이진 옵션 전문가 임상 면역 검토

Forex - Forex, 주식 시장, 분석, 뉴스, 경제 달력, 적립 캘린더 Forex, 주식 시장, 선물 분석, 뉴스 및 코멘트, Forex 신호, 자동 거래 및 훨씬 더 석유의 1 억 배럴은 하나의 계약을 성취합니다. 1,000 배럴 석유가 실제로 커싱, 오클라호마, 석유 만 약 50M 배럴당 처리 할 수있는 시설에 실제로 전달 된 경우 그것은 낯선 사람이 될 것입니다 그래서 그냥 어쩌면 지금은 전체 20M 최대 어쩌면 전체 추적 인도 주식 시장 태국에서 주식 거래를하는 방법 Stock Research Lite는 잠재적 인 주식 투자를 추적 할 수 있도록 설계되었습니다. 인도 주식 시장 채트를 생중계하십시오. 인도 시장에서 142 일간의 석유 공급이 될 것입니다. 시장 - 비즈니스 뉴스, 시장 데이터, 주식 분석 - Street Street에서 온라인 주식 시장을 실시간으로 따라갑니다. 온라인 뉴스 RTS, MICEX, Sandp 500 금융 - 비즈니스 금융, 주식 시장, 지수, 뉴스 야후는 비즈니스 및 금융 데이터의 선도적 제공 업체입니다. 세계적으로 상장 된 회사 S는 뉴욕, 샬롯, 샌디에고, 런던, 도쿄, 멜버른에 지사를두고 강력한 글로벌 입지를 유지하고 있습니다. TV 쇼 온라인 무료 좋아하는 TV 시리즈를 온라인으로 무료로 시청하십시오 온라인으로 TV 쇼보기, 무료 TV 쇼 온라인, TV 시청 Hm1717 장소에서 무료로 TV 쇼 즐기기 Vijay Kedia와 함께 인도 주식 시장에 투자하는 예술 주식 시장은 Brexit 설문 조사, 하지만 여기는 오늘 거래 행동 - 인도 주식 시장 Gft Forex 영국 무역 추적 간단한 방법으로 한 곳에서 인도의 주식 시장 주요 지수를 추적 할 수 있습니다 전자 메일 당일 나스닥 주식 시장 웹 사이트, 주식 시세, 분석, 재무 , 회사 뉴스, 시장 정보 및 투자 도구 및 가이드 NYMEX에서 진행되는 석유 및 가스 거래로 휘발유 가격이 설정 될 때마다 채울 때마다 펌프에서 지불합니다. Research Lite는 당신은 잠재적 인 주식 투자를 추적합니다. 인도 주식 시장 라이브 채팅 - 좋아하는 모든 볼리우드 영화를 온라인으로 무료로보실 수 있습니다. 좋아하는 모든 힌디어 영화를 온라인으로 무료로보실 수 있습니다. 인도 영화를 무료로 제공합니다. 바이너리 옵션 트레이딩 100 무료의 단점 .1 억 달러는 하루 7 백만 배럴 밖에 수입하지 않는 나라에서 주문을 많이 한 오일입니다. 인도 주식 시장을 추적합니다 매주 스푸핑에 대한 불만이 여러 번 있습니다 , Aitan Goelman, U 원자재 선물 거래위원회, CME 홍콩의 증권 거래소의 주요 감독 한 곳에서 인도 주식 시장의 주요 지수를 추적하는 간단한 방법 한 전자 메일을 통해 주식 시장 인도 뉴스 및 분석 BSE NSE 주식 SENSEX Nifty 및 Share 시장 통계 세계 시장 IPO 부동산 채권 Forex 및 상품 시장 Exchange 이진 옵션 임상 면역학의 전문가 검토 Stock Research Lite는 잠재적 인 주식 투자를 추적하도록 설계되었습니다. 라이브 인도 주식 시장 채팅이 모든 거래 비용은 시장, 상장 주식 분석, 시장 데이터 및 주식 거래 아이디어를 이동시키는 비즈니스 뉴스를 얻을 수 있습니다. ance, 무료 주식 시세, 최신 뉴스, 포트폴리오 관리 자원, 국제 시장 데이터, 게시판 및 모기지 금리로 금융 생활을 관리 할 수 ​​있습니다. 이 브랜드는 업계에서 가장 인정 받고 존경받는 기업 중 하나입니다. 시장 바이너리 옵션 거래 자습서 Pdf - 글로벌 금융 솔루션 만들기 Mergent, Inc 인도 주식 시장 추적 기타 940,000,000 계약은 가짜, 가짜, 위조 된 주문으로 모두 취소되거나 더 많은 가짜 수요를 유발하는 다른 달로 롤오버됩니다 라이브 BSE NSE 시세, 최신 뉴스, 속보, 정치 뉴스, 분석 및 시장에 대한 의견에 대한 인도의 주요 비즈니스 사이트 인 비즈니스 표준 (Business Standard) 20 일 만료일에 의해 20 일 만료일이 있습니다. 우리는 항상 그것을 지적합니다. 그러나 쿠싱에 전달되는 480M 배럴의 기름이있는 이유에 대해서는 조사가 없습니다. 경제적 배 타임즈 비즈니스 뉴스, 개인 금융, 금융 뉴스, 인도 주식 시장 투자, 경제 뉴스, SENSEX, NIFTY, NSE, BSE 라이브, IPO 뉴스 Economic Times India s Leading Business 신문은 비즈니스 뉴스, 금융 뉴스, 주식 몫 시장 뉴스, 경제 뉴스, 대출 은행 뉴스, 라이브 주식 및 뉴스를 제공합니다. 뮤추얼 펀드, 골드, 외환 및 부동산 추적에 대한 투자 분석 인도 주식 시장 CFTC는 2014 년 보고서에서 10 스푸핑 CME Group 소유의 파생 상품 시장 중 하나 인 Nymex와 Comex에서 2012 년 7 월부터 2013 년 7 월까지 프로브가 시작되었습니다. Comercio En Lnea En 기니 Ecuatorial 이것은 범죄가있는 미국 에너지 카르텔이 석유가없는 경우에도 석유 가격을 유지하는 방법입니다 실제 수요 바이너리 옵션 트레이딩 50 예금 4 Aes 헤지 펀드 산업이 길을 잃은 3 가지 이유 헤지 펀드 산업은 지난 20 년 동안 폭발적으로 증가했지만 최근의 수익률은 그들의 모든 이유 포클랜드 제도 증권 거래소 Ppt. Tracking 인도 주식 시장. 인도 증권 시장 시계 1 8 그것은 BSE, NSE, MCX 및 NCDEX 거래소의 자산을 포함하므로 IndicesSensex l Nifty Business Standard , 인도의 라이브 시장, 라이브 BSE NSE 견적, 최신 뉴스, 속보, 정치 뉴스, 분석 및 시장 견해에 대한 선도적 인 비즈니스 사이트입니다. Citation Clinical Translational Immunology 2014 3 e13 doi 10 1038 cti 2014 4 2014 년 3 월 14 일 온라인으로 게시됩니다. Vaccines leishmaniasis 예방. Rajiv Kumar 1 및 Christian Engwerda 1.1 QIMR Berghofer, Brisbane, 호주 퀸즈랜드 면역학 및 감염 연구소. C 엥겔 베다 교수, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland 4006, 호주 E-mail . 수령 2013 년 12 월 13 일 개정 2014 년 2 월 11 일 개정 2014 년 2 월 12 일 접수. 리만시 증증은 다양한 임상 증상을 포함하는 기생충 질환입니다. 세계의 열대 및 아열대 지역의 사람들 역학 및 실험 데이터에 따르면 질병으로부터의 보호는 대부분의 사람들이 달성 할 수 있음을 나타냅니다. 또한 우리는 기생충 성장을 조절하기 위해 숙주 면역계가 감염에 어떻게 반응해야하는지 알고 있습니다. 인간에 사용하기위한 백신 없음 여기에서 우리는 리 슈만 (Leishmania) 감염에 대한 숙주 면역에 대한 우리의 이해를 검토하고 기생충 헤모글로빈 수용체를 목표로하는 새로운 유망한 접근법을 강조하면서 백혈병 예방을위한 백신 개발에 대한 최근의 진전에 대해 논의합니다. 면역 leishmania 기생충 백신. Leishmania 속의 원생 기생충에 기인 한 벡터 매개 질병이 기생충은 포유류 숙주의 단핵 식세포에서 세포 내, 융모 성의 무자근과 같이 세포 외의 편모 포진과 같은 30 종의 Phlebotomine 사파리에 의해 전염된다. Leishmaniasis 범위 자기 치유, 지방화 된 피부 병변에 무증상 감염, 그리고 생명을 위협하는 진보적 인 내장 형태의 질병으로 발전 할 수있다. 리슈 마니아 증은 세계에서 가장 소홀한 질병 중 하나이며, 개발 도상국가의 빈민층에 주로 영향을 미친다. 아프리카의 열대 및 아열대 지역에 퍼져있다. , 아시아, 지중해, 남유럽 구세계 및 중남 아메리카 신세계이 질병은 88 개국에서 발병하고 있으며 그 중 72 개가 개발 도상국이다. 약 3 억 5 천만명이 리 슈만 편모충 증을 앓고 있으며 매년 150 만 건의 새로운 사례가 발생한다 3 Leishmania 기생충의 전염은 인류 대륙과 아시아에서 인간에게 벡터를 전달하는 반면, 아프리카, 유럽 및 아메리카에서는 인체에 ​​동물을 감염시키는 동물 군 (zoootic animal)이며 개와 설치류가 저수지로 작용한다. 그림 1 4 5 6 생명주기와 Leishmania 기생충의 전파 인간 질병에 책임이있는 Leishmania 기생충의 무자격 형태 VL, CL과 MCL은 여성 샌드위치가 혈액 식사 1을 받고, 다음으로 숙주 대 식세포 2에 의해 흡수되면서 피부에 주입됩니다. Promastigote는 대 식세포 3 내부의 비 - 편모, 무자 고형 형태로 전환 한 다음 이분법 4로 나눕니다. 대 식세포의 파열로 풀려나 5 다른 피를 먹는 동안 여성 샌드 플라이에 의해 흡수 될 수있다. 무자 고개 형태는 샌드 플라이 (sand fly)의 중간 덩어리에서 무릎 관절 형태로 전환되고 다시 다른 사람의 anthroponotic transmission 또는 저수지의 전염병 전파로 작동하는 동물 6. 전장 및 전설 107K. 일반적으로 kala-azar로 알려진 VLIS (Leismaniasis VL)는 올드 월드의 L 도노 바니와 L 자선에 의해 발생하며 신세계의 L 샤 가스는이 기생충을 우선적으로 사용합니다 내장을 통해 대 식세포를 감염 시키며 기생충은 보통 비장, 간 및 골수에서 발견됩니다. 임상 특징으로는 일반적으로 장기간, 저 등급 발열, 간세포 증 pancytopenia 및 다 클론 성 IgG 및 IgM과 감마 글로불린 혈증 7 대부분의 경우 치료되지 않은 VL은 궁극적으로 사망으로 이어질 것입니다. 매년 약 500 000 건의 VL이 발생합니다. 7 대부분의 VL 사례는 인도, 네팔, 방글라데시, 수단, 및 브라질 3 인도는 VL 3 8에 대한 세계에서 가장 중요한 초점 중 하나입니다. 8 Bihar 및 동부 우타르 프라데시 및 서 벵골 지역의 인접 지역은 특히 VL 9의 영향을 계속받습니다. 인도에서 VL의 연간 발생률은 약 100 000입니다 사례 및 Bihar의 상태는 이들 중 90 개 이상을 차지합니다. 9 VL - 사람 면역 결핍 바이러스의 발생률은 HIV 병독성이 감염된 지역입니다. 10. 만성 독감은 L. tropica L aethiopica와 L major에서 발생합니다. 구세계 그리고 L mexicana L guyanensis L amazonensis와 L braziliensis는 새로운 세계에서 가장 흔한 형태의 leishmaniasis이며, 모든 새로운 사례 중 50 75를 나타냅니다. 세계 보건기구 WHO에 따르면 매년 CL 케이스의 수는 약 115000000이며, CL 케이스의 90 개는 아프가니스탄, 알제리, 브라질, 이란, 페루 등 7 개 국가에서 발생합니다. , 사우디 아라비아 및 시리아 3 6 CL은 수많은 기생충을 포함하는 궤양 성 피부 병변의 발생을 특징으로합니다. CL의 임상 특징은 원인 종별로 다양 할 수 있지만 고전 병변은 구강에서 구진 또는 결절로 시작합니다. 기생충 접종이 천천히 진행된다 6. 점액 성 리슈 마니아 증 (Mucocutaneous leishmaniasis) MCL은 신세계에서 발생하며 주로 L braziliensis와 L panamensis에 의해 유발된다. 이들 종은 림프 또는 혈행 성 보급에 의해 입 및 위 호흡기의 점막 조직으로 전이 될 수 있으며 모든 MCL 볼리비아, 브라질 및 페루에서 발생합니다. MCL은 피부 병변 발생 후 수개월에서 수년까지 나타날 수 있습니다. VL 및 CL은 비교적 잘 이해되고 있으며, MCL의 병인은 아직 명확하지 않지만, 이 분야에서 최근의 진전이있다. 숙주 유전 인자가 질병의 발달에 중요하다고 여겨진다. 리슈 마니아에 대한 통제 수단은 화학 요법에 크게 의존하고있다. 현재 고용되어있다. 마약은 심각한 독성 부작용과 기생충 약제 내성 증가와 관련이 있습니다. 11 12 연구원은 다른 통제 조치, 특히 효과적인 백신의 개발 및 시행을 고려해야합니다. Leishmania 감염으로 치료받은 사람들은 평생 면역을 개발합니다. Leishmania 게놈 서열의 완성과 함께 Leishmania 감염 발병 기전과 숙주 방어 면역의 생성에 대한 우리의 이해의 진전은 백신 연구를위한 새로운 길을 열었습니다. 그러나 동물로부터 아이디어를 번역하는 것을 포함하여 주요 도전 과제가 남아 있습니다 모델 연구실에서 현장으로의 제품 전환이 리뷰는 leishmaniasis 예방 및 치료를위한 백신 개발에 대한 최근의 진보를 강조하고 향후 전망에 대해 논의 할 예정이다. 숙주의 면역 반응을 보호한다. 병원균에 대한 면역성은 효과적인 백신 개발에 중요합니다. Leishmania 기생충에 대해 생성 된 숙주 면역 반응에 대한 현재의 이해는 주로 동물 모델 연구를 기반으로합니다. 마우스 연구는 Leishmania 감염에 대한 방어 면역이 인터루킨 -12 의존성 , CD4 T 세포에 의한 인터페론 및 종양 괴사 인자 생성을 특징으로하는 기생충 특이 적 Th1 반응 13 14 15이 염증성 사이토 카인은 세포 내 기생충을 죽일 수있는 감염된 대 식세포에 의한 반응성 산소 및 질소 종의 생성에 필요합니다. 면역을 이해하여 만들어졌다. 인간 VL 환자에서 기생충 특이 CD4 T 세포 반응을 억제하는 조절 메커니즘 CD4 T 세포에 의해 생성 된 인터루킨 -10이 인터페론 생산의 강력한자가 독소 억제제이며 VL 환자의 비장 조직에서 기생충 지속을 촉진한다는 발견을 포함합니다 16 따라서 interleukin-10은 약물 치료와 병용하거나 치료 백신의 효능을 향상시킬 수있는 잠재적 인 치료 표적으로 확인되었습니다. 면역 기억의 생성은 효과적인 예방 접종의 요구 사항입니다. effector 및 central memory CD4 T 세포의 생성에 관한 연구 중앙 기억 T 세포가 영구 기생충이없는 경우에도 L 주요 감염에 대한 장기간 면역을 매개한다는 것을 나타냅니다. 따라서 요구 사항을 정의하고 중앙 기억 장치 CD4 T 세포 형성 및 유지에 대한 조건을 이해하면 백신 설계에 도움이 될 것입니다. Leishmania 기생충에 감염된 대다수의 사람들이 기생충 성장을 제어한다는 지식 1819 년에 심각한 질병을 일으키지 않고 기생충을 죽이는 데 필요한 면역 반응의 유형과이 면역을 억제하는 면역 반응에 대한 우리의 이해와 더불어 리 슈만 편모충 병에 대한 백신 개발이 현실적인 목표임을 의미한다. 왜 예방을 위해 백신이 필요한가? leishmaniasis를 치료하십시오. leishmaniasis의 치료는 화학 요법에 의존합니다. 가장 일반적으로 사용되는 약물은 5가 antimonials, 구강 miltefosine, amphotericin B, liposomal amphotericin B 및 paramomycin 아르 주요 문제는 이러한 약물 비용, 독성, 길이 및 기간의 문제와 관련이 있습니다 치료, 주사 경로, 예를 들어 정맥 내 주입 및 기생충 약제 내성의 개발 20 5 년 동안의 5 개 항균제 치료법이 수년간 치료의 첫 번째 행 이었지만, 고유 지역에서의 기생충 저항성 증가는 인도의 Bihar 주에서의 사용을 제한했다. 60 건의 환자가이 약으로 치료를받지 못합니다. 따라서 Amphotericin B 현재 VL 환자를 치료하기위한 주요 약물로 사용된다. 그러나이 약물은 또한 독성과 관련이 있으며 약물 내성 기생충에 대한보고가있다 .22 Miltefosine은 경구 용 약물로 개발되어 조기약을 보였으 나 현재에는 이 약으로 치료받은 환자의 재발 23,24 최근 amofotericin B의 ambisome 지질 제형의 단일 용량이 VL 환자의 치료에 효과적이며, 다기관 임상 시험에서 기존 치료법에 비해 독성 발병률이 낮았다. 그럼에도 불구하고이 유형의 약물 치료 프로토콜이 약물 내성 기생충의 개발을 촉진 할 수 있다는 우려가있다. 따라서 조합 약물 치료가 풍토 국에서의 사용을 위해 활발히 개발되고있다 27 28 그러나 마우스 모델 연구는 L donovani 화학 요법 선택의 진전에도 불구하고 약물에 대한 내성이 생길 수있다. 화학 요법만으로 질병을 제거 할 수 있으므로이 질병을 통제하고 제거하려는 장기적인 목표를 달성하려면 효과적인 백신이 절실히 필요합니다. 현재 및 현재의 백신 후보자. 다양한 임상 증후를 유발하는 다양한 리 슈만 (Leishmania) 종에도 불구하고 , 게놈 분석은 다른 임상 질환에 대해 광범위하게 효과적인 백신을 생성 할 수 있음을 시사하는 종간의 서열 상 동성이 상당하다는 것을 보여줍니다. 과거에는 leishmaniasis에 대한 효과적인 백신이 존재했습니다. 이것은 살아있는 독성 기생충과 접종하는 과정에서 leishmanization 그것은 구 소련, 중동 및 이스라엘에서 성공적으로 수행되었다. 30 31 그러나 치유가되지 않는 병변과 면역 억제를 일으키는 몇몇 개인들 때문에 병참 문제와 안전 문제 때문에 대부분의 국가에서 버려졌다. autoclaved Leishmania promastigotes 또한 백신으로 테스트되었습니다 aga inst CL 및 VL 죽은 기생충 백신의 시험은 1940 년대 초반 브라질에서 실시되었으며, 그 후 단독으로 또는 1 상, 2 상 및 3 상 임상 시험에서 보강제와 함께 시험되었다. 33 34 BCG와 함께 보조제를 마른 가압 멸균 된 Leishmania를 사용한 임상 시험, 이 접근법은 CL의 발병률을 18 18 35 36 감소시킬 수 있음을 보여 주었다. 유사한 안전성과 효능으로이란, 수단 및 에콰도르에서도 비슷한 시도가 수행되었다. 37 38 39 40 41 불행히도, 오토 클레이브 된 기생충은 시간이 경과함에 따라 효능이 감소하는 것으로 나타 났으 나 티 메로 살 보존 및 비 오토 클레이브 제제는 저장의 감소 된 효과를 보였다. 그러나 과거에 다른 현장 및 임상 시험 현장에서 얻은 결과의 차이를 포함하여 죽은 전체 백신 백신 개발의 타당성에 대한 우려가 남아있다. 그러한 제품을 훌륭한 임상 제조 표준에 맞게 생산합니다. 다양한 약독 화 된 기생충도 동물 모델에서 테스트되었습니다 Thes 기생충은 일반적으로 독성이있는 기생충과 비슷한 방식으로 숙주 세포에 흡수되며 복제하지 않고 얼마 동안 지속됩니다. 숙주가 기생충 항원에 대해 강력한 면역 반응을 나타낼 수 있습니다. 약독 화 및 생화학 적으로 변형 된 기생충은 비록 독성에 대한 전환에 관한 염려가 후자의 선택을 인간의 사용에 대해 의문스럽게 만들지 만 독성 유전자의 표적 제거는이 문제를 극복 할 수 있고 leishmaniasis에 대한 매력적인 백신 후보 물질을 생산할 수있다. dyhydrofolate와 같은 필수 유전자가없는 유전자 변형 Leishmania 기생충 reductase, biopterin reductase 또는 cystein proteases가 독성 기생충 균주의 공격에 대한 방어를 촉진하는 것으로 나타났습니다. 44 45 46 약물 감수성 Leishmania 돌연변이 47 단독 또는 보조제의 사용이 anti-leishmanial 면역을 유도하는 메커니즘으로 제안되었습니다. 비 - 파의 사용 L. tarantolae와 같은 thogenic Leishmania 종은 독성 L donovani 균주에 대한 방어를 자극 할 수있다. 그러나 죽이거나 약화 된 기생충을 사용하는 주된 문제점은 현장에서의 대규모 사용에 대한 안전성과 실현 가능성에 관한 우려이다. 백신 후보 물질 인 Leishmania 기생충의 항원 이들 중 몇 개는 생쥐 모델과 개과 동물에서 VL에서 테스트를 거쳤습니다. leishmaniasis에 대한 방어가 정의 된 후보 단백질로 달성 될 수 있음을 시사합니다. 기생충의 수명주기 동안 표현되는 fucose mannose ligand의 사포닌 제형. 는 실험용 마우스 및 햄스터 모델에서 안전하고 면역성이 있으며 면역성이있는 것으로 밝혀졌습니다. 이 배합은 현재 개과 동물 실험을 통해 허가 된 Leishmune 수의사 백신이되었습니다. 51 52 L donovani의 용해성 leishmania 항원의 지질 배합도 L의 햄스터 모델에서 백신 후보 물질로서 시험 됨. 도노바니 감염으로 인한 기생충 항원 증가, 기생충 특이 항체 반응 개선 및 기생충 특이성 T 세포 반응 개선으로 지연 형 과민 반응이 증가됨 53 54 포스 포로 티오 에이트가 결합 된 L 메이저에서 유래 된 리포좀 성 용해성 leishmania 항원 CpG ODN PS CpG 또는 포스 포디 어스터 CpG ODN PO CpG는 또한 CL 마우스 모델에서 시험되었으며 상당한 수준의 보호를 생성 하였다. L infantum의 배양 상등액으로부터 분리되고 muramyl dipeptide가 보조 된 배설 분비 단백질을 실험적으로 L infantum 56으로 감염된 개에서 시험 하였다 LiesAp-MDP 라 불리는이 백신은 자연 감염된 개가있는 프랑스 고유 지역의 현장 시험에서 송곳니 VL에 대해 중요하고 오래 지속되는 방어를 유발했습니다 .57 그러나 이러한 인간 분주 화 백신의 주된 장애물은 생산에서 생산까지입니다 임상 제조 표준, 유전자 변이 및 다형성 physis를 포함한다. 재조합 단백질은 단독으로 또는 보조제와 함께 또는 박테리아와 재조합 바이러스와 함께 전달 매개체로 사용된다. 58 59 또한 전임상 연구에서 백신으로 시험되었다. 최근 예방 적 재조합 항원을 확인하는 중요한 노력이있어왔다 실험 모델에서의 Leishmania 감염에 대한 항원 항원들 중 일부는 키 네오 프라 시드 막 단백질 -11, 60 61 스테롤 24-c - 메틸 트란스 페라 제, 62 아마 스타 특이 적 단백질 A2, 63 시스테인 프로테아제 B, 64 L braziliensis 신장 및 개시 인자, 65 K26 HASPB, 66 Leishmania-activated C kinase, 67 promastigote 표면 항원 2, 68 nucleoside 가수 분해 효소 69 및 표면 발현 된 당 단백질 gp63 70 대부분의 재조합 항원은 면역 원성 및 방어 효능에 대한 동물 모델에서 시험되었지만 극소수의 비인간 영장류, 개 또는 전임상 인체 연구 71 72 다중 서브 유닛 재조합 Lei MPL-SE와 함께 제형화할 때, 주요한 스트레스 유도 성 단백질 -1 및 L braziliensis 신장 및 개시 인자가 진핵 세포의 thiol 특이 적 항산화 물질 인 L 주요 동족체를 함유하는 shmania 백신, Leish-111F가 마우스 모델에서 보호를 제공하는 것으로 나타났다 LY-111F MPL-SE는 건강한 지원자에서 인간 1 기 및 2 기 임상 시험을 진행하는 최초의 정의 된 백신 후보 물질이다. 남아메리카, 브라질 및 페루의 CL 및 ML 환자 및 인도의 VL 치료 환자 76 77 78 79 모든 하위 유니트 백신과 마찬가지로, 잠재적 인 문제는 개인의 인간 림프구 항원 발현, 유전자 변이 및 다형성에 근거한 면역 원성의 변화를 포함합니다 기생충뿐만 아니라 백신에 사용 된 분자에서 기생충의 선택 압박을 유발할 수있는 잠재력이 있습니다. 