Nyob rau hauv lub zog muaj zog ntawm kev kho mob rau provocative thiab tiv thaiv kab mob, txoj kev loj hlob ntawm Janus kinase (JAK) inhibitors tau qhia lwm lub sij hawm ntawm cov tshuaj raug, qhov tseem ceeb reshaping kho cov qauv zoo tagnrho rau cov teeb meem nyuaj no. Ntawm cov khoom pov thawj sib txawv ntawm JAK inhibitors,upadacitinibtau nce raws li kev txhawb nqa kos npe, nthuav tawm cov txiaj ntsig tsis muaj txiaj ntsig uas ua rau muaj kev cog lus hloov pauv hauv kev tswj hwm ntawm kev nyab xeeb interceded messes.
Kev khawb rau hauv qhov nyuaj ntawm nws nthuav tawm ib qho kev nkag siab zoo ntawm nws txoj haujlwm ntawm kev ua haujlwm thiab kev kho kom zoo. Los ntawm tshwj xeeb tshaj tawm JAK cov tshuaj tseem ceeb hauv cytokine chij txoj hauv kev, nws tswj xyuas qhov sib npaug zoo ntawm cov txheej txheem tiv thaiv, tsom mus rau txoj hauv kev tsis sib haum xeeb hauv atomic txoj hauv kev ensnared nyob rau hauv lub pathogenesis ntawm provocative thiab tiv thaiv kab mob. Qhov kev hloov kho no tau muab cais ua tus thawj coj hauv lub luag haujlwm kom muaj zog ntxiv thiab muaj kev sib haum xeeb nyob rau hauv cov kev kho mob immunomodulatory.
Thaum peb tshawb txog qhov xwm txheej ntawm nws, peb nthuav tawm cov yam ntxwv zoo kawg nkaus tso nws ua qhov zoo sib xws hauv kev txiav txim siab ntev. Nws qhov kev xaiv siab rau JAK1, tsis zoo li lwm yam JAK inhibitors, tsis yog kev kwv yees zoo rau qhov kev ruaj ntseg zoo tshaj plaws tsis tau ntxiv rau qhov qhia tau tias muaj peev xwm hloov kho dua tshiab hauv kev sib tw rau ntau yam kev nyab xeeb interceded. Kev soj ntsuam kuaj mob tau qhia txog kev cog lus ntawm nws hauv kev xa cov txiaj ntsig zoo sib xws lossis zoo dua li cov kws kho mob biologic uas twb muaj lawm, qhia txog nws lub peev xwm los txiav qhov tshwj xeeb raws li kev kho mob hauv paus hauv kev kho mob armamentarium rau cov mob xws li mob pob qij txha, psoriatic pob qij txha, thiab atopic dermatitis.
Qhov kev tuaj ntawm nws hais txog ib kauj ruam loj heev rau kev kho tshuaj kho mob, qhov twg cov tshuaj yog tsim los rau cov khoom tsim nyog thiab zais cov kab mob. Los ntawm kev tsom mus rau qhov tsis meej pem hauv qhov kev ua haujlwm tsis txaus ntseeg, nws muaj kev txhawb nqa rau cov neeg mob sib tw nrog cov teeb meem ntawm kev kub ntxhov thiab kev tiv thaiv kab mob, npaj kom muaj zog dua, raug xaiv, thiab ua rau muaj kev kub ntxhov ntau heev.
Tag nrho cov nyob rau hauv tag nrho cov, qhov nce ntawm nws connotes ib tug kev hloov nyob rau hauv kev xam pom nyob rau hauv kev tswj ntawm fiery thiab tiv thaiv kab mob kab mob, qhov tseem ceeb ntawm txoj kev loj hlob mus rau qhov tseeb tshuaj. Raws li peb tshem tawm cov lus zais ntawm nws thiab ua pov thawj nws cov txiaj ntsig tseem ceeb ntawm kev txiav txim siab tsis tu ncua, peb sawv ntawm qhov kev txiav txim siab ntawm lwm hnub so hauv qhov chaw kho mob, qhov chaw kho mob muaj tswv yim tuav kev cog lus ntawm kev tsim cov txiaj ntsig ntxiv thiab txhim kho tus kheej txaus siab rau cov neeg tshawb nrhiav cov teeb meem ntawm resistant intervened tej yam kev mob.
Yuav ua li cas yog lub mechanism ntawm kev txiav txim uas teem upadacitinib sib nrug los ntawm lwm yam JAK inhibitors?
