Binary Alternativ Expert Review Of Klinisk Immunologi

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Ekonomisk Times Business News, Personlig Finans, Finansiell Nyheter, Indien Aktiemarknadsinvestering, Ekonomi Nyheter, SENSEX, NIFTY, NSE, BSE Live, IPO Nyheter Ekonomiska Tider Indien s ledande Business Tidningen erbjuder affärsnyheter, finansiella nyheter, aktiemarknaden nyheter, ekonomi nyheter, lån banknyheter, levande aktier och nyheter investeringsanalys på ömsesidiga fonder, guld, Forex och Real Estate spårning indiska aktiemarknaden CFTC sa i en 2014 rapport att 10 spoofing Prober har inletts från juli 2012 till juli 2013 hos Nymex och Comex, två av derivatmarknaderna som ägs av CME Group De Comercio En Lnea En Guinea Ecuatorial Så här håller den brottsliga amerikanska energikartellen priset på olja upp även när det inte finns något Verklig efterfrågan Binär Option Trading 50 Insättning 4 Ås Tre orsaker till att hedgefondsindustrin förlorade sin väg Hedgefondsindustrin har exploderat under de senaste 20 åren, men de senaste avkastningarna tyder på att hela sin anledning För att vara kan ha gått vilse i processen. Presentation på Falklandsöarbörsen Ppt. Tracking indiska aktiemarknaden. Indian Stock Market Watch 1 8 Den täcker tillgångar från BSE, NSE, MCX och NCDEX utbyten, så att du kan spåra IndicesSensex l Nifty Business Standard , Indiens främsta affärswebbplats för Live Markets, Live BSE NSE-citat, senaste nyheter, nyheter, politiska nyheter, analys och opinionsättning på marknader. Citation Clinical Translational Immunology 2014 3 e13 doi 10 1038 cti 2014 4 Publicerad online 14 mars 2014.Vacciner För att förhindra leishmaniasis Open. Rajiv Kumar 1 och Christian Engwerda 1.1 Immunology and Infection Laboratory, QIMR Berghofer, Brisbane, Queensland, Australien. Korrespondens Professor C Engwerda, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland 4006, Australien E-post . Mottagen 13 december 2013 Reviderad 11 februari 2014 Godkänd den 12 februari 2014.Leishmaniasis är en parasitisk sjukdom som omfattar en rad kliniska manifestationer affecti Ng personer i tropiska och subtropiska regioner i världen Epidemiologiska och experimentella data tyder på att skydd mot sjukdom kan uppnås hos de flesta människor Dessutom vet vi hur värdens immunsystem måste reagera på infektion för att kontrollera parasittillväxt Men det finns fortfarande Inget vaccin för användning hos människor Här granskar vi vår förståelse av värdimmunitet efter Leishmania-infektion och diskuterar även de senaste framstegen när det gäller utvecklingen av vacciner för att förhindra leishmaniasis, vilket framhäver ett nytt lovande tillvägagångssätt som inriktar sig mot parasiterna hemoglobin receptor. immunity leishmania parasiter vaccines. Leishmaniasis Är en vektorburet sjukdom orsakad av obligatoriska protozana parasiter av släktet Leishmania Dessa parasiter överförs av 30 olika arter av Phlebotomine sandflugor som extracellulära, flagellerade promastigoter och replikeras som intracellulära, avlagellatamastigoter i mononukleära fagocyter hos däggdjursvärdar 1 2 Leishmaniasis-intervall Från självläkning, Asymptomatisk infektion till lokaliserade hudskador och kan utvecklas till en livshotande progressiv visceral sjukdomssjukdom Leishmaniasis är en av världens mest försummade sjukdomar, som huvudsakligen påverkar mycket fattiga människor i utvecklingsländer. Det förekommer i hela tropiska och subtropiska regionerna i Afrika Asien, Medelhavsområdet, Södra Europa, Gamla Världen och Nya och Sydamerika Nya Världen Sjukdomen är endemisk i 88 länder, varav 72 är