ITIES Dotaz Zobrazit nápovědu
Clinical oral implants research, ISSN 1600-6275 vol. 11, suppl. no. 1, 2000
158 s. : il., tab., grafy ; 30 cm
Inhibítory faktora VIII (FVIII) predstavujú závažnú komplikáciu liečby hemofílie. Prioritou liečby pacientov s inhibítormi je eradikácia inhibítorov a indukcia imunitnej tolerancie (ITI), ktorá umožní opätovnú liečbu faktorom VIII. Úspešnosť ITI je 60–85 % čo znamená, že časť pacientov s inhibítormi je stále odkázaná na menej účinnú liečbu prípravkami s "bypassing" aktivitou. V súčasnosti sú vo vývoji nefaktorové lieky, ktoré umožnia prevenciu krvácaní aj u pacientov s inhibítormi. Prvým liekom uvedeným do praxe je bišpecifická protilátka proti faktorom IXa a X – emicizumab, ktorý bol registrovaný pre profylaxiu nielen u pacientov s inhibítormi, ale aj bez inhibítorov. Dostupnosť nefaktorovej liečby môže zásadne zmeniť doterajšiu paradigmu liečby hemofílie, vrátane prístupu k včasnej profylaxii a manažmentu ITI. V práci diskutujeme význam ITI, prezentujeme výsledky ITI v našom centre a prvé skúsenosti s nefaktorovou liečbou emicizumabom u troch pacientov vo veku 3,5–7 rokov. U dvoch pacientov sme emicizumab indikovali po zlyhaní ITI a u jedného pacienta po úspešnej ITI pre objektívne prekážky farmakokineticky riadenej profylaxie s FVIII. Pri absencii krvácania počas 7–13 mesiacov hodnotíme profylaxiu bišpecifickou protilátkou ako vysoko efektívnu.
Factor VIII (FVIII) inhibitors are the most challenging complication of haemophilia treatment. The priority is to eradicate the inhibitors and induce immune tolerance (ITI) to allow resumption of therapy with FVIII. The success rate of ITI is 60-85%, which means that some patients with inhibitors remain dependent on less effective treatment with bypassing agents. New, non-factor drugs are currently under development for effective prophylaxis in inhibitor patients. The first non-factor agent already in use is emicizumab, a bispecific antibody against factors IXa and X, which has been authorized for prophylaxis not only in patients with inhibitors but also in those without inhibitors. The availability of non-factor treatment can fundamentally change the current paradigm of haemophilia treatment, including access to early prophylaxis and ITI management. We discuss here the importance of ITI and we present the results of ITI in our centre and our first experience with non-factor treatment using emicizumab in three patients aged 3.5-7 years. Emicizumab was indicated in two patients with ITI failure and in one patient after successful ITI because of objective obstacles to pharmacokinetic guided prophylaxis with FVIII. In the absence of bleeding for 7-13 months, we evaluate bispecific antibody prophylaxis as being highly effective.
- Klíčová slova
- emicizumab,
- MeSH
- faktor VIII MeSH
- hemofilie A * farmakoterapie MeSH
- humanizované monoklonální protilátky terapeutické užití MeSH
- lidé MeSH
- předškolní dítě MeSH
- protilátky bispecifické terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- Publikační typ
- kazuistiky MeSH
Thieme flexibook
2. rev. ed 17, 510 s.
- Konspekt
- Stomatologie
- NLK Obory
- zubní lékařství
2., neubearb. und erw. Aufl. XV, 497 s.
- Konspekt
- Stomatologie
- NLK Obory
- zubní lékařství
Nedavne pokroky v molekulovej diagnostike hemofilie položili zaklady pre študium genotypovych a fenotypovych suvislosti a študium vplyvu genovych mutacii na vyskyt komplikacii choroby, akymi su inhibitory FVIII. V praci prezentujeme prve vysledky Narodneho genetickeho hemofilickeho programu, založeneho v r. 2014. Geneticky sme doteraz vyšetrili 173 pacientov s hemofiliou A, z nich 141 s ťažkym stupňom hemofilie, čo predstavuje 60 % populacie ťažkych hemofilikov na Slovensku. V subore ťažkych hemofilikov sme identifikovali 39 roznych mutacii, z nich 18 novych, doposiaľ neevidovanych v medzinarodnej mutačnej databaze. Zastupenie mutacii v našej populacii 141 pacientov s ťažkym stupňom hemofilie je v zhode s literaturou, inverzie intronov 22 a 1 u 59 (42 %), nonsense mutacie u 16 (11 %), veľke delecie u 4 (3 %), frame shift/stop kodon mutacie u 38 (27 %), splice site mutacie u 5 (4 %) a missense mutacie u 19 (13 %) pacientov. Analyza genovych mutacii u 34 pacientov s inhibitormi potvrdila porovnateľne riziko vzniku inhibitora pri inverziach (27 %), nonsense mutaciach (25 %) aj pri frame shift/stop kodon mutaciach (29 %), pričom vyššie riziko inhibitorov nesu mutacie ľahkeho oproti mutaciam ťažkeho reťazca – OR:2,57(0,85–7,77). Hodnotenie efektu imunotolerančnej indukcie (ITI) u 22 pacientov (26 ITI kur) podľa typu mutacie ukazalo kompletnu a parcialnu remisiu v 75 % pri inverziach a v 88–100 % pri ostatnych genovych mutaciach. Vysledky su ovplyvnene malou početnosťou suboru, problematika si vyžaduje ďalšie študium.
