Azathioprine in dermatology: The past, the present, and the future

CONTINUING

MEDICAL EDUCATION

Azathioprine in dermatology: The past, the present, and the future Akash A. Patel, MD, Robert A. Swerlick, MD, and Calvin O. McCall, MD Atlanta, Georgia For several decades, dermatologists have utilized azathioprine to treat numerous debilitating skin diseases. This synthetic purine analog is derived from 6-mercaptopurine. It is thought to act by disrupting nucleic acid synthesis and has recently been found to interfere with T-cell activation. The most recognized uses of azathioprine in dermatology are for immunobullous diseases, generalized eczematous disorders, and photodermatoses. In this comprehensive review, the authors present recent advancements in the understanding of azathioprine and address aspects not covered in prior reviews. They (1) summarize the history of azathioprine; (2) discuss metabolism, integrating information from recent publications; (3) review the mechanism of action with attention paid to the activities of azathioprine not mediated by its 6-mercaptopurine metabolites and review new data about inhibition by azathioprine of the CD28 signal transduction pathway; (4) thoroughly examine thiopurine s-methyltransferase genetics, its clinical relevance, and interethnic variations; (5) review prior uses of azathioprine in the field of dermatology and grade the level of evidence; (6) discuss the use of azathioprine in pregnancy and pediatrics; review (7) key drug interactions and (8) adverse effects; (9) suggest a dosing and monitoring approach different from prior recommendations; and (10) explore the future of azathioprine, focusing on laboratory considerations and therapeutic application. ( J Am Acad Dermatol 2006;55:369-89.) Learning objective: At the conclusion of this learning activity, participants should be familiar with the history and pharmacology of azathioprine; its use in dermatology, including proper dosing; and the potential risks associated with azathioprine administration.

I

n hopes of protecting 6-mercaptopurine (6-MP) from metabolic degradation, an imidazole ring was attached to the molecule in the mid-1950s, and as a result, azathioprine (trade name, Imuran; GlaxoSmithKline) was created.1 By 1960 it had swiftly made the transition from bench-top experimentation to bedside use.2 Because of the favorable therapeutic index of azathioprine over other traditional immunosuppressants like 6-MP, methotrexate, 5-fluorouracil, and actinomycin C,3,4 it has been utilized as a corticosteroid sparing agent and as monotherapy. The official US Food and Drug Administration indications are for the prevention of rejection in renal homotransplantation and for refractory, severe rheumatoid arthritis (RA), yet physicians have successfully employed azathioprine to

From the Department of Dermatology, Emory University School of Medicine. Funding sources: None. Conflict of interest: None identified. Reprint requests: Calvin O. McCall, MD, Department of Dermatology, Emory University School of Medicine, 5001 Woodruff Memorial Building. Atlanta, GA 30322-0001. 0190-9622/$32.00 ª 2006 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2005.07.059

Abbreviations used: HPLC: HPRT: IBD: 6-MP: RA: SLE: TPMT: XO:

high-performance liquid chromatography hypoxanthine phosphoribosyl transferase inflammatory bowel disease 6-mercaptopurine rheumatoid arthritis systemic lupus erythematosus thiopurine s-methyltransferase xanthine oxidase

treat myriad conditions, including inflammatory bowel disease (IBD; Crohn disease and ulcerative colitis), multiple sclerosis, myasthenia gravis, malignancies, and autoimmune conditions.5 Dermatologists have been at the forefront of the application of azathioprine and have been using the immunosuppressant to treat patients for more than 30 years. Although newer immunosuppressive medications and biologics have been incorporated into dermatologic practice, the continuing high costs of these medications, barriers to off-label use, and relative inexperience with them for disorders other than psoriasis have precluded the complete abandonment of older medications. Even in comparison with other long-established immunosuppressants such as cyclosporine, azathioprine is still 369

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substantially more affordable.6 As a consequence, dermatologists continue to actively use azathioprine for immunobullous diseases, severe atopic dermatitis, actinic dermatitis, and various other disabling skin conditions.7

HISTORY OF AZATHIOPRINE During the middle of the twentieth century, the basic concepts of immunology were dynamically evolving. Even though the understanding of immunologic mechanisms was rudimentary, investigators were putting forth remarkably insightful theories of immunologic tolerance8 and were experimentally creating acquired tolerance of skin homografts in rabbits, mice, and chickens.9 Coupled with this novel paradigm in immunology was the postulate that the growth of rapidly dividing cells may be inhibited by antagonists of nucleic acid bases.10-12 Thus the realities of antimetabolites and drug-induced immune tolerance were taking form.13 The success of several investigators in the pharmacologic inducement of immunologic tolerance in young14 and adult15 animal models was a giant leap forward in eventual immune suppression in human beings. These accomplishments were particularly important in the world of transplantation surgery. Although grafting techniques were advancing, the grafts were invariably ravaged by rejection; x-irradiation was thought to be the most promising approach to quell rejection. After successfully prolonging renal homografts in dogs with 6-MP,16 Sir Roy Calne searched for a less toxic drug to induce immune tolerance and inhibit organ transplant rejection. Before starting a Harkness fellowship at the Peter Bent Brigham Hospital, Calne went to the Burroughs Wellcome Research Laboratories in Tuckahoe, New York, and met with George Hitchings and Gertrude Elion. Utilizing the techniques of Fisher and Traube described in the ‘‘old German literature,’’ the Hitchings-Elion laboratory synthesized 6-MP in 1951 and, in a few short years, synthesized numerous 6-MP derivatives, including azathioprine.12 Excited about Calne’s research with 6-MP, they gave him these derivatives to test in his animal models.17 Calne demonstrated that one of the 6-MP derivatives, BW 57-322 (later known as azathioprine), was at least as effective as 6-MP but less toxic to the bone marrow.18,19 Other studies supported this observation.20 With success in animal models, azathioprine quickly made the transition to human transplantation and was used with corticosteroids for the first successful cadaveric renal transplantation on April 5, 1962.17 During the early 1960s, the era of immunosuppressive medications began. Treatment with

immunosuppressants began not only for organ transplantation but also for autoimmune diseases such as systemic lupus erythematosus (SLE) and autoimmune hemolytic anemia.21 Roughly 2 years before the first successful cadaveric renal transplantation, the Southeastern Cooperative Cancer Chemotherapy Study Group began the first human experimentation of azathioprine primarily for the treatment of leukemia.2 Soon afterward, this group reported that azathioprine was successful in the treatment of refractory thrombocytopenic purpura, SLE, allergic vasculitis, Se´zary syndrome, Goodpasture syndrome, and psoriasis.22 Before the end of the 1960s, the first reports of the successful use of azathioprine for the treatment of pemphigus were published,23,24 ushering in subsequent wider application of the agent for a number of debilitating skin diseases.

