Clinical and Histologic Analysis of the Efficacy of Topical Rapamycin Therapy Against Hypomelanotic Macules in Tuberous Sclerosis Complex
IMPORTANCE: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder leading to the aberrant activation of the mammalian target of rapamycin complex 1. Although the efficacy of mammalian target of rapamycin complex 1 inhibitors against tumors in patients with TSC, including facial angiofib...
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| Veröffentlicht in: | JAMA dermatology (Chicago, Ill.) Ill.), 2015-07, Vol.151 (7), p.722-730 |
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| creator | Wataya-Kaneda, Mari Tanaka, Mari Yang, Lingli Yang, Fei Tsuruta, Daisuke Nakamura, Ayumi Matsumoto, Shoji Hamasaki, Toshimitsu Tanemura, Atushi Katayama, Ichiro |
| description | IMPORTANCE: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder leading to the aberrant activation of the mammalian target of rapamycin complex 1. Although the efficacy of mammalian target of rapamycin complex 1 inhibitors against tumors in patients with TSC, including facial angiofibroma, has been well investigated, their efficacy against hypomelanotic macules in patients with TSC is unknown. OBJECTIVES: To evaluate objectively the efficacy of topical rapamycin treatment of hypomelanotic macules in patients with TSC and to elucidate the mechanisms of how rapamycin improves the macules. DESIGN, SETTING, AND PARTICIPANTS: We performed a prospective, baseline-controlled trial of 6 patients with TSC and hypomelanotic macules in non–sun-exposed and sun-exposed skin at the Department of Dermatology, Osaka University, from August 4, 2011, through September 27, 2012. Rapamycin gel, 0.2%, was applied to the lesions twice a day for 12 weeks. Histologic examinations and blood tests were conducted at the start and completion of treatment. Blood rapamycin levels were analyzed at completion. EXPOSURES: Topical rapamycin treatment for hypomelanotic macules. MAIN OUTCOMES AND MEASURES: Objective evaluation of rapamycin treatment of hypomelanotic macules in TSC with δ-L (L indicates the brightness of the color) levels on spectrophotometry at the start and completion (12 weeks) of treatment and at 4 and 12 weeks after discontinuation of treatment (16 and 24 weeks, respectively). RESULTS: Improvement of hypomelanotic macules (in δ-L values) was significant at 12 weeks (mean [SD], 2.501 [1.694]; P |
| doi_str_mv | 10.1001/jamadermatol.2014.4298 |
| format | Article |
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Although the efficacy of mammalian target of rapamycin complex 1 inhibitors against tumors in patients with TSC, including facial angiofibroma, has been well investigated, their efficacy against hypomelanotic macules in patients with TSC is unknown. OBJECTIVES: To evaluate objectively the efficacy of topical rapamycin treatment of hypomelanotic macules in patients with TSC and to elucidate the mechanisms of how rapamycin improves the macules. DESIGN, SETTING, AND PARTICIPANTS: We performed a prospective, baseline-controlled trial of 6 patients with TSC and hypomelanotic macules in non–sun-exposed and sun-exposed skin at the Department of Dermatology, Osaka University, from August 4, 2011, through September 27, 2012. Rapamycin gel, 0.2%, was applied to the lesions twice a day for 12 weeks. Histologic examinations and blood tests were conducted at the start and completion of treatment. Blood rapamycin levels were analyzed at completion. EXPOSURES: Topical rapamycin treatment for hypomelanotic macules. MAIN OUTCOMES AND MEASURES: Objective evaluation of rapamycin treatment of hypomelanotic macules in TSC with δ-L (L indicates the brightness of the color) levels on spectrophotometry at the start and completion (12 weeks) of treatment and at 4 and 12 weeks after discontinuation of treatment (16 and 24 weeks, respectively). RESULTS: Improvement of hypomelanotic macules (in δ-L values) was