Letter to the editor - no abstract available</p

Kinga Ścibior

Luiza Marek Jozefowicz

Rafal Czajkowski

English

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301ACTA DERMATOVENEROLOGICA CROATICAPUVA Induced Bullous Pemphigoid in a Patient with PsoriasisActa Dermatovenerol Croat                      2014;22(4):301-304                           LETTER TO THE EDITORA bullous eruption in a patient with psoriasis was first described by Bloom in 1929 (as cited by Weber) (1). Since then there have been several reports of bul-lous pemphigoid occurring during the treatment of psoriasis, especially after ultraviolet (UV) B exposure. Comorbidity of these two diseases without treatment has also been reported (2,3).Psoriasis is one of the most common chronic in-flammatory skin diseases. Its etiopathogenesis is un-known, but nonspecific inflammatory processes and specific immunologic factors have been described. Autoimmune processes occurring within the epi-dermis and immunologic responses to exogenous infectious agents are suspected as causes, but not confirmed. In contrast, bullous pemphigoid (BP) rep-resents a distinct autoimmune disease in which base-ment membrane zone (BMZ) molecules are most affected (4). BP is an autoimmune subepidermal bul-lous disease with circulating autoantibodies against BP antigen 1 (230kDa) and BP antigen 2 (180kDa). Antigen 2 is a transmembrane glycoprotein located in the hemidesmosomes and is the major antigenic target in this disorder (5,6). The BP180 NC16a domain is considered to be the most immunogenic site (7).The occurrence of BP in patients with psoriasis has occasionally been reported (8). Although the patho-genetic mechanism of comorbidity of psoriasis vul-garis and BP is unclear, a common immunogenetic mechanism might be involved (9). Most previously reported cases attributed the occurrence of BP in psoriasis to photochemotherapy and phototherapy (PUVA, UVA, UVB311nm), topical treatment with an-thralin, tar, and as a result of systemic application of anti-TNF antibodies (10). The role of PUVA therapy in the development of BP remains unknown. George at al. suggested that such changes may trigger the development of antibodies which may later cross-re-act with proteins, such as the BP antigen, causing a bullous eruption to appear. The possibility that PUVA induces the alteration of immunologic reactivity of T-helper and T-suppressor cells, allowing the develop-ment of autoantibodies against native proteins, has also been raised (6,11).A 55-year-old woman was referred to our depart-ment with a ten days history of bullous lesions, ero-sions, and exacerbated plaque psoriasis. Psoriasis was diagnosed in 1994, and various systemic and topical therapies (in combination or as single treatment) Figure 1. Bullous lesions located on a psoriatic plaque of the upper limb.Figure 2. Bullous lesion located on a psoriatic plaque and uninvolved skin of the lower limb.302 ACTA DERMATOVENEROLOGICA CROATICAwere prescribed, such as topical corticosteroids, cy-closporine, and methotrexate. Three courses of PUVA therapy (cumulative dose 291 J/cm²) had been given several days before hospitalization. On examination, extensive psoriatic plaques, ves-icles and tense blisters up to 3 cm in diameter, filled with clear fluid, located on both the normal skin and psoriatic lesions were observed all over the body. The highest intensity of bullous skin lesions was found in the upper limbs and lower limbs (Fig. 1 and 2). No le-sions were observed on the face or on the mucous membranes.Routine laboratory tests such as biochemical tests, complete blood count, and urinalysis were normal. Chest radiography and abdominal ultrasonography, tumor markers CEA, and AFP showed no abnormali-ties.Two biopsy specimens were taken from psoriatic and bullous lesions for histopathologic examination, and one biopsy was taken from a perilesional bullous area located on the right forearm for a direct immu-nofluorescence test (DIF). Histopathologic examina-tion revealed a subepidermal blister with eosinophils, fibrin, and neutrophils. Perivascular edema and lym-phohistiocytic infiltration with eosinophils was ob-served in upper dermis (Fig. 3). DIF test showed linear C3c deposits at the dermal-epidermal junction (Fig. 4). C3c was present at both the epidermal and der-mal sides of BMZ in salt-split skin examination (Fig. 5). Figure 4. Direct immunofluorescence (DIF) study of uninvolved skin showing linear deposits of C3c at the dermal-epidermal junction.Figure 5. Salt-split skin