Azathioprine and mercaptopurine

Observational studies

In a follow-up study of 157 patients receiving azathioprine or mercaptopurine for Crohn’s disease, the long-term risks (mainly hematological toxicity and malignancies) over 4 years of treatment were deemed to outweigh the therapeutic benefit [ ]. In contrast to these findings, both drugs were considered efficacious and reasonably safe in patients with inflammatory bowel disease, provided that patients are carefully selected and regularly investigated for bone marrow toxicity [ ]. Similar opinions were expressed regarding renal transplant patients. Conversion from ciclosporin to azathioprine in selected and carefully monitored patients had beneficial effects, by improving renal function, reducing cardiovascular risk factors, and reducing financial costs, without increasing the incidence of chronic rejection and graft loss [ ].

Experience in children with juvenile chronic arthritis or chronic inflammatory bowel disease has also accumulated, and the toxicity profile of azathioprine or mercaptopurine appears to be very similar to that previously found in the adult population [ , ].

Cardiovascular

Azathioprine has been associated with atrial fibrillation [ ].

• A 52-year-old man with steroid-dependent ulcerative colitis relapsed and was given azathioprine, which was withdrawn some months later because of episodes of lipothymia, with bouts of palpitation, nausea, and vomiting. During an exacerbation 2 years later he was given azathioprine 50 mg and 2 hours later developed nausea, vomiting, and general malaise. He had an irregular heartbeat, and an electrocardiogram showed atrial fibrillation with a ventricular rate of 120/minute. Azathioprine was withdrawn and propafenone given. Repeated electrocardiography showed sinus rhythm and there were no further episodes of atrial fibrillation.

Respiratory

Although azathioprine-associated pulmonary toxicity mostly occurs as part of the azathioprine hypersensitivity reaction, isolated interstitial pneumonitis has been reported in a 13-year-old girl with autoimmune chronic active hepatitis [ ]. It can resolve after drug withdrawal [ ].

• A 40-year-old man took azathioprine for 10 years for extensive ulcerative colitis. He then developed fever, cough, and catarrhal signs. Opportunistic infections were ruled out. Chest X-ray, a CT scan, and a lung biopsy showed interstitial inflammation. Azathioprine was withdrawn and he was given steroids; the pulmonary infiltrates gradually resolved.

Acute upper airway edema has been observed after a single dose of azathioprine [ ].

• A 57-year-old woman with a history of several drug allergies underwent renal transplantation for end-stage polycystic kidney disease and 1 hour later was given intravenous azathioprine 400 mg. She developed profound hypotension and bradycardia within 30 minutes, reversed by sympathomimetics. Shortly after extubation, she had severe breathing difficulties with loss of consciousness. Laryngoscopy showed massive swelling of the tongue and upper airways. Later, while still taking glucocorticoids, she was rechallenged with azathioprine and had milder hypotension and edema of the airways.

Even if no clear mechanism can account for this adverse effect, positive rechallenge strongly suggested that azathioprine was the culprit.

Bronchiolitis obliterans and non-infective pneumonia have been attributed to azathioprine [ ].

• A 71-year-old man with Crohn’s colitis, in whom prednisone 20 mg/day and mesalazine had been incompletely effective, the mesalazine was withdrawn and azathioprine 100 mg/day was started. After 2 weeks he developed a fever, worsening diarrhea, and abdominal pain. Intravenous glucocorticoids and then intravenous infliximab and ciclosporin were ineffective. He then developed shortness of breath and a non-productive cough and required oxygen. There was a leukocytosis (> 20 × 109/l) and a CT scan showed ground glass opacities predominantly in the upper lobes of the lungs bilaterally. A biopsy suggested bronchiolitis obliterans. Azathioprine was withdrawn and within 3 days the white cell count normalized and his clinical status improved.

• A 43-year-old woman taking prednisone for ulcerative colitis was given azathioprine 100 mg/day for 3 weeks. She developed increasing cough and shortness of breath, and continued to deteriorate despite oral antibiotics. She was cyanotic and hypoxic, and required intubation and ventilation. A CT scan showed a right middle lobe pneumonia with bibasal consolidation. Microbiology was negative. Azathioprine was withdrawn and she was given intravenous hydrocortisone. She improved and was weaned off the ventilator 5 days later. Her respiratory function normalized.

Nervous system

Neuritis multiplex occurred in a patient taking azathioprine for autoimmune hepatitis and resolved after conversion to cyclophosphamide [ ].