AZATHIOPRINE PHARMACOLOGY Chemical structure Unlike many serendipitous discoveries in science, the synthesis of azathioprine resulted from considerable forethought. Knowing that all cells require nucleic acids, Hitchings and Elion postulated that synthetic purine analogs may halt the growth of rapidly dividing cells.12 Thus their laboratory synthesized numerous synthetic purine analogs, including 6-MP. They endeavored to increase the efficacy of 6-MP by protecting it from rapid metabolic catabolism. Utilizing the basic structure of 6-MP, azathioprine was derived with the addition of an imidazole ring to the sulfur atom at the 6 position of the molecule. Thus azathioprine has the 2 principal moieties mercaptopurine and imidazole. Fashioned after the endogenous purines adenine, guanine, and hypoxanthine, both 6-MP and azathioprine share similar chemical structures. The intention of the researchers was for azathioprine to be a 6-MP prodrug resistant to immediate catabolism, permitting more selective activation in target cells. In little time, Hitchings and Elion demonstrated in animal models that azathioprine was more active and had a better therapeutic index than did 6-MP.1 Pharmacokinetics and metabolism Azathioprine is quickly and nearly completely absorbed from the digestive tract and does not cross the blood-brain barrier.25 The peak serum levels occur roughly 2 hours after ingestion, and the halflife, including all active metabolites, is approximately 5 hours.26 Azathioprine is extensively metabolized, and only about 2% is excreted, unchanged, in the urine.20 The metabolic products of azathioprine’s mercaptopurine moiety are essentially identical to 6-MP and differ only quantitatively.27

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Fig 1. Azathioprine metabolism.

The metabolism of azathioprine is rather complex (Fig 1).20,28-31 Azathioprine is rapidly, nonenzymatically cleaved in vivo by ubiquitous sulfhydryl compounds (cysteine, glutathione, hydrogen sulfide, other thiols, or possibly proteins).20,27,32 Quantum mechanical methods have been used recently to elucidate this first critical step by establishing that it results from the COOe, SH, and NH3 groups on these biogenic thiols.32 The product of this cleavage results in separation of the 2 principal moieties, mercaptopurine and the imidazole derivative (methylnitroimidazole). Once freed of its imidazole derivative, the mercaptopurine moiety undergoes metabolism from 3 competing enzymes. Activity of the 2 catabolic enzymes thiopurine s-methyltransferase (TPMT), an enzyme with great genetic polymorphism, and xanthine oxidase (XO) produces inactive metabolites. Decreased TPMT or XO activity results in the increased production of toxic metabolites, because more 6-MP is utilized by the competing anabolic enzyme, hypoxanthine phosphoribosyl transferase (HPRT). Decreased TPMT activity is frequently a

consequence of genetic polymorphisms, while decreased XO activity may be mediated by medications such as allopurinol. HPRT converts 6-MP to 6-thioinosine 5-monophosphate; this substrate is acted on by both inosine monophosphate dehydrogenase and TPMT. TPMT results in the formation of active methylated metabolites. The inosine monophosphate dehydrogenase pathway is more crucial, as it results in a substrate that is transformed by guanosine monophosphate synthetase into the active 6-thioguanine nucleotides. These 6-thioguanine nucleotides are the principal active metabolites of azathioprine. HPRT is the product of an X-linked gene. This gene is mutated in patients with Lesch-Nyhan syndrome.33 Hence patients with Lesch-Nyhan syndrome appear to have some resistance to azathioprine and do not manifest the usual responses.34 Mechanism of action Despite roughly 50 years of widespread clinical use of azathioprine, a full understanding of its mechanism of action is incomplete. Azathioprine

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is a purine antagonist and classically has been described as a cell-cycle specific drug, an s-phase inhibitor.35 The 6-thioguanine active metabolites of azathioprine disrupt the function of endogenous purines.10,11,36,37 Therefore the generally accepted mechanism of azathioprine’s cytotoxic and immunosuppressive activities is disruption of nucleic acids. This interference with the building blocks of DNA, RNA, and certain coenzymes is thought to disrupt the synthesis of DNA, RNA, and proteins.28,29,38 Lymphocytes lack a salvage pathway and rely on de novo synthesis of purines, and accordingly, azathioprine is thought to be relatively specific to lymphocytes.39 Since azathioprine interferes with purine synthesis and metabolism, the disruption on such a fundamental level may explain its delay of action, as it usually takes at least 1 to 2 months before clinical effects are seen. Besides its effects on DNA replication, azathioprine also affects the immune system in a number of ways. Azathioprine has been shown to reversibly reduce the number of monocytes in circulation and tissue in a dose-dependent manner, with little effect on neutrophils.25,40,41 Azathioprine has been reported to impair synthesis of gamma globulin in patients who have rheumatoid disorders with a mean reduction of immunoglobulin G synthesis by 33% and immunoglobulin M by 41%.42 Also, in vitro and in vivo data suggest that long-term immunosuppression with azathioprine decreases the number of cutaneous Langerhans cells.43-47 Higher concentrations of azathioprine also have been reported to impede responses of helper-T-cell-dependent B cells and function of suppressor T cells.48 It has been established through different laboratory systems that azathioprine impairs T-cell lymphocyte function and essential components of T-cell activation (e.g., interleukin-2), and is more selective for T lymphocytes than for B lymphocytes.1,49-51 Recently Tiede and colleagues reported a potential explanation of the immunosuppressive effects on T cells.52 Utilizing an in vitro system, Tiede’s group showed that azathioprine or 6-MP stimulation of T lymphocytes results in an increased percentage of apoptotic cells. This investigation showed that the principal active 6-MP metabolite, 6-thioguanine triphosphate, interacts with Rac1, a small guanosine triphosphate binding protein involved in the signal transduction pathway of CD28. CD28 is a transmembrane protein on T lymphocytes that mediates a necessary costimulatory signal for T-cell activation. Tiede’s recent publication reports that azathioprine inhibits Rac1 and, by doing so, inhibits important downstream targets such as mitogen-activated protein kinase, nuclear factor-kB, and bcl-xL.52 Thus,

