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Table of Contents 
E–CASE REPORT
Year : 2013  |  Volume : 58  |  Issue : 2  |  Page : 158
Perforating dermatosis in a patient receiving azathioprine


1 Department of Dermatology, Ramón y Cajal Hospital, Madrid, Spain
2 Department of Anatomy Payhology, Ramón y Cajal, Madrid, Spain

Date of Web Publication5-Mar-2013

Correspondence Address:
Emiliano Grillo
Department of Dermatology, Ramón y Cajal Hospital, Madrid
Spain
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.108077

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   Abstract 

Azathioprine (AZA) is an imidazole derivative of mercaptopurine. It antagonizes purine metabolism, and it may inhibit synthesis of DNA, RNA, and proteins. The 6-thioguanine nucleotides appear to mediate the majority of AZAs immunosuppressive and toxic effects. While cutaneous adverse side-effects are not uncommon, perforating dermatosis has not been reported in association to AZA. We speculate that immunological disorders induced by AZA in susceptible individuals could be related to perforating dermatosis.


Keywords: Azathioprine, drug reactions, perforating dermatosis


How to cite this article:
Grillo E, Vano-Galván S, Moreno C, Jaén P. Perforating dermatosis in a patient receiving azathioprine. Indian J Dermatol 2013;58:158

How to cite this URL:
Grillo E, Vano-Galván S, Moreno C, Jaén P. Perforating dermatosis in a patient receiving azathioprine. Indian J Dermatol [serial online] 2013 [cited 2019 Jun 24];58:158. Available from: http://www.e-ijd.org/text.asp?2013/58/2/158/108077

What was known? The cutaneous adverse effects produced by AZA are common and highly variable. They include maculopapular eruptions, urticaria, and purpuric eruptions besides others. However, perforating dermatosis has not been reported in association to azathioprine



   Introduction Top


Azathioprine (AZA) is an imidazole derivative of mercaptopurine; antagonizes purine metabolismΉ and may inhibit synthesis of DNA, RNA, and proteins. It may also interfere with cellular metabolism and inhibit mitosis. The 6-thioguanine nucleotides appear to mediate the majority of AZAs immunosuppressive and toxic effects.

Among other indications, AZA is approved by the Food and Drug Administration for the treatment of inflammatory bowel disease, mainly for the maintenance of remission. [1]

The cutaneous adverse effects are not uncommon and are highly variable. They may include maculopapular eruptions, urticaria, and purpuric eruptions besides others. [2] However, perforating dermatosis has not been reported in association to AZA. We report a case of perforating dermatosis associated to AZA in a patient with ulcerative pancolitis.


   Case Report Top


A 26-year-old previously healthy woman was admitted with profuse diarrhea and fever, having been diagnosed with ulcerative pancolitis confirmed by biopsy. This flare was controlled with only one complete cycle of systemic steroids, and afterwards, maintenance treatment was started with mesalazine.

Three days later, she developed a well-characterized adverse reaction to several preparations of mesalazine (Pentasa, Claversal) and developed profuse diarrhea. Therefore, the maintenance therapy was substituted with AZA in January, 2011. Three weeks later, the patient presented with a slightly pruritic lesions on the dorsum of the hands that had appeared progressively. No antecedent microtrauma was mentioned. Physical examination revealed reddish, umbilicated papules, 5 to 10 mm in diameter, with adherent central keratotic plugs [Figure 1] and [Figure 2]. Lesions were located mostly on the hands and a few of them on the lateral aspects of the neck. Routine laboratory tests showed normal serum glucose and renal function. The blood cell counts were completely normal.
Figure 1: Umbilicated erythematous papules with adherent central keratotic plug on the dorsum of the hands

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Figure 2: Detail of a keratotic papule on knuckles of the right hand

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A biopsy from a lesion on the back of the hands revealed a particular pattern of superficial dermal necrosis, with trans-epidermal elimination of verticalized collagenous fibers and necrotic debris, without any association with follicular structures consistent with perforating dermatosis (PD) [Figure 3] and [Figure 4].

Following clinical and laboratory investigations, treatment with tacrolimus 0.1% ointment was started with improvement of symptoms but without disappearance of lesions. AZA was withdrawn, and mesalazine was started with subsequent improvement of the skin involvement within few days. After 6 months of follow-up, the patient remains without lesions.
Figure 3: At low power magnification the lesion reveals irregular acanthosis of the epidermis with accumulation of slighty basophilic collagen in the dermal papillae and a keratotic corneal plug (H and E stain ×4)

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Figure 4: A close-up view of particular pattern of superficial dermal necrosis, with transepidermal elimination of verticalized collagenous fibers. (Masson stain ×40)

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   Discussion Top


AZA, a 6-mercaptopurine (6-MP) analogue, has been used for Crohn's disease and ulcerative colitis for over 30 years, mainly as a steroid-sparing agent.

Side-effects occur in about 10% to 15% of patients with inflammatory bowel disease treated with AZA. The most commonly encountered problems are nausea, vomiting, and malaise, especially if the dose is increased too rapidly. The other types of side-effects can be divided into 4 categories: Dose-dependent (such as bone marrow depression), dose-independent (including cutaneous lesions), infectious, and neoplastic ones.

Among the clinical side-effects of AZA, cutaneous signs and symptoms emerge as an infrequent problem that rarely results in discontinuation of treatment. [3] They may include maculopapular eruptions, urticaria, and purpuric eruptions. [4] A few case reports exist of disorders in the neutrophilic dermatosis spectrum, including erythema nodosum-like eruptions and acute disseminated exanthematous pustulosis induced by AZA. However, to the best of our knowledge, perforating dermatosis has not been reported in association with AZA.

