Aminosalicylates

Observational studies

Mesalazine caused apoptosis and reduced cell proliferation in the colorectal mucosa in 17 patients with sporadic polyps of the large bowel [ ]. This may be clinically relevant in lowering the rate of polyp recurrence after polypectomy, thereby contributing to chemoprevention of sporadic colonic carcinoma.

Comparative studies

In a randomized, double-blind study, balsalazide 3 g/day and mesalazine 1.2 g/day effectively maintained remission in 99 patients with ulcerative colitis [ ]. Adverse events were equally common in the two groups, the most common being headache, abdominal pain and diarrhea, respiratory infections, body pains, and flu-like symptoms.

In a 12-week trial in 168 patients with mild to moderate ulcerative colitis, olsalazine 3 g/day was as effective as mesalazine 3 g/day in inducing a remission [ ]. There were more adverse reactions in patients taking olsalazine (41 of 88) than mesalazine (29 of 80). Most of the adverse reactions related to bowel disturbances: diarrhea, vomiting, abdominal discomfort, heartburn, flatulence, and nausea. Diarrhea was more common in patients taking olsalazine. One patient taking mesalazine developed a lupus-like syndrome.

The effects of mesalazine and olsalazine in delivering active mesalazine to the colon and in producing a systemic load as a basis for potential long-term toxicity have been compared in a single-blind, randomized, crossover study in 15 patients with ulcerative colitis [ ]. The patients took either olsalazine 500 mg bd or mesalazine 500 mg tds, with a crossover after 7 days. Plasma and urine concentrations of mesalazine and acetylmesalazine were assayed. Olsalazine caused loose stools in one patient and diarrhea in two, whereas mesalazine caused diarrhea in one. The systemic load of active mesalazine was significantly higher after mesalazine than olsalazine, based on both therapeutically recommended doses and when calculated on an equimolar basis. Some patients treated with mesalazine had very high plasma and urinary concentrations of mesalazine and acetylmesalazine, which may have long-term safety implications.

The relapse-preventing effects and safety profiles of balsalazide 1.5 g bd, balsalazide 3 g bd, and mesalazine 0.5 g tds have been studied in a multicenter, randomized, double-blind trial in 133 patients with ulcerative colitis in remission [ ]. High-dose balsalazide was significantly more effective in maintaining remission compared with the other two treatments. All three treatments were well tolerated.

In a double-blind, multicenter study in 182 patients with active Crohn’s disease affecting the ileum and/or ascending colon, a modified-release formulation of budesonide 9 mg/day was more effective in inducing remission than mesalazine 2 g bd [ ]. Adverse events were similar in the two groups. Mild abnormalities of adrenal function tests were slightly more common with budesonide, but the clinical significance of these was unclear.

In a randomized, multicenter study in 94 patients, mesalazine 4 g/day for 12 weeks in a microgranular formulation was as effective as a standard dose of a glucocorticoid (6-methylpredisolone 40 mg/day) in mild to moderate Crohn’s ileitis (Crohn’s Disease Activity Index 180–350) [ ]. The group treated with methylprednisolone had a higher number of adverse events than those given mesalazine. The only adverse effect related to mesalazine was acute pancreatitis, which resolved on withdrawal.

Alicaforsen is an antisense oligonucleotide inhibitor of expression of intracellular adhesion molecule 1 protein, used in the treatment of ulcerative colitis. Mesalazine enemas and alicaforsen enemas have been compared in a randomized, double-blind, multicenter trial in 190 subjects [ ]. There was no significant difference in efficacy. However those who took alicaforsen seemed to have more durable improvement. There were no serious adverse events related to drug therapy in either group. Gastrointestinal adverse events were more common with mesalazine. Other adverse events included fatigue, sinusitis, arthralgia, headache, and rash. Overall 64% of subjects reported adverse events from mesalazine, 60% from alicaforsen.

It has been suggested that probiotics may be beneficial in ulcerative colitis, since intestinal bacteria have been implicated in its pathogenesis. Mesalazine 2400 mg/day and Lactobacillus GG (18 × 10 ⁹ viable bacteria/day) have been compared in 187 patients with quiescent ulcerative colitis [ ]. There was no significant difference in relapse rate between the groups, patients who relapsed were likely to relapse sooner with mesalazine. Adverse events were not discussed, but it was noted that no patients withdrew early.