instead of T-cell activation, azathioprine blocks the costimulatory signal and induces apoptosis. Through in vivo data from patients with IBD who underwent treatment with azathioprine, Tiede demonstrates that CD45RO memory T cells are the cells primarily affected, as these patients have an increased percentage of apoptotic CD45RO effector T cells. Thus Tiede’s findings further elucidate the efficacy of azathioprine in chronic inflammatory and autoimmune diseases. In addition to the principal effects mediated by the active 6-thioguanine nucleotides, other active derivatives and metabolites may be important in mediating azathioprine’s effects. On the basis of in vitro data regarding HPRT-deficient cell lines and lymphocytes from patients with Lesch-Nyhan syndrome, it appears that some of the cytotoxic effects of azathioprine are mediated from metabolites not dependent on the HPRT pathway.53,54 Upon cleavage of azathioprine by sulfhydrylcontaining compounds, a reactive imidazole derivative, methylnitroimidazole, is generated (Fig 1). Radical products of this reactive moiety are thought to result in cellular inhibition and death by damaging cellular macromolecules such as nucleic acids, proteins, and membranes.31 One study reports that replacement of azathioprine’s 6-MP moiety by almost any thiol-containing compound still results in an immunosuppressive compound—some showing even more in vitro activity than azathioprine.55 Therefore the methylnitroimidazole derivative may mediate a significant effect in vivo. This effect does not appear to be antagonized by the addition of exogenous purines in laboratory systems, so it is less likely to be involved in the inhibition of de novo purine pathways.31,53 In addition to the contributing effects of the methylnitroimidazole derivatives, the TPMT-mediated methylation of the HPRT product is also thought to contribute to the action of azathioprine (Fig 1). It is well known that patients deficient in TPMT are susceptible to much greater azathioprine toxicity owing to their inability to catabolize 6-MP into an inactive metabolite. However, TPMT also has been implicated in yielding reactive methylated products that have been shown to contribute to some of the cytotoxic and anti-inflammatory effects of azathioprine by presumably impairing de novo purine synthesis.29,30,56 Thiopurine methyltransferase The TPMT enzyme is perhaps the best-studied enzyme involved in thiopurine metabolism and serves as an excellent model of practical pharmacogenomics. It is of particular importance because

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Table I. Interethnic variation of TPMT activity Group

American Caucasians British Caucasians French Caucasians African Americans South Asians Ghanaians Kenyans Chinese Japanese Thai

N

Homozygous wild-type (%)

Heterozygote (%)

Homozygous mutation (%)

TPMT*2 (%)

TPMT*3A (%)

TPMT*3C (%)

Calculated 199 191 Calculated 99 217 101 192 553 75

92.5 89.9 85.9 90.7 98 85.3 89.1 95.3 97.3 89

7.4 9.6 13.6 9.2 2 14.4 10.9 4.7 2.4 11

0.14 0.5 0.5 0.2 0 0.5 0 0 0.4 0

0.2 0.5 0.5 0.4 0 0 0 0 0 0

3.2 4.5 5.7 0.8 1 0 0 0 0 0

0.2 0.3 0.8 2.4 0 7.6 5.4 2.3 1.5 5.3

Modified from McLeod.80

administration of azathioprine to a patient with TPMT deficiency results in significant accumulation of thioguanine nucleotides, and it becomes clinically manifest by increased hematopoietic toxicity, with potentially grave consequences.28,57,58 Gastrointestinal side effects do not appear to be related to TPMT deficiency and instead may be related to normal or wild-type TPMT activity.59 The TPMT gene has been cloned and sublocalized to chromosome band 6p22.3.60 It is 27 kb long and has either 9 or 10 exons.61 On the basis of qualitative and complex segregation analyses, inheritance of the TPMT gene is thought to follow an autosomal codominant inheritance pattern and its activity appears to be trimodal: 1 in 300 individuals are homozygous for very low TPMT activity (TPMTL/TPMTL), roughly 10% are heterozygous with intermediate activity (TPMTH/TPMTL), and approximately 90% are homozygous, demonstrating the high methylator phenotype (TPMTH/TPMTH).62,63 In a more recent cohort of 1,747 patients, 1 in 220 patients were found to have no detectable activity, 10% had low activity, 80% had normal activity, and 9% had high activity above the normal range.64 The phenotype assessment of TPMT has primarily been a functional assay using red blood cells. A newer, nonradioactive high-performance liquid chromatography (HPLC) method has been reported to be safer, quicker, and simpler than the originally described radiochemical assay.65-67 TPMT activity in red blood cells has been found to correlate well with TPMT activity in other cells such as lymphocytes,68 platelets,68 leukemic blasts,69 and kidney70 and liver cells.71,72 Several reports show good concordance between genotypic (viz., PCR-RFLP [polymerase chain reactionerestriction fragment length polymorphism] and DHPLC [denaturing HPLC] method) and phenotypic (viz., radiochemical assay and nonradiochemical HPLC) laboratory assessment.59,73,74

Testing for TPMT levels is extremely helpful in the care of dermatology patients in regard to achieving proper dosing,75 and it appears to be costeffective.76-78 For reasons not so well understood, TPMT heterozygotes have a wide range of activity.57 Therefore, at present, phenotypic testing for enzyme activity is probably more useful in clinical practice than is genotypic testing. The interindividual differences in the metabolism of azathioprine are primarily thought to arise from single nucleotide polymorphisms in the TPMT gene, and these polymorphisms ultimately affect the stability or activity of the 245 amino-acid protein product.79 The wild-type allele for high enzymatic activity is designated TPMT*1. Mutations or polymorphisms in this allele are thought to result in decreased or nonfunctional variants. Eleven different TPMT alleles have been described,59 and 3 alleles, TPMT*2, TPMT*3A, and TPMT*3C, appear to account for 80% to 95% of intermediate and low enzyme activity.80 Regarding interethnic variation of TPMT, significant differences exist. As depicted in Table I,80 the predominant mutation in African Americans, Africans, and East Asians is TPMT*3C, whereas the principal mutation in European and American Caucasians is TPMT*3A. Mean TPMT activity was found to be lower in African Americans than in Caucasian Americans, and men in both groups had slightly higher activity than did women.81 South Asians studied in the United Kingdom have fewer mutations and increased wild-type frequency than most other ethnic groups, including Caucasians and Africans.80,82,83 Koreans and Israeli Jewish patients seem to have a more normal distribution than a bimodal or trimodal TPMT distribution, and Israeli Jewish patients are closer to East Asians in regard to distribution than are Caucasian Americans or Europeans.84,85 Thirteen percent of Italian patients

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were found to have intermediate activity, and the most common defective alleles were TPMT*3A (3.9%), TPMT*3C (1%), and TPMT*2 (0.49%).74 TPMT*3C accounted for all the mutations in studies that involved West86 and East87 Africans. Intermixing with other ethnic groups may account for the few other mutations seen in African Americans.80 TPMT*3C seems to be a more common mutation than TPMT*3A in Egyptians.88

discontinue or reduce their corticosteroids to a very low dose (10 mg or less of prednisone equivalent) daily or a low dose (20 mg or less of prednisone equivalent) every other day. Many patients were able to completely discontinue their corticosteroids after several months of azathioprine treatment. Acceptable symptomatic control with azathioprine as monotherapy was also considered an excellent response. If the degree of benefit was difficult to assess, comments from the text of the citation were used.