Recent advances in molecular diagnosis of haemophilia have enabled the study of genotypic and phenotypic relationships and of the effect of gene mutations on the occurrence of serious disease complications, such as inhibitors. We present the first results of the National Genetic Haemophilia Program, established in 2014. So far, we have investigated 173 haemophilia A patients, of which 141 have severe haemophilia, representing 60% of the population of severe haemophiliacs in Slovakia. In severe haemophiliacs, we identified 39 different mutations, including 18 new mutations not yet listed in the international mutation database. The proportion of mutations in our population of 141 severe haemophiliacs is consistent with literature: inversions of introns 22 and 1 in 59 (42%), nonsense mutations in 16 (11%), large deletions in 4 (3%), frame shift/stop codon mutations in 38 (27%), splice site mutations in 5 (4%) and missense mutations in 19 (13%) of patients. Analysis of gene mutations in 34 inhibitor patients confirmed a comparable risk of inhibitor development in patients with inversions (27%), nonsense mutations (25%) and frame shift/stop codon mutations (29%), with a higher risk of mutations localized in parts of the F8 gene encoding the light chain of FVIII molecule compared to heavy chain mutations – OR: 2.57 (0.85-7.77). Evaluation of the success rate of immune tolerance induction (ITI) in 22 patients (26 ITI courses) according to the gene defects in inhibitor patients showed complete and partial remission in 75% and 88-100% of patients with inversions and other gene mutations, respectively. These results are influenced by the small number of patients and this issue requires further study.
- Klíčová slova
- mutace genu F8,
- MeSH
- faktor VIII antagonisté a inhibitory MeSH
- genetické testování MeSH
- hemofilie A * genetika MeSH
- klinická studie jako téma MeSH
- lidé MeSH
- mutace MeSH
- Check Tag
- lidé MeSH
Diabetes mellitus 2. typu (DM2T) je komplexné, chronické, v mnohých smeroch unikátne, nevyliečiteľné (ale lieči- teľné) ochorenie s celosvetovo sa zvyšujúcou prevalenciou. Cieľom tejto práce je analýza výskytu DM2T u pacien- tov prijatých pre akútne srdcové zlyhanie (ASZ) a pacientov prijatých pre akútny koronárny syndróm (AKS) počas ústavných pohotovostných služieb (ÚPS) na I. internej klinike v našom rajóne (cca 150 000 obyvateľov). Prijatých bolo 302 a vyšetrených 1 052 pacientov. Z nich bolo prijatých 45 pacientov (15 %) pre ASZ a 34 pacientov (11 %) pre AKS. Najčastejším typom ASZ bola akútna dekompenzácia chronického srdcového zlyhávania (CHSZ) (82 %). U 40 % pacientov prijatých pre akútne srdcové zlyhávanie bol prítomný diabetes mellitus. Z kardiovaskulárnych ko- morbidít sa najčastejšie vyskytovala artériová hypertenzi a. Najčastejšie sa vyskytujúcou nekardiovaskulárnou ko- morbiditou (30 % u pacientov s DM, 18 % u pacientov bez DM) bolo chronické ochorenie obličiek. Charakteristika pacientov prijatých pre AKS: 73 % pacientov prijatých pre NSTEMI, 24 % pacientov prijatých pre nestabilnú anginu pectoris a 3 % pacientov prijatých pre STEMI. Až 35 % prijatých pacientov bolo diabetikov. Akútne srdcové zlyha- nie bolo častejšou príčinou hospitalizácie ako akútny koronárny syndróm. U oboch skupín prijatých pacientov (ASZ v 40 % aj AKS v 35 %) bol častý výskyt DM2T. Teda leká r starajúci sa o pacienta s kardiovaskulárnymi ochoreniami má vedieť, či tento pacient je alebo nie je diabetikom.
