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15. 7th Drug hypersensitivity meeting: part two

Author

Elera, J.D., Boteanu, C., Blanco, M.A.J., Gonzalez-Mendiola, R., García, I.C., Alvarez, A., Martinez, J.J.L., Garrido, J.M., Barona, C.T., Chorda, C.P., Salgueiro, R.L., Palacios, M.D., De Rojas, D.H.F., Acar, E.A., Aktas, A., Ermertcan, A.T., Temiz, C., Lin, C-Y, Hui, C-Y.R., Chang, Y-C, Yang, C-H, Chung, W-H, Carolino, F., Silva, D., De Castro, E.D., Cernadas, J.R., Ensina, L.F., Aranda, C., Nunes, I.C., Lacerda, A., Martins, A.M., Goudouris, E., Ribeiro, M., Da Silva Franco, J.F., Queiroz, L., Solé, D., Dalgiç, C.T., Sin, A.Z., Günsen, F.D., Bulut, G., Ardeniz, F.Ö., Gülbahar, O., Gökmen, E.N.M., Kokuludag, A., De Francisco, A.M.M., De Vicente Jiménez, T.M., Mendoza Parra, A.M., Burgos Pimentel, A.M., Luque, A.G., Amaral, L., Leão, L.C., Pinto, N., Belo, J., Marques, J., Carreiro-Martins, P., Leiria-Pinto, P., Chaabane, A., Romdhane, H.B., Fredj, N.B., Chadly, Z., Boughattas, N.A., Aouam, K., Uyttebroek, A.P., Bridts, C.H., Romano, A., Ebo, D.G., Sabato, V., Lopes, A., Cosme, J., Aguiar, R., Lourenço, T., Paes, M-J, Spínola-Santos, A., Pereira-Barbosa, M., Cruz, C.R., Dos Reis, R.P., Tomaz, E., Pires, A.P., Inácio, F., Benito-Garcia, F., Mota, I., Correia, M., Gaspar, Â., Chambel, M., Piedade, S., Morais-Almeida, M., Nakonechna, A., Antipkin, Y., Umanets, T., Pineda, F., Arribas, F., Lapshyn, V., Miranda, P.A., De La Cruz Hoyos, B., Blanco, A.J., Del Pozo, M., Vultaggio, A., Nencini, F., Pratesi, S., Matucci, A., Maggi, E., Cegec, I., Nahal, D.J., Turk, V.E., Aumiler, M.R., Ausperger, K.M., Kraljickovic, I., Simic, I., Yamaguchi, Y., Watanabe, T., Satoh, M., Tanegashima, T., Oda, K., Wada, H., Aihara, M., Lee, J.J., Choi, J.C., Lee, H.Y., Fernandes, R-A.R., Faria, E., Pita, J., Sousa, N., Ribeiro, C., Carrapatoso, I., Bom, A.T., Rodolfo, A., Dias-Castro, E., Voronova, M., Valle, D.K., Coronel, V.P., Chordá, C.P., Madamba, R.C.Y., Ferrer, M., Goikoetxea, M.J., D’Amelio, C., Bernad, A., Vega, O., Gastaminza, G., Bibián, B.L., Salazar, M.L., Vilà-Nadal, G., Roman, A.M.F., Ortega, J.D., Muñoz, M.G., Gancedo, S.Q., Moreno, M.R.C., Hofmeier, K.S., Barzylovych, V., Pola, B., Lluncor, M., Fiandor, A., Bellón, T., Domínguez, J., Quirce, S., Yang, M-S, Kim, S-S, Kim, S-H, Kang, H-R, Park, H-W, Cho, S-H, Min, K-U, Chang, Y-S, Delahaye, C., Flabbee, J., Waton, J., Bauvin, O., Barbaud, A., Fadhel, N.B., Gulin, S.J., Chiriac, A., Cardoso, B.K., Viseu, R., Moreira, A., Cadinha, S., Neves, A.C., Barreira, P., Malheiro, D., Da Silva, J.P., Jurakic-Toncic, R., Ljubojevic, S., Turcic, P., Gilissen, L., Huygens, S., Goossens, A., Andreu, I., Romero, A.M., Cabezas, P.G., Parejo, P.A., Del Carmen Plaza-Serón, M., Doña, I., Blanca-López, N., Flores, C., Galindo, M.L., Molina, A., Perkins, J.R., Cornejo-García, J.A., García-Agúndez, J.A., García-Martín, E., Campo, P., Canto, M.G., Blanca, M., Guéant-Rodríguez, R.M., Jurado-Escobar, R., Barrionuevo, E., Salas, M., Canto, G., Guéant, J-L, Usui, T., Tailor, A., Faulkner, L., Farrell, J., Alfirevic, A., Kevin Park, B., Naisbitt, D.J., Trelles, O., Guerrero, M.A., Upton, A., Ueta, M., Sawai, H., Sotozono, C., Tokunaga, K., Kinoshita, S., Sukasem, C., Satapornpong, P., Tempark, T., Rerknimitr, P., Pairayayutakul, K., Klaewsongkram, J., Koomdee, N., Jantararoungtong, T., Santon, S., Puangpetch, A., Intusoma, U., Tassaneeyakul, W., Theeramoke, V., Ramirez, E., Borobia, A.M., Tong, H., Castañer, J.L., De Abajo, F.J., Galvao, V.R., Pavlos, R., McKinnon, E., Williams, K., Beeghly-Fadiel, A., Phillips, E., Castells, M., Boni, E., Russello, M., Mauro, M., Ue, K.L., Rutkowski, K., Gomis, V.S., Ferre, J.F., Rodriguez, A.E., Reig, V.C., Sanchez, J.F., Breynaert, C., Van Hoeyveld, E., Schrijvers, R., Irigoyen, R.F., Collado, D., Vida, Y., Najera, F., Perez-Inestrosa, E., Mesa-Antunez, P., Mayorga, C., Torres, M.J., Tannert, L.K., Mortz, C.G., Skov, P.S., Bindslev-Jensen, C., Pfützner, W., Dörnbach, H., Visse, J., Rauber, M., Möbs, C., Elzagallaai, A.A., Chow, L., Abuzgaia, A.M., Rieder, M.J., Trubiano, J., Woolnough, E., Cheng, C., Kato, K., Azukizawa, H., Hanafusa, T., Katayama, I., Fujiyama, T., Hashizume, H., Umayahara, T., Ito, T., Tokura, Y., Silar, M., Zidarn, M., Rupnik, H., Korosec, P., Redwood, A.J., Strautins, K., White, K., Chopra, A., Konvinse, K., Leary, S., Mallal, S., Cabañas, R., Fiandor, A.M., Sullivan, A., Whitaker, P., Peckham, D., Haw, W.Y., Polak, M.E., Mcguire, C., Ardern-Jones, M.R., Aoyama, Y., Shiohara, T., Correia, S., Gelincik, A., Demir, S., Sen, F., Bozbey, H.U., Olgac, M., Unal, D., Coskun, R., Colakoglu, B., Buyuozturk, S., Çatin-Aktas, E., Deniz, G., Laguna, J.J., Dionicio, J., Fernandez, T., Olazabal, I., Ruiz, M.D., Lafuente, A., Núñez, J., Fernández, T.D., Palomares, F., Fernández, R., Sanchez, M.I., Ruiz, A., Ariza, A., Alonso, A.B., Garófalo, C.D., Matute, O.V., Puga, M.F., Lapresa, M.J.G., Lasarte, G.G., Thinnes, A., Merk, H.F., Baron, J.M., Leverkus, M., Balakirski, G., Gibson, A., Ogese, M., Al-Attar, Z., Yaseen, F., Meng, X., Jenkins, R., Farrel, J., Alhilali, K., Xue, Y., Illing, P., Mifsud, N., Fettke, H., Lai, J., Ho, R., Kwan, P., Purcell, A., Ogese, M.O., Betts, C., Thomson, P., Alhaidari, M., Berry, N., O’Neill, P.M., Alzahrani, A., Azoury, M.E., Fili, L., Bechara, R., Scornet, N., Nhim, C., Weaver, R., Claude, N., Joseph, D., Maillere, B., Parronchi, P., Pallardy, M., Villani, A.P., Rozières, A., Bensaïd, B., Tardieu, M., Albert, F., Mutez, V., Baysal, T., Maryanski, J., Nicolas, J-F, Kanagawa, O., Vocanson, M., Hung, S-L, Harrison, C.J., Jenkins, R.E., French, N.S., Montañez, M.I., Fernandez, T.D., Martin-Serrano, A., Molina, N., Wood, S., Pirmohamed, M., Martín-Serrano, Á., Pérez-Inestrosa, E., Pérez-Sala, D., Guzmán, A.E., Ko, T-M, Chen, Y-T, Wu, J-Y, Sánchez-Gómez, F.J., González-Morena, J.M., Arreola, A.M., Corona, J.A.B., Flores, S.M., Cherit, J.D., Figueroa, N.V.D., Flores, J.L.C., Perkins, J., Pérez-Alzate, D., Bogas, G., Marti, L.M.T., De La Losa, F.P., Poves, F.A., Lopez, J.T., Santiago, T.L., Elera, J.D., Boteanu, C., Blanco, M.A.J., Gonzalez-Mendiola, R., García, I.C., Alvarez, A., Martinez, J.J.L., Garrido, J.M., Barona, C.T., Chorda, C.P., Salgueiro, R.L., Palacios, M.D., De Rojas, D.H.F., Acar, E.A., Aktas, A., Ermertcan, A.T., Temiz, C., Lin, C-Y, Hui, C-Y.R., Chang, Y-C, Yang, C-H, Chung, W-H, Carolino, F., Silva, D., De Castro, E.D., Cernadas, J.R., Ensina, L.F., Aranda, C., Nunes, I.C., Lacerda, A., Martins, A.M., Goudouris, E., Ribeiro, M., Da Silva Franco, J.F., Queiroz, L., Solé, D., Dalgiç, C.T., Sin, A.Z., Günsen, F.D., Bulut, G., Ardeniz, F.