June 2007

Erythema Nodosum–like Eruption as a Manifestation of Azathioprine Hypersensitivity in Patients With Inflammatory Bowel Disease

Author Affiliations

Author Affiliations: Department of Dermatology, Hôpital Tenon (Drs de Fonclare, Khosrotehrani, and Aractingi), Université Pierre et Marie Curie (Drs Khosrotehrani, Aractingi, Cosnes, and Beaugerie), and Departments of Pathology (Dr Duriez) and Gastroenterology (Drs Cosnes and Beaugerie), Hôpital Saint-Antoine, Assistance Publique–Hôpitaux de Paris, Paris, France.


Copyright 2007 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2007

Arch Dermatol. 2007;143(6):744-748. doi:10.1001/archderm.143.6.744

Background  Clinical manifestations of hypersensitivity to azathioprine may mimic symptoms of the initial disease. We report 5 cases of peculiar skin hypersensitivity reactions to azathioprine in patients with inflammatory bowel disease.

Observations  In 5 patients with a recent azathioprine regimen, manifestations appeared between 8 and 18 days after drug introduction. All patients had a high fever. Three patients initially had erythema nodosum; 2 patients had sterile pustules. All had elevated neutrophil counts and serum C-reactive protein levels, whereas eosinophil counts were normal, ruling out drug-induced rash with eosinophilia and systemic symptoms. In 3 patients who were rechallenged with azathioprine or with 6-mercaptopurine, dermatological lesions recurred within hours.

Conclusions  Erythema nodosum and pustules are rarely reported manifestations of azathioprine hypersensitivity. Both skin lesions may be related to the clinical activity of inflammatory bowel disease. Relapse of such lesions shortly after thiopurine rechallenge should raise the hypothesis of hypersensitivity rather than pharmacological manifestations.

Thiopurines are widely used as a maintenance treatment of Crohn disease and ulcerative colitis, as well as in other clinical contexts such as posttransplantation immunosuppressive therapy. The adverse effects reported with this drug have been classified as early events or as late events. Late adverse reactions are dose-dependent cytopenias and can be partly anticipated by evaluation of the patient's thiopurine methyltransferase activity. Early adverse reactions to azathioprine are common and include hypersensitivity.1,2 Unlike IgE-mediated allergy, the clinical manifestations of this systemic idiosyncratic reaction are heterogeneous and include fever, hepatitis, nephritis, pneumonia, hypotension, arthralgias, pancreatitis, pericarditis, digestive symptoms, and skin manifestations. Severe systemic hypersensitivity manifestations are uncommon. To our knowledge, erythema nodosum–like nodules or pustules have not been described as manifestations of hypersensitivity to azathioprine in inflammatory bowel disease. These skin manifestations can be associated with infections or may suggest worsening of the underlying bowel disease. This may lead to life-threatening delays in the diagnosis of hypersensitivity and in the discontinuation of azathioprine treatment. Herein, we describe azathioprine hypersensitivity in 5 patients manifesting unusual skin nodules and pustules.


The follFigure.owing observations were made in 5 patients (3 men and 2 women) between January 23, 2004, and May 21, 2006 (Table 1 and Table 2). Four patients had Crohn disease, and 1 patient had ulcerative colitis. All patients had levels of thiopurine methyltransferase activity within the normal range. Azathioprine treatment was introduced in all patients as a corticosteroid-sparing agent. The clinical symptoms occurred, on average, 8 to 18 days after the initiation of azathioprine treatment. All patients had high fever (temperature, 39°C) and skin eruption that was localized initially to the lower limbs. Patient 2 and patient 5 had secondary extension of the disease to other body parts. In 3 patients (patients 1, 4, and 5), the skin eruptions comprised painful erythematous nodules scattered on the legs that were suggestive of erythema nodosum (Figure, A). In 2 patients (patients 2 and 3), erythematous plaques with superficial pustules or isolated pustules were observed on the legs (Figure, C and D). Other manifestations included joint, abdominal, and muscular pain, with worsening of digestive symptoms in 1 patient (patient 2). Biologically, there was a constant increase in neutrophil counts in all patients, with acute inflammation and high levels of serum C-reactive protein. None of the patients initially had hypereosinophilia. Results of microbiological analyses were negative: cultures of blood, urine, and pustules were devoid of bacteria and fungi. Histological examination of skin biopsy specimens of nodules revealed predominantly septal inflammation of the hypodermis with normal aspects of the epidermis and dermis. In addition, the infiltrate comprised lymphocytes and macrophages with few neutrophils (Figure, B). There was no sign of vasculitis. Analysis demonstrated intraepidermic spongiotic pustules containing neutrophils; the surrounding epidermis was also infiltrated with neutrophils (Figure, E and F). No sign of vasculitis was observed in the dermis. In 1 patient (patient 3), hepatitis and pancreatitis were diagnosed (Table 2). The initial suspected diagnoses were infectious disease in 3 patients (patients 1, 3, and 4), digestive disease relapse in 1 patient (patient 2), and hypersensitivity in 1 patient (patient 5). After interruption of azathioprine therapy and initiation of corticosteroid therapy in 2 patients (patients 3 and 1), complete regression of all clinical and biological abnormalities, including neutrophilia, was noted within 2 weeks and persisted afterward. Three patients were rechallenged with azathioprine, the metabolic equivalent 6-mercaptopurine, or both. The rechallenge was scheduled at least 1 month after resolution of the initial symptoms. In all patients, relapse of the initial symptoms occurred within hours. In 1 patient (patient 4), this relapse was complicated by a sharp decrease in blood pressure. Symptoms again resolved within hours after drug withdrawal.

