¹Psoriasis and Phototherapy Clinic, Vancouver General Hospital, Vancouver, BC, Canada
²Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
³Department of Dermatology, Kerman University of Medical Sciences, Kerman, Iran

ABSTRACT

High intensity long-wavelength ultraviolet A (340-400 nm; UVA1) lamps were initially developed as skin research tools; over time they have proven to be useful for treating a number of chronic dermatoses. UVA1 units and dosimetry are strikingly different from conventional UV phototherapy. The therapeutic effect of UVA1 is related to the fact that its long wavelength penetrates the dermis more deeply than UVB. UVA1 radiation induces collagenase (matrix metalloproteinase-1) expression, T-cell apoptosis, and depletes Langerhans and mast cells in the dermis. UVA1 exposure stimulates endothelial cells to undergo neovascularization. Ultraviolet A1 exerts significant therapeutic effects in atopic dermatitis and morphea; there is also evidence for its use in other skin diseases, including cutaneous T-cell lymphoma and mastocytosis.

Key Words:
phototherapy, skin diseases, ultraviolet A1, UVA1

Introduction

The roots of ultraviolet A1 (UVA1) phototherapy can be traced to the development of a relatively “pure”, high-intensity UVA light source that was originally meant to be used for studying the physiologic cutaneous effects of UVA alone. UVA photons are approximately 1000 times less potent than UVB photons in eliciting photobiological responses, and thus, the technological challenge was to develop an artificial lamp that could deliver a biologically relevant UVA dose within a practical time frame and a sufficiently large irradiation field.¹ Using a specially filtered metal halide lamp, the spectral output was weighted towards longer, more penetrating UVA wavelengths (340-400 nm), and was distinctly different from that of fluorescent UVA tubes used for psoralen + UVA (PUVA) therapy. Over time UVA1 came to be used diagnostically for photoprovocation of conditions such as polymorphous light eruption and then as a novel treatment modality for certain inflammatory dermatoses.

UVA1 induces T-cell apoptosis, which is one of its proposed mechanisms for improving atopic dermatitis (AD), mycosis fungoides (MF), and localized scleroderma.² Consistent efficacious results with UVA1 have been observed with a variety of inflammatory, sclerosing, and neoplastic skin diseases that are characterized by dermal infiltrates rich in T lymphocytes.³ UVA1 is one of the most recent advances in phototherapy for localized scleroderma and systemic sclerosis, and has been used more extensively in Europe than North America or Asia.

UVA1 Phototherapy in Practice

UVA1 treatment units typically consist of metal halide lamps equipped with a series of special optical filters. Smaller units provide localized therapy, whereas whole-body treatment is best carried out using lie-down or standing UVA1 cabinets. Standing cabinets are more practical for whole-body treatment since liedown units can only expose one side of the body (i.e., anterior or posterior) at a time. Fluorescent tubes emitting predominantly in the UVA1 range have also been used for long wave UVA therapy, but these are not as powerful and efficient as filtered metal halide lamps. In North America UVA1 availability is limited, perhaps due to the relatively high equipment costs; UVA1 units are usually two to three times more expensive than conventional whole body UV treatment units.

UVA1 dosimetry has been categorized into low (≤40 J/cm²), medium (40-80 J/cm²), and high (80-130 J/cm²) dose regimens,⁴ and depending on the desired fluence and the irradiance of the UVA1 phototherapy unit, treatment times can range between 10 minutes and 1 hour per treatment session. Like other forms of UV phototherapy UVA1 requires a series of repeated exposures. However, with UVA1 the treatment fluence is usually held constant for a given course of therapy in contrast to UVB and PUVA, where the dosing is increased incrementally with each successive exposure. Prior to initiating treatment it may be appropriate to phototest the patient’s normal skin to screen for unusual UVA1 reactivity (e.g., occult polymorphous light eruption or UVA photosensitivity). The number of treatment sessions recommended for atopic dermatitis is usually 15 and for morphea or systemic scleroderma 20-40 treatments are given. Patients are treated daily with a break on the weekends. Continued improvement is often observed for up to several months after a treatment course; therefore, therapy is usually limited to 1-2 courses per year. In addition, since there is no data on the remission potential of UVA1, maintenance phototherapy is not routinely recommended. As the long-term side-effects of UVA1 are not well established, patients younger than 18 years should be treated judiciously.

Biologic and Mechanistic Effects of UVA1

UVA1 induces immediate tanning through oxidation of preexisting melanin and also causes delayed pigment darkening by an increase in melanin content.

Studies have shown that the mechanism of apoptosis with UVA1 differs from UVB and PUVA.⁵ UVA1 induces early apoptosis or preprogrammed cell death through two apoptotic pathways in lymphocytes and immature proliferating mast cells.⁶ The first pathway involves the production of superoxide anions and the second apoptotic pathway produces singlet oxygen species, which depolarize mitochondrial membranes.⁵ Apoptosis of T-cells underlies UVA1’s therapeutic effects in atopic dermatitis, mycosis fungoides (MF), and inflammatory scleroderma. Studies have been shown that UVA1 suppresses TNF-α, IL-12, IFN-γ, and ICAM-1.^7-10 IL-6 and IL-8, cytokines with pivotal importance in sclerotic skin diseases, are down regulated by UVA1 in localized scleroderma lesions.¹¹

Irradiation with UVA1 increases collagenase synthesis, as demonstrated by increased levels of collagenase mRNA and protein in cultured fibroblasts from morphea patients.¹² Recently, it has been revealed that UVA1 radiation suppresses calcineurin activity, both in vivo and in vitro. This loss in activity is due to singlet oxygen and superoxide generated by photosensitization. These findings provide a mechanistic basis for the hypothesis that UVA1 and calcineurin inhibitors both affect the same signal transduction pathway in the skin.¹³

Indications

Although the use of UVA1 has been reported in a range of conditions, the main indications of UVA1 phototherapy are atopic dermatitis, cutaneous T-cell lymphoma, sclerosing skin diseases, and mastocytosis (Table 1).

Atopic Dermatitis

In 1992 Krutmann et al showed that UVA1 improved patients with atopic dermatitis, thus becoming the first skin disease to be effectively treated by UVA1.² The main mechanisms by which UVA1 phototherapy induces remission in atopic dermatitis involves a range of immunomodulating effects that include apoptosis of infiltrating T-cells, suppression of cytokine levels, and reduction in Langerhans cell numbers.

UVA1 has been proved to be superior to combined UVA/ UVB therapy in several studies.¹⁴ Narrowband (NB) UVB and medium-dose UVA1 are equally effective in the treatment of patients with moderate to severe AD.¹⁵ Tzaneva et al showed that high-dose and medium-dose UVA1 therapies have comparable efficacy in severe atopic dermatitis. Both high- and medium-dose regimens achieved comparable results as demonstrated by similar reductions in clinical scores.¹⁶ Low-dose UVA1 phototherapy did not reduce severity of atopic dermatitis.¹⁷ Several controlled studies indicate that UVA1 is effective in acute, severe AD and superior to broadband UV regimens, and that a course of medium-dose UVA1 may be a safer modality than low-dose UVA1. Due to practical considerations (i.e., availability, exposure times, and clinical experience) conventional UV therapy remains the first treatment of choice for phototherapy in atopic dermatitis, with UVA1 being reserved for acute severe exacerbations.