마지막으로, leishmaniasis를 예방하는 DNA 백신도 개발 중입니다. 이 방법은 새로운 것은 아니지만 생산 비용의 절감, 물질의 안정성, 관련 항원의 지속적인 발현 및 효율적인 이펙터 생성과 기억 반응의 생성과 같은 몇 가지 이점을 가지고있다 .81 또한 하나 이상의 항원을 생산할 수있다 단일 구조로 세균 DNA의 메틸화되지 않은 CpG 모티프는 타고난 면역 세포를 활성화시켜 CD4 T 세포가 Th1 세포로 발전 할 수있는 인터루킨 -12를 생산할 수있는 이점을 제공합니다. 82 DNA에서 테스트되는 백신 항원 후보 물질 목록 CL 및 VL에 대한 백신은 표 1에 나와 있습니다. 표 1 - Leishmania 백신 항원은 후보 DNA 백신으로 테스트됩니다. 따라서 면역 원성 항원을 확인하고 백신 기술을 개발하는데 수년간 노력을 기울 였지만 아직까지 질병 퇴치 프로그램에 필요한 보호 수준을 제공 할 수있는 백신 후보 Guha 등 83은 DNA 백신 접근법을 사용하여 기생충 헤모글로빈 수용체 HbR을 표적으로하고 VL Leishmania 기생충의 실험 모델에서이를 테스트 한 결과 각종 대사 활동에 필요한 헤메를 필요로하지만 내인성 헴 합성 경로가 결여되어 이들을 의존적으로 만든다 숙주의 HbR은 기생충의 세포 표면에 발현되며 다른 종들 사이에서 보존된다. 이 수용체는 헤모글로빈 엔도 사이토 시스 84에 중요 할뿐 아니라 호스트 헤 키오 키나아와는 별개 인 헥소 키나아제 활성을 가지며, 85는 해당 조절 작용에 중요하다. 기생충 HbR의 특성으로 Guha와 동료들은이 분자를 DNA 백신 후보자로 시험했다. 모든 백신의 성공 여부는 효과적인 항원 특이 항체 반응의 생성, 기생충 특이성 T 세포의 뇌하수체 및 유지 관리 반응 및 적합한 이펙터 기능을 갖는 T 세포의 생성 Guha 등은 환자가 위트 h 활성 VL은 HbR에 대한 반응 항체를 생성하고, 이들 항체는 체외에서 보체 의존적으로 기생충 성장을 억제 할 수 있었다. 또한 마우스의 HbR-DNA 백신 접종이 항원 특이 적 IgG2a 항체의 생산을 자극하고 여러 개의 Th1 관련 사이토 카인을 동시에 생산할 수있는 항원 특이성 T 세포 반응, 즉 다기능 T 세포 반응 또한이 DNA 백신으로 면역화하면 독성 L 도노 바니 (Douvovani)로 감염된 햄스터와 마우스에서 무균 치료가 가능합니다 그림 2 주목할 가치가있다. 이 결과는 보조제가 없을 때 얻어지며 따라서 인간의 DNA 백신 후보 물질 인 HbR의 잠재력을 강조한다. 그러나 효능에 대한 독립적 인 검증을 포함한 추가 시험을 수행해야한다. 또한 앞에서 언급했듯이 DNA 백신은 동물 모델에서 큰 가능성을 보였으 나 아직 인간에 대한 유용성이 입증되지 않았습니다. 인간에서 DNA 백신을 테스트하기 위해 2 단계를 넘어선 임상 시험 기생충 HbR과 같은 DNA 백신 후보자의 주요 과제는 임상 시험 및 현장 설정에서 인간의 안전성 및 효능을 증명하는 것입니다. HbR-DNA의 효과 백신 a MHC-II 및 MHC-1 분자와 관련하여 항원 제시 세포 APC에 의해 CD4 및 CD8 T 세포에 항원이 제시되었다. 이것은 CD4 및 CD8 T 세포의 증식을 촉진 시켰고 다기능 CD4 및 CD8 T 세포의 생성을 유도했다. CD4 T 세포는 B 세포 혈장 세포에 의한 항체 생성을 증가시켰다 .4 다기능 CD4 및 CD8 T 세포 및 항체의 증가 된 결합 효과는 기생충의 완전한 클리어런스 5 b 백신을 접종하지 않은 생쥐와 햄스터에 L donovani 전립선 암이 감염되었다. 1 APC에 의해 CD4와 CD8 T 세포에 항원이 제시되었다. 모방 된 T 세포의 증식과 인터루킨 -10 생성 세포의 생성 3. 증대 된 기생충 성장 4. 전장 및 전설 166K. 발언 문제 및 향후 방향 포함. 백신 접종은 전염병을 통제하는 가장 비용 효율적인 방법이다. 백신 개발은 병원체 숙주 상호 작용의 면역 생물학을 이해하고 적절한 백신 후보 물질을 선택하고 적절한 보조제 또는 전달 수단을 선택하는 데 달려있다. 또한 백신은 오래 지속되는 면역을 생성 할 수 있어야한다. 백신 유효성을 효율적으로 평가할 수 있으며 전임상 시험에서 인간 임상 시험으로 전환 할 수 있어야합니다. 그러나 감염 또는 예방 접종 후에 확립 된 면역 조절 경로에 대한 더 나은 이해에도 불구하고 우리는 여전히 유효한 보조제로 임상 적 이점을 조절할 수있는 능력이 제한되어 있습니다 또는 약물 이상적으로, 백신은 또한 특정 질병에 대한 모든 원인 물질에 대해 효과적 이것은 향후 백신 개발 프로그램에서 중요한 고려 사항이 될 제품 개발 및 테스트에서 상당한 절약을 허용합니다. leishmaniasis에 대한 백신의 개발은 느립니다 그러나 최근에 증가 된 지식은 위의 모든 분야는 leishmaniasis의 예방 및 치료를 목표로 한 새로운 백신 제조 및 테스트를위한 새로운 방법을 모색하고 있습니다. 자금 출처를 확인하고 백신 개발의 긴 길을 걸을 수 있다면, 우리는 이것이 기생충 질병 중 하나임을 확신합니다. 궁극적으로 통제 될 수있다. Pearson RD, Sousa AQ 리 슈만 편모충의 임상 스펙트럼 Clin Infect Dis 1996 22 1 13 Article PubMed ISI CAS. 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Velez ID, Gilchrist K, Martinez S, Ramirez-Pineda JR, Ashman JA, Alves FP et al Safety and immunogenicity of a defined vaccine for the prevention of cutaneous leishmaniasis Vaccine 2009 28 329 337 Article PubMed. Nascimento E, Fernandes DF, Vieira EP, Campos-Neto A, Ashman JA, Alves FP et al A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1 MPL-SE vaccine when used in combination with meglumine antimoniate for the treatment of cutaneous leishmaniasis Vaccine 2010 28 6581 6587 Article PubMed. Llanos-Cuentas A, Calderon W, Cruz M, Ashman JA, Alves FP, Coler RN et al A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1 MPL-SE vaccine when used in combination with sodium stibogluconate for the treatment of mucosal leishmaniasis Vaccine 2010 28 7427 7435 Article PubMed. C hakravarty J, Kumar S, Trivedi S, Rai VK, Singh A, Ashman JA et al A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1 MPL-SE vaccine for use in the prevention of visceral leishmaniasis Vaccine 2011 29 3531 3537 Article PubMed. Tang DC, DeVit M, Johnston SA Genetic immunization is a simple method for eliciting an immune response Nature 1992 356 152 154 Article PubMed ISI CAS. Donnelly JJ, Ulmer JB, Shiver JW, Liu MA DNA vaccines Annu Rev Immunol 1997 15 617 648 Article PubMed ISI CAS. Gurunathan S, Klinman DM, Seder RA DNA vaccines immunology, application, and optimization Annu Rev Immunol 2000 18 927 974 Article PubMed ISI CAS. Guha R, Gupta D, Rastogi R, Vikram R, Krishnamurthy G, Bimal S et al Vaccination with leishmania hemoglobin receptor-encoding DNA protects against visceral leishmaniasis Sci Transl Med 2013 5 202ra121 Article PubMed. 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Basu R, Bhaumik S, Basu JM, Naskar K, De T, Roy S Kinetoplastid membrane protein-11 DNA vaccination induces complete protection against both pentavalent antimonial-sensitive and - resistant strains of Leishmania donovani that correlates with inducible nitric oxide synthase activity and IL-4 generation evidence for mixed Th1- and Th2-like responses in visceral leishmaniasis J Immunol 2005 174 71 60 7171 PubMed ISI CAS. Bhaumik S, Basu R, Sen S, Naskar K, Roy S, KMP-11 DNA immunization significantly protects against L donovani infection but requires exogenous IL-12as an adjuvant for comparable protection against L major Vaccine 2009 27 1306 1316 Article PubMed. Guha R, Das S, Ghosh J, Naskar K, Mandala A, Sundar S et al Heterologous priming-boosting with DNA and vaccinia virus expressing kinetoplastid membrane protein-11 induces potent cellular immune response and confers protection against infection with antimony resistant and sensitive strains of Leishmania Leishmania donovani Vaccine 2013 31 1905 1915 Article PubMed. Rafati S, Salmanian AH, Taheri T, Vafa M, Fasel N A protective cocktail vaccine against murine cutaneous leishmaniasis with DNA encoding cysteine proteinases of Leishmania major Vaccine 2001 19 3369 3375 Article PubMed ISI CAS. Rafati S, Nakhaee A, Taheri T, Taslimi Y, Darabi H, Eravani D et al Protective vaccination against experimental canine visceral leishmaniasi s using a combination of DNA and protein immunization with cysteine proteinases type I and II of L infantum Vaccine 2005 23 3716 3725 Article PubMed. Sharma A, Madhubala R Ubiquitin conjugation of open reading frame F DNA vaccine leads to enhanced cell-mediated immune response and induces protection against both antimony-susceptible and - resistant strains of Leishmania donovani J Immunol 2009 183 7719 7731 Article PubMed. Gamboa-Leon R, Paraguai de Souza E, Borja-Cabrera GP, Santos FN, Myashiro LM, Pinheiro RO et al Immunotherapy against visceral leishmaniasis with the nucleoside hydrolase-DNA vaccine of Leishmania donovani Vaccine 2006 24 4863 4873 Article PubMed. Aguilar-Be I, da Silva Zardo R, Paraguai de Souza E, Borja-Cabrera GP, Rosado-Vallado M, Mut-Martin M et al Cross-protective efficacy of a prophylactic Leishmania donovani DNA vaccine against visceral and cutaneous murine leishmaniasis Infect Immun 2005 73 812 819 Article PubMed. Research in the authors laboratory is funded by t he Australian NHMRC and the Australia-India Strategic Research Fund We thank Madeleine Flynn for help in preparing both figures. This work is licensed under a Creative Commons Attribution 3 0 Unported License To view a copy of this license, visit. Main navigation. Extra navigation. Sex, Gender and Health Research Guide A Tool for CIHR Applicants. CIHR is a signatory on the Government of Canada s Health Portfolio Sex - and Gender-Based Analysis Policy as well as the Tri-Council Policy Statement on Ethical Conduct for Research Involving Humans Both policies underscore the importance of integrating gender and sex into health research when appropriate, for there is significant evidence to demonstrate that biological, economic and social differences between women and men contribute to differences in health risks, health services use, health system interaction and health outcomes Accounting for gender and sex in health research has the potential to make health research more just, more rigorous and more useful As such, and as indicated in the Grants and Awards Guide CIHR expects that all research applicants will integrate gender and sex into their research designs when appropriate. As part of the grant application process, CIHR asks applicants to indicate if sex and or gender are accounted for in the study and to further elaborate on and justify their responses. Sex refers to a set of biological attributes in humans and animals It is primarily associated with physical and physiological features including chromosomes, gene expression, hormone levels and function, and reproductive sexual anatomy Sex is usually categorized as female or male but there is variation in the biological attributes that comprise sex and how those attributes are expressed Download Sex and Gender Infographic. Gender refers to the socially constructed roles, behaviours, expressions and identities of girls, women, boys, men, and gender diverse people It influences how people perceive themselves and each other, h ow they act and interact, and the distribution of power and resources in society Gender is usually conceptualized as a binary girl woman and boy man yet there is considerable diversity in how individuals and groups understand, experience, and express it Download Sex and Gender Infographic. Sex - and Gender-Based Analysis SGBA is an approach that systematically examines sex-based biological and gender-based socio-cultural differences between men, women, boys, girls and gender-diverse people The purpose of SGBA is to promote rigorous science that is sensitive to sex and gender and therefore has the potential to expand our understanding of health determinants for all people SGBA is meant to be applied within the context of a diversity framework that considers the ways in which determinants such as ethnicity, socioeconomic status, disability, sexual orientation, migration status, age and geography interact with sex and gender to contribute to exposures to various risk factors, disease course s and outcomes Applying SGBA brings these considerations into focus and can help formulate health research, policies and programs that are relevant to the diversity of the Canadian population. SGBA Resources. Below are some guidelines, tools and resources to help researchers and reviewers better account for sex and gender in health research. Biomedical Research. Clinical Research. Health Systems and Services Research. Population Health Research. Gender Measurement Instruments. Many gender scales can be used to collect information about gender in primary surveys and research studies The following list represents a selection of some of the most frequently used scales It is important to note that gender is not static it is socially constructed and changes over time It is important to take a critical approach when studying gender and in deciding how to consider it in a study. Gender Identity. Gender Roles. Gender Norms. Gender Relations. Additional Examples. Miller, VM, Kaplan, JR, Schork, NJ et al Stra tegies and methods to study sex differences in cardiovascular structure and function a guide for basic scientists Biology of sex differences 2011 2 1 1.Mogil, JS Perspective Equality need not be painful Nature 2016 535 7611 S7-S7.Beery, AK, Zucker, I Sex bias in neuroscience and biomedical research Neuroscience Biobehavioral Reviews 2011 35 3 565-572.Shah, K, McCormack, CE, Bradbury, NA Do you know the sex of your cells American Journal of Physiology-Cell