Recent advances in managing axial spondyloarthritis

Recent advances in managing axial spondyloarthritis | F1000Research "use strict";function _typeof(t){return(_typeof="function"==typeof Symbol&&"symbol"==typeof Symbol.iterator?function(t){return typeof t}:function(t){return t&&"function"==typeof Symbol&&t.constructor===Symbol&&t!==Symbol.prototype?"symbol":typeof t})(t)}!function(){var t=function(){var t,e,o=[],n=window,r=n;for(;r;){try{if(r.frames.__tcfapiLocator){t=r;break}}catch(t){}if(r===n.top)break;r=r.parent}t||(!function t(){var e=n.document,o=!!n.frames.__tcfapiLocator;if(!o)if(e.body){var r=e.createElement("iframe");r.style.cssText="display:none",r.name="__tcfapiLocator",e.body.appendChild(r)}else setTimeout(t,5);return!o}(),n.__tcfapi=function(){for(var t=arguments.length,n=new Array(t),r=0;r 3&&2===parseInt(n[1],10)&&"boolean"==typeof n[3]&&(e=n[3],"function"==typeof n[2]&&n[2]("set",!0)):"ping"===n[0]?"function"==typeof n[2]&&n[2]({gdprApplies:e,cmpLoaded:!1,cmpStatus:"stub"}):o.push(n)},n.addEventListener("message",(function(t){var e="string"==typeof t.data,o={};if(e)try{o=JSON.parse(t.data)}catch(t){}else o=t.data;var n="object"===_typeof(o)&&null!==o?o.__tcfapiCall:null;n&&window.__tcfapi(n.command,n.version,(function(o,r){var a={__tcfapiReturn:{returnValue:o,success:r,callId:n.callId}};t&&t.source&&t.source.postMessage&&t.source.postMessage(e?JSON.stringify(a):a,"*")}),n.parameter)}),!1))};"undefined"!=typeof module?module.exports=t:t()}(); dataLayer = dataLayer || []; // Standard GTM initialization - Google Consent Mode handles consent automatically (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= 'https://www.googletagmanager.com/gtm.js?id='+i+dl+ '>m_auth=hzk0Vc3qFsQYhCrIoHz68A>m_preview=env-1>m_cookies_win=x';f.parentNode.insertBefore(j,f); })(window,document,'script','dataLayer','GTM-MWFK8L5J'); ;window.NREUM||(NREUM={});NREUM.init={distributed_tracing:{enabled:true},privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]}}; ;NREUM.loader_config={accountID:"438030",trustKey:"438030",agentID:"772317073",licenseKey:"97f8f67f26",applicationID:"772317073"} ;NREUM.info={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net",licenseKey:"97f8f67f26",applicationID:"772317073",sa:1} ;/*! For license information please see nr-loader-spa-1.236.0.min.js.LICENSE.txt */ (()=>{"use strict";var e,t,r={5763:(e,t,r)=>{r.d(t,{P_:()=>l,Mt:()=>g,C5:()=>s,DL:()=>v,OP:()=>T,lF:()=>D,Yu:()=>y,Dg:()=>h,CX:()=>c,GE:()=>b,sU:()=>_});var n=r(8632),i=r(9567);const o={beacon:n.ce.beacon,errorBeacon:n.ce.errorBeacon,licenseKey:void 0,applicationID:void 0,sa:void 0,queueTime:void 0,applicationTime:void 0,ttGuid:void 0,user:void 0,account:void 0,product:void 0,extra:void 0,jsAttributes:{},userAttributes:void 0,atts:void 0,transactionName:void 0,tNamePlain:void 0},a={};function s(e){if(!e)throw new Error("All info objects require an agent identifier!");if(!a[e])throw new Error("Info for ".concat(e," was never set"));return a[e]}function c(e,t){if(!e)throw new Error("All info objects require an agent identifier!");a[e]=(0,i.D)(t,o),(0,n.Qy)(e,a[e],"info")}var u=r(7056);const d=()=>{const e={blockSelector:"[data-nr-block]",maskInputOptions:{password:!0}};return{allow_bfcache:!0,privacy:{cookies_enabled:!0},ajax:{deny_list:void 0,enabled:!0,harvestTimeSeconds:10},distributed_tracing:{enabled:void 0,exclude_newrelic_header:void 0,cors_use_newrelic_header:void 0,cors_use_tracecontext_headers:void 0,allowed_origins:void 0},session:{domain:void 0,expiresMs:u.oD,inactiveMs:u.Hb},ssl:void 0,obfuscate:void 0,jserrors:{enabled:!0,harvestTimeSeconds:10},metrics:{enabled:!0},page_action:{enabled:!0,harvestTimeSeconds:30},page_view_event:{enabled:!0},page_view_timing:{enabled:!0,harvestTimeSeconds:30,long_task:!1},session_trace:{enabled:!0,harvestTimeSeconds:10},harvest:{tooManyRequestsDelay:60},session_replay:{enabled:!1,harvestTimeSeconds:60,sampleRate:.1,errorSampleRate:.1,maskTextSelector:"*",maskAllInputs:!0,get blockClass(){return"nr-block"},get ignoreClass(){return"nr-ignore"},get maskTextClass(){return"nr-mask"},get blockSelector(){return e.blockSelector},set blockSelector(t){e.blockSelector+=",".concat(t)},get maskInputOptions(){return e.maskInputOptions},set maskInputOptions(t){e.maskInputOptions={...t,password:!0}}},spa:{enabled:!0,harvestTimeSeconds:10}}},f={};function l(e){if(!e)throw new Error("All configuration objects require an agent identifier!");if(!f[e])throw new Error("Configuration for ".concat(e," was never set"));return f[e]}function h(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");f[e]=(0,i.D)(t,d()),(0,n.Qy)(e,f[e],"config")}function g(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");var r=l(e);if(r){for(var n=t.split("."),i=0;i {r.d(t,{D:()=>i});var n=r(50);function i(e,t){try{if(!e||"object"!=typeof e)return(0,n.Z)("Setting a Configurable requires an object as input");if(!t||"object"!=typeof t)return(0,n.Z)("Setting a Configurable requires a model to set its initial properties");const r=Object.create(Object.getPrototypeOf(t),Object.getOwnPropertyDescriptors(t)),o=0===Object.keys(r).length?e:r;for(let a in o)if(void 0!==e[a])try{"object"==typeof e[a]&&"object"==typeof t[a]?r[a]=i(e[a],t[a]):r[a]=e[a]}catch(e){(0,n.Z)("An error occurred while setting a property of a Configurable",e)}return r}catch(e){(0,n.Z)("An error occured while setting a Configurable",e)}}},6818:(e,t,r)=>{r.d(t,{Re:()=>i,gF:()=>o,q4:()=>n});const n="1.236.0",i="PROD",o="CDN"},385:(e,t,r)=>{r.d(t,{FN:()=>a,IF:()=>u,Nk:()=>f,Tt:()=>s,_A:()=>o,il:()=>n,pL:()=>c,v6:()=>i,w1:()=>d});const n="undefined"!=typeof window&&!!window.document,i="undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self.navigator instanceof WorkerNavigator||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis.navigator instanceof WorkerNavigator),o=n?window:"undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis),a=""+o?.location,s=/iPad|iPhone|iPod/.test(navigator.userAgent),c=s&&"undefined"==typeof SharedWorker,u=(()=>{const e=navigator.userAgent.match(/Firefox[/\s](\d+\.\d+)/);return Array.isArray(e)&&e.length>=2?+e[1]:0})(),d=Boolean(n&&window.document.documentMode),f=!!navigator.sendBeacon},1117:(e,t,r)=>{r.d(t,{w:()=>o});var n=r(50);const i={agentIdentifier:"",ee:void 0};class o{constructor(e){try{if("object"!=typeof e)return(0,n.Z)("shared context requires an object as input");this.sharedContext={},Object.assign(this.sharedContext,i),Object.entries(e).forEach((e=>{let[t,r]=e;Object.keys(i).includes(t)&&(this.sharedContext[t]=r)}))}catch(e){(0,n.Z)("An error occured while setting SharedContext",e)}}}},8e3:(e,t,r)=>{r.d(t,{L:()=>d,R:()=>c});var n=r(2177),i=r(1284),o=r(4322),a=r(3325);const s={};function c(e,t){const r={staged:!1,priority:a.p[t]||0};u(e),s[e].get(t)||s[e].set(t,r)}function u(e){e&&(s[e]||(s[e]=new Map))}function d(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:"",t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:"feature";if(u(e),!e||!s[e].get(t))return a(t);s[e].get(t).staged=!0;const r=[...s[e]];function a(t){const r=e?n.ee.get(e):n.ee,a=o.X.handlers;if(r.backlog&&a){var s=r.backlog[t],c=a[t];if(c){for(var u=0;s&&u {let[t,r]=e;return r.staged}))&&(r.sort(((e,t)=>e[1].priority-t[1].priority)),r.forEach((e=>{let[t]=e;a(t)})))}function f(e,t){var r=e[1];(0,i.D)(t[r],(function(t,r){var n=e[0];if(r[0]===n){var i=r[1],o=e[3],a=e[2];i.apply(o,a)}}))}},2177:(e,t,r)=>{r.d(t,{c:()=>f,ee:()=>u});var n=r(8632),i=r(2210),o=r(1284),a=r(5763),s="nr@context";let c=(0,n.fP)();var u;function d(){}function f(e){return(0,i.X)(e,s,l)}function l(){return new d}function h(){u.aborted=!0,u.backlog={}}c.ee?u=c.ee:(u=function e(t,r){var n={},c={},f={},g=!1;try{g=16===r.length&&(0,a.OP)(r).isolatedBacklog}catch(e){}var p={on:b,addEventListener:b,removeEventListener:y,emit:v,get:x,listeners:w,context:m,buffer:A,abort:h,aborted:!1,isBuffering:E,debugId:r,backlog:g?{}:t&&"object"==typeof t.backlog?t.backlog:{}};return p;function m(e){return e&&e instanceof d?e:e?(0,i.X)(e,s,l):l()}function v(e,r,n,i,o){if(!1!==o&&(o=!0),!u.aborted||i){t&&o&&t.emit(e,r,n);for(var a=m(n),s=w(e),d=s.length,f=0;fn,p:()=>i});var n=r(2177).ee.get("handle");function i(e,t,r,i,o){o?(o.buffer([e],i),o.emit(e,t,r)):(n.buffer([e],i),n.emit(e,t,r))}},4322:(e,t,r)=>{r.d(t,{X:()=>o});var n=r(5546);o.on=a;var i=o.handlers={};function o(e,t,r,o){a(o||n.E,i,e,t,r)}function a(e,t,r,i,o){o||(o="feature"),e||(e=n.E);var a=t[o]=t[o]||{};(a[r]=a[r]||[]).push([e,i])}},3239:(e,t,r)=>{r.d(t,{bP:()=>s,iz:()=>c,m$:()=>a});var n=r(385);let i=!1,o=!1;try{const e={get passive(){return i=!0,!1},get signal(){return o=!0,!1}};n._A.addEventListener("test",null,e),n._A.removeEventListener("test",null,e)}catch(e){}function a(e,t){return i||o?{capture:!!e,passive:i,signal:t}:!!e}function s(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;window.addEventListener(e,t,a(r,n))}function c(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;document.addEventListener(e,t,a(r,n))}},4402:(e,t,r)=>{r.d(t,{Ht:()=>u,M:()=>c,Rl:()=>a,ky:()=>s});var n=r(385);const i="xxxxxxxx-xxxx-4xxx-yxxx-xxxxxxxxxxxx";function o(e,t){return e?15&e[t]:16*Math.random()|0}function a(){const e=n._A?.crypto||n._A?.msCrypto;let t,r=0;return e&&e.getRandomValues&&(t=e.getRandomValues(new Uint8Array(31))),i.split("").map((e=>"x"===e?o(t,++r).toString(16):"y"===e?(3&o()|8).toString(16):e)).join("")}function s(e){const t=n._A?.crypto||n._A?.msCrypto;let r,i=0;t&&t.getRandomValues&&(r=t.getRandomValues(new Uint8Array(31)));const a=[];for(var s=0;s {r.d(t,{Bq:()=>n,Hb:()=>o,oD:()=>i});const n="NRBA",i=144e5,o=18e5},7894:(e,t,r)=>{function n(){return Math.round(performance.now())}r.d(t,{z:()=>n})},7243:(e,t,r)=>{r.d(t,{e:()=>o});var n=r(385),i={};function o(e){if(e in i)return i[e];if(0===(e||"").indexOf("data:"))return{protocol:"data"};let t;var r=n._A?.location,o={};if(n.il)t=document.createElement("a"),t.href=e;else try{t=new URL(e,r.href)}catch(e){return o}o.port=t.port;var a=t.href.split("://");!o.port&&a[1]&&(o.port=a[1].split("/")[0].split("@").pop().split(":")[1]),o.port&&"0"!==o.port||(o.port="https"===a[0]?"443":"80"),o.hostname=t.hostname||r.hostname,o.pathname=t.pathname,o.protocol=a[0],"/"!==o.pathname.charAt(0)&&(o.pathname="/"+o.pathname);var s=!t.protocol||":"===t.protocol||t.protocol===r.protocol,c=t.hostname===r.hostname&&t.port===r.port;return o.sameOrigin=s&&(!t.hostname||c),"/"===o.pathname&&(i[e]=o),o}},50:(e,t,r)=>{function n(e,t){"function"==typeof console.warn&&(console.warn("New Relic: ".concat(e)),t&&console.warn(t))}r.d(t,{Z:()=>n})},2587:(e,t,r)=>{r.d(t,{N:()=>c,T:()=>u});var n=r(2177),i=r(5546),o=r(8e3),a=r(3325);const s={stn:[a.D.sessionTrace],err:[a.D.jserrors,a.D.metrics],ins:[a.D.pageAction],spa:[a.D.spa],sr:[a.D.sessionReplay,a.D.sessionTrace]};function c(e,t){const r=n.ee.get(t);e&&"object"==typeof e&&(Object.entries(e).forEach((e=>{let[t,n]=e;void 0===u[t]&&(s[t]?s[t].forEach((e=>{n?(0,i.p)("feat-"+t,[],void 0,e,r):(0,i.p)("block-"+t,[],void 0,e,r),(0,i.p)("rumresp-"+t,[Boolean(n)],void 0,e,r)})):n&&(0,i.p)("feat-"+t,[],void 0,void 0,r),u[t]=Boolean(n))})),Object.keys(s).forEach((e=>{void 0===u[e]&&(s[e]?.forEach((t=>(0,i.p)("rumresp-"+e,[!1],void 0,t,r))),u[e]=!1)})),(0,o.L)(t,a.D.pageViewEvent))}const u={}},2210:(e,t,r)=>{r.d(t,{X:()=>i});var n=Object.prototype.hasOwnProperty;function i(e,t,r){if(n.call(e,t))return e[t];var i=r();if(Object.defineProperty&&Object.keys)try{return Object.defineProperty(e,t,{value:i,writable:!0,enumerable:!1}),i}catch(e){}return e[t]=i,i}},1284:(e,t,r)=>{r.d(t,{D:()=>n});const n=(e,t)=>Object.entries(e||{}).map((e=>{let[r,n]=e;return t(r,n)}))},4351:(e,t,r)=>{r.d(t,{P:()=>o});var n=r(2177);const i=()=>{const e=new WeakSet;return(t,r)=>{if("object"==typeof r&&null!