Sclerotic Skin Diseases

Phototherapy is an effective therapeutic option in scleroderma and should be considered among the first approaches in the management of localized scleroderma or morphea. Collagen metabolism disturbance, autoimmune activity, and vascular dysregulation are the main pathways that lead to the development of scleroderma.¹⁸ UVA1 photons are the most deeply penetrating form of UV therapy and they appear to exhibit their effects in all three of the above pathways by induction of collagenase messenger RNA expression, depletion of skin T-cells and cytokines (IL-1, IL-6), and neovascularization.^19-21

High-dose UVA1 treatment for scleroderma was first conducted by Stege et al in 1997, who revealed that high-dose UVA1 phototherapy reduced sclerotic plaque thickness while increasing their elasticity.²² Andres et al in 2010 also showed that UVA1 phototherapy had a significant effect on collagen metabolism by reducing sclerotic plaque and lesional skin thickness, and improving skin elasticity.²³

Kreuter et al in a comparative study demonstrated that mediumdose UVA1 was superior to both low-dose UVA1 therapy and NBUVB therapy with no significant difference between low-dose UVA1 and NB-UVB.²¹ UVA1 phototherapy has also been used for patients with limited and diffuse systemic sclerosis. Morita et al treated sclerotic skin on the forearms of four patients with systemic sclerosis. Sclerotic skin lesions were softened after 10-30 exposures of medium-dose (60 J/cm²) UVA1 therapy, resulting in increased passive joint mobility and cutaneous elasticity in patients with sclerosis.²⁴ A case report documented UVA1’s effectiveness in softening sclerotic perioral skin and improving symptoms related to microstomia in systemic sclerosis.²⁵

Cutaneous T-cell Lymphoma (Mycosis Fungoides)

UVA1 phototherapy was used by Plettenber et al in three patients with stage IA and IB mycosis fungoides (MF). Complete clearance was achieved after 16 to 20 exposures, with a high- or mediumdose regimen.26 In another study, 13 patients with widespread plaque-type, nodular and erythrodermic MF were given 100 J/cm² UVA1 phototherapy 5 times/week. Eleven patients showed complete response and partial improvement was observed in two patients. Circulating CD4⁺/CD45RO⁺ and CD4⁺/CD95⁺ lymphocytes were significantly reduced with therapy.²⁷ Suh et al treated 15 MF patients with UVA1, with 13 and 2 patients showing complete and partial remissions, respectively. This study reported that UVA1 therapy induced excellent therapeutic efficacy in patients with MF, delivering a quick response, and is safe in early and advanced stages of MF.²⁸

Mastocytosis

UVA1 phototherapy reduces the density of dermal mast cells and has been reported to be effective for patients with urticaria pigmentosa. Four adult patients with generalized urticaria pigmentosa were treated with 130 J/cm² UVA1 for 2 weeks. Pruritus improved after three treatment sessions, and two patients with diarrhea and migraine experienced relief of these symptoms as well. None of these patients had relapsed after at least 10 months follow-up, although the authors did not specifically report on the response of the skin lesions to UVA1.²⁹ Gobello et al treated patients suffering from cutaneous mastocytosis with high- and medium-dose UVA1. In the majority of patients, the number of visible skin lesions was not significantly reduced; however, the number of mast cells in lesional skin decreased markedly in most patients. Pruritus and quality of life improved by the end of treatment and during the 6-month follow-up. No significant differences were observed between patients receiving high- or medium-dose UVA1.³⁰

Other Skin Conditions

Other diseases treated with UVA1 with varying degrees of response include lichen sclerosus et atrophicus, dyshydrotic hand eczema, scleredema, necrobiosis lipoidica, granuloma annulare, pityriasis lichenoides chronica, systemic lupus erythematosus, sarcoidosis, granulomatous slack skin, and graft-versus-host disease. There are no controlled clinical trials investigating the efficacy of UVA1 on psoriasis. Because of its cost, longer exposure time, and limited availability, UVA1 is not used for psoriasis.

Side-effects of UVA1

Side-effects of UVA1 are usually fewer than with other types of phototherapy and most studies have reported no serious adverse effects. Most notably, the frequency of UV-induced burning seems to be lower for UVA1 than for conventional UVB or PUVA. In our experience, the minimal erythema dose for UVA1 is typically greater than 130 J/cm². Side-effects with UVA1 phototherapy have been classified as acute or chronic. The most common acute sideeffects are hyperpigmentation, redness, dryness, and pruritus. Hyperpigmentation or tanning are virtually universal side-effects and can be striking, particularly within the active affected skin sites. Other observed side-effects include herpes simplex virus reactivation and polymorphic light eruption induction.³¹ Chronic side-effects in patients who receive UVA1 phototherapy include photoaging and possible photocarcinogenesis. Reports of skin cancer in patients treated with UVA1 are usually confounded with the use of other therapies known to also increase the risk of cutaneous malignancies. For instance, a case of melanoma was reported in a patient with mastocytosis after receiving UVA1 treatment, however, this individual had also received PUVA bath therapy in the past.³² As well, there are two cases of Merkel cell carcinoma after UVA1 phototherapy, but both patients had blood dyscrasias and were treated with immunosuppressants.³³

Contraindications to UVA1 therapy include photosensitivity disorders such as xeroderma pigmentosum and porphyria disorders. Relative contraindications also include a history of melanoma or nonmelanoma skin cancers, immunosuppressed individuals following organ transplant, and patients who have received prior radiation treatment, which potentially predisposes them to skin tumor development.⁴

Conclusion

UVA1 is a relatively new, unique, and possibly underutilized therapeutic modality available in photodermatology that has shown relatively good evidence for treating atopic dermatitis and sclerotic skin diseases. Overall, the side-effects from therapy are well tolerated by patients, with the long-term adverse effects and relative utility for other dermatoses still remaining to be better elucidated.

References

1. Mutzhas MF, Holzle E, Hofmann C, et al. A new apparatus with high radiation energy between 320-460 nm: physical description and dermatological applications. J Invest Dermatol 1981 Jan;76(1):42-7.
2. Krutmann J, Czech W, Diepgen T, et al. High-dose UVA1 therapy in the treatment of patients with atopic dermatitis. J Am Acad Dermatol 1992 Feb;26(2 Pt 1):225-30.
3. Dawe RS. Ultraviolet A1 phototherapy. Br J Dermatol 2003 Apr;148(4):626-37.
4. York NR, Jacobe HT. UVA1 phototherapy: a review of mechanism and therapeutic application. Int J Dermatol 2010 Jun;49(6):623-30.
5. Guhl S, Hartmann K, Tapkenhinrichs S, et al. Ultraviolet irradiation induces apoptosis in human immature, but not in skin mast cells. J Invest Dermatol 2003 Oct;121(4):837-44.
6. Godar DE. UVA1 radiation triggers two different final apoptotic pathways. J Invest Dermatol 1999 Jan;112(1):3-12.
7. Godar DE. UVA1 radiation triggers two different final apoptotic pathways. J Invest Dermatol 1999 Jan;112(1):3-12.
8. Gambichler T, Skrygan M, Tomi NS, et al. Significant downregulation of transforming growth factor-beta signal transducers in human skin following ultraviolet-A1 irradiation. Br J Dermatol 2007 May;156(5):951-6.
9. Skov L, Hansen H, Allen M, et al. Contrasting effects of ultraviolet A1 and ultraviolet B exposure on the induction of tumour necrosis factor-alpha in human skin. Br J Dermatol 1998 Feb;138(2):216-20.
10. Krutmann J, Grewe M. Involvement of cytokines, DNA damage, and reactive oxygen intermediates in ultraviolet radiation-induced modulation of intercellular adhesion molecule-1 expression. J Invest Dermatol 1995 Jul;105(1 Suppl):67S-70S.
11. Szegedi A, Simics E, Aleksza M, et al. Ultraviolet-A1 phototherapy modulates Th1/Th2 and Tc1/Tc2 balance in patients with systemic lupus erythematosus. Rheumatology (Oxford) 2005 Jul;44(7):925-31.
12. Kreuter A, Hyun J, Skrygan M, et al. Ultraviolet A1-induced downregulation of human beta-defensins and interleukin-6 and interleukin-8 correlates with clinical improvement in localized scleroderma. Br J Dermatol 2006 Sep;155(3):600-7.
13. Gruss C, Reed JA, Altmeyer P, et al. Induction of interstitial collagenase (MMP-1) by UVA-1 phototherapy in morphea fibroblasts. Lancet 1997 Nov 1;350(9087):1295-6.
14. Musson RE, Hensbergen PJ, Westphal AH, et al. UVA1 radiation inhibits calcineurin through oxidative damage mediated by photosensitization. Free Radic Biol Med 2011 May 15;50(10):1392-9.
15. de Kort WJ, van Weelden H. Bath psoralen-ultraviolet A therapy in atopic eczema. J Eur Acad Dermatol Venereol 2000 May;14(3):172-4.
16. Majoie IM, Oldhoff JM, van Weelden H, et al. Narrowband ultraviolet B and medium-dose ultraviolet A1 are equally effective in the treatment of moderate to severe atopic dermatitis. J Am Acad Dermatol 2009 Jan;60(1):77-84.
17. Tzaneva S, Seeber A, Schwaiger M, et al. High-dose versus medium-dose UVA1 phototherapy for patients with severe generalized atopic dermatitis. J Am Acad Dermatol 2001 Oct;45(4):503-7.
18. Kowalzick L, Kleinheinz A, Weichenthal M, et al. Low dose versus medium dose UV-A1 treatment in severe atopic eczema. Acta Derm Venereol 1995 Jan;75(1):43-5.
19. Breuckmann F, Stuecker M, Altmeyer P, et al. Modulation of endothelial dysfunction and apoptosis: UVA1-mediated skin improvement in systemic sclerosis. Arch Dermatol Res 2004 Oct;296(5):235-9.
20. Camacho NR, Sanchez JE, Martin RF, et al. Medium-dose UVA1 phototherapy in localized scleroderma and its effect in CD34-positive dendritic cells. J Am Acad Dermatol 2001 Nov;45(5):697-9.
21. Kerscher M, Volkenandt M, Gruss C, et al. Low-dose UVA phototherapy for treatment of localized scleroderma. J Am Acad Dermatol 1998 Jan;38(1):21-6.
22. Kreuter A, Hyun J, Stucker M, et al. A randomized controlled study of low-dose UVA1, medium-dose UVA1, and narrowband UVB phototherapy in the treatment of localized scleroderma. J Am Acad Dermatol 2006 Mar;54(3):440-7.
23. Stege H, Berneburg M, Humke S, et al. High-dose UVA1 radiation therapy for localized scleroderma. J Am Acad Dermatol 1997 Jun;36(6 Pt 1):938-44.
24. Andres C, Kollmar A, Mempel M, et al. Successful ultraviolet A1 phototherapy in the treatment of localized scleroderma: a retrospective and prospective study. Br J Dermatol 2010 Feb 1;162(2):445-7.
25. Morita A, Kobayashi K, Isomura I, et al. Ultraviolet A1 (340-400 nm) phototherapy for scleroderma in systemic sclerosis. J Am Acad Dermatol 2000 Oct;43(4):670-4.
26. Tewari A, Garibaldinos T, Lai-Cheong J, et al. Successful treatment of microstomia with UVA1 phototherapy in systemic sclerosis. Photodermatol Photoimmunol Photomed 2011 Apr;27(2):113-4.
27. Plettenberg H, Stege H, Megahed M, et al. Ultraviolet A1 (340-400 nm) phototherapy for cutaneous T-cell lymphoma. J Am Acad Dermatol 1999 Jul;41(1):47-50.
28. Zane C, Leali C, Airo P, et al. “High-dose” UVA1 therapy of widespread plaquetype, nodular, and erythrodermic mycosis fungoides. J Am Acad Dermatol 2001 Apr;44(4):629-33.
29. Suh KS, Kang JS, Baek JW, et al. Efficacy of ultraviolet A1 phototherapy in recalcitrant skin diseases. Ann Dermatol 2010 Feb;22(1):1-8.
30. Stege H, Schopf E, Ruzicka T, et al. High-dose UVA1 for urticaria pigmentosa. Lancet 1996 Jan 6;347(8993):64.
31. Gobello T, Mazzanti C, Sordi D, et al. Medium- versus high-dose ultraviolet A1 therapy for urticaria pigmentosa: a pilot study. J Am Acad Dermatol 2003 Oct;49(4):679-84.
32. McGrath H, Jr. Ultraviolet A1 (340-400 nm) irradiation and systemic lupus erythematosus. J Investig Dermatol Symp Proc 1999 Sep;4(1):79-84.
33. Wallenfang K, Stadler R. [Association between UVA1 and PUVA bath therapy and development of malignant melanoma]. Hautarzt 2001 Aug;52(8):705-7.
34. Calzavara-Pinton P, Monari P, Manganoni AM, et al. Merkel cell carcinoma arising in immunosuppressed patients treated with high-dose ultraviolet A1 (320-400 nm) phototherapy: a report of two cases. Photodermatol Photoimmunol Photomed 2010 Oct;26(5):263-5.

