Nyob rau hauv lub zog muaj zog ntawm kev kho mob rau provocative thiab tiv thaiv kab mob, ib tug ntse chav kawm ntawv ntawm cov tshuaj hu ua Janus kinase (JAK) inhibitors tau tshwm sim, qhia ib tug uplifting txoj kev rau resistant moj khaum. Ntawm cov kev pom zoo JAK inhibitors,upadacitinibtau tshwm sim raws li lub ntsiab lus ntawm convergence ntawm kev txaus siab inferable los ntawm nws unmistakable Cheebtsam ntawm kev ua ub no thiab xav tau kev pab nyob rau hauv ib tug ntau yam ntawm ailments. Hauv qhov blog no, peb tawm mus rau qhov kev tshawb nrhiav ntawm nws, dhia mus rau hauv nws cov yam ntxwv tshwj xeeb, cov ntawv thov muaj txiaj ntsig, thiab kev ruaj ntseg profiles los piav qhia nws qhov tseem ceeb hauv kev xyaum kho mob tam sim no.
Nws ua haujlwm raws li JAK inhibitor tshwj xeeb, siv nws qhov cuam tshuam los ntawm kev tsom mus rau Janus kinase txoj hauv kev, uas suav tias yog ib feem tseem ceeb hauv cov lus qhia tiv thaiv. Los ntawm kev tsom mus rau txoj kev tshwj xeeb no, nws tweaks lub zog ntawm cytokines cuam tshuam nrog tus ciav provocative, raws li alleviating txawv txav invulnerable cov tshuaj tiv thaiv ib txwm rau cov kab mob sib txawv thiab cov xwm txheej incendiary. Qhov kev ua haujlwm nuanced no lees paub tias nws yog tus kws tshaj lij muaj zog thiab muaj txiaj ntsig zoo, qhov chaw nws yog tus neeg sib tw pheej hmoo hauv qhov xwm txheej ntawm cov tshuaj immunomodulatory.
Qhov kev pab cuam ntawm nws muaj ntau yam sib txawv ntawm cov teeb meem ntawm incendiary thiab kev tiv thaiv kab mob, nrog rau cov kab mob rheumatoid pob qij txha, mob psoriatic pob qij txha, ankylosing spondylitis, thiab atopic dermatitis. Hais txog kev mob rheumatoid pob qij txha, nws tau nthuav tawm qhov muaj txiaj ntsig zoo hauv kev txhim kho kev mob nkeeg thiab txwv tsis pub muaj kev sib koom ua ke, raws li kev ua haujlwm los ntawm thiab cov txiaj ntsig tsis tu ncua. Tsis tas li ntawd, nyob rau hauv psoriatic mob pob qij txha thiab ankylosing spondylitis, nws qhia tau hais tias muaj peev xwm nyob rau hauv tending rau cov kev mob tshwm sim thiab easing rov qab mob zog, muab kev xav rov qab los rau cov neeg sib tw nrog cov xwm txheej tsis tu ncua. Tsis tas li ntawd, nyob rau hauv qhov chaw ntawm atopic dermatitis, nws nthuav qhia txoj kev cog lus rau kev daws cov teeb meem tsis zoo ntawm qhov teeb meem dermatological no, tshaj tawm lwm qhov hav zoov hauv kev kho mob.
Qhov tseem ceeb, zoo ib yam nrog kev kho kom haum xeeb, kev noj qab haus huv thiab kev muaj peev xwm ntawm nws ua kom ceev faj xav. Txawm hais tias feem ntau ua rau muaj kev kub ntxhov, kev siv nws yuav tsum tau ua tib zoo tshuaj xyuas qhov kev cia siab ntawm kev cuam tshuam, nrog rau cov kab mob, lub sijhawm thromboembolic, thiab kev kuaj mob tsis zoo. Cov neeg muab kev pabcuam khomob yuav tsum xyaum txiav txim siab hauv kev lees paub nws, ntsuas nws qhov yuav zoo tiv thaiv kev phom sij thiab kev xav ntawm tus neeg mob.
Dab tsi yog qhov txheej txheem ntawm kev ua ntawm upadacitinib, thiab nws txawv li cas ntawm cov tshuaj biologics?
Upadacitinibsawv sib nrug raws li ib qho tshwj xeeb thiab thim rov qab Janus kinase (JAK) inhibitor uas nyob hauv tsev hauv JAK1 cov protein, uas qhia txog qhov qis dua rau JAK2 thiab JAK3 [1]. Sib cais los ntawm cov kws kho mob tsis tu ncua xws li cov tshuaj tiv thaiv kab mob monoclonal lossis cov protein sib xyaw ua ke, nws cais nws tus kheej raws li cov khoom me me uas tswj tau rau lub koom haum ntawm qhov ncauj, qhia txog cov kauj ruam loj hauv kev txhim kho thiab kev nplij siab ntawm tus neeg mob.