Ö., Gülbahar, O., Gökmen, E.N.M., Kokuludag, A., De Francisco, A.M.M., De Vicente Jiménez, T.M., Mendoza Parra, A.M., Burgos Pimentel, A.M., Luque, A.G., Amaral, L., Leão, L.C., Pinto, N., Belo, J., Marques, J., Carreiro-Martins, P., Leiria-Pinto, P., Chaabane, A., Romdhane, H.B., Fredj, N.B., Chadly, Z., Boughattas, N.A., Aouam, K., Uyttebroek, A.P., Bridts, C.H., Romano, A., Ebo, D.G., Sabato, V., Lopes, A., Cosme, J., Aguiar, R., Lourenço, T., Paes, M-J, Spínola-Santos, A., Pereira-Barbosa, M., Cruz, C.R., Dos Reis, R.P., Tomaz, E., Pires, A.P., Inácio, F., Benito-Garcia, F., Mota, I., Correia, M., Gaspar, Â., Chambel, M., Piedade, S., Morais-Almeida, M., Nakonechna, A., Antipkin, Y., Umanets, T., Pineda, F., Arribas, F., Lapshyn, V., Miranda, P.A., De La Cruz Hoyos, B., Blanco, A.J., Del Pozo, M., Vultaggio, A., Nencini, F., Pratesi, S., Matucci, A., Maggi, E., Cegec, I., Nahal, D.J., Turk, V.E., Aumiler, M.R., Ausperger, K.M., Kraljickovic, I., Simic, I., Yamaguchi, Y., Watanabe, T., Satoh, M., Tanegashima, T., Oda, K., Wada, H., Aihara, M., Lee, J.J., Choi, J.C., Lee, H.Y., Fernandes, R-A.R., Faria, E., Pita, J., Sousa, N., Ribeiro, C., Carrapatoso, I., Bom, A.T., Rodolfo, A., Dias-Castro, E., Voronova, M., Valle, D.K., Coronel, V.P., Chordá, C.P., Madamba, R.C.Y., Ferrer, M., Goikoetxea, M.J., D’Amelio, C., Bernad, A., Vega, O., Gastaminza, G., Bibián, B.L., Salazar, M.L., Vilà-Nadal, G., Roman, A.M.F., Ortega, J.D., Muñoz, M.G., Gancedo, S.Q., Moreno, M.R.C., Hofmeier, K.S., Barzylovych, V., Pola, B., Lluncor, M., Fiandor, A., Bellón, T., Domínguez, J., Quirce, S., Yang, M-S, Kim, S-S, Kim, S-H, Kang, H-R, Park, H-W, Cho, S-H, Min, K-U, Chang, Y-S, Delahaye, C., Flabbee, J., Waton, J., Bauvin, O., Barbaud, A., Fadhel, N.B., Gulin, S.J., Chiriac, A., Cardoso, B.K., Viseu, R., Moreira, A., Cadinha, S., Neves, A.C., Barreira, P., Malheiro, D., Da Silva, J.P., Jurakic-Toncic, R., Ljubojevic, S., Turcic, P., Gilissen, L., Huygens, S., Goossens, A., Andreu, I., Romero, A.M., Cabezas, P.G., Parejo, P.A., Del Carmen Plaza-Serón, M., Doña, I., Blanca-López, N., Flores, C., Galindo, M.L., Molina, A., Perkins, J.R., Cornejo-García, J.A., García-Agúndez, J.A., García-Martín, E., Campo, P., Canto, M.G., Blanca, M., Guéant-Rodríguez, R.M., Jurado-Escobar, R., Barrionuevo, E., Salas, M., Canto, G., Guéant, J-L, Usui, T., Tailor, A., Faulkner, L., Farrell, J., Alfirevic, A., Kevin Park, B., Naisbitt, D.J., Trelles, O., Guerrero, M.A., Upton, A., Ueta, M., Sawai, H., Sotozono, C., Tokunaga, K., Kinoshita, S., Sukasem, C., Satapornpong, P., Tempark, T., Rerknimitr, P., Pairayayutakul, K., Klaewsongkram, J., Koomdee, N., Jantararoungtong, T., Santon, S., Puangpetch, A., Intusoma, U., Tassaneeyakul, W., Theeramoke, V., Ramirez, E., Borobia, A.M., Tong, H., Castañer, J.L., De Abajo, F.J., Galvao, V.R., Pavlos, R., McKinnon, E., Williams, K., Beeghly-Fadiel, A., Phillips, E., Castells, M., Boni, E., Russello, M., Mauro, M., Ue, K.L., Rutkowski, K., Gomis, V.S., Ferre, J.F., Rodriguez, A.E., Reig, V.C., Sanchez, J.F., Breynaert, C., Van Hoeyveld, E., Schrijvers, R., Irigoyen, R.F., Collado, D., Vida, Y., Najera, F., Perez-Inestrosa, E., Mesa-Antunez, P., Mayorga, C., Torres, M.J., Tannert, L.K., Mortz, C.G., Skov, P.S., Bindslev-Jensen, C., Pfützner, W., Dörnbach, H., Visse, J., Rauber, M., Möbs, C., Elzagallaai, A.A., Chow, L., Abuzgaia, A.M., Rieder, M.J., Trubiano, J., Woolnough, E., Cheng, C., Kato, K., Azukizawa, H., Hanafusa, T., Katayama, I., Fujiyama, T., Hashizume, H., Umayahara, T., Ito, T., Tokura, Y., Silar, M., Zidarn, M., Rupnik, H., Korosec, P., Redwood, A.J., Strautins, K., White, K., Chopra, A., Konvinse, K., Leary, S., Mallal, S., Cabañas, R., Fiandor, A.M., Sullivan, A., Whitaker, P., Peckham, D., Haw, W.Y., Polak, M.E., Mcguire, C., Ardern-Jones, M.R., Aoyama, Y., Shiohara, T., Correia, S., Gelincik, A., Demir, S., Sen, F., Bozbey, H.U., Olgac, M., Unal, D., Coskun, R., Colakoglu, B., Buyuozturk, S., Çatin-Aktas, E., Deniz, G., Laguna, J.J., Dionicio, J., Fernandez, T., Olazabal, I., Ruiz, M.D., Lafuente, A., Núñez, J., Fernández, T.D., Palomares, F., Fernández, R., Sanchez, M.I., Ruiz, A., Ariza, A., Alonso, A.B., Garófalo, C.D., Matute, O.V., Puga, M.F., Lapresa, M.J.G., Lasarte, G.G., Thinnes, A., Merk, H.F., Baron, J.M., Leverkus, M., Balakirski, G., Gibson, A., Ogese, M., Al-Attar, Z., Yaseen, F., Meng, X., Jenkins, R., Farrel, J., Alhilali, K., Xue, Y., Illing, P., Mifsud, N., Fettke, H., Lai, J., Ho, R., Kwan, P., Purcell, A., Ogese, M.O., Betts, C., Thomson, P., Alhaidari, M., Berry, N., O’Neill, P.M., Alzahrani, A., Azoury, M.E., Fili, L., Bechara, R., Scornet, N., Nhim, C., Weaver, R., Claude, N., Joseph, D., Maillere, B., Parronchi, P., Pallardy, M., Villani, A.P., Rozières, A., Bensaïd, B., Tardieu, M., Albert, F., Mutez, V., Baysal, T., Maryanski, J., Nicolas, J-F, Kanagawa, O., Vocanson, M., Hung, S-L, Harrison, C.J., Jenkins, R.E., French, N.S., Montañez, M.I., Fernandez, T.D., Martin-Serrano, A., Molina, N., Wood, S., Pirmohamed, M., Martín-Serrano, Á., Pérez-Inestrosa, E., Pérez-Sala, D., Guzmán, A.E., Ko, T-M, Chen, Y-T, Wu, J-Y, Sánchez-Gómez, F.J., González-Morena, J.M., Arreola, A.M., Corona, J.A.B., Flores, S.M., Cherit, J.D., Figueroa, N.V.D., Flores, J.L.C., Perkins, J., Pérez-Alzate, D., Bogas, G., Marti, L.M.T., De La Losa, F.P., Poves, F.A., Lopez, J.T., and Santiago, T.L.

