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Pemphigus vulgaris induced by 5-aminolaevulinic acid-based photodynamic therapy
Accepted Manuscript Title: Pemphigus vulgaris induced by 5-aminolaevulinic acid-based photodynamic therapy Authors: Qian Zhou, Peiru Wang, Linglin Zhang, Bo Wang, Lei Shi, Uma Keyal, Anil Kumar Bhatta, Guolong Zhang, Xiuli Wang PII: DOI: Reference:
S1572-1000(17)30229-6 http://dx.doi.org/doi:10.1016/j.pdpdt.2017.05.014 PDPDT 966
To appear in:
Photodiagnosis and Photodynamic Therapy
Received date: Revised date: Accepted date:
26-2-2017 16-5-2017 19-5-2017
Please cite this article as: Zhou Qian, Wang Peiru, Zhang Linglin, Wang Bo, Shi Lei, Keyal Uma, Bhatta Anil Kumar, Zhang Guolong, Wang Xiuli.Pemphigus vulgaris induced by 5-aminolaevulinic acid-based photodynamic therapy.Photodiagnosis and Photodynamic Therapy http://dx.doi.org/10.1016/j.pdpdt.2017.05.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pemphigus
vulgaris
induced
by
5-aminolaevulinic
acid-based photodynamic therapy
Qian Zhou, Peiru Wang, Linglin Zhang, Bo Wang, Lei Shi, Uma Keyal, Anil Kumar Bhatta, Guolong Zhang, Xiuli Wang
Institute of Photomedicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai 200443, P.R. China
Correspondence author: Dr Xiu Li Wang and Dr Guo Long Zhang, Institute of Photomedicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, 1278 Baode Road, Shanghai 200443, P.R. China E-mail: [email protected] E-mail: [email protected]
Text word count Text: 967 Fig: 2 Number of References: 6
Abstract Pemphigus vulgaris (PV) is an autoimmune disorder resulting from the interaction between autoantibodies and desmoglein. Here, we report a case of PV developed after 5-aminolaevulinic acid-based photodynamic therapy (ALA-PDT). The harmful and deleterious effects of UV radiation on the onset, during course, and perpetuation of PV have been observed for decades. Correlation between reactive oxygen species (ROS) and PV have also been reported. Oxidative proteins, which are modified by ROS, and subsequent production of antibodies by immune system seem to be responsible for PV developed following ALA-PDT. We emphasize that ALA-PDT should be added to the list of possible factors triggering PV and this condition should be considered if blistering arises following ALA-PDT.
Keywords: photodynamic therapy, pemphigus vulgaris, basal cell carcinoma, reactive oxygen species
Introduction 5-aminolaevulinic acid-based photodynamic therapy (ALA-PDT) is known to be an alternative therapy forNon-melanoma skin cancers. . Two patients with blistering diseases induced by PDT have been reported, which probably could be due to the immunomodulatory and immunosuppressive effects of phototoxicity [1,2]. In this paper, we report the first case of Pemphigus vulgaris (PV), one of an autoimmune blistering disease, developed after being treated with ALA-PDT.
Case report A 97-year-old woman was referred for ALA-PDT for biopsy-proven basal cell carcinoma(BCC) (Fig. 1A). Her medical history showed multiple actinic keratosis on the face which was proved by biopsy 2 years ago. Considering the elderly patient with, superficial and multiple skin lesions, we adopted ALA-PDT method for treatment. BCC lesions were treated with 20% 5-ALA cream (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co. Ltd, Shanghai, China) and incubated for 3h. The fluorescence of the PpIX could be observed under the Wood light which selectively accumulated atthe sites of the BCC (Fig. 1B). The lesions then were irradiated with 100 J/cm2 633 nm red light at 80 mW/cm2. The ALA-PDT procedure was repeated 3 times at 2-week interval. Facial lesions were significantly improved after two sessions of ALA-PDT (Fig. 1C). However seven days after the third treatment, two large areas of oozy and scabby erythema just inferior to the original site of the two lesions were developed progressively (Fig. 2A). Treatment with antibioticsdid not cure the lesions. After two weeks blisters developed on her back (Fig. 2B), and then gradually extended to the entire trunk and limbs. But we did not observe any blisters at the site of mucous membrane of her mouth. Pphysical examination revealed coalesced thick
lesions, with coarse granular,
scabby and seepage on the face, and scattered distribution of blisters on the trunk and limbs. The blisters were
tense and easy to rupture and contained clear fluid.
Nikolsky, sign was positive.The remainder of the skin examination was normal.
