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Jeremy P. Banky, MBBS; Adam T. Sheridan, FACD; Emma L. Storer, MBBS; Gillian Marshman, FACD
From the Churchill Hospital, Oxford Radcliffe Hospitals, Headington, Oxford, England (Drs Banky and Sheridan); and Flinders Medical Centre, Bedford Park, Australia (Drs Storer and Marshman).

Arch Dermatol. 2004;140:794-796.

REPORT OF A CASE
A 53-year-old white woman with epidermolysis bullosa (EB) pruriginosa presented to the dermatology clinic seeking therapy for localized severe and intractable pruritus. At the age of 4 years the patient developed an extremely pruritic bullous eruption characterized by fragile blisters, erosions, and excoriations affecting sites subject to friction and pressure, particularly the ankles and knees. By the age of 21 years, the patient had large lichenified plaques, areas of linear violaceous scarring, multiple milia, and erosions over much of the extensor surfaces of the legs, forearms, buttocks, and dorsum of the feet (Figure 1A and B). All of her 20 nails were grossly dystrophic (Figure 1C). Mucous membranes were normal. There was a family history of EB pruriginosa, as the patient's younger brother and daughter were similarly affected.

View larger version (117K): [in this window] [in a new window] Figure 1. Lichenified plaques, linear violaceous scarring, erosions, and milia are affecting the extensor surfaces of the legs (A), forearm (B), and feet (C). All toenails were dystrophic.

Electron microscopical features supported the diagnosis of EB pruriginosa: separation at the sublamina densa level of the dermoepidermal junction and abnormal anchoring fibrils that were scanty, disorganized, and not fully developed (Figure 2). Blood cell count and serum biochemistry findings were normal. Serum levels of thyroid hormones, ferritin, and IgE were all within normal ranges.

View larger version (162K): [in this window] [in a new window] Figure 2. Electron microscopic appearances of lesional skin on the shin showing (1) keratinocytes, (2) lamina densa above the level of separation, (3) separation at the sublamina densa level of the dermoepidermal junction, and (4) upper dermis (original magnification x 76 000).

Throughout the course of the disease, intractable pruritus was the most prominent and severe feature, far outweighing the significant cosmetic disability. Continuous rubbing and scratching generated large areas of disease over the shins and forearms. The patient often presented with areas of frank bleeding resulting from deep excoriations. Treatments included inpatient and outpatient care with a combination of intensive emolliation, potent topical corticosteroids, sedating antihistamines, and behavioral therapy. These resulted in short-term control of the cutaneous manifestations, but not sustained improvement or control of the pruritus. Thinning of the skin secondary to the ongoing use of potent topical steroids was also evident.

THERAPEUTIC CHALLENGE

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Epidermolysis bullosa pruriginosa is a rare condition of poorly understood pathogenesis. Therapeutic results are currently disappointing as targeted treatments are yet to be defined. In our patient, intractable pruritus was by far the most troublesome feature. A vicious cycle was established as the extreme itch precipitated paroxysms of scratching, resulting in new and persistent areas of disease. Our patient had been relatively unresponsive to topical steroids and long-term use had compounded the skin fragility by inducing significant cutaneous atrophy. The patient was reluctant to take any systemic medication. Our challenge was to find a safe and effective therapy that would target the pruritus without the side effects of topical corticosteroids.

SOLUTION

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Since systemic cyclosporine has been used in EB pruriginosa with some success,¹ topical tacrolimus was considered as an alternative therapeutic approach. Therapy was initiated with 0.03% tacrolimus ointment to the legs and forearms twice daily. Within 1 week of applying the ointment, a significant decrease in the pruritus was reported, resulting in a marked reduction in scratching. Progression of the lichenified plaques, linear violaceous scars, milia, and erosions was arrested and in some areas the lichenified plaques were reduced (Figure 3). The patient has used 0.03% tacrolimus ointment for 6 months without complication and remains under excellent symptomatic control.

View larger version (141K): [in this window] [in a new window] Figure 3. Six months after treatment the forearms demonstrate reduction in lichenification, with persistent background milia and scarring.

COMMENT

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Epidermolysis bullosa pruriginosa is a form of dystrophic EB characterized by prurigolike or lichenified lesions associated with scarring.² It is usually confined to the shins and forearms.² The ultrastructural hallmark is a sublamina densa split associated with an alteration in the number and structure of the anchoring fibrils at the dermal-epidermal junction.² The onset of clinical features may be evident in early childhood, as in our patient, but in some cases appears later, in the second and third decades of life.³

The mode of inheritance is variable. McGrath et al² described 8 unrelated cases of EB pruriginosa, of which 5 were sporadic, 2 were autosomal dominant, and 1 was recessive. Mellerio et al³ described both dominant and recessive type VII collagen gene (COL7A1) mutations underlying the EB pruriginosa phenotype. Yu-Yun Lee et al⁴ and Jiang et al⁵ examined separate Chinese families with dominant EB pruriginosa who had different COL7A1 mutations. Our patient has a brother and a daughter similarly affected, and the mode of inheritance appears to be autosomal dominant.