• A 37-year-old woman with autoimmune hepatitis taking azathioprine and prednisolone developed a left-sided hemisensory deficit followed by right foot drop and bilateral paresthesia in the ulnar nerve territory. An MRI scan and cerebral panangiography suggested cerebral vasculitis. Neurological investigations and electromyography showed neuritis multiplex probably due to vasculitis. There were serum autoantibodies to extractable nuclear antigens. Azathioprine was withdrawn and oral cyclophosphamide 150 mg/day introduced. Almost complete motoric remission was achieved after 3 months, but sensation remained reduced in the right peroneal nerve distribution.

Azathioprine can cause a posterior leukoencephalopathy [ ].

• A patient was given azathioprine for systemic lupus erythematosus and after 3 weeks developed a posterior leukoencephalopathy with headache, tonic–clonic seizures, loss of consciousness, bilateral loss of vision, and hypertension. A CT scan showed hypodense lesions in both bilateral occipital lobes, mainly in the white matter. The symptoms and follow-up MRI scan improved after control of hypertension and withdrawal of azathioprine.

Neuromuscular function

In two patients azathioprine caused profound muscular weakness, resulting in an inability to perform simple tasks, such as lifting even light objects, sitting upright, and walking a few steps [ ]. Withdrawal of azathioprine resulted in prompt improvement, and rechallenge led to recurrence of similar symptoms within hours.

Psychiatric

Azathioprine has been associated with psychiatric adverse events [ ].

• A 13-year-old boy with Wegener’s granulomatosis developed incapacitating obsessive–compulsive symptoms and severe panic attacks 4 weeks after switching from cyclophosphamide to azathioprine. He had obsessions about dying, committing suicide, and harming others, obsessive negative thoughts about himself and others, compulsive behavior, severe panic attacks more than once a day, and sleep disturbances. He was given fluvoxamine 100 mg/day, but 18 months later the symptoms suddenly disappeared, 3 weeks after he switched from azathioprine to methotrexate. In the next 4 years, he had no relapse.

Psychiatric adverse effects have not previously been reported with azathioprine. Neither does the database of the WHO Uppsala Monitoring Centre mention obsessive–compulsive symptoms or panic attacks as a possible adverse effect of azathioprine. However, the time course in this case and the absence of symptoms before and after azathioprine therapy suggest a causal relation. It is possible that the combination of subtle cerebral dysfunction as a result of the vasculitis and the use of azathioprine may have caused the symptoms in this patient.

Endocrine

Hyperprolactinemia has been attributed to azathioprine [ ].

• A 24-year-old woman, with a 3-year history of psoriasis, in the last trimester of her first pregnancy developed autoimmune thrombocytic purpura, which resolved after delivery. After 1 year, her liver function tests rose to 10 times normal values, associated with fatigue, weakness, and splenomegaly. Fine-needle liver aspiration showed autoimmune hepatitis. Her transaminases normalized with a glucocorticoid. She was then given azathioprine 50 mg/day instead of the glucocorticoid. After 1 month, her liver function tests rose about seven-fold and her prolactin concentrations by three-fold. She was again given a glucocorticoid and the azathioprine was continued. Six weeks later she was in remission, but her prolactin concentration was still high. There was no galactorrhea or amenorrhea, and the hyperprolactinemia was thought to have been be caused by azathioprine.

Hematologic

Hematological toxicity is the most commonly reported severe adverse effect of azathioprine, and is marked by predominant leukopenia, thrombocytopenia, and pancytopenia [ ]. In a 27-year survey of 739 patients treated with azathioprine 2 mg/kg for inflammatory bowel disease, dosage reduction or withdrawal of the drug because of bone marrow toxicity was necessary in 37 patients (5%) [ ]. There was moderate or severe leukopenia in 3.8% of patients; in three patients pancytopenia resulted in severe sepsis or death.

Leukopenia is the most serious adverse effect of azathioprine in patients with inflammatory bowel disease [ ]. It is variable and unpredictable and occurs 2 weeks to 11 years after the start of treatment (median 9 months); most cases recover 1 month after withdrawal.

The short-term and long-term toxicity of mercaptopurine has been investigated in 410 patients with inflammatory bowel disease treated for 20 years. There was significant leukopenia (3.5 × 109/l or less) in 11% [ ].

