{"id":1825,"date":"2019-10-29T11:05:04","date_gmt":"2019-10-29T10:05:04","guid":{"rendered":"https:\/\/www.newslab.sk\/2019\/10\/29\/nespecificke-crevne-zapaly-priciny-straty-odpovede-pacientov-na-biologicku-liecbu\/"},"modified":"2019-11-04T14:02:53","modified_gmt":"2019-11-04T13:02:53","slug":"nespecificke-crevne-zapaly-priciny-straty-odpovede-pacientov-na-biologicku-liecbu","status":"publish","type":"post","link":"https:\/\/www.newslab.sk\/en\/nespecificke-crevne-zapaly-priciny-straty-odpovede-pacientov-na-biologicku-liecbu\/","title":{"rendered":"Inflammatory bowel disease: causes of the loss of patient\u00b4s response to biologic therapy"},"content":{"rendered":"

*All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.<\/strong><\/span><\/p>\n

 <\/p>\n

\u00davod<\/strong><\/p>\n

Ne\u0161pecifick\u00e9 \u010drevn\u00e9 z\u00e1paly (IBD, I<\/em>nflamma<\/em>t<\/em>o<\/em>r<\/em>y<\/em> bowe<\/em>l<\/em> disea<\/em>– <\/em>se<\/em>) s\u00fa autoimunitn\u00e9 ochorenia, ktor\u00e9 patria do skupiny idiopatick\u00fdch \u010drevn\u00fdch z\u00e1palov a zah\u0155\u0148aj\u00fa 2 formy: Crohnovu chorobu (Crohn<\/em> disease<\/em>, CD) a ulcer\u00f3znu kolit\u00eddu (ulcerative<\/em> colitis<\/em>, UC). CD postihuje ktor\u00fako\u013evek \u010das\u0165 gastrointestin\u00e1lneho traktu, zatia\u013e \u010do pri UC je postihnut\u00e9 len hrub\u00e9 \u010drevo a oblas\u0165 kone\u010dn\u00edka. Obe tieto ochorenia predstavuj\u00fa z\u00e1va\u017en\u00fd medic\u00ednsky probl\u00e9m s celosvetovo rast\u00facou incidenciou(1) (obr\u00e1zok <\/em><\/strong>1)<\/em><\/strong>.<\/p>\n

Medzi sympt\u00f3my pacientov, ktor\u00ed trpia IBD, patria najm\u00e4 hna\u010dky, bolesti brucha, krvav\u00e1 stolica a vracanie. U mnoh\u00fdch boli pozorovan\u00e9 poruchy funkcie \u010drevnej epiteli\u00e1lnej bari\u00e9ry a mikrobi\u00e1lna dysbi\u00f3za(3). V s\u00fa\u010dasnosti toto ochorenie nie je vylie\u010dite\u013en\u00e9, terapia v\u0161ak pozost\u00e1va z lie\u010dby sympt\u00f3mov s cie\u013eom indukova\u0165 a n\u00e1sledne udr\u017ea\u0165 stav remisie, a teda zlep\u0161i\u0165 kvalitu \u017eivota pacienta. Vyu\u017e\u00edva sa kombin\u00e1cia r\u00f4znych liekov, predov\u0161etk\u00fdm aminosalicyl\u00e1ty, imunomodula\u010dn\u00e9 l\u00e1tky a kortikosteroidy, pri\u010dom v mnoh\u00fdch pr\u00edpadoch je potrebn\u00e9 aj podanie antibiot\u00edk \u010di chirurgick\u00fd z\u00e1krok.<\/p>\n

Spom\u00ednan\u00e9 medikamenty p\u00f4sobia syst\u00e9movo a vyzna\u010duj\u00fa sa r\u00f4znymi nev\u00fdhodami, ako je napr\u00edklad dlh\u00fd \u010das n\u00e1stu- pu protiz\u00e1palov\u00e9ho \u00fa\u010dinku alebo z\u00e1va\u017en\u00e9 ne\u017eiaduce \u00fa\u010dinky. Aj na z\u00e1klade t\u00fdchto poznatkov bola vytvoren\u00e1 biologick\u00e1 terapia, ktorej l\u00e1tky p\u00f4sobia lok\u00e1lne a cielene inhibuj\u00fa molekuly, ktor\u00e9 sa podie\u013eaj\u00fa na z\u00e1palov\u00fdch procesoch. Patria tu predov\u0161etk\u00fdm schv\u00e1len\u00e9 terapie proti TNF (faktor nekrotizuj\u00faci tumor, tumor necrosis factor<\/em>), ale aj l\u00e1tky blokuj\u00face napr\u00edklad integr\u00edny (natalizumab, vedolizumab) \u010di interleuk\u00edny IL \u2013 (12\/23) (ustekinumab). Napriek tomu, \u017ee ide o \u00fa\u010dinn\u00e9 lieky, existuje pomerne ve\u013ea pacientov, ktor\u00ed na t\u00fato lie\u010dbu nereaguj\u00fa v\u00f4bec alebo stratia odpove\u010f po\u010das lie\u010dby(4,5). Pr\u00e1ve preto je potrebn\u00e9 a zauj\u00edmav\u00e9 zisti\u0165, ak\u00e9 konkr\u00e9tne genetick\u00e9 zmeny existuj\u00fa medzi pacientmi, ktor\u00ed maj\u00fa na t\u00fato terapiu pozit\u00edvnu odpove\u010f, a t\u00fdmi, ktor\u00ed vykazuj\u00fa stratu odpovede.<\/p>\n

