules and those with left-sided disease restricted to the colon should receive 16 weeks of therapy with sulfasalazine. Individuals who do not respond to therapy with sulfasalazine or budesonide or those who develop hypersensitivity to sulfasalazine should receive a conventional corticosteroid (e.g., prednisone, prednisolone). Therapy with metronidazole and/or ciprofloxacin also has been recommended in patients who do not respond to sulfasalazine. and
Currently, there are inadequate data regarding the management of upper GI (e.g., esophageal, gastroduodenal, jejunoileal) Crohn's disease. Results of uncontrolled studies in a limited number of patients indicate that symptoms of upper GI Crohn's disease may respond to proton-pump inhibitors (e.g., omeprazole), frequently given in conjunction with corticosteroids or other immunosuppressant agents. Jejunoileitis, which is often accompanied by overgrowth of bacteria in the small intestine, may be treated with anti-infective therapy.
Response to initial therapy should be evaluated within several weeks. Treatment of active disease should be continued until remission of symptoms or, alternatively, treatment failure (lack of continued improvement) occurs. Patients who achieve remission should be considered for maintenance therapy
(see Maintenance of Remission of Crohn's Disease under Crohn's Disease: Treatment, in Uses), while alternative therapy (according to clinical status and possible reassessment of disease severity) should be instituted in those whose disease continues to be symptomatic. (See Moderately to Severely Active Crohn's Disease under Crohn's Disease: Treatment, in Uses.)
Moderately to Severely Active Crohn's Disease
Patients are considered to have moderately to severely active Crohn's disease if they have failed to respond to therapy for mildly to moderately active disease or have developed more severe symptoms (e.g., fever, substantial weight loss, abdominal pain/tenderness, intermittent nausea or vomiting, significant anemia) than those with mildly to moderately active disease, but no evidence of obstruction. Conventional corticosteroids (e.g., prednisone, prednisolone) or possibly, budesonide may be used for the management of moderately to severely active disease until resolution of symptoms and appropriate weight gain occurs (usually within 7-28 days). Most patients (greater than 50%), however, become corticosteroid dependent or resistant. Addition of 5-aminosalicylic acid derivatives to corticosteroids has not been associated with short- or long-term benefit, while adjunctive use of azathioprine or mercaptopurine with corticosteroids has been found to be beneficial. It should be considered, however, that up to 3-4 months of adjunctive therapy with these immunosuppressants may be needed before substantial benefits (including remission) become apparent, and, therefore, these drugs mainly are used for maintenance therapy. Parenteral methotrexate also has been shown to be effective in allowing corticosteroids to be tapered in corticosteroid-dependent patients. In addition, limited data indicate that mycophenolate mofetil may be beneficial in the management of moderately to severely active Crohn's disease.
Infliximab or, possibly, thalidomide may be used in patients who have had an inadequate response to conventional therapies (e.g., corticosteroids, mesalamine sulfasalazine, azathioprine, mercaptopurine, methotrexate) or in whom conventional therapies are contraindicated.
Anti-infective therapy (e.g., metronidazole, ciprofloxacin, other broad spectrum antibiotics) or drainage (percutaneous or surgical) may be necessary when infection or abscess is present in patients with moderately to severely active Crohn's disease.
Severely Active to Fulminant Crohn's Disease
Patients with severely active to fulminant Crohn's disease usually include those who have persisting symptoms despite oral corticosteroid or infliximab therapy or those who develop severe manifestations (e.g., high fever, persistent vomiting, rebound tenderness, evidence of GI obstruction or abscess) of the disease. Individuals without an abscess or those who have been receiving oral corticosteroids should be treated with parenteral corticosteroids, given as a continuous IV infusion or, possibly, by intermittent IV injections in divided doses. In patients with severe disease, IV corticotropin (ACTH) has been used rarely. Patients with an inflammatory abdominal mass should receive broad-spectrum anti-infectives in conjunction with parenteral corticosteroids; these individuals usually have intestinal perforation and surgery would be needed after an appropriate waiting period. In those unable to tolerate nutritional requirements, elemental feeding or parenteral hyperalimentation is indicated after 5-7 days of parenteral corticosteroid therapy.