Physiology 2014306 1 C3-C18.Prendergast, BJ, Onishi, KG, Zucker, I Female mice liberated for inclusion in neuroscience and biomedical research Neuroscience Biobehavioral Reviews 201440 1-5.Becker, JB, Prendergast, BJ, Liang, J W Female rats are not more variable than male rats a meta-analysis of neuroscience studies Biology of Sex Differences 20167 1 34.Danska, JS Sex matters for mechanism Science translational medicine 20146 258 258fs40-258fs40.Markle, JG, Fish, EN SeXX matters in immunity Trends in immunology 201435 3 97-104.Francon i, F, Campesi, I Sex and gender influences on pharmacological response an overview Expert review of clinical pharmacology 20147 4 469-485.Pelletier, R, Khan, NA, Cox, J et al Sex versus gender-related characteristics which predicts outcome after acute coronary syndrome in the young Journal of the American College of Cardiology 201667 2 127-135.Rochon, PA, Grunier A, Gill, SS et al Older men with dementia are at greater risk than women of serious events after initiating antipsychotic therapy Journal of the American Geriatrics Society 201361 1 55-61.Alabas, OA et al Gender role affects experimental pain responses A systematic review with meta analysis European Journal of Pain 201216 9 1211-1223.Bartley, EJ, Fillingim, RB Sex differences in pain a brief review of clinical and experimental findings British journal of anaesthesia 2013111 1 52-58.Morgan, R et al How to do or not to do gender analysis in health systems research Health policy and planning 2016czw037.Clow, B, Pederson, A, Hawor th-Brockman, M, Bernier, J Rising to the challenge Sex-and gender-based analysis for health planning, policy and research in Canada Halifax Atlantic Centre of Excellence for Women s Health 2009.Payne, S How can gender equity be addressed through health systems Copenhagen World Health Organization, 2009.RinGs Steering Committee Ten arguments for why gender should be a central focus for universal health coverage advocates London School of Hygiene and Tropical Medicine, 2014.Johnson, J, Sharman, Z, Vissandjee, B, Stewart, DE Does a change in health research funding policy related to the integration of sex and gender have an impact PloS one 20149 6 e99900.Bauer, GR Incorporating intersectionality theory into population health research methodology Challenges and the potential to advance health equity Social Science Medicine 2014110 10-17.Elliott, MN, Fremont, A, Morrison, PA, Pantoja, P, Lurie, N A New Method for Estimating Race Ethnicity and Associated Disparities Where Administrative Reco rds Lack Self Reported Race Ethnicity Health services research 200843 5p1 1722-1736.Bem, SL On the utility of alternative procedures for assessing psychological androgyny Journal of consulting and clinical psychology 197745 2 196.Spence, JT, Helmreich, RL and Stapp, J Ratings of self and peers on sex role attributes and their relation to self-esteem and conceptions of masculinity and femininity Journal of personality and social psychology 197532 1 29-39.Robinson, ME, Riley, JL, Myers, CD, Papas, RK, Wise, EA, Waxenberg, LB, Fillingim, RB Gender role expectations of pain relationship to sex differences in pain The Journal of Pain 2001 2 5 251-257.O Neil, JM, Helms, BJ, Gable, RK, David, L, Wrightsman, LS Gender-Role Conflict Scale College men s fear of femininity Sex Roles 198614 5-6 335-350.Levant, RF, Hirsch, LS, Celentano, E, Cozza, TM The male role An investigation of contemporary norms Journal of Mental Health Counseling 1992.Glick, P, Fiske, ST The ambivalent sexism inventory Diff erentiating hostile and benevolent sexism Journal of personality and social psychology 1996 70 3 491.Srlin, A, Lindholm, L, Ng, N, hman, A Gender equality in couples and self-rated health-A survey study evaluating measurements of gender equality and its impact on health International journal for equity in health 201110 1 1.Pelletier R, Ditto B, Pilote L A composite measure of gender and its association with risk factors in patients with premature acute coronary syndrome Psychosomatic Medicine 201577 5 517-26.Smith, PM, Koehoorn, M 2016 Measuring gender when you don t have a gender measure constructing a gender index using survey data International journal for equity in health 15 1 , 1.Clow, B, Pederson, A, Haworth-Brockman, M, Bernier, J Rising to the challenge Sex-and gender-based analysis for health planning, policy and research in Canada Halifax Atlantic Centre of Excellence for Women s Health 2009.Date modified 2017-02-24.Section menu. Secukinumab Inhibition of Interleukin-17A in Pa tients with Psoriatic Arthritis. In a phase 2 study, the inhibition of the interleukin-17A receptor improved signs and symptoms of psoriatic arthritis We sought to evaluate the efficacy and safety of secukinumab, an anti interleukin-17A monoclonal antibody, in such patients. In this double-blind, phase 3 study, 606 patients with psoriatic arthritis were randomly assigned in a 1 1 1 ratio to receive intravenous secukinumab at a dose of 10 mg per kilogram at weeks 0, 2, and 4, followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks, or placebo Patients in the placebo group were switched to subcutaneous secukinumab at a dose of 150 mg or 75 mg at week 16 or 24, depending on clinical response The primary end point was the proportion of patients with an American College of Rheumatology 20 ACR20 response at week 24, defined as a 20 improvement from baseline in the number of tender and swollen joints and at least three other important domains. ACR20 response rates at week 24 were significantly higher in the group receiving secukinumab at doses of 150 mg 50 0 and 75 mg 50 5 than in those receiving placebo 17 3 P 0 001 for both comparisons with placebo Secondary end points, including the ACR50 response and joint structural damage, were significantly better in the secukinumab groups than in the placebo group Improvements were sustained through 52 weeks Infections, including candida, were more common in the secukinumab groups Throughout the study mean secukinumab exposure, 438 5 days mean placebo exposure, 128 5 days , four patients in the secukinumab groups had a stroke 0 6 per 100 patient-years 95 confidence interval CI , 0 2 to 1 5 , and two had a myocardial infarction 0 3 per 100 patient-years 95 CI, 0 0 to 1 0 , as compared with no patients in the placebo group. Secukinumab was more effective than placebo in patients with psoriatic arthritis, which validates interleukin-17A as a therapeutic target Infections were more common in the secukinumab g roups than in the placebo group The study was neither large enough nor long enough to evaluate uncommon serious adverse events or the risks associated with long-term use Funded by Novartis Pharma number, NCT01392326.Media in This Article. Figure 1 Responses to Secukinumab at 24 Weeks and 52 Weeks Shown is the proportion of 606 patients who had an improvement of at least 20 in the American College of Rheumatology response criteria ACR20 response , among those receiving 150 mg of secukinumab, 75 mg of secukinumab, or placebo Data are shown for patients in the placebo-controlled portion of the efficacy study, which was conducted from baseline to week 24, and for patients who were randomly assigned to receive secukinumab at baseline through week 52 Missing data were imputed as no response to treatment through week 52 P values at week 24 were adjusted for multiplicity of testing In the primary analysis through week 24, patients who had less than 20 improvement in the number of tender and swo llen joints at week 16 were imputed to have had no response at weeks 20 and 24 There was no imputation on the basis of the response at week 16 for analyses performed at week 28 and for subsequent analyses Asterisks indicate P 0 001 for the comparison with placebo. Table 1 Demographic and Disease Characteristics of the Patients at Baseline. Article Activity. Psoriatic arthritis is a chronic, systemic inflammatory disease that affects peripheral joints, connective tissues, and the axial skeleton and is associated with psoriasis of the skin and nails 1,2 Inhibitors of tumor necrosis factor TNF have significantly improved outcomes among patients with psoriatic arthritis 3-6 However, some patients who have received these agents have not had adequate benefit, have not had a durable response, or have had adverse events 1,2 Effective therapies with a different mechanism of action are needed. Interleukin-17A is postulated to play a role in the pathogenesis of psoriatic arthritis Increased levels of cells that produce interleukin-17A are found in the circulation, joints, and skin plaques of patients with psoriatic arthritis, 7-10 and these levels have been shown to correlate with measures of disease activity and structural damage 11 A phase 2 study showed that the inhibition of the interleukin-17A receptor improved signs and symptoms of psoriatic arthritis 12 Secukinumab, a high-affinity, human immunoglobulin G1 monoclonal antibody that selectively binds to and neutralizes interleukin-17A, has shown efficacy in a number of immune-mediated inflammatory diseases, including psoriasis and ankylosing spondylitis 13,14.FUTURE 1 is an ongoing, 2-year, phase 3 study assessing the effect of secukinumab on signs and symptoms, joint structural damage, physical function, and quality of life among patients with psoriatic arthritis Here, we report efficacy data through week 24 primary end point and week 52 interim follow-up analysis Safety data are reported up to the interim follow-up analysis. Study Population. Study patients were 18 years of age or older, fulfilled the Classification Criteria for Psoriatic Arthritis CASPAR , 15 and had active disease, which was defined as three or more tender joints and three or more swollen joints, despite previous treatment with nonsteroidal antiinflammatory drugs, disease-modifying antirheumatic drugs, or TNF inhibitors The concomitant use of oral glucocorticoids at a dose of 10 mg per day of prednisone or its equivalent and methotrexate at a dose of 25 mg per week was permitted, provided that the dose was stable Patients who had previously received anti-TNF therapy were required either to have had an inadequate response or to have stopped treatment because of side effects For patients who had received anti-TNF agents, a washout period of 4 to 10 weeks before randomization was required. Key exclusion criteria included previous therapy with biologic drugs other than anti-TNF agents, treatment with more than three anti-TNF therapies, the pr esence of active inflammatory diseases other than psoriatic arthritis, and active infection in the 2 weeks before randomization or a history of ongoing, chronic, or recurrent infections Additional information is provided in the Supplementary Appendix available with the full text of this article at. Study Oversight. The study was approved by the institutional review board or ethics committee at each participating site and was conducted in accordance with the principles of the Declaration of Helsinki All patients provided written informed consent. The study was sponsored by Novartis Pharma and designed by the scientific steering committee and Novartis personnel Data were collected according to Good Clinical Practice guidelines by the study investigators