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Anti-TNF-alfa biologick\u00e1 lie\u010dba<\/strong><\/p>\n

Na z\u00e1klade poznatkov z ve\u013ek\u00fdch asocia\u010dn\u00fdch \u0161t\u00fadi\u00ed (GWAS, genome-wide association studies<\/em>), ktor\u00e9 sa zaoberali identifik\u00e1ciou rizikov\u00fdch lokusov pre z\u00e1palov\u00e9 \u010drevn\u00e9 ochorenia, sa podarilo identifikova\u0165 biologick\u00e9 dr\u00e1hy a poruchy v konkr\u00e9tnych g\u00e9noch, ktor\u00e9 sa t\u00fdkaj\u00fa z\u00e1palov\u00e9ho procesu(6). V\u010faka tomu bolo mo\u017en\u00e9 vytvori\u0165 lie\u010div\u00e1, ktor\u00e9 cielene inhibuj\u00fa konkr\u00e9tne molekuly. Jednou takouto molekulou je aj proz\u00e1palov\u00fd cytok\u00edn TNF. TNF je zn\u00e1my t\u00fdm, \u017ee podporuje z\u00e1palov\u00fa odpove\u010f pri r\u00f4znych ochoreniach vr\u00e1tane reumatoidnej artrit\u00eddy, ankylozuj\u00facej spondylit\u00eddy, CD, UC a psori\u00e1zy, pri\u010dom bolo dok\u00e1zan\u00e9, \u017ee pr\u00edznaky t\u00fdchto por\u00fach sa zlep\u0161uj\u00fa pri lie\u010dbe inhib\u00edtormi TNF.<\/p>\n

V r\u00e1mci biologickej lie\u010dby sa v s\u00fa\u010dasnosti na lie\u010dbu IBD pou\u017e\u00edvaj\u00fa \u0161tyri anti-TNF molekuly: infliximab, adalimumab, certolizumab pegol a golimumab(7,8) (obr\u00e1zok 2)<\/em><\/strong>. Mechanizmus p\u00f4sobenia anti-TNF prebieha dvoma r\u00f4znymi sp\u00f4sob- mi. Prv\u00fd mechanizmus p\u00f4sob\u00ed na z\u00e1klade indukcie apopt\u00f3zy T-buniek. Tento mechanizmus \u00fa\u010dinku je spolo\u010dn\u00fd pre infliximab, adalimumab a certolizumab(26). V druhom mechanizme sa anti-TNF via\u017ee na transmembr\u00e1nov\u00fd TNF, pri\u010dom je Fc \u010das\u0165 protil\u00e1tky rozpozn\u00e1van\u00e1 Fc receptormi, ktor\u00e9 sa nach\u00e1dzaj\u00fa na monocytoch. Tento mechanizmus je \u0161pecifick\u00fd pre anti-TNF molekuly, ktor\u00e9 obsahuj\u00fa Fc oblas\u0165, preto je v pr\u00edpade certolizumabu nemo\u017en\u00fd(27).<\/p>\n

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Strata odpovede na biologick\u00fa lie\u010dbu<\/h3>\n

Antagonisty TNF-\u03b1 s\u00fa \u00fa\u010dinn\u00e9 lieky, ktor\u00e9 zlep\u0161uj\u00fa kvalitu \u017eivota pacientov s IBD, zni\u017euj\u00fa po\u010det oper\u00e1ci\u00ed a hospitaliz\u00e1ci\u00ed. Napriek tomu pribli\u017ene 10 \u2013 30 % pacientov nereaguje na induk\u010dn\u00fa terapiu (prim\u00e1rna strata odpovede) a 23 \u2013 46 % strat\u00ed odpove\u010f po\u010das lie\u010dby (sekund\u00e1rna strata odpovede)(4,5). Pri lie\u010dbe IBD pacientov je d\u00f4le\u017eit\u00e9 ur\u010di\u0165, \u010di pr\u00ed\u010dinou zlyhania lie\u010dby je prim\u00e1rna alebo sekund\u00e1rna strata odpovede, kv\u00f4li tomu, aby sa pr\u00edpadne mohla zvoli\u0165 in\u00e1 forma terapie a aby sa optimalizovala pozit\u00edvna klinick\u00e1 odpove\u010f.<\/p>\n

