Mesalamine Intolerance Mimics Symptoms of Active Inflammatory Bowel Disease

Mesalamine is frequently used to treat inflammatory bowel disease (IBD). Although, bloody diarrhea, abdominal pain, and fever as a reaction to sulfasalazine exposure have long been recognized (1), allergic reactions to mesalamine preparations are rare. Side effects, such as nausea, dyspepsia, and diarrhea are described in up to 8% of patients (2). Reports of exacerbation of colitic symptoms caused by intolerance to mesalamine preparations are infrequent but have been described in adult patients (3–8). We describe three adolescent patients in whom mesalamine intolerance resembled symptoms of active IBD, making treatment more problematic. CASE REPORTS Patient 1 A 14-year-old boy was initially diagnosed with ulcerative colitis (UC) when he had diarrhea, hematochezia, and weight loss of 1-month duration. He began Azulfidine 4 g/d with no beneficial response after 2 weeks. Azulfidine was discontinued and treatment with prednisone initiated. Despite this, symptoms worsened and the patient was admitted to the hospital and treated with intravenous (IV) hydrocortisone (maximum dosage of 240 mg/d), complete bowel rest, and total parenteral nutrition. He responded well. Azulfidine was restarted and prednisone discontinued within a 2-month period. Soon after, he was lost to follow up, discontinued all his medications, and reportedly continued to do well. Nearly 6 years later he had acute onset of diarrhea, bleeding, and weight loss. His blood tests revealed a white blood cell count of 18.5 × 10 9 /L with 58% neutrophils and 25% bands, an erythrocyte sedimentation rate of 34 mm/h, hematocrit concentration of 43.1%, and an albumin concentration of 3.7 g/dL. Stool tests for bacterial pathogens, Clostridium difficile toxin, and ova and parasites were negative. Mesalamine (Asacol; Procter and Gamble, Cincinnati, OH, U.S.A.) 2.4 g/d was started, as was hydrocortisone rectal foam twice per day. During the next 2 weeks, the patient continued to lose weight (up to 20 lb total), his diarrhea and abdominal pain worsened, and nausea became a prominent complaint. He was admitted to the hospital, and hydrocortisone 160 mg/d IV was added to the mesalamine and rectal therapy. Total parenteral nutrition was also prescribed. Flexible sigmoidoscopy revealed erythema, edema, and ulcerations with exudate. Biopsies showed diffuse active inflammation of the rectum and sigmoid colon. Upper endoscopy, performed because of the persistence of nausea, results were normal. Results of an upper gastrointestinal and small bowel series appeared normal, but severe ulcerations and irregularity of the colon were noted. Despite treatment, the patient continued to do poorly and had persistent diarrhea, bleeding, and abdominal pain. His white count was 15 × 10 9 /L with 80% neutrophils, hematocrit concentration of 25%, and albumin concentration of 1.8 g/dL. The hydrocortisone dosage was increased, and mesalamine and rectal therapy continued. Significant abdominal pain and grossly bloody stools (800–1,400 mL per day) persisted. Because medical treatment was not successful, surgery was planned. At this time, mesalamine was discontinued (Fig. 1). Within the next few days, the diarrhea dramatically subsided, and the abdominal pain and nausea resolved. The patient was discharged 7 days later and gradually weaned over the next 4 months from prednisone to 6 mercaptopurine (6MP) (75 mg/d). Nine months later, the patient is asymptomatic on 6MP alone.FIG. 1.: Patient 1 (ulcerative colitis) hospital course, hospital days 1 to 28. Please note abrupt reduction in the volume and frequency of the stool after discontinuation of mesalamine (vertical line).Patient 2 A 17-year-old girl was diagnosed with UC after the acute onset of abdominal cramps, bloody diarrhea, weight loss, and nausea. She began therapy with mesalamine (Asacol) 2.4 g/d. No significant improvement in symptoms was noted, and 10 days later mesalamine was discontinued. The patient was treated with prednisone 50 mg/d with resolution of her abdominal cramps and diarrhea within the next 2 weeks. After prednisone dosage was gradually reduced to 40 mg/d, administration of Asacol (2.4 g/d) was restarted. The patient continued to do well, and her prednisone dosage was gradually reduced to 7.5 mg/d. At this point, stool frequency increased and stools become diarrheal. Abdominal cramps and nausea recurred. Symptoms resolved when prednisone dosage was increased and reappeared during an attempt to wean from prednisone. Repeated stool studies were negative for enteric pathogens and Clostridium difficile toxin. In an attempt to control symptoms, without