==r){if(e.has(r))return;e.add(r)}return r}};function o(e){try{return JSON.stringify(e,i())}catch(e){try{n.ee.emit("internal-error",[e])}catch(e){}}}},3960:(e,t,r)=>{r.d(t,{K:()=>a,b:()=>o});var n=r(3239);function i(){return"undefined"==typeof document||"complete"===document.readyState}function o(e,t){if(i())return e();(0,n.bP)("load",e,t)}function a(e){if(i())return e();(0,n.iz)("DOMContentLoaded",e)}},8632:(e,t,r)=>{r.d(t,{EZ:()=>u,Qy:()=>c,ce:()=>o,fP:()=>a,gG:()=>d,mF:()=>s});var n=r(7894),i=r(385);const o={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net"};function a(){return i._A.NREUM||(i._A.NREUM={}),void 0===i._A.newrelic&&(i._A.newrelic=i._A.NREUM),i._A.NREUM}function s(){let e=a();return e.o||(e.o={ST:i._A.setTimeout,SI:i._A.setImmediate,CT:i._A.clearTimeout,XHR:i._A.XMLHttpRequest,REQ:i._A.Request,EV:i._A.Event,PR:i._A.Promise,MO:i._A.MutationObserver,FETCH:i._A.fetch}),e}function c(e,t,r){let i=a();const o=i.initializedAgents||{},s=o[e]||{};return Object.keys(s).length||(s.initializedAt={ms:(0,n.z)(),date:new Date}),i.initializedAgents={...o,[e]:{...s,[r]:t}},i}function u(e,t){a()[e]=t}function d(){return function(){let e=a();const t=e.info||{};e.info={beacon:o.beacon,errorBeacon:o.errorBeacon,...t}}(),function(){let e=a();const t=e.init||{};e.init={...t}}(),s(),function(){let e=a();const t=e.loader_config||{};e.loader_config={...t}}(),a()}},7956:(e,t,r)=>{r.d(t,{N:()=>i});var n=r(3239);function i(e){let t=arguments.length>1&&void 0!==arguments[1]&&arguments[1],r=arguments.length>2?arguments[2]:void 0,i=arguments.length>3?arguments[3]:void 0;return void(0,n.iz)("visibilitychange",(function(){if(t)return void("hidden"==document.visibilityState&&e());e(document.visibilityState)}),r,i)}},1214:(e,t,r)=>{r.d(t,{em:()=>v,u5:()=>N,QU:()=>S,_L:()=>I,Gm:()=>L,Lg:()=>M,gy:()=>U,BV:()=>Q,Kf:()=>ee});var n=r(2177);const i="nr@original";var o=Object.prototype.hasOwnProperty,a=!1;function s(e,t){return e||(e=n.ee),r.inPlace=function(e,t,n,i,o){n||(n="");var a,s,c,u="-"===n.charAt(0);for(c=0;c 2?n-2:0),o=2;o {r(A[T],e,w),r(E[T],e,w)})),r(l._A,"fetch",y),t.on(y+"end",(function(e,r){var n=this;if(r){var i=r.headers.get("content-length");null!==i&&(n.rxSize=i),t.emit(y+"done",[null,r],n)}else t.emit(y+"done",[e],n)})),t}const O={},j=["pushState","replaceState"];function S(e){const t=function(e){return(e||n.ee).get("history")}(e);return!l.il||O[t.debugId]++||(O[t.debugId]=1,s(t).inPlace(window.history,j,"-")),t}var P=r(3239);const C={},R=["appendChild","insertBefore","replaceChild"];function I(e){const t=function(e){return(e||n.ee).get("jsonp")}(e);if(!l.il||C[t.debugId])return t;C[t.debugId]=!0;var r=s(t),i=/[?&](?:callback|cb)=([^&#]+)/,o=/(.*)\.([^.]+)/,a=/^(\w+)(\.|$)(.*)$/;function c(e,t){var r=e.match(a),n=r[1],i=r[3];return i?c(i,t[n]):t[n]}return r.inPlace(Node.prototype,R,"dom-"),t.on("dom-start",(function(e){!function(e){if(!e||"string"!=typeof e.nodeName||"script"!==e.nodeName.toLowerCase())return;if("function"!=typeof e.addEventListener)return;var n=(a=e.src,s=a.match(i),s?s[1]:null);var a,s;if(!n)return;var u=function(e){var t=e.match(o);if(t&&t.length>=3)return{key:t[2],parent:c(t[1],window)};return{key:e,parent:window}}(n);if("function"!=typeof u.parent[u.key])return;var d={};function f(){t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}function l(){t.emit("jsonp-error",[],d),t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}r.inPlace(u.parent,[u.key],"cb-",d),e.addEventListener("load",f,(0,P.m$)(!1)),e.addEventListener("error",l,(0,P.m$)(!1)),t.emit("new-jsonp",[e.src],d)}(e[0])})),t}var k=r(5763);const H={};function L(e){const t=function(e){return(e||n.ee).get("mutation")}(e);if(!l.il||H[t.debugId])return t;H[t.debugId]=!0;var r=s(t),i=k.Yu.MO;return i&&(window.MutationObserver=function(e){return this instanceof i?new i(r(e,"fn-")):i.apply(this,arguments)},MutationObserver.prototype=i.prototype),t}const z={};function M(e){const t=function(e){return(e||n.ee).get("promise")}(e);if(z[t.debugId])return t;z[t.debugId]=!0;var r=n.c,o=s(t),a=k.Yu.PR;return a&&function(){function e(r){var n=t.context(),i=o(r,"executor-",n,null,!1);const s=Reflect.construct(a,[i],e);return t.context(s).getCtx=function(){return n},s}l._A.Promise=e,Object.defineProperty(e,"name",{value:"Promise"}),e.toString=function(){return a.toString()},Object.setPrototypeOf(e,a),["all","race"].forEach((function(r){const n=a[r];e[r]=function(e){let i=!1;[...e||[]].forEach((e=>{this.resolve(e).then(a("all"===r),a(!1))}));const o=n.apply(this,arguments);return o;function a(e){return function(){t.emit("propagate",[null,!i],o,!1,!1),i=i||!e}}}})),["resolve","reject"].forEach((function(r){const n=a[r];e[r]=function(e){const r=n.apply(this,arguments);return e!==r&&t.emit("propagate",[e,!0],r,!1,!1),r}})),e.prototype=a.prototype;const n=a.prototype.then;a.prototype.then=function(){var e=this,i=r(e);i.promise=e;for(var a=arguments.length,s=new Array(a),c=0;c e())),t};function m(e,t){i.inPlace(t,["onreadystatechange"],"fn-",E)}function b(){var e=this,t=r.context(e);e.readyState>3&&!t.resolved&&(t.resolved=!0,r.emit("xhr-resolved",[],e)),i.inPlace(e,f,"fn-",E)}if(function(e,t){for(var r in e)t[r]=e[r]}(o,p),p.prototype=o.prototype,i.inPlace(p.prototype,J,"-xhr-",E),r.on("send-xhr-start",(function(e,t){m(e,t),function(e){h.push(e),a&&(y?y.then(A):u?u(A):(w=-w,x.data=w))}(t)})),r.on("open-xhr-start",m),a){var y=c&&c.resolve();if(!u&&!c){var w=1,x=document.createTextNode(w);new a(A).observe(x,{characterData:!0})}}else t.on("fn-end",(function(e){e[0]&&e[0].type===d||A()}));function A(){for(var e=0;e {r.d(t,{t:()=>n});const n=r(3325).D.ajax},6660:(e,t,r)=>{r.d(t,{A:()=>i,t:()=>n});const n=r(3325).D.jserrors,i="nr@seenError"},3081:(e,t,r)=>{r.d(t,{gF:()=>o,mY:()=>i,t9:()=>n,vz:()=>s,xS:()=>a});const n=r(3325).D.metrics,i="sm",o="cm",a="storeSupportabilityMetrics",s="storeEventMetrics"},4649:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageAction},7633:(e,t,r)=>{r.d(t,{Dz:()=>i,OJ:()=>a,qw:()=>o,t9:()=>n});const n=r(3325).D.pageViewEvent,i="firstbyte",o="domcontent",a="windowload"},9251:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageViewTiming},3614:(e,t,r)=>{r.d(t,{BST_RESOURCE:()=>i,END:()=>s,FEATURE_NAME:()=>n,FN_END:()=>u,FN_START:()=>c,PUSH_STATE:()=>d,RESOURCE:()=>o,START:()=>a});const n=r(3325).D.sessionTrace,i="bstResource",o="resource",a="-start",s="-end",c="fn"+a,u="fn"+s,d="pushState"},7836:(e,t,r)=>{r.d(t,{BODY:()=>A,CB_END:()=>E,CB_START:()=>u,END:()=>x,FEATURE_NAME:()=>i,FETCH:()=>_,FETCH_BODY:()=>v,FETCH_DONE:()=>m,FETCH_START:()=>p,FN_END:()=>c,FN_START:()=>s,INTERACTION:()=>l,INTERACTION_API:()=>d,INTERACTION_EVENTS:()=>o,JSONP_END:()=>b,JSONP_NODE:()=>g,JS_TIME:()=>T,MAX_TIMER_BUDGET:()=>a,REMAINING:()=>f,SPA_NODE:()=>h,START:()=>w,originalSetTimeout:()=>y});var n=r(5763);const i=r(3325).D.spa,o=["click","submit","keypress","keydown","keyup","change"],a=999,s="fn-start",c="fn-end",u="cb-start",d="api-ixn-",f="remaining",l="interaction",h="spaNode",g="jsonpNode",p="fetch-start",m="fetch-done",v="fetch-body-",b="jsonp-end",y=n.Yu.ST,w="-start",x="-end",A="-body",E="cb"+x,T="jsTime",_="fetch"},5938:(e,t,r)=>{r.d(t,{W:()=>o});var n=r(5763),i=r(2177);class o{constructor(e,t,r){this.agentIdentifier=e,this.aggregator=t,this.ee=i.ee.get(e,(0,n.OP)(this.agentIdentifier).isolatedBacklog),this.featureName=r,this.blocked=!1}}},9144:(e,t,r)=>{r.d(t,{j:()=>m});var n=r(3325),i=r(5763),o=r(5546),a=r(2177),s=r(7894),c=r(8e3),u=r(3960),d=r(385),f=r(50),l=r(3081),h=r(8632);function g(){const e=(0,h.gG)();["setErrorHandler","finished","addToTrace","inlineHit","addRelease","addPageAction","setCurrentRouteName","setPageViewName","setCustomAttribute","interaction","noticeError","setUserId"].forEach((t=>{e[t]=function(){for(var r=arguments.length,n=new Array(r),i=0;i 1?r-1:0),i=1;i {e.exposed&&e.api[t]&&o.push(e.api[t](...n))})),o.length>1?o:o[0]}(t,...n)}}))}var p=r(2587);function m(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:{},m=arguments.length>2?arguments[2]:void 0,v=arguments.length>3?arguments[3]:void 0,{init:b,info:y,loader_config:w,runtime:x={loaderType:m},exposed:A=!0}=t;const E=(0,h.gG)();y||(b=E.init,y=E.info,w=E.loader_config),(0,i.Dg)(e,b||{}),(0,i.GE)(e,w||{}),(0,i.sU)(e,x),y.jsAttributes??={},d.v6&&(y.jsAttributes.isWorker=!0),(0,i.CX)(e,y),g();const T=function(e,t){t||(0,c.R)(e,"api");const h={};var g=a.ee.get(e),p=g.get("tracer"),m="api-",v=m+"ixn-";function b(t,r,n,o){const a=(0,i.C5)(e);return null===r?delete a.jsAttributes[t]:(0,i.CX)(e,{...a,jsAttributes:{...a.jsAttributes,[t]:r}}),x(m,n,!0,o||null===r?"session":void 0)(t,r)}function y(){}["setErrorHandler","finished","addToTrace","inlineHit","addRelease"].forEach((e=>h[e]=x(m,e,!0,"api"))),h.addPageAction=x(m,"addPageAction",!0,n.D.pageAction),h.setCurrentRouteName=x(m,"routeName",!0,n.D.spa),h.setPageViewName=function(t,r){if("string"==typeof t)return"/"!==t.charAt(0)&&(t="/"+t),(0,i.OP)(e).customTransaction=(r||"http://custom.transaction")+t,x(m,"setPageViewName",!0)()},h.setCustomAttribute=function(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2];if("string"==typeof e){if(["string","number"].includes(typeof t)||null===t)return b(e,t,"setCustomAttribute",r);(0,f.Z)("Failed to execute setCustomAttribute.\nNon-null value must be a string or number type, but a type of was provided."))}else(0,f.Z)("Failed to execute setCustomAttribute.\nName must be a string type, but a type of was provided."))},h.setUserId=function(e){if("string"==typeof e||null===e)return b("enduser.id",e,"setUserId",!0);(0,f.Z)("Failed to execute setUserId.\nNon-null value must be a string type, but a type of was provided."))},h.interaction=function(){return(new y).get()};var w=y.prototype={createTracer:function(e,t){var r={},i=this,a="function"==typeof t;return(0,o.p)(v+"tracer",[(0,s.z)(),e,r],i,n.D.spa,g),function(){if(p.emit((a?"":"no-")+"fn-start",[(0,s.z)(),i,a],r),a)try{return t.apply(this,arguments)}catch(e){throw p.emit("fn-err",[arguments,this,"string"==typeof e?new Error(e):e],r),e}finally{p.emit("fn-end",[(0,s.z)()],r)}}}};function x(e,t,r,i){return function(){return(0,o.p)(l.xS,["API/"+t+"/called"],void 0,n.D.metrics,g),i&&(0,o.p)(e+t,[(0,s.z)(),...arguments],r?null:this,i,g),r?void 0:this}}function A(){r.e(439).then(r.bind(r,7438)).then((t=>{let{setAPI:r}=t;r(e),(0,c.L)(e,"api")})).catch((()=>(0,f.Z)("Downloading runtime APIs failed...")))}return["actionText","setName","setAttribute","save","ignore","onEnd","getContext","end","get"].forEach((e=>{w[e]=x(v,e,void 0,n.D.spa)})),h.noticeError=function(e,t){"string"==typeof e&&(e=new Error(e)),(0,o.p)(l.xS,["API/noticeError/called"],void 0,n.D.metrics,g),(0,o.p)("err",[e,(0,s.z)(),!1,t],void 0,n.D.jserrors,g)},d.il?(0,u.b)((()=>A()),!0):A(),h}(e,v);return(0,h.Qy)(e,T,"api"),(0,h.Qy)(e,A,"exposed"),(0,h.EZ)("activatedFeatures",p.T),T}},3325:(e,t,r)=>{r.d(t,{D:()=>n,p:()=>i});const n={ajax:"ajax",jserrors:"jserrors",metrics:"metrics",pageAction:"page_action",pageViewEvent:"page_view_event",pageViewTiming:"page_view_timing",sessionReplay:"session_replay",sessionTrace:"session_trace",spa:"spa"},i={[n.pageViewEvent]:1,[n.pageViewTiming]:2,[n.metrics]:3,[n.jserrors]:4,[n.ajax]:5,[n.sessionTrace]:6,[n.pageAction]:7,[n.spa]:8,[n.sessionReplay]:9}}},n={};function i(e){var t=n[e];if(void 0!==t)return t.exports;var o=n[e]={exports:{}};return r[e](o,o.exports,i),o.exports}i.m=r,i.d=(e,t)=>{for(var r in t)i.o(t,r)&&!i.o(e,r)&&Object.defineProperty(e,r,{enumerable:!0,get:t[r]})},i.f={},i.e=e=>Promise.all(Object.keys(i.f).reduce(((t,r)=>(i.f[r](e,t),t)),[])),i.u=e=>(({78:"page_action-aggregate",147:"metrics-aggregate",242:"session-manager",317:"jserrors-aggregate",348:"page_view_timing-aggregate",412:"lazy-feature-loader",439:"async-api",538:"recorder",590:"session_replay-aggregate",675:"compressor",733:"session_trace-aggregate",786:"page_view_event-aggregate",873:"spa-aggregate",898:"ajax-aggregate"}[e]||e)+"."+{78:"ac76d497",147:"3dc53903",148:"1a20d5fe",242:"2a64278a",317:"49e41428",348:"bd6de33a",412:"2f55ce66",439:"30bd804e",538:"1b18459f",590:"cf0efb30",675:"ae9f91a8",733:"83105561",786:"06482edd",860:"03a8b7a5",873:"e6b09d52",898:"998ef92b"}[e]+"-1.236.0.min.js"),i.o=(e,t)=>Object.prototype.hasOwnProperty.call(e,t),e={},t="NRBA:",i.l=(r,n,o,a)=>{if(e[r])e[r].push(n);else{var s,c;if(void 0!