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Prim\u00e1rna a sekund\u00e1rna strata odpovede<\/h4>\n

Pod\u013ea klinickej defin\u00edcie je prim\u00e1rna strata odpovede (PNR, primary non-response<\/em>) na anti-TNF-\u03b1 lie\u010dbu definovan\u00e1 ako nedostato\u010dn\u00e9 zlep\u0161enie klinick\u00fdch pr\u00edznakov a sympt\u00f3mov po induk\u010dnej lie\u010dbe(12). Sekund\u00e1rna strata odpovede (LOR, se- condary loss of response<\/em>) opisuje pacientov, ktor\u00ed reagovali na lie\u010dbu po\u010das induk\u010dnej f\u00e1zy, ale n\u00e1sledne stratili odpove\u010f po\u010das udr\u017eiavacej f\u00e1zy alebo ich odpove\u010f bola zn\u00ed\u017een\u00e1, respekt\u00edve trvala kr\u00e1tko(13).<\/p>\n

Mechanizmy, ktor\u00e9 s\u00fa spojen\u00e9 s PNR a LOR na anti-TNF lie\u010dbu v IBD zatia\u013e nie s\u00fa \u00faplne zn\u00e1me a op\u00edsan\u00e9, ale predpoklad\u00e1 sa, \u017ee medzi hlavn\u00e9 pr\u00ed\u010diny toho, pre\u010do doch\u00e1dza k strate odpovede na lie\u010dbu, patr\u00ed: farmakokinetick\u00e9 a farmakodynamick\u00e9 zlyhanie, imunogenicita, d\u00e1vkovac\u00ed re\u017eim pri lie\u010dbe a pr\u00ed\u010dinou m\u00f4\u017ee by\u0165 aj samotn\u00e1 charakteristika ochorenia (fenotyp, lokaliz\u00e1cia ochorenia, z\u00e1va\u017enos\u0165 ochorenia)(14).<\/p>\n

Farmakokinetick\u00e9 zlyhanie<\/h3>\n

Farmakokinetika je proces, ktor\u00fd opisuje reakciu organizmu na liek. Sleduje uvo\u013e\u0148ovanie z liekovej formul\u00e1cie, absorpciu, distrib\u00faciu, chemick\u00e9 zmeny, metabolizmus a sp\u00f4sob vyl\u00fa\u010denia z tela(15). Pri farmakokinetickom zlyhan\u00ed doch\u00e1dza k zn\u00ed\u017eeniu hlad\u00edn lie\u010diva alebo \u00fapln\u00e9mu vymiznutiu protil\u00e1tok. Pri takomto zlyhan\u00ed toti\u017e nast\u00e1va zr\u00fdchlen\u00fd neim\u00fanny kl\u00edrens lieku prostredn\u00edctvom syst\u00e9movej cirkul\u00e1cie v tkanive. Neim\u00fanny kl\u00edrens m\u00f4\u017ee by\u0165 sp\u00f4soben\u00fd taktie\u017e \u00fanikom lie\u010diva cez sliznicov\u00fa membr\u00e1nu do ulcerovanej \u010dasti sliznice, \u010do n\u00e1sledne vedie k v\u00fdraznej strate elektrolytov a prote\u00ednov vr\u00e1tane anti-TNF(16,17).<\/p>\n

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Farmakodynamick\u00e9 zlyhanie<\/h3>\n

Farmakodynamika sa zaober\u00e1 \u00fa\u010dinkom lieku na organizmus a sleduje biochemick\u00fd, fyziologick\u00fd a molekul\u00e1rny efekt na telo, mechanizmus \u00fa\u010dinku, vz\u0165ah medzi koncentr\u00e1ciou a \u00fa\u010dinkom a ved\u013eaj\u0161ie \u00fa\u010dinky(18,19). U pacientov s IBD je farmakodynamick\u00e9 zlyhanie charakterizovan\u00e9 ako nedostatok zlep\u0161enia sympt\u00f3mov v d\u00f4sledku prechodu ochorenia na dr\u00e1hu, ktor\u00e1 nie je riaden\u00e1 TNF. Napriek tomu, \u017ee koncentr\u00e1cia lie\u010diva v plazme je dostato\u010dn\u00e1, nedoch\u00e1dza k tvorbe protil\u00e1tok a lie\u010dba nem\u00e1 \u017eiaden klinick\u00fd efekt. V lie\u010dbe s\u00fa potom \u00fa\u010dinn\u00e9 in\u00e9 ako anti-TNF l\u00e1tky, napr\u00edklad antiintegr\u00ednov\u00e9 protil\u00e1tky, ktor\u00e9 blokuj\u00fa adh\u00e9ziu leukocytov na kapil\u00e1rnu stenu(14).<\/p>\n