Upadacitinib, ib qho me me uas muaj qhov chaw nrog cov chav kawm ntawm Janus kinase (JAK) inhibitors, tau tshwm sim raws li kev hloov pauv kev ua si rau cov kab mob kub hnyiab thiab tsis muaj zog. Cov teeb meem no tau piav qhia los ntawm kev tsis sib haum xeeb ntawm lub moj khaum invulnerable, ua rau tsis tu ncua ua rau hnyav dua thiab cov ntaub so ntswg raug mob. Los ntawm kev tsom mus rau JAK pawg ntawm cov tshuaj, nws siv nws cov tshuaj tiv thaiv kab mob, muab txoj hauv kev ntse los daws cov kev mob siab no [1].
Thaum lwm cov JAK inhibitors zoo li tofacitinib thiab baricitinib tso tawm ntau qhov cuam tshuam rau ntau yam JAK catalysts, nws cais nws tus kheej los ntawm nws qhov tshwj xeeb txwv ntawm JAK1. Cov ntsiab lus nthuav dav no yog lub hauv paus ntawm nws cov tshuaj pharmacological, cais nws ntawm nws cov neeg koom tes [2].
Los ntawm kev tsom mus rau JAK1 ntau dhau, nws cuam tshuam qhov kev txav mus los ntawm qhov tseem ceeb uas muaj txiaj ntsig zoo rau cytokines, suav nrog interleukin -6 (IL-6), interferon-gamma (IFN- ), thiab granulocyte-macrophage xeev animating variable ( GM-CSF). Cov cytokines no suav tias yog qhov tseem ceeb hauv kev tsav tsheb cov tshuaj tiv thaiv tiv thaiv thiab txhawb kev ua kom hnyav ntxiv. Los ntawm nws cov kev cai tshwj xeeb ntawm cytokine chij txoj hauv kev, nws ua tiav stifles fiery cycles thiab rov tsim kho homeostasis nyab xeeb [3].
Qhov kev xaiv tshwj xeeb ntawm nws rau JAK1 tuav qhov tseem ceeb ntawm kev kho kom rov zoo. Los ntawm kev cuam tshuam ncaj qha rau JAK1- cuam tshuam cov chij, nws txwv tsis pub muaj kev cuam tshuam nrog lwm cov tshuaj JAK, tej zaum yuav txo qis kev twv txiaj ntawm kev cuam tshuam thiab ua rau muaj kev sib haum xeeb ntawm kev txaus siab thiab kev noj qab haus huv. Qhov kev xaiv qhov profile no tau sau cov kev xav txog nws lub peev xwm rau nruab nrab cov sijhawm tsis zoo uas cuam tshuam nrog JAK inhibitors, piv txwv li, herpes zoster reactivation thiab venous thromboembolism [4].
Cov kev tshawb fawb soj ntsuam tau pom cov txiaj ntsig tau zoo rau nws hla ntau yam kev cuam tshuam uas cuam tshuam tsis zoo. Hauv qhov mob rheumatoid sib koom tes (RA), nws pom tau tias muaj kev vam meej zoo dua li kev kho mob cuav thiab lwm yam mob kho cov tshuaj tiv thaiv kab mob (DMARDs), suav nrog methotrexate [5]. Ntxiv mus, nws tau pom muaj kev vam meej hauv psoriatic pob qij txha o (kev tshaj tawm kev pabcuam pej xeem), nrog kev hloov pauv loj hauv kev sib koom ua ke thiab cov cim ntawm daim tawv nqaij [6]. Tsis tas li ntawd, nyob rau hauv atopic dermatitis (Txhim Kho), nws tau pom tias muaj qhov txaus txaus hauv kev txo qis kev mob hnyav thiab ua haujlwm ntawm tus kheej txaus siab [7].
Qhov zoo tshaj plaws ntawm kev ua si thiab kev xaiv ntawm nws feature nws muaj peev xwm muaj tseeb raws li ib qho tseem ceeb nthuav mus rau pab armamentarium rau incendiary thiab invulnerable interceded mob. Ua li ntawd, zoo ib yam li kev kho mob ntse, kev soj ntsuam tas li yog qhov tseem ceeb rau kev nkag siab zoo dua nws qhov kev noj qab haus huv, tsim nyog, thiab kev siv zoo. Ncaj nraim ntawm kev tshuaj ntsuam sib piv nws thiab lwm yam JAK inhibitors thiab cov kws kho mob biologic yuav tsum paub txog nws qhov zoo thiab qhov tsis zoo nyob hauv ntau tus neeg mob.