AZATHIOPRINE USE IN DERMATOLOGY Important considerations The dermatologic use of azathioprine in the United States remains completely off-label. Physicians have utilized azathioprine for decades, and it is available in relatively inexpensive, generic formulation. Since it is no longer patented and not as lucrative as newer, more costly medications, the pharmaceutical industry appears to have lost interest in studying azathioprine. Therefore the number of new clinical studies is becoming more limited, and proposals to broaden the official indications from the Food and Drug Administration are not likely. The use of azathioprine in dermatology is supported by numerous studies, reports, and expert opinion. However, by the strictest evidence-based medicine standards, the level of evidence supporting the use of azathioprine for many conditions is not as strong as for some newer medications. The lack of strong evidence may be due to the time-honored recognition of the efficacy of azathioprine and the relative newness of evidence-based medicine to the field of dermatology. For instance, dermatologists have been using azathioprine to successfully treat immunobullous diseases for nearly 35 years. Consequently, this application has become well recognized, and azathioprine has thus been ‘‘grandfathered’’ into the dermatologic armamentarium despite the lack of multiple prospective randomized, double-blinded controlled trials to support its use. Even though the level of evidence for all applications is not uniformly strong, compelling data support the use of azathioprine in eczema, actinic dermatitis, and immunobullous diseases. Tables IIeV are a detailed compilation of the prior uses of azathioprine reported in the dermatology literature. To better understand the quality of evidence, a levelof-evidence mark was assigned to each reported use. Since there is no standard for grading the level of evidence in dermatology, the grading system utilized for this review (as depicted in Table VI) is an application of a straightforward scheme previously published.89 Patients reported to have an excellent response in Tables IIeV are those who were able to eventually

Immunobullous diseases The first published use of azathioprine to treat pemphigus vulgaris appeared in 1969.23,24 Numerous reports that describe its use in pemphigus have been published since then (Table II).90-111 Nearly all of these publications describe the usefulness of azathioprine in reducing the dose of corticosteroids. In addition to pemphigus, pemphigoid has been widely reported to be treated with azathioprine.112-125 Although one prospective study showed no significant benefit with the addition of azathioprine as an adjuvant to prednisolone,116 the possibility of underdosing has been suggested.126 Some clinicians believe that azathioprine is effective in the treatment of pemphigoid and prefer it over other immunosuppressant medications.127 It has been our experience (unpublished, open-label use) that azathioprine is consistently more effective in treating bullous pemphigoid than cicatricial pemphigoid or pemphigus. Psoriasis and eczematous diseases As shown in Table III the use of azathioprine has been widely reported for psoriasis,22,128-133 eczema (atopic dermatitis, hand eczema, adult eczema),128,134-141 and contact dermatitis.142,143 Interest in azathioprine for the treatment of psoriasis appears to have waned, but several recent publications have documented its successful use in adult and childhood eczema. Of all the evidence supporting the use of azathioprine in dermatology, its use in eczematous diseases appears to be the strongest. It has been our experience that azathioprine works extremely well to control generalized eczematous and pruritic conditions. Photodermatoses Chronic actinic dermatitis has been described during the past 40 years and refers to a group of disorders aggravated by ultraviolet and visible light. Chronic actinic dermatitis includes numerous photodermatoses such as photosensitive eczema, photosensitivity dermatitis, persistent light reaction, and actinic reticuloid.144 As indicated in Table IV, strong

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Table II. Use of azathioprine in immunobullous diseases Reference group

Level of evidence*

Indication (diagnosis reported)

N

1993

36

B

Bullous pemphigoid

100e150 mg/d

[6 mo

Ahmed112

1977

15

C

Bullous pemphigoid

1.5 mg/kg/d

Unclear

Venning114 Greaves125 Roeder123

1992 1971 1999

28 12 1

C D E

1e2.5 mg/kg/d 2.5 mg/kg/d 100 mg/d

Unclear Unclear Unclear

Burton119,120 Van Dijk104 Burton118 Dave117 Dantzig113 Pawlofsky124 Warren115 Mondino121

1978 1973 1974 1974 1973 1985 1993 1983

12 5 12 4 1 1 1 9

C D D E E E E C

2.5 mg/kg/d 75e250 mg/d 2.5 mg/kg/d 50e200 mg/d 150 mg/d 150 mg/d 25e75 mg/d 1.5 mg/kg/d

Unclear Unclear Unclear [2 mo [11 mo [3 mo [3 y Unclear

Tauber122

1991

11

D

2 mg/kg/d

Unclear

Walker99 Ahmed95 Lynde97 Fine100 Wananukul107 Harangi106 Lam96

1978 1983 1984 1988 1999 2001 1992

1 1 1 1 3 1 1

E E E E E E E

50e100 mg/d 150 mg/d 50e125 mg/d 50e125 mg/d 2 mg/kg/d 2 mg/kg/d 100 mg/d

[1 y Unclear [1 y [1 y [7 mo [4 y Unclear

Verrini103

2002

1

E

100 mg/d

Unclear

Roenigk92 Tan-Lim93

1973 1990

10 12

C C

Bullous pemphigoid Bullous pemphigoid Bullous pemphigoid and psoriasis Pemphigoid Pemphigoid Pemphigoid Pemphigoid Cicatricial pemphigoid Cicatricial pemphigoid Cicatricial pemphigoid Ocular cicatricial pemphigoid Ocular cicatricial pemphigoid Juvenile pemphigus Juvenile pemphigus Juvenile pemphigus Juvenile pemphigus Juvenile pemphigus Juvenile pemphigus Paraneoplastic pemphigus Paraneoplastic pemphigus Pemphigus Pemphigus

50e250 mg/d 50e150 mg/d

[1 y Unclear

Ljubojevic108 Van Dijk104 Burton118

2002 1973 1974

129 5 4

C D E

Pemphigus Pemphigus Pemphigus

100e150 mg/d 50e200 mg/d 2.5 mg/kg/d

[1 mo Unclear Unclear

Jablonska110

1970

2

E

100e200 mg/d

Unclear

Van Vloten105 Aberer94 Lever91

1972 1987 1984

1 29 21

E B C

Pemphigus erythematosus Pemphigus foliaceus Pemphigus vulgaris Pemphigus vulgaris

150 mg/d 1e3 mg/kg/d 100 mg/d

Unclear [4 y [1 y

Carson102 Lever90 Mourellou98 Scully101

1996 72 1977 6 1995 15 1999 [17

C D D D

Pemphigus Pemphigus Pemphigus Pemphigus

vulgaris vulgaris vulgaris vulgaris

50e250 mg/d 50e150 mg/d 100 mg/d 1e3 mg/kg/d

Unclear [2 y Unclear [3 mo

Krakowski24 Wolff23

1969 1969

1 4

E E

Pemphigus vulgaris Pemphigus vulgaris

75e150 mg/d 2e3 mg/kg/d

[4 mo Unclear

Jablonska110 Burton109 Charow111

1970 1970 1971

6 4 1

E E E

Pemphigus vulgaris Pemphigus vulgaris Pemphigus vulgaris

100e200 mg/d 2.5 mg/kg/d Unclear

2e3 wk [3 mo Unclear

Guillaume

116

*See Table VI for explanation of level of evidence. y Comments in quotation marks are taken from the text of the citation.