The histologic examination of the blisters on the back showed suprabasilar and intraepidermal acantholysis (Fig. 2D, 2E). Direct immunofluorescence for epidermal autoantibodies demonstrated intercellular deposition of complexes IgG and C3, consistent with the diagnosis of PV (Fig. 2F). However, indirect immunofluorescence was negative. Culture from the blister failed to show bacterial or mycological growth, and there was no evidence of malignant tumor. Routine laboratory tests for blood and urine were within normal limits. Rheumatoid factor, antinuclear antibodies, anti-DNA antibodies, and anti-SSA antibodies were all negative. The patient was treated with intravenous methylprednisolone 40 mg (0.60 mg/kg) daily,combined with topical Polymyxin B cream. The erosions and blisters healed gradually (Fig. 2C). Four weeks after the admission, she was discharged on oral methylprednisolone 24mg/d with progressive tapering. The lesions showed of marked improvement after 3 months of treatment.
Discussion Pemphigus is a rare autoimmune mucocutaneous blistering disease which is characterized by epithelial blistering and acantholysis in the granular layer of the skin due to antibodies against epidermal antigens. Although the triggering mechanisms remain unclear, pemphigus has been reported to be induced by heterogeneous factors, such as drugs, physical agents (burns, light, surgery, and ionizing radiation), infections, and neoplasms. It has been suggested that radiotherapy could alter the epithelial antigen or unmasking certain epidermal antigens, resulting in the
subsequent production of autoantigen.The lesions usually appear on the irradiated area and subsequently extend to the classic distribution of PV[3]. To the best of our knowledge, no previous study has reported ALA-PDT-induced PV. The association between PV and ALA-PDT may be coincidental, but a hypothesis has been raised to explain the mechanisms involved in the PV eruption after ALA-PDT. The mechanisms for PV may be similar to those described ofradiotherapy including the epithelial antigen modification and subsequent antibody recognition. However, the initial trigger for the development of the antigen modification is still obscure. It is well known thatPDT is a method by utilizing light activated photosensitizers producing reactive oxygen species (ROS) targeting the tissues . Naziroğlu et al [4] demonstrated that the increased production of ROS from activated neutrophils can reduce the concentrations of antioxidant, vitamins and enzymes in PV patients. Moreover, Abida et al [5] found the significant correlation between oxidative stress biomarkers and the PV, suggested that ROS may be also involved in pathogenic mechanism of induced-pemphigus vulgaris. We speculated that ALA-PDT could produce the increasing of ROS and causes oxidative modifications of proteins, such as desmoglein [5]. The oxidatively modified proteins are the target of the immune system, and then immune system produced the antibodies leading to the acantholysis [5]. This hypothesis could explain the eruption of PV in the irradiated lesions. However, in our case, the PV also generalized elsewhere on the body. To date, about 20 cases of radiotherapy-induced pemphigus have been reported. It also occurred, in most cases, initially within the area of irradiation and subsequently extended to other
regions [3,6]. The exact mechanism is still unclear. It is possible that the newly generated antigens trigger a systemic immunological reaction, causing generalized PV. We speculated that it may be the underlying mechanism in the case we presented here. ALA-PDT may trigger modifications on desmoglein leading to the systemic manifestation of PV. This is also probably a case of paraneoplastic pemphigus. Although some clinical characteristics of paraneoplastic pemphigus in our casemissed (severe oral involvement in the erythema-multiforme like pattern, small airway occlusion, etc.), a possible role of the neoplasia (basal cell carcinoma) cannot be ruled out. In conclusion, we have firstly reported an elderly patient developing PV after being treated by ALA-PDT in order to highlight that ALA-PDT should be added to the list of possible triggers for PV. However, there is no conclusive evidence that the eruption of PV is caused by ALA-PDT. Accordingly, we suggest that the PV developed after ALA-PDT may be a haphazard more than an intrinsic relation. And a large case-control study is needed to further validate.
Conflict of interest The authors declare no conflict of interest.
Acknowledgement The present study was supported by grants from National Natural Science Foundation of China [81272990, 81472538], Multicenter clinical study of early diagnosis and
treatment for facial non-melanoma skin cancers, the sub-topic of Key project of Natural science foundation of Shanghai [15411950302], Clinical Science and Technology Innovation Project of Shanghai Hospital Development Center [SHDC12015123] and Key projects of Shanghai Municipal Commission of Health and Family Planning [201640016].