Abstract

No abstract available

Published
2016

18. Improvement of the Ocular Prognosis of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A National Survey in Japan.

Author

Kojima M, Mieno H, Ueta M, Nakata M, Teramukai S, Sunaga Y, Ochiai H, Iijima M, Kokaze A, Watanabe H, Kurosawa M, Azukizawa H, Asada H, Watanabe Y, Yamaguchi Y, Aihara M, Ikezawa Z, Mizukawa Y, Ohyama M, Shiohara T, Hama N, Abe R, Hashizume H, Nakajima S, Nomura T, Kabashima K, Tohyama M, Hashimoto K, Takahashi H, Niihara H, Morita E, Sueki H, Kinoshita S, and Sotozono C

Subjects
Humans, Retrospective Studies, Japan epidemiology, Male, Female, Incidence, Middle Aged, Prognosis, Adult, Aged, Adolescent, Betamethasone therapeutic use, Betamethasone administration & dosage, Child, Young Adult, Surveys and Questionnaires, Child, Preschool, Aged, 80 and over, Stevens-Johnson Syndrome epidemiology, Stevens-Johnson Syndrome diagnosis, Glucocorticoids therapeutic use
Abstract

Purpose: To investigate the incidence and prognostic factors of ocular sequelae in Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) cases arising between 2016 and 2018 in Japan, and compare the findings with those presented in the previous 2005-2007 survey., Design: Retrospective, national trend survey., Methods: Dermatologic case report forms (CRFs) (d-CRFs) were sent to 257 institutions that treated at least 1 SJS/TEN case, and 508 CRFs were collected from 160 institutions. Ophthalmologic CRFs (o-CRFs) regarding patient demographic data, onset date, ocular findings (first appearance, day of worst severity, and final follow-up), topical treatment (betamethasone), outcome (survival or death), and ocular sequelae (visual disturbance, eye dryness) were sent to the ophthalmologists in those 160 institutions. The results of this survey were then compared with that of the previous 2005-2007 survey., Results: A total of 240 cases (SJS/TEN: 132/108) were included. The incidence of ocular sequelae incidence was 14.0%, a significant decrease from the 39.2% in the previous survey (SJS/TEN: 87/48). In 197 (82.1%) of the cases, systemic treatment was initiated within 3 days after admission, an increase compared to the previous survey (ie, treatment initiated in 82 [60.7%] of 135 cases). Of the 85 cases with an Acute Ocular Severity Score of 2 and 3, 62 (72.9%) received corticosteroid pulse therapy and 73 (85.9%) received 0.1% betamethasone therapy; an increase compared to the 60.0% and 70.8%, respectively, in the previous survey. Ocular-sequelae-associated risk factors included Acute Ocular Severity Score (P < .001) and specific year in the survey (P < .001)., Conclusions: The ophthalmologic prognosis of SJS/TEN has dramatically improved via early diagnosis, rapid assessment of acute ocular severity, and early treatment., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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19. Differential Effects of HLA-B∗15:11 and HLA-A∗31:01 on Carbamazepine-Induced Cutaneous Adverse Reactions.

Author

Fukunaga K, Tsukagoshi E, Kurata M, Mizukawa Y, Niihara H, Morita E, Watanabe Y, Yamaguchi Y, Watanabe H, Nakajima S, Nomura T, Kabashima K, Tohyama M, Azukizawa H, Asada H, Hasegawa A, Hama N, Ozeki T, Mashimo Y, Sekine A, Matsunaga K, Tanaka Y, Nakamura R, Abe R, Mushiroda T, and Saito Y

Subjects
Humans, HLA-B Antigens genetics, Skin, Carbamazepine adverse effects, HLA-A Antigens genetics, Drug-Related Side Effects and Adverse Reactions, Stevens-Johnson Syndrome
Published
2024
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20. Development and Validation of a Novel Score to Predict Mortality in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: CRISTEN.

Author

Hama N, Sunaga Y, Ochiai H, Kokaze A, Watanabe H, Kurosawa M, Azukizawa H, Asada H, Watanabe Y, Yamaguchi Y, Aihara M, Mizukawa Y, Ohyama M, Hashizume H, Nakajima S, Nomura T, Kabashima K, Tohyama M, Hasegawa A, Takahashi H, Mieno H, Ueta M, Sotozono C, Niihara H, Morita E, Brüggen MC, Feingold IM, Jeschke MG, Dodiuk-Gad RP, Oppel EM, French LE, Chen WT, Chung WH, Chu CY, Kang HR, Ingen-Housz-Oro S, Nakamura K, Sueki H, and Abe R

Subjects
Humans, Female, Male, Middle Aged, Aged, Adult, Retrospective Studies, Risk Factors, Aged, 80 and over, Severity of Illness Index, Young Adult, Adolescent, Prognosis, Stevens-Johnson Syndrome mortality, Stevens-Johnson Syndrome diagnosis
Abstract

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening, severe mucocutaneous adverse reactions. Severity prediction at early onset is urgently required for treatment. However, previous prediction scores have been based on data of blood tests., Objective: This study aimed to present a novel score that predicts mortality in patients with SJS/TEN in the early stages based on only clinical information., Methods: We retrospectively evaluated 382 patients with SJS/TEN in a development study. A clinical risk score for TEN (CRISTEN) was created according to the association of potential risk factors with death. We calculated the sum of these risk factors using CRISTEN, and this was validated in a multinational survey of 416 patients and was compared with previous scoring systems., Results: The significant risk factors for death in SJS/TEN comprised 10 items, including patients' age of ≥65 years, ≥10% body surface area involvement, the use of antibiotics as culprit drugs, the use of systemic corticosteroid therapy before the onset, and mucosal damage affecting the ocular, buccal, and genital mucosa. Renal impairment, diabetes, cardiovascular disease, malignant neoplasm, and bacterial infection were included as underlying diseases. The CRISTEN model showed good discrimination (area under the curve [AUC] = 0.884) and calibration. In the validation study, the AUC was 0.827, which was statistically comparable to those of previous systems., Conclusion: A scoring system based on only clinical information was developed to predict mortality in SJS/TEN and was validated in an independent multinational study. CRISTEN may predict individual survival probabilities and direct the management and therapy of patients with SJS/TEN., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Published
2023
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22. Risk factors for sepsis and effects of pretreatment with systemic steroid therapy for underlying condition in SJS/TEN patients: Results of a nationwide cross-sectional survey in 489 Japanese patients.

Author

Sunaga Y, Hama N, Ochiai H, Kokaze A, Lee ES, Watanabe H, Kurosawa M, Azukizawa H, Asada H, Watanabe Y, Yamaguchi Y, Aihara M, Mizukawa Y, Ohyama M, Abe R, Hashizume H, Nakajima S, Nomura T, Kabashima K, Tohyama M, Takahashi H, Mieno H, Ueta M, Sotozono C, Niihara H, Morita E, and Sueki H

Subjects
Cross-Sectional Studies, Humans, Japan epidemiology, Retrospective Studies, Risk Factors, Steroids adverse effects, Sepsis complications, Sepsis drug therapy, Sepsis epidemiology, Stevens-Johnson Syndrome drug therapy, Stevens-Johnson Syndrome epidemiology, Stevens-Johnson Syndrome etiology
Abstract

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). Sepsis has been shown to be the main cause of death in SJS/TEN. The European SCAR study reported that 14.8 % of SJS/TEN patients were receiving systemic steroid therapy for their underlying condition prior to onset. However, it remained unclear whether this factor affected the mortality rate., Objective: This study was performed to identify risk factors for sepsis in SJS/TEN patients. In addition, we compared patients who had and had not received systemic steroid therapy for their underlying condition., Methods: A primary survey regarding the numbers of SJS/TEN patients between 2016 and 2018 was sent to 1205 institutions in Japan. A secondary survey seeking more detailed information was sent to institutions reporting SJS/TEN patients. We analyzed 315 SJS patients and 174 TEN patients using a logistic regression model, Wilcoxon's rank-sum test, χ 2 test, and Fisher's exact test., Results: Significant risk factors for sepsis included TEN, diabetes, and intensive care unit (ICU) admission. The mortality rate was significantly higher among patients with sepsis. Patients who had received systemic steroid therapy had a lower incidence of fever, and showed a higher mortality rate., Conclusion: Based on a nationwide epidemiological survey of SJS/TEN in Japan, we identified risk factors for sepsis and found that patients who had received steroid therapy for their underlying condition had a lower incidence of fever and a higher mortality rate., Competing Interests: Conflict of Declaration The authors have no conflict of interest to declare., (Copyright © 2022 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Published
2022
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23. The nationwide epidemiological survey of Stevens-Johnson syndrome and toxic epidermal necrolysis in Japan, 2016-2018.