Qhov tseem ceeb rau nws txoj haujlwm pharmacological, JAK cov tshuaj ua haujlwm ua haujlwm tseem ceeb hauv cov ciav dej ntawm cov cytokines sib txawv hauv cov tshuaj tiv thaiv thiab kev nyab xeeb. Los ntawm nws cov kev txwv tshwj xeeb ntawm JAK1, nws cuam tshuam rau txoj hauv kev ntawm txoj hauv kev ntawm kev txhawb nqa ntawm provocative cytokines, suav nrog interleukin-6 (IL-6), interferon-gamma (IFN- ), thiab granulocyte-macrophage kev sib haum xeeb animating variable (GM-CSF) [2]. Qhov kev sib haum xeeb no nyob rau hauv cytokine chij txoj hauv kev ua rau muaj kev cuam tshuam loj heev, ua tiav hauv qhov kev sib tw ntawm kev sib tw thiab kev kho kom rov qab los ntawm kev sib npaug.
Sib cais los ntawm kev coj noj coj ua hauv ntiaj teb ntawm biologics uas lub hom phiaj qhia meej cytokines lossis lawv cov receptors, nws ua haujlwm ntawm qhov tsis muaj qhov tsis txaus ntseeg hauv cov ciav dej chij, muab nws nrog kev nthuav dav ntawm kev ua haujlwm. Cov txheej txheem sib cais no tuav pov hwm rau cov txiaj ntsig tau txais txiaj ntsig ntsig txog kev muaj peev xwm, kev nyab xeeb, thiab muaj peev xwm ua rau muaj ntau yam kev kub ntxhov thiab kev tiv thaiv kab mob [3].
Qhov tshwj xeeb pharmacokinetic profile ntawm nws, piav qhia los ntawm nws qhov ncauj bioavailability thiab tshwj xeeb JAK1 hindrance, qhia txog nws qhov tseeb muaj peev xwm raws li tus kws kho mob hloov kho tau yooj yim thoob plaws ntau qhov chaw kho mob. Los ntawm kev tsom mus rau JAK1, nws tshawb nrhiav txoj hauv kev tsis txaus ntseeg ntawm qhov tsis txaus ntseeg tweak, muab txoj hauv kev tsim los daws cov teeb meem tshwm sim thaum muaj kev tiv thaiv tsis muaj txiaj ntsig tseem ceeb rau kev hais lus kev noj qab haus huv thiab kev vam meej.
Tsis tas li ntawd, qhov tshwj xeeb ntawm kev ua haujlwm tau pom los ntawm nws nthuav dav nws txoj kev kho kom zoo thiab tuav cov txiaj ntsig rau kev txhim kho cov txiaj ntsig kev kho mob thiab nthuav dav qhov muaj txiaj ntsig zoo rau cov neeg mob sib tw nrog cov teeb meem kub ntxhov thiab tiv thaiv kab mob. Qhov tseem ceeb ntawm cov ntsiab lus tseem ceeb ntawm cytokine chij txoj hauv kev qhia txog qhov tseeb thiab lub zog ntawm nws, tshaj tawm lwm lub sijhawm hauv kev kho tshuaj kho mob thiab txhawb kev muaj peev xwm ua haujlwm rau kev nkag siab txog kev txiav txim siab thiab mob rau cov thawj coj.
Feem ntau, qhov los ntawm nws raws li ib qho tshwj xeeb JAK inhibitor tshaj tawm qhov kev hloov pauv ntawm kev saib xyuas hauv kev kho mob kub hnyiab thiab tiv thaiv kab mob, ua kom muaj kev sib koom ua ke ntawm kev tsim kho, kev kho kom raug, thiab kev saib xyuas neeg mob. Nws cov yam ntxwv tsis muaj tseeb, suav nrog kev qhib qhov ncauj, tshwj xeeb JAK1 tsom mus rau, thiab muaj zog cytokine tshuav nyiaj li cas, qhia txog nws qhov seem uas yog cov khoom muaj txiaj ntsig zoo npaj los hloov kho qhov chaw kho mob thiab txhim kho cov txiaj ntsig rau cov neeg tshawb nrhiav txoj kev nyab xeeb interceded messes.
Dab tsi yog qhov kev siv tshuaj kho mob ntawm upadacitinib hauv ntau yam kab mob inflammatory thiab autoimmune?