==o)for(var u=document.getElementsByTagName("script"),d=0;d {s.onerror=s.onload=null,clearTimeout(h);var i=e[r];if(delete e[r],s.parentNode&&s.parentNode.removeChild(s),i&&i.forEach((e=>e(n))),t)return t(n)},h=setTimeout(l.bind(null,void 0,{type:"timeout",target:s}),12e4);s.onerror=l.bind(null,s.onerror),s.onload=l.bind(null,s.onload),c&&document.head.appendChild(s)}},i.r=e=>{"undefined"!=typeof Symbol&&Symbol.toStringTag&&Object.defineProperty(e,Symbol.toStringTag,{value:"Module"}),Object.defineProperty(e,"__esModule",{value:!0})},i.j=364,i.p="https://js-agent.newrelic.com/",(()=>{var e={364:0,953:0};i.f.j=(t,r)=>{var n=i.o(e,t)?e[t]:void 0;if(0!==n)if(n)r.push(n[2]);else{var o=new Promise(((r,i)=>n=e[t]=[r,i]));r.push(n[2]=o);var a=i.p+i.u(t),s=new Error;i.l(a,(r=>{if(i.o(e,t)&&(0!==(n=e[t])&&(e[t]=void 0),n)){var o=r&&("load"===r.type?"missing":r.type),a=r&&r.target&&r.target.src;s.message="Loading chunk "+t+" failed.\n("+o+": "+a+")",s.name="ChunkLoadError",s.type=o,s.request=a,n[1](s)}}),"chunk-"+t,t)}};var t=(t,r)=>{var n,o,[a,s,c]=r,u=0;if(a.some((t=>0!==e[t]))){for(n in s)i.o(s,n)&&(i.m[n]=s[n]);if(c)c(i)}for(t&&t(r);u {i.r(o);var e=i(3325),t=i(5763);const r=Object.values(e.D);function n(e){const n={};return r.forEach((r=>{n[r]=function(e,r){return!1!==(0,t.Mt)(r,"".concat(e,".enabled"))}(r,e)})),n}var a=i(9144);var s=i(5546),c=i(385),u=i(8e3),d=i(5938),f=i(3960),l=i(50);class h extends d.W{constructor(e,t,r){let n=!(arguments.length>3&&void 0!==arguments[3])||arguments[3];super(e,t,r),this.auto=n,this.abortHandler,this.featAggregate,this.onAggregateImported,n&&(0,u.R)(e,r)}importAggregator(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:{};if(this.featAggregate||!this.auto)return;const r=c.il&&!0===(0,t.Mt)(this.agentIdentifier,"privacy.cookies_enabled");let n;this.onAggregateImported=new Promise((e=>{n=e}));const o=async()=>{let t;try{if(r){const{setupAgentSession:e}=await Promise.all([i.e(860),i.e(242)]).then(i.bind(i,3228));t=e(this.agentIdentifier)}}catch(e){(0,l.Z)("A problem occurred when starting up session manager. This page will not start or extend any session.",e)}try{if(!this.shouldImportAgg(this.featureName,t))return void(0,u.L)(this.agentIdentifier,this.featureName);const{lazyFeatureLoader:r}=await i.e(412).then(i.bind(i,8582)),{Aggregate:o}=await r(this.featureName,"aggregate");this.featAggregate=new o(this.agentIdentifier,this.aggregator,e),n(!0)}catch(e){(0,l.Z)("Downloading and initializing ".concat(this.featureName," failed..."),e),this.abortHandler?.(),n(!1)}};c.il?(0,f.b)((()=>o()),!0):o()}shouldImportAgg(r,n){return r!==e.D.sessionReplay||!1!==(0,t.Mt)(this.agentIdentifier,"session_trace.enabled")&&(!!n?.isNew||!!n?.state.sessionReplay)}}var g=i(7633),p=i(7894);class m extends h{static featureName=g.t9;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];if(super(r,n,g.t9,i),("undefined"==typeof PerformanceNavigationTiming||c.Tt)&&"undefined"!=typeof PerformanceTiming){const n=(0,t.OP)(r);n[g.Dz]=Math.max(Date.now()-n.offset,0),(0,f.K)((()=>n[g.qw]=Math.max((0,p.z)()-n[g.Dz],0))),(0,f.b)((()=>{const t=(0,p.z)();n[g.OJ]=Math.max(t-n[g.Dz],0),(0,s.p)("timing",["load",t],void 0,e.D.pageViewTiming,this.ee)}))}this.importAggregator()}}var v=i(1117),b=i(1284);class y extends v.w{constructor(e){super(e),this.aggregatedData={}}store(e,t,r,n,i){var o=this.getBucket(e,t,r,i);return o.metrics=function(e,t){t||(t={count:0});return t.count+=1,(0,b.D)(e,(function(e,r){t[e]=w(r,t[e])})),t}(n,o.metrics),o}merge(e,t,r,n,i){var o=this.getBucket(e,t,n,i);if(o.metrics){var a=o.metrics;a.count+=r.count,(0,b.D)(r,(function(e,t){if("count"!==e){var n=a[e],i=r[e];i&&!i.c?a[e]=w(i.t,n):a[e]=function(e,t){if(!t)return e;t.c||(t=x(t.t));return t.min=Math.min(e.min,t.min),t.max=Math.max(e.max,t.max),t.t+=e.t,t.sos+=e.sos,t.c+=e.c,t}(i,a[e])}}))}else o.metrics=r}storeMetric(e,t,r,n){var i=this.getBucket(e,t,r);return i.stats=w(n,i.stats),i}getBucket(e,t,r,n){this.aggregatedData[e]||(this.aggregatedData[e]={});var i=this.aggregatedData[e][t];return i||(i=this.aggregatedData[e][t]={params:r||{}},n&&(i.custom=n)),i}get(e,t){return t?this.aggregatedData[e]&&this.aggregatedData[e][t]:this.aggregatedData[e]}take(e){for(var t={},r="",n=!1,i=0;i t.max&&(t.max=e),e 2&&void 0!==arguments[2])||arguments[2];super(e,r,j.t,n),c.il&&((0,t.OP)(e).initHidden=Boolean("hidden"===document.visibilityState),(0,N.N)((()=>(0,s.p)("docHidden",[(0,p.z)()],void 0,j.t,this.ee)),!0),(0,O.bP)("pagehide",(()=>(0,s.p)("winPagehide",[(0,p.z)()],void 0,j.t,this.ee))),this.importAggregator())}}var P=i(3081);class C extends h{static featureName=P.t9;constructor(e,t){let r=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(e,t,P.t9,r),this.importAggregator()}}var R,I=i(2210),k=i(1214),H=i(2177),L={};try{R=localStorage.getItem("__nr_flags").split(","),console&&"function"==typeof console.log&&(L.console=!0,-1!==R.indexOf("dev")&&(L.dev=!0),-1!==R.indexOf("nr_dev")&&(L.nrDev=!0))}catch(e){}function z(e){try{L.console&&z(e)}catch(e){}}L.nrDev&&H.ee.on("internal-error",(function(e){z(e.stack)})),L.dev&&H.ee.on("fn-err",(function(e,t,r){z(r.stack)})),L.dev&&(z("NR AGENT IN DEVELOPMENT MODE"),z("flags: "+(0,b.D)(L,(function(e,t){return e})).join(", ")));var M=i(6660);class B extends h{static featureName=M.t;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(r,n,M.t,i),this.skipNext=0;try{this.removeOnAbort=new AbortController}catch(e){}const o=this;o.ee.on("fn-start",(function(e,t,r){o.abortHandler&&(o.skipNext+=1)})),o.ee.on("fn-err",(function(t,r,n){o.abortHandler&&!n[M.A]&&((0,I.X)(n,M.A,(function(){return!0})),this.thrown=!0,(0,s.p)("err",[n,(0,p.z)()],void 0,e.D.jserrors,o.ee))})),o.ee.on("fn-end",(function(){o.abortHandler&&!this.thrown&&o.skipNext>0&&(o.skipNext-=1)})),o.ee.on("internal-error",(function(t){(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,o.ee)})),this.origOnerror=c._A.onerror,c._A.onerror=this.onerrorHandler.bind(this),c._A.addEventListener("unhandledrejection",(t=>{const r=function(e){let t="Unhandled Promise Rejection: ";if(e instanceof Error)try{return e.message=t+e.message,e}catch(t){return e}if(void 0===e)return new Error(t);try{return new Error(t+(0,D.P)(e))}catch(e){return new Error(t)}}(t.reason);(0,s.p)("err",[r,(0,p.z)(),!1,{unhandledPromiseRejection:1}],void 0,e.D.jserrors,this.ee)}),(0,O.m$)(!1,this.removeOnAbort?.signal)),(0,k.gy)(this.ee),(0,k.BV)(this.ee),(0,k.em)(this.ee),(0,t.OP)(r).xhrWrappable&&(0,k.Kf)(this.ee),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}onerrorHandler(t,r,n,i,o){"function"==typeof this.origOnerror&&this.origOnerror(...arguments);try{this.skipNext?this.skipNext-=1:(0,s.p)("err",[o||new F(t,r,n),(0,p.z)()],void 0,e.D.jserrors,this.ee)}catch(t){try{(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,this.ee)}catch(e){}}return!1}}function F(e,t,r){this.message=e||"Uncaught error with no additional information",this.sourceURL=t,this.line=r}let U=1;const q="nr@id";function G(e){const t=typeof e;return!e||"object"!==t&&"function"!==t?-1:e===c._A?0:(0,I.X)(e,q,(function(){return U++}))}function V(e){if("string"==typeof e&&e.length)return e.length;if("object"==typeof e){if("undefined"!=typeof ArrayBuffer&&e instanceof ArrayBuffer&&e.byteLength)return e.byteLength;if("undefined"!=typeof Blob&&e instanceof Blob&&e.size)return e.size;if(!("undefined"!=typeof FormData&&e instanceof FormData))try{return(0,D.P)(e).length}catch(e){return}}}var X=i(7243);class W{constructor(e){this.agentIdentifier=e,this.generateTracePayload=this.generateTracePayload.bind(this),this.shouldGenerateTrace=this.shouldGenerateTrace.bind(this)}generateTracePayload(e){if(!this.shouldGenerateTrace(e))return null;var r=(0,t.DL)(this.agentIdentifier);if(!r)return null;var n=(r.accountID||"").toString()||null,i=(r.agentID||"").toString()||null,o=(r.trustKey||"").toString()||null;if(!n||!i)return null;var a=(0,_.M)(),s=(0,_.Ht)(),c=Date.now(),u={spanId:a,traceId:s,timestamp:c};return(e.sameOrigin||this.isAllowedOrigin(e)&&this.useTraceContextHeadersForCors())&&(u.traceContextParentHeader=this.generateTraceContextParentHeader(a,s),u.traceContextStateHeader=this.generateTraceContextStateHeader(a,c,n,i,o)),(e.sameOrigin&&!this.excludeNewrelicHeader()||!e.sameOrigin&&this.isAllowedOrigin(e)&&this.useNewrelicHeaderForCors())&&(u.newrelicHeader=this.generateTraceHeader(a,s,c,n,i,o)),u}generateTraceContextParentHeader(e,t){return"00-"+t+"-"+e+"-01"}generateTraceContextStateHeader(e,t,r,n,i){return i+"@nr=0-1-"+r+"-"+n+"-"+e+"----"+t}generateTraceHeader(e,t,r,n,i,o){if(!("function"==typeof c._A?.btoa))return null;var a={v:[0,1],d:{ty:"Browser",ac:n,ap:i,id:e,tr:t,ti:r}};return o&&n!==o&&(a.d.tk=o),btoa((0,D.P)(a))}shouldGenerateTrace(e){return this.isDtEnabled()&&this.isAllowedOrigin(e)}isAllowedOrigin(e){var r=!1,n={};if((0,t.Mt)(this.agentIdentifier,"distributed_tracing")&&(n=(0,t.P_)(this.agentIdentifier).distributed_tracing),e.sameOrigin)r=!0;else if(n.allowed_origins instanceof Array)for(var i=0;i 2&&void 0!==arguments[2])||arguments[2];super(r,n,Z.t,i),(0,t.OP)(r).xhrWrappable&&(this.dt=new W(r),this.handler=(e,t,r,n)=>(0,s.p)(e,t,r,n,this.ee),(0,k.u5)(this.ee),(0,k.Kf)(this.ee),function(r,n,i,o){function a(e){var t=this;t.totalCbs=0,t.called=0,t.cbTime=0,t.end=E,t.ended=!1,t.xhrGuids={},t.lastSize=null,t.loadCaptureCalled=!1,t.params=this.params||{},t.metrics=this.metrics||{},e.addEventListener("load",(function(r){_(t,e)}),(0,O.m$)(!1)),c.IF||e.addEventListener("progress",(function(e){t.lastSize=e.loaded}),(0,O.m$)(!1))}function s(e){this.params={method:e[0]},T(this,e[1]),this.metrics={}}function u(e,n){var i=(0,t.DL)(r);i.xpid&&this.sameOrigin&&n.setRequestHeader("X-NewRelic-ID",i.xpid);var a=o.generateTracePayload(this.parsedOrigin);if(a){var s=!1;a.newrelicHeader&&(n.setRequestHeader("newrelic",a.newrelicHeader),s=!0),a.traceContextParentHeader&&(n.setRequestHeader("traceparent",a.traceContextParentHeader),a.traceContextStateHeader&&n.setRequestHeader("tracestate",a.traceContextStateHeader),s=!0),s&&(this.dt=a)}}function d(e,t){var r=this.metrics,i=e[0],o=this;if(r&&i){var a=V(i);a&&(r.txSize=a)}this.startTime=(0,p.z)(),this.listener=function(e){try{"abort"!==e.type||o.loadCaptureCalled||(o.params.aborted=!0),("load"!==e.type||o.called===o.totalCbs&&(o.onloadCalled||"function"!=typeof t.onload)&&"function"==typeof o.end)&&o.end(t)}catch(e){try{n.emit("internal-error",[e])}catch(e){}}};for(var s=0;s 1?e[1]=i:e.push(i)}else e[0]&&e[0].headers&&s(e[0].headers,n)&&(this.dt=n);function s(e,t){var r=!1;return t.newrelicHeader&&(e.set("newrelic",t.newrelicHeader),r=!0),t.traceContextParentHeader&&(e.set("traceparent",t.traceContextParentHeader),t.traceContextStateHeader&&e.set("tracestate",t.traceContextStateHeader),r=!0),r}}function x(e,t){this.params={},this.metrics={},this.startTime=(0,p.z)(),this.dt=t,e.length>=1&&(this.target=e[0]),e.length>=2&&(this.opts=e[1]);var r,n=this.opts||{},i=this.target;"string"==typeof i?r=i:"object"==typeof i&&i instanceof Y?r=i.url:c._A?.URL&&"object"==typeof i&&i instanceof URL&&(r=i.href),T(this,r);var o=(""+(i&&i instanceof Y&&i.method||n.method||"GET")).toUpperCase();this.params.method=o,this.txSize=V(n.body)||0}function A(t,r){var n;this.endTime=(0,p.z)(),this.params||(this.params={}),this.params.status=r?r.status:0,"string"==typeof this.rxSize&&this.rxSize.length>0&&(n=+this.rxSize);var o={txSize:this.txSize,rxSize:n,duration:(0,p.z)()-this.startTime};i("xhr",[this.params,o,this.startTime,this.endTime,"fetch"],this,e.D.ajax)}function E(t){var r=this.params,n=this.metrics;if(!this.ended){this.ended=!0;for(var o=0;o 2&&void 0!==arguments[2])||arguments[2];super(e,t,we.t,r),this.importAggregator()}}new class{constructor(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:(0,_.ky)(16);c._A?(this.agentIdentifier=t,this.sharedAggregator=new y({agentIdentifier:this.agentIdentifier}),this.features={},this.desiredFeatures=new Set(e.features||[]),this.desiredFeatures.add(m),Object.assign(this,(0,a.j)(this.agentIdentifier,e,e.loaderType||"agent")),this.start()):(0,l.Z)("Failed to initial the agent. Could not determine the runtime environment.")