Perforating dermatosis has been described in association with diabetes, chronic renal disease, and malignancy as well as following various inflammatory cutaneous conditions, but it has never been related to inflammatory bowel disease. [5],[6]

In the absence of underlying renal or diabetic problems in our patient, we speculate that perforating lesions are different stages of a common pathological process rather than a chance finding. This is supported by the temporal relationship with the AZA administration and the subsequent disappearance of the lesions after AZA withdrawn. This led us to speculate a possible casual relationship between the administration of AZA and the development of perforating dermatosis.

Drug-induced maculopapular rashes, with histological findings suggestive of perforating collagenosis, have previously been described in an oncological patient treated with bevacizumab, [7] as well as under other different drugs like sirolimus, penicillamine, gefitinib, indinavir, and sorafenib. [8],[9],[10],[11]

Pathogenesis of PD is poorly understood. Therefore, it remains unclear the way AZA can induce this entity.

AZA suppresses intracellular inosinic acid synthesis, thereby interfering with adenine and guanine ribonucleotide production. [12] This reduction in intracellular purine synthesis results in decreased numbers of circulating B and T lymphocytes, [13] reduced immunoglobulin synthesis, [14] and diminished interleukin-2 secretion. [15] These immune disorders could cause a malfunction of fibroblasts in people with genetic susceptibility to produce focal damage to collagen and the elimination of the disrupted collagen through the epidermis.

We hypothesize that TGFb3 could play a role in the pathogenesis of this entity, as overexpression of this factor has been reported in patients with perforating dermatosis. [16]

We speculate that this immunological disorder induced by AZA in susceptible individuals could be related to perforating dermatosis.

To our knowledge, this is the first report of a possible correlation between AZA and perforating disorders and may initiate further investigation in similar observations.

 
   References Top

1.Gisbert JP, Linares PM, McNicholl AG, Maté J, Gomollón F. Meta-analysis; The efficacy of azathioprine and mercaptopurine in ulcerative colitis. Aliment Pharmacol Ther 2009;30:126-37.  Back to cited text no. 1
    
2.Corbett M, Schlup M. Azathioprine hypersensitivity mimicking underlying inflammatory bowel disease. Intern Med J 2001;31:366-7.  Back to cited text no. 2
[PUBMED]    
3.Schaffellner S, Jakoby E, Kniepeiss D, Stadlbauer V, Duller D, Iberer F, et al. Center experience in liver transplantation (LTX): Management of dermal side effects caused by sirolimus. Int Immunopharmacol 2005;5:137-40.  Back to cited text no. 3
[PUBMED]    
4.Elston GE, Johnston GA, Mortimer NJ, Harman KE. Acute generalized exanthematous pustulosis associated with azathioprine hypersensitivity. Clin Exp Dermatol 2007;32:52-3.  Back to cited text no. 4
[PUBMED]    
5.Saray Y, Seckin D, Bilezikci B. Acquired perforating dermatosis: Clinicopathological features in twenty-two cases. J Eur Acad Dermatol Venereol 2006;20:679-88.  Back to cited text no. 5
    
6.Patterson JW. The perforating disorders. J Am Acad Dermatol 1984;10:561-81.  Back to cited text no. 6
[PUBMED]    
7.Vano-Galvan S, Moreno C, Medina J, Pérez-García B, García-López JL, Jaén P. Perforating dermatosis in a patient receiving bevacizumab. Eur Acad Dermatol Venereol 2009;23:972-4.  Back to cited text no. 7
    
8.Lübbe J, Sorg O, Malé PJ, Saurat JH, Masouyé I. Sirolimus-induced inflammatory papules with acquired reactive perforating collagenosis. Dermatology 2008;216:239-42.  Back to cited text no. 8
    
9.Fernández-Guarino M, Aldanondo I, González-García C, Garrido P, Marquet A, Pérez-García B. Gefitinib-induced perforating dermatosis. Actas Dermosifiliogr 2006;97:208-11.  Back to cited text no. 9
    
10.Calista D, Morri M. Acquired reactive perforating collagenosis induced by indinavir in 2 patients with HIV disease. Eur J Dermatol 2008;18:84-5.  Back to cited text no. 10
    
11.Minami-Hori M, Ishida-Yamamoto A, Komatsu S, Liduka H. Transient perforating folliculitis induced by sorafenib. J Dermatol 2010;37:833-4.  Back to cited text no. 11
    
12.Elion GB. The purine path to chemotherapy. Science 1989;244:41-7.  Back to cited text no. 12
    
13.McKendry RJ. Pruine analogues. In: Second Line Agents in the Treatment of Rheumatic Diseases. Dixon J, Furst BE, editors. New York: Marcel Decker; 1991.  Back to cited text no. 13
    
14.Trotter JL, Rodey GE, Gebel HM. Azathioprine decreases suppressor T cells in patients with multiple sclerosis. N Engl J Med 1982;306:365-6.  Back to cited text no. 14
    
15.Bacon PA, Salmon M. Modes of action of second-line agents. Scand J Rheumatol 1987;64:17-24.  Back to cited text no. 15
    
16.Kawakami T, Soma Y, Mizoguchi M, Saito R. Immunohistochemical analysis of transforming growth factor-beta3 expression in acquired reactive perforating collagenosis. Br J Dermatol 2002;146:171-3.  Back to cited text no. 16
    

What is new? Immunological disorders induced by azathioprine in susceptible individuals could be related to perforating dermatosis.


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

This article has been cited by
1 Azathioprine
Reactions Weekly. 2013; 1461(1): 9
[Pubmed] | [DOI]



 

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