test showing C3c deposits at the epidermal and dermal sides of the substrate.Letter to the editor Acta Dermatovenerol Croat     2014;22(4):301-304Indirect immunofluorescence study (IIF) was done us-ing monkey esophagus substrate and demonstrated IgG antibasement membrane zone antibodies (Fig. 6).Enzyme-linked immunosorbent assay (ELISA) confirmed high titers of anti-BP180 (>200 E/ml) and anti-BP230 (140 E/ml) with negative results for anti-envoplakin, anti-Dsg1, anti-Dsg3, and anti-Col7A an-tibodies.After BP was diagnosed, the patient received prednisolone orally at a dose of 50 mg daily (0.8 mg/kg body weight). After 1 week, during skin con-trol examination there were no new lesions, and the existing ones were reduced. Prednisolon was gradu-Figure 3. Subepidermal blister with eosinophils, fi-brin, and neutrophils. Perivascular edema and lym-phohistiocytic infiltration with eosinophils present in upper dermis (hemalaun and eosin; x 400).303ACTA DERMATOVENEROLOGICA CROATICAally reduced (10 mg every week) until the skin lesions disappeared completely. Residual psoriatic plaques were treated with 1% hydrocortisone ointment si-multaneously.Bullous pemphigoid is sometimes considered a marker of oncogenesis, but patients with BP are most-ly elderly, with a high base rate of cancer incidence. In our patient additional studies did not confirm tumor presence. She also did not receive any drugs that can contribute to the development of the disease (mainly diuretics and antihypertensives). PUVA-therapy ap-plied during psoriasis treatment was the most likely BP induction factor. Skin lesions as a result of possible UVA overdosage were excluded. Histopathology and immunofluorescence clearly showed that our patient suffered from BP. UV radiation was most obvious trig-ger of bullous pemphigoid in our patients.Comorbidity of the two diseases supports the hypothesis that autoimmunity has a partial role in the etiology of psoriasis. There have been several re-ports about the coexistence of these two diseases. It has been reported that UV radiation and an irrita-tion therapies used in the treatment of psoriasis may lead to bullous pemphigoid. In predisposed cases psoralen together with UVA therapy causes the de-position of antibasement membrane zone antibodies through immunological alterations (2,3).Exposure of psoriatic lesions to ultraviolet radia-tion (UVR) likely triggered to production of BP au-toantibodies as a result of BP antigen configuration changes or as a secondary phenomenon demonstrat-ed that BP180kD and alpha-6 integrin interaction is not only mediated by the BP epitope but is necessary for hemidesmosome formation (12,13). One possibili-ty is that UVR may alter BMZ antigenicity and produc-tion of antibodies against the BMZ molecules (14).UVR is known to induce or aggravate several au-toimmune bullous diseases. The precise mechanism by which this radiation induces blistering is not well understood, but several possible mechanisms have been proposed. One is release or activation of bound antigen and/or the inducement of antibody fixation by UV radiation (15). This concept was proposed on the basis of in vitro studies using serum from a pa-tient with BP in which UVB radiation generated by a hot quartz lamp and high-dose radiographs led to in-creased binding of antibodies to the BMZ (15).Other proposed mechanisms include the activa-tion of intracellular signaling pathways after binding of antibodies and increased production of inflamma-tory mediators such as interleukins (IL-1, IL-8), tumor necrosis factor-alpha (TNF-α), and granulocyte mac-rophage colony-stimulating factor (GM-CSF) (16,17). However, no definite mechanism of action for UVR induced blistering has been proposed. It is well know that psoralen-UVA (PUVA) therapy can itself induce acral bullous lesions, which cannot be attributed to immunologic causes, therapy overdose, or excessive psoralen uptake. It is more likely that the blistering is induced by direct damage to the dermo-epidermal junctional caused by the combination of UVA radia-tion and psoralen (15,18-20).In treatment of psoriasis, we should avoid the use of systemic corticosteroids; the treatment of choice for comorbidity of psoriasis and BP is methotrex-ate. Even if the observed anti-inflammatory effect is short-term, long-term side effects far outweigh the benefits. In our case, we decided to apply short oral course of systemic corticosteroids because of rapid exacerbation of BP lesions with only single psoriatic plaques. The clinical result was very satisfactory, and we did not observe psoriasis exacerbation after dis-continuation of prednisolone therapy. Proper treat-ment in such clinical cases should be decided indi-vidually, taking into account history of the disease, clinical course of psoriasis, and existing concomitant diseases.References1.  