Two cases of refractory discoid lupus erythematosus successfully treated with topical tocoretinate
- Author(s): Terao, Mika;
- Matsui, Saki;
- Katayama, Ichiro
- et al.
Published Web Locationhttps://doi.org/10.5070/D30r49c68v
Two cases of refractory discoid lupus erythematosus successfully treated with topical tocoretinateDepartment of Dermatology, Osaka University Graduate School of Medicine
Mika Terao, Saki Matsui, Ichiro Katayama
Dermatology Online Journal 17 (4): 15
Discoid lupus erythematosus (DLE), the most common lupus erythematosus (LE)-specific chronic manifestation of the skin, is often resistant to therapy. Atrophy, scarring, and pigmentation are often observed. In this study, we report two cases of DLE that were successfully treated with tocoretinate, a compound containing a mixture of retinoic acid and tocopherol. Atrophy and pigmentation improved in both cases. The mechanism of action of tocoretinate is discussed.
Lupus erythematosus (LE) is a chronic, inflammatory autoimmune disease that results in skin lesions in 70 percent to 85 percent of patients . Discoid LE (DLE) is the most common LE-specific chronic manifestation and occurs frequently in women, especially in the fourth and fifth decades . The limited cutaneous form with head and neck involvement accounts for 70 percent of cases and the generalized form accounts for the remaining 30 percent of cases . The typical lesion starts as a disk-shaped erythematous plaque followed by grayish-white hyperkeratosis. DLE is often refractory to a wide range of topical and systemic treatments. Atrophy and scarring, which are often observed after resolution of the lesions, are cosmetic problems greatly affecting a patient’s quality of life.
The previously reported treatments for DLE include sunblock, topical steroids, intralesional injection of corticosteroids, systemic antimalarials , tazarotene , mycophenolate mofetil , and laser therapy . Retinoids, specifically tretinoin, are also considered useful for the treatment of refractory DLE and hypertrophic LE [7, 8].
Herein, we report two patients with DLE successfully treated with topical tocoretinate, a synthetic esterified compound of tocopherol and retinoic acid. The preparation is commercially available as a 0.25 percent ointment (Pola Pharma, Inc) and was developed as an ulcer treatment.
A 43-year-old woman presented with well-defined, scaly, erythematous plaques exhibiting pigmentation, erosion, ulceration, and atrophy on her cheeks and ears (Figure 1a and Figure 1c). A skin biopsy from her cheek revealed hyperkeratosis, dilated follicular orifices filled with keratin, vacuolar degeneration of the basal keratinocytes, and pigment incontinence. Perivascular and perifollicular mononuclear cell infiltration was also observed. DLE was diagnosed based on these findings. Antinuclear antibody (ANA) (1:160, diffuse and speckled pattern), anti-ribonucleoprotein (RNP) antibody, anti-Sm antibody, and anti-SS-A antibody were positive. Previous unsuccessful treatments included topical glucocorticoids and sunscreen. Her lesions were accompanied by erosions and ulcers, hence topical tocoretinate twice daily was initiated. Topical application of tocoretinate not only epithelialized the ulcers but also reduced the erythema after 1 month. The patient was satisfied with this unexpected outcome of tocoretinate use and wished to continue the application even after her ulcers epithelialized. Pigmentation started disappearing 3 months later and skin atrophy improved by 1 year. The patient continued the application of tocoretinate for 18 months and was satisfied with the outcome of the treatment (Figure 1b and Figure 1d). No side effects were observed and systemic treatments were not administrated during this period.
|Figure 2. Clinical features of Case 2. Erythematous plaques with pigmentation and atrophy on the left temple before (a) and 11 months after beginning tocoretinate treatment (b). (c) Hematoxylin-eosin staining of biopsied lesion. Bar = 500 μm.|
A 37-year-old man presented with erythematous plaques with erosion, pigmentation, and atrophy on his left temple (Figure 2a). A skin biopsy revealed hyperkeratosis, dilated follicular orifices filled with keratin, vacuolar degeneration of the basal keratinocytes, and pigment incontinence. Perivascular and periappendageal mononuclear cell infiltrates were also observed. DLE was diagnosed based on these findings. ANA (1:40, homogenous and speckled pattern) and anti-SS-A antibody were positive. Anti-phospholipid antibody syndrome was diagnosed based on positive anti- cardiolipin antibody, anti-cardiolipin/β2 glycoprotein 1 complex antibody, lupus anticoagulant, and activated partial thromboplastin time (APTT) (44 seconds). The cutaneous plaque was resistant to topical glucocorticoids and tacrolimus treatment; topical tocoretinate treatment was initiated. The erosion disappeared and the erythema was reduced after 2 weeks. The patient intermittently continued the application of tocoretinate. Eleven months later, the skin atrophy observed in the center part of the lesion had almost disappeared (Figure 2b). No side effects were observed during treatment. The patient was administered low-dose aspirin for anti-phospholipid antibody syndrome during this period, but no other systemic therapies.