}get config(){return{info:(0,t.C5)(this.agentIdentifier),init:(0,t.P_)(this.agentIdentifier),loader_config:(0,t.DL)(this.agentIdentifier),runtime:(0,t.OP)(this.agentIdentifier)}}start(){const t="features";try{const r=n(this.agentIdentifier),i=[...this.desiredFeatures];i.sort(((t,r)=>e.p[t.featureName]-e.p[r.featureName])),i.forEach((t=>{if(r[t.featureName]||t.featureName===e.D.pageViewEvent){const n=function(t){switch(t){case e.D.ajax:return[e.D.jserrors];case e.D.sessionTrace:return[e.D.ajax,e.D.pageViewEvent];case e.D.sessionReplay:return[e.D.sessionTrace];case e.D.pageViewTiming:return[e.D.pageViewEvent];default:return[]}}(t.featureName);n.every((e=>r[e]))||(0,l.Z)("".concat(t.featureName," is enabled but one or more dependent features has been disabled (").concat((0,D.P)(n),"). This may cause unintended consequences or missing data...")),this.features[t.featureName]=new t(this.agentIdentifier,this.sharedAggregator)}})),(0,T.Qy)(this.agentIdentifier,this.features,t)}catch(e){(0,l.Z)("Failed to initialize all enabled instrument classes (agent aborted) -",e);for(const e in this.features)this.features[e].abortHandler?.();const r=(0,T.fP)();return delete r.initializedAgents[this.agentIdentifier]?.api,delete r.initializedAgents[this.agentIdentifier]?.[t],delete this.sharedAggregator,r.ee?.abort(),delete r.ee?.get(this.agentIdentifier),!1}}}({features:[J,m,S,class extends h{static featureName=oe;constructor(t,r){if(super(t,r,oe,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;const n=this.ee;let i;(0,k.QU)(n),this.eventsEE=(0,k.em)(n),this.eventsEE.on(se,(function(e,t){this.bstStart=(0,p.z)()})),this.eventsEE.on(ae,(function(t,r){(0,s.p)("bst",[t[0],r,this.bstStart,(0,p.z)()],void 0,e.D.sessionTrace,n)})),n.on(ce+ne,(function(e){this.time=(0,p.z)(),this.startPath=location.pathname+location.hash})),n.on(ce+ie,(function(t){(0,s.p)("bstHist",[location.pathname+location.hash,this.startPath,this.time],void 0,e.D.sessionTrace,n)}));try{i=new PerformanceObserver((t=>{const r=t.getEntries();(0,s.p)(te,[r],void 0,e.D.sessionTrace,n)})),i.observe({type:re,buffered:!0})}catch(e){}this.importAggregator({resourceObserver:i})}},C,xe,B,class extends h{static featureName=de;constructor(e,r){if(super(e,r,de,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;if(!(0,t.OP)(e).xhrWrappable)return;try{this.removeOnAbort=new AbortController}catch(e){}let n,i=0;const o=this.ee.get("tracer"),a=(0,k._L)(this.ee),s=(0,k.Lg)(this.ee),u=(0,k.BV)(this.ee),d=(0,k.Kf)(this.ee),f=this.ee.get("events"),l=(0,k.u5)(this.ee),h=(0,k.QU)(this.ee),g=(0,k.Gm)(this.ee);function m(e,t){h.emit("newURL",[""+window.location,t])}function v(){i++,n=window.location.hash,this[ve]=(0,p.z)()}function b(){i--,window.location.hash!==n&&m(0,!0);var e=(0,p.z)();this[pe]=~~this[pe]+e-this[ve],this[ye]=e}function y(e,t){e.on(t,(function(){this[t]=(0,p.z)()}))}this.ee.on(ve,v),s.on(be,v),a.on(be,v),this.ee.on(ye,b),s.on(ge,b),a.on(ge,b),this.ee.buffer([ve,ye,"xhr-resolved"],this.featureName),f.buffer([ve],this.featureName),u.buffer(["setTimeout"+le,"clearTimeout"+fe,ve],this.featureName),d.buffer([ve,"new-xhr","send-xhr"+fe],this.featureName),l.buffer([me+fe,me+"-done",me+he+fe,me+he+le],this.featureName),h.buffer(["newURL"],this.featureName),g.buffer([ve],this.featureName),s.buffer(["propagate",be,ge,"executor-err","resolve"+fe],this.featureName),o.buffer([ve,"no-"+ve],this.featureName),a.buffer(["new-jsonp","cb-start","jsonp-error","jsonp-end"],this.featureName),y(l,me+fe),y(l,me+"-done"),y(a,"new-jsonp"),y(a,"jsonp-end"),y(a,"cb-start"),h.on("pushState-end",m),h.on("replaceState-end",m),window.addEventListener("hashchange",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("load",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("popstate",(function(){m(0,i>1)}),(0,O.m$)(!0,this.removeOnAbort?.signal)),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}}],loaderType:"spa"})})(),window.NRBA=o})(); window.jQuery || document.write(' ') CKEDITOR_BASEPATH='https://f1000research.com/js/vendor/ckeditor/' window.reactTheme = 'research'; window.MathJax = { CommonHTML: { linebreaks: { automatic: true } }, 'HTML-CSS': { linebreaks: { automatic: true } }, SVG: { linebreaks: { automatic: true } }, AuthorInit: function() { MathJax.Hub.Register.MessageHook('End Process', function () { let timeout = false; // holder for timeout id const delay = 250; // delay after event is "complete" to run callback const reflowMath = function() { const dispFormulas = document.querySelectorAll('.disp-formula.panel'); if (!dispFormulas) { return; } for (const dispFormula of dispFormulas) { const child = dispFormula.querySelector('.MathJax_Preview').nextSibling.firstChild; const isMultiline = MathJax.Hub.getAllJax(dispFormula)[0].root.isMultiline; if (dispFormula.offsetWidth < child.offsetWidth || isMultiline) { MathJax.Hub.Queue(['Rerender', MathJax.Hub, dispFormula]); } } }; window.addEventListener('resize', function() { clearTimeout(timeout); // clear the timeout timeout = setTimeout(reflowMath, delay); // start timing for event "completion" }); }); }, }; if (window.location.hash == '#_=_'){ window.location = window.location.href.split('#')[0] } !function(f,b,e,v,n,t,s){if(f.fbq)return;n=f.fbq=function() {n.callMethod? n.callMethod.apply(n,arguments):n.queue.push(arguments)} ;if(!f._fbq)f._fbq=n; n.push=n;n.loaded=!0;n.version='2.0';n.queue=[];t=b.createElement(e);t.async=!0; t.src=v;s=b.getElementsByTagName(e)[0];s.parentNode.insertBefore(t,s)}(window, document,'script','https://connect.facebook.net/en_US/fbevents.js'); fbq('init', '1641728616063202'); fbq('track', "PixelInitialized", {}); (function(h,o,t,j,a,r){ h.hj=h.hj||function(){(h.hj.q=h.hj.q||[]).push(arguments)}; h._hjSettings={hjid:2318163,hjsv:6}; a=o.getElementsByTagName('head')[0]; r=o.createElement('script');r.async=1; r.src=t+h._hjSettings.hjid+j+h._hjSettings.hjsv; a.appendChild(r); })(window,document,'https://static.hotjar.com/c/hotjar-','.js?sv='); search file_upload Submit your research search menu close search Browse Gateways & Collections How to Publish Submit your Research My Submissions Article Guidelines Article Guidelines (New Versions) Open Data, Software and Code Guidelines Open Data and Accessible Source Materials Guidelines (HSS) Open Data, Software and Code Guidelines (PSE) Prepublication Checks Production Process Posters and Slides Guidelines Document Guidelines Article Processing Charges Peer Review Finding Article Reviewers About How it Works For Reviewers Our Advisors Policies Glossary FAQs For Developers Newsroom Contact My Research Submissions Content and Tracking Alerts My Details Sign In file_upload Submit your research { "@context": "https://schema.org", "@type": "ScholarlyArticle", "mainEntityOfPage": { "@type": "WebPage", "@id": "https://f1000research.com/articles/9-697" }, "headline": "Recent advances in managing axial spondyloarthritis", "datePublished": "2020-07-13T11:41:01", "dateModified": "2020-07-13T11:41:01", "author": [ { "@type": "Person", "name": "Priyanka Agrawal" }, { "@type": "Person", "name": "Pedro M. Machado" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": "Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease that predominantly affects the axial skeleton. The advent of biologic drugs has transformed the management of patients with axSpA. However, non-steroidal anti-inflammatory drugs remain the first-line drug treatment for axSpA. The optimal management of patients with axSpA requires a combination of pharmacological and non-pharmacological treatment modalities, namely exercise and physical therapy. This review looks at novel therapeutic options in patients with axSpA. It also summarises current evidence regarding radiographic progression and treat-to-target in axSpA." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/9-697/v1", "name": "Recent advances in managing axial spondyloarthritis" } } ] } Home Browse Recent advances in managing axial spondyloarthritis ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Agrawal P and Machado PM. Recent advances in managing axial spondyloarthritis [version 1; peer review: 2 approved] . F1000Research 2020, 9 (Faculty Rev):697 ( https://doi.org/10.12688/f1000research.22577.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Review Recent advances in managing axial spondyloarthritis [version 1; peer review: 2 approved] Priyanka Agrawal 1 , Pedro M. Machado 1-3 Priyanka Agrawal 1 , Pedro M. Machado 1-3 PUBLISHED 13 Jul 2020 Author details Author details 1 Department of Rheumatology, Northwick Park Hospital NHS Trust, London, UK 2 Department of Rheumatology, University College London Hospitals NHS Foundation Trust, London, UK 3 Centre for Rheumatology, Division of Medicine & Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK Priyanka Agrawal Roles: Writing – Original Draft Preparation Pedro M. Machado Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease that predominantly affects the axial skeleton. The advent of biologic drugs has transformed the management of patients with axSpA. However, non-steroidal anti-inflammatory drugs remain the first-line drug treatment for axSpA. The optimal management of patients with axSpA requires a combination of pharmacological and non-pharmacological treatment modalities, namely exercise and physical therapy. This review looks at novel therapeutic options in patients with axSpA. It also summarises current evidence regarding radiographic progression and treat-to-target in axSpA. READ ALL READ LESS Keywords Axial spondyloartrhitis, ankylosing spondylitis, treatment, management, biologics, outcomes. Corresponding Author(s) Pedro M. Machado ( [email protected] ) Close Corresponding author: Pedro M. Machado Competing interests: PMM has received consulting/speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB. PA declares that she has no competing interests. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2020 Agrawal P and Machado PM. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Agrawal P and Machado PM. Recent advances in managing axial spondyloarthritis [version 1; peer review: 2 approved] . F1000Research 2020, 9 (Faculty Rev):697 ( https://doi.org/10.12688/f1000research.22577.1 ) First published: 13 Jul 2020, 9 (Faculty Rev):697 ( https://doi.org/10.12688/f1000research.22577.1 ) Latest published: 13 Jul 2020, 9 (Faculty Rev):697 ( https://doi.org/10.12688/f1000research.22577.1 ) Introduction Axial spondyloarthritis (axSpA) belongs to a clinically heterogeneous group of inflammatory rheumatic diseases that share common genetic, histological, and clinical features. It encompasses ankylosing spondylitis (AS) (or radiographic axSpA [r-axSpA]) and non-radiographic axSpA (nr-axSpA) 1 . Over the last couple of decades, we have witnessed remarkable advances in the pathogenesis, management and treatment of axSpA. The discovery of anti-tumour necrosis factor (anti-TNF) has revolutionised the treatment of this chronic condition. More recently, interleukin-17 (IL-17) has been discovered as an alternative therapeutic target and there is promise from small molecules such as Janus kinase (JAK) inhibitors 2 . In this article, we shall discuss the management of axSpA with a primary focus on the recent advances. We shall review potential new biologics on the horizon. We shall also consider the use of biosimilars, radiographic progression in axSpA and the controversy surrounding the treat-to-target (T2T) approach. Management of axial spondyloarthritis AxSpA can interfere with patients’ daily activities, including schooling, work, and social life 3 , 4 . The goals of treatment are to reduce disease activity (signs and symptoms), to prevent disability and structural damage, and to maintain work productivity, health-related quality of life, and social participation 5 . Non-steroidal anti-inflammatory drugs (NSAIDs) and physical therapy remain the mainstays of treatment of axSpA. The Assessment of Spondylarthritis International Society (ASAS) and European League Against Rheumatism (EULAR) (2016 update) recommend that patients with pain and stiffness should use an NSAID as first-line drug treatment up to the maximum dose while taking risks and benefits into account. For patients who respond well to NSAIDs, continuous use of this medication is preferred in case on-demand use results in worsening of symptoms 6 . The 2019 American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network (ACR/SAA/SPARTAN) recommendations similarly advise that adults with active axSpA receive continuous NSAIDs over on-demand NSAIDs. However, in adults with stable axSpA, on-demand treatment with NSAIDs is recommended over continuous treatment 5 . There is controversy regarding the role of NSAIDs in preventing radiographic progression in axSpA. Slower radiographic progression was observed in AS patients taking celecoxib continuously (that is, daily) for a 2-year period, compared with patients taking it on demand, in a study by Wanders et al . 