further increase in the prednisone dosage, the mesalamine dosage was increased to 3.6 g/d. Because the diarrhea and abdominal cramps continued to worsen, Asacol was discontinued (Fig 2). All symptoms resolved within the next 24 hours. The patient began therapy with Azulfidine 2 g/d and was weaned from prednisone in 1 month. Six months later, she remains asymptomatic with Azulfidine therapy alone.FIG. 2.: Patient 2 (ulcerative colitis) clinical course, weeks of the disease 0 to 59. Severity of the bleeding, nausea, and abdominal pain graded 0, none; 1, mild; 2, moderate; and 3, severe. Please note worsening of the symptoms with increased dosage of mesalamine and abrupt resolution of the bleeding, abdominal pain, and nausea after discontinuation of mesalamine (vertical line). No reoccurrence of the symptoms with sulfasalazine (SASP) despite weaning from prednisone; 3 gr of SASP provides 1.5 gr of 5ASA.Patient 3 A l3-year-old girl with Crohn ileocolitis was diagnosed when she had abdominal pain, hematochezia, and anemia. An upper gastrointestinal and small bowel series revealed narrowing of the terminal ileum with proximal dilatation. Colonoscopy revealed patchy ulcerations with exudate. Microscopically, there was patchy, active inflammation with granuloma formation. With Azulfidine therapy (3 g/d), she did well for 18 months. At that point she developed abdominal pain, diarrhea, and weight loss. Her stool studies were negative for enteric pathogens and Clostridium difficile toxin, erythrocyte sedimentation rate was 90 mm/h, and albumin concentration was 3.3 g/dL. Azulfidine was discontinued, and she was treated with prednisone 40 mg/d and mesalamine (Asacol) 2.4 g/d. She responded well, and prednisone dosage was gradually reduced to 15 mg/d within the next 3 months. All attempts to further decrease the dosage of prednisone failed, with recurrence of diarrhea, abdominal cramps, and nausea. The patient began 6MP therapy, while continuing treatment with 15 mg/d of prednisone and Asacol. Her prednisone dosage was gradually decreased to 7.5 mg/d despite persistence of mild symptoms. Two months later, the diarrhea and abdominal cramps worsened again, did not respond to an increase in mesalamine dosage, but resolved completely within 96 hours after Asacol was discontinued (Fig 3). The patient was weaned from prednisone and is now asymptomatic with 6MP therapy alone.FIG. 3.: Patient 3 (Crohn ileocolitis) clinical course, months of the disease, 18 to 50. Severity of the abdominal pain and nausea graded: 0,none; 1, mild; 2, moderate; and 3, severe. Please note abrupt resolution of the abdominal pain and nausea after discontinuation of mesalamine (vertical line).DISCUSSION Mesalamine preparations are used commonly to induce and maintain remission in mild to moderately active IBD. Although these medications are generally well tolerated, adverse effects from hypersensitivity and intolerance can occur. Hypersensitivity reactions are similar to those seen with sulfasalazine (SASP) (7). Skin rash, fever, and systemic reactions have been described (7). Nonetheless, 85% to 90% of patients allergic to SASP may tolerate mesalamine preparations (9,11,12). More severe reactions associated with use of mesalamine occur infrequently and include bone marrow suppression (13,14), arthritis (15), pneumonitis (10), pericarditis (15,16), and pancreatitis (17,18). The most common symptoms of mesalamine intolerance are headache and gastrointestinal upset. Gastrointestinal symptoms, such as diarrhea, abdominal pain, nausea, and dyspepsia, are described in 6% to 8% of adults taking mesalamine and constitute the most common reason for discontinuing mesalamine. These symptoms are dose dependent and resolve promptly with decreased dosage (7), although the frequency of these side effects does not increase with increase of mesalamine dosage (2). Severe reactions to SASP have been recognized since 1978, when Werlin and Grand (1) published the first observations of bloody diarrhea, abdominal pain, and fever as a reaction to the SASP exposure in pediatric patients with UC. Since then, reports have described similar reactions in adult patients treated with various mesalamine preparations: Asacol (3,4,8), Pentasa (4), Salofalk (4), Rowasa enemas (5), and olsalazine (6). To confirm the presence of mesalamine intolerance, a mesalamine challenge can be performed during a quiescent phase of the disease. Kapur et al. (4) and Sturgeon et al. (5) have described the histologic and endoscopic changes from such a challenge. Significant erythema, edema, and petechiae of the colonic mucosa were noted 24 to 48 hours after exposure to a topical mesalamine preparation (Rowasa, Pentasa, Asacol, and Salofalk). Microscopically, shifts from an eosinophilic to a neutrophilic infiltrate in the lamina propria, edema, and crypt destruction were observed. No such challenge was performed in our patients. Austin et al. (8) reported exacerbation of diarrhea and signs of allergic reaction (rash and fever) from mesalamine that were not associated with changes in laboratory tests. Chakraborty (3) described significantly decreased hemoglobin and albumin concentrations, and unchanged white count and differential count 8 days after challenge with mesalamine in one patient intolerant to mesalamine, and unchanged laboratory values in another. Unfortunately other case reports of colitis exacerbation caused by preparations containing the S-aminosalicylate (SASA) moiety do not comment on changes in laboratory values (4–6). In our cases, no change in inflammatory markers (white blood cell count, erythrocyte sedimentation rate, and albumin concentration) was noted in patient 3 before or after resolution of symptoms, as opposed to patient 1 in whom biochemical improvement followed symptomatic response. Peripheral eosinophilia was not observed in either patient. No laboratory data are available for patient 2. The precise mechanism of action of mesalamine is not clear. The levels of leukotrienes and prostaglandins are elevated in rectal dialysates of patients with active UC. Both of these levels decrease in patients responding to mesalamine treatment (19). In the report by Fine et al. (20) a patient with chronic nongranulomatous enterocolitis, who was intolerant to mesalamine, had secretory diarrhea associated with markedly elevated levels of leukotrienes and decreased levels of prostaglandins. In 1971, Vane (21) described similar changes in the serum levels of eicosanoids in response to aspirin and other nonsteroidal anti-inflammatory drugs. This suggests that patients intolerant to mesalamine respond similarly to both mesalamine and nonsteroidal anti-inflammatory drugs, which may explain the worsening of diarrhea and inflammation. To the best of our knowledge, this observation is not yet confirmed in other patients intolerant to mesalamine or any other SASA preparation. Corticosteroids, by interfering with phospholipase activity, decrease production of leukotrienes and thus decrease expression of inflammation (19). If used together with mesalamine, this effect of prednisone may mask the signs of mesalamine intolerance until the dosage of corticosteroid has been decreased. We have found no other reports describing exacerbation of Crohn disease caused by SASA. In contrast with the patients with UC, diarrhea was not evident in our patient with Crohn disease. Nausea, malaise, and abdominal cramps were the most prominent symptoms. When mesalamine intolerance is established, questions regarding the use of other SASA preparations arise. A comparative study of the tolerance of mesalamine (Asacol), olsalazine (Dipentum), and balsalazide in 43 patients reported 6 unable to tolerate mesalamine because of abdominal pain, nausea, and vomiting (12). These patients did well with administration of olsalazine or balsalazide. Only 4 patients (9%) were intolerant to all three preparations. This observation suggests that a trial of other SASA may be warranted in patients intolerant to one of the mesalamine preparations. Dosage and absorption may explain intolerance to some mesalamine preparations. Two grams of Azulfidine delivers only 1 g of SASA, whereas 2.4 g of Asacol contains 2.4 g of SASA (1). Rijk et al. (22) demonstrated faster urinary excretion as well as higher urinary concentrations of controlled released preparations (Asacol, Salofalk, and Pentasa), compared with azo-bound preparations (Azulfidine, Dipentum) in healthy volunteers receiving a single dose. Similarly, Stretch et al. (23) demonstrated that patients with UC had considerably higher absorption of SASA from mesalamine (Asacol) than from olsalazine (Dipentum®) or SASP (23). In summary, mesalamine preparations are generally well tolerated in children with IBD. Infrequently, mesalamine may cause exacerbation of IBD or produce symptoms indistinguishable from those of active disease. One should consider mesalamine intolerance in patients who exhibit discrepancy between symptoms of the disease activity and laboratory parameters, and in patients who appear steroid resistant or dependent while receiving mesalamine. We suggest that in these patients, decreasing the dose and/or withholding mesalamine preparations should be considered, and results observed. This approach may help to decrease morbidity from unnecessary use of steroids, as well as avoid unwarranted surgery.