Key Words:
actinic keratosis; basal cell carcinoma; Bowen’s disease; methyl aminolevulinate; PDT; photodynamic therapy

Topical Methyl Aminolevulinate (MAL)-PDT

Photodynamic therapy (PDT) treats superficial skin cancers and pre-cancerous lesions through photosensitized reactions requiring oxygen. Over the past several decades, PDT has been extensively investigated as an experimental therapy for human cancers. There is now growing interest in the use of PDT not only for nonmelanoma skin cancer (NMSC), but also for other skin tumors such as lymphoma, as well as for nononcological indications, such as psoriasis, localized scleroderma, acne, and skin rejuvenation.^1-4 In Europe, as well as in the US, porphyrin-inducing precursors, such as 5-aminolevulinic-acid (ALA) and MAL have been proven effective for the treatment of actinic keratoses (AKs) and basal cell carcinomas.^5-7 Both ALA and MAL induce protoporphyrin IX (PpIX) locally in the skin. Photodynamic therapy combines the simultaneous presence of a photosensitizer activated by an appropriate wavelength of light. For topical PDT, upon illumination, PpIX is transformed to the excited state and then returns to its ground state through a type-II photo-oxidative reaction.5 In this reaction, these molecules transfer energy to oxygen producing highly reactive oxygen species (ROS), singlet oxygen in particular. ROS accumulates locally within the affected tissue leading to direct cellular damage by apoptosis or necrosis, and indirect stimulation of inflammatory cell mediators.⁶

Previous studies have shown that MAL in combination with red light (570-670nm) has provided good clinical outcomes in the treatment of NMSC (both sBCC and Bowen’s disease) and AKs.⁷ MAL, the methylated ester of ALA, is a new topical photosensitizer that may offer advantages over ALA in terms of its deeper skin penetration (up to 2mm in depth) due to potentially enhanced lipophilicity and greater specificity for neoplastic cells.⁸ In a typical PDT session, the lesion surface is prepared by light curettage of any surface crusts and scales. The 3 hour application of 160mg/g MAL prior to irradiation with 37J/cm2 from a light-emitting diode system (emission peak of 632nm) corresponds to the time point of the highest ratio of fluorescence depth to tumor depth2 under occlusion. Two treatments 1 week apart for AKs, sBCC, and BD have been recommended; however, a single treatment session is possible and may be potentially sufficient for very thin AKs. For partially cleared responses, a second treatment course (consisting of two weekly PDT sessions) at 3 months may be considered.⁹ This article reviews key published trials of topical MAL-PDT for AK, sBCC, and BD.

AKs

A US randomized, multicenter, double-blind, placebo controlled study was performed in 80 patients with mild-to-moderate AKs on the face and scalp. Forty-two patients (260 lesions) were treated with MAL-PDT and 38 patients (242 lesions) received the placebo cream. MAL was applied for 3 hours followed by illumination with noncoherent red light (75J/cm2). Treatment was repeated after 1 week. A complete response rate of 89% with MAL-PDT and 38% with placebo was assessed after 3 months follow-up. An excellent or good cosmetic outcome was reported in more than 90% of patients treated with MAL.¹⁰

Tarstedt et al.11 reported response rates in an open label, prospective study that compared 2 regimens:

1. A single treatment session
2. 2 MAL-PDT sessions 1 week apart.

One hundred six patients received the single treatment and 105 patients received the second regimen. For thin lesions, clearance rates showed no significant difference (93% with single session vs. 89% with double sessions) For thicker lesions, clearance rates were higher for double sessions (84%) when compared with single treatment (70%). The authors concluded that single treatment is effective for thin AKs. Repeated treatments were needed for thicker or resistant lesions.

In another randomized, multicenter study, MAL-PDT (n=360 lesions) was compared with a single-thaw cycle of cryotherapy (n=421 lesions) or placebo (n=74 lesions). The PDT treatment arm consisted of 2 treatment sessions 1 week apart using 75J/cm2 with a noncoherent red light (570-670nm). After 3 months, clearance rates for MAL-PDT were significantly higher (91%) compared with cryosurgery (68%) and placebo (30%). Of the MAL-PDT treated patients, 83% were rated as having an excellent cosmetic outcome by an investigator vs. 51% of those treated with cryotherapy; the corresponding patient assessments were 76% and 56% respectively.¹²

A large randomized, intraindividual, right-left comparative study of 119 patients with face/scalp AKs was performed.14 The aim of the study was to compare 1 MAL PDT session to double freeze-thaw cryotherapy. After a 3-hour application of MAL using 37J/cm2 with double treatment 7 days apart, cure rates were seen when using MAL-PDT (87%) compared with cryotherapy (76%). Of patients treated with MAL-PDT, 10% required re-treatment after 3 months vs. 21% for cryotherapy. Cosmetic outcome significantly favored MAL-PDT (i.e., 77% vs. 50%).13 A recent study, however, showed lower efficacy with MAL-PDT (78% clearance) on the extremities compared with cryotherapy (88% clearance).¹⁴

In a recent multicenter, double-blind, randomized study by Pariser,15 the efficacy of MAL-PDT using a red light-emitting diode (n=363 lesions) was evaluated vs. placebo (n=360 lesions) for grade 1 (slightly palpable) and grade 2 (moderately thick) AKs on the face and scalp. Lesion complete response rates were significantly superior for MAL-PDT (86.2%) vs. placebo (52.5%). The patient complete response rate was 59.2% for MAL-PDT subjects, and lower for those who had vehicle PDT alone (14.9%). Scalp lesions responded better with MAL-PDT (93%) than did facial lesions (87%). Grade 1 lesions had slightly higher complete response rates than grade 2 lesions (89% vs. 80%). Furthermore, larger lesions with diameters of >20mm had poorer response rates compared with smaller lesions (74% vs. 86%).