Balsalazide 2.25 g/day on 10 days per month in combination with a high-potency probiotic mixture (VSL#3) 450 billion/day for 15 days has been compared with VSL#3 alone for 15 days in maintaining remission after an attack of acute uncomplicated diverticulitis [ ]. There was no significant difference in response between the groups and no adverse reactions during the 12-month follow-up in both groups.

Short-chain fatty acids, especially butyrate, are a preferred source of energy for the colonic epithelium. There is evidence to suggest that butyrate enemas are effective in the treatment of ulcerative colitis. The seeds of Plantago ovata (a source of fermentable dietary fiber) increase fecal concentrations of butyrate and acetate. In a randomized, open, parallel-group, multicenter study in 105 patients with ulcerative colitis, P. ovata seeds 10 mg bd were as effective as mesalazine 500 mg tds in maintaining remission over 12 months [ ]. Adverse reactions were similar in the two groups, and included constipation, flatulence, nausea, and diarrhea.

Placebo-controlled studies

In an 18-month, double-blind, randomized, placebo-controlled trial in 318 patients, mesalazine 4 g/day did not significantly affect the postoperative course of Crohn’s disease compared with placebo [ ]. There was some relapse-preventing effect in patients with isolated small bowel disease. The overall incidence of adverse reactions was similar with mesalazine and placebo. Of the serious adverse reactions reported, only one case of alopecia was considered to be possibly or probably related to mesalazine.

In a double-blind, placebo-controlled, multicenter trial in 65 patients with ulcerative proctitis in clinical and endoscopic remission, mesalazine in suppositories 500 mg/day as sole treatment was effective, well tolerated, and safe for maintenance of remission over 24 months [ ]. The incidence of adverse reactions was similar with mesalazine and placebo. The most frequent adverse reactions with mesalazine were rectal disorders, abdominal pain, and headache.

Daily mesalazine 4 g orally plus placebo enema and mesalazine 2 g orally plus mesalazine 2 g rectally as a liquid enema have been compared in the treatment of mild to moderate ulcerative colitis in a multicenter, randomized, double-blind trial in 130 patients [ ]. The two treatments were equally effective in inducing disease remission. Both were well tolerated, and the frequencies of adverse reactions were similar in the two groups.

In a randomized, double-blind, placebo-controlled trial in 328 patients with quiescent Crohn’s disease, olsalazine 2 g/day given for 52 weeks was not superior to placebo in maintaining remission [ ]. Gastrointestinal adverse reactions were significantly more frequent in the olsalazine group; diarrhea was the most commonly reported adverse effect.

General adverse effects and reactions

Adverse reactions to sulfasalazine are frequent, and the withdrawal rate for this reason can be as high as 30% [ ]. Common adverse reactions related to sulfapyridine include headache, nausea, anorexia, and malaise. Other allergic or toxic adverse reactions include fever, rash, hemolytic anemia, hepatitis, pancreatitis, paradoxical worsening of colitis, and reversible sperm abnormalities [ ]. Sulfasalazine appears to cause frequent severe adverse reactions in adult-onset Still’s disease and systemic-onset juvenile rheumatoid arthritis, as suggested by a long-term, follow-up study of 41 patients with adult-onset Still’s disease and 109 consecutive patients with rheumatoid arthritis [ ]. Adverse reactions included abdominal pain, nausea and vomiting, urticaria, facial flushing, high fever, hypotension, severe myelosuppression, and fulminant hepatitis, which resulted in death in one patient.

Skin reactions are common with sulfasalazine, and general sensitization can occur, as with other sulfa derivatives. The clinical features, besides skin rash, include granulomatous liver disease, positive lupus phenomenon, hypocomplementemia, and fever [ ]. More serious skin conditions can also occur. In the case of mild reactions, patients can often be desensitized by giving small (and then progressively increasing) doses. Various complex autoimmune syndromes can occur [ ]; in long-term studies of the use of sulfasalazine in rheumatoid arthritis, 12–20% of evaluable patients developed antinuclear antibodies during treatment [ ]. Tumor-inducing effects have not been described.

The role of mesalazine in the acute and long-term treatment of ulcerative colitis has been reviewed [ ]. Mesalazine is equivalent to or better than sulfasalazine and better than placebo in inducing remission of acute disease, and comparable to sulfasalazine and better than placebo for long-term maintenance of remission. Adverse reactions are uncommon, but include idiosyncratic worsening of colitis and renal toxicity. Mesalazine is safe during pregnancy and breastfeeding. In maintenance therapy, it may reduce the risk of developing colorectal carcinoma.