7 . A post-hoc analysis of this study showed that this effect was more pronounced in patients with elevated acute-phase reactants or in patients with a high or very high Ankylosing Spondylitis Disease Activity Score (ASDAS), which includes C-reactive protein (CRP) as one of the variables 8 . However, this inhibitory effect on new bone formation in the spine of patients with AS was not observed in a more recent randomised multicentre trial (ENRADAS) comparing continuous diclofenac intake over the course of 2 years versus on-demand treatment 9 . Conversely, a 2-year observational study in patients with AS showed a reduction in the progression of structural damage of the spine of patients with a high NSAID intake compared with those with a low NSAID intake. This protective effect was seen nearly exclusively in patients with syndesmophytes and elevated CRP at baseline 10 . More recently, it was suggested that continuous use of NSAIDs reduces radiographic progression in sacroiliac joints in patients with early axSpA 11 . Non-pharmacological treatment modalities are important in the management of patients with axSpA. ASAS-EULAR recommend that patients should be educated about axSpA and encouraged to exercise on a regular basis and stop smoking; physical therapy should be considered 6 . The inclusion of aerobic components, cardiorespiratory exercises, and educational programs in traditional programs of exercises may lead to improved clinical outcomes, although the most effective exercise protocol remains unclear 12 . Promising effects of cardiorespiratory and strength exercises on emotional distress, fatigue, and ability to do a full day’s activities were shown in a small pilot Scandinavian study in patients with axSpA 13 . Biologics in the treatment of axial spondyloarthritis Until very recently there were five licensed anti-TNF drugs (adalimumab, certolizumab, etanercept, golimumab and infliximab) for the indication of AS and four (adalimumab, etanercept, certolizumab and golimumab) for the indication of nr-axSpA (in the US, only certolizumab was approved for the indication of nr-axSpA). The IL-17 blocker secukinumab has been approved by both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the indication of AS. Ixekizumab was initially (2019) approved by the FDA for AS, and in July 2020, the FDA expanded the approval of ixekizumab to include nr-axSpA; almost simultaneously, the EMA also approved ixekizumab for the treatment of both AS and nr-axSpA. ASAS-EULAR-recommended disease activity cutoffs to start anti-TNF treatment are either a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of at least 4 or an ASDAS of at least 2.1 after treatment with two different NSAIDs for at least 4 weeks in total 6 . British Society of Rheumatology (BSR) and British Health Professionals in Rheumatology recommendations 14 define high disease activity as BASDAI and spinal pain visual analogue scale (VAS) scores of at least 4. According to the BSR, BASDAI and VAS scores should be measured on two occasions at least 4 weeks apart and patients need to have failed two NSAIDs for at least 2 weeks each unless contraindicated. The 2019 ACR-SAA-SPARTAN recommendations also advise anti-TNF drugs in patients with axSpA when activity persists despite NSAID treatment. Anti-TNF monoclonal antibodies should be preferred in patients with concomitant inflammatory bowel disease (IBD) or recurrent iritis. According to these recommendations, IL-17 blockers are advised for patients with active disease who have heart failure or demyelinating disease as a contraindication to anti-TNF and in primary non-responders to anti-TNF. Secukinumab and ixekizumab are not recommended in patients with IBD or recurrent uveitis. In the 2019 ACR-SAA-SPARTAN recommendations, tofacitinib, a JAK inhibitor currently not approved for axSpA, is highlighted as a potential second-line option for patients with contraindications to a TNF inhibitor (TNFi) other than infections. Recommendations regarding tofacitinib may change pending the results of larger clinical trials 5 . Owing to the likelihood for symptom recurrence, discontinuation of biologics is not recommended by ACR-SAA-SPARTAN. If tapering is considered, patients should be counselled regarding the potential for increased disease activity 5 . In Table 1 , an overview of biological disease-modifying anti-rheumatic drugs (DMARDs) and targeted synthetic DMARDs in axSpa and related chronic inflammatory conditions is presented. Table 1. Overview of biological disease-modifying anti-rheumatic drugs (DMARDs) and targeted synthetic DMARDs in axial spondyloarthritis and related chronic inflammatory conditions. Target Drug Axial spondyloarthritis Psoriatic arthritis Psoriasis Crohn’s disease Rheumatoid arthritis Uveitis TNF Adalimumab (mAb to TNF) Certolizumab (mAb to TNF) Etanercept (fusion protein against TNF) Golimumab (mAb to TNF) Infliximab (mAb to TNF) IL-1 Anakinra (IL-1R antagonist) B cells Rituximab (mAb to CD20) T cells Abatacept (inhibitor of T-cell co- stimulation) IL-6 Tocilizumab (mAb to IL-6R) Sarilumab (mAb to IL-6R) IL-17 Secukinumab (mAb to IL-17A) Ixekizumab (mAb to IL-17A) Brodalumab (mAb to IL-17R) Bimekizumab (mAb to IL-17A and IL-17F) Netakimab/BCD-085 (mAb to IL-17R) IL-12 and IL-23 Ustekinumab (mAb to IL-12/23p40) Guselkumab (mAb to IL-23p19) Tildrakizumab (mAb to IL23p19) Risankizumab (mAb to IL23p19) PDE4 Apremilast (PDE4 inhibitor) JAK Tofacitinib (JAK1/3 inhibitor) Filgotinib (JAK1 inhibitor) Upadacitinib (JAK1 inhibitor) GM-CSF Namilumab (mAB to GM-CSF) Key: Efficacy shown in at least one randomised controlled trial Some data from pilot or proof-of-concept trials suggest a positive effect Some data from pilot or proof-of-concept trials suggest a lack of effect Lack of efficacy shown in at least one randomised controlled trial No conclusive data available about efficacy GM-CSF, granulocyte macrophage-colony-stimulating factor; IL, interleukin; JAK, Janus kinase; mAb, monoclonal antibody; PDE4, phosphodiesterase 4; TNF, tumour necrosis factor Biologic drugs that have recently shown efficacy The efficacy of ixekizumab, a high-affinity monoclonal antibody (mAb) against IL-17A, has been demonstrated in both biologic-naïve and TNFi-experienced patients with r-axSpA (NCT02696785 and NCT02696798) 15 – 17 . More recently, the first study demonstrating the efficacy of ixekizumab in nr-axSpA was also published 18 . Positive secukinumab (NCT02696031) data in nr-axSpA were also recently presented in abstract form, but the manuscript has yet to be published 19 . Bimekizumab, a mAb that potently and selectively neutralises both IL-17A and IL-17F, has demonstrated substantial improvements in both musculoskeletal and skin outcomes 20 . Brodalumab, a human anti-IL-17 receptor A mAb has also demonstrated efficacy in phase 3 studies in both AS and nr-axSpA 21 . The bimekizumab and brodalumab studies have been published in abstract form only. Netakimab/BCD-085, a humanised mAb against IL-17 with genetically modified Fc- and CDR-regions, has shown efficacy in active AS in a dose-finding phase 2 clinical trial (abstract publication 22 ). JAK inhibitors are emerging as an effective therapeutic approach in patients with axSpA. Both tofacitinib (JAK1–3 inhibitor) and filgotinib (selective JAK1 inhibitor) have shown efficacy and safety in phase 2 placebo-controlled trials of patients with AS. Tofacitinib was superior to placebo in reducing signs, symptoms and objective endpoints of patients with active AS and had a safety profile similar to what has been reported in the literature 23 . More recently, van der Heijde et al . showed that filgotinib was efficacious and safe for patients with active AS and inadequate response or intolerance to NSAIDs 24 . Therefore, further investigation of filgotinib in AS is warranted 24 (NCT03117270). Finally, results of the first randomised trial of upadacitinib (selective JAK1 inhibitor) versus placebo in patients with AS were recently published; upadacitinib was efficacious and well tolerated in patients with active AS who had not responded to or had a contraindication to treatment with NSAIDs. These data support further investigation of upadacitinib for the treatment of axSpA 25 . Biologic drugs that have not shown efficacy Uncontrolled or controlled trials with anakinra (IL-1 blocker) 26 , 27 , abatacept (inhibitor of T-cell co-stimulation) 28 , rituximab (B-cell depletion agent) 29 , 30 and tocilizumab (IL-6 blocker) 31 , 32 have shown no consistent efficacy in patients with AS. Of note, conventional synthetic DMARDs have also failed to show efficacy in axial disease. Apremilast is a small-molecule inhibitor of phosphodiesterase 4 (PDE4) that modulates the inflammatory response. In a small (n = 38), 12-week, double-blind, placebo-controlled, phase 2 study of symptomatic AS patients with positive magnetic resonance imaging (MRI) 33 , apremilast did not meet its primary endpoint (change in BASDAI score at week 12) but was associated with numerically greater improvement in all clinical assessments compared with placebo. A subsequent double-blind, placebo-controlled, phase 3 study assessing the efficacy and safety of apremilast in active AS was completed (NCT01583374). Preliminary online reports suggest that this was a negative study (primary endpoint not met: ASAS20 at week 16) (source: NCT01583374). This study has not been published yet. In a randomised, double-blind, placebo-controlled, dose-finding phase 2 study, treatment with risankizumab (a humanised mAb targeting IL-23A) did not show evidence of clinically meaningful improvements compared with placebo in patients with active AS; the primary endpoint, ASAS40 response at week 12, was not met. This study suggested that despite a genetic association with the IL-23 pathway, IL-23 may not be a relevant driver of disease pathogenesis and clinical manifestations in AS (NCT02047110) 34 . In three placebo-controlled trials, the efficacy of ustekinumab (an anti-IL-12/23 antibody) in the treatment of axial SpA was not demonstrated. The safety profile was consistent with that of studies in other indications 35 (NCT02437162, NCT02438787 and NCT02407223). Siebert et al . recently published an editorial on the reasons for failure of IL-23p19 inhibition in AS 36 . The authors hypothesise that established AS may have “transitioned pathogenetically” to a mature type 17 phenotype, making it unresponsive to IL-23p19 blockade and other upstream treatment strategies, such as IL-6 inhibition, that would normally modulate the IL-17 response 36 . Therefore, neutralising upstream molecules would be less effective than specifically targeting IL-17A. Furthermore, other effector pathologic pathways driving the IL-17 response are probably still unknown and need to be identified 36 . In Table 2 , ongoing axSpA drug