References [1] Guarneri C, Vaccaro M, Erosive pustular dermatosis of the scalp following topical methylaminolaevulinate photodynamic therapy, J Am Acad Dermatol. 60(2009) 521-522. doi: 10.1016/j.jaad.2008.09.006. [2] Rakvit P, Kerr AC, Ibbotson SH, Localized bullous pemphigoid induced by photodynamic therapy, Photodermatol Photoimmunol Photomed. 27(2011)(5) 251-253. doi: 10.1111/j.1600-0781.2011.00609.x. [3] Badri T, Hammami H, Lachkham A, Benmously-Mlika R, Mokhtar I, Fenniche S, Radiotherapy-induced pemphigus vulgaris with autoantibodies targeting a 110 kDa
epidermal
antigen,
Int
J
Dermatol.
50(2011)1475-9.
doi:
10.1111/j.1365-4632.2011.04889.x. [4] Naziroğlu M, Kökçam I, Simşek H, Karakilçik AZ, Lipid peroxidation and antioxidants in plasma and red blood cells from patients with pemphigus vulgaris, J Basic Clin Physiol Pharmacol. 14(2003) 31-42. [5] Abida O, Ben Mansour R, Gargouri B, Ben Ayed M, Masmoudi A, Turki H, Masmoudi H, Lassoued S, Catalase and Lipid Peroxidation Values in Serum of Tunisian Patients with Pemphigus Vulgaris and Foliaceus, Biol Trace Elem Res. 150(2012) 74-80. doi: 10.1007/s12011-012-9497-3 [6] Jang HW, Chun SH, Lee JM, Jeon J, Hashimoto T, Kim IH, Radiotherapy-induced pemphigus vulgaris, J Dermatol. 41(2014) 851-2. doi: 10.1111/1346-8138.12582.
Figure Legends Fig. 1. Clinical features of patients. Patients developed BCC lesions on her face(A). Brick red fluorescence of PpIX was observed on BCC lesions after incubation of 20% ALA cream 3 hours under the wood light (B). The lesions on face were improved after two ALA-PDT procedures (C).
Fig. 2. Clinical features of the pemphigus vulgaris on face (A) and on back (B). Histopathological diagnosis of pemphigus vulgaris. The facial pemphigus vulgaris lesions got improved with the treatment of methylprednisolone (C). Histopathology demonstrated suprabasilar and intraepidermal acantholysis with dermal infltrate composed of lymphocytes, neutrophils, and eosinophils (D, E). (D) 100x magnifcation of hematoxylin and eosin stain. (E) 400x magnifcation of hematoxylin and eosin stain (HE). Direct immunofluorescence of epidermal autoantibodies demonstrated intercellular deposition of complexes IgG (F).
Fig 1
Fig 2
S1572-1000(17)30229-6 http://dx.doi.org/doi:10.1016/j.pdpdt.2017.05.014 PDPDT 966
To appear in:
Photodiagnosis and Photodynamic Therapy
Received date: Revised date: Accepted date:
26-2-2017 16-5-2017 19-5-2017
Please cite this article as: Zhou Qian, Wang Peiru, Zhang Linglin, Wang Bo, Shi Lei, Keyal Uma, Bhatta Anil Kumar, Zhang Guolong, Wang Xiuli.Pemphigus vulgaris induced by 5-aminolaevulinic acid-based photodynamic therapy.Photodiagnosis and Photodynamic Therapy http://dx.doi.org/10.1016/j.pdpdt.2017.05.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pemphigus
vulgaris
induced
by
5-aminolaevulinic
acid-based photodynamic therapy
Qian Zhou, Peiru Wang, Linglin Zhang, Bo Wang, Lei Shi, Uma Keyal, Anil Kumar Bhatta, Guolong Zhang, Xiuli Wang
Institute of Photomedicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai 200443, P.R. China
Correspondence author: Dr Xiu Li Wang and Dr Guo Long Zhang, Institute of Photomedicine, Shanghai Skin Disease Hospital, Tongji University School of Medicine, 1278 Baode Road, Shanghai 200443, P.R. China E-mail: [email protected] E-mail: [email protected]
Text word count Text: 967 Fig: 2 Number of References: 6
Abstract Pemphigus vulgaris (PV) is an autoimmune disorder resulting from the interaction between autoantibodies and desmoglein. Here, we report a case of PV developed after 5-aminolaevulinic acid-based photodynamic therapy (ALA-PDT). The harmful and deleterious effects of UV radiation on the onset, during course, and perpetuation of PV have been observed for decades. Correlation between reactive oxygen species (ROS) and PV have also been reported. Oxidative proteins, which are modified by ROS, and subsequent production of antibodies by immune system seem to be responsible for PV developed following ALA-PDT. We emphasize that ALA-PDT should be added to the list of possible factors triggering PV and this condition should be considered if blistering arises following ALA-PDT.