Dual therapy with ciclosporin and prednisone has been compared with triple therapy with ciclosporin, prednisone, and azathioprine in a randomized trial in 250 renal transplant patients [ ]. Patients in the triple therapy group had less frequent severe episodes of acute rejection and more frequent episodes of leukopenia than the double therapy group (28% versus 4%). There were no other differences in the adverse effects profiles, in particular the incidence of infectious complications.

Macrocytic anemia and isolated thrombocytopenia without severe clinical consequences have sometimes been observed. Pure red cell aplasia can occur, but the few relevant reports concern only isolated instances involving renal transplant patients [ , ]. The facts in one patient suggested that parvovirus B19 infection resulting from the immunosuppressive effects of azathioprine should also be considered as a possible indirect cause [ ]. Although blood cell disorders usually occur in the first 4 weeks of treatment, strict and regular surveillance of blood cell counts continuing for as long as treatment is maintained is usually recommended, since delayed hematological toxicity remains possible.

Megaloblastic change occurs in 16–82% of bone marrow aspirates, but long-term use of azathioprine rarely causes severe anemia. In addition, azathioprine can cause refractory pure red cell aplasia, particularly after kidney transplantation [ ]. Refractory anemia was reported in a patient with 17p– syndrome after heart transplantation [ ].

Among patients receiving mycophenolate mofetil or azathioprine the latter had lower hemoglobin concentrations after 1 and 6 months; mean corpuscular hemoglobin concentrations were also lower at 1 week and 1 months after transplantation but were comparable at 6 months [ ].

• Immune hemolytic anemia has been reported in a 67-year-old man taking mercaptopurine for chronic myelomonocytic leukemia [ ]. Serology showed a positive direct antiglobulin test and confirmed the presence of mercaptopurine drug-dependent antibodies. He improved and the direct antiglobulin test was no longer positive 20 days after mercaptopurine withdrawal.

Azathioprine can cause pancytopenia and subsequent myelodysplasia or secondary leukemia. Complex genetic alterations involving chromosome 7 are characteristic.

• A 49-year-old woman with multiple sclerosis received azathioprine for 5 years (cumulative dose 45 g) [ ]. She developed fatigue and a sinus tachycardia. She had a pancytopenia with a normochromic anemia (hemoglobin 6.2 g/dl), a mild leukopenia (leukocyte count 3.5 × 109/l), and thrombocytopenia (platelet count 22 × 109/l) requiring platelet transfusion. A bone marrow aspirate showed dysplasia of all three lineages, with reduced thrombopoiesis and ineffective erythropoiesis. Cytogenetic analysis showed a complex aberrant clone, including loss of the critically deleted regions in 5q31 and 7q31, as well as structural changes in 12p. Refractory cytopenia with multilineage dysplasia was diagnosed according to the WHO classification of myelodysplastic syndromes. Allogeneic sibling transplantation was planned, but she developed a spontaneous recurrent subdural hematoma and died due to persistent bleeding refractory to platelet transfusion.

Aplastic anemia due to azathioprine therapy after corneal transplantation has reportedly caused bilateral macular hemorrhage [ ].

• A 38-year-old man underwent therapeutic penetrating keratoplasty for non-healing fungal keratitis in his left eye. Although the infection was controlled, he underwent a second corneal transplantation after 2 years. Since there was corneal vascularization in three quadrants, he was given oral azathioprine postoperatively. Four months later he developed gastrointestinal bleeding and a sudden reduction in vision in both eyes. His platelet count was less than 30 × 109/l, his hemoglobin 4.1 g/dl, and a bone marrow aspirate was hypocellular. There were macular hemorrhages in both eyes. The hemorrhages resolved within 2 months.

Gastrointestinal

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 syndrome. In two patients with azathioprine-induced diarrhea proven by positive rechallenge, the period of sensitization ranged from 1 week to 1 year [ ].

In two cases, azathioprine caused severe gastrointestinal symptoms that could have been easily confused with an acute exacerbation of the underlying inflammatory bowel disease [ ].

• A 32-year-old man with ulcerative colitis improved with prednisolone, mesalazine, and antibiotics. The dose of prednisolone was reduced and the disease flared up again. He was therefore given azathioprine and an increased dose of prednisolone, with rapid clinical improvement. After 3 weeks, he reported increasing abdominal pain, worse diarrhea, and weight loss of 3 kg. He stopped taking azathioprine and the pain improved. Because of progressive disease and active pancolitis at colonoscopy, he was given high-dose prednisolone, mesalazine, and ciprofloxacin, without improvement. He was therefore given intravenous azathioprine, but developed devastating diarrhea and weight loss of more than 6 kg in 24 hours, his CRP rose from 5 to 305 μg/ml, and he developed hypovolemic shock. He recovered after treatment with parenteral nutrition for 7 days.