Dose

Treatment duration

Year

Degree of benefity

‘‘Controlled’’ at 6 months, 14 patients ‘‘Steroid-sparing . . . of real benefit’’ Unclear; deaths reported Excellent, 11 patients Excellent, with acitretin use Excellent, 9 patients Excellent, 4 patients Excellent, all patients Excellent, 3 patients Excellent response ‘‘Proved to be effective’’ Excellent response 10 of 18 eyes did not progress ‘‘Use of AZA [azathioprine] was disappointing’’ Excellent response Excellent response Excellent response Excellent response Excellent, 2 patients Excellent response Only skin cleared (not eyes/mucus membranes) Patient had improvement but died (stroke) Excellent, 8 patients Used with plasmapheresis to decrease antibody ‘‘Remission in most’’ Excellent, all patients ‘‘Unable to tolerate,’’ 3 patients Excellent, all patients Excellent response ‘‘Highly effective and safe’’ ‘‘Safe and effective’’ in combination Excellent, [27 patients ‘‘Steroid-saving effect’’ Excellent, 14 patients Unclear; death reported (cytomegalovirus) Excellent response ‘‘Beneficial’’ and ‘‘steroidsaving’’ ‘‘No effect on skin lesions’’ Excellent, 3 patients Excellent response

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Table III. Use of azathioprine in psoriasis and eczematous diseases Reference group

Year

N

Level of evidence*

Indication (diagnosis reported)

Dose

Treatment duration

Degree of benefit

Berth-Jones134 2002 37

A

Atopic dermatitis, severe 2.5 mg/kg/d

3 mo

Lear140 Kuanprasert138 Buckley139 Meggitt137

1996 2002 1998 2001

35 38 10 12

C C D C

Atopic Atopic Atopic Atopic

Unclear 25e200 mg/d 0.7e2.5 mg/kg/d 1e2.5 mg/kg/d

1e21 mo [1 mo [1 y 4 mo

Scerri128 Younger136 Morrison135 Murphy141

1999 10 1991 3 1978 3 2002 48

D C E C

50e150 mg/d 100 mg/d 50e100 mg/d 2e3.5 mg/kg/d

Unclear 9 mo [6 wk [3 mo

Scerri128 Sharma143 Verma142 Corley22 Primka133

1999 6 1998 15 2000 43 1966 1 1998 3

D C C E E

50e150 mg/d 100e150 mg/d 50e1001 mg/d 0.4e5.5 mg/kg/d 50e150 mg/d

Unclear [6 mo [6 mo [5 mo [3 mo

Scerri128 Greaves132 Munro130,131 Hacker129

1999 6 1970 10 1973 29 1992 1

D C C E

Atopic eczema Eczema, severe Eczema, severe Childhood atopic dermatitis, severe Pompholyx Contact dermatitis Contact dermatitis Psoriasis and arthritis Psoriasis and bullous pemphigoid Psoriasis, plaque Psoriasis, severe Psoriasis, severe Psoriasis, severe

50e150 mg/d 2.5 mg/kg/d 2e4 mg/kg/d 100 mg/d

Unclear Excellent, all patients 6 wk Excellent, 5 patients 2 wke31 mo Excellent, 19 patients [12 y Excellent response

dermatitis, severe dermatitis, severe eczema, severe dermatitis

Significant SASSAD scorey reduced by 27% Excellent, [20 patients Excellent, 31 patients Excellent, 8 patients Excellent, 7 (TPMTdosed) patients Excellent, 7 patients Excellent, all patients Excellent, all patients Excellent, 41 (TPMTdosed) patients Excellent, all patients Excellent, 13 patients Excellent, 38 patients Excellent response Excellent, all patients

*See Table VI for explanation of level of evidence. y Six area, six sign, atopic disease score. Assesses erythema, exudation, excoriation, dryness, cracking, and lichenification of the hands, feet, arms, legs, head/neck, and trunk.

Table IV. Use of azathioprine in photodermatoses Reference group

Year

Roed-Peterson146 1980 Haynes147 1984 Kingston145 Murphy150 Lim148 Leigh149 Scerri128 Norris152

Level of evidence*

N

2 1

1987 1 1989 8 1994 \51 1984 14 1999 2 1989 2

E E E A C or D D E E

Indication (diagnosis reported)

Actinic reticuloid Actinic reticuloid

Dose (mg/day)

Treatment duration

Degree of benefit

100e150 [5 mo 125 [2 y

Excellent, both patients Excellent response in combination Actinic reticuloid 100 [6 mo Excellent response Chronic actinic dermatitis 150 1.5e12 mo Excellent, 5 patients Chronic actinic dermatitis 50e200 Unclear Described as ‘‘efficacious’’ Chronic actinic dermatitis 100e200 1e31 mo Excellent, 10 of 14 patients Chronic actinic dermatitis 100e150 Unclear Excellent, both patients Polymorphous light eruption 50e150 [3 mo Excellent, both patients

*See Table VI for explanation of level of evidence.

data support the use of azathioprine in the treatment of chronic actinic dermatitis.128,145-150 Some consider it the first choice for long-term immunosuppression of this condition.151 Azathioprine has also been reported to be helpful in severe polymorphous light eruption.152 Other uses Azathioprine has been reported to be successful not only in immunobullous, photodermatotic, and

eczematous diseases but also in a number of other severe or recalcitrant conditions. As shown in Table V, azathioprine has been used to treat Behc¸et syndrome,153,154 pityriasis rubra pilaris,155 erythema multiforme,156-158 lichen planus,159-161 vasculitis,162-167 cutaneous lupus,163,168-170 Reiter syndrome,171 graftversus-host disease,172,173 prurigo nodularis,174 Sulzberger and Garbe,175 and acne fulminans.176 The evidence for Behc¸et syndrome is encouraging, and early treatment with azathioprine has been

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Table V. Use of azathioprine in other dermatologic diseases Reference Group

Year

Woolfson176 Yazici154 Nethercott153 Schofield156

1987 1 1990 37 1974 1 1993 11

E A E D

Jones158

1981

2

E

Pavlovic157

2001

1

E

Gaziev173

2001 17

Penas172

2002

N

Level of evidence*

Indication (diagnosis reported)

Dose

Treatment duration

3 mg/kg/d 2.5 mg/kg/d 150 mg/d 100e150 mg/d

8 mo 2y [21 mo Unclear

Degree of benefit

150 mg/d

[6 mo

Excellent response

D

Acne fulminans Behc¸et syndrome Behc¸et, incomplete Erythema multiforme, persistent Erythema multiforme, persistent Erythema multiforme, persistent GVHD, severe chronic

1.5 mg/kg/d

Unclear

9

D

GVHD, sclerodermatous

1.5 mg/kg/d

[7 mo

Callen163 Tsokos168 Shehade170 Ashinoff169 Verma161 Klein159 Lear160 Hunter155 Lear174 Calin171 Freeman175 Jayne167

1991 6 1985 1 1986 1 1988 2 2001 9 1992 1 1996 2 1972 5 1996 2 1986 8 1984 2 2003 71

