BACKGROUND: Infliximab selectively targets recently activated effector cells and, as an induction agent, might enable the safe elimination of mycophenolate from maintenance immunosuppression in kidney transplantation. METHODS: This is a phase II international multicenter open-label single-arm confidence interval (CI)-based clinical trial of the BIO-DrIM EU consortium aimed at assessing the efficacy and safety of rabbit antithymocyte globulin and infliximab induction in kidney transplantation. Sixty-seven primary kidney transplant recipients at low risk (panel-reactive antibodies <20%, no donor-specific antibodies [DSA]) received rabbit antithymocyte globulin (2 × 1.5 mg/kg, postoperative days 0 and 1) and infliximab (5 mg/kg, postoperative day 2), followed by mycophenolate-free tacrolimus-based immunosuppression for 12 mo. The primary endpoint was efficacy failure, defined as a composite of acute rejection, graft loss, or poor graft function (estimated glomerular filtration rate <40 mL/min) at 12 mo and was based on the endpoint of the comparator study. Additionally, a historical propensity-matched control cohort was established. RESULTS: Primary endpoint occurred in 22 of 67 patients (32.84%), with upper bound of an exact 1-sided 95% CI of 43.47%, which met the predefined criteria (efficacy failure of <40% and upper-bound 95% CI of <50%) and was similar in the historical matched cohort. By 12 mo, 79.1% of patients remained on the study protocol. Lower rates of BK replication (6% versus 22.4%; P = 0.013) but higher rates of de novo DSAs (11.9% versus 1.5%; P = 0.039) were observed in the study cohort. CONCLUSIONS: A similar efficacy of the study immunosuppression regimen to the comparator study and the historical matched cohort was found. However, a higher de novo DSA emergence points to an increased risk of antibody-mediated rejection (NCT04114188).
- MeSH
- antilymfocytární sérum * MeSH
- imunosupresiva škodlivé účinky MeSH
- imunosupresivní léčba MeSH
- infliximab škodlivé účinky MeSH
- inhibitory enzymů MeSH
- lidé MeSH
- přežívání štěpu MeSH
- protilátky MeSH
- rejekce štěpu prevence a kontrola MeSH
- takrolimus * škodlivé účinky MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- multicentrická studie MeSH
BACKGROUND: Nonadherence to immunosuppressives, a risk factor for poor posttransplant outcomes, can be assessed by self-report using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS). Available in written and interview versions, and previously validated on content, the BAASIS is widely used in research and clinical practice. The aim of this study was to investigate its psychometric properties. METHODS: Using a literature search and our BAASIS database, this meta-analysis identified completed studies in adult transplant recipients whose data were usable to examine the BAASIS' reliability and 3 validity aspects: (1) relationships with other variables (electronic monitoring, other self-report scales, tacrolimus blood-level variability, collateral report, depressive symptoms, psycho-behavioral constructs, and interventions); (2) response processes; and (3) internal structure. Testing used random-effects logistic regressions. RESULTS: Our sample included 12 109 graft recipients from 26 studies. Of these 26, a total of 20 provided individual participant data. Evidence of the BAASIS' stability over time supports its reliability. Validity testing of relationships with other variables showed that BAASIS-assessed nonadherence was significantly associated with the selected variables: electronically monitored nonadherence ( P < 0.03), other self- and collaterally-reported nonadherence ( P < 0.001), higher variability in tacrolimus concentrations ( P = 0.02), higher barriers ( P < 0.001), lower self-efficacy ( P < 0.001), lower intention ( P < 0.001), and higher worries ( P = 0.02). Nonadherence also decreased after regimen change interventions ( P = 0.03). Response process evaluation indicated good readability and slightly higher nonadherence with the written version. Structurally, items on taking and timing shared variability. CONCLUSIONS: The BAASIS shows good validity and reliability as a self-report instrument to assess medication nonadherence in transplantation.
- MeSH
- adherence k farmakoterapii MeSH
- dospělí MeSH
- imunosupresiva * terapeutické užití MeSH
- lidé MeSH
- psychometrie MeSH
- reprodukovatelnost výsledků MeSH
- takrolimus * MeSH
- zpráva o sobě MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
BACKGROUND: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression. METHODS: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025. DISCUSSION: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents. TRIAL REGISTRATION: EU CT-Number: 2022-500024-30-00.