The development of EB pruriginosa phenotype has yet to be defined.⁶ Molecular heterogeneity and compound heterozygosity in COL7A1 mutations have been demonstrated in patients with EB pruriginosa.³ Other genetic and environmental factors are also likely to contribute to this specific phenotype, as mutations in COL7A1 have been demonstrated in patients with both EB pruriginosa and dystrophic EB of nonpruriginous phenotype.³

Treatment is aimed at controlling pruritus and halting the progression of cutaneous lesions. Potent topical steroids and intralesional triamcinolone have been reported to reduce the pruritus in some cases, but do not produce sustained improvement.² Systemic therapy with histamine₁ antihistamines, corticosteroids, or etidronate had no sustained effect.² Oral administration of cyclosporine has been reported in 1 case as controlling the cutaneous lesions and decreasing the pruritus.¹

The aim of treatment in our patient was to eliminate the pruritus, as her scratching was traumatizing the skin and contributing to disease progression. The pathogenesis of the pruritus is poorly understood. Raised serum levels of IgE have been noted in some patients with EB pruriginosa, although elevated IgE levels do not specifically account for a pruriginosa phenotype.³

Tacrolimus is a macrolide immunosuppressant produced by the soil fungus Streptomyces tsukubaensis. Topical application of tacrolimus in treating atopic eczema^7-10 is well described. Cases of steroid-induced rosacea,¹¹ pyoderma gangrenosum,¹² lichen planus,¹³ and ichthyosis linearis circumflexa¹⁴ have been successfully treated with topical tacrolimus.

Topical tacrolimus was considered in our patient because the literature suggests that it has an antipruritic action.^15-17 The exact mode of this action is unclear. De Paulis et al¹⁶ showed that tacrolimus acted on skin mast cells challenged with anti-IgE antibodies to inhibit histamine release in a concentration-dependent manner and impair de novo synthesis of prostaglandin D₂. Eberlein-König et al¹⁷ demonstrated that tacrolimus diminished the enhancing effect of interleukin-3 on anti-IgE-antibody–induced histamine release from basophils. The relevance of this phenomenon to EB pruriginosa is unclear because it is considered a mechanobullous disease.

Treatment with topical tacrolimus in our patient had minimal effect upon preexisting visible disease. The lack of a dramatic effect on established skin lesions was not unexpected, as EB pruriginosa is associated with an underlying COL7A1 mutation and tacrolimus does not affect collagen synthesis.¹⁸

We believe that topical tacrolimus has potential benefits over topical corticosteroids when treating EB pruriginosa. There are currently no reports of systemic adverse effects after topical tacrolimus application.¹⁹ Although topical corticosteroids are generally well tolerated, they may cause systemic problems such as acne, hyperglycemia, growth retardation, and adrenal insufficiency when applied to large areas.²⁰ Most importantly, tacrolimus, unlike topical steroids, does not cause cutaneous atrophy.^{18, 21} These were important considerations in our patient whose pathological cutaneous fragility was compounded by steroid-induced atrophy.

To the best of our knowledge, this is the first reported case of EB pruriginosa successfully treated with topical tacrolimus. By alleviating our patient's itch, disease progression was slowed and her quality of life was markedly improved. With its steroid-sparing effects and lack of documented systemic adverse reactions, we consider topical tacrolimus to be of significant benefit in treating EB pruriginosa.

Submissions Clinicians, local and regional societies, residents, and fellows are invited to submit cases of challenges in management and therapeutics to this section. Cases should follow the established pattern. Submit 4 double-spaced copies of the manuscript with right margins nonjustified and 4 sets of the illustrations. Photomicrographs and illustrations must be clear and submitted as positive color transparencies (35-mm slides) or black-and-white prints. Do not submit color prints unless accompanied by original transparencies. Material should be accompanied by the required copyright transfer statement, as noted in "Instructions for Authors." Material for this section should be submitted to George J. Hruza, MD, Laser and Dermatologic Surgery Center Inc, 14377 Woodlake Dr, Suite 111, St Louis, MO 63017.

AUTHOR INFORMATION

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Correspondence: Jeremy P. Banky, MBBS, Dermatology Registrar, Churchill Hospital, Oxford Radcliffe Hospitals, Headington, Oxford, OX37LJ England (jembanky{at}hotmail.com).

Accepted for publication September 23, 2003.

The authors have no relevant financial interest in this article.