Limited data indicate that patients who do not respond to parenteral corticosteroids may respond to other immunosuppressive agents (e.g., IV cyclosporine, tacrolimus). Although definitive data are lacking concerning the use of infliximab in patients with severe Crohn's disease, some clinicians state that the drug may be used in patients with severe disease who do not respond to parenteral corticosteroids. Individuals who have responded to parenteral therapy (e.g., corticosteroids, cyclosporine, tacrolimus) may be switched gradually to the equivalent oral therapy, while surgery is indicated in those who do not respond or whose symptoms worsen.
Perianal and Fistulizing Crohn's Disease
Patients with acute suppurative disease, including perianal and/or perirectal abscesses, often require surgical intervention. Although controlled studies regarding the use of anti-infective agents in the management of perianal and fistulizing Crohn's disease are lacking, limited data suggest that use of metronidazole or ciprofloxacin alone or, alternatively, combination therapy with the 2 anti-infectives may provide benefit in nonsuppurative fistulizing disease.
Metronidazole and/or ciprofloxacin mainly are used for short-term therapy, although relapse usually occurs upon discontinuance; however, safety and efficacy of long-term anti-infective therapy have not been established and further study and experience are needed to elucidate fully the long-term benefits of such therapy. In addition, there are no controlled studies with fistula closure, as the primary end point, demonstrating that immunosuppressive therapy with azathioprine or mercaptopurine is effective in fistulizing disease. Current clinical practice concerning use of these agents is based on a pooled analysis of 5 controlled trials in which fistula closure was considered a secondary end point and in several uncontrolled case studies. Data from these studies indicate that long-term (several years) therapy with azathioprine or mercaptopurine may be effective in the management of fistulizing Crohn's disease. Use of cyclosporine for fistulizing disease is based on results of uncontrolled case studies; short-term administration of cyclosporine has been beneficial in several patients. Results of one controlled and several uncontrolled case studies have shown that tacrolimus also may be beneficial in the management of fistulizing Crohn's disease.
Infliximab has been effective in the management of fistulizing Crohn's disease; the drug is used to reduce the number of draining enterocutaneous and rectovaginal fistulas and to maintain fistula closure. Further study is needed to determine the relative safety and efficacy of infliximab and other therapies used for the management of fistulizing Crohn's disease (e.g., azathioprine, ciprofloxacin and/or metronidazole, mercaptopurine, surgical intervention). Some clinicians suggest that, although data are not available to date to support use of infliximab as first-line therapy for fistulizing Crohn's disease, use of the drug should be considered when fistulas have not responded to appropriate anti-infective regimens (e.g., ciprofloxacin and/or metronidazole) and/or immunosuppressive therapy (e.g., azathioprine, mercaptopurine).
Maintenance of Remission of Crohn's Disease
The goals of maintenance therapy are to prolong periods of remission and improve quality of life. Once remission has been achieved, choice of maintenance therapy should be evaluated individually, based on the condition (e.g., length of remission, type of remission [medical or surgical]) and characteristics of each patient. Maintenance of remission remains problematic because of the difficulty in identifying subgroups of patients who undergo early clinical or subclinical flare-ups and who would benefit from appropriate and timely treatment.
There are no drug treatments available to prevent relapse of Crohn's disease; however, clinical relapse may be delayed by using anti-inflammatory or anti-infective agents, or to a greater extent by using immunomodulating drugs. Most patients who have received corticosteroid therapy for active Crohn's disease (including conventional corticosteroids or budesonide) usually develop relapse within a year, unless they receive maintenance therapy. Neither sulfasalazine nor mesalamine appears to be effective in maintaining remission of Crohn's disease after medically induced clinical remission. Some clinicians state that mesalamine may be the optimal therapy for maintenance of remission in patients with ileal or jejunoileal disease, although the drug is associated with substantially lower efficacy in those with colonic disease. Mesalamine has been used with equivocal results for maintenance therapy of Crohn's disease. In some, but not other, placebo-controlled studies in patients with medically induced remission, relapse rates were lower with mesalamine relative to placebo. In several placebo-controlled studies, budesonide was effective for maintenance therapy in patients with medically-induced remission for up to about 6 months of therapy; however, no substantial difference was observed at 1 year of therapy.