Crossover studies have shown that mesalazine has about a 10-fold lower potential than sulfasalazine for inducing allergic reactions or causing intolerance. Adverse reactions with all aminosalicylates include (generally more frequent with sulfasalazine) headache, nausea, abdominal pain, dyspepsia, fatigue, rash, fever, rarely exacerbation of the disease, pancreatitis, pericarditis, pneumonitis, liver disease, nephritis, and bone marrow depression. Watery diarrhea is an adverse effect unique to olsalazine, while anorexia, folate malabsorption, hemolysis, neutropenia, agranulocytosis, male infertility, and neuropathy are unique to sulfasalazine.

Adverse reactions to sulfasalazine 2–3 g/day and mesalazine 1.2–2.4 g/day in 685 patients have been reviewed for a median follow-up period of 7 and 5 years respectively [ ]. Adverse reactions were observed overall in 20% of patients taking sulfasalazine and 6.5% of those taking mesalazine. The commonest adverse reactions due to sulfasalazine (reported by more than 10% of patients) were dyspepsia, rash, and headache, while the commonest due to mesalazine were rash, diarrhea, headache, fever, abdominal pain, impaired renal function, dyspepsia, and edema. Fertility was affected in all 42 male patients taking sulfasalazine who were assessed, but improved when they changed to mesalazine.

A pharmacovigilance report from France reported 128 adverse events during 15.6 million days of therapy with Pentasa in 1993 and 1994. Adverse events with a high likelihood of causality included diarrhea, pancreatitis, liver abnormalities, blood dyscrasias, renal insufficiency, and cardiac disorders, including myocarditis. Most of these rare adverse events did not appear to be dose-related in the therapeutic range [ ]. A meta-analysis of studies of the effectiveness of mesalazine in maintaining remission in Crohn’s disease showed an adverse effect frequency of 14% in patients taking mesalazine and 15% in patients taking placebo. The most frequent adverse effect attributable to mesalazine was diarrhea [ ].

The dose response relation of oral mesalazine in inflammatory bowel disease has been briefly reviewed [ ]. Higher doses (3 g/day) are more effective in inducing and maintaining remission than lower doses (1.5 g/day). None of the known adverse reactions to mesalazine is clearly dose-related in the therapeutic range of doses.

An analysis of suspected serious adverse reactions reported to the Committee on Safety of Medicines in the UK in 1991–98 has failed to show a safety advantage for mesalazine over sulfasalazine in the treatment of inflammatory bowel disease [ ]. Pancreatitis and interstitial nephritis were significantly more common with mesalazine.

Adverse reactions to olsalazine would be expected to be those of mesalazine, and this is largely the case. However, diarrhea has been sufficiently common to suggest that it may be a particular problem with olsalazine, with an incidence of some 13%; it is probably a small-intestinal secretory diarrhea [ , ]. Similarly, cholestatic hepatitis, confirmed on rechallenge, did not recur with mesalazine in similar doses [ ]. In one case there was a marked hypersensitivity reaction in a man previously intolerant of sulfasalazine, but the circumstances suggested a reaction to mesalazine rather than to the double molecule [ ].

Cardiovascular

A single Scandinavian case report has reliably attributed a fatal myocarditis to mesalazine [ ]. Pericarditis occurred in a 44-year-old man with a 4 year history of Crohn’s disease taking mesalazine 3 g/day [ ]. There were also electrocardiographic changes that mimicked Brugada syndrome. Acute myopericarditis has again been reported in patients taking mesalazine; in one case there was also mitral valve insufficiency [ , ].

The time between the start of treatment and the onset of mesalazine-associated pericarditis usually ranges from a few days to 7 months. However, the delay can be longer.

• A 53-year-old man with Crohn’s disease, who had taken mesalazine 500 mg/day for the past 8 years, developed pericarditis with an effusion [ ]. The pericarditis resolved rapidly on drug withdrawal. Investigations excluded other common causes of pericarditis.

• Pericarditis in a 16-year-old boy with inflammatory bowel disease taking mesalazine resolved on withdrawal, but recurred after starting sulfasalazine 500 mg tds [ ].

• Acute pericarditis has been reported in a 17-year-old man with severe ulcerative colitis who had taken mesalazine 1.5 g/day for 2 weeks [ ]. The pericarditis resolved on withdrawal and recurred on rechallenge with a low dose (62.5 mg) of mesalazine 3 weeks later.