Weber PJ, Salazar JE. Bullous eruption in a psoria-tic patient. Arch Dermatol 1989;125:690, 693-4.2.  Grattan CEH. Evidence of an association between bullous pemphigoid and psoriasis. Br J Dermatol 1985;113:281-3.Figure 6. Indirect immunofluorescence (IIF) test on monkey esophagus substrate showing IgG antibase-ment membrane zone antibodies (titer 1:2560).Letter to the editor Acta Dermatovenerol Croat     2014;22(4):301-304304 ACTA DERMATOVENEROLOGICA CROATICA3.  Denli YG, Uslular C, Acar MA. Bullous pemphigoid in a psoriatic patient. J Eur Acad Dermatol Vene-reol 2000;14:313-33.4.  Wilczek A, Sticherling M. Concomitant psoriasis and bullous pemphigoid: coincidence or patho-genic relationship? Int J Dermatol 2006;45:1353-7.5.  Tabuchi K, Nomura M, Murashita H, Fujisawa Y, Tsuji S, Okubo H, et al. Coexistence of pemphigus vulgaris and bullous pemphigoid in the upper ae-rodigestive tract. Auris Nasus Larynx 2006;33:231-3.6.  Barnadas MA, Gilaberte M, Pujol R, Agustí M, Gelpí C, Alomar A. Bullous pemphigoid in a patient with psoriasis during the course of PUVA therapy: stu-dy by ELISA test. Int J Dermatol. 2006;45:1089-92.7.  Guidice GJ, Emery DJ, Zelickson BD, Anhalt GJ, Liu Z, Diaz LA. Bullous pemphigoid and herpes gestationis autoantibodies recognize a common non-collagenous site on the BP180 ectodomain. J Immunol 1993;151:5742-50.8.  Perl S, Rappersberger K, Fodinger D, Anegg, Hö-nigsmann H, Ortel B. Bullous pemphigoid induced by PUVA therapy. Dermatology 1996;193:245-7.9.  Fivenson DP, Breneman DL, Rosen GB, Hersh CS, Cardone S, Mutasim D. Nicotinamide and tetracy-cline therapy of bullous pemphigoid. Arch Der-matol 1994;130:753-8.10.  Jankowski M, Czajkowski R, Ścibior K, Schwartz RA. Coexistence of psoriasis vulgaris and vitiligo with bullous pemphigoid: a case report. Int J Der-matol 2014;53:e359-61. 11. George PM. Bullous pemphigoid possibly induced by psoralen plus ultraviolet A therapy. Photoder-matol Photoimmunol Photomed 1995;11:185-7.12. Muramatsu T, Yamashina Y, Shirai T, Ohnishi T. UVB irradiation reduces the expression of pemphigoid antigens in organ-cultured normal human skin. Arch Dermatol Res 1994;286:142-4.13. Hopkinson SB, Findlay K, de Hart GW, Jones JC. In-teraction of BP180 (type XVII collagen) and a 6 in-tegrin is necessary for stabilization of hemidesmo-some structure. J Invest Dermatol 1998;111:1015-22.14.  Washio H, Hara H, Suzuki H, Yoshida M, Hashimoto T. Bullous pemphigoid on psoriasis lesions after UVA radiation. Acta Derm Venereol 2005;85:561-3.15.  Salmhofer W, Soyer HP, Wolf P, Födinger D, Hödl S, Kerl H. UV light-induced linear IgA dermatosis. J Am Acad Dermatol 2004;50:109-15.16. Kondo S, Kono T, Sauder DN, McKenzie RC. IL-8 gene expression and production in human kera-tinocytes and their modulation by UVB. J Invest Dermatol 1993;103:690-4.17. Feliciani C, Toto P, Amerio P, Pour SM, Coscione G, Shivji G, et al. In vitro and in vivo expression of in-terleukin-1α and tumor necrosis factor-α mRNA in pemphigus vulgaris: interleukin-1α and tumor necrosis factor-α are involved in acantholysis. J In-vest Dermatol 2000;114:71-7.18. Grabbe S, Schütte B, Bruckner-Tuderman L, Schwarz T. PUVA induzierte akrobullöse dermato-le. [PUVA-induced acrobullous dermatosis] Hau-tarzt 1996;47:465-8.19.  Friedmann PF, Coburn P, Dahl MG, Diffey BL, Ross J, Ford GP, et al. PUVA-induced blisters, complement deposition, and damage to the dermoepidermal junction. Arch Dermatol 1987;123:1471-7.20. Jenerowicz D, Zmudzinska M, Pawlaczyk M. Extra-corporeal photophoresis in the treatment of skin diseases. Adv Dermatol Allergol 2003;20:80-6.Luiza Marek-Jozefowicz, Kinga Scibior, Rafał CzajkowskiDepartment of Dermatology, Sexually Transmitted Diseases and Immunodermatology, Nicolaus Coperni-cus University in Torun. Ludwik Rydygier Medical Col-lege in Bydgoszcz. Corresponding author:Luiza Marek-Jozefowicz, MD Antoni Jurasz University Hospital No 1, 9 Sklodowskiej-Curie street 85-094 Bydgoszcz POLAND lui06@interia.plReceived: September 23, 2013Accepted: September 1, 2014Letter to the editor Acta Dermatovenerol Croat     2014;22(4):301-304

PUVA Induced Bullous Pemphigoid in a Patient with Psoriasis

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