Author

Sunaga Y, Kurosawa M, Ochiai H, Watanabe H, Sueki H, Azukizawa H, Asada H, Watanabe Y, Yamaguchi Y, Aihara M, Mizukawa Y, Ohyama M, Hama N, Abe R, Hashizume H, Nakajima S, Nomura T, Kabashima K, Tohyama M, Takahashi H, Mieno H, Ueta M, Sotozono C, Niihara H, Morita E, and Kokaze A

Subjects
Adult, Aged, Aged, 80 and over, Dose-Response Relationship, Drug, Female, Humans, Japan epidemiology, Male, Middle Aged, Mortality, Prevalence, Retrospective Studies, Severity of Illness Index, Stevens-Johnson Syndrome diagnosis, Stevens-Johnson Syndrome drug therapy, Stevens-Johnson Syndrome etiology, Treatment Outcome, Glucocorticoids administration & dosage, Stevens-Johnson Syndrome epidemiology
Abstract

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). The first national epidemiological survey of SJS/TEN was carried out in 2008. We conducted a new survey to identify changes from the previous survey., Objective: The present survey aimed to estimate the number of SJS/TEN patients in Japan between 2016 and 2018 (primary survey) and to clarify clinical epidemiological profiles (secondary survey)., Methods: A primary survey asking for numbers of SJS/TEN patients during the study period was sent to 1205 institutions nationwide. A secondary survey was sent to institutions reporting SJS/TEN patients, seeking detailed information., Results: Yearly prevalence per million was 2.5 for SJS and 1 for TEN. The secondary survey allowed analysis of 315 SJS cases and 174 TEN cases from 160 institutions. Mean age was 53.9 years in SJS, and 61.8 years in TEN. Mortality rate was 4.1 % for SJS and 29.9 % for TEN. In TEN, mean age and mortality rates had increased from the previous survey. The ratio of expected to observed mortality calculated by SCORTEN score was lowest with high-dose steroid therapy (0.40), followed by steroid pulse therapy (0.52)., Conclusion: The present findings suggest that the mortality rate of TEN has increased because of increases in mean ages of patients and patients with malignant neoplasm as underlying disease. When comparing the ratio of expected mortality to actual mortality, high-dose steroid therapy achieved the greatest reduction in mortality., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Published
2020
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24. Acquired agminated melanocytic nevus in the acral area is a potential mimicker of acral lentiginous melanoma: A three-case series report and published work review.

Author

Ogawa K, Fujimoto M, Takai T, Mitsui Y, Iwasa K, Ohsita A, Komori S, Asai J, Azukizawa H, Miyagawa F, Yurugi S, Kuwahara M, Sasaki C, Ando J, and Asada H

Subjects
Dermoscopy, Diagnosis, Differential, Humans, Melanoma diagnosis, Nevus, Pigmented diagnosis, Skin Neoplasms diagnosis
Abstract

Agminated nevus refers to a clustered group of melanocytic nevi confined to a localized area of the body. It rarely involves acral skin, but recognition of acquired agminated nevus (AAN) in the acral area is clinically important because it may mimic acral lentiginous melanoma (ALM). However, acral AAN has only been described in a few case reports and its clinical characteristics remain unclear. We report three additional cases of acral AAN to further analyze the differential points between ALM. Clinical images, including those of dermoscopy, of three cases of acral AAN were reviewed. The lesions were located on the sole or lateral border of the foot. All acral AAN were flat and large in size (>20 mm in greatest dimension), and associated with asymmetry and irregular border. However, no parallel ridge pattern suggesting ALM was observed on dermoscopy. In two patients, the lesions on the sole were totally resected; microscopic evaluation of these two lesions confirmed junctional nests of banal melanocytes. AAN lesions on the sole with chronic mechanical pressure are slightly larger and more diffuse; thus, they may be more likely to be overdiagnosed as malignancy upon inspection than those in the non-acral area. Understanding the concept of the disease and careful dermoscopic evaluation leads to an accurate diagnosis., (© 2020 Japanese Dermatological Association.)

Published
2020
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25. HLA-B*51:01 and CYP2C9*3 Are Risk Factors for Phenytoin-Induced Eruption in the Japanese Population: Analysis of Data From the Biobank Japan Project.

Author

Hikino K, Ozeki T, Koido M, Terao C, Kamatani Y, Mizukawa Y, Shiohara T, Tohyama M, Azukizawa H, Aihara M, Nihara H, Morita E, Murakami Y, Kubo M, and Mushiroda T

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Asian People genetics, Biological Specimen Banks, Case-Control Studies, Child, Drug Eruptions genetics, Female, Genotype, Humans, Japan, Male, Middle Aged, Retrospective Studies, Risk Factors, Young Adult, Anticonvulsants adverse effects, Cytochrome P-450 CYP2C9 genetics, Drug Eruptions etiology, HLA-B51 Antigen genetics, Phenytoin adverse effects
Abstract

CYP2C9*3 and HLA-B alleles are reportedly associated with phenytoin-induced eruption in some East Asian populations; however, this finding is not readily applicable to the Japanese population. Thus, we aimed to investigate the risk alleles using samples and data from BioBank Japan. A total of 747 patients (24 cases and 723 tolerant controls) were selected for analysis. Case-control association studies were conducted, using CYP2C9*3, CYP2C9*27, CYP2C19*2, CYP2C19*3, and HLA-B allele genotype data. CYP2C9*3 carrier status was significantly associated with phenytoin-induced eruption (P = 0.0022, odds ratio 7.05, 95% confidence interval, 2.44-20.4). HLA-B*51:01 showed the most prominent association (P = 0.010, odds ratio 3.19, 95% confidence interval, 1.37-7.48). Including both of these features improved predictive performance, measured as area under the receiver operating characteristic curve, by 10%. CYP2C9*3 and HLA-B*51:01 allele carrier statuses are significantly associated with phenytoin-induced eruption; thus, checking this carrier status before prescription would decrease the incidence of phenytoin-induced eruption in clinical practice., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Published
2020
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26. Confusion in determination of two types of cutaneous adverse reactions to drugs, maculopapular eruption and erythema multiforme, among the experts: A proposal of standardized terminology.

Author

Hashizume H, Abe R, Azukizawa H, Fujiyama T, Hama N, Mizukawa Y, Morita E, Nakagawa Y, Nakajima S, Niihara H, Teraki Y, Tohyama M, Watanabe H, and Tokura Y

Subjects
Drug Eruptions diagnosis, Erythema Multiforme chemically induced, Exanthema chemically induced, Female, Humans, Male, Dermatology standards, Drug Eruptions classification, Erythema Multiforme diagnosis, Exanthema diagnosis, Terminology as Topic
Abstract

The clinical classification of cutaneous adverse reactions by drugs should be clearly distinguished to avoid conceptual confusion and inconsistency. Although dermatologists appear to have established a roughly common consensus for cutaneous adverse reactions, some types are more rigorously defined than other, possibly misleading classifications. To assess the consensus on the clinical classifications, we investigated the concordance rate of diagnosis by Japanese experts through a snap visual inspection of various clinical pictures exhibiting erythema multiforme and maculopapular eruption types of cutaneous adverse reactions. The experts were shown images on a screen and were then asked to decide whether to classify cases as maculopapular eruption or erythema multiforme type, and the concordance rates were calculated. Overall, the mean concordance rate was 71.6% (standard deviation, 17.3%), and only 33.8% of cases had a 90% or more concordance rate. Our study shows that the determinations of erythema multiforme and maculopapular eruption types by the existing classification criteria were confusing even among experts, which prompted us to standardize the terminology. We propose clinically defining erythema multiforme type as generalized macules mainly of 1 cm or more with a tendency of elevation and coalescence, and maculopapular eruption type as generalized erythema other than erythema multiforme type. Currently, the clinical definitions of cutaneous adverse reactions are poorly described, which may be problematic upon analyzing large volumes of data. Our proposal for a new terminology will enhance the accuracy and consistency of information for the correct analysis of cutaneous adverse reactions., (© 2019 Japanese Dermatological Association.)

Published
2020
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27. Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms or non-drug-related erythroderma with a persistent human herpesvirus 6 infection.

Author

Mitsui Y, Ogawa K, Miyagawa F, Azukizawa H, Yoshikawa T, and Asada H

Subjects
Administration, Oral, Aged, Cytomegalovirus isolation & purification, Dermatitis, Exfoliative drug therapy, Dermatitis, Exfoliative immunology, Dermatitis, Exfoliative virology, Diagnosis, Differential, Drug Hypersensitivity Syndrome drug therapy, Drug Hypersensitivity Syndrome immunology, Drug Hypersensitivity Syndrome virology, Female, Herpesvirus 6, Human isolation & purification, Humans, Lymphocyte Activation drug effects, Lymphocyte Activation immunology, Prednisolone administration & dosage, Viral Load, Virus Activation immunology, Cytomegalovirus immunology, Dermatitis, Exfoliative diagnosis, Drug Hypersensitivity Syndrome diagnosis, Herpesvirus 6, Human immunology
Published
2020
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28. Impact of Jumihaidokuto (Shi-Wei-Bai-Du-Tang) on Treatment of Chronic Spontaneous Urticaria: A Randomized Controlled Study.