significant at 12 weeks (mean [SD], 2.501 [1.694]; P < .05), 16 weeks (1.956 [1.567]; P < .01), and 24 weeks (1.836 [1.638]; P < .001). Although efficacy tended to be prominent in sun-exposed skin, we did not observe significant differences (in δ-L values) between sun-exposed and non–sun-exposed skin at 12 weeks (mean [SD], 1.859 [0.629] and 3.142 [2.221], respectively), 16 weeks ( 1.372 [0.660] and 2.539 [2.037], respectively), and 24 weeks (1.201 [0.821] and 2.471 [2.064], respectively). No adverse events were observed, and rapamycin was not detected in the blood of any patient. Electron microscopic analysis of hypomelanotic macules revealed that topical rapamycin treatment significantly improved the uniformity of the melanosome numbers in the TSC melanocytes (pretreatment macules: mean [SD], 25.71 [21.90] [range, 5-63]; posttreatment macules: 42.43 [3.60] [range, 38-49]; P < .001). Moreover, rapamycin treatment induced the recovery of melanosomes in TSC–knocked-down melanocytes from depleted amounts (mean [SD], 16.43 [11.84]) to normal levels (42.83 [14.39]; P < .001). CONCLUSIONS AND RELEVANCE: Topical rapamycin treatment was effective and safe against hypomelanotic macules arising from TSC. This efficacy of rapamycin was corroborated as stemming from the improvement of impaired melanogenesis in TSC melanocytes.</description><identifier>ISSN: 2168-6068</identifier><identifier>EISSN: 2168-6084</identifier><identifier>DOI: 10.1001/jamadermatol.2014.4298</identifier><identifier>PMID: 25692384</identifier><language>eng</language><publisher>United States: American Medical Association</publisher><subject>Administration, Cutaneous ; Adolescent ; Adult ; Antibiotics, Antineoplastic - adverse effects ; Antibiotics, Antineoplastic - blood ; Antibiotics, Antineoplastic - therapeutic use ; Child ; Child, Preschool ; Female ; Humans ; Hypopigmentation - drug therapy ; Hypopigmentation - metabolism ; Hypopigmentation - pathology ; Male ; Melanins - metabolism ; Melanosomes - ultrastructure ; Microscopy, Electron ; Prospective Studies ; Sirolimus - adverse effects ; Sirolimus - blood ; Sirolimus - therapeutic use ; Skin Neoplasms - drug therapy ; Skin Neoplasms - metabolism ; Skin Neoplasms - pathology ; Spectrophotometry ; Tuberous Sclerosis - drug therapy ; Tuberous Sclerosis - metabolism ; Tuberous Sclerosis - pathology ; Young Adult</subject><ispartof>JAMA dermatology (Chicago, Ill.), 2015-07, Vol.151 (7), p.722-730</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a396t-ca68f89a266485495cf42085d77edecaf558a1245d7bfbb1f0dda90f729959b43</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://jamanetwork.com/journals/jamadermatology/articlepdf/10.1001/jamadermatol.2014.4298$$EPDF$$P50$$Gama$$H</linktopdf><linktohtml>$$Uhttps://jamanetwork.com/journals/jamadermatology/fullarticle/10.1001/jamadermatol.2014.4298$$EHTML$$P50$$Gama$$H</linktohtml><link.rule.ids>64,314,776,780,3326,27903,27904,76236,76239</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25692384$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wataya-Kaneda, Mari</creatorcontrib><creatorcontrib>Tanaka, Mari</creatorcontrib><creatorcontrib>Yang, Lingli</creatorcontrib><creatorcontrib>Yang, Fei</creatorcontrib><creatorcontrib>Tsuruta, Daisuke</creatorcontrib><creatorcontrib>Nakamura, Ayumi</creatorcontrib><creatorcontrib>Matsumoto, Shoji</creatorcontrib><creatorcontrib>Hamasaki, Toshimitsu</creatorcontrib><creatorcontrib>Tanemura, Atushi</creatorcontrib><creatorcontrib>Katayama, Ichiro</creatorcontrib><title>Clinical and Histologic Analysis of the Efficacy of Topical Rapamycin Therapy Against Hypomelanotic Macules in Tuberous Sclerosis Complex</title><title>JAMA dermatology (Chicago, Ill.)