and were analyzed by the sponsor Statistical analyses were performed by statisticians employed by the sponsor and were reviewed by all the authors Agreements between the sponsor and the investigators included provisions relating to confident iality of the study data The first draft of the manuscript was written by a medical writer funded by the sponsor All the authors vouch for the accuracy and completeness of the data and analyses and for the fidelity of this report to the study protocol which is available at. Study Design. From September 29, 2011, to October 1, 2012, we conducted this multicenter, randomized, double-blind, placebo-controlled trial at 104 sites in North America and South America, Europe, the Middle East, Australia, and Asia After a 4-week screening period, eligible patients were randomly assigned in a 1 1 1 ratio by means of an interactive voice Web response system to one of two secukinumab dose groups or a placebo group Patients in the secukinumab groups received an intravenous dose of 10 mg per kilogram of body weight at baseline and weeks 2 and 4, followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks thereafter Patients in the placebo group were treated according to the s ame intravenous-to-subcutaneous administration schedule. At week 16, investigators who were unaware of study-group assignments classified all the patients as having had a response which was defined as an improvement of 20 or more from baseline in the number of tender and swollen joints or no response Placebo-treated patients underwent randomization for a second time in a 1 1 ratio to receive subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks, starting at week 16 for patients who were classified as having had no response or week 24 for those who were classified as having had a response In the efficacy analyses, the placebo-controlled period included data through week 24, with imputation for patients who switched to active treatment at week 16 In the safety analyses, the placebo-controlled period included data only through week 16, when patients received the originally assigned study medication. The randomization of patients was stratified according to previous anti - TNF therapy Approximately 70 of the patients were required to have received no previous anti-TNF therapy. The primary objective was to assess the proportion of patients meeting the criteria for 20 improvement according to the criteria of the American College of Rheumatology ACR20 response 16 at week 24 The ACR20 response was defined as an improvement of 20 or more from baseline in the number of tender joints from an analysis of 78 joints , in the number of swollen joints from an analysis of 76 joints , and in three of the following five domains a patient s global assessment of disease, a physician s global assessment of disease, and a patient s assessment of pain with all three evaluations measured on a visual-analogue scale of 0 to 100 disability as measured by the score on the Health Assessment Questionnaire Disability Index HAQ-DI , which ranges from 0 to 3, with higher scores indicating greater disability and the level of acute-phase reactants as measured by the level of high-sen sitivity C-reactive protein or the erythrocyte sedimentation rate. Secondary objectives included assessment of the following categories at week 24 the proportion of patients with improvement of at least 75 and 90 in the score on the psoriasis area-and-severity index PASI 75 and PASI 90, respectively 17 among patients with at least 3 of body-surface area that was affected by psoriasis at baseline a change from baseline in the 28-joint Disease Activity Score on the basis of levels of C-reactive protein DAS28-CRP , with scores ranging from 2 to 10, and a score of more than 5 1 indicating active disease, a score of up to 3 2 indicating low disease activity, and a score of less than 2 6 indicating remission 18 quality of life, as assessed with the use of the physical component summary score of the Medical Outcomes Study 36-Item Short-Form Health Survey SF-36 , version 2, with scores ranging from 0 to 100, and 0 indicating maximum disability and 100 indicating no disability, and a minimum cl inically important difference of at least 2 5 points used for the analysis 19 physical function, as assessed with the use of the HAQ-DI 20 the proportion of patients with improvement of at least 50 according to the criteria of the ACR ACR50 response and radiographic progression In addition, among patients who had either dactylitis or enthesitis at baseline, the presence of dactylitis was assessed by means of a dactylitic digit count, with a score of 1 for the presence of dactylitis and 0 for the absence in each digit, for an overall score ranging from 0 to 20 the presence of enthesitis was assessed by means of a 4-point enthesitis index to measure the presence score of 1 or absence score of 0 of tenderness at the lateral epicondyle humerus left and right and proximal achilles left and right. Radiographic progression was assessed with the use of the van der Heijde modified total Sharp score mTSS , which ranges from 0 to 528, with higher scores indicating greater erosion or narrowing o f joint spaces 21 Radiography of the hands, wrists, and feet was performed at baseline, at week 16 or 24 depending on response , and at week 52 Two independent readers scored all images centrally Exploratory objectives included assessment of the proportion of patients with improvement of at least 70 according to the criteria of the ACR ACR70 response Prespecified subgroup analyses on the basis of previous anti-TNF therapy were performed for key efficacy end points Efficacy assessments were conducted at baseline and throughout the study, with key assessments at week 24 primary end point and week 52 interim follow-up analysis. Safety was evaluated by means of open assessment of adverse events, serious adverse events, and routine laboratory values The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4 0, 22 was used to grade the severity of adverse events Potential major adverse cardiac events were adjudicated by an independent expert committee Blood sample s were obtained at baseline and weeks 24 and 52 for assessment of secukinumab immunogenicity with the use of a homogeneous Meso Scale Discovery bridging assay 23.Statistical Analysis. We calculated that the enrollment of 600 patients 200 in each study group would provide a power of more than 90 to detect a treatment difference between a secukinumab regimen and placebo with respect to the primary end point, assuming response rates for placebo and secukinumab of 22 and 49 , respectively, at a two-sided significance level of 0 025 Primary and secondary efficacy analyses included all patients according to the treatment assigned at randomization Statistical analyses at week 24 used the imputation of missing values as a nonresponse for binary variables, a mixed-effects repeated-measures model for continuous variables, and linear extrapolation for radiographic data Analyses followed a predefined hierarchical hypothesis-testing strategy to adjust for multiplicity to maintain a familywise type I error of 5 According to this strategy, the statistical significance of each secondary end point could be investigated only if the previous end point was significant P 0 025 for end points tested at individual doses P 0 05 for pooled analyses The statistical-hierarchy testing order was as follows ACR20 response, PASI 75, PASI 90, DAS28-CRP, physical component summary of SF-36, HAQ-DI, ACR50, mTSS for pooled secukinumab doses , dactylitis and enthesitis for pooled secukinumab doses , and mTSS for individual doses Patients in the placebo group who were switched to active treatment at week 16 were imputed to have had no response in the analysis at week 24 To avoid bias, secukinumab-treated patients who had no response at week 16 were also imputed to have had no response at week 24.For binary variables, P values are from a logistic-regression model with treatment and previous use of anti-TNF therapy as factors, with body weight at baseline as a covariate The baseline score was a covariate in the analysis of some end points For continuous variables, P values are from a repeated-measures mixed model, with treatment regimen, analysis visit, and previous use of anti-TNF therapy as factors and with body weight and baseline score as continuous covariates Treatment according to analysis visit and baseline score according to analysis visit were used as interaction terms, and an unstructured covariance structure was assumed. Both inferential analyses with imputation and descriptive summaries on observed data were performed on data from week 28 to week 52 In the inferential analysis of binary variables during this period, patients who withdrew from the study were considered to have had no response from the time of withdrawal In contrast to the method that was used in the primary analysis, in the analyses from week 20 through week 52, no imputation was applied as a result of the clinical response of a patient at week 16 Patients for whom responses could not be calculated at a speci fic time point were classified as having had no response Analyses of clinical responses to secukinumab from week 28 to week 52 include only patients who underwent the first randomization to active treatment. Safety analyses included all patients who underwent randomization and who received at least one dose of a study drug Additional information regarding the statistical analysis is provided in the Supplementary Appendix All reported P values are two-sided. Of the 606 patients who underwent randomization 202 in each study group , 553 91 3 completed the 24-week evaluation period and 515 85 0 completed the 52-week evaluation period Fig S1 in the Supplementary Appendix The patients demographic and disease characteristics and previous or concomitant use of medications were similar across the study groups at baseline Table 1 Table 1 Demographic and Disease Characteristics of the Patients at Baseline More than half the patients 53 6 had psoriasis affecting at least 3 of their body-surface area 53 5 had dactylitis, and 61 4 had enthesitis A total of 70 6 of the patients had received no previous anti-TNF therapy, and 60 7 were receiving concomitant methotrexate. Secukinumab was superior to placebo with respect to all the primary and secondary end points that were prespecified in the hierarchical statistical testing At week 24, the proportion of patients with an ACR20 response was significantly higher among patients receiving secukinumab at either the 150-mg dose or the 75-mg dose than among those receiving placebo 50 0 and 50 5 , respectively, vs 17 3 P 0 001 for both comparisons with placebo Table 2 Table 2 Comparison of Efficacy at Week 24 during the Placebo-Controlled Phase and Figure 1 Figure 1 Responses to Secukinumab at 24 Weeks and 52 Weeks Shown is the proportion of 606 patients who had an improvement of at least 20 in the American College of Rheumatology response criteria ACR20 response , among those receiving 150 mg of secukinumab, 75 mg of secukinumab, or placebo Da ta are shown for patients in the placebo-controlled portion of the efficacy study, which was conducted from