utvecklingsländer Cirka 350 miljoner människor riskerar att få leishmaniasis och 1 5 2 miljoner nya fall uppstår årligen 3 Överföringen av Leishmania parasiter är antroponotisk mänsklig för vektor till mänsklig i indiska subkontinenten och Asien, medan i Afrika, Europa och Amerika är det zoonotiskt djur som vektor till människan, där hundar och gnagare fungerar som reservoar Figur 1 4 5 6 Livscykel och överföring av Leishmania parasiter. Den promastigote formen av Leishmania parasiter som är ansvariga för människors sjukdom VL, CL och MCL injiceras i huden som en kvinnlig sandfluga tar en blodmjöl 1 och tas sedan upp av värdmakrofager 2 Promastigotes konverterar till den icke-flagellerade amastigotformen inuti makrofagerna 3 och delas därefter genom binär fission 4 Amastigoterna Frigörs av sprickan av makrofager 5 och kan sedan tas upp av en kvinnlig sandfluga under en annan blodmjöl. Amastigotformen omvandlas sedan i promastigoteformen i midgutten av sandflugan och kan sedan överföras till en annan mänsklig antroponotisk överföring Eller till djur som fungerar som reservoarer zoonotisk överföring 6. Fullständig figur och legend 107K. Visceral leishmaniasis VL, allmänt känd som kala-azar, orsakas av L donovani och L infantum i den gamla världen och L chagasi i den nya världen Dessa parasiter föredrag Infektera makrofager över hela vattnet, och parasiter finns vanligen i mjälten, lever och benmärg. Kliniska egenskaper inkluderar typiskt långvarig feber i låg grad, hepatosplenom Galj, viktminskning, pankytopeni och polyklonal IgG och IgM hypergammaglobulinemi 7 Obehandlad VL kommer i de flesta fall till slut att leda till döden Ungefär 500 000 nya fall av VL inträffar årligen 7 De flesta 90 VL-fallen förekommer i fem länder, nämligen Indien, Nepal, Bangladesh, Sudan Och Brasilien 3 Indien är ett av de viktigaste foci i världen för VL 3 8 Biharstaten och grannområdena i östra Uttar Pradesh och västra Bengalen förblir särskilt drabbade av VL 9 Den årliga förekomsten av VL i Indien är cirka 100 000 Fall och staten Bihar står för mer än 90 av dessa 9 Förekomsten av VL-humant immunbristvirusHIV-coinfektion är nu också ett allvarligt problem i dessa endemiska regioner 10.Cutan leishmaniasis CL orsakas av L tropica L aethiopica och L major i Den gamla världen, och av L mexicana L guyanensis L amazonensis och L braziliensis i den Nya världen CL är den vanligaste formen av leishmaniasis världen över, som representerar 50 75 av alla nya fall Det kan Vara mycket svårt att behandla, långvariga och disfigurerande Enligt Världshälsoorganisationen WHO är antalet CL-fall cirka 1 1 5 miljoner årligen och 90 av CL-fall förekommer i sju länder Afghanistan, Algeriet, Brasilien, Iran, Peru , Saudiarabien och Syrien 3 6 CL kännetecknas av utvecklingen av en ulcerös hudskada som innehåller många parasiter. Även om de kliniska egenskaperna hos CL kan variera på grund av olika orsaksslag, börjar en klassisk skada som en papul eller nodulär vid platsen för Parasit inokulering och expanderar långsamt 6.Mukokutan leishmaniasis MCL uppträder i den Nya Världen och orsakas främst av L braziliensis och L panamensis Dessa arter kan metastasera till slemhinnor i munnen och övre luftvägarna genom lymfatisk eller hemematogen spridning och 90 av alla MCL Fall förekommer i Bolivia, Brasilien och Peru MCL kan presenteras från flera månader till år efter utvecklingen av en kutan lesion Även om patogenesen av VL och CL är relativt väl förstådd, patogenesen hos MCL är fortfarande oklart, även om det har funnits något nytt framsteg på detta område. Det antas att värdegenetiska faktorer är viktiga