- MeSH
- dospělí MeSH
- imunosupresiva škodlivé účinky MeSH
- imunosupresivní léčba MeSH
- kvalita života MeSH
- lidé MeSH
- rejekce štěpu diagnóza prevence a kontrola MeSH
- takrolimus škodlivé účinky MeSH
- Torque teno virus * MeSH
- transplantace ledvin * škodlivé účinky MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: Acute rejection remains a vexing problem in vascularized composite allotransplantation (VCA). Available immunosuppressive regimens are successful at minimizing alloimmune response and allowing VCA in humans. However, repeated rejection episodes are common, and systemic side effects of the current standard regimen (Tacrolimus, MMF, Prednisone) are dose limiting. Novel immunomodulatory approaches to improve allograft acceptance and minimize systemic toxicity are continuously explored in preclinical models. We aimed to systematically summarize past and current approaches to help guide future research in this complex field. METHODS: We conducted a systematic review of manuscripts listed in the MEDLINE and PubMed databases. For inclusion, articles had to primarily investigate the effect of a therapeutic approach on prolonging the survival of a skin-containing preclinical VCA model. Non-VCA studies, human trials, anatomical and feasibility studies, and articles written in a language other than English were excluded. We followed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. RESULTS: The search retrieved 980 articles of which 112 articles were ultimately included. The majority of investigations used a rat model. An orthotopic hind limb VCA model was used in 53% of the studies. Cell and drug-based approaches were investigated 58 and 52 times, respectively. We provide a comprehensive review of immunomodulatory strategies used in VCA preclinical research over a timeframe of 44 years. CONCLUSION: We identify a transition from anatomically non-specific to anatomical models mimicking clinical needs. As limb transplants have been most frequently performed, preclinical research focused on using the hind limb model. We also identify a transition from drug-based suppression therapies to cell-based immunomodulation strategies.
- MeSH
- imunomodulace MeSH
- imunosupresiva farmakologie terapeutické užití MeSH
- krysa rodu rattus MeSH
- kůže MeSH
- lidé MeSH
- rejekce štěpu prevence a kontrola MeSH
- takrolimus terapeutické užití MeSH
- vaskularizovaná kompozitní alotransplantace * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- systematický přehled MeSH
S imunoglobulinem IgG4 asociované onemocnění (IgG4-related disease - IgG4-RD) je heterogenní skupina chorob s multiorgánovým poškozením, která byla rozpoznána v posledních 12 letech. Cílem tohoto textu je podat přehled zkušeností s léčbou této choroby. Glukokortikoidy zůstávají stále léčbou první volby, ale dlouhodobé podávání glukokortikoidů v monoterapii je spojeno s četnými nežádoucími účinky a komplikacemi. V případě kombinace glukokortikoidů s některým z léků ze skupiny imunosupresiv je možné podávat nižší dávky glukokortikoidů po kratší čas a počet léčebných odpovědí je vyšší než při použití pouhých glukokortikoidů. Rituximab je možno použít jako monoterapii anebo v kombinaci s glukokortikoidy a imunosupresivními léky. Který z imunosupresivních léků považovat za nejvhodnější, není známo. Pouze jedna studie srovnávala léčbu kombinací glukokortikoidů a mykofenolát mofetilu s léčbou glukokortikoidy a cyklofosfamidem. Počet léčebných odpovědí byl v obou ramenech stejný, ale délka remise byla delší ve skupině pacientů léčených glukokortikoidy a cyklofosfamidem. Rituximab dosahuje vysoký počet léčebných odpovědí (90 %) i v monoterapii, ale je možné jeho účinek dále potencovat glukokortikoidy a imunosupresivy. Rituximab je nyní preferován a doporučován pro udržovací léčbu v dávce 1000 mg 1× za 6 měsíců. U pacientů s multiorgánovým postižením se nám osvědčila kombinace rituximabu, cyklofosfamidu a dexametazonu následovaná aplikací rituximabu s jednorázovou dávku dexametazonu v 6měsíčních intervalech. V klinickém zkoušení jsou dva nové a nadějné léky: abatacept a dupilimab. Základem pro úspěšnou léčbu je podobně jako u jiných chorob časná diagnostika se zahájením léčby před vznikem ireversibilních fibrotických změn v postižených orgánech.