baseline to week 24, and for patients who were randomly assigned to receive secukinumab at baseline through week 52 Missing data were imputed as no response to treatment through week 52 P values at week 24 were adjusted for multiplicity of testing In the primary analysis through week 24, patients who had less than 20 improvement in the number of tender and swollen joints at week 16 were imputed to have had no response at weeks 20 and 24 There was no imputation on the basis of the response at week 16 for analyses performed at week 28 and for subsequent analyses Asterisks indicate P 0 001 for the comparison with placebo At week 24, the proportion of patients with an ACR50 response was significantly higher in the secukinumab groups than in the placebo group Table 2 , as was the proportion of patients with an ACR70 response in prespecified exploratory analyses Fig S2 in the Supplemen tary Appendix Significant improvements with secukinumab versus placebo were observed for all other secondary end points at week 24 that were prespecified in hierarchical statistical testing, including PASI 75 and PASI 90 responses, the change from baseline in DAS28-CRP, the SF-36 physical component summary, HAQ-DI scores, and the proportion of patients who had resolution of dactylitis and enthesitis Table 2 Patients in the secukinumab groups also had significantly less radiographic progression, as measured by the change from baseline on the mTSS at week 24, than did patients in the placebo group P 0 05 for both comparisons Table 2 and Fig S3 in the Supplementary Appendix. In prespecified exploratory subgroup analyses, improvements in ACR response rates and disease activity at week 24 in the secukinumab groups, as compared with the placebo group, were observed regardless of previous exposure to anti-TNF agents Table S1 in the Supplementary Appendix At week 24, among patients who had rece ived no previous anti-TNF therapy, an ACR20 response was reported in 78 of 143 patients 54 5 who received 150 mg of secukinumab and in 79 of 142 patients 55 6 who received 75 mg of secukinumab, as compared with 25 of 143 patients 17 5 in the placebo group At the same time, among patients who had a previous inadequate response to anti-TNF therapy or who had unacceptable side effects, an ACR20 response was reported in 23 of 59 patients 39 0 who received 150 mg of secukinumab, 23 of 60 patients 38 3 who received 75 mg of secukinumab, and 10 of 59 patients 16 9 in the placebo group In a post hoc analysis, ACR20 response rates were better in the secukinumab groups than in the placebo group at week 24, regardless of concomitant methotrexate use Fig S4 in the Supplementary Appendix. Clinical benefits in the secukinumab groups were sustained through 52 weeks of therapy Table S2 in the Supplementary Appendix On the basis of a conservative estimate of efficacy with missing values imputed as no re sponse, at week 52 in the secukinumab groups, an ACR20 response was reported in 121 of 202 patients 59 9 among those receiving 150 mg and in 115 of 202 patients 56 9 among those receiving 75 mg Figure 1 On the basis of observed data, the corresponding numbers for the ACR20 response were 121 of 174 patients 69 5 and 115 of 172 patients 66 9 , respectively Table S2 and Fig S5 in the Supplementary Appendix ACR50 and ACR70 results are presented in Table S2 and Figures S2 and S5 in the Supplementary Appendix Patients in the placebo group had improvements in ACR20 response rates after switching to secukinumab Fig S6 in the Supplementary Appendix. During the 16-week placebo-controlled period, adverse events were reported in 64 9 of patients receiving 150 mg of secukinumab, in 60 4 of those receiving 75 mg of secukinumab, and in 58 4 of those receiving placebo Rates of nonfatal serious adverse events and discontinuations were similar across the study groups Table 3 Table 3 Adverse Events throug h Week 16 Placebo-Controlled Period and the Entire Safety-Data Period Nasopharyngitis, headache, and upper respiratory tract infection were the most common adverse events and were more frequent among patients in the secukinumab groups than among those in the placebo group During the placebo-controlled period, infections were more common among patients in the secukinumab groups. Across the entire safety-data reporting period, the maximum exposure to secukinumab was 103 weeks, with a mean exposure of 438 5 days and a median exposure of 456 days During this period, the exposure-adjusted rates of serious adverse events among patients receiving secukinumab were 11 5 and 7 4 per 100 patient-years among those receiving 150 mg and 75 mg, respectively Table 3 Serious adverse events are listed in Table S3 in the Supplementary Appendix Through 16 weeks, one patient receiving 75 mg of secukinumab had a stroke After week 16, an additional three patients had a stroke, totaling four patients for the e ntire safety reporting period all these patients were receiving 75 mg of secukinumab exposure-adjusted rate, 0 6 per 100 patient-years 95 confidence interval CI , 0 2 to 1 5 In addition, two patients one in each secukinumab group had a myocardial infarction rate, 0 3 per 100 patient-years 95 CI, 0 0 to 1 0 Of these six patients, four continued to participate in the study Additional details regarding these patients are provided in Table S4 in the Supplementary Appendix No strokes or myocardial infarctions were observed in the placebo group rate, 0 per 100 patient-years 95 CI, 0 0 to 5 2 The maximum exposure to placebo was 33 weeks mean exposure, 128 5 days median exposure, 112 days. Overall, adverse events leading to discontinuations of a study drug were noted in less than 5 of the patients and were similar among the three groups Oral candidiasis was reported in 4 patients each in the secukinumab 150-mg and 75-mg groups in the 150-mg group, there were reports of esophageal candidiasis in 1 patient and a candida infection of the skin in another All cases of candidiasis, including one serious case, responded to oral therapy, and patients continued in the study No other serious opportunistic infections or cases of active tuberculosis new or reactivation of latent infection were reported Malignant or unspecified tumors were reported in 1 of 295 patients 0 3 receiving 150 mg of secukinumab, 3 of 292 patients 1 0 receiving 75 mg of secukinumab, and 1 of 202 patients 0 5 receiving placebo Three of 10 patients with anti-secukinumab antibodies at baseline showed anti-secukinumab antibodies and neutralizing antibodies in all or most post-baseline samples Treatment-emergent anti-secukinumab antibodies were detected in 1 of 587 patients 0 2 receiving secukinumab. In this phase 3 study, we found that selective inhibition of interleukin-17A with secukinumab was significantly better than placebo in improving the signs and symptoms of psoriatic arthritis, along with patient-reported p hysical functioning and quality of life, with responses sustained during 52 weeks of therapy In addition, there was a small reduction in the progression of measures of structural joint damage among patients receiving secukinumab Preclinical data implicate the interleukin-17 pathway in the irreversible structural damage observed in inflammatory arthritis 11,24-26 Our data provide further evidence that interleukin-17A may be a mediator of this process. It is noteworthy that there was no apparent dose response relationship between the two secukinumab groups with respect to efficacy assessments up to week 24, although such an analysis was not a predefined end point This lack of difference may be at least partly due to the same intravenous loading dose that was administered to patients in the two secukinumab groups Further evaluation of the dose response relationship in subsequent subcutaneous administration of secukinumab is needed. Even though many patients with psoriatic arthritis benefit from anti-TNF therapy, unmet needs remain, including an unacceptable side-effect profile in some patients, lack of primary efficacy, loss of efficacy, and immunogenicity with these agents in some patients 4,27-30 Secukinumab showed efficacy among patients who had received previous anti-TNF therapy and those who had received no such therapy, although improvements were smaller among patients who had received previous anti-TNF therapy. The safety profile of secukinumab was consistent with the findings in previous studies involving patients with psoriatic arthritis and moderate-to-severe plaque psoriasis 13,31 Elevated cardiovascular risk among patients with psoriatic arthritis has been reported previously 32-34 In our study, two patients who were receiving secukinumab had a myocardial infarction and four had a stroke mean exposure to secukinumab across the study, 438 5 days No myocardial infarctions or strokes were observed in the placebo group during the shorter placebo-controlled period mean exposure, 128 5 days Consistent with observations from phase 3 studies involving patients with psoriasis, 13 candida infections were more frequent among patients receiving secukinumab than among those receiving placebo, since interleukin-17 plays a role in host defense against bacterial and fungal infections, particularly at mucosal sites 35.Several different statistical methods have been applied to trials involving patients with psoriatic arthritis We used a rigorous assessment of efficacy at week 24, with the imputation of missing data as no response, which provided a conservative estimate One limitation of our study is that it did not include assessment of axial disease In addition, the use of the same high intravenous loading dose in the two secukinumab groups made it difficult to identify any potential dose response relationships For ethical reasons and consistent with clinical trials of other biologic agents, the placebo-controlled period of this trial was short Thus, the lo ng-term efficacy and safety of secukinumab as compared with placebo cannot be determined. In conclusion, the use of secukinumab showed efficacy in the key clinical domains of psoriatic arthritis Adverse events that were associated with secukinumab included infections and cardiovascular events Longer and larger studies will be required to assess uncommon serious adverse effects and adverse effects associated with long-term use of secukinumab These results suggest an important role for interleukin-17A in the pathogenesis of psoriatic arthritis and validate inhibition of this cytokine as a therapeutic approach in this disease. Supported by Novartis Pharma. Disclosure forms provided by the authors are available with the full text of this article at. We thank the patients who participated in study John Gallagher, a medical consultant for Novartis Pharma and Chris Strutynskyj-Stannard and Joanne Swainston, medical writers who are employed by Seren Communications, an Ashfield company, part of UDG Healthcare. Source Information. From the Swedish Medical Center and the University of Washington both in Seattle P J M University of Glasgow, Glasgow I B M , and Guy s and St Thomas NHS Foundation Trust, London B K both in the United Kingdom University of California, San Diego, School of Medicine, San Diego A K Memorial University, St John s, NL, Canada P R Leiden University Medical Center, Leiden D H , and University of Amsterdam and Atrium Medical Center, Amsterdam R L all in the Netherlands University of Queensland, Brisbane, Australia P N Novartis Pharmaceuticals, East Hanover, NJ L P J Y and Novartis Pharma, Basel, Switzerland H B R S M. Address reprint requests to Dr Mease at Seattle Rheumatology Associates, 601 Broadway, Suite 600, Seattle, WA 98122, or at. A complete list of the investigators in the FUTURE 1 Study Group is provided in the Supplementary Appendix available at. 