för utvecklingen av sjukdom. Kontrollåtgärder för leishmanias är starkt beroende av kemoterapi. För närvarande anställd Droger är förknippade med svåra toxiska biverkningar och ökad resistans mot resistens mot parasiter 11 12 Detta har tvingat forskare att tänka på andra kontrollåtgärder, och särskilt utveckling och genomförande av ett effektivt vaccin Folk som botas av Leishmania-infektioner utvecklar livslång immunitet. Därför förebyggande av Leishmaniasis genom profylaktisk vaccination är genomförbar Förskott i vår förståelse av Leishmania infektionspatogenes och genereringen av värdskyddande immunitet, tillsammans med färdiga Leishmania genom-sekvenser, har öppnat nya vägar för vaccinforskning. Emellertid kvarstår stora utmaningar, inklusive översättning av idéer från djur modell S till kliniska inställningar och övergången av produkter från laboratoriet till fältet Denna översyn kommer att lyfta fram de senaste framstegen i utvecklingen av vacciner för att förebygga och eller behandla leishmaniasis och diskutera framtidsutsikter. Skyddande immunsvar i värden. En god förståelse av Immunitet genererad mot patogener är viktig för att utveckla ett effektivt vaccin Vår nuvarande förståelse av värdimmunsvar som genereras mot Leishmania-parasiter baseras huvudsakligen på studierna i djurmodeller Studier hos möss visar att skyddande immunitet mot Leishmania-infektion kräver utveckling av interleukin-12-beroende , Parasitspecifika Th1-svar, kännetecknade av interferon - och tumörnekrosfaktorproduktion av CD4-T-celler 13 14 15 Dessa inflammatoriska cytokiner krävs för alstring av reaktiva syre - och kvävearter genom infekterade makrofager som möjliggör dödande av intracellulära parasiter. Nya framsteg har också Gjorts för att förstå immun Oregulatoriska mekanismer som undertrycker parasitspecifika CD4-T-cellsvar i humana VL-patienter. Dessa inkluderar upptäckten att interleukin-10 producerad av CD4-T-celler är en potent autokrin inhibitor av interferonproduktion och främjar parasit-persistens i mjältvävnad från VL-patienter 16 Således har interleukin-10 identifierats som ett potentiellt terapeutiskt mål för användning i kombination med läkemedelsbehandling eller för att förbättra terapeutisk vaccin effektivitet. Generering av immunologiskt minne är ett krav på effektiv vaccination Studier på genereringen av effektor och CD4 T-celler med central minne Indikerar att centrala minnes-T-celler medger långvarig immunitet mot L-storinfektion, även i avsaknad av långvariga parasiter 17. Således definierar krav och förståelse för villkoren för centralminne CD4-T-cellbildning och - underhåll kommer att vara till hjälp vid vaccindesign. Kunskap om att majoriteten av individer som smittats med Leishmania parasiter kontrollerar parasiten växer H utan att orsaka allvarlig sjukdom, 18 19 kombinerat med vår förståelse för de typer av immunsvar som krävs för att döda parasiter och de som undertrycker denna immunitet, innebär att utveckla vacciner mot leishmaniasis är ett realistiskt mål. Varför behöver vi ett vaccin för att förhindra och eller Behandling av leishmaniasis. Behandling av leishmaniasis är beroende av kemoterapi. De vanligaste läkemedlen är pentavalenta antimonaler, oral miltefosin, amfotericin B, liposomal amfotericin B och paramomycin. Ett huvudproblem är att dessa läkemedel är förknippade med problem med kostnad, toxicitet, längd och varaktighet av Behandling, injektionsväg till exempel intravenös infusion och utveckling av resistens mot parasitläkemedel 20 Pentavalenta antimonaler var den första behandlingslinjen i många år, men ökande parasitresistens