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Imunogenicita<\/h3>\n

Imunogenicita je schopnos\u0165 l\u00e1tky (ako je napr\u00edklad antig\u00e9n) vyvola\u0165 imunitn\u00fa odpove\u010f v \u017eivom organizme. Pri zlyhan\u00ed v d\u00f4sledku imunogenicity je detegovan\u00e1 vysok\u00e1 koncentr\u00e1cia protil\u00e1tok proti lie\u010divu a nulov\u00e1 koncentr\u00e1cia lie\u010diva, pri\u010dom farmakoterapia ost\u00e1va bez klinickej odpovede. V takomto pr\u00edpade je potrebn\u00e1 zmena lie\u010diva. Strata odpovede na inhib\u00edtory TNF v d\u00f4sledku vytvorenia neutralizuj\u00facich protil\u00e1tok proti lieku a subterapeutick\u00fdch koncentr\u00e1ci\u00ed lie\u010diva je ve\u013ek\u00fdm probl\u00e9mom v mana\u017emente pacientov s IBD a vyskytuje sa aj pri prim\u00e1rnej, aj sekund\u00e1rnej strate odpovede(20).<\/p>\n

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Genetick\u00e9 pozadie biologickej terapie<\/h3>\n

Je zn\u00e1me, \u017ee genetick\u00e9 varianty v g\u00e9ne TPMT <\/em>ovplyv\u0148uj\u00fa \u00fa\u010dinnos\u0165 lie\u010div zo skupiny imunomodul\u00e1torov, konkr\u00e9tne azatiopr\u00ednu. Pacienti nes\u00faci konkr\u00e9tne varianty v tomto g\u00e9ne sa delia na pomal\u00fdch, intermedi\u00e1rnych a r\u00fdchlych metaboliz\u00e9rov, na z\u00e1klade \u010doho nereaguj\u00fa na lie\u010dbu, pr\u00edpadne u nich doch\u00e1dza k z\u00e1va\u017en\u00fdm ved\u013eaj\u0161\u00edm \u00fa\u010dinkom pri u\u017e\u00edvan\u00ed tohto typu lieku(21). Preto sa pred nasadzovan\u00edm tiopur\u00ednov vy\u0161etruje aj genotyp tohto g\u00e9nu. Predpoklad\u00e1 sa, \u017ee genetick\u00e9 pozadie pacientov m\u00f4\u017ee ovplyv\u0148ova\u0165 aj reakcie jednotliv\u00fdch pacientov na biologick\u00fa lie\u010dbu. Sk\u00faman\u00edm genetick\u00e9ho pozadia biologickej terapie a z\u00e1palov\u00fdch dr\u00e1h, ktor\u00e9 s\u00favisia s IBD a ved\u00fa k expresii TNF, sa zaoberali viacer\u00e9 \u0161t\u00fadie(22). Boli v nich identifikovan\u00e9 polymorfizmy, ktor\u00e9 s\u00fa asociovan\u00e9 so stratou odpovede, ale aj tak\u00e9, ktor\u00e9 maj\u00fa priazniv\u00fd \u00fa\u010dinok v s\u00favislosti s reakciou na lie\u010dbu. Prostredn\u00edctvom identifik\u00e1cie polymorfizmov a ich biologick\u00fdch vplyvov mo\u017eno zisti\u0165, ktor\u00ed pacienti bud\u00fa z lie\u010dby pr\u00edslu\u0161n\u00fdm agensom profitova\u0165 a, naopak, ktor\u00ed bud\u00fa potrebova\u0165 in\u00fd typ lie\u010diva. V s\u00fa\u010dasnosti je identifik\u00e1cia tak\u00fdchto polymorfizmov a zis\u0165ovanie ich funk\u010dn\u00fdch vplyvov v \u0161t\u00e1diu v\u00fdskumu a v praxi sa zatia\u013e tieto g\u00e9ny nevy\u0161etruj\u00fa.<\/p>\n