Keywords: photodynamic therapy, pemphigus vulgaris, basal cell carcinoma, reactive oxygen species
Introduction 5-aminolaevulinic acid-based photodynamic therapy (ALA-PDT) is known to be an alternative therapy forNon-melanoma skin cancers. . Two patients with blistering diseases induced by PDT have been reported, which probably could be due to the immunomodulatory and immunosuppressive effects of phototoxicity [1,2]. In this paper, we report the first case of Pemphigus vulgaris (PV), one of an autoimmune blistering disease, developed after being treated with ALA-PDT.
Case report A 97-year-old woman was referred for ALA-PDT for biopsy-proven basal cell carcinoma(BCC) (Fig. 1A). Her medical history showed multiple actinic keratosis on the face which was proved by biopsy 2 years ago. Considering the elderly patient with, superficial and multiple skin lesions, we adopted ALA-PDT method for treatment. BCC lesions were treated with 20% 5-ALA cream (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co. Ltd, Shanghai, China) and incubated for 3h. The fluorescence of the PpIX could be observed under the Wood light which selectively accumulated atthe sites of the BCC (Fig. 1B). The lesions then were irradiated with 100 J/cm2 633 nm red light at 80 mW/cm2. The ALA-PDT procedure was repeated 3 times at 2-week interval. Facial lesions were significantly improved after two sessions of ALA-PDT (Fig. 1C). However seven days after the third treatment, two large areas of oozy and scabby erythema just inferior to the original site of the two lesions were developed progressively (Fig. 2A). Treatment with antibioticsdid not cure the lesions. After two weeks blisters developed on her back (Fig. 2B), and then gradually extended to the entire trunk and limbs. But we did not observe any blisters at the site of mucous membrane of her mouth. Pphysical examination revealed coalesced thick
lesions, with coarse granular,
scabby and seepage on the face, and scattered distribution of blisters on the trunk and limbs. The blisters were
tense and easy to rupture and contained clear fluid.
Nikolsky, sign was positive.The remainder of the skin examination was normal.
The histologic examination of the blisters on the back showed suprabasilar and intraepidermal acantholysis (Fig. 2D, 2E). Direct immunofluorescence for epidermal autoantibodies demonstrated intercellular deposition of complexes IgG and C3, consistent with the diagnosis of PV (Fig. 2F). However, indirect immunofluorescence was negative. Culture from the blister failed to show bacterial or mycological growth, and there was no evidence of malignant tumor. Routine laboratory tests for blood and urine were within normal limits. Rheumatoid factor, antinuclear antibodies, anti-DNA antibodies, and anti-SSA antibodies were all negative. The patient was treated with intravenous methylprednisolone 40 mg (0.60 mg/kg) daily,combined with topical Polymyxin B cream. The erosions and blisters healed gradually (Fig. 2C). Four weeks after the admission, she was discharged on oral methylprednisolone 24mg/d with progressive tapering. The lesions showed of marked improvement after 3 months of treatment.
Discussion Pemphigus is a rare autoimmune mucocutaneous blistering disease which is characterized by epithelial blistering and acantholysis in the granular layer of the skin due to antibodies against epidermal antigens. Although the triggering mechanisms remain unclear, pemphigus has been reported to be induced by heterogeneous factors, such as drugs, physical agents (burns, light, surgery, and ionizing radiation), infections, and neoplasms. It has been suggested that radiotherapy could alter the epithelial antigen or unmasking certain epidermal antigens, resulting in the
subsequent production of autoantigen.The lesions usually appear on the irradiated area and subsequently extend to the classic distribution of PV[3]. To the best of our knowledge, no previous study has reported ALA-PDT-induced PV. The association between PV and ALA-PDT may be coincidental, but a hypothesis has been raised to explain the mechanisms involved in the PV eruption after ALA-PDT. The mechanisms for PV may be similar to those described ofradiotherapy including the epithelial antigen modification and subsequent antibody recognition. However, the initial trigger for the development of the antigen modification is still obscure. It is well known thatPDT is a method by utilizing light activated photosensitizers producing reactive oxygen species (ROS) targeting the tissues . Naziroğlu et al [4] demonstrated that the increased production of ROS from activated neutrophils can reduce the concentrations of antioxidant, vitamins and enzymes in PV patients. Moreover, Abida et al [5] found the significant correlation between oxidative stress biomarkers and the PV, suggested that ROS may be also involved in pathogenic mechanism of induced-pemphigus vulgaris. We speculated that ALA-PDT could produce the increasing of ROS and causes oxidative modifications of proteins, such as desmoglein [5]. The oxidatively modified proteins are the target of the immune system, and then immune system produced the antibodies leading to the acantholysis [5]. This hypothesis could explain the eruption of PV in the irradiated lesions. However, in our case, the PV also generalized elsewhere on the body. To date, about 20 cases of radiotherapy-induced pemphigus have been reported. It also occurred, in most cases, initially within the area of irradiation and subsequently extended to other
regions [3,6]. The exact mechanism is still unclear. It is possible that the newly generated antigens trigger a systemic immunological reaction, causing generalized PV. We speculated that it may be the underlying mechanism in the case we presented here. ALA-PDT may trigger modifications on desmoglein leading to the systemic manifestation of PV. This is also probably a case of paraneoplastic pemphigus. Although some clinical characteristics of paraneoplastic pemphigus in our casemissed (severe oral involvement in the erythema-multiforme like pattern, small airway occlusion, etc.), a possible role of the neoplasia (basal cell carcinoma) cannot be ruled out. In conclusion, we have firstly reported an elderly patient developing PV after being treated by ALA-PDT in order to highlight that ALA-PDT should be added to the list of possible triggers for PV. However, there is no conclusive evidence that the eruption of PV is caused by ALA-PDT. Accordingly, we suggest that the PV developed after ALA-PDT may be a haphazard more than an intrinsic relation. And a large case-control study is needed to further validate.