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Clinical and pathological features in patient 1 and patient 2 in Table 1 and Table 2. Erythema nodosum on the lower limbs in patient 1 (A) and a histologic section of a punch biopsy specimen from a nodule in patient 1 stained with hematoxylin-eosin (B) (original magnification ×400). The epidermal and dermoepidermal layers were devoid of abnormality. There is hypodermal infiltration of the septa by macrophages, lymphocytes, and histiocytes, including a few giant cells, without any sign of necrosis or vasculitis. Pustular plaques on both legs in patient 2, with a close-up of superficial pustules. E, Two intact intraepidermal unilocular pustules in patient 2 are seen at low magnification (original magnification (C) ×40). These pustules are accompanied (D) by mild inflammation of the dermis. F, Neutrophils are seen inside a pustule in patient 2 (hematoxylin-eosin, original magnification ×400).

Table 1. 
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Observations of Hypersensitivity to Azathioprine
Table 2. 
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Diagnosis of Hypersensitivity to Azathioprine

We report 5 cases of pustular or erythema nodosum–like eruption associated with high fever (mean temperature, 39°C) due to azathioprine hypersensitivity. In accord with previous studies,1,2,4,5 thiopurine methyltransferase activity was not predictive of this type of adverse effect. In the context of initiation of immunosuppressive therapy, the presence of high fever with nodules and pustules was suggestive of acute bacterial or fungal infection that was rapidly ruled out by results of blood cultures.

After the initiation of azathioprine treatment, symptoms occurred in a temporal manner suggesting hypersensitivity. Similarly, the resolution of symptoms after discontinuation of treatment, the relapse after rechallenge, and the short interval between rechallenge and relapse of the symptoms strongly indicated hypersensitivity to thiopurines.5 The primary reactive compound is probably not azathioprine but a metabolite, as rechallenge with 6-mercaptopurine produced similar manifestations of hypersensitivity.

Hypersensitivity is a well-known complication of azathioprine therapy. Maculopapular rash seems to be the most frequent cutaneous manifestation of drug hypersensitivity. None of the patients in our study met the criteria for drug-induced rash with eosinophilia and systemic symptoms. Although some patients displayed systemic symptoms such as liver or pancreas abnormalities, none had eosinophilia or maculopapular rash. Two patients (patients 2 and 3) had a peculiar pustular rash. As far as we know, azathioprine has not been reported to be responsible for acute generalized pustular exanthematic rash, a well-described type of drug reaction.6 In patient 3, the pustular rash was distinct from the usual acute generalized pustular exanthematic rash, as it was confined to the lower limbs. To our knowledge, pustular rash and erythema nodosum have each been described only once in association with azathioprine hypersensitivity in situations other than inflammatory bowel disease.7,8

Pustules and erythema nodosum are associated with inflammatory bowel disease. One of our patients initially had a flare of his digestive symptoms, and another patient had inflammatory joint pain. These observations suggest that azathioprine hypersensitivity in some cases may mimic the symptoms of inflammatory bowel disease. Similarly, anterior uveitis, a rare complication associated with inflammatory bowel disease, has been associated with azathioprine therapy in a patient with ulcerative colitis.9 Azathioprine hypersensitivity has been reported to mimic the initial disease in other disorders such as myasthenia10,11 and dermatomyositis.8 Neutrophilic dermatoses such as Sweet syndrome and pyoderma gangrenosum have been described as secondary to azathioprine therapy in inflammatory bowel disease.12 Neutrophilic dermatosis may be secondary to a pharmacological effect of azathioprine. The histological findings of the pustular rash with neutrophilic infiltration could be compatible with such a diagnosis. However, histological examination of the nodules did not reveal marked edema or neutrophilic infiltration characteristic of Sweet syndrome. Further, the short interval between rechallenge and relapse of the symptoms at a higher intensity (after a 1-month washout period) indicated an immunological reaction against azathioprine or its metabolites.

In the patients described herein, azathioprine was interrupted because of suggestion of excessive immunosuppression causing infection, inefficiency, or hypersensitivity. After ruling out infection in 3 of 5 patients, it seemed plausible that azathioprine could be reintroduced on the basis that the manifestations were due to inflammatory bowel disease. The findings from our study suggest that hypersensitivity should be considered as an alternate diagnosis and that rechallenge should be avoided or conducted under close surveillance, as we observed a sharp decrease in blood pressure in 1 patient necessitating resuscitation.