</title><addtitle>JAMA Dermatol</addtitle><description>IMPORTANCE: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder leading to the aberrant activation of the mammalian target of rapamycin complex 1. Although the efficacy of mammalian target of rapamycin complex 1 inhibitors against tumors in patients with TSC, including facial angiofibroma, has been well investigated, their efficacy against hypomelanotic macules in patients with TSC is unknown. OBJECTIVES: To evaluate objectively the efficacy of topical rapamycin treatment of hypomelanotic macules in patients with TSC and to elucidate the mechanisms of how rapamycin improves the macules. DESIGN, SETTING, AND PARTICIPANTS: We performed a prospective, baseline-controlled trial of 6 patients with TSC and hypomelanotic macules in non–sun-exposed and sun-exposed skin at the Department of Dermatology, Osaka University, from August 4, 2011, through September 27, 2012. Rapamycin gel, 0.2%, was applied to the lesions twice a day for 12 weeks. Histologic examinations and blood tests were conducted at the start and completion of treatment. Blood rapamycin levels were analyzed at completion. EXPOSURES: Topical rapamycin treatment for hypomelanotic macules. MAIN OUTCOMES AND MEASURES: Objective evaluation of rapamycin treatment of hypomelanotic macules in TSC with δ-L (L indicates the brightness of the color) levels on spectrophotometry at the start and completion (12 weeks) of treatment and at 4 and 12 weeks after discontinuation of treatment (16 and 24 weeks, respectively). RESULTS: Improvement of hypomelanotic macules (in δ-L values) was significant at 12 weeks (mean [SD], 2.501 [1.694]; P < .05), 16 weeks (1.956 [1.567]; P < .01), and 24 weeks (1.836 [1.638]; P < .001). Although efficacy tended to be prominent in sun-exposed skin, we did not observe significant differences (in δ-L values) between sun-exposed and non–sun-exposed skin at 12 weeks (mean [SD], 1.859 [0.629] and 3.142 [2.221], respectively), 16 weeks ( 1.372 [0.660] and 2.539 [2.037], respectively), and 24 weeks (1.201 [0.821] and 2.471 [2.064], respectively). No adverse events were observed, and rapamycin was not detected in the blood of any patient. Electron microscopic analysis of hypomelanotic macules revealed that topical rapamycin treatment significantly improved the uniformity of the melanosome numbers in the TSC melanocytes (pretreatment macules: mean [SD], 25.71 [21.90] [range, 5-63]; posttreatment macules: 42.43 [3.60] [range, 38-49]; P < .001). Moreover, rapamycin treatment induced the recovery of melanosomes in TSC–knocked-down melanocytes from depleted amounts (mean [SD], 16.43 [11.84]) to normal levels (42.83 [14.39]; P < .001). CONCLUSIONS AND RELEVANCE: Topical rapamycin treatment was effective and safe against hypomelanotic macules arising from TSC. This efficacy of rapamycin was corroborated as stemming from the improvement of impaired melanogenesis in TSC melanocytes.</description><subject>Administration, Cutaneous</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Antibiotics, Antineoplastic - adverse effects</subject><subject>Antibiotics, Antineoplastic - blood</subject><subject>Antibiotics, Antineoplastic - therapeutic use</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Female</subject><subject>Humans</subject><subject>Hypopigmentation - drug therapy</subject><subject>Hypopigmentation - metabolism</subject><subject>Hypopigmentation - pathology</subject><subject>Male</subject><subject>Melanins - metabolism</subject><subject>Melanosomes - ultrastructure</subject><subject>Microscopy, Electron</subject><subject>Prospective Studies</subject><subject>Sirolimus - adverse effects</subject><subject>Sirolimus - blood</subject><subject>Sirolimus - therapeutic use</subject><subject>Skin Neoplasms - drug therapy</subject><subject>Skin Neoplasms - metabolism</subject><subject>Skin Neoplasms - pathology</subject><subject>Spectrophotometry</subject><subject>Tuberous Sclerosis - drug therapy</subject><subject>Tuberous Sclerosis - metabolism</subject><subject>Tuberous Sclerosis - pathology</subject><subject>Young