Title: Case 1. Depigmentation therapy in vitiligo universalis with cryotherapy and 4-hydroxyanisole. Introduction: Vitiligo is a disease characterized by the loss of melanocytes, resulting in progressive depigmentation of skin. Residual normally pigmented patches in patients with vitiligo universalis are of cosmetic concern to patients. Treatment options are based on case series or case reports and include cryotherapy, laser and topical therapies. Aim and scopes: use a less toxic, but efficient depigmentation method for removing the residual pigmentation of a patient with generalised vitiligo, which was resistant to all other classical therapies modes. Material and methods: A 65-year-old man with a 45-year history of vitiligo after several unsuccessful attempts to restore his pigmentation with topical corticosteroids and phototherapy, he had begun the treatment of removing the remaining pigment. A 12-month course of topical hydroquinone 4% cream resulted in no improvement. The patient was treated with single-session cryotherapy, using a closed cryogenic system (Cry-Acl Brymill Corporation, Vernon, CT, USA) with an open probe mounted on the tip. Uniform freezing of the involved area was obtained by holding the orifice approximately 40 mm from the skin and slowly painting the surface with vaporized liquid nitrogen. Two freeze–thaw cycles were performed Then after 3 weeks, twice-daily treatment with topical mequinol (4-hydroxyanisole; 4-HA) 20% in an oil and water mixture was started. Results: During a 14-month course of treatment, the patient was clear of all pigment within the treated sites, with no side-effects. Six months after discontinuation of topical treatment, he began to develop small patchy areas of repigmentation, which were easily removed by single-session cryotherapy. Comments: In this case, when rapid depigmentation is desirable, physical treatment works faster than bleaching compounds (1). Cryotherapy is a widely available and cheap physical procedure that has been used successfully in patients with vitiligo universalis. Owing to the high sensitivity to cryodamage of melanocytes compared with other skin cell types, we preferred to use an open cryoprobe, which allows gentler and more superficial freezing, and the direct spraying of the skin permits treatment of larger areas in a shorter time. Indeed, although some authors claim that physical depigmentation is permanent (3) repigmentation does occur after laser treatment (1) and in our case it also occurred after cryotherapy. An explanation for this phenomenon is that the melanocytes might be not entirely damaged, especially the follicular population. This PPT is loaded as student material "as is", from the Vitiligo Master Class Barcelona November 2011; VRF does not endorse or otherwise approve it.

1. I. Depigmentation therapy in vitiligo universalis with cryotherapy and 4-hydroxyanisole S. Di Nuzzo, A. Masotti and A.H. Koller Section of Dermatology, Department of Surgical Sciences, University of Parma - Italy

2. Brief Introduction... Vitiligo is a disease that is characterized by the loss of melanocytes , resulting in progressive depigmentation of skin. Residual normally pigmented patches in patients with vitiligo universalis are of cosmetic concern to patients.

3. Treatment options are based on case series or case reports and include: cryotherapy laser topical therapies.

4. Case patient who was treated with: 1.session of cryotherapy Topical 4-hydroxyanisole (4-HA).

5. Anamnesis -A 65-year-old man & 45-year history of vitiligo -after several unsuccessful attempts to restore his pigmentation with: topical corticosteroids & phototherapy, -he had begun treatment to remove the remaining pigment in his 6 th decades. -A 12-month course of topical hydroquinone 4% cream resulted in no appreciable improvement.

6. Physical examination total body depigmentation was seen, with some residual pigmented patchy areas of variable sizes and shapes over the face, particularly on the cheeks, eyelids and ears. (Fig.1a).

7. Method - Treatment -The patient was treated with single-session cryotherapy, using a closed cryogenic system (Cry-Acl Brymill Corporation, Vernon, CT, USA) with an open probe mounted on the tip. Uniform freezing of the involved area was obtained by holding the orifice approximately 40 mm from the skin and slowly painting the surface with vaporized liquid nitrogen . Two freeze–thaw cycles were performed. -In 2 days, a mild oedema without bullae resolved, leaving a superficial brownish crust on an erythematous background. -After 3 weeks the erythema had resolved, and the skin colour and texture was normal (Fig. 1b). (Fig. 1b).