Both azathioprine and mercaptopurine are effective for maintenance therapy in patients with medically-induced remission of Crohn's disease. Response generally is apparent after 3-6 months of therapy. Although clinical benefits beyond 4 years of therapy remain to be established, limited data indicate that such benefits may persist longer than 4 years. Methotrexate also has been used effectively for maintenance of Crohn's disease. Infliximab may be used to maintain clinical remission in patients with moderately to severely active disease who have had an inadequate response to conventional therapies (e.g., azathioprine, corticosteroids, mercaptopurine, mesalamine, sulfasalazine).
Drug therapy for prevention of disease relapse following surgically induced remission has not been firmly established. Limited data indicate that mesalamine or, possibly, sulfasalazine may reduce the risk of postoperative recurrence for up to 3 years. However, equivocal results were reported in patients with surgically induced remission receiving mesalamine.
(See Maintenance of Remission of Crohn's Disease under Crohn's Disease: Use of Mesalamine in Crohn's Disease, in Uses.)In patients with surgically induced remission of Crohn's disease, mercaptopurine appears to be more effective than placebo and efficacy of azathioprine appears to be similar to that of mesalamine. Limited data also indicate that high-dose (20 mg/kg) metronidazole therapy may reduce postoperative recurrence for up to 1 year; however, long-term studies are needed to elucidate further the efficacy of such therapy. Ornidazole (another nitroimidazole-derivative anti-infective agent; currently not commercially available in the US) has been shown to prevent early postoperative endoscopic recurrence and postpone symptomatic relapse.
Surgery in Patients with Crohn's Disease
Surgical resection is not a cure for Crohn's disease. However, surgical intervention is needed in greater than 60% of patients to treat intractable hemorrhage, perforation, persistent or recurrent obstruction, abscess, or unresponsive fulminant disease. Some clinicians state that since therapy to reduce the risk of postoperative recurrence is available
(see Maintenance of Remission of Crohn's Disease under Crohn's Disease: Treatment, in Uses), there is little justification to prolong ineffective drug therapy and delay surgery in patients with complications of Crohn's disease whose quality of life would be improved by surgical intervention.
Crohn's Disease in Pediatric Patients
Crohn's disease in pediatric patients generally is managed by controlling disease activity and symptoms, providing nutritional intervention (to ensure adequate food intake and reverse impaired weight and growth velocities) and psychologic support, and monitoring for extraintestinal manifestations (e.g., arthralgias, arthritis). Similar to adults, choice of therapy depends on severity and location of the disease.
Sulfasalazine (initial dosage of 25-40 mg/kg daily increased to 50-75 mg/kg daily [up to 4 g daily], given with 1 mg of folic acid daily) or mesalamine (initial oral dosage of 20-30 mg/kg daily increased up to 60 mg/kg daily) has been used in pediatric patients with mild ileal, ileocecal, ileocolonic, or colonic Crohn's disease; topical mesalamine or corticosteroid enemas may be used in left-sided colitis. Systemic corticosteroids (e.g., prednisone 1-2 mg/kg daily up to 60 mg daily) usually have been used in those with mild esophageal or gastroduodenal disease. Children with mild perianal disease or those intolerant to sulfasalazine or mesalamine may receive metronidazole (10-20 mg/kg daily, up to a maximum of 1 g daily). Budesonide (as pH-dependent-release preparations administered in a dosage of 0.45 mg/kg daily up to a maximum dosage of 9 mg daily) has been used for the management of mildly to moderately active Crohn's disease in a limited number of children 9.5-18 years of age. Budesonide is more effective than mesalamine, but less effective than conventional corticosteroids (e.g., prednisone).
For the management of moderately to severely active disease, systemic corticosteroids (e.g., prednisone or methylprednisolone 1-2 mg/kg daily up to 60 mg daily) may be used; some clinicians suggest that an immunosuppressive agent (e.g., mercaptopurine) be used conjunctively with corticosteroids, once initial diagnosis is made. IV metronidazole or another anti-infective should be used with corticosteroids if infection or abscess is present.