i endemiska regioner har begränsat användningen av dem i delstaten Bihar i Indien, nästan 60 fall är eldfasta mot behandling med detta läkemedel 21 Följaktligen amphotericin B Används nu som huvuddrogen för behandling av VL-patienter Men detta läkemedel är också förknippat med toxicitet och det finns rapporter om läkemedelsresistenta parasiter 22 Miltefosin utvecklades som ett oralt läkemedel och visade ett tidigt löfte men det finns nu ökande incidenter av Återfall hos patienter som behandlats med detta läkemedel 23 24 25 Nyligen visades en enstaka dos av ambisom lipidformulering av amfotericin B vara effektiv vid behandling av VL-patienter, med en lägre förekomst av toxicitet jämfört med konventionell behandling i ett kliniskt multicentriskt prov 26 Det finns emellertid oro att denna typ av läkemedelsbehandlingsprotokoll kan främja utvecklingen av läkemedelsresistenta parasiter. Därför utvecklas kombinationsläkemedelsterapi aktivt för användning i endemiska regioner 27 28 Studier i en musmodell föreslår dock att L donovani Kan utveckla resistens mot droger, även när de används i kombination 29 Därför är det osannolikt att trots kemoterapeutiska alternativ är det osannolikt att Kemoterapi ensam kommer att möjliggöra sjukdomseliminering och därmed finns ett brådskande behov av ett effektivt vaccin om långsiktiga mål för att kontrollera och eliminera denna sjukdom ska uppnås. Förenta och nuvarande vaccinkandidater. Olika olika Leishmania-arter orsakar en rad kliniska manifestationer Genomisk analys indikerar en stor grad av sekvenshomologi mellan arter, vilket tyder på att det kan vara möjligt att generera väsentligt effektiva vacciner mot olika kliniska sjukdomar. Ett effektivt vaccin mot leishmaniasis har existerat i det förflutna. Denna inblandning med levande virulenta parasiter i en process som kallas Leishmanization Det praktiserades framgångsrikt i det tidigare Sovjetunionen, Mellanöstern och Israel 30 31 Men det övergavs i de flesta länder på grund av logistiska problem och säkerhetsproblem, på grund av att vissa individer utvecklar icke-helande skador och immunförsvar 32. Vem dödades Autoklaverade Leishmania promastigoter testades också som vacciner aga Inst CL och VL Test av dödade parasitvacciner ägde rum i Brasilien i början av 1940-talet och testades därefter antingen ensam eller i kombination med adjuvans i fas I, II och III studier 33 34 Kliniska försök med autoklaverad Leishmania, adjuverad med BCG, Visade att detta tillvägagångssätt kunde minska incidensen av CL med 18 78 35 36 Liknande prövningar genomfördes i Iran, Sudan och Ecuador med variabel säkerhet och effekt 37 38 39 40 41 Tyvärr visade de autoklaverade parasiterna minskande potens med tiden, även om studier med timerosal Konserverade och icke-autoklaverade preparat har visat reducerade lagringseffekter 42. Dock kvarstår bekymmer om möjligheten att utveckla dödade vacciner med hel parasit, inklusive variationen i resultat som erhållits från olika fält - och kliniska provplatser tidigare och potentiella svårigheter i Producerar en sådan produkt till goda kliniska tillverkningsstandarder. Diverse dämpade parasiter har också testats i djurmodeller E parasiter tas i allmänhet upp av värdceller på liknande sätt som virulenta parasiter och kvarstår under en tid utan replikering. Detta gör det möjligt för värden att montera robusta immunsvar mot parasitantigener. Radiodämpade och biokemiskt förändrade parasiter har visat sig ge gott skydd i Möss och hamstrar utan adjuvans 43 Även om oro för omvandling tillbaka till virulens gör det senare alternativet tvivelaktigt för mänskligt bruk. Men målriktad eliminering av virulensgener kan övervinna detta problem och kan ge attraktiva vaccinkandidater mot leishmanias. Genetiskt modifierade Leishmania-parasiter saknar väsentliga gener som dyhydrofolat Reduktas, biopterinreduktas eller cysteinproteaser har visat sig stimulera skydd mot utmaning med virulenta parasitstammar. 