Immunoglobulin IgG4 related disease (IgG4-RD) is a heterogeneous disorder with multi-organ involvement recognised as a separate entity at the beginning of this century only. Evolving therapy is reviewed in this paper. Glucocorticoids are first choice drug but long administration of glucocorticoids is connected with many adverse effects. In case of combination glucocorticoids and immunosuppressive agents lower doses of glucocorticoids are needed, the response rate is higher and therapy is better tolerated. Rituximab is drug, that is possible use as monotherapy or in combination with glucocorticoids and immunosuppressive drugs. Only one study compared two immunosuporessive drugs, mycophenolate mofetil and cyclophosphamide. The response rated was similar but remissions were longer after glucocorticoids with cyclophosphamide then glucocorticoids with mycofenolat mofetil. No other comparative study of combination of various imunossupressive drugs with glucocorticoids was published. Rituximab has high number (90 %) of response rate in monotherapy, but can be used in combination with glucocorticoids and immunosuppressives. Rituximab is now preferred and recommended for maintenance therapy administered in 6-month interval. In case of advanced disease, we prefer therefore combination of rituximab, cyclofosphamide and dexamethasone for initial therapy followed by maintenance with rituximab in 6 months interval. There are two new drugs under investigation abatacept and dupilimab with promising results. Although we have very intensive therapies for good results of therapy early diagnosis before irreversible fibrotic changes in IgG4-RD involved organs is still needed.
- Klíčová slova
- dupilumab,
- MeSH
- abatacept farmakologie terapeutické užití MeSH
- glukokortikoidy farmakologie terapeutické užití MeSH
- IgG4 asociovaná nemoc * farmakoterapie MeSH
- imunosupresiva farmakologie terapeutické užití MeSH
- lidé MeSH
- rituximab farmakologie terapeutické užití MeSH
- sirolimus farmakologie terapeutické užití MeSH
- takrolimus farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Achieving fast immunosuppression blood exposure after kidney transplantation is key to abrogating both preformed and de novo anti-donor humoral and cellular alloresponses. However, while tacrolimus (TAC) is the cornerstone immunosuppressant inhibiting adaptive alloimmunity, its blood exposure is directly impacted by different single-nucleotide polymorphisms (SNPs) in CYP3A TAC-metabolizing enzymes. Here, we investigated how functional TAC-CYP3A genetic variants (CYP3A4*22/CYP3A5*3) influence the main baseline clinical and immunological risk factors of biopsy-proven acute rejection (BPAR) by means of preformed donor-specific antibodies (DSAs) and donor-specific alloreactive T cells (DSTs) in a large European cohort of 447 kidney transplants receiving TAC-based immunosuppression. A total of 70 (15.7%) patients developed BPAR. Preformed DSAs and DSTs were observed in 12 (2.7%) and 227 (50.8%) patients, respectively. According to the different CYP3A4*22 and CYP3A5*3 functional allele variants, we found 4 differential new clusters impacting fasting TAC exposure after transplantation; 7 (1.6%) were classified as high metabolizers 1 (HM1), 71 (15.9%) as HM2, 324 (72.5%) as intermediate (IM), and 45 (10.1%) as poor metabolizers (PM1). HM1/2 showed significantly lower TAC trough levels and higher dose requirements than IM and PM (p < 0.001) and more frequently showed TAC underexposure (<5 ng/ml). Multivariate Cox regression analyses revealed that CYP3A HM1 and IM pharmacogenetic phenotypes (hazard ratio (HR) 12.566, 95% CI 1.99-79.36, p = 0.007, and HR 4.532, 95% CI 1.10-18.60, p = 0.036, respectively), preformed DSTs (HR 3.482, 95% CI 1.99-6.08, p < 0.001), DSAs (HR 4.421, 95% CI 1.63-11.98, p = 0.003), and delayed graft function (DGF) (HR 2.023, 95% CI 1.22-3.36, p = 0.006) independently predicted BPAR. Notably, a significant interaction between T-cell depletion and TAC underexposure was observed, showing a reduction of the BPAR risk (HR 0.264, 95% CI 0.08-0.92, p = 0.037). Such variables except for DSAs displayed a higher predictive risk for the development of T cell-mediated rejection (TCMR). Refinement of pretransplant monitoring by incorporating TAC CYP3A SNPs with preformed DSAs as well as DSTs may improve current rejection-risk stratification and help induction treatment decision-making.