• A 50-year-old woman with Crohn’s disease and active disease throughout the colon was given prednisolone, mesalazine, and azathioprine 50 mg/day. After 3 weeks, the dose of azathioprine was increased to 100 mg/day, but she developed nausea, severe diarrhea, and abdominal tenderness. The symptoms subsided after azathioprine was withdrawn. She was then given mercaptopurine, without significant adverse effects.

Azathioprine can cause severe small-bowel villous atrophy, diarrhea, and malabsorption, reversible after withdrawal.

• A 20-year-old man with autoimmune hepatitis developed severe small-bowel villous atrophy and chronic diarrhea after taking azathioprine 50 mg/day [ ]. The diarrhea was unresponsive to oral pancreatic enzymes or a gluten-free diet, and severe malabsorption required parenteral nutrition for more than 1.5 years, until the association with azathioprine was identified. Within 2 weeks after withdrawal, the diarrhea resolved completely and parenteral nutrition was discontinued. Mucosal biopsies before and 4 months after azathioprine withdrawal showed complete reversal of severe duodenal villous atrophy and marked up-regulation of mucosal dipeptidyl peptidase IV and PepT1 messenger RNA. The patient subsequently maintained normal liver function tests on low-dose prednisone alone, with normal stools and stable nutritional status for more than 4 years.

Liver

Thiopurines can cause liver damage, and the incidence varies in different studies. Although rarely severe, any increase in liver enzyme activity justifies careful and regular monitoring of liver function and the results may be a reason for withdrawing treatment [ ]. In a retrospective study, hepatitis was found in 21 (2%) of 1035 renal transplant patients, and it was suggested that hepatitis B or C infection increases the risk of azathioprine hepatotoxicity [ ]. In 29 cardiac transplant recipients who had had probable azathioprine-induced liver dysfunction, cyclophosphamide was given, with improvement of liver enzyme activities and no increase in the rate of graft rejection or significant changes in the doses of other immunosuppressive drugs [ ].

Hepatotoxicity, defined as alanine transaminase or alkaline phosphatase activities greater than twice the upper normal limit, was studied in 161 patients with inflammatory bowel disease over a median follow-up of 271 days [ ]. There was abnormal liver function in 21 patients (13%), hepatotoxicity in 16 (10 %) after a median of 85 days, and thiopurines were withdrawn in five patients because of hepatotoxicity.

Azathioprine can cause reversible cholestasis [ ], perhaps due to bile duct injury [ ].

Direct hepatocellular injury with acute cytolytic hepatitis has been reported rarely [ ].

In one patient, azathioprine-induced lymphoma with massive liver infiltration was the probable cause of fulminant hepatic failure [ ].

Other histological features that have been described include lesions of the hepatic venous system (peliosis hepatis, sinusoidal dilatation, perivenous fibrosis, and nodular regenerative hyperplasia) and these can be associated with portal hypertension [ ]. Particularly severe and potentially fatal veno-occlusive liver disease has been reported in patients with renal and allogeneic bone marrow transplants taking chronic treatment [ ], but complete histological reversal can be observed [ ].

• In a 33-year-old man azathioprine-induced veno-occlusive disease was treated with a transjugular intrahepatic portosystemic shunt over 26 months, with progressive worsening 15 months after renal transplantation [ ].

Four patients with renal transplants developed hepatic veno-occlusive disease after immunosuppression with azathioprine. The diagnosis was based on typical histopathological findings: perivenular fibrosis, trilobular sinusoidal dilatation and congestion, and perisinusoidal fibrosis. The patients presented with severe progressive portal hypertension followed by fulminant liver failure and death. The disease was associated with cytomegalovirus infection, and it was not related to the dose of azathioprine [ ]. Veno-occlusive liver disease has also been described shortly after liver transplantation [ , ]. A history of acute liver rejection affecting the hepatic veins was supposedly a contributing factor in these patients, and the presence of non-inflammatory small hepatic vein lesions was a possible early indicator of hepatotoxicity. Liver biopsy should therefore be considered in liver recipients who have biological features of hepatitis, so that treatment can be withdrawn rapidly if necessary.

Azathioprine allergy can be associated with biochemical hepatitis and a normal liver biopsy, apart from marked lipofuscin deposition [ ]. These findings, combined with patchy isotope uptake on technetium scintigraphy, are suggestive of focal hepatocellular necrosis.