D E E E D E E D E A E B

LE, cutaneous LE, cutaneous LE, cutaneous LE, cutaneous (palms, soles) Lichen planus, severe Lichen planus, generalized Lichen planus, generalized Pityriasis rubra pilaris Prurigo nodularis Reiter syndrome Sulzberger-Garbe syndrome Vasculitis, ANCA positive

100e150 mg/d 100 mg/d 150 mg/d 25e100 mg/d 100 mg/d 150 mg/d 50e100 mg/d 50e200 mg/d 100 mg/d 1e2 mg/kg/d 100e125 mg/d 2 mg/kg/d

Unclear [6 mo Unclear Unclear 3e7 mo [10 mo [2 mo [2 mo [6 mo 2 mo [6 mo 18 mo

Heurkens162 Callen163 Pickering164 Thomas165 Hafeez166

1991 1991 1972 1983 1998

C D E E E

Vasculitis, rheumatoid Vasculitis, leukocytoclastic Wegener granuloma Polyarteritis nodosa Vasculitis, cutaneous

2 mg/kg/d 150e250 mg/d 50e200 mg/d 2 mg/kg/d 25 mg/d

Unclear Unclear [7 mo Unclear [2 y

Excellent, 16 patients in combination Excellent, 8 patients in combination Excellent, 1 patient Excellent response Excellent response Excellent, both patients Excellent, 8 patients Excellent response Excellent, both patients Excellent, all patients Excellent, both patients Excellent, 5 patients Excellent, both patients Allowed reduction in cyclophosphamide dose Excellent, all patients Excellent, five patients Excellent response Unclear Excellent response

9 6 1 4 1

100e150 mg/d [3 mo

Excellent response Statistically ‘‘beneficial’’y Excellent response Excellent, all patients Excellent, both patients

ANCA, Antineutrophil cytoplasmic antibody; GVHD, graft-versus-host disease; LE, lupus erythematosus. *See Table VI for explanation of level of evidence. y Comment in quotation marks is taken from the text of the citation.

shown to favorably affect the long-term prognosis of the disease.177 In regard to vasculitis, azathioprine appears to be effective and has been promoted by some to safely control vasculitis when other less toxic medications fail.178 Beyond the applications listed in Tables IIeV, azathioprine continues to be actively used in fields outside dermatology. Rheumatologists have employed azathioprine to treat SLE,179-183 scleroderma,184,185 and dermatomyositis.186-188 Azathioprine has also been utilized by gastroenterologists, neurologists, and surgeons for numerous other conditions. Dosing and study design issues Except for very recent studies,137,141 the dose of azathioprine in nearly all prior publications was determined arbitrarily or from body weight. Moreover, previously published dosing strategies

based on TPMT activity75,189,190 underdose patients, in our collective experience. Some have postulated that the lack of statistical significance in prior studies to substantiate the efficacy of azathioprine as an adjuvant may arise from underdosing patients with high TMPT activity.126 Dermatologists have only recently begun checking TPMT activity before initiating therapy. Since TPMT was not measured in most prior studies, the lack of benefit may be accounted for by inadequate dosing. In the few studies137,141 in which TPMT was used for dosing, azathioprine was shown to be efficacious in the majority of the patients who underwent treatment. Furthermore, in all of the prospective randomized, double-blind controlled trials reviewed, azathioprine was shown to have a statistically significant benefit.134,150,171 Therefore the efficacy of azathioprine may also be underestimated in the literature owing to inadequate study design.

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Table VI. Levels of evidence Level

A B C

D E

Type

Prospective randomized, double-blind controlled trial Large open-label study (prospective clinical trial with n $ 20) Small open-label study (prospective clinical trial with n \ 20) or large retrospective series (n $ 20) Small, retrospective case series (n $ 5) Anecdotal, retrospective case reports (n \ 5)

Based on scheme published in Lebwohl et al.89

PREGANCY AND PEDIATRIC USE Pregnancy considerations The official Food and Drug pregnancy category for azathioprine is D; there is evidence of risk to human fetuses, but benefits from use in pregnancy may be acceptable despite the risks. Azathioprine and 6-MP have been shown to cross the human placenta in low concentrations and appear in fetal plasma after 24 hours.191 Although both drugs have been found in the placenta and amniotic fluid of patients taking azathioprine, the inactive metabolite thiouric acid has the greatest concentration.192 The immature fetal liver lacks the enzyme necessary for conversion of 6-MP to the active metabolites, so the developing fetus likely has some protection from azathioprine toxicity early in pregnancy.192,193 Azathioprine’s teratogenicity has not been conclusively established, and no clear-cut relationship between the drug and the few sporadic reports of congenital anomalies has been accepted.193 Numerous pregnancies among patients taking immunosuppressive medications have occurred since the 1960s. Normal neonate development and no congenital abnormalities have been reported in infants born to mothers taking azathioprine for renal transplantation,194-196 liver transplantation,197 SLE,198,199 IBD,200 and relapsing polychondritis.201 Most large studies of transplantation patients have shown that azathioprine is tolerated fairly well in pregnancy, but the most commonly accepted concerns include infants born prematurely and infants small for gestational age.202 Some studies have suggested that the rate of congenital malformations is dose-dependent and varies from 3% to 9% in infants exposed antenatally.203 The malformations reported with azathioprine include microcephaly, myelomeningocele, preaxial polydactyly, thymic atrophy, adrenal hypoplasia, and hypospadias.193,203 Hematologic abnormalities have also been reported,204,205 but it appears that maintaining the maternal leukocyte count within normal limits may

avert neonatal leukopenia and thrombocytopenia.204 Reports of infection have been minimal, but cytomegalovirus206 and gram-negative infections193 have been reported. Since malformations occur in roughly 3% of pregnancies in the general population, many have refuted some of the reports of malformations attributed to azathioprine exposure. For instance, righthand preaxial polydactyly (thumb) was reported in an otherwise healthy neonate of a patient taking azathioprine.207 There is some disagreement with this purported association because the neonate presented with polydactyly instead of oligodactyly. Oligodactyly is always the manifestation of exposure to agents capable of producing limb malformations in one reported experience.208 Azathioprine may in fact be unrelated to some of the reported anomalies, and alternatively, such defects may be due to the underlying disease state instead. Although some controversy exists about the causality of specific malformations, the general consensus is to reserve azathioprine for those pregnant patients with severe or life-threatening disease. Fertility issues and intrauterine device Azathioprine does not appear to adversely affect fertility.193 One SLE patient with 2 prior spontaneous abortions was able to conceive and deliver a healthy baby after initiation of treatment with azathioprine.199 Semen analysis in 23 male patients with IBD and at least 3 months of azathioprine treatment failed to show any abnormalities or significant change in any measured parameters.209 Even though the relationship of azathioprine to failure of an intrauterine device appears in some reference texts, the association does not seem strong. There is only 1 published report of 2 patients taking azathioprine who had intrauterine devices and became pregnant.210 Both of these patients were renal transplant recipients taking prednisone and azathioprine and were using a copper intrauterine device (Cu7). The patients continued their pregnancy and delivered babies with no congenital malformations. Lactation Minimal concentrations of azathioprine and its metabolites have been found in breast milk.193,211 The hemoglobin, leukocyte count, platelet count, and growth rate were normal in a breast-fed infant of a patient on azathioprine.211 There is no evidence that significant concentrations are secreted, but the potential risk of immune suppression and the theoretical risk of carcinogenesis outweigh the potential benefits of nursing according to the World Health Organization.212