When treating AKs, biopsies should be considered for thick, keratotic lesions to rule out squamous cell carcinoma. Calzavara-Pinton et al.¹⁶ have shown that even if squamous cell carcinoma is limited to microinvasive involvement, the treatment outcome is poor.

Superficial BCCs

The recent British Photodermatology Group guidelines for topical PDT concluded MAL-PDT to be effective for sBCC.⁹ In an attempt to compare clearance rates and cosmetic outcomes between MAL-PDT (n=60) and double freeze-thaw cryotherapy (n=58) in sBCC, a 5-year European randomized trial was performed in 118 patients. This protocol used MAL applied for 3 hours at 75J/cm2 with noncoherent red light (570-670nm) for 1 session. Partially treated patients at 3 months were given 2 further MAL-PDT sessions (n=20) or repeat cryotherapy (n=16). Complete clinical response rates after 3 months’ follow-up for MAL-PDT were 97% of 102 lesions, while that of cryotherapy was 95% of 98 lesions; the difference between these 2 treatments was not statistically significant. At 5 years’ follow-up, clearance rates were similar for the MAL-PDT group (75%) and cryotherapy (74%). Of the lesions initially cleared with MAL-PDT, 22% had recurred vs. 20% after cryotherapy. Cosmetic outcome was judged superior following PDT (87% vs. 49%).¹⁷
Double MAL-PDT treatment cycles for ‘difficult-to-treat’ sBCC (and nBCC) were reported by 2 prospective multicenter studies. This included recurrent, large-sized lesions and/or those occurring on the mid-face or ears. In the first study, 87% of patients (n=94) had ‘difficult-to-treat’ lesions occurring on the face or scalp. The protocol was a single cycle of MAL-PDT (MAL 3h, 75J/cm2, 570-670nm or 580-740nm, 50-200mW/cm2) involving 2 treatment sessions 1 week apart. For partially treated lesions after 3 months’ follow-up, a second cycle was repeated. Complete clearance at 3 months was 85% for sBCC after histological review (75% for nBCC). After 2 years, the recurrence rate was 22% for sBCC (14% for nBCC). Ninety-four percent of patients were assessed to have a good to excellent cosmetic outcome.¹⁸
In the second study, efficacy, safety, and cosmetic outcomes were examined in 95 patients with BCCs that were ‘difficult-to-treat’ and at high risk for surgical complications. A total of 148 BCCs (sBCC and nBCC) were treated with the same PDT protocol (MAL 3h, 75J/cm2, 570-670nm, 50-200mW/cm2) with re-treatment for non-complete response lesions at 3 months. Overall, histologically-confirmed lesion complete response rate was 89% (93% sBCC and 82% nBCC) after 3 months’ follow-up. Fifteen percent of lesions had histologically confirmed recurrence within 2 years increasing to 20% within 4 years. Ninety-seven percent of patients rated their cosmetic outcome as good to excellent at 3 months.¹⁹

Bowen’s Disease

A large randomized, controlled, multicenter study reported similar clearance response rates following MAL-PDT (86%), single freeze-thaw cryotherapy (82%), and 1 month application of 5-fluorouracil (83%) in 225 patients with histologically confirmed Bowen’s disease. MAL-PDT (MAL 3h, 75J/cm2, 570-670nm, 70-200mW/cm2) was given as a single cycle 1 week apart. Lesions with a partial response at 3 months were re-treated. Cosmetic outcome was superior for MAL-PDT in 94% of patients vs. 66% with cryotherapy, and 76% with fluorouracil.²⁰ Clearance rates after 2 years for MAL-PDT was 68% vs. 60% with cryotherapy and 59% with fluorouracil.⁷

Conclusion

MAL is an effective low molecular weight topical porphyrin-inducer that is typically used in combination with a red light-emitting diode for PDT. It offers therapeutic benefit for thin and moderate thickness AKs. It should be considered as a treatment option for superficial BCCs and Bowen’s disease, particularly in situations where surgery may be problematic or where patients have multiple lesions. However, long-term cure rates, as mentioned above for Bowen’s disease and sBCC, are only 68% and 75% respectively. Because of the appreciable nonresponse and recurrence rates, patients treated with PDT for either disease should be monitored closely during the first 2-3 years after PDT, which is when most lesion recurrences occur. According to studies, patients’ high preference for MAL-PDT may be mainly due to its good to excellent cosmetic outcome and general tolerability of side-effects. No direct comparative studies have yet been reported with MAL and ALA. Important parameters, such as the depth of penetration of MAL-PDT, tumor thickness, location, and careful patient selection are key elements for efficacy. In the US, MAL-PDT is currently FDA-approved for the treatment of AKs only, whereas in Canada, MAL-PDT is officially indicated for the treatment of both AKs and sBCCs.

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7. Lehmann P. Methyl aminolaevulinate-photodynamic therapy: a review of clinical trials in the treatment of actinic keratoses and nonmelanoma skin cancer. Br J Dermatol 156(5):793-801 (2007 May).
8. Peng Q, Soler AM, Warloe T, et al. Selective distribution of porphyrins in thick basal cell carcinoma after topical application of methyl 5-aminolevulinate. J Photochem Photobiol B 62(3):140-5 (2001 Sep).
9. Morton CA, McKenna KE, Rhodes LE. Guidelines for topical photodynamic therapy: update. Br J Dermatol 159(6):1245-66 (2008 Dec).
10. Pariser DM, Lowe NJ, Stewart DM, et al. Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial. J Am Acad Dermatol 48(2):227-32 (2003 Feb).
11. Tarstedt M, Rosdahl I, Berne B, et al. A randomized multicenter study to compare two treatment regimens of topical methyl aminolevulinate (Metvix)-PDT in actinic keratosis of the face and scalp. Acta Derm Venereol 85(5):424-8 (2005).
12. Freeman M, Vinciullo C, Francis D, et al. A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study. J Dermatolog Treat 14(2):99-106 (2003 Jun).
13. Morton C, Campbell S, Gupta G, et al. Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study. Br J Dermatol 155(5):1029-36 (2006 Nov).
14. Kaufmann R, Spelman L, Weightman W, et al. Multicentre intraindividual randomized trial of topical methyl aminolaevulinate photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities. Br J Dermatol 158(5):994-9 (2008 May).
15. Pariser D, Loss R, Jarratt M, et al. Topical methyl-aminolevulinate photodynamic therapy using red light-emitting diode light for treatment of multiple actinic keratoses: A randomized, double-blind, placebo-controlled study. J Am Acad Dermatol 59(4):569-76 (2008 Oct).
16. Calzavara-Pinton PG, Venturini M, Sala R, et al. Methylaminolaevulinate-based photodynamic therapy of Bowen’s disease and squamous cell carcinoma. Br J Dermatol 159(1):137-44 (2008 Jul).
17. Basset-Seguin N, Ibbotson SH, Emtestam L, et al. Topical methyl aminolaevulinate photodynamic therapy versus cryotherapy for superficial basal cell carcinoma: a 5 year randomized trial. Eur J Dermatol 18(5):547-53 (2008 Sep-Oct).
18. Horn M, Wolf P, Wulf HC, et al. Topical methyl aminolaevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional treatment. Br J Dermatol 149(6):1242-9 (2003 Dec).
19. Vinciullo C. MAL-PDT in ‘difficult-to-treat’ basal cell carcinoma, an Australian study: 48 month follow-up data. Presented at: the 3rd Meeting of the European Association of Dermato-Oncology Rome, June 23-25, 2006. J Invest Dermatol 126(Suppl 2):534 (2006).
20. Morton C, Horn M, Leman J, et al. Comparison of topical methyl aminolevulinate photodynamic therapy with cryotherapy or fluorouracil for treatment of squamous cell carcinoma in situ: results of a multicenter randomized trial. Arch Dermatol 142(6):729-35 (2006 Jun).