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Jednonukleotidov\u00e9 polymorfizmy asociovan\u00e9 s odpove\u010fou na anti-TNF terapiu<\/h3>\n

V doteraz uskuto\u010dnen\u00fdch \u0161t\u00fadi\u00e1ch, ktor\u00e9 sa venovali tejto problematike, boli identifikovan\u00e9 viacer\u00e9 jednonukleotidov\u00e9 polymorfizmy (SNPs, single<\/em> nu<\/em>cle<\/em>otide<\/em> polymorphisms<\/em>) ovplyv\u0148uj\u00face odpove\u010f pacientov na anti-TNF lie\u010dbu. Sum\u00e1rny preh\u013ead t\u00fdchto polymorfizmov spolu s lokaliz\u00e1ciou v gen\u00f3me, so z\u00e1pisom variantu, s frekvenciou minoritnej alely a biologick\u00fdm \u00fa\u010dinkom je uveden\u00fd v tabu\u013ek\u00e1ch 1 a 2<\/em><\/strong>.<\/p>\n

V dostupnej literat\u00fare t\u00fdkaj\u00facej sa \u0161tudovania reakci\u00ed IBD pacientov na lie\u010dbu pomocou inhib\u00edtorov TNF-\u03b1 sa n\u00e1m podarilo n\u00e1js\u0165 30 polymorfizmov, ktor\u00e9 boli asociovan\u00e9 s negat\u00edvnou alebo pozit\u00edvnou odpove\u010fou na anti-TNF lie\u010dbu. Konkr\u00e9tne 17 z nich je asociovan\u00fdch so stratou odpovede, 16 poukazovalo na pozit\u00edvnu odpove\u010f a 3 polymorfizmy sa nach\u00e1dzali v oboch t\u00fdchto skupin\u00e1ch, \u010di\u017ee vykazovali aj pozit\u00edvnu, aj negat\u00edvnu odpove\u010f na biologick\u00fa lie\u010dbu.<\/p>\n

Tieto \u0161t\u00fadie a ich v\u00fdsledky nazna\u010duj\u00fa, \u017ee polymorfizmy spojen\u00e9 s vysokou aktivitou napr\u00edklad TLR5 u pacientov s CD a taktie\u017e polymorfizmy sp\u00f4sobuj\u00face vysok\u00e9 hladiny IL-12 a IL-18 u pacientov s UC boli asociovan\u00e9 so stratou odpovede na biologick\u00fa lie\u010dbu. Na druhej strane, polymorfizmy v g\u00e9noch, ktor\u00e9 s\u00fa zapojen\u00e9 do regul\u00e1cie NF-\u03baB dr\u00e1hy (NFKBIA<\/em>), sign\u00e1lnej dr\u00e1hy TNF-\u03b1 (TNFRSF1A<\/em>) a \u010fal\u0161\u00edch cytok\u00ednov\u00fdch dr\u00e1h (IL<\/em>18<\/em> a J<\/em>AK2<\/em>) s\u00fa asociovan\u00e9 s pozit\u00edvnou odpove\u010fou na anti-TNF terapiu(25).<\/p>\n

Napr\u00edklad v asoci\u00e1cii s pozit\u00edvnou odpove\u010fou na biologick\u00fa lie\u010dbu u pacientov s CD bolo identifikovan\u00fdch sedem SNP (rs3804099, rs1816702, rs11465996, rs4149570, rs2430561(23),\u00a0 rs187238,\u00a0 rs12343867(25)) (t<\/em><\/strong>ab<\/em><\/strong>u\u013eka<\/em><\/strong>\u00a0 2)<\/em><\/strong>, ale u pacientov s CD boli identifikovan\u00e9 aj polymorfizmy asociovan\u00e9 s negat\u00edvnou odpove\u010fou na biologick\u00fa lie\u010dbu, a to rs352139(23), rs5744174(24), rs8126756(25) (tabu\u013eka<\/em><\/strong> 1)<\/em><\/strong>.<\/p>\n

Polymorfizmy\u00a0 rs4848306, rs10499563(23), rs696(25) vykazovali zase u pacientov s UC pozit\u00edvnu odpove\u010f (tabu\u013eka 2)<\/em><\/strong>, no \u010fal\u0161\u00edch 12 identifikovan\u00fdch polymorfizmov rs4696480, rs4251961, rs2569190, rs11465996, rs6927172, rs2275913(23), rs4612666, rs1554973, rs11938228(25), rs2234711, rs17250932, rs3212217(24) bolo asociovan\u00fdch so stratou odpovede pri UC (tabu\u013eka 1)<\/em><\/strong>.<\/p>\n