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Secukinumab is an anti interleukin-17A monoclonal antibody that has been shown to control the symptoms of ankylosing spondylitis in a phase 2 trial We conducted two phase 3 trials of secukinumab in patients with active ankylosing spondylitis. In two double-blind trials, we randomly assigned patients to receive secukinumab or placebo In MEASURE 1, a total of 371 patients received intravenous secukinumab 10 mg per kilogram of body weight or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab 150 mg or 75 mg or matched placebo every 4 weeks starting at week 8 In MEASURE 2, a total of 219 pati ents received subcutaneous secukinumab 150 mg or 75 mg or matched placebo at baseline at weeks 1, 2, and 3 and every 4 weeks starting at week 4 At week 16, patients in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg The primary end point was the proportion of patients with at least 20 improvement in Assessment of Spondyloarthritis International Society ASAS20 response criteria at week 16.In MEASURE 1, the ASAS20 response rates at week 16 were 61 , 60 , and 29 for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively P 0 001 for both comparisons with placebo in MEASURE 2, the rates were 61 , 41 , and 28 for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively P 0 001 for the 150-mg dose and P 0 10 for the 75-mg dose The significant improvements were sustained through 52 weeks Infections, including candidiasis, were more common with secukinumab than with placebo during the pl acebo-controlled period of MEASURE 1 During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn s disease were 0 7, 0 9, and 0 7 cases per 100 patient-years, respectively, in secukinumab-treated patients. Secukinumab at a subcutaneous dose of 150 mg, with either subcutaneous or intravenous loading, provided significant reductions in the signs and symptoms of ankylosing spondylitis at week 16 Secukinumab at a subcutaneous dose of 75 mg resulted in significant improvement only with a higher intravenous loading dose Funded by Novartis Pharma numbers, NCT01358175 and NCT01649375.Media in This Article. Figure 1 Numbers of Patients in MEASURE 1 Who Were Screened, Underwent Randomization, and Completed 52 Weeks of the Study In MEASURE 1, the secukinumab groups received intravenous secukinumab at a dose of 10 mg per kilogram of body weight at baseline, week 2, and week 4, followed by subcutaneous secukinumab at a dose o f 150 mg or 75 mg, starting at week 8 and then every 4 weeks The placebo group received intravenous placebo at baseline, week 2, and week 4, followed by subcutaneous placebo every 4 weeks starting at week 8 Patients initially assigned to receive placebo were randomly reassigned at week 16 to receive secukinumab, with active treatment starting either at week 16 for those without a response to placebo or at week 24 for those with a response to placebo Analyses of primary and secondary efficacy end points at week 16 included all patients according to the assigned study treatment at baseline. Figure 2 Numbers of Patients in MEASURE 2 Who Were Screened, Underwent Randomization, and Completed 52 Weeks of the Study In MEASURE 2, the patients received subcutaneous secukinumab, at a dose of 150 mg or 75 mg, or placebo at baseline at weeks 1, 2, and 3 and every 4 weeks thereafter Patients initially assigned to receive placebo were randomly reassigned at week 16 to receive secukinumab Analyses of primary and secondary efficacy end points at week 16 included all patients according to the assigned study treatment at baseline. Article Activity. Ankylosing spondylitis is a chronic, immune-mediated disease that is characterized by inflammation and new bone formation in the axial skeleton 1,2 and that often results in progressive, irreversible structural damage, disability, deterioration of functioning, and a reduced quality of life 3,4 Therapy with nonsteroidal antiinflammatory drugs NSAIDs is often insufficient to control symptoms, and there is no evidence that conventional disease-modifying antirheumatic drugs DMARDs are efficacious in axial disease 5 Anti tumor necrosis factor TNF therapy is currently recommended for patients with persistent disease activity despite conventional treatment 5 In some patients, however, such therapy fails to achieve adequate disease control or has unacceptable side effects 6-10.Several lines of evidence have identified the interleukin-17 pathway as a promising therapeutic target in spondyloarthritis 11-17 Indeed, numbers of interleukin-17 producing cells are elevated in the circulation and target tissues in patients with ankylosing spondylitis 14-18.Secukinumab is a fully human, anti interleukin-17A monoclonal antibody with proven efficacy in psoriasis 19 In a phase 2 study, intravenous secukinumab significantly suppressed the symptoms of ankylosing spondylitis 9 We present the results of two phase 3 trials, MEASURE 1 and MEASURE 2, investigating the efficacy and safety of secukinumab in patients with active ankylosing spondylitis. Study Design and Oversight. These randomized, double-blind, placebo-controlled phase 3 trials, which are ongoing, are being conducted at 106 centers across Asia, Europe, North America, and South America MEASURE 1 is a 2-year study followed by a 3-year extension study, and MEASURE 2 is a 5-year study see Fig S1 in the Supplementary Appendix available with the full text of this article at Data from the prima ry analysis at week 16 and the 1-year follow-up analysis after all patients had completed the visit at week 52 of both studies are presented here. Each study was designed by the sponsor, Novartis, in collaboration with the authors The institutional review board at each participating center approved the protocols Data were collected according to Good Clinical Practice guidelines by the study investigators and were analyzed by the sponsor All the authors contributed to the interpretation of the data and had access to the full data sets The statistical analyses were performed by statisticians employed by the sponsor and were reviewed by all the authors Agreements between the sponsor and the investigators included provisions relating to confidentiality of the study data The initial draft of the manuscript was written by a medical writer from Seren Communications, funded by the sponsor All the authors vouch for the accuracy and completeness of the data and analyses, as well as for the fideli ty of this report to the trial protocols which are available at. Eligible patients were 18 years of age or older and had ankylosing spondylitis fulfilling the modified New York criteria 20 They also had a score of 4 or higher on the Bath Ankylosing Spondylitis Disease Activity Index BASDAI scores range from 0 to 10, with higher scores indicating more severe disease activity 21 and a score for spinal pain of 4 cm or more on a 10-cm visual-analogue scale with higher numbers indicating greater disease activity , despite treatment with the maximum doses of NSAIDs that were associated with an acceptable side-effects profile. Previous use of DMARDs and anti-TNF agents was allowed Washout periods for these agents, other than sulfasalazine and methotrexate, were required before initiation of the study treatment Patients previously treated with not more than one anti-TNF agent could participate if they had an inadequate response to an approved dose for 3 months or more or had unacceptable side ef fects with at least one dose hereafter collectively referred to as patients with an inadequate response to anti-TNF agents Patients could continue to receive the following medications at a stable dose sulfasalazine 3 g per day , methotrexate 25 mg per week , prednisone or equivalent 10 mg per day , and NSAIDs. Key exclusion criteria were total spinal ankylosis, evidence of infection or cancer on chest radiography, active systemic infection within 2 weeks before baseline, and previous treatment with cell-depleting therapies or biologic agents other than anti-TNF agents Written informed consent was obtained from all the patients. Study Procedures. After a 4-week screening period, patients were randomly assigned in a 1 1 1 ratio to one of two secukinumab groups or the placebo group In MEASURE 1, patients received an intravenous loading infusion of secukinumab at a dose of 10 mg per kilogram of body weight at baseline and weeks 2 and 4, followed by subcutaneous injections of secukinumab at a dose of 150 mg or 75 mg every 4 weeks starting at week 8 patients in the placebo group were treated according to the same schedule of intravenous and subcutaneous doses In MEASURE 2, patients received subcutaneous injections of secukinumab at a dose of 150 mg or 75 mg or placebo at baseline at weeks 1, 2, and 3 and every 4 weeks starting at week 4 At week 16 in both studies, patients in the placebo group were randomly reassigned to receive secukinumab at a dose of 150 mg or 75 mg, according to the schedule outlined in the Supplementary Appendix Patients who met Assessment of Spondyloarthritis International Society 20 ASAS20 response criteria i e improvement of 20 and absolute improvement of 1 unit on a 10-unit scale in at least three of the four main ASAS domains, with no worsening by 20 in the remaining domain at week 16 switched to secukinumab at week 24 in MEASURE 1 In both MEASURE 1 and MEASURE 2, patients continued to receive subcutaneous secukinumab at a dose of 150 mg or 75 mg e very 4 weeks from week 16 until the end of the study. Disease activity and efficacy assessments were conducted at baseline and throughout the study, with key assessments at week 16 primary analysis and week 52 follow-up analysis Blood samples were collected at baseline and immediately before dose administration at weeks 4, 16, 24, and 52 for assessment of secukinumab immunogenicity with the use of a bridging immunoassay Meso Scale Discovery 22.Outcome Measures. In each study, the primary efficacy end point was the proportion of patients who met ASAS20 response criteria at week 16 23 Secondary end points assessed at week 16 included ASAS40 response criteria improvement of 40 and absolute improvement of 2 units on a 10-unit scale in at least three of the four main ASAS domains, with no worsening in the remaining domain , change from baseline in the high-sensitivity C-reactive protein CRP level, ASAS5 6 response 20 improvement in five of the six ASAS response domains , and changes from base line in the following scores total BASDAI score, the summary score for the physical component in version 2 of the Medical Outcomes Study 36-Item Short-Form Health Survey SF-36 scores range from 0 maximum disability to 100 no disability for individual domains, with a normative composite