Hair Research and Treatment Centre, and Division of Dermatology, University of British Columbia, Vancouver, British Columbia, Canada

ABSTRACT

Twenty-two percent of women in North America have unwanted facial hair, which can cause embarrassment and result in a significant emotional burden. Treatment options include plucking, waxing (including the sugar forms), depilatories, bleaching, shaving, electrolysis, laser, intense pulsed light (IPL), and eflornithine 13.9% cream (Vaniqa®, Barrier Therapeutics in Canada and Shire Pharmaceuticals elsewhere). Eflornithine 13.9% cream is a topical treatment that does not remove the hairs, but acts to reduce the rate of growth and appears to be effective for unwanted facial hair on the mustache and chin area. Eflornithine 13.9% cream can be used in combination with other treatments such as lasers and IPL to give the patient the best chance for successful hair removal.

Key Words:
eflornithine, unwanted facial hair, hair removal

Unwanted facial hair (UFH) in women is a common problem, and is most often a result of ethnic background or heredity. In a small percentage of women, it may be caused by androgen overproduction, increased sensitivity to circulating androgens, or other metabolic and endocrine disorders. Approximately 22% of women are affected by the presence of UFH growth on the mustache and chin area, and this can be a source of distress, leading to anxiety, depression and a reduced quality of life.¹

It is very important to determine the underlying causes. Most are ethnic or hereditary; however, one must rule out any signs of androgen excess, e.g., an increase in body hair, irregular menstrual cycles, acne, alopecia, and seborrhea.

Polycystic Ovary Syndrome (PCOS) is the most common cause of androgen excess, and 70%-80% of patients with androgen excess demonstrate hirsutism, though this sign may be less prevalent among women of Asian extraction. There is a strong familial predilection for hirsutism, primarily because the underlying endocrine disorders in this population and the factors regulating the development of hair growth have a strong genetic component.²

Patients should be adequately advised of the available treatment modalities for hair removal. No single method of hair removal is appropriate for all body locations or patients, and the one adopted will depend on the character, area and amount of hair growth, as well as on the patient’s age and their personal preference.³

Treatment options for removing excess facial hair are limited and can vary in effectiveness, the degree of discomfort, and cost. Current methods for removing this unwanted hair include such over-the-counter methods as plucking, waxing (including the sugar forms), depilatories, shaving, and home electrolysis. Hair removal methods that could take place in a doctor’s office include laser, and intense pulsed light (IPL). An additional modality is a topical cream that inhibits hair growth: eflornithine 13.9% cream (Vaniqa®, Barrier Therapeutics in Canada and Shire Pharmaceuticals elsewhere).¹

These methods are temporary with the time of regrowth ranging from a few days to a few months. For hirsutism associated with PCOS, treatments include oral contraceptives and/or antiandrogens, such as spironolactone, cyproterone acetate, flutamide and finasteride.⁴

Eflornithine HCl 13.9% Cream

Eflornithine HCl 13.9% cream is an irreversible inhibitor of ornithine decarboxylase, an enzyme that has been associated with the prolongation of the anagen or growth phase of the hair.⁶ Consequently, it reduces the rate of hair growth for all hairs. It appears to be effective regardless of whether the unwanted facial hair is hereditary or is due to medical conditions such as an androgen excess disorder, e.g., PCOS. After 24 weeks of treatment in clinical trials, it was shown to be effective on the chin and upper lip.⁷

Eflornithine, also known as difluoromethylornithine or DFMO, was synthesized in the 1970s as a potential anticancer drug. In 1980, Bacchi, et al. reported that this drug was effective in the treatment of African trypanosomiasis in a mouse model,⁸ and this finding later led to clinical studies in humans. In 1990, the US FDA granted marketing approval and orphan drug status for eflornithine to treat this disease. Clinical observations identified hair loss as a side-effect of eflornithine therapy and led to the development of Vaniqa®, which gained US regulatory approval in July 2001, as the first and only prescription cream clinically proven to slow the growth of unwanted facial hair in women.⁹

Pharmacokinetics

In an open-label, multiple-dose study of 10 women with excessive facial hair, Malhotra, et al. determined percutaneous absorption and the pharmacokinetics of eflornithine following topical treatment with eflornithine HCl 13.9% cream. The mean percutaneous absorption was minimal and most of what was absorbed was excreted unchanged in the urine without being metabolized by the body. The steady-state peak serum concentration was < 10.44ng/ml. Trough plasma concentrations reached steady state (4.61-5.5ng/ml) after 4 days of twice-daily topical treatment. Multiple dosing had no apparent effect on disposition kinetics.¹⁰

Combination Therapy

It is a common misconception that eflornithine 13.9% cream competes with other methods of hair removal and therefore should not be used in combination with them, particularly laser and IPL treatments. However, that is not the case. Eflornithine 13.9% cream can slow hair growth and may reduce the frequency of the need for hair removal by other means.^11,12 It is also useful in treating hair that is unresponsive to laser therapy, such as white or vellus hairs.

Studies have shown that the two processes can be started simultaneously, and eflornithine treatment can continue right through laser treatments.¹
According to Azziz,² treatment should be undertaken using combination therapy, to possibly include:

1. hormonal suppression, e.g., oral contraceptives, long-acting gonadotropin-releasing hormonal analogues and insulin sensitizers
2. peripheral androgen blockade, e.g., spironolactone, cyproterone acetate, flutamide, or finasteride
3. mechanical/cosmetic amelioration and destruction of the unwanted hairs, e.g., electrolysis, lasers, IPL, depilatories, shaving, waxing
4. application of eflornithine 13.9% topical cream.

Adverse Events for Eflornithine

Skin-related side-effects such as stinging, burning and tingling are seen occasionally, particularly when eflornithine is applied to broken or abraded skin.13 Eflornithine offers a low degree of percutaneous absorption and low systemic exposure to eflornithine, offering a favorable clinical safety profile with minimal side-effects.^11,14 This drug is classified as a pregnancy category C agent, so risk to the fetus cannot be ruled out.

Patient Communication

The results of therapy may not always be satisfactory, so it is very important to advise the patient of the available treatment modalities for temporary or permanent hair reduction. No single method is appropriate for all body locations or patients. The one adopted will depend on the character, area and amount of hair growth as well as on the patient’s age and personal preferences.

Conclusion

Unwanted facial hair can cause embarrassment and lead to anxiety and depression. There are a limited number of treatments available that vary in efficacy, degree of discomfort, and cost. Eflornithine 13.9% cream, by itself or in combination with other treatments, has been shown to be effective for the treatment of UFH. Future experience will dictate the most effective niche for Vaniqa® within this family of treatments.

An adaptation of this article was recently published in Skin Therapy Letter – Family Practice Edition 1(2):6-7.

References

1. Dawber RP. Guidance for the management of hirsutism. Curr Med Res Opin 21(8):1227-34 (2005 Aug).
2. Azziz R. The evaluation and management of hirsutism. Obstet Gynecol 101 (5 Pat 1):995-1007 (2003 May).
3. Trueb RM. Causes and management of hypertrichosis. Am J Clin Dermatol 3(9):617-27 (2002).
4. Archer JS, Chang RJ. Hirsutism and acne in polysystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 18(5):737-54 (2004 Oct).
5. Alajlan A, Shapiro J, Rivers JK, MacDonald N, Wiggin J, Lui H. Paradoxical hypertrichosis after laser epilation. J Am Acad Dermatol 53(1):85-8 (2005 Jul).
6. Hynd PI, Nancarrow MJ. Inhibition of polyamine synthesis alters hair follicle function and fiber composition. J Invest Dermatol 106(2):249-53 (1996 Feb).
7. Hickman JG, Huber F, Palmisano M. Human dermal safety studies with eflornithine HCL 13.9% cream (Vaniqa), a novel treatment for excessive facial hair. Curr Med Res Opin 16(4):235-44 (2001).
8. Coyne PE. The eflornithine story. J Amer Acad Dermatol 45(5):784-6 (2001 Nov).
9. Pepin J, Milord F, Guern C, Schechter PH, Difluoromethylornithine for arseno-resistant Trypanosome brucei gambiense sleeping sickness. Lancet 2:1431-3 (1987).
10. Malhotra B, Noveck R. Behr D, Palmisano M. Percutaneous absorption, and pharmacokinetics of eflornithine HCl 13.9% cream in women with unwanted facial hair. J Clin Pharmacol 41(9):972-8 (2001 Sep).
11. Tan E, Hamzavi I, Shapiro J, Lui H. Combined treatment with laser and topical eflornithine is more effective than laser treatment alone for removing unwanted facial hair – a placebo controlled trial. Presented at: The 4th Intercontinental Meeting of Hair Research Societies; June 17-19, 2004; Berlin, Germany. Abstract #P10.144.
12. Smith SR, Piacquadio D, Beger B. A randomized, double-blind, vehicle controlled, bilateral comparison study of the efficacy and safety of eflornithine HCl 13.9% cream in combination with laser in the treatment of unwanted facial hair in women. Presented at: The 61st Annual Meeting of the American Academy of Dermatology; March 21-26, 2003; San Francisco, CA. Abstract #P649.
13. Shapiro J, Lui H. Vaniqa – Eflornithine 13.9% Cream. Skin Therapy Lett 6(7):1-2,5 (2001 Apr).
14. Shenenberger DW, Utecht LM. Removal of unwanted facial hair. Am Fam Physician 66(10):1907-11 (2002 Nov).