There may be an increased risk of azathioprine-induced liver damage in renal transplant patients with chronic viral hepatitis, and it has been suggested that there may be an association between azathioprine therapy and the development of hepatocellular carcinoma in patients with Crohn's disease [ ].

• Fatal fibrosing cholestatic hepatitis has been reported in a 63-year-old cardiac transplant patient with acquired post-transplant hepatitis C virus infection whose immunosuppressive regimen included azathioprine [ ]. Histology showed several features of azathioprine hepatotoxicity, namely veno-subocclusive lesions and nodular regenerative diffuse hyperplasia, suggesting a pathogenic role of azathioprine.

In 79 renal transplant patients with chronic viral hepatitis, azathioprine maintenance treatment (n = 34) was associated with a poorer outcome than in 45 patients who discontinued azathioprine [ ]. Cirrhosis was more frequent in the first group (six versus one), and more patients died with a functioning graft (14 versus two), mostly because of liver dysfunction (n = 5) or infection (n = 6). These results suggest that azathioprine further accelerates the course of the liver disease in these patients.

Nodular regenerative hyperplasia of the liver can occur with any of the purine analogues (azathioprine, 6-mercaptopurine, and 6-thioguanine) [ ]. It has been described in four patients with inflammatory bowel disease taking azathioprine [ ]. All had either abnormal liver function tests and/or a low platelet count. The biochemical and hematological abnormalities resolved after azathioprine withdrawal. Male sex was a major susceptibility factor. In another series, two patients taking azathioprine developed nodular regenerative hyperplasia; both were heterozygous for the TPMT*3A mutation [ ].

• A 50-year-old woman with nodular sclerosis developed azathioprine-induced hepatotoxicity within the first weeks of treatment [ ], the usual time-course. Positive rechallenge confirmed the role of azathioprine.

However, delayed occurrence of hepatitis is also possible.

• Canalicular cholestasis with portal fibrosis and ductal proliferation has been reported after 24 years of azathioprine in a 57-year-old woman with myasthenia gravis [ ].

An unusual diffuse liver disease with sinusoidal dilatation [ ] has been described.

In vitro, glycyrrhizic acid and liquorice had a protective effect against azathioprine hepatotoxicity; glycyrrhizic acid protected human hepatocytes from intracellular glutathione depletion on exposure to azathioprine 1 μmol/l [ ]. In another in vitro study a novel glutathione transferase (GST)-dependent pathway in the biotransformation of azathioprine was described [ ]. Glutathione transferases A1-1, A2-2, and M1-1, all abundantly expressed in human liver, had the highest activity among the 14 isoenzymes tested. The uncatalysed reaction of azathioprine with glutathione was less than 1% of the glutathione transferase-catalysed biotransformation. GST M1-1 is polymorphic, with a frequently occurring null allele, and GST A1-1 and GST A2-2 are variably expressed in humans, implying significant differences in the rate of mercaptopurine production from azathioprine. Individuals who expressing high GST activity are predisposed to adverse reactions to azathioprine, both by promoting excessively high concentrations of mercaptopurine and its toxic metabolites and by depleting cellular glutathione.

Azathioprine can cause nodular regenerative hyperplasia, a rare hepatic lesion defined by diffuse nodularity of the hepatic parenchyma, without annular fibrosis, with alternating areas of atrophy and hyperplasia. In a multicenter study of patients taking azathioprine between 1994 and 2005, 37 cases were identified [ ]. The median dose of azathioprine was 2 mg/kg/day. The median time to diagnosis was 48 months after the start of therapy. Portal hypertension was the presenting feature in 31 patients with complications in 14, including nine with acute variceal bleeding and five with ascites; 15 underwent primary or secondary treatment for portal hypertension, including beta-blockers and nitrates (n = 11), endoscopic therapy (n = 9), embolization (n = 2), and transjugular intrahepatic portosystemic shunting (n = 2). One patient underwent liver transplantation for hepatic encephalopathy following TIPS insertion. There were no deaths or cases of hepatocellular carcinoma.

Pancreas

Pancreatitis due to azathioprine or mercaptopurine has usually been reported as part of the hypersensitivity syndrome [ ]. 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 [ ]. Pancreatitis was not dose-related within the therapeutic range of doses and often recurred in patients who were rechallenged with either drug [ , ]. Fatal hemorrhagic pancreatitis occurred in one patient, but a role of concomitant drugs was also possible [ ]. 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 [ ].

