Hypersensitivity azathioprine

Agents targeting the excessive immune response or cytokines involved in IBD are potential treatment options (Table 16-3). Azathioprine and its active metabolite 6-mercaptopurine (6-MP) are inhibitors of purine biosynthesis and reduce IBD-associated GI inflammation. They are most useful for maintaining remission of IBD or reducing the need for long-term use of corticosteroids. Use in active disease is limited by their slow onset of action, which may be as long as 3 to 12 months. Adverse effects associated with azathioprine and 6-MP include hypersensitivity reactions resulting in pancreatitis, fever, rash, hepatitis, and leukopenia.25,26... 

With azathioprine and 6-MP, monitor for hypersensitivity reactions, including severe skin rashes and pancreatitis. Educate the patient regarding signs and symptoms of pancreatitis (nausea, vomiting, and abdominal pain). 

Q64 The dose of allopurinol should be reduced in patients receiving aza-thioprine. Both allopurinol and azathioprine may cause hypersensitivity reactions. 

When azathioprine is administered concomitantly with allopurinol, there is a risk of enhanced effects and increased toxicity of azathioprine. Doses of azathioprine should be reduced to one quarter of the usual dose. Both allopurinol and azathioprine may cause hypersensitivity reactions. 

Hypersensitivity to azathioprine pregnancy in rheumatoid arthritis patients. 

Patients with frequent relapses despite apparently adequate prophylactic treatment should be reviewed carefully. Associated milk intolerance or coeliac disease need treatment on their merits. Colonoscopic evidence of dysplasia raises the question of undiagnosed malignancy. Occasionally the prophylactic agents themselves can cause watery diarrhoea (particularly olsalazine) or a hypersensitivity colitic disease. Prophylactic azathioprin should be considered in those in whom relapse is frequent despite use of aminosalicylates or if they are poorly tolerated. In the effective dose of 2 mg/kg adverse effects of bone marrow depression are uncommon, but still occur, and regular haematological review is essential (monthly or bi-monthly). Azathioprin-induced pancreatitis is an uncommon but well-recognised entity. 

Dose-related toxicities of azathioprine or 6-mercaptopurine include nausea, vomiting, bone marrow depression (leading to leukopenia, macrocytosis, anemia, or thrombocytopenia), and hepatic toxicity. Routine laboratory monitoring with complete blood count and liver function tests is required. Leukopenia or elevations in liver chemistries usually respond to medication dose reduction. Severe leukopenia may predispose to opportunistic infections leukopenia may respond to therapy with granulocyte stimulating factor. Hypersensitivity reactions to azathioprine or 6-mercaptopurine occur in 5% of patients. These include fever, rash, pancreatitis, diarrhea, and hepatitis. 

Gastrointestinal disturbances with nausea, vomiting, and diarrhea are frequent in patients taking azathioprine or mercaptopurine. Diarrhea may be isolated or part of the azathioprine hypersensitivity sjmdrome. In two patients with azathioprine-induced diarrhea proven by positive rechallenge, the period of sensitization ranged from 1 week to 1 year (19). 

Pancreatitis due to azathioprine or mercaptopurine has usually been reported as part of the hypersensitivity syndrome (SEDA-16,520) (SEDA-20,341). It has mostly been observed in patients with inflammatory bowel disease, and required withdrawal of treatment in 1.3% of patients with Crohn s disease (3). Pancreatitis was not dose-related within the therapeutic range of doses and often recurred in patients who were rechallenged with either drug (SEDA-20, 341) (35). Fatal hemorrhagic pancreatitis occurred in one patient, but a role of concomitant drugs was also possible (SEDA-20, 341). Pancreatitis or hyperamylasemia were not significantly different in renal transplant patients randomly assigned to receive azathioprine or ciclosporin, and other causative factors were found in most patients with pancreatitis (36). 

Rashes or other aUergic-tjrpe cutaneous reactions are usually noted during the azathioprine hypersensitivity syndrome. Isolated but convincing reports point to the occurrence of vasculitis with microscopic polyarteritis (SEDA-21, 381) and Sweet s syndrome, which recurred after subsequent azathioprine exposure (SEDA-22, 410). 

Severe myalgia and symmetrical polyarthritis are sometimes reported in patients taking azathioprine. Eight cases of azathioprine-associated arthritis were identified in the WHO Drug Monitoring Database, including six cases with a typical hypersensitivity syndrome and two cases in whom joint involvement was the only reported symptom (40). Rhabdomyolysis has also been reported as a possible feature of the azathioprine hypersensitivity syndrome (SEDA-20, 341). 

A genetic predisposition is suspected, with a possible association between the hypersensitivity syndrome and the Bw4 and Bw6 phenotypes (SED-13, 1121). Mercaptopurine has sometimes been re-administered safely after a severe hypersensitivity reaction to azathioprine (49), suggesting a major role for the imidazole moiety of azathioprine. However, typical allergic reactions to mercaptopurine can also occur (SEDA-21, 381). 

Saway PA, Heck LW, Bonner JR, Kirklin JK. Azathioprine hypersensitivity. Case report and review of the literature. Am J Med 1988 84(5) 960-4. 

Cooper C, Cotton DW, Minihane N, Cawley ML Azathioprine hypersensitivity manifesting as acute focal hepatocellular necrosis. J R Soc Med 1986 79(3) 171-3. 