Author

Murota H, Azukizawa H, and Katayama I

Subjects
Adult, Aged, Chronic Urticaria pathology, Drug Therapy, Combination methods, Female, Humans, Male, Middle Aged, Plant Extracts pharmacology, Quality of Life, Severity of Illness Index, Treatment Outcome, Young Adult, Chronic Urticaria drug therapy, Histamine Antagonists administration & dosage, Plant Extracts administration & dosage
Abstract

Objective: To study the effect of Jumihaidokuto (Shi-Wei-Bai-Du-Tang, ) in the management of chronic spontaneous urticaria., Methods: A randomized two-arm, parallel group study was conducted to compare the effect of Jumihaidokuto (6 g daily) with a control for 8 weeks. Concomitant therapy (e.g., antihistamines) was continued. Twenty-one subjects with severe chronic urticaria were enrolled in this study. The primary treatment outcome was the severity score proposed by the Japanese Dermatological Association. Secondary outcomes were quality of life (Skindex-16), itch intensity (Visual Analogue Scale), and patients' subjective disability due to wheal or itch. After the subjects were randomly assigned to groups by block randomization, 10 received Jumihaidokuto, and 11 did not. All subjects had already taken antihistamines., Results: Improvement was significant when comparing the severity score of the Jumihaidokuto group with that of the control group (P<0.01). Skindex-16 values for both groups gradually decreased in the same fashion., Conclusion: Concomitant use of Jumihaidokuto with antihistamine was more effective than antihistamine alone in the management of chronic idiopathic urticaria. (Trial Registration No. UMIN000007251).

Published
2019
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29. Superficial sebaceous carcinoma: The correlations between the clinical, dermoscopic and histopathological findings of a rare variant of sebaceous carcinoma.

Author

Mitsui Y, Ogawa K, Fukumoto T, Sasaki C, Sonobe H, Azukizawa H, Koga K, and Asada H

Subjects
Adenocarcinoma, Sebaceous pathology, Aged, Biopsy, Dermoscopy, Diagnosis, Differential, Female, Humans, Keratosis, Actinic diagnosis, Keratosis, Actinic pathology, Sebaceous Gland Neoplasms pathology, Sebaceous Glands diagnostic imaging, Skin diagnostic imaging, Skin pathology, Adenocarcinoma, Sebaceous diagnosis, Sebaceous Gland Neoplasms diagnosis, Sebaceous Glands pathology
Published
2019
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30. Facial pustules due to drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms may histopathologically mimic eosinophilic pustular folliculitis: A case report.

Author

Ogawa K, Mitsui Y, Miyamoto S, Nakamura-Nishimura Y, Nakanishi Y, Azukizawa H, and Asada H

Subjects
Aged, Face pathology, Humans, Male, Drug Hypersensitivity Syndrome metabolism, Drug Hypersensitivity Syndrome pathology, Eosinophilia metabolism, Eosinophilia pathology, Eosinophils metabolism, Eosinophils pathology, Exanthema metabolism, Exanthema pathology, Folliculitis metabolism, Folliculitis pathology, Hair Follicle metabolism, Hair Follicle pathology, Skin Diseases, Vesiculobullous metabolism, Skin Diseases, Vesiculobullous pathology
Abstract

Pustules with facial and/or neck edema is one characteristic feature of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) at the early stage. Although several retrospective histopathologic studies on DIHS/DRESS have been reported, the detailed histopathologic findings of facial pustules for DIHS/DRESS are unavailable. We herein report a case of DIHS/DRESS with facial pustules that was histopathologically similar to eosinophilic pustular folliculitis (EPF). Eosinophilic infiltration into expanded follicles and sebaceous glands, which is highly characteristic of EPF, was detected in pustules due to DIHS/DRESS in this case. There are numerous pathophysiological similarities between DIHS/DRESS and EPF, which may cause their histopathologic similarity. Our findings suggest that facial pustules of DIHS/DRESS may histopathologically mimic EPF., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2019
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31. Anti-PL-12 antibody-positive antisynthetase syndrome with recurrent digital ulcers.

Author

Miyagawa F, Azukizawa H, Mimori T, and Asada H

Subjects
Adult, Autoantibodies immunology, Female, Humans, Myositis blood, Myositis immunology, Raynaud Disease blood, Raynaud Disease pathology, Recurrence, Skin immunology, Skin pathology, Skin Ulcer blood, Skin Ulcer pathology, Amino Acyl-tRNA Synthetases immunology, Autoantibodies blood, Myositis complications, Raynaud Disease immunology, Skin Ulcer immunology
Published
2019
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32. Revival of favus in Japan caused by Trichophyton schoenleinii.

Author

Iwasa K, Ogawa K, Azukizawa H, Tanabe H, Iwanaga T, Anzawa K, Mochizuki T, and Asada H

Subjects
Female, Hair Follicle pathology, Humans, Japan, Middle Aged, Tinea Favosa drug therapy, Tinea Favosa microbiology, Treatment Outcome, Antifungal Agents therapeutic use, Hair Follicle microbiology, Tinea Favosa diagnosis, Trichophyton isolation & purification
Abstract

Favus is a type of dermatophytosis known to produce yellow scutula around hair follicles. Most cases of this disease worldwide are infections of Trichophyton schoenleinii. Favus has rarely been reported in Japan throughout the last four decades, and T. schoenleinii has not been clinically isolated in any case during the period. Here, we report a case of favus of vellus hair observed in a 63-year-old Japanese woman. Fungal culture showed negative; however, we detected fungal elements in the crust and hair bulbs by Grocott staining. Pathogenic fungi were identified as T. schoenleinii by polymerase chain reaction-based DNA sequencing, targeting the internal transcribed spacer regions of the rRNA gene using the formalin-fixed, paraffin-embedded tissue sample. She was successfully treated with p.o. administration of terbinafine and topical application of luliconazole cream., (© 2019 Japanese Dermatological Association.)

Published
2019
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33. Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms due to lamotrigine differs from that due to other drugs.

Author

Tashiro Y, Azukizawa H, Asada H, Niihara H, Morita E, Yamauchi T, Mizukawa Y, Kusakabe Y, Numazawa S, Izumi M, Sueki H, and Watanabe H

Subjects
Adult, Drug Hypersensitivity Syndrome blood, Epilepsy drug therapy, Female, Humans, Leukocyte Count, Male, Middle Aged, Retrospective Studies, Anticonvulsants adverse effects, Drug Hypersensitivity Syndrome etiology, Lamotrigine adverse effects
Abstract

Drug-induced hypersensitivity syndrome (DIHS), also referred to as drug reaction with eosinophilia and systemic symptoms (DRESS), is a multi-organ systemic drug reaction characterized by hematological abnormalities and reactivation of human herpesvirus-6 (HHV-6). DIHS/DRESS is typically associated with a limited number of drugs, such as the anticonvulsants. Our group has treated 12 patients for DIHS/DRESS due to lamotrigine (LTG), but their presentation differed from that of patients with DIHS/DRESS caused by other drugs. The aim of the present study was to identify significant differences between DIHS/DRESS caused by LTG versus other drugs. We retrospectively reviewed data of 12 patients with DIHS/DRESS caused by LTG and 32 patients with DIHS/DRESS due to other drugs. The increase in alanine aminotransferase level was significantly milder in the LTG group than the DIHS/DRESS group due to other drugs. The percentage of atypical lymphocytes in the blood during DIHS/DRESS was lower in the LTG group. Serum levels of lactate dehydrogenase and thymus and activation-regulated chemokine were also lower in the LTG group. There were fewer DIHS/DRESS patients with HHV-6 reactivation in the LTG group than in the group treated with other drugs. Lymphocyte transformation after DIHS/DRESS onset was faster in the LTG group. The two groups did not differ with respect to the interval from first drug intake to rash, white blood cell count, blood eosinophilia or DRESS score. There were no significant histopathological differences between the two groups. The features of LTG-associated DIHS/DRESS and DIHS/DRESS due to other drugs differ., (© 2019 Japanese Dermatological Association.)

Published
2019
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34. First Japanese case of atypical Spitz tumor exhibiting ROS1 rearrangement.

Author

Mitsui Y, Ogawa K, Takeda M, Nakanishi T, Azukizawa H, and Asada H

Subjects
Adult, Ear, Humans, Japan, Male, Nevus, Epithelioid and Spindle Cell diagnosis, Nevus, Epithelioid and Spindle Cell pathology, Skin pathology, Skin Neoplasms diagnosis, Skin Neoplasms pathology, Gene Rearrangement, Nevus, Epithelioid and Spindle Cell genetics, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins genetics, Skin Neoplasms genetics
Published
2018
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35. Preoperative assessment of tumour thickness and vascularity using high-frequency ultrasonography in ten cases of cutaneous melanoma.

Author

Shobatake C, Miyagawa F, Ogawa K, Azukizawa H, Hirai T, Kuwahara M, and Asada H

Subjects
Adult, Aged, Aged, 80 and over, Biopsy, Needle, Female, Humans, Immunohistochemistry, Male, Melanoma blood supply, Melanoma surgery, Middle Aged, Preoperative Care methods, Regional Blood Flow, Sampling Studies, Sensitivity and Specificity, Skin blood supply, Skin pathology, Skin Neoplasms blood supply, Skin Neoplasms surgery, Melanoma, Cutaneous Malignant, Melanoma diagnostic imaging, Melanoma pathology, Skin Neoplasms diagnostic imaging, Skin Neoplasms pathology, Ultrasonography, Doppler, Color methods
Published
2018
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36. First Japanese case report of atypical Spitz tumor with an ALK rearrangement.