Tag nrho hauv tag nrho, nws hais txog kev nce qib tseem ceeb hauv kev kho mob rau kev ua rau muaj kev cuam tshuam thiab muaj kev nyab xeeb. Nws qhov kev cuam tshuam tshwj xeeb ntawm JAK1 muaj qhov tsis txaus ntseeg ntawm cov tshuaj siv tshuaj, tejzaum nws hloov mus rau kev txhim kho ntxiv thiab kev noj qab haus huv zoo. Raws li kev ntsuam xyuas kev nce qib, kev paub ntxiv rau hauv nws cov khoom, kev siv zoo tagnrho, thiab cov txiaj ntsig ntev ntev yuav zoo li nws txoj haujlwm hauv cov txheej txheem kho mob, thaum kawg ua haujlwm ntawm cov neeg mob sib tw nrog cov xwm txheej nyuaj no.
upadacitinib qhov kev xaiv tshwj xeeb profile pab txhawb rau nws cov peev xwm kho mob thiab kev nyab xeeb li cas?
Qhov tshwj xeeb txwv ntawm JAK1 los ntawmupadacitinibtuav kev cog lus loj hauv kev hloov kho qhov xwm txheej ntawm kev kho kom haum xeeb rau cov teeb meem tiv thaiv kab mob thiab tiv thaiv kab mob. Qhov kev xaiv no muaj ntau qhov txiaj ntsig zoo uas tuaj yeem txhim kho kev muaj peev xwm thiab kev ruaj ntseg profile ntawm tus thawj JAK inhibitor.
Ib qho txiaj ntsig tseem ceeb ntawm nws qhov tshwj xeeb txwv ntawm JAK1 yog nyob rau hauv nws lub peev xwm tiag tiag rau kev ua haujlwm ntawm kev kho kom zoo. Los ntawm kev tsom mus rau JAK1- cuam tshuam txoj hauv kev, nws tuaj yeem siv ntau qhov zais zais ntawm cov neeg tua hluav taws tseem ceeb xws li IL-6 thiab IFN- . Cov cytokines xav tias qhov chaw ceev hauv kev tsav tsheb neurotic cycles tseem ceeb sib txawv provocative thiab tiv thaiv kab mob. Los ntawm kev tsom ntsoov rau JAK1, nws tuaj yeem nthuav qhia qhov tsim nyog txaus hauv hosing distorted muaj kev cuam tshuam kev nyab xeeb thiab tshuaj xyuas qhov khaus [4].
Tsis tas li ntawd, qhov kev xaiv ntawm nws qhov kev txwv tsis pub muaj kev ntseeg siab kom deb npaum li qhov txwv tsis pub cuam tshuam. Tsis yog txhua yam zoo li ntau yam JAK inhibitors uas tuaj yeem cuam tshuam ntau yam tshuaj JAK, suav nrog JAK2 thiab JAK3 cuam tshuam nrog hematopoiesis thiab muaj peev xwm tiv taus ntawm tes, nws qhov chaw ua haujlwm nyob ib puag ncig JAK1 tuaj yeem txo qis kev twv txiaj ntawm qee lub sijhawm tsis zoo cuam tshuam nrog ntau JAK kev txwv. Qhov tshwj xeeb tsom mus rau qhov no tuaj yeem ua rau muaj qhov tshwm sim ntawm hematological anomalies thiab txo cov kev tiv thaiv kev tiv thaiv ib txwm pom nrog tsawg dua JAK inhibitors [5].
Txawm hais tias nws muaj peev xwm ua tau zoo thiab txo qis qhov cuam tshuam, nws qhov kev xaiv profile kuj tseem qhia txog kev noj qab haus huv zoo. Ob qhov kev tshawb nrhiav kev kho mob thiab kev kho mob ua ntej tau qhia tias muaj feem cuam tshuam ntawm kev twv txiaj tsis zoo ntawm qhov tsis pom zoo nrog nws sib piv nrog lwm cov JAK inhibitors. Eminently, kev txhawj xeeb, piv txwv li, herpes zoster reactivation thiab venous thromboembolism, uas tau cuam tshuam nrog JAK kev txwv, tej zaum yuav txo tau los ntawm nws qhov tshwj xeeb hindrance ntawm JAK1 thiab nws txwv cov nyhuv rau lwm yam JAK catalysts embroiled nyob rau hauv cov cycles [6].