trials are presented. Table 2. Ongoing clinical trials in axial spondyloarthritis. Drug Mechanism of action Study design Patient group Trial number Secukinumab (intravenous) Human monoclonal IgG1 kappa antibody against IL-17 Phase 3, multicentre, DB RCT axSpA NCT04156620 Ixekizumab Humanised mAb against IL-17A Long Term Extension Study of a Phase 3, multicentre, DB RCT axSpA NCT03129100 Brodalumab Human mAb that binds to the IL-17 receptor Phase 3, multicentre, DB RCT axSpA NCT02985983 Bimekizumab Humanised monoclonal IgG1 antibody against IL-7A and IL-17F Phase 3, multicentre, DB RCT r-axSpA nr-axSpA NCT03928743 NCT03928704 Tildrakizumab Human mAb against IL-23 Phase 3, multicentre, open label, non-randomised axSpA NCT03552276 Netakimab/BCD-085 Humanised mAb against IL-17 with genetically modified Fc- and CDR-regions Phase 3, multicentre, DB RCT r-axSpA NCT03447704 Upadacitinib JAK1 selective inhibitor Phase 3, DB RCT axSpA NCT04169373 Namilumab Human monoclonal IgG1 kappa antibody against GM-CSF Phase 2a, proof-of-concept, DB RCT axSpA NCT03622658 axSpA, axial spondyloarthritis; DB RCT, Double-Blind Placebo-Controlled Randomised Clinical Trial; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; mAb, monoclonal antibody; nr-axSpA, non-radiographic axial spondyloarthritis; r-axSpA, radiographic axial spondyloarthritis Biosimilars The World Health Organization has defined a “similar biotherapeutic product” (also called “biosimilar”) as a biotherapeutic product that is similar in terms of quality, safety and efficacy to an already licensed original or “reference biotherapeutic product” (also called “originator” drug) 37 . In adults with stable AS receiving an originator anti-TNF, ACR-SAA-SPARTAN strongly recommends continuing treatment with the originator anti-TNF over mandated switching to its biosimilar 5 . The BSR published a position statement 38 on the use of biosimilars in clinical practice. The key principles of this document are that (1) all biologics and biosimilars should be prescribed by brand name rather than by international non-proprietary name, (2) clinical effectiveness and patient safety should be the overriding principles for prescribing any biologic agent, (3) substitution should be done only with the consent of the prescribing clinician, (4) decisions should be made in partnership with the patients, and (5) registration with the BSR Biologic Registers or other appropriate UK register is recommended. Therefore, switching should be based on a shared decision-making process between patients and rheumatologists, should be a clinically informed decision not made solely for economic reasons, and should take contextual factors of the health-care system into account 39 . Biosimilars are now often prescribed as the first biologic drug treatment, and many patients have been successfully switched from originator drugs to the biosimilar. They have resulted in substantial savings on the use of biologic therapy, providing greater accessibility to patients. There are now biosimilars for adalimumab (Amgevita, Cyltezo, Hyrimoz and Imraldi), etanercept (Benepali, Erelzi and Eticovo) and infliximab (Inflectra, Ixifi, Remicade, Remsima and Renflexis) and many more being produced/tested. Role of biologics in the inhibition of radiographic progression The clinical efficacy of biologics in axSpA has been robustly demonstrated. However, it is still unclear whether they can prevent the progression of structural damage, particularly new bone formation. There are also methodological challenges that have contributed to this uncertainty, namely the fact that radiographic progression is a slow process that requires at least 2 years in order to be reliably detected and the ethical impossibility of performing a comparative study with a 2-year placebo arm (given the known clinical efficacy of biologics in patients who do not respond to conventional treatments) 2 . Importantly, radiographic progression is a heterogeneous process that varies significantly not only between patients but also within the same patient (bursts of radiographic progression can be followed by periods of a relatively low rate of progression or even no progression). Some risk factors for radiographic progression have been identified: the presence of syndesmophytes (the strongest risk factor; previous damage predicts further damage), male gender, HLA-B27 positivity, long disease/symptom duration, high CRP, MRI activity, high disease activity and smoking. It is hypothesised that more intensive T2T approaches might contribute to decreasing the rate of radiographic progression, particularly in high-risk groups 40 . Karmacharya et al . 40 recently undertook a systematic review and meta-analysis on the effect of different therapies on radiographic progression in axSpA and suggested a protective effect of TNFi treatment on spinal radiographic progression of AS after at least 4 years of treatment in studies with low risk of bias. Observational data therefore suggest that anti-TNF treatment might prevent new bone formation in axSpA. Regarding NSAIDs (also discussed above) and secukinumab, only data up to 2 years were available, and no effect was found. SURPASS is an ongoing trial comparing the effect of secukinumab on radiographic progression in AS as compared with an adalimumab biosimilar 41 . The primary endpoint of this first head-to-head, phase 3b, randomised, biologic-controlled study is “the absence of progression as measured by the modified Stoke Ankylosing Spondylitis Spine Score” 41 . Hopefully, this study will give us more information regarding the comparative structural efficacy of TNF blockers versus IL-17 blockers, thus contributing to evidence-based decision-making. Treat-to-target approach The concept of T2T strategies is well founded in the management of chronic diseases that have a well-defined and usually very objective measure that is highly associated with future health outcomes and evidence that maintaining the levels of this measure below a certain threshold will lead to better long-term health 42 . The T2T approach in axSpA is indirectly supported by associations between levels of axSpA disease activity (particularly ASDAS) and future radiographic progression but lacks robust direct evidence. The 2019 ACR-SAA-SPARTAN recommendations mention that “focus on a specific target could lead to rapid cycling through all currently available treatments in some patients” 5 . The 2016 update of the ASAS/EULAR recommendations for the management of axSpA recommends that “treatment should be guided according to a predefined treatment target” but controversy remains as to what this target should be 6 . Importantly, this document also states that “the target should be a shared decision between patient and rheumatologist, taking all relevant situational factors into consideration” 6 . However, data from a randomised controlled trial comparing the efficacy of a T2T approach versus standard of care in axSpA are still lacking. Furthermore, the cost effectiveness of a T2T strategy in clinical practice will require testing 43 . The 2017 international task force update of recommendations on T2T in axSpA and psoriatic arthritis 44 advises that the treatment target should be clinical remission/inactive disease of musculoskeletal (arthritis, dactylitis, enthesitis and axial disease) and extra-articular manifestations. In axSpA, the ASDAS is a preferred measure to define the target. The Tight Control in Spondyloarthritis (TICOSPA) study is a prospective, randomised (cluster) study to evaluate the potential benefit of a T2T approach in comparison with standard of care in patients with axSpA (TICOSPA, NCT03043846). Results from this study were presented in June at the EULAR 2020 conference (THU0370); the authors reported that usual care resulted in a good outcome in a substantial number of patients but the tight control and treat-to-target strategy was not superior for the primary outcome (ASAS Health Index) despite a greater number of bDMARDs prescription; nevertheless, a general trend in favour of the tight control arm was observed, with a comparable safety profile, and was found to be favourable from a societal health economic perspective. A German 1-year randomised controlled study taking an intense treatment approach versus routine treatment (STRIKE, NCT02897115) was prematurely terminated because of slow recruitment. Another phase 3 clinical trial, the Treat-to-target in Axial Spondyloarthritis (AScalate) study, is currently recruiting and is a randomised, open-label multicentre trial to investigate the efficacy of a T2T treatment strategy with secukinumab as a first-line biologic compared with a standard-of-care treatment over 36 weeks in patients with active axSpA (NCT03906136). A phase 4 trial, the Treat-to-target With Secukinumab in Axial Spondyloarthritis (TRACE) study, is also looking at T2T with secukinumab in axSpA (NCT03639740). Conclusions With so many new biologics on the horizon, the future looks promising for managing patients with axSpA. However, there is an unmet need for results from head-to-head studies directly comparing the efficacy and safety of different biologics in axSpA. This would help determine the optimal sequencing of treatments. There are limitations in using disease activity scores and radiographic progression as markers of treatment response and hence research into suitable biomarkers needs to be undertaken. Acknowledgements PMM is supported by the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the National Health Service (UK), the NIHR or the Department of Health (UK). Faculty Opinions recommended References 1. Dubash S, McGonagle D, Marzo-Ortega H: New advances in the understanding and treatment of axial spondyloarthritis: From chance to choice. Ther Adv Chronic Dis. 2018; 9 (3): 77–87. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 2. Jones A, Ciurtin C, Ismajli M, et al. : Biologics for treating axial spondyloarthritis. Expert Opin Biol Ther. 2018; 18 (6): 641–52. PubMed Abstract | Publisher Full Text 3. Boonen A, Sieper J, van der Heijde D, et al. : The burden of non-radiographic axial spondyloarthritis. Semin Arthritis Rheum. 2015; 44 (5): 556–62. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 4. Ward MM: Quality of life in patients with ankylosing spondylitis. Rheum Dis Clin North Am. 1998; 24 (4): 815–27. PubMed Abstract 5. Ward MM, Deodhar A, Gensler LS, et al. : 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Care Res (Hoboken). 2019; 71 (10): 1285–99. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 6. van der Heijde D, Ramiro S, Landewé R, et al. : 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017; 76 (6): 978–91. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 7. Wanders A, van der Heijde D, Landewé R, et al. : Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: A randomized clinical trial. Arthritis Rheum. 2005; 52 (6): 1756–65. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 8. Kroon F, Landewé R, Dougados M, et al. : Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis. Ann Rheum Dis. 2012; 71 (10): 1623–9. PubMed Abstract | Publisher Full Text 9. Sieper J, Listing J, Poddubnyy D, et al. : Effect of continuous versus on-demand treatment of ankylosing spondylitis with diclofenac over 2 years on radiographic progression of the spine: Results from a randomised multicentre trial (ENRADAS). Ann Rheum Dis. 2016; 75 (8): 1438–43. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 10. Poddubnyy D, Rudwaleit M, Haibel H, et al. : Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: Results from the German Spondyloarthritis Inception Cohort. Ann Rheum Dis. 2012; 71 (10): 1616–22. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 11. Rumiantceva D, Dubinina T, Rumyantseva O, et al. : SAT0278 Nsaids reduces radiographic progression in sacloiliac joints in early axial spondyloarthritis. Ann Rheum Dis. 2018; 77 (Suppl 2): 1003. Publisher Full Text 12. Perrotta FM, Musto A, Lubrano E: New Insights in Physical Therapy and Rehabilitation in Axial Spondyloarthritis: A Review. Rheumatol Ther. 2019; 6 (4): 479–86. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 13. Sveaas SH, Berg IJ, Fongen C, et al. : High-intensity cardiorespiratory and strength exercises reduced emotional distress and fatigue in patients with axial spondyloarthritis: A randomized controlled pilot study. Scand J Rheumatol. 2018; 47 (2): 117–21. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 14. Hamilton L, Barkham N, Bhalla A, et al. : BSR and BHPR guideline for the treatment of axial spondyloarthritis (including ankylosing spondylitis) with biologics. Rheumatology (Oxford). 2017; 56 (2): 313–6. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 15. van der Heijde D, Cheng-Chung Wei J, Dougados M, et al. : Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. 2018; 392 (10163): 2441–51. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 16. Deodhar A, Poddubnyy D, Pacheco-Tena C, et al. : Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis: Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo-Controlled Trial in Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol. 2019; 71 (4): 599–611. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 17. Dougados M, Wei JCC, Landewé R, et al. : Efficacy and safety of ixekizumab through 52 weeks in two phase 3, randomised, controlled clinical trials in patients with active radiographic axial spondyloarthritis (COAST-V and COAST-W). Ann Rheum Dis. 2020; 79 (2): 176–85. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 18. Deodhar A, van der Heijde D, Gensler LS, et al. : Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): A randomised, placebo-controlled trial. Lancet. 2020; 395 (10217): 53–64. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 19. Deodhar A, Blanco R, Dokoupilova E, et al. : Secukinumab 150 mg Significantly Improved Signs and Symptoms of Non-radiographic Axial Spondyloarthritis: Results from a Phase 3 Double-blind, Randomized, Placebo-controlled Study [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). Accessed November 26. Reference Source 20. Ritchlin CT, Kavanaugh A, Merola JF, et al. : Dual Neutralization of IL-17A and IL-17F with Bimekizumab in Patients with Active, Psa: Results from a 48-Week Phase 2b, Randomized, Double Blind, Placebo-Controlled, Dose- Ranging Study. Abstr Arthritis Rheumatol. 2018; 70 (suppl 1). Reference Source 21. Wei JCC, et al. : OP0234 Efficacy and safety of Brodalumab, an anti-interleukin-17 receptor A monoclonal antibody, in patients with axial spondyloarthritis: a 16 week results of a phase 3, multicenter, randomized, double-blind, placebo-controlled study. In Oral Presentations . Annals of the Rheumatic Diseases. 2019; 78 (Suppl 2): 195.1–195 (BMJ Publishing Group Ltd and European League Against Rheumatism). Publisher Full Text 22. Mazurov V, Erdes S, Kunder E, et al. : OP0028 Efficacy and safety of bcd-085, a novel il-17 inhibitor, in ankylosing spondylitis. results of phase 2 clinical study. Annals of the Rheumatic Diseases. 2018; 77 (Suppl 2): 64. Publisher Full Text 23. van der Heijde D, Deodhar A, Wei JC, et al. : Tofacitinib in patients with ankylosing spondylitis: A phase II, 16-week, randomised, placebo-controlled, dose-ranging study. Ann Rheum Dis. 2017; 76 (8): 1340–7. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 24. van der Heijde D, Baraliakos X, Gensler LS, et al. : Efficacy and safety of filgotinib, a selective Janus kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): Results from a randomised, placebo-controlled, phase 2 trial. Lancet. 2018; 392 (10162): 2378–87. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 25. van der Heijde D, Song IH, Pangan AL, et al. : Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis (SELECT-AXIS 1): A multicentre, randomised, double-blind, placebo-controlled, phase 2/3 trial. Lancet. 2019; 394 (10214): 2108–17. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 26. Tan AL, Marzo-Ortega H, O'Connor P, et al. : Efficacy of anakinra in active ankylosing spondylitis: A clinical and magnetic resonance imaging study. Ann Rheum Dis. 2004; 63 (9): 1041–5. PubMed Abstract | Publisher Full Text | Free Full Text 27. Haibel H, Rudwaleit M, Listing J, et al. : Open label trial of anakinra in active ankylosing spondylitis over 24 weeks. Ann Rheum Dis. 2005; 64 (2): 296–8. PubMed Abstract | Publisher Full Text | Free Full Text 28. Song IH, Heldmann F, Rudwaleit M, et al. : Treatment of active ankylosing spondylitis with abatacept: An open-label, 24-week pilot study. Ann Rheum Dis. 2011; 70 (6): 1108–10. PubMed Abstract | Publisher Full Text 29. Song IH, Heldmann F, Rudwaleit M, et al. : Different response to rituximab in tumor necrosis factor blocker-naive patients with active ankylosing spondylitis and in patients in whom tumor necrosis factor blockers have failed: A twenty-four-week clinical trial. Arthritis Rheum. 2010; 62 (5): 1290–7. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 30. Song IH, Heldmann F, Rudwaleit M, et al. : One-year follow-up of ankylosing spondylitis patients responding to rituximab treatment and re-treated in case of a flare. Ann Rheum Dis. 2013; 72 (2): 305–6. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 31. Sieper J, Porter-Brown B, Thompson L, et al. : Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: Results of randomised, placebo-controlled trials. Ann Rheum Dis. 2014; 73 (1): 95–100. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 32. Sieper J, Braun J, Kay J, et al. : Sarilumab for the treatment of ankylosing spondylitis: Results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN). Ann Rheum Dis. 2015; 74 (6): 1051–7. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 33. Pathan E, Abraham S, van Rossen E, et al. : Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in ankylosing spondylitis. Ann Rheum Dis. 2013; 72 (9): 1475–80. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 34. Baeten D, Østergaard M, Wei JCC, et al. : Risankizumab, an IL-23 Inhibitor, for Ankylosing Spondylitis: Results of a Randomised, Double-Blind, Placebo-Controlled, Proof-Of-Concept, Dose-Finding Phase 2 Study. Ann Rheum Dis. 2018; 77 (9): 1295–302. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 35. Deodhar A, Gensler LS, Sieper J, et al. : Three Multicenter, Randomized, Double-Blind, Placebo-Controlled Studies Evaluating the Efficacy and Safety of Ustekinumab in Axial Spondyloarthritis. Arthritis Rheumatol. 2019; 71 (2): 258–70. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 36. Siebert S, Millar NL, McInnes IB: Why Did IL-23p19 Inhibition Fail in AS: A Tale of Tissues, Trials or Translation? Ann Rheum Dis. 2019; 78 (8): 1015–8. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 37. Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs): WHO Expert Committee on Biological Standardization, Sixtieth report (19-23 October 2009). WHO Technical Report Series No. 977, 2013 - Annex 2. Reference Source 38. January 2017 Position statement: biosimilar medicines. Reference Source 39. Kay J, Schoels MM, Dörner T, et al. : Consensus-based Recommendations for the Use of Biosimilars to Treat Rheumatological Diseases. Ann Rheum Dis. 2018; 77 (2): 165–74. PubMed Abstract | Publisher Full Text | Faculty Opinions Recommendation 40. Karmacharya P, Duarte-Garcia A, Dubreuil M, et al. : Effect of Therapy on Radiographic Progression in Axial Spondyloarthritis: A Systematic Review and Meta-Analysis. Arthritis Rheumatol. 2020; 72 (5): 733–49. PubMed Abstract | Publisher Full Text | Free Full Text | Faculty Opinions Recommendation 41. Baraliakos X, Østergaard M, Gensler LS, et al. : Comparison of the Effects of Secukinumab and Adalimumab Biosimilar on Radiographic Progression in Patients With Ankylosing Spondylitis: Design of a Randomized, Phase IIIb Study (SURPASS). Clin Drug Investig. 2020; 40 (3): 269–78. PubMed Abstract | Publisher Full Text 42. Atar D, Birkeland KI, Uhlig T: 'Treat to Target': Moving Targets From Hypertension, Hyperlipidaemia and Diabetes to Rheumatoid Arthritis. Ann Rheum Dis. 2010; 69 (4): 629–30. PubMed Abstract | Publisher Full Text 43. Machado PM, Deodhar A: Treat-to-target in Axial Spondyloarthritis: Gold Standard or Fools' Gold? Curr Opin Rheumatol. 2019; 31 (4): 344–8. PubMed Abstract | Publisher Full Text 44. Smolen JS, Schöls M, Braun J, et al. : Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force. Ann Rheum Dis. 2018; 77 (1): 3–17. PubMed Abstract | Publisher Full Text | Free Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 13 Jul 2020 ADD YOUR COMMENT Comment Author details Author details 1 Department of Rheumatology, Northwick Park Hospital NHS Trust, London, UK 2 Department of Rheumatology, University College London Hospitals NHS Foundation Trust, London, UK 3 Centre for Rheumatology, Division of Medicine & Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK Priyanka Agrawal Roles: Writing – Original Draft Preparation Pedro M. Machado Roles: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests PMM has received consulting/speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB. PA declares that she has no competing interests. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 13 Jul 2020, 9:697 https://doi.org/10.12688/f1000research.22577.1 Copyright © 2020 Agrawal P and Machado PM. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Agrawal P and Machado PM. Recent advances in managing axial spondyloarthritis [version 1; peer review: 2 approved] . F1000Research 2020, 9 (Faculty Rev):697 ( https://doi.org/10.12688/f1000research.22577.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Editorial Note on the Review Process Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Reviewers who approved this article Daniel Wendling , Department of Rheumatology, CHRU Besançon, France Competing interests: No competing interests were declared. (for version 1) Peter Cheung , Division of Rheumatology, National University Hospital, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University Singapore, Singapore Competing interests: No competing interests were declared. (for version 1) Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 13 Jul 2020 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 1 13 Jul 20 Faculty Reviews are review articles written by the prestigious Members of Faculty Opinions . The articles are commissioned and peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Daniel Wendling , Department of Rheumatology, CHRU Besançon, France Competing interests: No competing interests were declared. View more View less Peter Cheung , Division of Rheumatology, National University Hospital, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University Singapore, Singapore Competing interests: No competing interests were declared. View more View less Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Stay Updated Sign up for content alerts and receive a weekly or monthly email with all newly published articles Register with F1000Research Already registered? Sign in Not now, thanks close PLEASE NOTE If you are an AUTHOR of this article, please check that you signed in with the account associated with this article otherwise we cannot automatically identify your role as an author and your comment will be labelled as a “User Comment”. If you are a REVIEWER of this article, please check that you have signed in with the account associated with this article and then go to your account to submit your report, please do not post your review here. If you do not have access to your original account, please contact us . All commenters must hold a formal affiliation as per our Policies . The information that you give us will be displayed next to your comment. User comments must be in English, comprehensible and relevant to the article under discussion. We reserve the right to remove any comments that we