Hair Research and Treatment Centre, and Division of Dermatology, University of British Columbia, Vancouver, British Columbia, Canada

Hirsutism

Excessive facial hair in women, or hirsutism, is a common problem that may be caused by androgen overproduction, increased sensitivity to circulating androgens, or other metabolic and endocrine disorders. Approximately 80% of women are affected by the presence of
excessive hair growth in areas usually recognized as places where male secondary sexual characteristics occur. This can be a source of distress, leading to anxiety, depression and a reduced quality of life.

Differential Diagnosis

It is very important to determine the etiology of this condition. Diagnostic evaluation of the potentially hirsute patient first involves confirmation of the presence of hirsutism and then exclusion of associated or etiological abnormalities and disorders. Investigate or rule
out underlying conditions that produce excess androgens using tests such as:

• Serum testosterone
• Serum DHEA (Dehydroepiandrosterone)
• Rule out testosterone secreting tumors.

Hair Removal Techniques

Treatment Options

Current methods for removing unwanted hair include plucking, waxing (including the sugar forms), depilatories, shaving, electrolysis, laser, intense pulsed light (IPL), and eflornithine 13.9% cream. All these methods are temporary with the time of regrowth ranging from a few days to a few months. Short of surgical removal of the hair follicle, the only permanent treatment is electrolysis. However, the practice of electrolysis lacks standardization. For hirsutism associated with Polycystic Ovary Syndrome (PCOS), treatments include oral contraceptive pills or antiandrogens, such as spironolactone, flutamide and finasteride.

Patients should be adequately advised of the available treatment modalities for hair removal. No single method of hair removal is appropriate for all body locations or patients, and the one adopted will depend on the character, area and amount of hair growth as well as on the age of the patient and their personal preference.

Women and Hirsutism

Women who have hirsutism will need to be evaluated to rule out causes of elevated androgens. PCOS needs to be excluded if there are suspicious clinical features. Medications such as spironolactone and oral contraceptives, e.g., cyproterone acetate + ethinyl estradiol, can be of value.

Ornithine Decarboxylase (ODC)

ODC is an enzyme that has been associated with the prolongation of the anagen or growth phase of the hair. Thus, when ODC is decreased, the length of time the hair is in the growth phase is also reduced.

Eflornithine HCl 13.9%, rather than removing the hair, is an irreversible inhibitor of ODC, thus it reduces the rate of hair growth. It appears to be effective regardless of whether the unwanted facial hair is hereditary or whether it is due to medical conditions such as an androgen excess disorder, e.g., PCOS.

Combination Therapy

Eflornithine 13.9% cream can slow hair growth and thus reduce the frequency of the need for hair removal by other means, such as lasers and IPL treatments. Studies have shown that the two processes can be started simultaneously, and eflornithine treatment can continue right through laser treatments. [Dawber RP. Curr Med Res Opin 21(8):1227-34 (2005 Aug).] Treatment should be undertaken using combination therapy to possibly include:

1. hormonal suppression, e.g., oral contraceptives, long-acting gonadotropin-releasing hormonal analogues and insulin sensitizers
2. peripheral androgen blockade, e.g., spironolactone, flutamide, cyproterone acetate or finasteride
3. mechanical/cosmetic amelioration and destruction of the unwanted hairs, e.g., electrolysis, lasers, IPL, depilatories, shaving, waxing, etc.
4. application of eflornithine 13.9% topical cream.[Azziz R. Obstet Gynecol 101 (5 Pat 1):995-1007 (2003 May).]

Paradoxical hypertrichosis has, however, been reported in a small number of patients receiving laser or IPL treatment for excess hair
removal. [Alajlan A, et al. J Am Acad Dermatol 53(1):85-8 (2005 Jul).]

Conclusion

Hirsutism can cause embarrassment and lead to anxiety and depression. There are a limited number of treatments available that vary in efficacy, degree of discomfort and cost. It is very important to make sure that the patient is aware of all the available treatment modalities, since no one method is effective for all patients or body locations, and results from therapy may not always be satisfactory.

This article has been adapted from an article by Drs. Shapiro and Lui to be published in the November 2005 issue of Skin Therapy Letter®.

ABSTRACT

This new compound product containing 50µg/gm calcipotriol and 0.5mg/gm betamethasone dipropionate was recently introduced in Canada for the treatment of psoriasis. Clinical trials demonstrated that this compound was more active than either agent used alone. Recent changes in the product monograph involving the reduction in dose to once daily use has raised questions about the relevance of some previous comparisons of twice daily Dovobet*. Pooling the available data from 5,500 patients in clinical trials for Dovobet* will allow an inter-trial comparison of the various treatment arms, demonstrating that Dovobet*, when applied once daily is significantly more effective than with twice daily applications of either its individual components used alone.

Key Words: psoriasis, calcipotriol,betamethasone dipropionate

Calcipotriol and corticosteroids are both established treatments for psoriasis.¹ Recently, studies have reported that combination therapy applied twice daily with 50µg/gm calcipotriol and 0.5mg/gm betamethasone dipropionate (Dovobet*, LEO Pharma) is significantly more effective than either monotherapy with each component or the vehicle.^2-4 In Europe, this product is marketed as Daivobet®.

Once-Daily Dovobet*

In an international, multicenter, prospective, randomized, double-blind, vehicle-controlled, parallel group, 4 week study, Guenther, et al, demonstrated that there was no statistically significant difference in the mean percentage change in the Psoriasis Area and Severity Index (PASI) from baseline to end of treatment between once daily vs. twice daily use of this compound (-5.4%, p=0.052).⁵ There are a number of advantages for reducing the applications to once-daily from twice daily, including reduced cost to the patient, and improved patient compliance. However, the most important is the need to reduce long-term exposure to steroids for psoriasis patients. The irreversible side-effects and tachyphylaxis that are associated with topical steroids should be avoided whenever other proven and safer alternatives exist, since psoriatic patients often self medicate for long periods of time without physician supervision and monitoring.

A recent change in the product monograph involving the reduction in dose to once daily use, raises questions about the relevance of some previous studies that compared twice daily Dovobet* to twice daily use of calcipotriol (Dovonex®, LEO Pharma) or betamethasone dipropionate (Diprosone®, LEO Pharma).⁶ These trials all explored the use of Dovobet* for treating large numbers of adult patients with psoriasis. All studies involved the maximal use of 100gm of ointment per week for 4 weeks, had virtually identical inclusion/exclusion criteria, and assessed patients on the basis of the percentage reduction in their Psoriasis Area and Severity Index (PASI) scores. In most cases, a similar group of investigators and site staff was used in the various trials. Together, these factors suggest that a pooling of data to allow the inter-trial comparison of various treatment arms will yield reliable results (see Tables 1 and 2 for meta-analyses of the data).

Table 1: Pooled results used to compare once daily Dovobet* with twice daily monotherapies.⁶

The mean difference between treatment groups is provided in Table 2, along with their 95% Confidence Intervals. In both comparisons, the once daily use of Dovobet* demonstrates statistically significant improvement over the twice daily marketed comparator product.

Table 2: Mean differences between treatment groups.⁶

Treatment Regimen

One potential treatment approach for using Dovobet* and Dovonex® to treat psoriasis includes “jump starting” the patient with once-daily Dovobet*, followed by a gradual transition within 4 weeks to Dovonex® or emollients for maintenance. Dovobet* can subsequently be reintroduced on weekends as an intermittent pulse therapy when partial relapse or flares occur.