Author

Ogawa K, Fukumoto T, Azukizawa H, Takeda M, and Asada H

Subjects
Biomarkers, Tumor genetics, Child, Facial Neoplasms genetics, Gene Rearrangement, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Japan, Male, Nevus, Epithelioid and Spindle Cell genetics, Skin Neoplasms genetics, Anaplastic Lymphoma Kinase genetics, Facial Neoplasms pathology, Nevus, Epithelioid and Spindle Cell pathology, Skin Neoplasms pathology
Published
2017
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37. Development of novel double-decker microneedle patches for transcutaneous vaccine delivery.

Author

Ono A, Azukizawa H, Ito S, Nakamura Y, Asada H, Quan YS, Kamiyama F, Katayama I, Hirobe S, and Okada N

Subjects
Administration, Cutaneous, Adult, Animals, Antigens administration & dosage, Antigens immunology, Female, Hemagglutinins, Viral administration & dosage, Hemagglutinins, Viral immunology, Humans, Immunoglobulin G blood, Influenza Vaccines administration & dosage, Influenza Vaccines adverse effects, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Middle Aged, Rats, Wistar, Skin metabolism, Skin Irritancy Tests, Young Adult, Drug Delivery Systems adverse effects, Microinjections adverse effects, Needles adverse effects, Transdermal Patch adverse effects, Vaccination instrumentation
Abstract

Microneedle (MN) patches have great potential as transcutaneous vaccine delivery devices because MNs can effectively deliver vaccine antigen into the skin through the micropores formed in the stratum corneum by low-invasive and painless skin puncturing. This study aims to develop novel double-decker MN patches which have not only high safety and efficacy but also broad applicability to various vaccine antigens. We developed two types of MN patches (PGA-MN and Nylon-MN) that are made from polyglycolic acid and Nylon-6. In pre-clinical studies, both MN patches could demonstrably deliver antigens into resected human dermal tissue, prolong antigen deposition and increase antigen-specific IgG levels after vaccination compared with conventional injections. We demonstrated both MN patches could be safely applied to human skin because no broken MNs or significant skin irritation were observed after applications in the clinical research. PGA-MN was suggested to be superior to Nylon-MN regarding human skin puncturability based on measurements of transepidermal water loss and needle failure force. A high content of tetravalent influenza hemagglutinin antigens loaded on PGA-MN could stably maintain HA titers at 35°C for 1year. Overall, double-decker MN patches can reliably and safely puncture human skin and are promising as effective transcutaneous vaccine delivery devices., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Published
2017
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38. Novel interferon-γ enzyme-linked immunoSpot assay using activated cells for identifying hypersensitivity-inducing drug culprits.

Author

Kato K, Kawase A, Azukizawa H, Hanafusa T, Nakagawa Y, Murota H, Sakaguchi S, Asada H, and Katayama I

Subjects
Adult, Aged, Aged, 80 and over, Biomarkers blood, Cells, Cultured, Drug Eruptions blood, Drug Eruptions immunology, Enzyme-Linked Immunospot Assay, Female, Humans, Interferon-gamma immunology, Male, Middle Aged, Predictive Value of Tests, Reproducibility of Results, T-Lymphocytes immunology, T-Lymphocytes metabolism, Young Adult, Drug Eruptions diagnosis, Interferon-gamma blood, Interferon-gamma Release Tests, Lymphocyte Activation drug effects, T-Lymphocytes drug effects
Abstract

Background: The drug-induced lymphocyte stimulation test (DLST), also referred to as lymphocyte transformation test (LTT), is used to identify the culprit drug in cases of cutaneous adverse drug reactions (cADR). Although DLST is a widely used in vitro test, its sensitivity and specificity are unsatisfactory. Recent reports suggest that the detection of drug-induced interferon (IFN)-γ production using enzyme-linked immunoSpot (ELISpot) assay (conventional IFN-γ ELISpot) is useful for identifying culprit drugs in cADR cases., Objective: The aim of this study was to establish a novel method for identifying culprit drugs in patients with cADR by efficiently detecting drug-specific IFN-γ production using activated cells., Methods: Sixteen patients with cADR, including drug-induced hypersensitivity syndrome, erythema multiforme-like eruption, maculopapular exanthema, Stevens-Johnson syndrome, and toxic epidermal necrolysis, caused by clinically convincing culprit drugs were enrolled in this study. In some cases, the blood samples were obtained at two or three different time points. Peripheral blood mononuclear cells (PBMCs) from total 20 samples were analyzed using both the DLST and drug-induced conventional IFN-γ ELISpot. In addition, drug-induced IFN-γ ELISpot was performed using PBMCs, which were stimulated with anti-cluster of differentiation (CD)-3/CD28 antibody-coated microbeads and interleukin (IL)-2 for 7 days before exposure to the culprit drugs (modified IFN-γ ELISpot)., Results: Among the culprit drugs tested in each patient, the modified IFN-γ ELISpot was positive in 17 samples (13 patients) while DLST and conventional IFN-γ ELISpot were positive in eight and four samples (six and three patients), respectively., Conclusion: The modified IFN-γ ELISpot using activated PBMCs was more sensitive than the conventional IFN-γ ELISpot was for detecting drug-induced IFN-γ production, which could be a useful in vitro tool for identifying culprit drugs in cADR cases., (Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Published
2017
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39. Successful treatment with gefitinib after Stevens-Johnson syndrome associated with afatinib therapy in a patient with adenocarcinoma of the lung.

Author

Otsuka T, Tanaka A, Azukizawa H, Sasaki S, Ishijima M, Matsuki T, Osa A, Nakatani T, Kuroyama M, Hirata H, and Kijima T

Abstract

We report a case of a 65-year-old woman with stage IV lung adenocarcinoma who experienced Stevens-Johnson syndrome (SJS) during afatinib therapy. The patient received afatinib as the first-line therapy after the confirmation of harboring an exon 19 deletion mutation in the epidermal growth factor receptor (EGFR) gene. The patient presented with multiple erythematous papules mainly on the body trunk and thigh 32 days after afatinib administration. Subsequently, diffuse erosions of oral mucosa and purpuric macules with flat atypical targets emerged. Skin biopsy specimen showed the histology compatible with epidermal necrosis and the patient was diagnosed as having SJS. The symptoms of SJS were recovered by systemic steroid and immunoglobulin treatment. Gefitinib was administered as the third-line therapy after the second-line therapy with carboplatin plus pemetrexed had failed. Tumor shrinkage was obtained shortly and has been maintained without the recurrence of SJS. Rechallenge of tyrosine kinase inhibitor by gefitinib could be an alternative treatment option in patients who experienced SJS by afatinib., Competing Interests: Compliance with ethical standardsTakashi Kijima received lecture fee from AstraZeneca Co. Ltd. and Boehringer Ingelheim Co. Ltd., and the others declare that they have no conflict of interest.

Published
2016
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40. Broad and Largely Concordant Molecular Changes Characterize Tolerogenic and Immunogenic Dendritic Cell Maturation in Thymus and Periphery.

Author

Ardouin L, Luche H, Chelbi R, Carpentier S, Shawket A, Montanana Sanchis F, Santa Maria C, Grenot P, Alexandre Y, Grégoire C, Fries A, Vu Manh TP, Tamoutounour S, Crozat K, Tomasello E, Jorquera A, Fossum E, Bogen B, Azukizawa H, Bajenoff M, Henri S, Dalod M, and Malissen B

Subjects
Animals, Antigen Presentation, Cell Differentiation, Cells, Cultured, Interferon Regulatory Factors genetics, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Chemokine metabolism, Toll-Like Receptors immunology, Transcriptome, Virus Replication, Central Tolerance, Dendritic Cells immunology, Peripheral Tolerance, T-Lymphocytes, Regulatory immunology, Thymus Gland immunology
Abstract

Dendritic cells (DCs) are instrumental in the initiation of T cell responses, but how thymic and peripheral tolerogenic DCs differ globally from Toll-like receptor (TLR)-induced immunogenic DCs remains unclear. Here, we show that thymic XCR1(+) DCs undergo a high rate of maturation, accompanied by profound gene-expression changes that are essential for central tolerance and also happen in germ-free mice. Those changes largely overlap those occurring during tolerogenic and, more unexpectedly, TLR-induced maturation of peripheral XCR1(+) DCs, arguing against the commonly held view that tolerogenic DCs undergo incomplete maturation. Interferon-stimulated gene (ISG) expression was among the few discriminators of immunogenic and tolerogenic XCR1(+) DCs. Tolerogenic XCR1(+) thymic DCs were, however, unique in expressing ISGs known to restrain virus replication. Therefore, a broad functional convergence characterizes tolerogenic and immunogenic XCR1(+) DC maturation in the thymus and periphery, maximizing antigen presentation and signal delivery to developing and to conventional and regulatory mature T cells., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Published
2016
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41. B-1 B cell progenitors transiently and partially express keratin 5 during differentiation in bone marrow.