In pediatric patients who become corticosteroid dependent or resistant, mercaptopurine or azathioprine may be used, while methotrexate therapy (10-15 mg/m) should be considered in those who had an inadequate response to or did not tolerate mercaptopurine or azathioprine. Infliximab has been used in a limited number of pediatric patients for the management of the signs and symptoms of active Crohn's disease. In children with refractory perianal fistulas, use of cyclosporine (4 mg/kg daily) may be considered.
Use of Mesalamine in Crohn's Disease
Active Crohn's Disease
Extended-release oral mesalamine preparations have been used in the management of Crohn's disease. It has been suggested that administration of extended-release oral mesalamine may be especially useful in the management of this condition since the drug is partially released from these preparations in the ileum, which may facilitate an anti-inflammatory effect in patients with ileitis.
Efficacy of oral mesalamine has been studied in several placebo-controlled studies in patients with mildly to moderately active Crohn's disease. In many of these studies, the Crohn's Disease Activity Index (CDAI) was used for clinical assessment. The CDAI score is based on subjective observations by the patient (e.g., the daily number of liquid or very soft stools, severity of abdominal pain, general well-being) and objective evidence (e.g., number of extraintestinal manifestations, presence of an abdominal mass, use or nonuse of antidiarrheal drugs, the hematocrit, body weight). Results of these studies have been equivocal.
In a 16-week multicenter, randomized, double-blind, dose-ranging, placebo-controlled study in 310 adults with mildly to moderately active ileal, ileocolonic, or colonic Crohn's disease, patients were randomized to receive placebo or oral mesalamine extended-release capsules (Pentasa) in a dosage of 1, 2, or 4 g daily. Remission (defined as a reduction from baseline CDAI of more than 50 points and a final CDAI score of less than 150 assessed at the final visit) was observed in 43 or 18% of patients receiving mesalamine 4 g daily or placebo, respectively, while a mean reduction of 72 or 21 points from baseline CDAI was observed, respectively. In addition, substantial improvements in time to remission and percentage of treatment failures (secondary parameters) also were observed in patients receiving the highest mesalamine dosage, when compared with placebo. CDAI reductions from baseline in patients receiving 1- or- 2 g daily dosages of mesalamine did not differ significantly from those receiving placebo. Location of the active disease was not associated with statistically different responses, although mean reductions of 93 points from baseline CDAI were observed in patients with ileitis receiving mesalamine 4 g daily compared with reductions of 2 points from baseline CDAI in those receiving placebo.
Investigators of this study conducted a second trial, very similar to the one described. In this 16-week randomized, double-blind, placebo-controlled study, patients with mildly to moderately active Crohn's disease were randomized to receive placebo or mesalamine (2 or 4 g daily) administered orally as extended-release capsules. Pooled analysis of the 2 trials in combination with data from another randomized, double-blind, placebo-controlled study in patients with mildly to moderately active Crohn's disease indicate that mesalamine, given in 4-g daily dosages, was associated with an 18-point greater reduction in CDAI than placebo, a difference that was not considered clinically important.
Results of several other placebo-controlled studies also failed to show an improved clinical response to oral mesalamine extended-release preparations when compared with placebo; however, in several of the studies, a lower dosage (e.g., 1 or 2 g daily) was used. Some clinicians state that high oral mesalamine dosages (exceeding 3 g daily) usually are needed for the treatment of Crohn's disease.