Side-effects

All trials using the twice daily application of Dovobet* demonstrated fewer reported side-effects than with calcipotriol alone.⁷ Once daily applications mean that patients have less exposure to the drugs and presumably less chance developing side-effects, especially those associated with steroids.

Conclusion

Dovobet*, when applied only once daily, is as effective as twice daily applications, and significantly more effective than twice daily applications of calcipotriol or betamethasone dipropionate. In addition, the once-daily application of a single combination ointment is more patient-friendly and likely to encourage compliance.

* registered trademark of LEO Pharmaceutical Products used under the license by LEO Pharma Inc., Thornhill, Ontario, Canada.

References

1. Greaves MW, Weinstein, GD. Treatment of psoriasis. N Engl J Med 1995 Mar; 332(9):581-8.
2. van Rossum MM, van Erp PE, van de Kerkhof PC. Treatment of psoriasis with a new combination of calcipotriol and betamethasone dipropionate: a flow cytometric study. Dermatology 203(2):148-52 (2001).
3. Douglas WS, Poulin Y, Decroix J, et al. A new calcipotriol/betamethasone formulation with rapid onset of action was superior to monotherapy with betamethasone dipropionate for calcipotriol in psoriasis vulgaris. Acta Derm Venereol 82:131-5 (2002).
4. Guenther L, van de Kerkhof PC, Snellman E, et al. Efficacy and safety of a new combination of calcipotriol and betamethasone dipropionate (once or twice daily) compared to calcipotriol (twice daily) in the treatment of psoriasis vulgaris: a randomized, double-blind, vehicle-controlled clinical trial. Br J Dermatol 147(2):316-23 (2002 Aug).
5. Guenther L, Cambazard F, Van De Kerkhof PGM, et al. Efficacy and safety of a new combination of calcipotriol and betamethasone dipropionate (once or twice daily) compared to calcipotriol (twice daily) in the treatment of psoriasis vulgaris: a randomized, double-blind, vehicle-controlled clinical trial. Br J Dermatol 147:316-23 (2002).
6. Data on file, LEO Pharma.
7. Poulin Y. Calcipotriol and betamethasone dipropionate (Dovobet*, Daivobet®): A new formulation for the treatment of psoriasis. Skin Therapy Lett 7(6):1-3 (2002 Jun).

Hair Research and Treatment Centre, and Division of Dermatology, University of British Columbia, Vancouver, British Columbia, Canada

ABSTRACT

Eflornithine HCl 13.9% cream is the first topical prescription treatment to be approved by the US FDA for the reduction of unwanted facial hair in women. It irreversibly inhibits ornithine decarboxylase (ODC), an enzyme that catalyzes the ratelimiting step for follicular polyamine synthesis, which is necessary for hair growth. In clinical trials eflornithine cream slowed the growth of unwanted facial hair in up to 60% of women. Improvement occurs gradually over a period of 4–8 weeks or longer. Most reported adverse reactions consisted of minor skin irritation.

Key Words:
eflornithine, ornithine decarboxylase inhibitor, reduction of unwanted facial hair in women

The first topical prescription treatment for the reduction of unwanted facial hair in women, eflornithine HCl 13.9% cream (Vaniqa, Bristol-Myers Squibb), was approved by the US FDA in August 2000. This product is an irreversible inhibitor of ornithine decarboxylase (ODC), an enzyme that is critical for the biosynthesis of cationic polyamines, which are necessary for cell growth. Vaniqa appears to be effective regardless of whether the unwanted facial hair is hereditary or whether it is due to medical conditions such as an androgen excess disorder, e.g., polycystic ovarian syndrome.

The Hair Growth Cycle

All hair undergoes an intrinsic, rhythmic, cyclical growth pattern consisting of three phases. Periods of growth (anagen) are followed by periods in which the bulbar portion of the follicle is almost totally degraded through apoptosis (catagen), which is then followed by the resting phase (telogen). The duration of anagen on the face is usually 16 weeks, whereas on the scalp it typically continues for 150 weeks. Catagen lasts for 1 week on both the scalp and face, and telogen lasts for 6 weeks on the face, and 12 weeks on the scalp. Each hair follicle consists of a permanent and non-permanent portion with the lowermost aspect of the permanent portion located at the level of the insertion of the arrector pili muscle, also known as the “follicular bulge”.

The rate of growth for hair is approximately 0.44mm/day on the scalp, and 0.27mm/day for beards. Seasonal variation does exist with a higher rate of growth in the summer (July/August), as compared to the winter months (Jan/Feb). This variability correlates with fluctuations in androgen levels where higher levels of testosterone occur during the summer months.

In principle, there are three ways to slow down hair growth: 1) decrease the anagen phase, 2) delay the onset of anagen following the telogen phase, or 3) prolong telogen. While neither the telogen phase, nor the onset of anagen can yet be prolonged pharmacologically, the anagen phase can be reduced.

Ornithine Decarboxylase

ODC is an enzyme that is key to the formation of cationic polyamines, which in turn are necessary for cellular migration, differentiation and proliferation. Polyamines are low molecular weight, aliphatic, non-protein, nitrogenous bases that are predominantly found in proliferating tissues.

The Polyamine Pathway

L-Ornithine → Putrescine → Spermidine → Spermine
Ornithine decarboxylase

ODC activity and its biosynthetic products, putrescine and spermidine are usually low in normal resting cells, but high in proliferating cells, such as within anagen follicles. As well, ODC and putrescine were found to be higher in psoriatic skin, and putrescine is twice as high in the serum of psoriatic patients.¹

In terms of hair growth, investigators reported that ODC activity increased in rodent skin within four hours after hair plucking. This is much sooner than the earliest reported increases in matrix cell labeling indices after hair plucking,^2–4 which implies that ODC activity increases prior to the onset of increased mitotic activity. In embryonic human epidermis, ODC was found to be expressed in the ectodermal cells at sites where follicles develop, and to persist in cells at the leading edge of the follicular placode. ODC is abundantly expressed in the proliferating bulb cells of anagen follicles, and entry of the follicle into catagen is accompanied by a down-regulation of ODC expression, which persists until the next follicular growth cycle is initiated. In animal vibrissae, ODC is expressed in a group of outer root sheath cells near the follicle bulge, which is the putative site of hair follicle stem cells.^5,6 ODC activity is particularly high at the level of the bulb.

Increased ODC activity, has thus been associated with prolongation of anagen, and conversely, when ODC is decreased, anagen is reduced, thereby slowing hair growth. ODC activity is also reduced during the telogen phase.⁷

Pharmacokinetics

The mean percutaneous absorption for eflornithine 13.9% cream is less than 1%, and the steady-state peak serum concentration is less than 10ng/ml. It is not metabolized and is excreted unchanged in the urine. The time required to reach steady-state is 4 hours. The plasma half-life is 8 hours.⁸

Table 1: 58% of Vaniqa group demonstrated improvement versus 34% of placebo (p <.001)

Clinical Trial Results⁹

Two multi-center, double-blinded, vehicle controlled, randomized studies were carried out in the US and Europe. The first trial was conducted in 10 US centers: n=285 (189 Vaniqa cream/96 vehicle), and second took place at 8 centers in the US and 1 in Europe: n=309 (206 Vaniqa/103 vehicle). All ethnic groups and skin types were included, and all women were removing at least 5 hairs/cm² on the chin and upper lip at least twice/week prior to study entry.

The treatment regimen consisted of twice daily application of the creams for 24 weeks, followed by 8 weeks of no treatment.

Patients were seen at baseline, day 2, and weeks 2, 4, 8, 12, 16, 20, 24, and 32. At all visits a clinical assessment, self-assessment, video imaging, photographs and safety data were taken. Efficacy was determined by a Physician’s Global Assessment using a 4- point scale: clear to almost clear, marked improvement, improved, no improvement. All clinical assessments were made 48 hours after shaving. Statistically and clinically significant improvement was noted in the eflornithine group as compared to the vehicle control group at 8 weeks and continued for 24 weeks. However, hair regrowth approached pretreatment levels within 8 weeks of treatment withdrawal.

The subject self-assessment showed marked improvement with the use of Vaniqa. The mean overall level of discomfort or bother was reduced by 33% for the eflornithine group after 24 weeks based on a self-assessment questionnaire and a visual analog scale. There were no significant differences for patients using the placebo vehicle in this same period of time.¹⁰

Adverse Events

Skin related side effects such as stinging, burning and tingling occurred in a few patients, particularly when eflornithine was applied to broken or abraded skin. Only 2% discontinued eflornithine due to an adverse reaction in the United States. This drug is classified as a Pregnancy Category C agent, so risk to the fetus cannot be ruled out.