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Use in pediatric patients As indicated in Tables II and III, azathioprine has been used successfully in pediatric dermatology patients. It has also been used effectively in pediatric patients with IBD,213-216 SLE,182 and dermatomyositis.186 Azathioprine appears to be safe in pediatric patients, and the side-effect profile is similar to that for adults.217 In most reports, the patients were on azathioprine for a limited period and had a durable remission with therapy. However, because of immunosuppression concerns regarding the risk of infection and potential development of malignancy, azathioprine should be reserved for those pediatric patients in whom safer therapies fail. Therapy should be tapered off once sufficient remission is obtained for several months. For instance, in our experience in treating severe generalized eczematous dermatitis, we often prescribe treatment for 6 months to a year and then taper off azathioprine therapy over 6 months to a year.

DRUG INTERACTIONS Several drugs have been reported to interact with azathioprine. The most obvious interaction is with allopurinol, an XO inhibitor used most often to treat gout. Since azathioprine is catabolized in part by XO, concomitant use may result in severe azathioprine toxicity and hematologic complications. Much has been written about this important interaction and possible deleterious consequences.218-223 Hematologic complications appear to arise 4 to 6 weeks after combination therapy and reverse with cessation.220 These complications can become costly and may require hospitalization.223 Most experts discourage concurrent use, but if both medications are absolutely essential, one-quarter to one-third of the original azathioprine dose is recommended with close laboratory monitoring. Azathioprine has also been reported to induce warfarin resistance.224-228 There have been reports of patients on warfarin who bled severely after azathioprine was discontinued.224 Recurrent thrombosis with initiation of azathioprine therapy has also been reported.226 The mechanism by which azathioprine induces warfarin resistance is not exactly known but may be due to pharmacodynamic or pharmacokinetic factors.228 The warfarin dose may have to be increased 3 to 4 times to compensate for azathioprine’s interaction.226 This interaction appears to be dose-dependent, as it becomes apparent with azathioprine doses greater than 100 mg daily.227 The international normalized ratio should be closely monitored with any change in azathioprine dosage. Besides allopurinol and warfarin, several other medications have been reported to interact with

azathioprine. Benzoic acid derivatives, such as sulfasalazine, balsalazide, olsalazine, and mesalamine, may increase active thioguanine nucleotides and subsequently result in potential hematologic side effects.229,230 In vitro data231,232 suggest that this interaction may be the result of TMPT inhibition, but an in vivo study229 failed to show any change in TPMT activity. While leukopenia has been demonstated,230 the severity of the interaction between these benzoic acid derivatives and azathioprine is not as well established as allopurinol. Furosemide has been shown in vivo to inhibit TPMT activity,233 but its clinical relevance remains unknown. The prolonged use of trimethoprim-sulfamethoxazole in renal transplantation patients on azathioprine has been reported to cause neutropenia and thrombocytopenia.234

ADVERSE EFFECTS Common side effects Azathioprine is generally well tolerated and has a favorable therapeutic index compared with many other traditional immunosuppressants. Patients who overdosed on massive amounts of azathioprine, 500 mg235 and 7,500 mg,236 were not left with any permanent impairment. The most common symptomatic side effects of azathioprine are gastrointestinal, ranging from nausea to diarrhea. It is not uncommon for patients to experience mild nausea, vomiting, and gastrointestinal discomfort within the first 10 days of treatment. There have been case reports of patients with symptoms that imitate viral gastroenteritis (nausea, vomiting, anorexia, diarrhea, and fever) hours after a single dose of 25 mg.237 Many if not all of these symptoms may respond to dose adjustment,238 dividing the dose, or taking the medication with food.239 However, azathioprine should be immediately discontinued in those patients with severe gastrointestinal symptoms, as they may be developing an intolerant or hypersensitivity reaction (see ‘‘Uncommon side effects’’ below). Within a few weeks of initiating therapy, some patients may also experience fatigue and malaise that may necessitate reduction of dose or discontinuation. Some of these patients may be developing azathioprine hepatotoxicity, but this side effect is generally not common. It may occur several weeks after initiation of therapy and can be easily detected with routine laboratory evaluation. Bone marrow depression is a wellaccepted concern with azathioprine. To avert hematologic toxicities, laboratory monitoring of complete blood count is important during the initial weeks of therapy, even if the TPMT activity is normal. Dermatologic problems are more frequent in transplantation patients than in nontransplantation

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patients on azathioprine.240 Pale skin types, excess sun exposure, and duration of allograft seem to be important risk factors in the development of skin lesions.241 Common skin problems include alopecia, verrucae, zoster, increased skin color, and malignant neoplasms.240 Kaposi sarcoma,242-245 dermatomycoses,246,247 cytomegalovirus infection,248 and scabies249-252 have also been reported with azathioprine use. Uncommon side effects Allergic contact dermatitis, confirmed by means of patch testing, has been reported in persons who come into physical contact with azathioprine tablets.253-255 More severe systemic hypersensitivity reactions have been reported in patients taking azathioprine.239,256-262 This azathioprine intolerance or hypersensitivity reaction commonly occurs within the first 4 weeks of therapy.256 The findings of hypersensitivity greatly vary and can range from fever, nausea, vomiting, diarrhea, arthralgia, and malaise to hypotension, shock, and possibly even death.257 Most of the cases are reported in patients with neurologic diseases, rheumatologic disorders, and transplantation patients. Only 6 cases have been reported in patients with dermatologic disease.256 However, our own experience would suggest that hypersensitivity reactions are not particularly rare. Hypersensitivity symptoms typically resolve in a few days (between 12 hours and 20 days) after discontinuation of azathioprine.258 Pancreatitis has been associated with azathioprine therapy but occurs mostly in patients with underlying gastroenterologic disorders.263-265 Symptoms and laboratory abnormalities rapidly resolve with the cessation of azathioprine therapy.263 Hepatic veno-occlusive disease has also been reported and is found most often in patients with nondermatologic diseases, mostly renal transplantation patients or patients with gastroenterologic disorders.266-272 Malignancy potential Perhaps the most concerning potential adverse effect of azathioprine therapy is the potential to develop malignancy. Animal and in vitro models suggest that at high, supratherapeutic doses, azathioprine is mutagenic and carcinogenic.51,273-276 Laboratory data suggest that ultraviolet light and azathioprine may be synergistic and increase the risk of skin carcinomas.277,278 Patients on higher doses and longer durations of azathioprine have been shown to have an increased risk of skin cancer, particularly squamous cell carcinoma.279,280 Aggressive squamous cell carcinoma has been reported in dermatology patients with