• Constrictive pericarditis has been reported in a 37-year-old woman with chronic ulcerative colitis who had taken mesalazine 2 g/day for 2 weeks [ ]. She recovered after radical pericardiectomy.

Bradycardia has been attributed to mesalazine.

• Severe symptomatic bradycardia has been reported in a 29-year-old woman with ulcerative colitis who was taking mesalazine [ ]. The bradycardia resolved on withdrawal. Six weeks later mesalazine was restarted for a relapse of her colitis, and symptomatic bradycardia recurred. Again this resolved on withdrawal.

Chest pain has been attributed to mesalazine [ ].

• A 37-year-old man with ulcerative colitis developed severe retrosternal chest pain with non-specific ST-T wave changes in the inferolateral leads of the electrocardiogram after taking mesalazine 800 mg qds for 1 week. Cardiac enzymes, coronary angiography, left ventricular function, and pulmonary angiography were normal. Mesalazine was omitted and glucocorticoids were tapered. He recovered completely and his electrocardiogram normalized. Two weeks later he was given mesalazine 800 mg qds and again developed retrosternal chest pain with T wave inversion in the lateral leads.

Mesalazine was withdrawn and his symptoms resolved-within 24 hours. His chest pain did not recur over an 18 month follow-up period while not taking mesalazine.

Raynaud’s phenomenon has been attributed to sulfasalazine [ , ].

Respiratory

“Sulfasalazine lung”, fibrosing alveolitis, and eosinophilic pleurisy are variants on a well-recognized although unusual lung complication. Most commonly it presents with cough, fever, eosinophilia, dyspnea, and pulmonary infiltrates [ ]. Sputum production, a history of allergy, rash, chest pain, and weight loss are inconsistent findings. The disease usually develops 1–9 months after the start of treatment and the fibrosing alveolitis can be fatal [ ]. The lung pathology is variable, the commonest change being an eosinophilic pneumonia with peripheral eosinophilia and interstitial inflammation with or without fibrosis. In case reports, the majority of patients with suspected sulfasalazine-induced lung disease improved within weeks of drug withdrawal [ ]. Whether the salicylate or the sulfa moiety is responsible is unclear; both can cause pulmonary eosinophilia. Differentiation from lung disease simply associated with ulcerative colitis can be difficult, particularly because the drug-induced form sometimes causes an interstitial pneumonitis without evidence of an allergic reaction [ ] and rechallenge can be dangerous [ ].

Peripheral lung infiltrates with blood eosinophilia are rare effects of sulfasalazine. Sulfasalazine-induced hypersensitivity lung disease with simultaneous Legionella pneumophila infection has been reported [ ].

• A 68-year-old woman who had taken sulfasalazine for rheumatoid arthritis for 6 months developed bronchiolitis obliterans organizing pneumonia (BOOP) associated with an eosinophilia of 970 × 10 ⁶ /l [ ].

• A 32-year-old woman with ulcerative colitis developed bilateral pulmonary infiltrates with peripheral eosinophilia 2 weeks after starting to take sulfasalazine and mesalazine enemas, and both drugs were withdrawn. Based on a high antibody titer, Legionnaires’ disease was diagnosed and empirical therapy with a macrolide antibiotic was started; she improved within a few days. Three months later sulfasalazine was restarted, followed 3 days later by acute pulmonary symptoms (bilateral confluent opacities) and blood eosinophilia. The abnormalities resolved completely after drug withdrawal and prophylactic antibiotic therapy.

Various adverse respiratory effects of mesalazine have been reported.

• A patient who took mesalazine for 2 years had a symptomatic bilateral lung reaction, with interstitial infiltrates and impaired function; the condition developed insidiously but recovered within 8 months after drug withdrawal [ ]. The condition was not necessarily identical to the lung reaction seen with sulfasalazine.

• Pleural effusion with pulmonary infiltration has been reported in a 72-year-old woman with ulcerative colitis taking mesalazine 800 mg tds [ ]. The lung pathology resolved after drug withdrawal.

• An eosinophilic pleural effusion has been reported in a 35-year-old male non-smoker who had taken mesalazine 2.4 g/day orally for 2 weeks for a diarrheal illness [ ]. He recovered after mesalazine was withdrawn.

• A 35-year-old woman with ulcerative colitis who had taken mesalazine 1.5 g/day for about 40 days developed a low-grade fever with bilateral eosinophilic pulmonary infiltrates (confirmed by transbronchial lung biopsy) [ ]. Spontaneous clinical and radiological resolution occurred on withdrawal. A drug lymphocyte stimulation test was positive for mesalazine.

