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Topical tacrolimus in the treatment of localized scleroderma

European Journal of Dermatology. Volume 13, Number 6, 590-2, November - December 2003, Clinical report

Summary

Author(s) : Giuseppe MANCUSO, Renza Maria BERDONDINI , Department of Dermatology, Municipal Hospital of Lugo, via Pescantini 33, 48022 Lugo (RA), Italy .

Summary : Although the cause of localized scleroderma is unknown, an autoimmune mechanism is suspected. We describe two patients with localized scleroderma treated with topical tacrolimus, an immunosuppressive macrolide antibiotic. Topical tacrolimus 0.1% ointment applied twice daily under occlusion led to a significant clinical improvement of late sclerotic lesions and complete clearance of early inflammatory skin lesions in 3 months. These were the first cases of successful topical tacrolimus therapy in localized scleroderma and should be regarded as a promising treatment option for LS, especially on account of its high tolerability that permits prolonged use without side‐effects.

Keywords : topical tacrolimus, immunosuppressive drug, localized scleroderma

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ARTICLE

Auteur(s) : Giuseppe MANCUSO, Renza Maria BERDONDINI

Department of Dermatology, Municipal Hospital of Lugo, via Pescantini 33, 48022 Lugo (RA), Italy

Article accepted 01/09/2003

Although disease activity in localized scleroderma (LS) is towards spontaneous resolution after a certain period of time, disability, both physical and cosmetic, prompts patients to search for satisfactory therapy. Numerous treatments have been used with limited success, such as intravenous penicillin, infiltration with glucocorticosteroids, topical calcipotriene, phototherapy, nonsteroidal anti-inflammatory drugs, and vasoactive or immunosupressive drugs [1-5]. To our knowledge there has been no previous experience of topical tacrolimus, an immunosuppressive macrolide antibiotic [6], in the treatment of LS. We studied the possible efficacy of 0.1% tacrolimus ointment (Protopic, Fusjisawa) applied twice daily with plastic wrap occlusion at night for a period of 12 weeks in two patients affected by LS.

Case report

Case 1

A 32-year-old white man presented with a 7-year history of two sclerotic plaques, one on the lumbar area and the other on the abdominal area. Examination showed a 6.0 × 5.0 cm sized, hypopigmented, atrophic, indurated plaque with a mild lilac edge on the lumbar area (Fig. 1a) and a 5.0 × 4.0 cm sized morphologically similar plaque on the abdominal area. Histologic examination confirmed the diagnosis of LS. A 1-month trial of clobetasol dipropionate ointment on both lesions caused no improvement. The corticosteroid treatment was discontinued around 3 months before the study began. Topical 0.1% tacrolimus was applied twice daily on the lumbar area lesion and petrolatum twice daily on the other abdominal lesion used as a control. Both lesions were medicated in the evening with plastic wrap occlusion which was removed the following morning. After 4 weeks of treatment, the erythema in the lumbar area lesion disappeared and some softening was noted; after 12 weeks of treatment, the hypopigmentation had improved considerably and the lesion was significantly softer (Fig. 1b). The abdominal control lesion, on the other hand, was unchanged.

Case 2

A 50-year-old white woman had eythematous, thickened plaques on her back and on both legs, which had appeared approximately 4 months earlier. Examination revealed a 4x5 cm, ill-defined erythematous, thickened and indurated plaque on the back and similar lesions of a different size on the legs. Histologic examination confirmed the diagnosis of LS. Tacrolimus ointment was applied under occlusion twice daily in the back region and petrolatum twice daily on the lesions of the legs, in both sites without occlusion in the morning and with occlusion at night. After 4 weeks of treatment with topical tacrolimus, the lesion had softened, and the erythema had disappeared. After 12 weeks the plaque on the back resolved, leaving smooth and soft tanned skin with normal structure and folding capability. These results were confirmed by histological evaluation of biopsy specimens before and after the treatment (Fig. 2a and 2b). A post-treatment specimen was taken from a previously affected area next to the site of the previous biopsy. Eight months later, the site of the topical tacrolimus treated lesion was almost normal in appearance. The control lesions on the legs were on the contrary unchanged.
No local or systemic side effects were observed in either patient during the treatment. In particular, there were no consistent changes in any laboratory parameters, including the blood levels of tacrolimus that were below the detection limit of quantification (1.5 ng/mL).