Kev kho mob preliminaries ntawmupadacitinibtau divulged nws zoo heev yuav hla ntau yam incendiary thiab tiv thaiv kab mob, hais txog nws yooj yooj yim thiab dav restorative materialness.
Rheumatoid Joint mob (RA): Kev tshawb nrhiav dav tau nyob rau hauv nws ua tus thawj coj hauv kev kho mob rau RA, qhia txog qhov tseem ceeb hauv kev mob nkeeg rau cov thawj coj, kev hloov kho lub peev xwm tiag tiag, thiab kev txaus siab ntawm tus kheej ntawm cov neeg sib tw nrog nruab nrab mus rau RA [4].
Psoriatic Joint mob (kev tshaj tawm kev pabcuam pej xeem): Hauv kev tshaj tawm kev pabcuam pej xeem hauv pawg thawj coj, nws tau tshwm sim los ua ib qho kev txhawb nqa, qhia txog kev muaj peev xwm tseem ceeb hauv kev sib koom ua ke thiab daim tawv nqaij taw qhia thaum txhawb kev muaj txiaj ntsig zoo hauv cov neeg mob sib ntaus sib tua nrog kev tshaj tawm kev pabcuam pej xeem [5 ].
Ulcerative Colitis (UC): Lub peev xwm pab tau nws ncav cuag UC, qhov teeb meem tsis tu ncua ntawm lub plab, qhov uas nws tau nthuav tawm cov kauj ruam tseem ceeb hauv kev txhawb nqa kev txo qis thiab txhim kho mucosal kho tus nqi hauv cov neeg muaj teeb meem los ntawm nruab nrab mus rau UC [6].
Atopic Dermatitis (Txhim Kho): Nyob rau hauv qhov chaw ntawm Promotion lub rooj tsavxwm, nws tau ntog raws li ib tug cog lus khub, qhia nws muaj tseeb muaj peev xwm nyob rau hauv kev txhim kho daim tawv nqaij leeway thiab txo pruritus nyob rau hauv cov neeg mob tshawb nrhiav intricacies ntawm nruab nrab mus rau loj tshaj tawm [7].
Kev Tshawb Fawb Sab Nraud: Yav dhau los cov chaw tso tawm, cov txheej txheem kho kom zoo ntawm nws txuas ntxiv zuj zus, nrog cov kws tshaj lij khawb rau hauv nws cov kev npaj siv rau ntau qhov xwm txheej, piv txwv li, ankylosing spondylitis, goliath cell arteritis, thiab lupus nephritis, ntawm lwm tus [8].
Cov ntaub ntawv pov thawj kev kho mob muaj zog txhawb kev muaj peev xwm ntawm nws thoob plaws cov kab mob sib txawv no qhia txog nws qhov tseem ceeb hauv kev kho mob tseem ceeb nrog lub peev xwm los hloov kho cov qauv kev kho mob thiab txhim kho cov neeg mob tau txais txiaj ntsig hauv cov teeb meem kub ntxhov thiab tiv thaiv kab mob. Qhov dav ntawm nws qhov kev kho kom haum xeeb thiab qhov muaj txiaj ntsig ntawm nws cov txiaj ntsig tus neeg sawv cev rau lwm lub sijhawm hauv cov tshuaj raug raug, muab kev ntseeg siab dua thiab cov lus teb tsis txaus ntseeg rau cov neeg sib tw nrog qhov hnyav ntawm lub siab boggling resistant intervened tej yam kev mob.
Yuav ua li cas kev ruaj ntseg profile ntawm upadacitinib piv rau lwm yam JAK inhibitors thiab biologic agents?
Thaum noj qab haus huv profile ntawmupadacitinibyog rau feem ntau zoo, nws yog ib qho tseem ceeb los xav txog tej yam txaus ntshai thiab antagonistic cuam tshuam nrog rau nws siv.
Ib qho ntawm cov kev txhawj xeeb tseem ceeb nrog JAK inhibitors, suav nrog nws, yog kev twv txiaj ntxiv ntawm cov kab mob vim yog kev zais ntawm lub moj khaum invulnerable. Hauv kev kho mob ua ntej, nws tau cuam tshuam nrog tus nqi siab dua ntawm cov kab mob ua pa sab saud, kab mob herpes zoster (shingles), thiab cov kab mob sib kis tau sib txawv nrog kev kho mob cuav [9].
Ib qho ntxiv muaj peev xwm twv txiaj ntsig txog JAK inhibitors yog kev txhim kho ntawm hematological anomalies, xws li hlau tsis muaj peev xwm, neutropenia, thiab lymphopenia. Ib txwm kuaj ntshav suav yog qhia thaum kho nrog nws [10].