Author

Hanafusa T, Kato K, Azukizawa H, Miyazaki J, Takeda J, and Katayama I

Subjects
Animals, Antibody Formation, Antigen Presentation, Biomarkers metabolism, Bone Marrow Cells drug effects, Bone Marrow Cells immunology, Cell Lineage, Cells, Cultured, Genotype, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Immunoglobulin M biosynthesis, Keratin-15 genetics, Lipopolysaccharides pharmacology, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Precursor Cells, B-Lymphoid drug effects, Precursor Cells, B-Lymphoid immunology, Promoter Regions, Genetic, Time Factors, Bone Marrow Cells metabolism, Cell Differentiation, Keratin-15 metabolism, Precursor Cells, B-Lymphoid metabolism
Abstract

Background: Keratin 5 (K5) is a cytoskeletal tissue-specific protein expressed in the epithelial cells of skin and esophagus and ectopic K5 expression in lymphocytes has never been reported., Objective: Here we demonstrate an ectopic epidermal self-protein expression in B-1 B cell by fate mapping of K5-expressing cells., Methods: K5-Cre×CAG-CAT-loxP-EGFP double Tg (K5×GFP) mice that express enhanced GFP under the control of the K5 promoter were employed., Results: Unexpectedly, B220(+)GFP(+) cells were found in LN, spleen, peripheral blood and peritoneal cavity. These cells were IgM(+)IgD(low)CD23(-)CD43(+)CD19(+)CD93(-), indicating that they were B-1 B cells. The number of B220(+)GFP(+) cells was significantly larger in spleen than in the other tissues tested. Although GFP(+) B-1 cells did not express K5 in the periphery, Lin(-)CD93(+)B220(low-neg)CD19(+) B-1 B cell progenitors expressed GFP and B220(+)CD93(+) progenitor cells expressed K5 and MHC-class II in BM, indicating that GFP(+) B-1 cells transiently expressed K5 and the progenitor cells were potential APC. GFP(+) B-1 cells in the periphery continued expressing MHC class II and had exogenous antigen-presenting capacity comparable to non-follicular B cells. GFP(+) B-1 cells spontaneously secreted more IgM than GFP(-) B-1 cells in vitro., Conclusion: These results indicate that B-1 B cells transiently and partially express K5 in BM and are potent for both natural antibody production and antigen presentation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Published
2016
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43. Possible association of anti-tumor necrosis factor-α antibody therapy with the development of scleroderma-like changes with lichen planus.

Author

Inoue-Nishimoto T, Hanafusa T, Igawa K, Azukizawa H, Yokomi A, Yokozeki H, and Katayama I

Subjects
Adalimumab therapeutic use, Adult, Biopsy, Needle, Drug Eruptions etiology, Drug Eruptions pathology, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Immunohistochemistry, Lichen Planus drug therapy, Lichen Planus pathology, Psoriasis diagnosis, Risk Assessment, Scleroderma, Localized drug therapy, Scleroderma, Localized pathology, Severity of Illness Index, Treatment Outcome, Tumor Necrosis Factor-alpha administration & dosage, Adalimumab adverse effects, Lichen Planus chemically induced, Psoriasis drug therapy, Scleroderma, Localized chemically induced, Tumor Necrosis Factor-alpha antagonists & inhibitors
Published
2015
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44. Efficacy of additional i.v. immunoglobulin to steroid therapy in Stevens-Johnson syndrome and toxic epidermal necrolysis.

Author

Aihara M, Kano Y, Fujita H, Kambara T, Matsukura S, Katayama I, Azukizawa H, Miyachi Y, Endo Y, Asada H, Miyagawa F, Morita E, Kaneko S, Abe R, Ochiai T, Sueki H, Watanabe H, Nagao K, Aoyama Y, Sayama K, Hashimoto K, and Shiohara T

Subjects
Adult, Aged, Female, Humans, Male, Middle Aged, Treatment Outcome, Adrenal Cortex Hormones therapeutic use, Immunoglobulins, Intravenous therapeutic use, Stevens-Johnson Syndrome drug therapy
Abstract

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and life-threatening cutaneous adverse drug reactions. While there is no established therapy for SJS/TEN, systemic corticosteroids, plasma exchange and i.v. immunoglobulin (IVIG) have been used as treatment. The efficacy of IVIG is still controversial because total doses of IVIG used vary greatly from one study to another. The aim of this study was to evaluate the efficacy of IVIG, administrated for 5 days consecutively, in an open-label, multicenter, single-arm study in patients with SJS or TEN. IVIG (400 mg/kg per day) administrated for 5 days consecutively was performed as an additional therapy to systemic steroids in adult patients with SJS or TEN. Efficacy on day 7 of IVIG was evaluated. Parameters to assess clinical outcome were enanthema including ophthalmic and oral lesions, cutaneous lesions and general condition. These parameters were scored and recorded before and after IVIG. We enrolled five patients with SJS and three patients with TEN who did not respond sufficiently to systemic steroids before IVIG administration. All of the patients survived and the efficacy on day 7 of the IVIG was 87.5% (7/8 patients). Prompt amelioration was observed in skin lesions and enanthema in the patients in whom IVIG therapy was effective. Serious side-effects from the use of IVIG were not observed. IVIG (400 mg/kg per day) administrated for 5 days consecutively seems to be effective in patients with SJS or TEN. IVIG administrated together with steroids should be considered as a treatment modality for patients with refractory SJS/TEN. Further studies are needed to define the therapeutic efficacy of IVIG., (© 2015 Japanese Dermatological Association.)

Published
2015
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45. Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch.

Author

Hirobe S, Azukizawa H, Hanafusa T, Matsuo K, Quan YS, Kamiyama F, Katayama I, Okada N, and Nakagawa S

Subjects
Administration, Cutaneous, Adult, Animals, Antibody Formation, Chickens, Hemagglutinins administration & dosage, Hemagglutinins adverse effects, Hemagglutinins immunology, Humans, Immunization adverse effects, Immunization instrumentation, Influenza Vaccines adverse effects, Influenza Vaccines immunology, Influenza, Human immunology, Male, Middle Aged, Solubility, Young Adult, Hyaluronic Acid chemistry, Influenza A Virus, H1N1 Subtype immunology, Influenza A Virus, H3N2 Subtype immunology, Influenza A virus immunology, Influenza Vaccines administration & dosage, Influenza, Human prevention & control, Transdermal Patch adverse effects
Abstract

Transcutaneous immunization (TCI) is an attractive vaccination method compared with conventional injectable vaccines because it is easier to administer without pain. We developed a dissolving microneedle patch (MicroHyala, MH) made of hyaluronic acid and showed that transcutaneous vaccination using MH induced a strong immune response against various antigens in mice. In the present study, we investigated the clinical safety and efficacy of a novel transcutaneous influenza vaccine using MH (flu-MH), which contains trivalent influenza hemagglutinins (15 μg each). Subjects of the TCI group were treated transcutaneously with flu-MH, and were compared with subjects who received subcutaneous injections of a solution containing 15 μg of each influenza antigen (SCI group). No severe local or systemic adverse events were detected in either group and immune responses against A/H1N1 and A/H3N2 strains were induced equally in the TCI and SCI groups. Moreover, the efficacy of the vaccine against the B strain in the TCI group was stronger than that in the SCI group. Influenza vaccination using MH is promising for practical use as an easy and effective method to replace conventional injections systems., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Published
2015
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46. Homeostatic NF-κB Signaling in Steady-State Migratory Dendritic Cells Regulates Immune Homeostasis and Tolerance.

Author

Baratin M, Foray C, Demaria O, Habbeddine M, Pollet E, Maurizio J, Verthuy C, Davanture S, Azukizawa H, Flores-Langarica A, Dalod M, and Lawrence T

Subjects
Animals, Autoantigens genetics, Autoantigens immunology, Autoimmunity, Cell Movement, Dendritic Cells cytology, Gene Expression Profiling, Gene Expression Regulation, I-kappa B Kinase deficiency, I-kappa B Kinase genetics, I-kappa B Kinase immunology, Lymph Nodes cytology, Lymph Nodes immunology, Mice, Mice, Knockout, Microarray Analysis, NF-kappa B genetics, Skin cytology, Skin immunology, Spleen cytology, Spleen immunology, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory immunology, Dendritic Cells immunology, Gene Regulatory Networks immunology, Homeostasis immunology, Immune Tolerance, NF-kappa B immunology, Signal Transduction immunology
Abstract

Migratory non-lymphoid tissue dendritic cells (NLT-DCs) transport antigens to lymph nodes (LNs) and are required for protective immune responses in the context of inflammation and to promote tolerance to self-antigens in steady-state. However, the molecular mechanisms that elicit steady-state NLT-DC maturation and migration are unknown. By comparing the transcriptome of NLT-DCs in the skin with their migratory counterparts in draining LNs, we have identified a novel NF-κB-regulated gene network specific to migratory DCs. We show that targeted deletion of IKKβ in DCs, a major activator of NF-κB, prevents NLT-DC accumulation in LNs and compromises regulatory T cell conversion in vivo. This was associated with impaired tolerance and autoimmunity. NF-κB is generally considered the prototypical pro-inflammatory transcription factor, but this study describes a role for NF-κB signaling in DCs for immune homeostasis and tolerance that could have implications in autoimmune diseases and immunity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2015
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47. Sequelae in 145 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms: survey conducted by the Asian Research Committee on Severe Cutaneous Adverse Reactions (ASCAR).