Adult</subject><issn>2168-6068</issn><issn>2168-6084</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkc1OxCAUhYnRqFFfwIVh6WZGoJSB5WSijonGRMd1c0tBMbTU0ib2EXxrqeMfGy7wnXNvOAidUTKnhNCLV6ihMl0NffBzRiifc6bkDjpkVMiZIJLv_tZCHqCTGF9JWpIQntF9dMByoVgm-SH6WHnXOA0eQ1PhtYvJMjw7jZcN-DG6iIPF_YvBl9YmTI_TeRPaL8kDtFCP2jV482I6aEe8fAbXxB6vxzbUxkMT-uR1B3rwJuIJHErThSHiR-1TMTVYhbr15v0Y7Vnw0Zx870fo6epys1rPbu-vb1bL2xlkSvQzDUJaqYAJwWXOVa4tZ0Tm1WJhKqPB5rkEyni6KG1ZUkuqChSxC6ZUrkqeHaHzrW_bhbfBxL6oXdTGp2FNGqygQuVUcspVQsUW1WnS2BlbtJ2roRsLSoopieJ_EsWURDElkYRn3z2GsjbVr-zn3xNwugWS_u-VUpVxnn0CcQ6S8w</recordid><startdate>20150701</startdate><enddate>20150701</enddate><creator>Wataya-Kaneda, Mari</creator><creator>Tanaka, Mari</creator><creator>Yang, Lingli</creator><creator>Yang, Fei</creator><creator>Tsuruta, Daisuke</creator><creator>Nakamura, Ayumi</creator><creator>Matsumoto, Shoji</creator><creator>Hamasaki, Toshimitsu</creator><creator>Tanemura, Atushi</creator><creator>Katayama, Ichiro</creator><general>American Medical Association</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20150701</creationdate><title>Clinical and Histologic Analysis of the Efficacy of Topical Rapamycin Therapy Against Hypomelanotic Macules in Tuberous Sclerosis Complex</title><author>Wataya-Kaneda, Mari ; Tanaka, Mari ; Yang, Lingli ; Yang, Fei ; Tsuruta, Daisuke ; Nakamura, Ayumi ; Matsumoto, Shoji ; Hamasaki, Toshimitsu ; Tanemura, Atushi ; Katayama, Ichiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a396t-ca68f89a266485495cf42085d77edecaf558a1245d7bfbb1f0dda90f729959b43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Administration, Cutaneous</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Antibiotics, Antineoplastic - adverse effects</topic><topic>Antibiotics, Antineoplastic - blood</topic><topic>Antibiotics, Antineoplastic - therapeutic use</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Female</topic><topic>Humans</topic><topic>Hypopigmentation - drug therapy</topic><topic>Hypopigmentation - metabolism</topic><topic>Hypopigmentation - pathology</topic><topic>Male</topic><topic>Melanins - metabolism</topic><topic>Melanosomes - ultrastructure</topic><topic>Microscopy, Electron</topic><topic>Prospective Studies</topic><topic>Sirolimus - adverse effects</topic><topic>Sirolimus - blood</topic><topic>Sirolimus - therapeutic use</topic><topic>Skin Neoplasms - drug therapy</topic><topic>Skin Neoplasms - metabolism</topic><topic>Skin Neoplasms - pathology</topic><topic>Spectrophotometry</topic><topic>Tuberous Sclerosis - drug therapy</topic><topic>Tuberous Sclerosis - metabolism</topic><topic>Tuberous Sclerosis - pathology</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wataya-Kaneda, Mari</creatorcontrib><creatorcontrib>Tanaka, Mari</creatorcontrib><creatorcontrib>Yang, Lingli</creatorcontrib><creatorcontrib>Yang, Fei</creatorcontrib><creatorcontrib>Tsuruta, Daisuke</creatorcontrib><creatorcontrib>Nakamura, Ayumi</creatorcontrib><creatorcontrib>Matsumoto, Shoji</creatorcontrib><creatorcontrib>Hamasaki, Toshimitsu</creatorcontrib><creatorcontrib>Tanemura, Atushi</creatorcontrib><creatorcontrib>Katayama, Ichiro</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>JAMA dermatology (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wataya-Kaneda, Mari</au><au>Tanaka, Mari</au><au>Yang, Lingli</au><au>Yang, Fei</au><au>Tsuruta, Daisuke</au><au>Nakamura, Ayumi</au><au>Matsumoto, Shoji</au><au>Hamasaki, Toshimitsu</au><au>Tanemura, Atushi</au><au>Katayama, Ichiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Clinical and Histologic Analysis of the Efficacy of Topical Rapamycin Therapy Against Hypomelanotic Macules in Tuberous Sclerosis Complex</atitle><jtitle>JAMA dermatology (Chicago, Ill.)