consider to be inappropriate, offensive or otherwise in breach of the User Comment Terms and Conditions . Commenters must not use a comment for personal attacks. When criticisms of the article are based on unpublished data, the data should be made available. I accept the User Comment Terms and Conditions Please confirm that you accept the User Comment Terms and Conditions. Affiliation ✕ refresh Please enter your institution. Note: To add your institution or organisation, start typing the name and then select the correct name from the list. Where applicable, the name will appear in both the original language and in English. Do not paste in the name. If the name does not appear in the drop-down list, we will display the information you have entered. ✕ refresh Country/Region * USA UK Canada China France Germany Afghanistan Aland Islands Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory British Virgin Islands Brunei Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos (Keeling) Islands Colombia Comoros Congo Cook Islands Costa Rica Cote d'Ivoire Croatia Cuba Cyprus Czech Republic Democratic Republic of the Congo Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Federated States of Micronesia Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard Island and Mcdonald Islands Holy See (Vatican City State) Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Israel Italy Jamaica Japan Jersey Jordan Kazakhstan Kenya Kiribati Kosovo (Serbia and Montenegro) Kuwait Kyrgyzstan Lao People's Democratic Republic Latvia Lebanon Lesotho Liberia Libya Liechtenstein Lithuania Luxembourg Macao Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Minor Outlying Islands of the United States Moldova Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island North Korea North Macedonia Northern Mariana Islands Norway Oman Pakistan Palau Palestinian Territory Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Puerto Rico Qatar Reunion Romania Russian Federation Rwanda Saint Helena Saint Kitts and Nevis Saint Lucia Saint Pierre and Miquelon Saint Vincent and the Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia and the South Sandwich Is South Korea South Sudan Spain Sri Lanka Sudan Suriname Svalbard and Jan Mayen Swaziland Sweden Switzerland Syria Taiwan Tajikistan Tanzania Thailand The Gambia The Netherlands Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu UK USA Uganda Ukraine United Arab Emirates United States Virgin Islands Uruguay Uzbekistan Vanuatu Venezuela Vietnam Wallis and Futuna West Bank and Gaza Strip Western Sahara Yemen Zambia Zimbabwe Please select your country/region. You must enter a comment. Competing Interests Please disclose any competing interests that might be construed to influence your judgment of the article's or peer review report's validity or importance. Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Please state your competing interests The comment has been saved. An error has occurred. Please try again. Cancel Post var lTitle = "Recent advances in managing axial spondyloarthritis".replace("'", ''); var linkedInUrl = "http://www.linkedin.com/shareArticle?url=https://f1000research.com/articles/9-697/v1" + "&title=" + encodeURIComponent(lTitle) + "&summary=" + encodeURIComponent('Read the article by '); var deliciousUrl = "https://del.icio.us/post?url=https://f1000research.com/articles/9-697/v1&title=" + encodeURIComponent(lTitle); var redditUrl = "http://reddit.com/submit?url=https://f1000research.com/articles/9-697/v1" + "&title=" + encodeURIComponent(lTitle); linkedInUrl += encodeURIComponent('Agrawal P and Machado PM'); var offsetTop = /chrome/i.test( navigator.userAgent ) ? 4 : -10; var addthis_config = { ui_offset_top: offsetTop, services_compact : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_expanded : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_custom : [ { name: "LinkedIn", url: linkedInUrl, icon:"/img/icon/at_linkedin.svg" }, { name: "Mendeley", url: "http://www.mendeley.com/import/?url=https://f1000research.com/articles/9-697/v1/mendeley", icon:"/img/icon/at_mendeley.svg" }, { name: "Reddit", url: redditUrl, icon:"/img/icon/at_reddit.svg" }, ] }; var addthis_share = { url: "https://f1000research.com/articles/9-697", templates : { twitter : "Recent advances in managing axial spondyloarthritis. Agrawal P and Machado PM, published by " + "@F1000Research" + ", https://f1000research.com/articles/9-697/v1" } }; if (typeof(addthis) != "undefined"){ addthis.addEventListener('addthis.ready', checkCount); addthis.addEventListener('addthis.menu.share', checkCount); } $(".f1r-shares-twitter").attr("href", "https://twitter.com/intent/tweet?text=" + addthis_share.templates.twitter); $(".f1r-shares-facebook").attr("href", "https://www.facebook.com/sharer/sharer.php?u=" + addthis_share.url); $(".f1r-shares-linkedin").attr("href", addthis_config.services_custom[0].url); $(".f1r-shares-reddit").attr("href", addthis_config.services_custom[2].url); $(".f1r-shares-mendelay").attr("href", addthis_config.services_custom[1].url); function checkCount(){ setTimeout(function(){ $(".addthis_button_expanded").each(function(){ var count = $(this).text(); if (count !== "" && count != "0") $(this).removeClass("is-hidden"); else $(this).addClass("is-hidden"); }); }, 1000); } close How to cite this report {{reportCitation}} Cancel Copy Citation Details $(function(){R.ui.buttonDropdowns('.dropdown-for-downloads');}); $(function(){R.ui.toolbarDropdowns('.toolbar-dropdown-for-downloads');}); $.get("/articles/acj/22577/24923") new F1000.Clipboard(); new F1000.ThesaurusTermsDisplay("faculty-reviews", "article", "24923"); $(document).ready(function() { $( "#frame1" ).on('load', function() { var mydiv = $(this).contents().find("div"); var h = mydiv.height(); console.log(h) }); var tooltipLivingFigure = jQuery(".interactive-living-figure-label .icon-more-info"), titleLivingFigure = tooltipLivingFigure.attr("title"); tooltipLivingFigure.simpletip({ fixed: true, position: ["-115", "30"], baseClass: 'small-tooltip', content:titleLivingFigure + " " }); tooltipLivingFigure.removeAttr("title"); $("body").on("click", ".cite-living-figure", function(e) { e.preventDefault(); var ref = $(this).attr("data-ref"); $(this).closest(".living-figure-list-container").find("#" + ref).fadeIn(200); }); $("body").on("click", ".close-cite-living-figure", function(e) { e.preventDefault(); $(this).closest(".popup-window-wrapper").fadeOut(200); }); $(document).on("mouseup", function(e) { var metricsContainer = $(".article-metrics-popover-wrapper"); if (!metricsContainer.is(e.target) && metricsContainer.has(e.target).length === 0) { $(".article-metrics-close-button").click(); } }); var articleId = $('#articleId').val(); if($("#main-article-count-box").attachArticleMetrics) { $("#main-article-count-box").attachArticleMetrics(articleId, { articleMetricsView: true }); } }); var figshareWidget = $(".new_figshare_widget"); if (figshareWidget.length > 0) { window.figshare.load("f1000", function(Widget) { // Select a tag/tags defined in your page. In this tag we will place the widget. _.map(figshareWidget, function(el){ var widget = new Widget({ articleId: $(el).attr("figshare_articleId") //height:300 // this is the height of the viewer part. [Default: 550] }); widget.initialize(); // initialize the widget widget.mount(el); // mount it in a tag that's on your page // this will save the widget on the global scope for later use from // your JS scripts. This line is optional. //window.widget = widget; }); }); } close Error Close Add Reset F1000.MICROSERVICES.AFFILIATION = ''; $(document).ready(function () { $('.js-affiliations-form').each((index, form) => { new AffiliationForm({ formId: form.id, institutionErrorSelector: '.comment-enter-institution', departmentErrorSelector: '.comment-enter-department', placeSelector: '.js-add-comment-place', stateSelector: '.js-add-comment-state', zipCodeSelector: '.js-add-comment-zipcode', countrySelector: '.js-add-comment-country', countryErrorSelector: '.comment-enter-country', }); }); }); $(document).ready(function () { var reportIds = { "66605": 1, "66604": 1, }; $(".referee-response-container,.js-referee-report").each(function(index, el) { var reportId = $(el).attr("data-reportid"), reportCount = reportIds[reportId] || 0; $(el).find(".comments-count-container,.js-referee-report-views").html(reportCount); }); var uuidInput = $("#article_uuid"), oldUUId = uuidInput.val(), newUUId = "ac89ec41-a48b-48b4-8b2e-c999379334b3"; uuidInput.val(newUUId); $("a[href*='article_uuid=']").each(function(index, el) { var newHref = $(el).attr("href").replace(oldUUId, newUUId); $(el).attr("href", newHref); }); }); An innovative open access publishing platform offering rapid publication and open peer review, whilst supporting data deposition and sharing. Browse Gateways Collections How it Works Contact For Developers Cookie Notice Privacy Notice RSS Submit Your Research Follow us © 2012-2026 F1000 Research Ltd. ISSN 2046-1402 | Legal | Partner of Research4Life • CrossRef • ORCID • FAIRSharing R.templateTests.simpleTemplate = R.template(' $text $text $text $text $text '); R.templateTests.runTests(); var F1000platform = new F1000.Platform({ name: "f1000research", displayName: "F1000Research", hostName: "f1000research.com", id: "1", editorialEmail: "[email protected]", infoEmail: "[email protected]", usePmcStats: true }); $(function(){R.ui.dropdowns('.dropdown-for-authors, .dropdown-for-about, .dropdown-for-myresearch');}); // $(function(){R.ui.dropdowns('.dropdown-for-referees');}); $(document).ready(function () { if ($(".cookie-warning").is(":visible")) { $(".sticky").css("margin-bottom", "35px"); $(".devices").addClass("devices-and-cookie-warning"); } $(".cookie-warning .close-button").click(function (e) { $(".devices").removeClass("devices-and-cookie-warning"); $(".sticky").css("margin-bottom", "0"); }); $("#tweeter-feed .tweet-message").each(function (i, message) { var self = $(message); self.html(linkify(self.html())); }); $(".partner").on("mouseenter mouseleave", function() { $(this).find(".gray-scale, .colour").toggleClass("is-hidden"); }); }); Sign In Remember me Forgotten your password? Sign In Cancel Email or password not correct. Please try again Please wait... $(function(){ // Note: All the setup needs to run against a name attribute and *not* the id due the clonish // nature of facebox... $("a[id=googleSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("GOOGLE"); $("form[id=oAuthForm]").submit(); }); $("a[id=facebookSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("FACEBOOK"); $("form[id=oAuthForm]").submit(); }); $("a[id=orcidSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("ORCID"); $("form[id=oAuthForm]").submit(); }); }); If you've forgotten your password, please enter your email address below and we'll send you instructions on how to reset your password. The email address should be the one you originally registered with F1000. Email address not valid, please try again You registered with F1000 via Google, so we cannot reset your password. To sign in, please click here . If you still need help with your Google account password, please click here . You registered with F1000 via Facebook, so we cannot reset your password. To sign in, please click here . If you still need help with your Facebook account password, please click here . Code not correct, please try again Reset password Cancel Email us for further assistance. Server error, please try again. If your email address is registered with us, we will email you instructions to reset your password. If you think you should have received this email but it has not arrived, please check your spam filters and/or contact for further assistance. Please wait... Register $(document).ready(function () { signIn.createSignInAsRow($("#sign-in-form-gfb-popup")); $(".target-field").each(function () { var uris = $(this).val().split("/"); if (uris.pop() === "login") { $(this).val(uris.toString().replace(",","/")); } }); });