44 45 46 Användningen av läkemedelskänsliga Leishmania-mutanter 47 ensamma eller med adjuvans har föreslagits som en mekanism för att inducera anti-leishmanial immunitet, vilket har Användningen av icke-pa Thogenic Leishmania arter som L tarantolae som kan stimulera skydd mot virulenta L donovani stammar 48 Men huvudproblemet med att använda dödade eller dämpade parasiter är de problem som rör säkerhet och genomförbarhet för storskalig användning i fältet. Andra metoder innefattar att använda immunogen yta Antigener av Leishmania parasiter som vaccinkandidater Flera av dessa har testats i musmodeller och hund VL med data som tyder på att skydd mot leishmaniasis kan uppnås med definierade kandidatproteiner. En saponinformulering av fukosmannosligand som uttrycks genom parasitens livscykel, Befanns vara säker, skyddande och immunogen i en experimentell mus - och hamstermodell 49 50 Denna formulering har nu blivit Leishmune-veterinärvaccinet, licensierat efter en serie av hund-VL-fältstudier 51 52 Lipidformuleringar av lösligt leishmania-antigen från L donovani var också Testas som vaccinkandidater i en hamstermodell av L Donovani-infektion och detta gav skydd med ökade hypersensiva reaktioner med fördröjd typ som svar på parasitantigen, förhöjda parasitspecifika antikroppssvar och förbättrade parasitspecifika T-cellsvar 53 54 Liposomalt lösligt leishmaniaantigen från L major inkorporerat med fosfortioat CpG ODN PS CpG Eller fosfodiaster CpG ODN PO CpG har också testats i en musmodell av CL och genererade signifikanta skyddsnivåer 55 De utsöndringssekretoriska proteinerna isolerade från odlingssupernatanter av L-infantum och adjuverade med muramyldipeptid testades hos hundar som experimentellt infekterades med L-infantum 56 Detta vaccin, benämnt LiESAp-MDP, inducerade signifikant och långvarigt skydd mot hund VL i en fältförsök i en endemisk område i Frankrike med naturligt infekterade hundar 57 En stor hindring för dessa fraktionerade vacciner för mänskliga applikationer är dock deras produktion till gott Kliniska tillverkningsstandarder, liksom genvariation och polymor Fismer i fältisoler. Rekombinanta proteiner, antingen ensamma eller kombinerade med adjuvans eller med rekombinant bakterievirus som leveransfordon, 58 59 har också testats som vacciner i prekliniska studier. Det har gjorts betydande ansträngningar under senare tid för att identifiera rekombinanta antigener som kan skydda Mot Leishmania-infektion i försöksmodeller Några av dessa antigener innefattar kinetoplastidmembranprotein-11, 60 61 sterol 24-c-metyltranferas, 62 amastigote-specifikt protein A2, 63 cysteinprotein B, 64 L braziliensisöjning och initieringsfaktor, 65 K26 HASPB, 66 Leishmania-aktiverat C-kinas, 67 promastigote-ytantigen 2, 68 nukleosidhydrolas 69 och ytuttryckt glykoprotein gp63 70 Även om de flesta av dessa rekombinanta antigener har testats i djurmodeller för deras immunogenicitet och skyddande effekt har endast ett fåtal utvecklats till kliniska prövningar i Icke-mänskliga primater, hundar eller i prekliniska humana studier 71 72 En multisubunit rekombinant Lei Shmania-vaccinet, Leish-111F, innehållande en L-huvudhomolog av eukaryotisk tiole-specifik antioxidant, L-huvudstarkinducerbar protein-1 och L-braziliensisöjning och