Celkovo v s\u00fabore IBD pacientov boli v asoci\u00e1cii s pozit\u00edvnou odpove\u010fou na biologick\u00fa lie\u010dbu identifikovan\u00e9 polymorfizmy \u00a0rs187084, \u00a0rs3804099, \u00a0rs11465996, \u00a0rs7222094, rs4149570, rs4848306, rs10499563, rs2430561(23), rs1946518, rs12343867, rs696, rs10754558(25), rs3212217(24)\u00a0 (<\/em><\/strong>t<\/em><\/strong>abu\u013ek<\/em><\/strong>a<\/em><\/strong> 2<\/em><\/strong>)<\/em><\/strong>.<\/p>\n

A naopak, v asoci\u00e1cii s negat\u00edvnou odpove\u010fou na biologick\u00fa lie\u010dbu u pacientov s IBD bolo identifikovan\u00fdch t\u00fdchto 7 polymorfizmov: rs352139, rs1554973, rs6927172, rs361525, rs2275913(23), rs4612666, rs4251961(25) (<\/em><\/strong>t<\/em><\/strong>abu\u013ek<\/em><\/strong>a<\/em><\/strong> 1<\/em><\/strong>)<\/em><\/strong>.<\/p>\n

Polymorfizmus rs5030728 je zauj\u00edmav\u00fd t\u00fdm, \u017ee v z\u00e1vislosti od testovan\u00e9ho modelu (dominantn\u00fd, reces\u00edvny, homozygotn\u00fd, heterozygotn\u00fd) a z\u00e1rove\u0148 v kombin\u00e1cii s typom ochorenia (IBD, CD, UC) bol na jednej strane asociovan\u00fd s pozit\u00edvnou reakciou na lie\u010dbu a na strane druhej so stratou odpovede(23,25) (tabu\u013eka 1, tabu\u013eka 2)<\/em><\/strong>.<\/p>\n

Z\u00e1ver<\/h3>\n

K strate odpovede na biologick\u00fa lie\u010dbu u pacientov trpiacich IBD, ale aj in\u00fdmi autoimunitn\u00fdmi ochoreniami doch\u00e1dza z r\u00f4znych pr\u00ed\u010din. Uk\u00e1zalo sa, \u017ee aj pr\u00edtomnos\u0165 konkr\u00e9tnych SNP u pacientov m\u00f4\u017ee v\u00fdrazne ovplyv\u0148ova\u0165 reakcie na podan\u00fa terapiu. Prostredn\u00edctvom sk\u00famania genetick\u00e9ho pozadia biologickej terapie boli doteraz identifikovan\u00e9 viacer\u00e9 polymorfizmy, ktor\u00e9 s\u00fa asociovan\u00e9 so stratou odpovede, ale aj tak\u00e9, ktor\u00e9 maj\u00fa priazniv\u00fd \u00fa\u010dinok na pacientov s IBD. Pomocou t\u00fdchto SNP mo\u017eno zisti\u0165, ktor\u00ed pacienti bud\u00fa z lie\u010dby pr\u00edslu\u0161n\u00fdm agensom profitova\u0165, a naopak, ktor\u00ed bud\u00fa potrebova\u0165 in\u00fd typ lie\u010diva. Identifik\u00e1cia polymorfizmov m\u00e1 v\u00fdznam nie- len v pr\u00edpade anti-TNF lie\u010dby, ale tie\u017e v pr\u00edpade ak\u00fdchko\u013evek in\u00fdch terapi\u00ed, a samozrejme, pri stanoven\u00ed rizika a predispoz\u00edcie vzniku r\u00f4znych ochoren\u00ed, a to predov\u0161etk\u00fdm v dne\u0161nej dobe, ke\u010f sa genomick\u00e1 medic\u00edna usiluje o dosiahnutie personalizovanej medic\u00edny.<\/p>\n