Early adverse effects of azathioprine, including hypersensitivity manifestations, seem to be more common in patients with Crohn disease compared with patients with autoimmune hepatitis (29% vs 2% of treated patients).13 In that study, the significant difference between the 2 groups was independent of thiopurine methyltransferase levels, azathioprine initiation dosage, or simultaneous intake of prednisone. Overall, it seems that patients with inflammatory bowel disease tend to have specific and frequent manifestations of azathioprine hypersensitivity. Whether this particular sensitivity of patients with Crohn disease is genetically determined is unknown. In accord with this hypothesis, recent pharmacogenetic investigations have pointed to other polymorphisms in the metabolic chain of purines that are associated with early adverse effects of azathioprine and 6-mercaptopurine; the inosine triphosphate pyrophosphatase 94C→A polymorphism is related to increased flulike syndrome, cutaneous eruption, and pancreatitis in patients with inflammatory bowel disease.14

In conclusion, we demonstrate herein that erythema nodosum–like skin lesions are a potential clinical sign of hypersensitivity reaction to thiopurines. A careful analysis of the timing of exposure to azathioprine and the appearance of erythema nodosum and other signs of hypersensitivity can provide important clues to the underlying cause of this condition. In the clinical situation in which erythema nodosum and other signs of hypersensitivity are present following the introduction of azathioprine, discontinuation of the drug is warranted.

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Article Information

Correspondence: Kiarash Khosrotehrani, MD, PhD, Department of Dermatology, Hôpital Tenon, 4 Rue de la Chine, 75020 Paris, France (kiarash.khosrotehrani@tnn.aphp.fr).

Financial Disclosure: None reported.

Accepted for Publication: August 29, 2006.

Author Contributions: Drs de Fonclare and Khosrotehrani contributed equally to this work. Study concept and design: de Fonclare and Khosrotehrani. Acquisition of data: de Fonclare, Khosrotehrani, Duriez, and Cosnes. Analysis and interpretation of data: de Fonclare, Khosrotehrani, Aractingi, Cosnes, and Beaugerie. Drafting of the manuscript: de Fonclare, Khosrotehrani, and Duriez. Critical revision of the manuscript for important intellectual content: de Fonclare, Khosrotehrani, Aractingi, Cosnes, and Beaugerie. Administrative, technical, and material support: de Fonclare, Khosrotehrani, and Cosnes. Study supervision: Aractingi and Beaugerie.

McGovern  DPTravis  SPDuley  JShobowale-Bakre  el MDalton  HR Azathioprine intolerance in patients with IBD may be imidazole-related and is independent of TPMT activity. Gastroenterology 2002;122838- 839
Gearry  RBBarclay  MLBurt  MJ  et al.  Thiopurine S-methyltransferase (TPMT) genotype does not predict adverse drug reactions to thiopurine drugs in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2003;18395- 400
Maddocks  JLLennard  LAmess  JAmos  RThomas  RM Azathioprine and severe bone marrow depression [letter]. Lancet 1986;1156
McLeod  HLKrynetski  EYRelling  MVEvans  WE Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 2000;14567- 572
Beaugerie  LPardi  DS Drug-induced microscopic colitis: proposal for a scoring system and review of the literature. Aliment Pharmacol Ther 2005;22277- 284
Roujeau  JCBioulac-Sage  PBourseau  C  et al.  Acute generalized exanthematous pustulosis: analysis of 63 cases. Arch Dermatol 1991;1271333- 1338
Goldenberg  DLStor  RA Azathioprine hypersensitivity mimicking an acute exacerbation of dermatomyositis. J Rheumatol 1975;2346- 349
Jeurissen  MEBoerbooms  AMvan de Putte  LBKruijsen  MW Azathioprine induced fever, chills, rash, and hepatotoxicity in rheumatoid arthritis. Ann Rheum Dis 1990;4925- 27
Mayo  JMColmenarejo  MBVaquerizo  PJGutierrez  MV Hypersensitivity reaction to azathioprine in a patient with ulcerative colitis: infrequent manifestations [letter]. Inflamm Bowel Dis 2004;10700
Tumani  HGeorge  ANau  R Myasthenic crisis caused by azathioprine-induced fever [in German]. Nervenarzt 1997;68336- 338
Watts  GFCorston  R Hypersensitivity to azathioprine in myasthenia gravis. Postgrad Med J 1984;60362- 363
Paoluzi  OACrispino  PAmantea  A  et al.  Diffuse febrile dermatosis in a patient with active ulcerative colitis under treatment with steroids and azathioprine: a case of Sweet's syndrome: case report and review of literature. Dig Liver Dis 2004;36361- 366
Bajaj  JSSaeian  KVarma  RR  et al.  Increased rates of early adverse reaction to azathioprine in patients with Crohn's disease compared to autoimmune hepatitis: a tertiary referral center experience. Am J Gastroenterol 2005;1001121- 1125
Marinaki  AMAnsari  ADuley  JA  et al.  Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics 2004;14181- 187