summary score of 50 , 24 and the score on the Ankylosing Spondylitis Quality of Life ASQoL scale scores range from 0 best quality to 18 poorest quality 25 ASAS partial remission a score of 2 units in each of the four core ASAS domains and overall safety were also assessed. In each study, a preplanned follow-up analysis was performed after all patients had completed the visit at week 52 Safety analyses, performed with the use of the Common Terminology Criteria for Adverse Events, version 4 03, 26 included all safety data reported up to the cutoff date after all patients had completed at least 52 weeks of treatment in either study Exploratory analyses of efficacy were performed at week 52.Statistical Analy sis. We calculated that for MEASURE 1 to have 90 power with a 2 5 type I error rate, assuming an ASAS20 response rate of 60 for the secukinumab groups and 20 for the placebo group, 27 we would need to assign at least 39 patients to each study group, on the basis of Fisher s exact test The target population was increased to 116 patients per group to ensure sufficient safety data, providing 94 to 99 power to detect significant differences between the secukinumab and placebo groups for each of the secondary end points We used the same power calculations in MEASURE 2 The target sample of 74 patients per group provided 99 power to detect significant between-group differences for the ASAS20 response rate and 79 to 99 power for the secondary end points. In each study, analyses of primary and secondary efficacy end points at week 16 included all patients according to the treatment assigned at randomization Closed testing procedures 28 were used to maintain a familywise error rate of 5 across the secukinumab groups and end points The hypotheses for the primary objective in either secukinumab treatment group versus the placebo group were tested simultaneously at the 0 025 level On the basis of the rejection of one or both of these hypotheses, analysis of the secondary end points was completed according to a prespecified hierarchy in the sequence described in Figure S2 in the Supplementary Appendix. The primary end point and other binary end points were evaluated by means of logistic regression with treatment and anti-TNF response status as factors and weight as a covariate Missing values, including those due to discontinuation of the study treatment, were imputed as nonresponses Between-group differences in continuous variables were evaluated with the use of a mixed-model repeated-measures MMRM approach, with missing data assumed to be missing at random and with study group, assessment visit, and anti-TNF response status as factors Weight and baseline values of the end points we re included in the model as continuous covariates Interaction terms included study group and baseline value according to assessment visit For the change in the high-sensitivity CRP level, the log e ratio of the post-baseline value to the baseline value was used to normalize the distribution of the high-sensitivity CRP level at each assessment The end points assessed at week 16 were analyzed descriptively with the use of observed values from week 20 onward In a separate analysis of these end points from week 20 onward, missing values for binary variables were imputed as nonresponses, and missing values for continuous variables were imputed with the use of MMRM analysis. Safety end points were evaluated for all patients who received at least one dose of the study drug these end points were summarized descriptively A data and safety monitoring committee reviewed unblinded safety data at regular intervals. Study Participants. In MEASURE 1, from November 9, 2011, through January 21, 2013, we r andomly assigned 371 patients to receive an intravenous loading dose of secukinumab 10 mg per kilogram followed by subcutaneous secukinumab at a dose of 150 mg 125 patients , an intravenous loading dose of secukinumab 10 mg per kilogram followed by subcutaneous secukinumab at a dose of 75 mg 124 , or placebo 122 At week 16, a total of 351 patients 95 remained in the study 20 patients discontinued the study for the reasons outlined in Figure 1 Figure 1 Numbers of Patients in MEASURE 1 Who Were Screened, Underwent Randomization, and Completed 52 Weeks of the Study In MEASURE 1, the secukinumab groups received intravenous secukinumab at a dose of 10 mg per kilogram of body weight at baseline, week 2, and week 4, followed by subcutaneous secukinumab at a dose of 150 mg or 75 mg, starting at week 8 and then every 4 weeks The placebo group received intravenous placebo at baseline, week 2, and week 4, followed by subcutaneous placebo every 4 weeks starting at week 8 Patients initially assigne d to receive placebo were randomly reassigned at week 16 to receive secukinumab, with active treatment starting either at week 16 for those without a response to placebo or at week 24 for those with a response to placebo Analyses of primary and secondary efficacy end points at week 16 included all patients according to the assigned study treatment at baseline In MEASURE 2, from October 28, 2012, through July 29, 2013, we randomly assigned 219 patients to receive subcutaneous secukinumab at a dose of 150 mg 72 patients , subcutaneous secukinumab at a dose of 75 mg 73 , or placebo 74 At week 16, a total of 200 patients 91 remained in the study 19 patients discontinued the study for the reasons outlined in Figure 2 Figure 2 Numbers of Patients in MEASURE 2 Who Were Screened, Underwent Randomization, and Completed 52 Weeks of the Study In MEASURE 2, the patients received subcutaneous secukinumab, at a dose of 150 mg or 75 mg, or placebo at baseline at weeks 1, 2, and 3 and every 4 weeks th ereafter Patients initially assigned to receive placebo were randomly reassigned at week 16 to receive secukinumab Analyses of primary and secondary efficacy end points at week 16 included all patients according to the assigned study treatment at baseline. Baseline demographic and disease characteristics were similar between studies and among the groups within each study Table 1 Table 1 Demographic and Baseline Characteristics of the Patients in MEASURE 1 and MEASURE 2 Full Analysis Set and Table S1 in the Supplementary Appendix The mean time since diagnosis was 6 5 to 8 3 years in MEASURE 1 and 5 3 to 7 0 years in MEASURE 2 the total BASDAI score was 6 1 to 6 5 and 6 6 to 6 8, respectively 69 to 80 and 73 to 79 of patients were positive for HLA-B27, respectively and approximately 26 to 39 of patients in each group had inadequate responses to anti-TNF agents in the two studies Approximately 3 of patients in MEASURE 1 and 2 of those in MEASURE 2 had a history of inflammatory bowel diseas e at baseline. Primary End Point. The primary end point was met in both secukinumab groups in MEASURE 1 and in the group that received 150 mg of secukinumab subcutaneously in MEASURE 2 In MEASURE 1, ASAS20 response rates at week 16 were 61 with subcutaneous secukinumab at a dose of 150 mg, 60 with subcutaneous secukinumab at a dose of 75 mg, and 29 with placebo P 0 001 for both comparisons with placebo In MEASURE 2, ASAS20 response rates at week 16 were 61 with subcutaneous secukinumab at a dose of 150 mg, 41 with subcutaneous secukinumab at a dose of 75 mg, and 28 with placebo P 0 001 and P 0 10 for comparisons of the higher and lower doses, respectively, with placebo Figure 3 Figure 3 Response Rates through Week 16 Placebo-Controlled Phase and through Week 52 among Patients Randomly Assigned to Secukinumab or Placebo at Baseline in MEASURE 1 and MEASURE 2 Shown are the proportions of patients with Assessment of Spondyloarthritis International Society 20 ASAS20 responses improvement of 20 and absolute improvement of 1 unit on a 10-unit scale in at least three of the four main ASAS domains, with no worsening by 20 in the remaining domain and the proportion with ASAS40 responses improvement of 40 and absolute improvement of 2 units on a 10-unit scale in at least three of the four main ASAS domains, with no worsening in the remaining domain in MEASURE 1 Panels A and B and MEASURE 2 Panels C and D The predefined statistical hypothesis-testing hierarchy was designed to maintain the familywise type I error rate at 5 across the primary and ranked secondary end points Missing data were imputed as nonresponses up to week 16 Observed data are presented from week 20 to week 52 indicated by the gray box in each panel P values at week 16 were adjusted for multiple testing An asterisk denotes P 0 05, a dagger P 0 01, and a double dagger P 0 001 for the comparison with placebo. Secondary End Points. In MEASURE 1, all predefined secondary end points were met in both secukinumab groups Table 2 Table 2 Efficacy End Points at Week 16 in the MEASURE 1 and MEASURE 2 Studies Full Analysis Set and Fig S5 in the Supplementary Appendix ASAS40 response rates at week 16 were 42 and 33 in the groups that received subcutaneous secukinumab at the higher and lower doses, respectively, as compared with 13 in the placebo group P 0 001 for both comparisons with placebo Figure 3 and Table 2.In MEASURE 2, all predefined secondary end points except ASAS partial remission were met with subcutaneous secukinumab at a dose of 150 mg responses with subcutaneous secukinumab at a dose of 75 mg did not differ significantly from responses with placebo on the basis of hierarchical testing Table 2 and Fig S5 in the Supplementary Appendix ASAS40 response rates at week 16 were 36 with subcutaneous secukinumab at a dose of 150 mg and 26 with subcutaneous secukinumab at a dose of 75 mg, as compared with 11 with placebo P 0 001 and P 0 10 for comparisons of the higher and lower doses, respectively, wi th placebo Figure 3 and Table 2.Long-Term Efficacy. At week 52, a total of 319 patients 86 remained in MEASURE 1, and 181 patients 83 in MEASURE 2 The clinical responses observed at week 16 were maintained through 52 weeks of treatment among patients randomly assigned to secukinumab at baseline, on the basis of both observed data and a more conservative assessment of efficacy in which missing values were imputed as nonresponses Figure 3 and Fig S3 and Tables S2 and S3 in the Supplementary Appendix In addition, patients randomly assigned to placebo had improvements in ASAS20 response rates on switching to secukinumab Fig S4 in the Supplementary Appendix. Adverse events during the placebo-controlled periods of both studies are shown in Table 3 Table 3 Safety Profile during the 16-Week, Placebo-Controlled Induction Period of the MEASURE 1 and MEASURE 2 Studies as well as in Table S4 in the Supplementary Appendix The incidence of infection was higher with secukinumab than with placebo 30 vs 12 in MEASURE 1 and 32 vs 27 in MEASURE 2.During the entire safety period of MEASURE 1, exposure-adjusted incidence rates of serious adverse events were 8 0 and 8 6 events per 100 patient-years among patients who received at least one dose of secukinumab at the higher and lower doses, respectively including patients who were randomly assigned to secukinumab at baseline and those who switched from placebo to active treatment Table S5 in the Supplementary Appendix The rates of infection were 73 5 and 59 4 events per 100 patient-years of exposure for subcutaneous