Li-En Tao, Xue-Yan Chen, Bing-Xi Yan, Xiao-Yong Man*

Department of Dermatology,Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,Zhejiang 310009,China.

Introduction

Azathioprine (AZA), an imidazolyl derivative of 6-mercaptopurine,was first used to prevent organ rejection in people who have received a kidney transplant in 1960s.Since then, it has become an effective corticosteroidsparing agent in a series of autoimmune inflammatory diseases.1AZA hypersensitivity syndrome(AHS)is a rare adverse drug reaction characterized by acute fever,arthralgia, abdominal pain, nausea, and associated cutaneous eruptions such as Sweet syndrome.2Lifethreatening high fever and myopathy may occur if such a hypersensitivity reaction remains unrecognized in patients with autoimmune disease.

In this case, the patient presented typically with almost all of the previously reported symptoms after taking AZA,including high fever, rash on the face and extremities,nodular erythema on the lower extremities, myopathy,intracranial hypertension,hepatotoxicity,and an elevated C-reactive protein concentration.The point of this case is to remind the clinician to recognize, evaluate and treat AZA hypersensitivity.Skin lesions maybe an important clue to the early diagnosis of AZA hypersensitivity and aid promptly recognition and timely treatment to this potentially life-threatening adverse effect of the drug.

Case report

A 42-year-old Chinese woman presented with a 1-week history of a skin rash with mild itching, myopathy,arthralgia,and high fever.She had no vomiting or diarrhea.Six months earlier, she had been diagnosed with a demyelinating disease;she was treated with methylprednisolone and discharged from the hospital without symptoms.She took prednisone at 30mg daily thereafter.Approximately2weeksbeforepresentation,themethylprednisolone was replaced by AZA (Imuran, Azasan) because of the adverse effects of methylprednisolone.She took AZA at 100mg daily, and seven days later, she developed fever,chills, nodular erythema, and myopathy.She considered that this may have been caused by an infection and was treated with oral antibiotics at a local clinic.However,the symptoms did not improve and even became exacerbated.Therefore, the patient was admitted to our department.Upon arrival, her temperature was 39.1oC.Furthermore,she reported headache and myopathy of the extremities.Physical examination revealed a skin rash on her face and extremities,especially erythema nodusum on her lower legs(Fig.1A).Individual lesions were 5-to 10-mm,indurated,erythematous nodules.

The patient had class I muscle strength.Liver function testing showed elevated transaminases (alanine aminotransferase,84U/L;aspartate transaminase,105U/L)with no evidence of eosinophilia.A lumbar puncture was then performed, and the intracranial pressure of cerebrospinal fluid was 410 mmH2O (normal limit is 200 mmH2O).Other examination findings were normal.Microbiological and radiological examinations revealed no signs of infection.Magnetic resonance imaging examination showed no intracranial mass lesion or cerebrospinal outflow obstruction.The neurological examination was also normal.The previously prescribed AZA was discontinued.The temperature decreased within 2 days and the erythema disappeared (Fig.1B).The patient's muscle strength examination recovered to class IV.The serum creatine phosphokinase (CK) and creatine phosphokinase-myocardial band levels, antinuclear antibody titer, urinalysis, and chest x-ray were all within normal limits.Her work-up for sepsis yielded negative findings,and other laboratory findings were unremarkable.

Figure 1.Photographs of the patient taken at the indicated times(A)during treatment with azathioprine and (B) after discontinuation of azathioprine.

Figure 2.Gene sequence of the patient with azathioprine hypersensitivity syndrome.Mutations of ITPA c.138G＞GA:46Q＞Q/Q (A),ITPA c.561G＞GA:187E＞E/E (B), MTHFR c.1286A＞AC:429E＞E/A(C),c.1305C＞T:435F＞F(D),and TPMT c.474T＞TC:158I＞I/I(E)are present.ITPA: inosine triphosphatase; MTHFR: methylenetetrahydrofolate reductase; TPMT: thiopurine methyltransferase.

A surgical biopsy specimen was taken from her leg,and skin histology showed a dermal perivascular diffuse infiltrate of lymphocytes.However, the high fever and erythema recurred 3 days later.The patient developed arthralgia,malaise,and cutaneous lesions.The skin lesions again erupted on the forearms and distal legs with an appearance similar to that of the initial lesions.After a detailed inquiry, the patient told us that after clinical improvement of the skin rash,she had restarted the AZA at a dose of 50mg because she was concerned about the onset of demyelinating disease.Otherwise,no change was made.Therefore,the AZA was discontinued again.The next day,her high fever and nodular erythema were abated.Her liver function was normal(alanine aminotransferase,29U/L;aspartate transaminase,22U/L).Her C-reactive protein concentration was slightly increased (32.5mg/L), and her procalcitonin concentration was normal (0.14μg/L).Therefore,based on the fact that the symptoms improved or recurred with discontinuation or restarting of the AZA,a causal relationship between administration of AZA and the onset of symptoms was established and the patient was diagnosed with AHS.3

Discussion

Our patient developed a high fever, rash on the face and extremities, nodular erythema on the lower extremities,myopathy, intracranial hypertension, hepatotoxicity, and an elevated C-reactive protein concentration after taking AZA.Prompt recognition, evaluation, and treatment are needed to prevent complications of AZA hypersensitivity.Skin lesions may be an important early clue to the diagnosis of AZA hypersensitivity and aid in prompt recognition and treatment of this potentially life-threatening adverse drug effect.1According to these clinical manifestations, the Registry of Severe Cutaneous Adverse Reaction score for drug rash with eosinophilia and systemic symptoms syndrome is 4, which is a probable case.After 1.5 years of follow-up, the patient did not take AZA and no recurrence of the above symptoms was observed.

Polymorphisms in three pharmacogenetically important genes,thiopurine methyltransferase,methylenetetrahydrofolate reductase (MTHFR), and inosine triphosphatase,have been considered candidates to explain adverse drug reactions to thiopurine therapy.4Therefore, these three genes were sequenced in the current patient.Mutations for inosine triphosphatase(c.138G＞GA:46Q＞Q/Q;c.561G＞GA:187E＞E/E), MTHFR (c.1286A＞AC:429E＞E/A;c.1305C＞T:435F＞F), and thiopurine methyltransferase(c.474T＞TC:158I＞I/I)were detected(Fig.2).It seems that the missense mutation of MTHFR may result in severe deficiency of the MTHFR enzyme and play a role in AHS,5but this is poorly understood.