• A 29-year-old woman with ulcerative colitis taking mesalazine 1 g tds developed respiratory distress [ ]. Her respiratory symptoms (chest pain and respiratory distress, especially exertional dyspnea) occurred 48 hours after she started to take mesalazine and disappeared immediately on withdrawal. Similar symptoms recurred on rechallenge 3 weeks later in a lower dose of 500 mg bd. Chest X-ray and white cell count a day later were normal.

• Bronchiolitis obliterans has been reported in an 18-year-old female non-smoker with ulcerative colitis, 3 months after reintroduction of mesalazine 1.6 g/day orally [ ]. She recovered after mesalazine withdrawal and treatment with glucocorticoids.

• Interstitial pulmonary disease (lymphocytic alveolitis and mild interstitial pulmonary fibrosis) has been reported in a 70-year-old woman with ulcerative colitis who had taken mesalazine 2.4 g/day for 3 months [ ]. Halving the dose of mesalazine to 1.2 g/day led to resolution of her lung disorder without relapse of ulcerative colitis.

• A limited form of Wegener’s granulomatosis with a bronchiolitis obliterans organizing pneumonia-like variant has been reported in a 19-year-old man, a non-smoker, with ulcerative colitis, 6 months after the introduction of mesalazine 2.25 g tds orally [ ]. He recovered after mesalazine withdrawal and treatment with glucocorticoids.

Nervous system

An unusual but not unique case of transverse myelitis was reported in 1991, and other published case reports suggest links with chorea and ataxia [ ].

Individual cases of other nervous system adverse reactions have appeared.

• Vivid dreams and daytime hallucinations occurred in a woman taking sulfasalazine [ ].

• Aseptic meningitis occurred in a patient with pre-existing Sjögren’s syndrome; and the drug link was confirmed by positive rechallenge [ ].

• In a slow acetylator, an axonal sensorimotor neuropathy could have been due to sulfasalazine [ ].

Seizures with acute encephalopathy have been reported in a woman taking sulfasalazine for polyarthritis [ ].

Hematologic

In a randomized, double-blind, placebo-controlled trial, 70 patients with established ankylosing spondylitis and a mean disease duration of 17 years were investigated in two centers for 26 weeks, comparing sulfasalazine 3 g/day with placebo. In the treatment group there were significantly more cases of anemia, leukopenia, eosinophilia, and thrombocytopenia [ ].

Sulfasalazine causes Heinz body anemia in patients with abnormal hemoglobin and hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency [ ].

• A 79-year-old woman who had been taking sulfasalazine for ulcerative colitis for 5 years developed a positive Coombs’ test and a hemoglobin of 8.2 g/dl. Agglutination occurred when a mixture of sulfasalazine and the patient’s serum was added to normal erythrocytes treated with the endopeptidase ficin, but there was no reactivity when control serum was used or when sulfasalazine was omitted. Preincubation of sulfasalazine with normal erythrocytes gave negative results on addition of the patient’s serum, excluding the possibility of a penicillin-like reaction. The patient had normal glucose-6-phosphate dehydrogenase activity and there were no Heinz bodies in a blood smear.

However, about 1.7% of patients with ulcerative colitis develop immune hemolytic anemia, even in the absence of sulfasalazine, so cause and effect is not always possible to determine.

Agranulocytosis is very unusual but well described with sulfasalazine, and can occur suddenly and very early in treatment [ ]. The risk in sulfasalazine users with arthritic disorders (6/1000 users) was about 10 times higher than that in users with inflammatory bowel disease (0.6/1000 users) [ ]. Agranulocytosis is supposedly more common in slow acetylators [ ]. However, in one study the risk of agranulocytosis was not increased in slow acetylators [ ]. Leukopenia occurred in a patient taking mesalazine after a similar reaction to sulfasalazine [ ].

Sulfasalazine reduces folic acid absorption, but rarely to a clinically significant extent, although megaloblastic anemia has rarely been documented [ , ].

Methemoglobinemia can occur in slow acetylators of sulfapyridine [ ].

Thrombocytopenia has occasionally been attributed to mesalazine [ ] and olsalazine [ ].

• A possible association between mesalazine and pancytopenia has been reported in a 23-year-old man with Crohn’s disease [ ]. The pancytopenia resolved after withdrawal.