Discussion

Although the cause of LS remains unknown, an autoimmune mechanism is suspected because of its frequent association with antinuclear antibodies, rheumatoid factor, antihistone antibodies and anti-single-stranded DNA [7]. There are some reports [3-5] in the literature concerning the efficacy of immunosuppressive drugs administered by systemic route in LS, albeit with potentially hazardous side effects which justify their use only in patients with severe disabling disease. We are not aware of any report of attempts to treat LS with topical tacrolimus, an immunosuppressive macrolide antibiotic. Tacrolimus is an 822 Da molecule that is effective in atopic eczema because of a probable skin barrier defect which facilitates the penetration of this relatively large molecule through the skin. In other skin disorders topical tacrolimus showed efficacy only if applied with occlusive methods [8, 9]. In this study, topical tacrolimus under occlusion was found to induce improvement of late sclerotic (patient 1) and complete clearance of early inflammatory lesions (patient 2). These beneficial effects were detected in topical tacrolimus treated lesions but not in untreated control plaques of the same patients. It is, therefore, unlikely that the observed changes were caused by spontaneous remission. The favourable results which we achieved indicate that topical tacrolimus under occlusion may be a promising option treatment for LS, especially on account of its high tolerability that allows prolonged use without local or systemic side-effects. In contrast to topical corticosteroids, tacrolimus ointment did not have an atrophogenic effect on the skin [6]. Further randomized controlled studies on a larger scale are obviously needed to confirm these positive results.
The mechanism of action of topical tacrolimus is unclear, especially in relation to the uncertain pathogenesis of LS [1]. It is probable that an important role is played by the drug's immunomodulating and anti-inflammatory activity, which is linked to the inhibition of T lymphocyte activation and the reduced production of inflammatory lymphokines [6]. n

References

1. Sapadin AN, Fleischmajer R. Treatment of scleroderma. Arch Dermatol 2002; 138: 99-105.

2. Jablonska S, Blaszczyk M. New treatments in scleroderma: dermatologic perspective. J Eur Acad Dermatol Ven 2002; 16: 433-5.

3. Seyger MM, van den Hoogen FH, de Boo T, de Jong EM. Low-dose methotrexate in the treatment of widespread morphea. J Am Acad Dermatol 1998; 39: 220-5.

4. Uziel Y, Feldman BM, Krafchik BR, Yeung RS, Laxer RM. Methotrexate and corticosteroid therapy for pediatric localized scleroderma. J Pediatr 2000; 136: 91-95.

5. Morton SJ, Powell RJ. Cyclosporin and tacrolimus: their use in a routine clinical setting for scleroderma. Rheumatology 2000; 39: 865-69.

6. Cheer SM, Plosker GL. Tacrolimus ointment. A review of is therapeutic potential as a topical therapy in atopic dermatitis. Am J Clin Dermatol 2001; 2: 389-406.

7. Arnett FC, Tan FK, Yosef U et al. Autoantibodies to the extracellular matrix microfibrillar protein, fibrillin 1, in patients with localized scleroderma. Arthritis Rheum 1999; 42: 2656-59.

8. Remitz A, Reitamo S, Erkko P, Granlund H, Lauerma AI. Tacrolimus ointment improves psoriasis in a microplaque assay. Br J Dermatol 1999; 141: 103-107.