Txawm hais tias cov txiaj ntsig zoo ntawm nws qhov kev xaiv tau cog lus tseg, kev tshawb fawb txuas ntxiv yog qhov tseem ceeb kom nkag siab txog cov txiaj ntsig kho mob ntawm qhov nthuav dav pharmacological profile tag nrho. Kev sib raug zoo ncaj qha nrog lwm tus JAK inhibitors los ntawm tsis muaj kev txwv tsis pub ua ntej yuav yog qhov ceev hauv kev qhia meej txog kev noj qab haus huv ntawm tus txheeb ze thiab kev tsim nyog ntawm nws hauv qhov tseeb. Raws li yuav ua li cas peb txhais tau qhov kev hloov pauv tsis txaus ntseeg ntawm JAK chij txoj hauv kev thiab kab mob pathogenesis txhim kho, lub peev xwm siab tshaj plaws ntawm nws raws li kev kho kom haum rau cov neeg mob uas muaj teeb meem kub hnyiab thiab tiv thaiv kab mob tej zaum yuav pom, qhia lwm lub sijhawm ntawm cov tshuaj raug nyob hauv thaj tsam ntawm kev tiv thaiv kab mob.
Dab tsi yog cov kev sim tshuaj tseem ceeb thiab kev tshawb fawb tshawb fawb uas tau ua rau peb nkag siab txog upadacitinib?
Kev txhim kho ntawmupadacitinibtau raug tsav los ntawm qhov kev pab cuam kho mob ua ntej muaj zog, hla ntau yam kev tiv thaiv kab mob thiab tiv thaiv kab mob. Cov txheej txheem ua ntej no tau muab cov kev paub tseem ceeb rau hauv cov tshuaj kom txaus, kev noj qab haus huv, thiab tej zaum yuav rov qab siv tau:
1. Rheumatoid Jointitis (RA): Qhov kev pab cuam SELECT kev kho mob ua ntej, muaj ob peb theem 3 kev ntsuam xyuas, tau soj ntsuam qhov muaj peev xwm thiab kev ruaj ntseg ntawm nws hauv cov neeg mob uas muaj mob me me mus rau RA [7]. Cov thawj coj no tau qhia txog kev hloov kho tseem ceeb hauv kev ua mob, muaj peev xwm tiag tiag, thiab cov txiaj ntsig hluav taws xob nrog nws sib piv nrog kev kho tsis raug thiab methotrexate.
2. Psoriatic Jointitis (kev tshaj tawm kev pabcuam pej xeem): Daim ntawv tshaj tawm SELECT-public kev pabcuam 1 thiab SELECT-public kev pabcuam tshaj tawm 2 ua ntej tau tshawb nrhiav kev siv ntawm nws hauv cov neeg mob nrog kev tshaj tawm kev pabcuam pej xeem [8]. Cov kev ntsuam xyuas no tau qhia txog kev hloov pauv tseem ceeb hauv kev sib koom tes thiab cov tawv nqaij, nrog rau qhov muaj peev xwm tiag tiag, nrog rau nws qhov sib txawv nrog kev kho mob cuav thiab adalimumab (ib TNF inhibitor).
3. Atopic Dermatitis (Txhim Kho): Qhov Kev Ua 1 thiab Ntsuas 2 qhov ua ntej tau soj ntsuam qhov muaj peev xwm thiab kev nyab xeeb ntawm nws hauv cov neeg mob uas muaj kev txhawb nqa loj mus rau nruab nrab [9]. Cov kev ntsuam xyuas no tau qhia txog kev hloov kho tseem ceeb hauv daim tawv nqaij leeway thiab tingle txo nrog nws sib piv nrog kev kho cuav.
4. Ulcerative Colitis (UC): U-Ua tiav kev lees paub thiab kev txhawb nqa kev tshawb fawb tau tshawb fawb txog kev siv nws hauv cov neeg mob uas muaj qhov nruab nrab mus rau UC [10]. Cov txheej txheem ua ntej no tau pom cov txiaj ntsig tau zoo hauv kev ua tiav kev kho mob txo qis thiab cov mucosal recuperating nrog nws sib piv nrog kev kho mob cuav.
5. Cov tsos mob sib txawv: Nws kuj tseem raug soj ntsuam hauv qhov sib txawv ntawm lwm yam kev kub ntxhov thiab kev tiv thaiv kab mob, piv txwv li, ankylosing spondylitis, lupus nephritis, thiab dab cell arteritis, nrog rau kev kho mob ua ntej ntsuas nws qhov muaj peev xwm muaj tseeb nyob ib puag ncig [11].