Meys E, Devogelaer JP, Geubel A, Rahier J, Nagant de Deuxchaisnes C. Fever, hepatitis and acute interstitial nephritis in a patient with rheumatoid arthritis. Concurrent manifestations of azathioprine hypersensitivity. J Rheumatol 1992 19(5) 807-9. 

Burden AD, Beck MH. Contact hypersensitivity to azathioprine. Contact Dermatitis 1992 27(5) 329-30. 

Godeau B, Paul M, Autegarden JE, Leynadier F, Astier A, Schaeffer A. Hypersensitivity to azathioprine mimicking gastroenteritis. Absence of recurrence with 6-mercaptopurine. Gastroenterol Clin Biol 1995 19(1) 117-19. 

Azathioprine Hypersensitivity pneumonitis Sulfasalazine Hypersensitivity pneumonitis. 

These interaetions are not elearly established, and the reaction appears to he rare and unpredictable. All that can he constructively said is that patients taking both drugs should he very closely monitored for any signs of hypersensitivity (e.g. skin reactions) or low white cell count (sore throat, fever), especially if they have renal impairment. The UK manufacturer of captopril recommends that diffeiential white hlood cell counts should be performed before adding allopurinol, then every 2 weeks during the first 3 months of treatment, and periodically thereafter. Similar caution and advice is given by the UK manufacturers of several other ACE inhibitors. For other possible interactions with ACE inhihitors that might result in an increased risk of leucopenia see also ACE inhihitors + Azathioprine , p.l8 and ACE inhibitors + Procainamide , p.33. 

Hypersensitivity reactions Aminosalicylates (sulfasalazine and mesalazine), azathioprine/6-MP, sulfonamides... 

Farkas J (1981) Perioral dermatitis from marjoram, bay leaf and cinnamon. Contact Dermatitis 7 121 Stampf J, Castagnoli N, Epstein W, et al. (1990) Suppression of urushiol-induced delayed-type hypersensitivity responses in mice with serum IgG immunoglobulin from human hyposensitized donors. J Invest Dermatol 95 363-365 Baadsgaard O (1986) Circulating and in situ lymphocyte subsets and Langerhans cells in patients with Compositae oleoresin dermatitis and increased ultraviolet A sensitivity during treatment with azathioprine. J Am Acad Dermatol 14 577-581... 

Burden AD, Beck MH (1992) Contact hypersensitivity to azathioprine. Contact Dermatitis 27 329-330 Soni BP, Sherertz EF (1996) Allergic contact dermatitis from azathioprine. Am J Contact Dermat 7 116-117... 

Observational studies Patients with Crohn s disease (n = 14) or ulcerative colitis (n = 15) with previous hypersensitivity reactions to azathioprine were given gradually increasing doses of mercaptopurine from 0.5 to 1.0-1.5 mg/kg/day [108 "]. In nine patients mercaptopurine was withdrawn in the first 2 weeks because of early hypersensitivity reactions the other 20 patients tolerated it. 

A 50-year-old man had a severe hypersensitivity reaction to azathioprine resulting in hepatitis however, he tolerated mercaptopurine for 6 years without hepatotoxicity, despite high concentrations of methyl-mercaptopurine [116" ]. 

Hypersensitivity reactions In 21 patients with inflammatory bowel disease who had hypersensitivity reactions to azathioprine or mercaptopurine within 6 weeks, thioguanine 10-40 mg/day elicited hypersensitivity reactions in only four, after a median of 9 days pancreatitis did not recur [1185]. 

Observational studies in 106 patients with Crohn s disease taking azathioprine, there was at least one adverse reaction in 56, and 18 had to stop taking it, often because of hypersensitivity reactions, there was nausea and vomiting in 29 and leukopenia in 36 [125 =]. 

An unusual case of contact hypersensitivity to azathioprine has been reported [131 ]. 

NaOs Beau s lines, transverse depressions on the nails, developed in two patients taking azathioprine, a 68-year-old African-American woman and a 62-year-old man in each case there was evidence of an associated hypersensitivity reaction, in one case with neutropenia and raised aminotransferase activities and in the other raised aminotransferase activities [132 ]. 

TPMT genotype polymorphisms (TPMT 2, 3A, 3B, and 3C) have been studied in 108 patients with vascuhtis associated with positive antineutrophil cytoplasmic antibodies (ANCA), who were given azathioprine and followed for 47 months [144. Adverse reactions (leukopenia, anemia, thrombocytopenia, gastrointestinal adverse reactions including hepatitis, and hypersensitivity reactions) did not differ between patients who were heterozygous and those who were homozygous or between the ter-tiles of patients who were homozygous. 

Nagy F, Molnar T, Szepes Z, Farkas K, Nyari T, Lonovics J. Efficacy of 6-mercapto-purine treatment after azathioprine hypersensitivity in inflammatory bowel disease. World J Gastroenterol 2008 14(27) 4342-6. 

Andrejic J, Rojas-Balcazar J, Dennis M, Berkelhammer C. Azathioprine-induced hypersensitivity hepatitis tolerance to 6-mercaptopurine. Inflamm Bowel Dis 2010 16(11) 1828-9. 

Schmitt K, Pfeiffer U, Stiehrle HE, Thuermann PA. Absence of azathioprine hypersensitivity after administration of its active metabolite 6-mercaptopurine. Acta Derm Venereol 2000 80(2) 147-8. 

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