9. Reich K, Vente C, Neumann C. Topical tacrolimus for pyoderma gangrenosum. Br J Dermatol 1998; 139: 755-57.

Trauma-induced perforating folliculitis

Auteur(s) : Miloš D. PAVLOVI&#262, Radoš D. ZE&#268EVI&#262, ^† Miroslav STAMANCOVI&#262, *Olivera STOJADINOVI&#262, ^‡Lidija ZOLOTAREVSKI

Departments of Dermatology, ^†Ophthalmology and ^‡Pathology, Military Medical Academy, Crnotravska 17, 11002 Belgrade, Serbia; *Department of Dermatology, New York University Medical Center, New York, NY

A 26-year-old conscript was seen for recurrent crops of umbilicated papules, located predominantly over his dorsal hands, and less over the forearms, shins and dorsal aspects of his feet, appearing after minor trauma. The lesions had occurred since his childhood leaving whitish macules or atrophic scars. Umbilicated papules, some with keratinous plugs, were seen over the dorsa of his hands and fingers, measuring from a few mm to 1 cm (Fig. 1). The lesions were occasionally mildly pruritic. One of the papules was biopsied. The follicular epithelium was disrupted in the area in the infundibulum within the epidermis and the perforation was surrounded by cellular debris and an infiltrate composed of lymphocytes and neutrophils. Surrounding epidermis was acanthotic. Within the papillary dermis, around blood vessels, there was a mixed inflammatory infiltrate (Fig. 2). An extensive laboratory work-up was unrevealing. In two weeks, topical keratolytics brought about the disappearance of the lesions.
Another patient, a 22-year-old conscript, was referred to our outpatient clinic for moderately tender recurrent papules on his hands. The lesions had begun to appear 6 months previously apparently provoked by repeated sharp trauma to the skin of his hands and forearms. A two-week course of a potent corticosteroid ointment under occlusion led to almost complete resolution of the lesions. A few weeks later, after having resumed his mechanics duties, the papules gradually reappeared. Purple-red umbilicated papules and some linear plaques up to 3 cm in length were seen over the dorsal aspects of his hands. Laboratory analyses were within normal limits. One of the papules was biopsied and histopathological examination confirmed perforating folliculitis.
Perforating folliculitis is manifested by chronic, relapsing eruption of discrete, keratotic, follicular papules involving the hairy parts of the extensor surfaces of the extremities and the buttocks [1]. The disorder has been described in patients with chronic renal failure, juvenile acanthosis nigricans, psoriasis, diabetes mellitus, HIV infection, and primary sclerosing cholangitis [1-3]. Chang and Fernandez [2], among 9 patients with acquired perforating disease associated with chronic renal failure, noted several patients with perforating folliculitis and koebnerization. According to a revised classification of the Koebner phenomenon, perforating folliculitis has been assigned to the category III - occasional traumatic localization of lesions [4]. Our patients' disease is unusual with respect to its exclusive confinement to sites of mechanic, mostly sharp, trauma without accompanying “spontaneous” lesions on other body areas. Hence, this form of perforating folliculitis might be also named “mechanic”, as the absence of spontaneous lesions excludes the Koebner phenomenon. Moreover, in contrast with previously reported patients with perforating folliculitis and koebnerization [2, 4], our patients do not have an associated disease, like chronic renal failure or diabetes mellitus. n

References

1. Sehgal VN, Jain S, Thappa DM, Bhattacharya SN, Logani K. Perforating dermatoses: a review and report of four cases. J Dermatol 1993; 20: 329-40.

2. Chang P, Fernandez V. Acquired perforating disease: report of nine cases. Int J Dermatol 1993; 32: 874-6.

3. Rubio FA, Herranz P, Robayna G, Pena JM, Contreras F, Casado M. Perforating folliculitis: report of a case in an HIV-infected man. J Am Acad Dermatol 1999; 40: 300-2.

4. Weiss G, Shemer A, Trau H. The Koebner phenomenon: review of the literature. J Eur Acad Dermatol Venereol 2002; 16: 241-8.