Sib piv nrog lwm cov JAK inhibitors, nws tau pom tias muaj feem tsawg dua ntawm qee lub sijhawm tsis zoo, xws li herpes zoster thiab venous thromboembolism (VTE), tejzaum nws yog vim nws qhov tshwj xeeb ntawm JAK1 [11]. Yuav ua li cas nws yuav, ncaj qha tsis muaj kev txwv tsis pub xeem yog tseem txwv, thiab kev tshawb nrhiav ntxiv yuav tsum tau soj ntsuam tag nrho cov kev noj qab haus huv tag nrho.
Thaum sib piv nrog cov kws tshaj lij biologic, piv txwv li, cov tshuaj tiv thaiv kab mob qog noj ntshav (TNF) inhibitors lossis interleukin inhibitors, nws tuaj yeem muab kev noj qab haus huv zoo dua li cov lus teb cuam tshuam txog infusion thiab immunogenicity [12]. Ua li ntawd, ntsuas qhov kev txaus ntshai thiab qhov zoo rau cov neeg mob ib leeg, suav nrog cov xwm txheej, piv txwv li, comorbidities thiab koom nrog cov tshuaj yog qhov tseem ceeb.
Tag nrho hauv tag nrho, nws hais txog qhov kev loj hlob loj hauv thaj chaw ntawm kev kho mob rau kev tiv thaiv kab mob thiab tiv thaiv kab mob. Nws cov ntsiab lus nthuav dav ntawm kev ua haujlwm raws li ib qho tshwj xeeb JAK inhibitor muaj ib txoj hauv kev los daws cov kev tswj hwm kev nyab xeeb, nrog rau cov kev xav tau ntawm cov kab mob sib txawv. Thaumupadacitinibtau nthuav tawm qhov muaj txiaj ntsig zoo hauv kev kho mob ua ntej, nws yog qhov ceev kom mob siab rau tshuaj xyuas nws cov ntaub ntawv kev nyab xeeb, tshuaj xyuas qhov cuam tshuam rau kev cuam tshuam, thiab ntsuas qhov phom sij thiab qhov zoo rau txhua tus neeg mob. Raws li kev soj ntsuam txuas ntxiv mus tshawb xyuas qhov muaj peev xwm siab tshaj plaws ntawm nws thiab lwm yam JAK inhibitors, cov kws kho mob tuaj yeem siv cov tshuaj tsim kho no los muab cov kev kho kom haum xeeb thiab ua tiav rau cov neeg mob uas muaj teeb meem kub ntxhov thiab tiv thaiv kab mob.
Cov ntaub ntawv:
[1] 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.
[2] 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.
[3] McInnes, IB, & Schett, G. (2017). Lub pathogenesis ntawm rheumatoid mob caj dab. New England Journal of Medicine, 376(22), 2094-2108.
[4] 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.
[5] 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.
[6] Sandborn, WJ, Feagan, BG, Rutgeerts, P., Hanauer, SB, Colombel, JF, Sands, BE, ... & D'Haens, GR (2019). Upadacitinib ua induction thiab kev kho mob rau ulcerative colitis. New England Journal of Medicine, 380(18), 1698-1707.
[7] Guttman-Yassky, E., Teixeira, HD, Simpson, EL, Papp, KA, Tahey, D., Patterson, AM, ... & Blauvelt, A. (2021). Ib zaug ib hnub upadacitinib piv rau cov placebo hauv cov tub ntxhais hluas thiab cov neeg laus uas muaj mob atopic dermatitis (Measure Up 1 thiab Measure Up 2): tshwm sim los ntawm ob qhov kev rov ua dua ob qhov muag tsis pom, randomized tswj theem 3 kev tshawb fawb. Lub Lancet, 397(10290), 2151-2168.
[8] Winthrop, KL, Silverfield, J., Izano, M., Bartok, B., Cohen, SB, Newmark, R., ... & Somers, EC (2019). Cov nyhuv ntawm tofacitinib rau cov tshuaj tiv thaiv kab mob pneumococcal thiab mob khaub thuas hauv cov kab mob rheumatoid. Annals ntawm cov kab mob rheumatic, 78(5), 688-695.
[9] Cohen, SB, Buch, MH, Tanaka, Y., Abernethy, DR, Gordon, K., Cawley, P., ... & Vazquez-Ortiz, M. (2021). Upadacitinib kev nyab xeeb profile: cov ntaub ntawv sib xyaw ua ke los ntawm kev xaiv rheumatoid mob caj dab kho mob. Rheumatology Advances in Practice, 5(2), rkab043.