Substantial benefit of mesalamine versus placebo was observed in a small 16-week randomized, double-blind, placebo-controlled study in 38 adults with mildly to moderately active ileocolonic or colonic Crohn's disease (mean baseline CDAI of 231.7 or 204.8 in patients receiving mesalamine or placebo, respectively) who were randomized to receive oral mesalamine 400-mg delayed-release tablets (Asacol; 20 patients) in a dosage of 800 mg 4 times daily or placebo (18 patients). Individuals were permitted to continue oral corticosteroids if they were receiving fixed dosages of the drugs (not exceeding 20 mg of prednisone daily or equivalent). Complete clinical response (defined as a reduction from baseline CDAI of 70 points or more and a final CDAI score of less than 150, assessed after 4, 8, and 16 weeks of treatment) was observed in 60 or 22% of patients receiving mesalamine or placebo, respectively. Partial clinical response (defined as a reduction from baseline CDAI of 70 points or more, and a final CDAI score of 150 or more, assessed after 4, 8, and 16 weeks of treatment) was observed in 15 or 0% of patients receiving mesalamine or placebo, respectively.
Conventional or more recently available corticosteroids appear to be more effective than mesalamine in the management of active Crohn's disease. Results of a comparator-drug (mesalamine versus budesonide) controlled study (patients having a median baseline CDAI score of 272) have shown that clinical improvement was substantially lower in adults receiving 2-g twice daily dosages of oral mesalamine delayed-release tablets than in those receiving 9-mg daily dosages of oral budesonide delayed-release capsules (45% for mesalamine versus 69% for budesonide). In addition to a higher clinical improvement rate, quality-of-life scores (e.g., anxiety, depressed mood, sense of well-being, self-control, general health, vitality) also were improved to a greater extent in patients receiving budesonide than in those receiving mesalamine.
Rectal administration of mesalamine has been effective in a limited number of patients for the management of active Crohn's disease, but the role of such therapy in this condition is not as well defined as in the management of ulcerative colitis. In addition, rectal mesalamine appears to be less effective in reducing signs and symptoms of Crohn's disease than those of ulcerative colitis. Efficacy in patients with ileitis alone has not been established, but many clinicians suggest that the limited delivery of rectally administered drug to the ileum makes it unlikely that substantial clinical benefit would be achieved in such patients.
Maintenance of Remission Crohn's Disease
The relative efficacy of mesalamine as maintenance therapy for Crohn's disease is controversial, since the drug has been used with equivocal results. Some clinicians state that oral mesalamine may be the optimal treatment in patients with ileal or jejunoileal disease; however, the drug is associated with substantially lower efficacy in those with colonic disease. Several controlled studies indicate that use of oral mesalamine in the management of inactive ileitis is associated with a substantially lower frequency of relapse than placebo. In one double-blind placebo-controlled trial, oral mesalamine extended-release capsules (2 g daily) reduced frequency of relapse only in those patients who were in remission for less than 3 months at initiation of therapy; average remission rates at 2 years of therapy were 45 or 29% in patients receiving oral mesalamine or placebo, respectively. In addition, results of a double-blind, placebo-controlled trial in 125 patients in remission (CDAI score of less than 150) indicate that oral mesalamine delayed-release tablets (2.4 g daily) did not substantially reduce the frequency of relapse at 3 or 6 months; relapse (defined as CDAI score of greater than 150) rates at 3 months of therapy were 12 or 22%, respectively, in patients receiving oral mesalamine or placebo, while such rates at 6 months of therapy were 28 or 41%, respectively. However, relapse rates in patients receiving mesalamine (34%) or placebo (55%) were significantly different at 12 months of therapy.
Efficacy of controlled- or delayed-release oral mesalamine has been evaluated in several placebo-controlled trials in patients achieving remission following medical or surgical therapy. While in some of these studies in patients with medically or surgically induced remission, fewer relapses were reported with mesalamine than with placebo, in others, no statistically significant differences were found when the drug was compared with placebo. Results of a pooled analysis in patients receiving mesalamine to reduce postoperative recurrence of Crohn's disease have indicated that in 4 out of 7 studies, administration of oral mesalamine (compared with no therapy) was beneficial in reducing endoscopic or clinical recurrence, while in 2 other studies, a statistically non-significant trend in favor of therapy was shown. Results of another pooled analysis using oral mesalamine indicate that following surgically induced remission, clinical recurrence may be substantially reduced in patients with ileal disease or in those with prolonged disease duration. However, the overall effect usually was modest and further study is needed to evaluate the role of the drug in maintenance therapy of Crohn's disease.