initieringsfaktor, i formulering med MPL-SE, har visat sig ge skydd i musmodeller Av CL och VL, 73 74 men misslyckades med att förhindra hund VL som orsakats av naturlig infektion av L infantum 75 Ändå är Leish-111F MPL-SE den första definierade vaccinkandidaten att utvecklas till kliniska prövningar av human fas I och fas II hos friska frivilliga I Sydamerika, CL - och ML-patienter i Brasilien och Peru och patienter härdade av VL i Indien 76 77 78 79 Som med alla subenhetsvacciner inkluderar potentiella problem variationer i immunogenicitet, baserat på humant lymfocytantigenuttryck hos individer, genvariation och polymorfismer i Parasiter, liksom möjligheten att driva selektivt tryck av parasiter bort från de molekyler som används i vacciner. Slutligen genomgår DNA-vacciner för att förhindra leishmaniasis utveckling och D-test Detta tillvägagångssätt är inte nytt 80 men har flera fördelar, såsom låga produktionskostnader, materialstabilitet, hållbart uttryck av relevanta antigener och effektiv generering av effektor och minnesimmunresponser 81 Dessutom kan mer än ett antigen produceras Genom en enda konstruktion Det icke-metylerade CpG-motivet av bakteriellt DNA ger den ytterligare fördelen att aktivera medfödda immunceller för att producera interleukin-12, som kan främja CD4-T-celler för att utvecklas till Thl-celler 82 En lista över vaccinantigenkandidater som testas i DNA Vacciner för CL och VL visas i tabell 1.Tabell 1 - Leishmania vaccin antigener testas som kandidata DNA-vacciner. Därför verkar det trots många års försök att identifiera immunogena parasitantigener och framsteg inom vaccineteknik inte vara en Vaccinkandidat som kan leverera den skyddsnivå som behövs för ett sjukdomselimineringsprogram. Ett betydande förskott har dock nyligen beskrivits i a Studera av Guha et al 83 där de riktade sig mot parasithemoglobinreceptorn HbR med användning av ett DNA-vaccin-tillvägagångssätt och testat det i en experimentell modell av VL Leishmania-parasiter kräver heme för olika metaboliska aktiviteter, emellertid saknar de en endogen heme-syntesväg, vilket gör dem beroende På värden HbR uttrycks på parasitens cellyta och konserveras bland olika arter. Denna receptor är inte bara viktig för hemoglobinendocytos, 84 men har också hexokinasaktivitet, som skiljer sig från värdhexokinas, 85 som är viktigt för att reglera glykolys. Dessa viktiga Egenskaper hos parasit HbR ledde Guha och kollegor att testa denna molekyl som DNA-vaccinkandidat. Framgången av något vaccin beror på många faktorer, inklusive generering av effektiva antigenspecifika antikroppssvar, priming och underhåll av parasitspecifik T-cell Svar och genereringen av T-celler med lämpliga effektorfunktioner Guha et al fann att patienterna vittnar H aktiva VL producerade reaktiva antikroppar mot HbR och att dessa antikroppar kunde hämma parasittillväxt på ett komplementberoende sätt in vitro. De visade också att HbR-DNA-vaccinering av möss stimulerade produktionen av antigenspecifika IgG2a-antikroppar och främja genereringen av Antigen-specifika T-cellsvar som kunde producera flera Th1-relaterade cytokiner samtidigt som är ett polyfunktionellt T-cellsvar Dessutom möjliggjorde immunisering med detta DNA-vaccin steril botemedel i hamstrar och möss efter utmaning med virulent L donovani Figur 2 Detta Är anmärkningsvärt Dessa resultat erhölls i frånvaro av adjuvans och på så sätt lyfter fram potentialen hos HbR som en DNA-vaccinkandidat för human användning. Men ytterligare testning, inklusive oberoende validering av effektivitet, måste utföras. Dessutom, och som tidigare nämnts, DNA Vacciner har visat