</jtitle><addtitle>JAMA Dermatol</addtitle><date>2015-07-01</date><risdate>2015</risdate><volume>151</volume><issue>7</issue><spage>722</spage><epage>730</epage><pages>722-730</pages><issn>2168-6068</issn><eissn>2168-6084</eissn><abstract>IMPORTANCE: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder leading to the aberrant activation of the mammalian target of rapamycin complex 1. Although the efficacy of mammalian target of rapamycin complex 1 inhibitors against tumors in patients with TSC, including facial angiofibroma, has been well investigated, their efficacy against hypomelanotic macules in patients with TSC is unknown. OBJECTIVES: To evaluate objectively the efficacy of topical rapamycin treatment of hypomelanotic macules in patients with TSC and to elucidate the mechanisms of how rapamycin improves the macules. DESIGN, SETTING, AND PARTICIPANTS: We performed a prospective, baseline-controlled trial of 6 patients with TSC and hypomelanotic macules in non–sun-exposed and sun-exposed skin at the Department of Dermatology, Osaka University, from August 4, 2011, through September 27, 2012. Rapamycin gel, 0.2%, was applied to the lesions twice a day for 12 weeks. Histologic examinations and blood tests were conducted at the start and completion of treatment. Blood rapamycin levels were analyzed at completion. EXPOSURES: Topical rapamycin treatment for hypomelanotic macules. MAIN OUTCOMES AND MEASURES: Objective evaluation of rapamycin treatment of hypomelanotic macules in TSC with δ-L (L indicates the brightness of the color) levels on spectrophotometry at the start and completion (12 weeks) of treatment and at 4 and 12 weeks after discontinuation of treatment (16 and 24 weeks, respectively). RESULTS: Improvement of hypomelanotic macules (in δ-L values) was significant at 12 weeks (mean [SD], 2.501 [1.694]; P < .05), 16 weeks (1.956 [1.567]; P < .01), and 24 weeks (1.836 [1.638]; P < .001). Although efficacy tended to be prominent in sun-exposed skin, we did not observe significant differences (in δ-L values) between sun-exposed and non–sun-exposed skin at 12 weeks (mean [SD], 1.859 [0.629] and 3.142 [2.221], respectively), 16 weeks ( 1.372 [0.660] and 2.539 [2.037], respectively), and 24 weeks (1.201 [0.821] and 2.471 [2.064], respectively). No adverse events were observed, and rapamycin was not detected in the blood of any patient. Electron microscopic analysis of hypomelanotic macules revealed that topical rapamycin treatment significantly improved the uniformity of the melanosome numbers in the TSC melanocytes (pretreatment macules: mean [SD], 25.71 [21.90] [range, 5-63]; posttreatment macules: 42.43 [3.60] [range, 38-49]; P < .001). Moreover, rapamycin treatment induced the recovery of melanosomes in TSC–knocked-down melanocytes from depleted amounts (mean [SD], 16.43 [11.84]) to normal levels (42.83 [14.39]; P < .001). CONCLUSIONS AND RELEVANCE: Topical rapamycin treatment was effective and safe against hypomelanotic macules arising from TSC. This efficacy of rapamycin was corroborated as stemming from the improvement of impaired melanogenesis in TSC melanocytes.</abstract><cop>United States</cop><pub>American Medical Association</pub><pmid>25692384</pmid><doi>10.1001/jamadermatol.2014.4298</doi><tpages>9</tpages></addata></record> |
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| subjects | Administration, Cutaneous Adolescent Adult Antibiotics, Antineoplastic - adverse effects Antibiotics, Antineoplastic - blood Antibiotics, Antineoplastic - therapeutic use Child Child, Preschool Female Humans Hypopigmentation - drug therapy Hypopigmentation - metabolism Hypopigmentation - pathology Male Melanins - metabolism Melanosomes - ultrastructure Microscopy, Electron Prospective Studies Sirolimus - adverse effects Sirolimus - blood Sirolimus - therapeutic use Skin Neoplasms - drug therapy Skin Neoplasms - metabolism Skin Neoplasms - pathology Spectrophotometry Tuberous Sclerosis - drug therapy Tuberous Sclerosis - metabolism Tuberous Sclerosis - pathology Young Adult |
| title | Clinical and Histologic Analysis of the Efficacy of Topical Rapamycin Therapy Against Hypomelanotic Macules in Tuberous Sclerosis Complex |
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