Author

Kano Y, Tohyama M, Aihara M, Matsukura S, Watanabe H, Sueki H, Iijima M, Morita E, Niihara H, Asada H, Kabashima K, Azukizawa H, Hashizume H, Nagao K, Takahashi H, Abe R, Sotozono C, Kurosawa M, Aoyama Y, Chu CY, Chung WH, and Shiohara T

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Child, Drug Hypersensitivity Syndrome epidemiology, Eosinophilia complications, Eosinophilia epidemiology, Female, Follow-Up Studies, Humans, Japan epidemiology, Male, Middle Aged, Taiwan epidemiology, Young Adult, Diabetes Mellitus, Type 1 epidemiology, Drug Hypersensitivity Syndrome complications, Infections epidemiology, Thyroid Diseases epidemiology
Abstract

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe adverse drug reaction caused by specific drug. It is characterized by visceral organ involvement and reactivation of various human herpesviruses. Although sporadic reports have documented certain conditions that appear after the resolution of DIHS/DRESS, little information is available on sequelae after resolution of DIHS/DRESS in a large patient population. The Asian Research Committee on Severe Cutaneous Adverse Reactions, comprised of doctors from Japan and Taiwan, conducted a survey on sequelae and deterioration of the underlying disease in patients with DIHS/DRESS. This was achieved by directly interviewing patients who had been followed-up by experts or through a questionnaire mailed to patients. Questions were asked about new onset cardiovascular disease, collagen disease or autoimmune disease, gastrointestinal disease, renal disease, respiratory disease, neoplasms, and other diseases such as herpes zoster and diabetes mellitus, as well as deterioration of the underlying disease. A total of 145 patients were analyzed in this study. The following newly developed diseases after recovery from DIHS/DRESS were observed: Graves' disease (n = 2), Hashimoto's disease (n = 3), painless thyroiditis (n = 2), fulminant type 1 diabetes mellitus (n = 5), and infectious diseases (n = 7). Several DIHS/DRESS patients with pre-existing renal dysfunction required lifelong hemodialysis. DIHS/DRESS is a condition that increases the risk of new onset of disease. Long-term observation of DIHS/DRESS can provide an opportunity to investigate substantial diseases from onset to the full-blown stage. Patients with DIHS/DRESS require careful long-term follow-up., (© 2015 Japanese Dermatological Association.)

Published
2015
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48. Genetic variants associated with phenytoin-related severe cutaneous adverse reactions.

Author

Chung WH, Chang WC, Lee YS, Wu YY, Yang CH, Ho HC, Chen MJ, Lin JY, Hui RC, Ho JC, Wu WM, Chen TJ, Wu T, Wu YR, Hsih MS, Tu PH, Chang CN, Hsu CN, Wu TL, Choon SE, Hsu CK, Chen DY, Liu CS, Lin CY, Kaniwa N, Saito Y, Takahashi Y, Nakamura R, Azukizawa H, Shi Y, Wang TH, Chuang SS, Tsai SF, Chang CJ, Chang YS, and Hung SI

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Anticonvulsants pharmacokinetics, Case-Control Studies, Cytochrome P-450 CYP2C9, Eosinophilia genetics, Female, Genome-Wide Association Study, Humans, Japan, Malaysia, Male, Middle Aged, Pharmacogenetics, Phenytoin pharmacokinetics, Polymorphism, Single Nucleotide, Taiwan, Young Adult, Anticonvulsants adverse effects, Aryl Hydrocarbon Hydroxylases genetics, Eosinophilia chemically induced, Phenytoin adverse effects, Stevens-Johnson Syndrome genetics
Abstract

Importance: The antiepileptic drug phenytoin can cause cutaneous adverse reactions, ranging from maculopapular exanthema to severe cutaneous adverse reactions, which include drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions remains unknown., Objective: To investigate the genetic factors associated with phenytoin-related severe cutaneous adverse reactions., Design, Setting, and Participants: Case-control study conducted in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n=61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n=44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS), direct sequencing of the associated loci, and replication analysis were conducted using the samples from Taiwan. The initial GWAS included samples of 60 cases with phenytoin-related severe cutaneous adverse reactions and 412 population controls from Taiwan. The results were validated in (1) 30 cases with severe cutaneous adverse reactions and 130 phenytoin-tolerant controls from Taiwan, (2) 9 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and 2869 population controls from Japan, and (3) 6 cases and 374 population controls from Malaysia., Main Outcomes and Measures: Specific genetic factors associated with phenytoin-related severe cutaneous adverse reactions., Results: The GWAS discovered a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. Direct sequencing of CYP2C identified missense variant rs1057910 (CYP2C9*3) that showed significant association with phenytoin-related severe cutaneous adverse reactions (odds ratio, 12; 95% CI, 6.6-20; P=1.1 × 10(-17)). The statistically significant association between CYP2C9*3 and phenytoin-related severe cutaneous adverse reactions was observed in additional samples from Taiwan, Japan, and Malaysia. A meta-analysis using the data from the 3 populations showed an overall odds ratio of 11 (95% CI, 6.2-18; z=8.58; P < .00001) for CYP2C9*3 association with phenytoin-related severe cutaneous adverse reactions. Delayed clearance of plasma phenytoin was detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers, providing a functional link of the associated variants to the disease., Conclusions and Relevance: This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

Published
2014
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49. Immune reconstitution inflammatory syndrome in a patient with adult-onset Still's disease: graft-versus-host-like skin reaction with possible asymptomatic human herpes virus reactivation during steroid tapering.

Author

Yamaga K, Hanafusa T, Azukizawa H, Tanemura A, Nii T, Nishide M, Narazaki M, and Katayama I

Subjects
Aged, Antibodies, Viral blood, Asymptomatic Diseases, Graft vs Host Disease immunology, Herpesvirus 3, Human immunology, Humans, Male, Skin Diseases immunology, Steroids, Substance Withdrawal Syndrome, Glucocorticoids adverse effects, Immune Reconstitution Inflammatory Syndrome chemically induced, Prednisolone adverse effects, Still's Disease, Adult-Onset complications, Still's Disease, Adult-Onset drug therapy
Published
2014
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50. Barrier abnormality due to ceramide deficiency leads to psoriasiform inflammation in a mouse model.

Author

Nakajima K, Terao M, Takaishi M, Kataoka S, Goto-Inoue N, Setou M, Horie K, Sakamoto F, Ito M, Azukizawa H, Kitaba S, Murota H, Itami S, Katayama I, Takeda J, and Sano S

Subjects
Animals, Dermatitis immunology, Dermatitis pathology, Disease Models, Animal, Epidermis pathology, Female, Humans, Interleukin-17 metabolism, Interleukin-23 genetics, Interleukin-23 metabolism, Interleukins genetics, Interleukins metabolism, Keratinocytes metabolism, Keratinocytes pathology, Langerhans Cells immunology, Langerhans Cells metabolism, Langerhans Cells pathology, Male, Mice, Mice, Knockout, Psoriasis immunology, Psoriasis pathology, Serine C-Palmitoyltransferase metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism, T-Lymphocytes pathology, Water metabolism, Interleukin-22, Ceramides deficiency, Dermatitis metabolism, Epidermis metabolism, Psoriasis metabolism, Serine C-Palmitoyltransferase genetics
Abstract

It has been recognized that ceramides are decreased in the epidermis of patients with psoriasis and atopic dermatitis. Here, we generated Sptlc2 (serine palmitoyltransferase long-chain base subunit 2)-targeted mice (SPT-cKO mice), thereby knocking out serine palmitoyltransferase (SPT), the critical enzyme for ceramide biosynthesis, in keratinocytes. SPT-cKO mice showed decreased ceramide levels in the epidermis, which impaired water-holding capacity and barrier function. From 2 weeks of age, they developed skin lesions with histological aberrations including hyperkeratosis, acanthosis, loss of the granular layer, and inflammatory cell infiltrates. Epidermal Langerhans cells showed persistent activation and enhanced migration to lymph nodes. Skin lesions showed upregulation of psoriasis-associated genes, such as IL-17A, IL-17F, IL-22, S100A8, S100A9, and β-defensins. In the skin lesions and draining lymph nodes, there were increased numbers of γδ T cells that produced IL-17 (γδ-17 cells), most of which also produced IL-22, as do Th17 cells. Furthermore, IL-23-producing CD11c(+) cells were observed in the lesions. In vivo treatment of SPT-cKO mice with an anti-IL-12/23p40 antibody ameliorated the skin lesions and reduced the numbers of γδ-17 cells. Therefore, we conclude that a ceramide deficiency in the epidermis leads to psoriasis-like lesions in mice, probably mediated by IL-23-dependent IL-22-producing γδ-17 cells.

Published
2013
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