secukinumab at doses of 150 mg and 75 mg, respectively During the entire safety period of MEASURE 2, exposure-adjusted incidence rates of serious adverse events were 6 6 and 7 7 events per 100 patient-years for subcutaneous secukinumab at doses of 150 mg and 75 mg, respectively Table S5 in the Supplementary Appendix Incidence rates of infection in the groups that received subcutaneous secukinumab at the higher and lower doses wer e 60 5 and 89 1 events per 100 patient-years of exposure, respectively No patients in either study discontinued treatment because of a serious infection. Candida infections were reported in three patients treated with subcutaneous secukinumab in MEASURE 1 genital candidiasis in a patient receiving the 75-mg dose, oral candidiasis in a patient receiving the 75-mg dose, and candida thrush infection in a patient receiving the 150-mg dose and in three patients treated with subcutaneous secukinumab in MEASURE 2 one case of candida infection at the 75-mg dose and two cases of oral candidiasis one each at the lower and higher doses The pooled exposure-adjusted incidence of candidiasis in secukinumab-treated patients across the two studies was 0 9 events per 100 patient-years of exposure Table 4 Table 4 Safety Profile during the Entire Safety Reporting Period in the MEASURE 1 and MEASURE 2 Studies These events did not lead to study discontinuation and resolved spontaneously or with standard ant ifungal treatment. Grade 3 neutropenia was documented at a single visit in each of three patients receiving subcutaneous secukinumab at the 75-mg dose in MEASURE 1 and in one patient receiving subcutaneous secukinumab at the 150-mg dose in MEASURE 2 Grade 4 neutropenia was reported in one patient receiving subcutaneous secukinumab at the 75-mg dose at a single visit in MEASURE 1 pooled incidence of grade 3 or 4 neutropenia in the two studies 0 7 events per 100 patient-years of exposure Table 4 None of these events led to treatment interruption or discontinuation, and only one grade 3 case was associated with infection a nonserious upper respiratory tract infection. Adjudicated major adverse cardiac events were recorded in two patients treated with subcutaneous secukinumab in MEASURE 1 myocardial infarction in a patient receiving the 75-mg dose and stroke in a patient receiving the 150-mg dose and in one patient treated with subcutaneous secukinumab in MEASURE 2 fatal myocardial infarctio n in a patient receiving the 75-mg dose The pooled exposure-adjusted incidence rate of adjudicated major adverse cardiac events across both studies was 0 4 events per 100 patient-years of exposure to secukinumab Table 4.Four cancers were reported in MEASURE 1 B-cell lymphoma in a patient receiving subcutaneous secukinumab at the 75-mg dose , breast cancer in a patient receiving subcutaneous secukinumab at the 150-mg dose , transitional-cell carcinoma of the bladder in a patient receiving subcutaneous secukinumab at the 150-mg dose , and lymphoma in a patient receiving placebo In MEASURE 2, there was a single case of malignant melanoma in a patient receiving subcutaneous secukinumab at the 150-mg dose These five events resulted in discontinuation of the study treatment. Crohn s disease was an adverse event in three patients in the group receiving subcutaneous secukinumab at a dose of 75 mg in MEASURE 1 Two cases were in patients with a history of Crohn s disease, and one was in a patient with a history of a polyp and an adenoma in the colon all three cases were nonserious Crohn s disease was a serious adverse event in two patients receiving subcutaneous secukinumab in MEASURE 2 one each in the 75-mg and 150-mg groups the patient receiving the lower dose of secukinumab was considered to have an exacerbation of preexisting Crohn s disease related to the study treatment, and this resulted in discontinuation The pooled exposure-adjusted incidence rate of Crohn s disease across both studies was 0 7 events per 100 patient-years of exposure to secukinumab Table 4.Uveitis was reported in six patients receiving secukinumab five of whom had a history of uveitis and two patients receiving placebo one of whom had a history of uveitis in MEASURE 1, with a single serious case in the 150-mg group that resolved and did not lead to discontinuation of the study treatment Table S6 in the Supplementary Appendix A single case of uveitis was reported with subcutaneous secukinumab at the 1 50-mg dose in MEASURE 2, in a patient with no history of uveitis. There was one death in MEASURE 1 a suicide in the placebo group and one death in MEASURE 2 a fatal myocardial infarction in a patient receiving 75 mg of secukinumab subcutaneously There were no suicides or adverse events related to suicidality among secukinumab-treated patients. After treatment was started, antidrug antibodies were detected at week 52 in two patients in MEASURE 1 who were receiving subcutaneous secukinumab at a dose of 150 mg neutralizing antibodies to secukinumab were detected in one of these patients Neither patient had a loss of the ASAS20 response or had any immune-related adverse events No antidrug antibodies were detected after the start of treatment in MEASURE 2.Secukinumab significantly reduced the signs and symptoms of ankylosing spondylitis, as compared with placebo, in both phase 3 trials, extending the positive results of the phase 2 study 9 An ASAS20 response, the primary end point, was achiev ed in approximately 60 of patients in both groups receiving intravenous loading followed by subcutaneous secukinumab 150 mg or 75 mg in MEASURE 1 and in the group receiving 150-mg of subcutaneous secukinumab in MEASURE 2, showing that despite the much greater exposure conferred by intravenous loading, no incremental increase in efficacy was observed, as compared with the subcutaneous loading regimen Benefits over placebo were also observed for most of the secondary efficacy end points at week 16, including the ASAS40 response, high-sensitivity CRP level, ASAS5 6 response, and scores on the BASDAI, the physical component of SF-36, and the ASQoL scale, and were sustained through 52 weeks of therapy Notably, in MEASURE 1 and MEASURE 2, the rates for ASAS40 and ASAS5 6 responses, which are based on more stringent criteria than those for the ASAS20 response, both reached approximately 60 in the 150-mg dose groups among patients who completed 52 weeks of therapy. Subcutaneous secukinumab at a dose of 75 mg was shown to be ineffective in MEASURE 2, since there were no significant differences in the hierarchically tested end points, as compared with placebo These results suggest that the efficacy of secukinumab at the 75-mg dose in MEASURE 1 may have been due to the greater exposure at week 16 as a result of the intravenous loading regimen, not to the 75-mg subcutaneous maintenance dose Despite the significant results observed with secukinumab at the 75-mg dose in MEASURE 1, a descriptive analysis showed an increasing dose separation between the 150-mg and 75-mg treatment groups with the use of more stringent response criteria ASAS40 response and ASAS partial remission as time points approached week 52 Moreover, in MEASURE 2, subcutaneous secukinumab at the 150-mg dose showed consistently greater efficacy than subcutaneous secukinumab at the 75-mg dose for all primary and secondary end points at week 16 except ASAS partial remission , as well as at week 52 Thus, 150 mg admin istered subcutaneously appears to be the more effective dose for secukinumab in patients with ankylosing spondylitis. Anti-TNF agents are the only approved biologic agents for ankylosing spondylitis, with a number of other therapies failing to show benefits 29-33 Although head-to-head trials would be required to fully assess the efficacy and safety of secukinumab versus TNF-inhibitors, the ASAS20 response rates achieved with secukinumab at week 16 in our studies were similar to those reported in phase 3 studies of anti-TNF agents in which most of the patients had not received previous anti-TNF therapy response rates of 58 to 64 at weeks 12 to 24 , 6,7,27,34,35 even though 30 to 40 of the patients in our studies had had no response to previous anti-TNF treatment Thus, secukinumab not only is effective in patients who have not received TNF agents previously but also may be effective in patients in whom previous anti-TNF treatment failed. The safety profile of secukinumab in the present stu dies is consistent with that in previous studies of secukinumab for ankylosing spondylitis and moderate-to-severe plaque psoriasis 9,19 The incidence of infections or infestations was higher with secukinumab than with placebo in MEASURE 1 During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn s disease were 0 7, 0 9, and 0 7 events per 100 patient-years, respectively, among secukinumab-treated patients In MEASURE 1, increases in serum cholesterol and triglyceride levels were generally mild grade 1 or 2 Dyslipidemia was not evident in MEASURE 2 or in studies of secukinumab for other indications 9,19,36,37 Across our two studies, two secukinumab-treated patients had myocardial infarction and one patient had a stroke One case of myocardial infarction, in a patient receiving subcutaneous secukinumab at the 75-mg dose in MEASURE 2, resulted in death on day 29 the patient was found on autopsy to have extensive p reexisting coronary artery disease One patient, who was receiving placebo, committed suicide There were no suicides or suicidality-related adverse events among secukinumab-treated patients in either study The immunogenicity of secukinumab was low, and anti-secukinumab antibodies were not associated with immune reactions or reduced efficacy. In conclusion, secukinumab showed efficacy in key clinical domains of ankylosing spondylitis The results suggest that interleukin-17A plays a role in the pathogenesis of ankylosing spondylitis, and they validate inhibition of this cytokine as a potential therapeutic approach. Supported by Novartis Pharma. Disclosure forms provided by the authors are available with the full text of this article at. Drs Baeten and Sieper contributed equally to this article. This article was updated on December 24, 2015, at. We thank the patients who participated in the two studies John Gallagher, medical consultant for Novartis Pharma and Ben Drever, Joanne Fitz-Gerald, Jes sica Breen, and Alan Pedder, medical writers from Seren Communications. Source Information. From the Academic Medical Center, University of Amsterdam, Amsterdam D B Charit University Medicine Berlin, Berlin J S , and Rheumazentrum Ruhrgebiet, Herne J B X B both in Germany Paris Descartes University and Department of Rheumatology, Hpital Cochin, Paris M D Leeds Musculoskeletal Biomedical Research Unit, Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom P E Oregon Health and Science University, Portland A D Novartis Pharmaceuticals, East Hanover, NJ B P R M and Novartis Pharma, Basel, Switzerland M A S M H B R. Address reprint requests to Dr Baeten at Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands, or at. A complete list of the investigators in the MEASURE 1 and MEASURE 2 Study Groups is provided in the Supplementary Appendix available at. 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