Diabetes mellitus type 2 (DM2T) is a complex, chronic, in many ways unique, incurable (but treatable) disease with a worldwide increase of prevalence. The aim of this work is to analyse presence of DM2T in patients admitted due to acute heart failure (AHF) and patients admitted due to acute coronary syndrome (ACS) during the emergency services at I. Internal Clinic in our region (about 150 000 inhabitants). 302 patients were admitted and 1 052 were examined. 45 patients (15%) were admitted due to AHF and 34 patients (11%) due to ACS. The most frequent type of AHF was acute decompensation of chronic heart failure (CHHF) (82%). Diabetes mellitus was present in 40 % pa- tients admitted due to acute heart failure. Hypertensi on was the most frequent among cardiovascular comorbid- ities. The most common non-cardiovascular comorbidity (30% patients with DM, 18% patients without DM) was chronic kidney disease. Characteristics of patients admitted for ACS: 73% of patients admitted for NSTEMI, 24% of patients admitted for unstable angina and 3% of patients admitted for STEMI. Up to 35% of patients admitted were diabetics. Acute heart failure was more frequent cause of hospitalization than acute coronary syndrome. DM2T was quite common in both groups of patients admitted (40% in AHF and 35% in ACS). In conclusion, physicians manag- ing patients with cardiovascular disease should know whether the patient is diabetic or not.
- MeSH
- akutní koronární syndrom * etiologie komplikace metabolismus MeSH
- diabetes mellitus 2. typu * komplikace krev metabolismus MeSH
- komorbidita * MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- srdeční selhání * etiologie komplikace metabolismus MeSH
- statistika jako téma MeSH
- urgentní lékařství statistika a číselné údaje MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
Factor VIII (FVIII) inhibitor formation is a major clinical concern during replacement therapy in patients with hemophilia A. Immune tolerance induction (ITI) is the only therapeutic approach to attempt inhibitor eradication and establishment of long-term immune tolerance to FVIII. Hemophilia Inhibitor Previously Untreated Patient (PUP) Study (HIPS) was a prospective clinical trial to investigate changes in the immune system of PUPs with severe hemophilia A. Five patients who developed persistent FVIII inhibitors during HIPS entered an ITI extension arm (HIPS-ITI). During HIPS-ITI, inhibitor patients received ITI with the same FVIII product (a single source of recombinant, human full-length FVIII) used in HIPS until successful tolerance, declared failure, or a maximum of 2 years after HIPS-ITI enrollment, whichever came first. Blood samples and clinical data were collected monthly. Longitudinal FVIII-binding antibody signatures, associated binding specificities, and apparent affinities were determined for each patient at each sampling time point. ITI was successful or partially successful in 2 patients and failed in 3. Both groups presented with distinct FVIII-specific antibody signatures. ITI success required the disappearance of FVIII inhibitors, which was associated with the eradication or sustained titer minimization of high-affinity FVIII-specific antibodies, particularly of the immunoglobulin G1 (IgG1) and IgG4 subclasses. In contrast, ITI failure, as reflected by FVIII inhibitor persistence, was associated with persistent high-affinity FVIII-specific antibodies. Interestingly, 1 patient with partial ITI success and 1 patient with ITI failure developed apparent oligoreactive FVIII-binding antibodies during ITI. The explanation of the true nature of these antibodies requires more comprehensive follow-ups in future studies. This trial was registered at www.clinicaltrials.gov as #NCT01652027.
Prevention of bleeding and its consequences is the main goal of hemophilia treatment and determines treatment choices for patients who develop inhibitors. To assess bleeding before and during immune tolerance induction (ITI) and its association with ITI regimen and inhibitor titer, we selected and analyzed data on patients receiving high-titer inhibitors from the international prospective PedNet cohort study. In total, 222 patients with severe hemophilia A and inhibitor titers of >5 Bethesda units (BU) were followed from the first positive to the first negative inhibitor result (median overall follow-up, 1.7 years). Mean annual (joint) bleeding rates (AJBR) and 95% confidence intervals (CIs) were compared according to treatment and inhibitor titer using multivariable negative binomial regression. Before ITI, 115 patients showed an ABR of 6.1 (5.0-7.4) and an AJBR 2.6 (2.1-3.2). Bleeding was independent of inhibitor titer. During ITI, 202 patients had an ABR of 4.4 (3.9-5.1) and an AJBR of 1.7 (1.5-2.0). AJBR during ITI increased with inhibitor titer (hazard ratio [HR] for ≥200 BU vs 5 to 39 BU [4.9; CI, 3.2-7.4]) and decreased with daily ITI infusions (HR, 0.4; CI, 0.3-0.6) or activated prothrombin complex concentrate prophylaxis (HR, 0.4; CI, 0.2-0.8), whereas ITI dose and recombinant activated factor VII prophylaxis did not independently affect bleeding. These data provide evidence for a protective effect of repeated FVIII infusions (ITI) on bleeding in patients who have developed inhibitors; these data should be used to plan ITI and/or serve as a comparator for prophylaxis with nonreplacement therapy.
- MeSH
- faktor VIII MeSH
- hemofilie A * komplikace MeSH
- imunologická tolerance MeSH
- kohortové studie MeSH
- krvácení etiologie MeSH
- lidé MeSH
- prospektivní studie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