Dosage and Cost

Vaniqa is supplied in a 30gm tube, and should be applied twice daily. The area should not be washed for 4 hours after application, but cosmetics and sunscreens can be applied over treated areas once the cream has dried. The cost is $50.00 USD for a 30gm tube.

Conclusion

Eflornithine HCl 13.9% cream, used twice daily is effective for unwanted facial hair in women and complements other current hair removal methods by slowing the rate of hair regrowth. In order to prevent regrowth, eflornithine treatment must be continued indefinitely.

References

1. Lowe NJ. Epidermal ornithine decarboxylase, polyamines, cell proliferation, and tumor promotion. Arch Dermatol 116(7):822–5 (1980 Jul).
2. Morrison DM, Goldsmith LA. Ornithine decarboxylase in rat skin. J Invest Dermatol 70(6):309–13 (1978 Jun).
3. Ogawa H, Hattori M. Regulation mechanisms of hair growth. Curr Probl Dermatol 11:159–70 (1983).
4. Probst E, Krebs A. Ornithine decarboxylase activity in relation to DNA synthesis in mouse interfollicular epidermis and hair follicles. Biochim Biophys Acta 407(2):147–57 (1975 Oct).
5. Nancarrow MJ, Nesci A, Hynd PI, Powell BC. Dynamic expression of ornithine decarboxylase in hair growth. Mech Dev 84(1–2):161–4 (1999 Jun).
6. Nancarrow MJ, Powell BC, Hynd PI. Expression of ornithine decarboxylase during embryonic development of wool follicles. Exp Dermatol 8(4):326–8 (1999 Aug).
7. Hynd PI, Nancarrow MJ. Inhibition of polyamine synthesis alters hair follicle function and fiber composition. J Invest Dermatol 106(2):249–53 (1996 Feb).
8. Malhotra B. Percutaneous absorption, pharmacokinetics and dermal safety of eflornithine 15% cream in hirsute women. At: American Academy of Dermatology Annual Meeting (2000), San Francisco, California.
9. Schrode K. Randomized double blind vehicle controlled safety and efficacy evaluation of eflornithine 15% cream in the treatment of women with excessive facial hair. At: American Academy of Dermatology Annual Meeting (2000), San Francisco, California.
10. Huber F. Outcome of a quality of life assessment used in clinical trials for hirsute women treated with topical eflornithine 15% cream. At: American Academy of Dermatology Annual Meeting (2000), San Francisco, California.

ABSTRACT

Although PDT remains an investigational treatment modality in dermatology, several important areas of development may ultimately lead to official and practical acceptance of PDT for the skin. Indeed the skin is usually the first organ in which many of the newer second generation photosensitizers are evaluated.

Key Words:
Photodynamic Therapy, PUVA, PDT, Psoriasis

The modern era of PDT began in the 1970s with the pioneering work by Dougherty et al at the Roswell Park Memorial Cancer Institute in Buffalo using hematoporphyrin derivative.¹ It is perhaps somewhat ironic that although the skin was the first organ in which PDT was systematically evaluated, as of mid 1997 the only official regulatory approvals for PDT are for the treatment of internal malignancies involving the lung, genitourinary system, and gastrointestinal tract using porfimer sodium (Photofrin®), the first generation photosensitizer.

For treating diseased tissue, PDT, like PUVA, involves the sequential administration of drug followed by light. However, PDT involves the photochemical generation of reactive singlet oxygen that interacts with tissue components, whereas PUVA’s effects appear to depend more on reactions independent of O₂.

New photosensitizers

Persistent generalized cutaneous photosensitivity due to photosensitizer retention in the skin has been the main limitation of porfimer sodium, which is administered parenterally. This has led to the development of second generation photosensitizers, some of which appear to be cleared far more rapidly from the skin than porfimer sodium (Table). With topically active agents such as 5-aminolevulinic acid (5-ALA) and ATMPn, skin photosensitivity is restricted to areas of direct drug application. 5-ALA is unique in that it is actually a low molecular weight porphyrin precursor that is metabolized in situ within the skin to protoporphyrin IX, which possesses significant PDT activity.

Are lasers essential for PDT?

PDT has become synonymous with the use of porphyrins and lasers for treating skin cancer. While lasers are indispensable for delivering light to internal organs via fiberoptic endoscopy, they are relatively expensive and inefficient light sources for photosensitizer activation in the skin. The critical property for any PDT light source is that its spectral output provides sufficient power at an activation wavelength that is appropriate for the photosensitizer being used. In the future, non-coherent, broad or narrow band light sources such as incandescent bulbs, arc lamps, fluorescent tubes, and light-emitting diodes may prove to be the light sources of choice for dermatologic PDT. These latter devices are usually cheaper to operate, more compact, and more effective for irradiating large surfaces than lasers.

Does PDT work?

• Skin cancer Although the literature documents an extensive collective experience for PDT of skin cancer (reviewed in Reference 2) there is a dearth of either long term follow-up data (i.e. more than 2-5 years of reported follow up) or histologic evaluation of treated sites. Moreover, in dermatology, there is only one published, controlled trial of PDT. In treating Bowen’s disease, the combination of ALA and a broad band lamp was felt to be as effective as cryotherapy, but with fewer adverse effects.³ More studies such as this will be needed in order to more precisely define the role of PDT for skin cancer management.

Novel indications for PDT

• Non-hypertrophic actinic keratoses of the face and scalp In a vehicle-controlled study, topical ALA and red laser light have recently been shown to clear up to 91% of these keratoses.⁴ Multicenter phase III studies of topical ALA for this indication are currently underway in the US.
• Psoriasis PDT has been shown to demonstrate significant immunomodulatory effects in animal models of arthritis.⁵ Thus there is a rationale for using PDT in treating inflammatory disorders such as psoriasis. One potential advantage of PDT over PUVA is that PDT may not be intrinsically carcinogenic. Pilot studies have demonstrated clearing of psoriasis using topical⁶ and systemic photosensitizers.⁷
• Removal of unwanted terminal hair Topical ALA selectively photosensitizes pilosebaceous structures and Grossman et al have used ALA-PDT to remove unwanted terminal hair with some degree of success.⁸ How this modality will compare to the current generation of hair removal lasers will await controlled clinical studies.

If the potential therapeutic advantages of using PDT to treat actinic keratoses, non-melanoma skin cancers, psoriasis and hair removal continue to be demonstrated in clinical trials, Dermatologists would welcome PDT as an effective, safe and cheaper treatment alternative to current therapy, including lasers. Photodynamic therapy should no longer be looked upon as a procedure looking for a disease to treat.
Dr. Stuart Maddin, Editor

Table: Photosensitizers for PDT

References

1. Dougherty TJ, Kaufman JE, Goldfarb A, Weishaupt KR, Boyle D, Mittleman A. Photoradiation therapy for the treatment of malignant tumors. Cancer Research 1978;38:2628-35.
2. Bissonnette R, Lui H. Current Status of Photodynamic Therapy in Dermatology. Dermatologic Clinics 1997;15:507-519.
3. Morton CA, Whitehurst C, Moseley H, McColl JH, Moore JV, Mackie RM. Comparison of photodynamic therapy with cryotherapy in the treatment of Bowen’s disease. British Journal of Dermatology 1996;135:766-71.
4. Jeffes EW, McCullough JL, Weinstein GD, et al. Photodynamic Therapy of Actinic Keratosis With Topical 5-Aminolevulinic Acid – a Pilot Dose-Ranging Study. Archives of Dermatology 1997;133:727-732.
5. Chowdhary RK, Ratkay LG, Neyndorff HC, et al. The use of transcutaneous photodynamic therapy in the prevention of adjuvant-enhanced arthritis in MRL/lpr mice. Clinical Immunology & Immunopathology 1994;72:255-63.
6. Boehncke WH, Sterry W, Kaufmann R. Treatment of psoriasis by topical photodynamic therapy with polychromatic light [letter]. Lancet 1994;343:801.
7. Hruza L, Lui H, Hruza G, al e. Response of psoriasis to photodynamic therapy using benzoporphyrin derivative monoacid ring A. Lasers Surg Med Suppl 1995;7:43.
8. Grossman M, Wimberly J, Dwyer P, Flotte T, Anderson RR. PDT for hirsutism. Lasers Surg Med Suppl 1995;7:44.