 <\/p>\n

LITErAT\u00darA<\/strong><\/p>\n

    \n
  1. http:\/\/www.24 com\/voimages\/web_image\/upload\/<\/a> file\/20140606\/76761402057831265.pdf<\/li>\n
  2. https:\/\/inflammatoryboweldisease.net\/types-of-ibd\/ulc<\/li>\n
  3. Fakhoury M, Negrulj R, Mooranian A, et Inflammatory bowel disease: clinical aspects and treatments. Int J Inflam 2014; 7: 113-120.<\/li>\n
  4. Sherman M, Tsynman DN, Kim A, et al. Sustained improvement in health-related quality of life measures in patients with inflammatory bowel disease receiving prolonged anti-tumor necrosis factor J Dig Dis 2014; 15(4): 174-179.<\/li>\n
  5. Roda G, Jharap B, Neeraj N, et Loss of response to anti-TNFs: definition, epidemiology, and management. Clin Transl Gastroenterol 2016; 7(1): e135.<\/li>\n
  6. de Lange KM, Moutsianas L, Lee JC, et Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet 2017; 49(2): 256-261.<\/li>\n
  7. Sandborn WJ, \u00a0Hanauer \u00a0SB, \u00a0Katz \u00a0S, \u00a0et \u00a0al. \u00a0Etanercept \u00a0for \u00a0active Crohn\u2019s disease: a randomized, double-blind, placebo-controlled Gastroenterology 2001; 121(5): 1088-1094.<\/li>\n
  8. Rutgeerts P, Sandborn WJ, Fedorak RN, et al. Onercept for moderate-to-severe Crohn\u2019s disease: a randomized, double-blind, placebo-controlled Clin Gastroenterol Hepatol 2006; 4(7): 888-893.<\/li>\n
  9. https:\/ \/ki.se\/en\/cns\/inflix imab-r emicade?_ ga=2.53474475.209084293. 1538337985-1676560418.1538337985<\/li>\n
  10. https:\/\/ki.se\/en\/cns\/adalimumab-humira?_ga=2.95204511. 1538337985-1676560418.1538337985<\/li>\n
  11. h t t p s :\/\/k i .s e \/e n \/cn s \/certolizuma b-pegol – cimzia ?_ ga=2.133559309.209084293.1538337985-1676560418.1538337985<\/li>\n
  12. Sprakes MB, Ford AC, Warren L, et Efficacy, tolerability, and predictors of response to infliximab therapy for Crohn\u2019s disease: a large single centre experience. J Crohns Colitis 2012; 6(2): 143-153.<\/li>\n
  13. Allez M, Karmiris K, Louis E, et al. Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in inflammatory bowel diseases: definitions, frequency and pharmacological J Crohns Colitis 2010; 4(4): 355-366.<\/li>\n
  14. Ding NS, Hart A, De Cruz Systematic review: predicting and optimising response to anti\u2010TNF therapy in Crohn\u2019s disease\u2013algorithm for practi- cal management. Aliment Pharmacol Ther 2015; 43(1): 30-51.<\/li>\n
  15. Harris P, Nagy S, Vardaxis N, et Mosby\u2019s Dictionary of Medicine, Nursing and Health Professions-Australian & New Zealand Edition-eBook. Elsevier Health Sciences 2004. 2208 p.<\/li>\n
  16. Brandse JF, van den Brink GR, Wildenberg, ME, et Loss of infliximab into feces is associated with lack of response to therapy in patients with severe ulcerative colitis. Gastroenterology 2015; 149(2): 350-355.<\/li>\n
  17. Nattiv R, Wojcicki JM, Garnett EA, et High-dose infliximab for treatment of pediatric ulcerative colitis: a survey of clinical practice. World J Gastroenterol 2012; 18(11): 1229.<\/li>\n
  18. Singh NN, Ellis Pharmacological therapies 1998; 267-293.<\/li>\n
  19. Duffus Glossary for chemists of terms used in toxicology. Pure and applied chemistry 1993; 65(9): 2003-2122.<\/li>\n
  20. Afif W, Loftus EV, Faubion WA, et Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol 2010; 105(5): 1133-1139.<\/li>\n
  21. Wu Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance. Clinical proteomics 2011; 8(1): 12.<\/li>\n
  22. Bek S, Nielsen JV, Bojesen AB, et Systematic review: genetic biomarkers associated with anti\u2010TNF treatment response in inflammatory bowel diseases. Aliment Pharmacol Ther 2016; 44(6): 554-567.<\/li>\n
  23. Bank S, Andersen PS, Burisch J, et al. Associations between functional polymorphisms in the NF\u03baB signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel Pharmacogenomics J 2014; 14(6): 526-534.<\/li>\n
  24. Bank S, Andersen PS, Burisch J, et al. Genetically determined high activity of IL-12 and IL-18 in ulcerative colitis and TLR5 in Crohns disease were associated with non-response to anti-TNF Pharma- cogenomics J 2017; 18(1): 87-97.<\/li>\n
  25. Bank S, Julsgaard M, Abed OK, et al. Polymorphisms in the NF kB, TNF\u2010alpha, IL\u20101beta, and IL\u201018 pathways are associated with response to anti\u2010TNF therapy in Danish patients with inflammatory bowel Aliment Pharmacol Ther 2019 49(7): 890-903.<\/li>\n
  26. Atreya R, Zimmer M, Bartsch B, et Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14+ macrophages. Gastroenterology 2011; 141(6): 2026-2038.<\/li>\n
  27. Levin AD, Wildenberg ME, van den Brink GR. Mechanism of action of anti-TNF therapy in inflammatory bowel J Crohns Colitis 2016; 10(8): 989-997.<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"

