Azathioprine and chlorambucil: mechanism of action and use in ...

Human
Table 1. Selected dermatologic diseases where azathioprine has shown to be of benefit
Immunobullous disease Eczema
Bullous pemphigoid Contact dermatitis
Pemphigoid Photodermatitis
Cicatricial pemphigoid Actinic reticuloid
Juvenile pemphigus Chronic actinic dermatitis
Pemphigus foliaceous Other
Pemphigus vulgaris Erythema multiforme
Paraneoplastic pemphigus Cutaneous lupus erythematosus
Pemphigus erythematosus Lichen planus
Eczematous diseases Cutaneous vasculitis
Psoriasis Graft-versus-host disease
Atopic dermatitis
Adapted from Patel, et. al. 1
Veterinary
Table 2. Selected dermatologic diseases where azathioprine may be of benefit
Pemphigus foliaceous 21, 22 Lupoid onychitis ** 23
Pemphigus vulgaris 21, 22 Uveodermatologic syndrome
Superficial pemphigus complex 21, 22 Epidermolysis bullosa acquisita 24
Systemic lupus erythematosus 22 Perianal fistula **
Vesicular cutaneous lupus erythematosus 25 Erythema multiforme 26
Cutaneous reactive histiocytosis ** 27
Idiopathic sterile granuloma and
? Atopic dermatitis** 28
pyogranuloma 22
** indicates that other forms of drug therapy are the gold standard for treatment of this condition, but
azathioprine may be of benefit in refractory cases
Adverse effects
Haematologic
Cytopenias and severe bone marrow suppression have been reported in both the human and
veterinary literature, and may occur weeks to months after initiating treatment. Humans may suffer from
bone marrow suppression years after initiating therapy, as steady state levels of azathioprine in the blood
may take month to years to achieve. 2 While neutropenia is the most common cytopenia noted, anaemia and
thrombocytopenia may also occur. 29 TPMT genotype testing is advocated in human medicine to identify
those individuals at risk for developing acute or delayed onset neutropenia. While TPMT activity has been
measured in dogs, cats and horses, its relevance to the development of adverse effects is unknown.
While pretreatment TPMT activity is a useful indicator of susceptible individuals in humans,
continuous hematological monitoring is still mandatory in humans and animals. Leukopenia induced by
azathioprine, while potentially life threatening, is usually reversible with discontinuation of treatment or a
dose reduction.
Gastrointestinal
Nausea and vomiting, though widely reported in the human literature, are uncommonly encountered
in veterinary medicine. Symptoms usually occur in the first few weeks of therapy and may self resolve.
Administration of azathioprine with food or in a divided dose may help to reduce the incidence of
gastrointestinal upset. 2
Hepatotoxicity is the second most common gastrointestinal side effect and is independent of TPMT
activity. 30 In most cases, hepatotoxicity is an unpredictable side effect and the mechanism of hepatocyte
injury is poorly characterized. In dogs, elevation of alkaline phosphatase, alanine aminotransferase and
bilirubin may be transient, in other cases they may be persistent and progressive leading to hepatic failure
and death. In a small pilot study using azathioprine for the treatment of canine atopic dermatitis, serum levels
of alanine aminotransferase and alkaline phosphatase rose in 83% of dogs by the second week of daily
treatment, and clinical signs of hepatitis were reported in 3 of 12 dogs (25%) necessitating the need for
removal from the study. 28
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