Tocoretinate is the synthetic esterified compound of tocopherol, which has vitamin E activity, and retinoic acid, which is a derivative of vitamin A. Tocoretinate has been used for the treatment of skin ulcers in Japan because of its ability to enhance fibroblast migration and proliferation . In addition to its ability to improve skin ulcerations, tocoretinate also improves the skin manifestations evident with scleroderma, morphea, hypertrophic scars, and lichen amyloidosis [10, 11]. Tocoretinate induces early differentiation markers of keratinocytes, such as involucrin in normal human keratinocytes in culture, likely related to its retinoic acid activity .
In this study, tocoretinate was used to treat erosions in two DLE patients who were refractory to topical glucocorticoids. The application of tocoretinate improved not only the erosions but also the skin pigmentation, erythema, and atrophy present in both patients. Tocoretinate is a retinoic acid compound that demonstrates the effects of retinoids, but causes little irritation to the skin compared with other retinoic acids. It is likely the retinoic acid activity of tocoretinate improved the DLE lesions. A few reports suggest that retinoids, specifically tretinoin, have been effective in the treatment of refractory DLE and hypertrophic LE [7, 8]. Topical retinoic acid increases collagen synthesis, promotes epidermal turnover, inhibits melanogenesis, and inhibits inflammation [12, 13]. These effects may have contributed to the improvement of the DLE lesions in our patients. The goals of therapy in a patient with DLE are to improve the appearance of the patient and to prevent scars, atrophy, and dyspigmentation. Tocoretinate appears suitable for accomplishing these goals. The use of tocoretinate also avoids the adverse effects, such as skin atrophy and telangiectasia, related to the use of long-term topical glucocorticoids. Double blind placebo-controlled studies are needed in the future to confirm the effects of tocoretinate.
In conclusion, these cases suggest that tocoretinate could be a safe and effective option for the treatment of the skin manifestations seen in DLE.
References1. Cardinali, C., et al., The spectrum of cutaneous manifestations in lupus erythematosus--the Italian experience. Lupus. 2000;9(6):417-23. [PubMed]
2. Fabbri, P., et al., Cutaneous lupus erythematosus: diagnosis and management. Am J Clin Dermatol. 2003;4(7):449-65. [PubMed]
3. Werth, V., Current treatment of cutaneous lupus erythematosus. Dermatol Online J. 2001 Feb;7(1):2. [PubMed]
4. Edwards, K.R. and W.A. Burke, Treatment of localized discoid lupus erythematosus with tazarotene. J Am Acad Dermatol. 1999 Dec;41(6):1049-50. [PubMed]
5. Goyal, S. and H.C. Nousari, Treatment of resistant discoid lupus erythematosus of the palms and soles with mycophenolate mofetil. J Am Acad Dermatol. 2001 Jul;45(1):142-4. [PubMed]
6. Kuhn, A., et al., Successful treatment of discoid lupus erythematosus with argon laser. Dermatology. 2000;201(2):175-7. [PubMed]
7. Callen, J.P., Management of skin disease in patients with lupus erythematosus. Best Pract Res Clin Rheumatol. 2002 Apr;16(2):245-64. [PubMed]
8. Drake, L.A., et al., Guidelines of care for cutaneous lupus erythematosus. American Academy of Dermatology. J Am Acad Dermatol. 1996 May;34(5 Pt 1):830-6. [PubMed]
9. Yamada, E., et al., Tocoretinate inhibited the contraction of collagen gel matrices by human dermal fibroblasts with tenascin-C expression. J Dermatol Sci. 1999 Dec;22(1):45-53. [PubMed]
10. Terao, M., et al., Clinical effect of tocoretinate on lichen and macular amyloidosis. J Dermatol. 2011 Feb;38(2):179-84. [PubMed]
11. Mizutani, H., et al., Topical tocoretinate improved hypertrophic scar, skin sclerosis in systemic sclerosis and morphea. J Dermatol. 1999 Jan;26(1):11-7. [PubMed]
12. Darlenski, R., C. Surber, and J.W. Fluhr, Topical retinoids in the management of photodamaged skin: from theory to evidence-based practical approach. Br J Dermatol. 2010 Dec;163(6):1157-65. [PubMed]
13. Jones, D.A., The potential immunomodulatory effects of topical retinoids. Dermatol Online J. 2005 Mar 1;11(1):3. [PubMed]
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