    *All tables, charts, graphs and pictures that are featured in this article can be found in the .pdf attachment at the end of the paper.   \u00davod Ne\u0161pecifick\u00e9 \u010drevn\u00e9 z\u00e1paly (IBD, Inflammatory bowel disea– se) s\u00fa autoimunitn\u00e9 ochorenia, ktor\u00e9 patria do skupiny idiopatick\u00fdch \u010drevn\u00fdch z\u00e1palov a zah\u0155\u0148aj\u00fa 2 formy: Crohnovu chorobu (Crohn disease, CD) a<\/p>\n","protected":false},"author":7,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_mi_skip_tracking":false,"footnotes":""},"categories":[1299],"tags":[1316,1318,1319,1317,1315],"class_list":["post-1825","post","type-post","status-publish","format-standard","hentry","category-nove-metody-liecby-en","tag-biological-therapy","tag-inflammatory-bowel-diseases","tag-nonresponse-to-anti-tnf-","tag-single-nucleotide-polymorphisms","tag-tnf--en","typ_clanku-review-article"],"acf":{"abstrakt":"

    Inflammatory bowel diseases are autoimmune diseases of the gastrointestinal tract characterized by chronic inflammation. Currently, it is supposed that in the pathogenesis, there is a link between immunological, microbio- logical, genetics, and also environmental factors. The incidence of inflammatory bowel diseases is increasing, and conventional therapy is not fully effective. Therefore new methods of treatment have been introduced, summarily referred to as biological therapy. These drugs, in contrast with conventional therapy, does not act systemically, but they are rather targeted against specific cytokines, which are involved in inflammatory processes. Biological treatment is an effective strategy for treating multiple autoimmune diseases, which can induce and even maintain the remission of the disease, and the quality of life of patients with Crohn\u2019s disease and ulcerative colitis can be significantly improved. However, a certain percentage of patients do not respond or lose response to this type of treatment over time. This paper provides a brief overview of the reasons for loss of clinical response among patients receiving biologics, namely to anti-TNF therapy.<\/p>\n

    Keywords<\/strong>: biological therapy, single nucleotide polymorphisms, inflammatory bowel diseases, nonresponse to anti-TNF-\u03b1, TNF-\u03b1<\/p>\n

     <\/p>\n","casopis":[{"ID":1883,"post_author":"7","post_date":"2019-10-28 13:35:57","post_date_gmt":"2019-10-28 12:35:57","post_content":"

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    • Accidental capture of the toxic strain Corynebacterium diphteriae<\/li>\r\n<\/ul>","post_title":"newsLab","post_excerpt":"","post_status":"publish","comment_status":"closed","ping_status":"closed","post_password":"","post_name":"newslab-004","to_ping":"","pinged":"","post_modified":"2019-11-04 13:53:35","post_modified_gmt":"2019-11-04 12:53:35","post_content_filtered":"","post_parent":0,"guid":"https:\/\/www.newslab.sk\/casopis\/newslab-4\/","menu_order":0,"post_type":"casopis","post_mime_type":"","comment_count":"0","filter":"raw"}],"strana":"94-98","upload_clanok":{"ID":1823,"id":1823,"title":"NEWSLAB_2-2019_Lojov\u00e1","filename":"NEWSLAB_2-2019_Lojov\u00e1.pdf","filesize":208011,"url":"https:\/\/www.newslab.sk\/wp-content\/uploads\/2019\/10\/NEWSLAB_2-2019_Lojov\u00e1.pdf","link":"https:\/\/www.newslab.sk\/en\/nespecificke-crevne-zapaly-priciny-straty-odpovede-pacientov-na-biologicku-liecbu\/newslab_2-2019_lojova-2\/","alt":"","author":"7","description":"","caption":"","name":"newslab_2-2019_lojova-2","status":"inherit","uploaded_to":1825,"date":"2019-10-29 09:52:21","modified":"2019-10-29 09:52:21","menu_order":0,"mime_type":"application\/pdf","type":"application","subtype":"pdf","icon":"https:\/\/www.newslab.sk\/wp-includes\/images\/media\/document.png"}},"_links":{"self":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1825","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/users\/7"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/comments?post=1825"}],"version-history":[{"count":0,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/posts\/1825\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/media?parent=1825"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/categories?post=1825"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newslab.sk\/en\/wp-json\/wp\/v2\/tags?post=1825"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}