type 1 skin and greater than 4 years of azathioprine therapy.281 Those with more immune suppression, such as heart transplantation patients, appear to be at greater risk than those with lesser suppression, like kidney transplantation patients.279,282 One study showed a lag phase of 3½ years between the initiation of immunosuppressive therapy and the appearance of premalignant lesions.283 The calculated risk of developing skin cancer in another study of renal transplantation patients increased from 7% to 45% to 70% for 1, 11, and 20 years of immunosuppression, respectively.284 Therefore skin type, sun exposure, dose, and length of azathioprine treatment are important factors in determining the risk of the development of skin cancer. Dermatology patients with adequate sun counseling, smaller doses, and less than 3 years of azathioprine treatment are less likely to develop skin cancer than are other high-risk patients. Determining the risk for more serious malignancies from azathioprine treatment is much more difficult than estimating the risk for skin cancer. Numerous studies of various patient populations present conflicting conclusions. Some reports show no increased risk of malignancy,285,286 while several other studies show a greater risk.287-289 The increased risk of lymphoma in 1 study of RA patients was 1 case per 1,000 patient years of azathioprine treatment,289 and in another study of RA patients, the attributable malignancy risk was roughly 5.7 per 1,000 patient-years at risk after azathioprine initiation.287 Patients with psoriasis and dermatomyositis who have been undergoing azathioprine treatment for more than 5 years have been reported to develop non-Hodgkin lymphoma.290 Like skin cancer, internal malignancies such as lymphoma are increased in patients with higher doses and longer duration of immune suppression. In a large study of RA patients, those treated for more than 6 years with immunosuppressants had an increased risk of malignancy compared with patients treated less than 1 year.288 Correspondingly, in a study of multiple sclerosis patients taking azathioprine, the adjusted odds ratios for the risk of developing cancer increased from 1.3 to 2.0 to 4.4 for treatment of less than 5 years, between 5 and 10 years, and beyond 10 years, respectively.291 In another study of heart transplantation patients, those with lower doses of immunosuppression were shown to have a decreased incidence of lymphomas.292 Important considerations Some adverse effects attributed to azathioprine are difficult to sort out. For instance, alopecia has

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been observed in renal transplant recipients taking azathioprine. Alopecia is well documented in patients after renal transplantation, and these patients eventually regrow their hair despite taking immunosuppressive medications. Reports of RA and multiple sclerosis patients taking azathioprine and developing alopecia are nearly nonexistent, so alopecia may be related more to renal transplantation than to azathioprine itself.238 The same type of argument can be raised for pancreatitis and veno-occlusive disease in patients with underlying gastroenterologic disease. When reviewing the reports of adverse effects, one should consider the inherent differences in the patient population. Patients in dermatology are generally healthier and taking smaller doses and shorter courses of azathioprine than transplant recipients. Therefore extrapolation of adverse effects from one patient population to another may not be predictive of adverse effects in a different population. Assessing the potential side effects of azathioprine is further complicated because it is often used in combination with corticosteroids and other immunosuppressants. Moreover, the degree of immune suppression rather than azathioprine itself may be the cause of many of the long-term side effects. One study failed to show any significant difference in the dermatologic side effects between renal transplantation patients receiving cyclosporine and those receiving azathioprine,293 and another study failed to show any difference in the risk of skin cancer among patients on long-term cyclosporine, azathioprine, and combination therapy.284 These considerations are important to keep in mind when attempting to predict risk in dermatology patients taking azathioprine, particularly the risk of developing malignancy. Even though the risk of carcinogenesis is not well established, it should not be ignored. Patients should be counseled that there is a theoretic risk of developing a malignancy (particularly squamous cell carcinoma and lymphoma), but the slight risk is probably even smaller than with other reported populations, such as transplantation patients.

Table VII. Dosing scheme

Groups

No activity (homozygous mutation) Low activity (heterozygous)* Normal activity (homozygous wild type) High activity (high homozygous)

TPMT activity (U/mL RBCs)

\5 5e13.7 13.8e19.5

[19.5

Suggested maximum dose (mg/kg)

Recommend not using 1 2.5

3

RBCs, red blood cells. *Azathioprine use in persons who have values in the lower range should be initiated with caution and frequent laboratory monitoring, as there may be delayed and lineage-specific effects on the bone marrow.

dosing strategy is different from prior recommendations in published reports75,189 and reference texts190 because we find that these previous dosing schemes underdose patients. A TPMT value should be obtained before starting treatment because the procedure is relatively inexpensive, easily obtainable in the United States, extremely valuable in determining the proper dose, and able to identify patients who should not undergo treatment with azathioprine. Patients generally have responses after a few months of therapy, and a trial should not be considered a failure unless the patient has been on an adequate dose for at least 3 months. A recent metaanalysis showed a significant odds ratio of clinical effect to duration of therapy beyond 17 weeks.294 Laboratory monitoring often varies according to the physician’s level of comfort in prescribing azathioprine. We recommend a TPMT, pregnancy test, complete blood cell count, and complete metabolic panel at baseline. After initiation of therapy, we suggest following the complete blood cell count bimonthly and the complete metabolic panel monthly for the first 2 months of therapy, then monthly for a few months, and then every 3 months. Complete skin examinations should be performed regularly if the patient has been on azathioprine for more than 2 years.

DOSING AND MONITORING Azathioprine is available in scored 50 mg tablets and 100 mg vials for intravenous injections. It is relatively inexpensive in the United States, as a month’s supply generally costs between $100 and $200. On the basis of our collective experience of using azathioprine to treat more than 100 patients over the past 20 years (unpublished, open-label use), we propose a new dosing scheme (Table VII). Our

FUTURE CONSIDERATIONS Azathioprine has been utilized for several decades, yet in only 2 studies we reviewed were TPMT levels measured.137,141 It is possible that many patients found to be unresponsive to azathioprine were underdosed, and those determined to have significant hematologic toxicity had no or low TPMT activity. Therefore future study designs should incorporate TPMT activity for proper dosing. Genotype

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testing may eventually become routine and may allow for further individualization of therapy on the basis of actual single nucleotide polymorphisms. Potential derivatives of azathioprine may also affect patient care in the future. Azathioprine recently has been found to inhibit the CD28 pathway. This exciting discovery may eventually lead to derivatives that are more specific in mediating T-cell inhibition. Therefore these derivatives may have a better therapeutic index and greater efficacy in chronic inflammatory and autoimmune diseases than azathioprine. The imidazole moiety also has been found to have potential therapeutic value in laboratory in vitro and in vivo systems. Synthesis of a new molecule with azathioprine’s imidazole moiety may also come to fruition in the future. Azathioprine is an effective immunosuppressant that is extremely valuable in treating pemphigoid, generalized eczematous disorders, and actinic dermatitis. Because newer immunosuppressants are much more expensive and relatively unproven in many instances, azathioprine probably will remain in dermatology for years to come.

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