REFERENCES

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1. Yamasaki H, Tada J, Yoshioka T, Arata J. Epidermolysis bullosa pruriginosa (McGrath) successfully controlled by oral cyclosporin. Br J Dermatol. 1997;137:308-310. ISI | PUBMED 2. McGrath JA, Schofield OMV, Eady RAJ. Epidermolysis bullosa pruriginosa: dystrophic epidermolysis bullosa with distinctive clinicopathological features. Br J Dermatol. 1994;130:617-625. FULL TEXT | ISI | PUBMED 3. Mellerio JE, Ashton GHS, Mohammedi R, et al. Allelic heterogeneity of dominant and recessive COL7A1 mutations underlying epidermolysis bullosa pruriginosa. J Invest Dermatol. 1999;112:984-987. FULL TEXT | ISI | PUBMED 4. Yu-Yun Lee J, Pulkkinen L, Liu HS, Chen YF, Uitto J. Glycine-to-arginine substitution in the triple-helical domain of type VII collagen in a family with dominant dystrophic epidermolysis bullosa pruriginosa. J Invest Dermatol. 1997;108:947-949. FULL TEXT | ISI | PUBMED 5. Jiang W, Bu D, Yang Y, Zhu X. A novel splice site mutation in collagen type VII gene in a Chinese family with dominant dystrophic epidermolysis bullosa pruriginosa. Acta Derm Venereol. 2002;82:187-191. FULL TEXT | ISI | PUBMED 6. Horn HM, Tidman MJ. The clinical spectrum of dystrophic epidermolysis bullosa. Br J Dermatol. 2002;146:267-274. FULL TEXT | ISI | PUBMED 7. Ruzicka T, Bieber T, Schopf E, et al. A short-term trial of tacrolimus ointment for atopic dermatitis. N Engl J Med. 1997;337:816-821. FREE FULL TEXT 8. Hanifin JM, Ling MR, Langley R, Breneman D, Rafal E, for the Tacrolimus Ointment Study Group. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients, I: efficacy. J Am Acad Dermatol. 2001;44(suppl):S28-S38. 9. Reitamo S, Wollenberg A, Schopf E, et al. Safety and efficacy of 1 year of tacrolimus ointment monotherapy in adults with atopic dermatitis. Arch Dermatol. 2000;136:999-1006. FREE FULL TEXT 10. Kang S, Lucky AW, Pariser D, Lawrence I, Hanifin JM, for the Tacrolimus Ointment Study Group. Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. J Am Acad Dermatol. 2001;44(suppl):S58-S64. 11. Goldman D. Tacrolimus ointment for the treatment of steroid-induced rosacea: a preliminary report. J Am Acad Dermatol. 2001;44:995-998. FULL TEXT | ISI | PUBMED 12. Richter-Hintz D, Schuppe HC, Homey B, Lehmann P, Ruzicka T. Topical tacrolimus (FK506) is effective in the treatment of pyoderma gangrenosum. [comment] J Am Acad Dermatol. 2000;42:304-305. ISI | PUBMED 13. Lener EV, Brieva J, Schachter M, West LE, West DP. Successful treatment of erosive lichen planus with topical tacrolimus. Arch Dermatol. 2001;137:419-422. FREE FULL TEXT 14. Suga Y, Tsuboi R, Hashimoto Y, Yoshiike T, Ogawa H. A case of ichthyosis linearis circumflexa successfully treated with topical tacrolimus. J Am Acad Dermatol. 2000;42:520-522. FULL TEXT | ISI | PUBMED 15. Nakagawa H, Etoh T, Ishibashi Y, et al. Tacrolimus ointment for atopic dermatitis [letter]. Lancet. 1994;344:883. ISI | PUBMED 16. De Paulis A, Stellato C, Cirillo R, Ciccarelli A, Oriente A, Marone G. Anti-inflammatory effect of FK-506 on human skin mast cells. J Invest Dermatol. 1992;99:723-728. FULL TEXT | ISI | PUBMED 17. Eberlein-König B, Ruzicka T, Michel G, Przybilla B. Modulation of histamine release in vitro by FK506 and interleukin-3 is determined by sequence of incubation. Arch Dermatol Res. 1997;289:606-608. FULL TEXT | ISI | PUBMED 18. Reitamo S, Rissanen J, Remitz A, et al. Tacrolimus ointment does not affect collagen synthesis: results of a single-center randomized trial. J Invest Dermatol. 1998;111:396-398. FULL TEXT | ISI | PUBMED 19. Skaehill PA. Tacrolimus in dermatologic disorders. Ann Pharmacother. 2001;35:582-588. ABSTRACT 20. Lee NP, Arriola ER. Topical corticosteroids: back to basics. West J Med. 1999;171:351-353. ISI | PUBMED 21. Nasr IS. Topical tacrolimus in dermatology. Clin Exp Dermatol. 2000;25:250-254. FULL TEXT | ISI | PUBMED

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