Raws li kev tshuaj ntsuam xyuas ntawm nws txuas ntxiv txhim kho, peb yuav txhais li cas nws cov peev xwm kho dua tshiab thiab kev ruaj ntseg profile yuav txuas ntxiv, npaj rau nws yuav siv tau ntau yam kev ua rau muaj kev tiv thaiv kab mob thiab tiv thaiv kab mob.
Nyob rau hauv tag nrho,upadacitinibhais txog txoj hauv kev tseem ceeb hauv kev kho mob rau kev tiv thaiv kab mob thiab tiv thaiv kab mob. Nws qhov tshwj xeeb xaiv profile, tsom rau JAK1, cais nws los ntawm lwm yam JAK inhibitors thiab muab lub peev xwm rau kev txhim kho ntxiv thiab muaj txiaj ntsig zoo. Txawm hais tias cov kev kho mob tas mus li ua ntej yuav ua li cas peb tuaj yeem txhais cov ntsiab lus tseem ceeb no, cov kws tshawb fawb tau tsim muaj kev cia siab, tab sis tseem muaj kev tiv thaiv txog kev kho lub peev xwm ntawm nws nyob rau hauv kev saib xyuas rau cov neeg mob uas tsis quav ntsej txog qhov sib txawv provocative thiab tiv thaiv kab mob.
Cov ntaub ntawv:
[1] Banerjee, S., Biehl, A., Gadina, M., Hasni, S., & Schwartz, DM (2017). JAK-STAT signaling raws li lub hom phiaj rau inflammatory thiab autoimmune kab mob: tam sim no thiab yav tom ntej prospects. Tshuaj, 77(5), 521-546.
[2] Parmentier, JM, Voss, J., Bem, C., Picklev, J., Zavialova, E., Harjunpää, H., ... & Smolen, JS (2018). Hauv vitro thiab hauv vivo tus cwj pwm ntawm JAK1 xaiv ntawm upadacitinib (ABT-494). BMC rheumatology, 2(1), 1-14.
[3] McInnes, IB, & Schett, G. (2017). Lub pathogenesis ntawm rheumatoid mob caj dab. New England Journal of Medicine, 376(22), 2094-2108.
[4] Banerjee, S., Biehl, A., Gadina, M., Hasni, S., & Schwartz, DM (2017). JAK-STAT signaling raws li lub hom phiaj rau inflammatory thiab autoimmune kab mob: tam sim no thiab yav tom ntej prospects. Tshuaj, 77(5), 521-546.
[5] Quintás-Cardama, A., Vaddi, K., Liu, P., Manshouri, T., Li, J., Scherle, PA, ... & Verstovsek, S. (2010). Preclinical characterization ntawm kev xaiv JAK1/2 inhibitor INCB018424: kho qhov cuam tshuam rau kev kho mob ntawm myeloproliferative neoplasms. Ntshav, Phau ntawv Journal ntawm American Society of Hematology, 115(15), 3109-3117.
[6] Cohen, SB, van Vollenhoven, RF, Winthrop, KL, Zubrzycka-Sienkiewicz, A., Zuckerman, A., Kivitz, AJ, ... & Vastesaeger, N. (2022). Kev nyab xeeb profile ntawm upadacitinib nyob rau hauv rheumatoid mob caj dab: kev tsom xam los ntawm kev xaiv theem III kev sim tshuaj ntsuam xyuas. Annals of the Rheumatic Diseases, 81(4), 504-512.
[7] Burmester, GR, Kremer, JM, Van den Bosch, F., Kivitz, A., Bessette, L., Li, Y., ... & Takeuchi, T. (2018). Kev nyab xeeb thiab kev ua tau zoo ntawm upadacitinib hauv cov neeg mob rheumatoid mob caj dab thiab cov lus teb tsis txaus rau cov kab mob sib xyaw ua ke-hloov tshuaj tiv thaiv kab mob rheumatic (SELECT-NEXT): ib qho randomised, ob-dig muag, placebo-tswj theem 3 mus sib hais. Lub Lancet, 391(10139), 2503-2512.
[8] Mease, PJ, Gladman, DD, Aviña-Zubieta, A., Müller, A., Kreusch, N., Ganguly, R., ... & Helliwell, PS (2021). Kev ua tau zoo thiab kev nyab xeeb ntawm Upadacitinib hauv cov neeg mob uas muaj mob Psoriatic mob caj dab: 24- Cov Ntaub Ntawv Lub Limtiam los ntawm Theem 3 SELECT-PsA 1 Txoj Kev Kawm. Rheumatology thiab Therapy, 8(3), 1217-1238.