Conflict of interest The authors declare no conflict of interest.
Acknowledgement The present study was supported by grants from National Natural Science Foundation of China [81272990, 81472538], Multicenter clinical study of early diagnosis and
treatment for facial non-melanoma skin cancers, the sub-topic of Key project of Natural science foundation of Shanghai [15411950302], Clinical Science and Technology Innovation Project of Shanghai Hospital Development Center [SHDC12015123] and Key projects of Shanghai Municipal Commission of Health and Family Planning [201640016].
References [1] Guarneri C, Vaccaro M, Erosive pustular dermatosis of the scalp following topical methylaminolaevulinate photodynamic therapy, J Am Acad Dermatol. 60(2009) 521-522. doi: 10.1016/j.jaad.2008.09.006. [2] Rakvit P, Kerr AC, Ibbotson SH, Localized bullous pemphigoid induced by photodynamic therapy, Photodermatol Photoimmunol Photomed. 27(2011)(5) 251-253. doi: 10.1111/j.1600-0781.2011.00609.x. [3] Badri T, Hammami H, Lachkham A, Benmously-Mlika R, Mokhtar I, Fenniche S, Radiotherapy-induced pemphigus vulgaris with autoantibodies targeting a 110 kDa
epidermal
antigen,
Int
J
Dermatol.
50(2011)1475-9.
doi:
10.1111/j.1365-4632.2011.04889.x. [4] Naziroğlu M, Kökçam I, Simşek H, Karakilçik AZ, Lipid peroxidation and antioxidants in plasma and red blood cells from patients with pemphigus vulgaris, J Basic Clin Physiol Pharmacol. 14(2003) 31-42. [5] Abida O, Ben Mansour R, Gargouri B, Ben Ayed M, Masmoudi A, Turki H, Masmoudi H, Lassoued S, Catalase and Lipid Peroxidation Values in Serum of Tunisian Patients with Pemphigus Vulgaris and Foliaceus, Biol Trace Elem Res. 150(2012) 74-80. doi: 10.1007/s12011-012-9497-3 [6] Jang HW, Chun SH, Lee JM, Jeon J, Hashimoto T, Kim IH, Radiotherapy-induced pemphigus vulgaris, J Dermatol. 41(2014) 851-2. doi: 10.1111/1346-8138.12582.
Figure Legends Fig. 1. Clinical features of patients. Patients developed BCC lesions on her face(A). Brick red fluorescence of PpIX was observed on BCC lesions after incubation of 20% ALA cream 3 hours under the wood light (B). The lesions on face were improved after two ALA-PDT procedures (C).
Fig. 2. Clinical features of the pemphigus vulgaris on face (A) and on back (B). Histopathological diagnosis of pemphigus vulgaris. The facial pemphigus vulgaris lesions got improved with the treatment of methylprednisolone (C). Histopathology demonstrated suprabasilar and intraepidermal acantholysis with dermal infltrate composed of lymphocytes, neutrophils, and eosinophils (D, E). (D) 100x magnifcation of hematoxylin and eosin stain. (E) 400x magnifcation of hematoxylin and eosin stain (HE). Direct immunofluorescence of epidermal autoantibodies demonstrated intercellular deposition of complexes IgG (F).
Fig 1
Fig 2