In a review of definite or probable drug-associated pancreatitis spontaneously reported to the Dutch adverse drug reactions system during 1977–98, azathioprine was the suspected drug in four of 34 patients, two of whom had positive rechallenge [ ]. Although most of the carefully described reports of azathioprine-induced pancreatitis were found in patients with inflammatory bowel disease, transplant recipients can also suffer this complication.

• Over a year after renal transplantation, a 48-year-old man, who took azathioprine, ciclosporin, and prednisolone, developed acute necrotizing pancreatitis [ ]. Improvement was obtained after azathioprine withdrawal, but he again took azathioprine and had similar symptoms within 30 hours after a single dose.

• Pancreatitis has been reported after a progressive increase in dose of 6-thioguanine in a 10-year-old infant [ ]. She had had two previous episodes of pancreatitis after mercaptopurine.

In Denmark, 1317 patients redeemed a total of 15 811 prescriptions for azathioprine during 1991 and 2000. The incidence rate for acute pancreatitis was one per 659 treatment year. The risk increased with presence of gallstone disease, alcohol-related diseases, inflammatory bowel disease, and the use of glucocorticoids. Thus, the relative risk of acute pancreatitis is increased in azathioprine users [ ].

Azathioprine-associated acute pancreatitis is strongly associated with Crohn’s disease and occurs less commonly with other underlying conditions [ ]. The incidence of acute pancreatitis was 4.9% in 224 patients with Crohn’s disease, 1.5% in 129 with autoimmune hepatitis, 0.5% in 388 with kidney transplants, and 0.4% in 254 with liver transplants.

The chemical structure of 6-thioguanine, which results from the metabolism of azathioprine/mercaptopurine, is very similar to that of mercaptopurine. Therefore, a history of previous adverse effects with mercaptopurine should be anticipated in patients considered for 6-thioguanine treatment.

Urinary tract

A woman with Wegener’s granulomatosis progressed to renal failure within 10 days of starting azathioprine for vasculitis [ ]. A renal biopsy showed acute tubulointerstitial nephritis and no active glomerulonephritis.

Skin

Rashes or other allergic-type cutaneous reactions are usually noted during the azathioprine hypersensitivity syndrome. Isolated but convincing reports point to the occurrence of vasculitis with microscopic polyarteritis [ ] and Sweet’s syndrome, which recurred after subsequent azathioprine exposure [ ].

Pellagra with a photosensitivity-like rash and skin peeling syndrome has also been noted [ ].

A febrile diffuse skin eruption occurred in a patient taking azathioprine and a glucocorticoid [ ].

• A 53-year-old man with moderately active ulcerative colitis developed a febrile diffuse skin eruption after taking a glucocorticoid and azathioprine for a few days. Azathioprine was withdrawn. Skin biopsies showed features typical of Sweet’s syndrome (neutrophilic dermatosis). The eruption gradually improved and there was complete regression after further glucocorticoid treatment.

Acute generalized exanthematous pustulosis has been associated with azathioprine [ ].

• A 54-year-old woman with diabetes was given prednisolone and azathioprine 50 mg/day for pemphigus foliaceus and after 20 days developed disabling arthralgia, a fever (40.7 °C), hypotension (85/45 mmHg), and a generalized, non-follicular pustular eruption with background erythema over 24 hours. Initially she was treated for septic shock with intravenous fluids and cefuroxime. However, later her symptoms were thought to be consistent with hypersensitivity to azathioprine, which was withdrawn. She improved over the next 48 hours and the pustular eruption and systemic symptoms resolved, with mild desquamation. Patch and prick tests with azathioprine were negative.

Musculoskeletal

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 [ ]. Rhabdomyolysis has also been reported as a possible feature of the azathioprine hypersensitivity syndrome [ ].

In two patients with Crohn’s disease, azathioprine was suspected to have caused severe gait disorders with an inability to walk [ ]. Within 1 month of treatment, both had joint pains or diffuse arthralgias that were the presumed cause of pseudoparalysis of the legs. In one patient other causes were carefully ruled out and similar symptoms recurred shortly after azathioprine was re-introduced.

The risk of fractures has been studied in a case–control study in 124 655 patients. Azathioprine was associated with an increase in overall risk of fractures, but not spine, hip, or forearm fractures [ ]. Methotrexate and ciclosporin were not associated with a risk of fractures. This association might be related to the underlying disease for which azathioprine was being used.