8. Method-Treatment -Twice-daily treatment with topical mequinol (4-hydroxyanisole; 4-HA) 20% in an oil and water mixture was started. -During a 14-month course of treatment , the patient was clear of all pigment within the treated sites, with no side-effects. -Six months after discontinuation of topical treatment, he began to develop small patchy areas of repigmentation , which were easily removed by single-session cryotherapy ..

9. Discussion Complete depigmentation of normally pigmented areas should be considered in patients with vitiligo universalis. In this case, when rapid depigmentation is desirable, physical treatment works faster than bleaching compounds (1). As a result of selective targeting of melanosomes in melanocytes, treatment with lasers is very effective in inducing depigmentation.(1,2). 1 Njoo MD, Vodegel RM, Westerhof W. Depigmentation therapy in vitiligo universalis with topical 4-methoxyphenol and the Q-switched ruby laser. J Am Acad Dermatol 2000;42: 760–9. 2 Rao J, Fitzpatrick RE. Use of the Q-switched 755-nm alexandrite laser to treat recalcitrant pigment after depigmentation therapy for vitiligo. Dermatol Surg 2004; 30: 1043–5.

10. Cryotherapy: - is a widely available and cheap physical procedure that has been used successfully in patients with vitiligo universalis. -In one case series, five patients with residual pigmented patches were treated with 1–3 sessions of cryotherapy using a closed flat contact probe (3). Owing to the high sensitivity to cryodamage of melanocytes compared with other skin cell types , in our patients case it was preferred to use an open cryoprobe , which allows gentler and more superficial freezing, and the direct spraying of the skin permits treatment of larger areas in a shorter time. 3. Radmanesh M. Depigmentation of the normally pigmented patches in universal vitiligo patients by cryotherapy.

11. Post-treatment... After depigmentation, the patient must be advised to minimize sun exposure and to use sunscreens , because of the high risk of sunburn and repigmentation. Indeed, although some authors claim that physical depigmentation is permanent (3), repigmentation does occur after laser treatment (1) and in our case it also occurred after cryotherapy. An explanation for this phenomenon is that the melanocytes might be not entirely damaged, especially the follicular population.

12. Sequential application of melanocytotoxic compounds might prevent subsequent colonization of interfollicular epidermis. In our case, due to the involvement of the eyelids, we chose 4-HA rather than hydroquinone , which might cause adverse ocular reactions (4). In addition, cutaneous side-effects such as irritation are less common and less severe with 4-HA than those reported with hydroquinone. 4 Hedges TR III, Kenyon KR, Hanninen LA, Mosher DB. Corneal and conjunctival effects of monobenzone in patients with vitiligo. Arch Ophthalmol 1983; 101: 64–8.

13. 4-HA(hydroxyanisole): -is a phenolic compound, which was first shown by Riley (5) to be a strong melanocytotoxic agent. -it is intracellularly metabolized by tyrosinase to form catechol and then o-quinone , which is highly cytotoxic. -Although 4-HA has been widely used in a low concentration formulation to treat several forms of skin hyperpigmentation, it has rarely been used in vitiligo (1).

14. Conclusion The excellent response low side-effect profile ease of use speed to clearance patient comfort of 4-HA, as illustrated by our case indicate that cryotherapy in combination with 4-HA may be a viable option for depigmentation in patients with vitiligo universalis.

15. References 1 Njoo MD, Vodegel RM, Westerhof W. Depigmentation therapy in vitiligo universalis with topical 4-methoxyphenol and the Q-switched ruby laser. J Am Acad Dermatol 2000; 42 : 760–9. 2 Rao J, Fitzpatrick RE. Use of the Q-switched 755-nm alexandrite laser to treat recalcitrant pigment after depigmentation therapy for vitiligo. Dermatol Surg 2004; 30 : 1043–5. 3 Radmanesh M. Depigmentation of the normally pigmented patches in universal vitiligo patients by cryotherapy. J Eur Acad Dermatol Venereol 2000; 14 : 149–52. 4 Hedges TR III, Kenyon KR, Hanninen LA, Mosher DB. Corneal and conjunctival effects of monobenzone in patients with vitiligo. Arch Ophthalmol 1983; 101 : 64–8. 5 Riley PA. Hydroxyanisole depigmentation: in-vivo studies. J Pathol 1969; 97 : 185–91.