stort löfte i djurmodeller, men har ännu inte visat sitt nyttjande hos människor. Det har varit nej Kliniska prövningar bortom fas II för att testa DNA-vacciner hos människor Således är en stor utmaning för kandidater för DNA-vaccin, såsom parasit HbR, demonstration av säkerhet och effekt hos människor i både klinisk prövning och fältinställningar. Effekten av HbR-DNA Vaccination En möss och hamstrar vaccinerades med HbR-DNA-vaccinet före infektion med L donovani promastigotes 1. Antigenerna presenterades av antigen-presenterande celler APC till CD4- och CD8-T-celler i sammanhang av MHC-II - och MHC-I-molekyler respektive 2 Detta ledde till ökad proliferation av både CD4- och CD8-T-celler 3 och generering av multifunktionella CD4- och CD8-T-celler CD4-T-celler, förstärkt antikroppsgenerering genom B-celler-plasmaceller 4 Den kombinerade effekten av ökade multifunktionella CD4- och CD8-T-celler och antikroppar resulterade i Fullständig clearance av parasiten 5 b Ej vaccinerade möss och hamstrar infekterades med L donovani promastigotes 1 Antigener presenterades av APC till CD4 och CD8 T-celler, 2 vilket resulterade i l Imiterad T-cellsproliferation och generering av interleukin-10 producerande celler 3 som leder till förbättrad parasittillväxt 4. Fullständig figur och legend 166K. Konklusion av kommentarer problem och framtida riktning. Vaccination är den mest kostnadseffektiva sätten att kontrollera infektionssjukdomar. Framgången av Vaccinutveckling beror på förståelse av immunobiologin för patogenvärdesinteraktioner, urval av lämpliga vaccinkandidater och val av rätt adjuvans eller leveransfordon Vidare måste vaccinet generera långvarig immunitet, de bästa immunförsvaret av skydd måste identifieras så att Vaccin effektivitet kan utvärderas effektivt och det måste kunna övergå från preklinisk provning till mänskliga försök. Trots en bättre förståelse av immunreglerande vägar som upprättats efter infektion eller vaccination har vi fortfarande en begränsad kapacitet att modulera dessa till klinisk fördel med tillgängliga adjuvanser Eller droger Ideellt bör vaccinet också vara Effektiv mot alla orsakssjukdomar för en viss sjukdom Detta skulle möjliggöra avsevärd besparing i produktutveckling och testning, vilket kommer att vara ett viktigt övervägande vid framtida vaccinutvecklingsprogram. Utvecklingen av ett vaccin mot leishmaniasis har varit långsamt. Men ökad kunskap som har vunnits de senaste åren i Alla ovanstående områden banar väg för förnyade ansträngningar för att göra och testa nya vacciner som syftar till att förebygga och eller behandla leishmaniasis. Om finansieringskällor kan identifieras och begå till den långa vägen för vaccinutveckling, är vi övertygade om att det här är en parasitsjukdom som Kan slutligen kontrolleras. Pearson RD, Sousa AQ Kliniskt spektrum av Leishmaniasis Clin Infect Dis 1996 22 1 13 Artikel PubMed ISI CAS. Sacks D, Kamhawi S Molekylära aspekter av parasit-vektor och vektor värd interaktioner i leishmaniasis Annu Rev Microbiol 2001 55 453 483 Artikel PubMed ISI CAS. Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J et al Leishmaniasis worldwid E och globala uppskattningar av dess förekomst PLoS One 2012 7 e35671 Artikel PubMed CAS. Alvar J, Canavate C, Molina R, Moreno J, Nieto J Canine leishmaniasis Förskott i parasitologi 2004 57 1 88 PubMed. 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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. 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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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