- MeSH
- cytochrom P-450 CYP3A * genetika imunologie metabolismus MeSH
- hodnocení rizik MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- paměťové B-buňky * imunologie MeSH
- T-lymfocyty * imunologie MeSH
- takrolimus * farmakologie terapeutické užití MeSH
- transplantace ledvin * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Local immunosuppression in vascularized composite allotransplantation (VCA) aims to minimize immunosuppressant-related toxic and malignant side effects. Promising allograft survival data have been published by multiple workgroups. In this systematic review, we examine preclinical animal studies that investigated local immunosuppression in VCA. MATERIAL AND METHODS: We conducted a systematic review of manuscripts listed in the MEDLINE and PubMed database concerning preclinical VCA models. Papers included had to be available as full-text and written in English. Non-VCA studies, human trials, and studies using cell-based therapy strategies were excluded. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Literature research retrieved 980 articles. Ten studies published between 2010 and 2019 met the inclusion and exclusion criteria. Seven out of ten articles demonstrated a significant prolongation of allograft survival by using local immunosuppression. Five articles employed tacrolimus (TAC) as the main immunosuppressive agent. Seven studies performed hind-limb VCA in a rat model. CONCLUSION: The easily accessible location of skin containing VCAs makes it an ideal candidate for local immunosuppression. Published preclinical data are very promising in terms of improved allograft survival and reduced systemic toxicity.
- MeSH
- imunosupresiva aplikace a dávkování terapeutické užití MeSH
- imunosupresivní léčba metody MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- prasata MeSH
- rejekce štěpu prevence a kontrola MeSH
- takrolimus aplikace a dávkování terapeutické užití MeSH
- vaskularizovaná kompozitní alotransplantace * MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- systematický přehled MeSH
Autoři popisují případ 39letého nemocného s 8 let trvající folliculitis decalvans. Onemocnění progredovalo Effectivzdor systémové léčbě antibiotiky, izotretinoinem, lokálními kortikosteroidy a kalcineurinovými inhibitory. Zastavení progrese na 6 měsíců bylo dosaženo pulzní intravenózní léčbou kortikosteroidy následovanou terapií doxycyklinem. Diskutován je klinický a histopatologický obraz a diferenciální diagnostika. Připojena je klasifikace jizvících alopecií a návrh terapeutického algoritmu folliculitis decalvans.
Authors describe the case of a 39-year-old patient with eight years history of folliculitis decalvans. The disease progressed despite systemic treatment with antibiotics, isotretinoin, topical corticosteroids and calcineurin inhibitors. Stable condition was achieved by pulse intravenous corticosteroid therapy followed by oral doxycycline for six months. The clinical and histopathological features and differential diagnosis are discussed. The classification of scarring alopecias and therapeutic algorithm of folliculitis decalvans are attached.
- Klíčová slova
- folliculitis decalvans, jizvící alopecie,
- MeSH
- alopecie * diagnóza farmakoterapie klasifikace MeSH
- antibakteriální látky terapeutické užití MeSH
- chronická nemoc MeSH
- dermatózy skalpu * diagnóza farmakoterapie patologie MeSH
- diferenciální diagnóza MeSH
- dospělí MeSH
- hormony kůry nadledvin terapeutické užití MeSH
- lidé MeSH
- takrolimus terapeutické užití MeSH
- vlasový folikul anatomie a histologie patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Cíle: Cílem této studie je prokázat účinnost takrolimu (TAC), látky s imunosupresivními účinky díky inhibici kalcineurinu, v léčbě cerebrálních vazospazmů indukovaných subarachnoidální hemoragií (SAH) na modelu potkana. Materiály a metody: Do studie bylo po získání souhlasu etické komise zahrnuto 18 potkanů (samců) Sprague-Dawley. Potkani mohli v Morrisově vodním bludišti plavat ve čtyřech směrech, dokud nebylo dosaženo plató křivek kognitivních funkcí (4 dny). Po nácviku plaveb byly u potkanů v celkové anestezii fixovány všechny čtyři končetiny a hlava byla držena ve flexi pod úhlem 20° v pronační poloze. SAH byla indukována podáním 0,4 cm3/kg autologní arteriální krve do cisterna magna. Takrolimus (0,5 mg/kg, 2 dávky) byl podán intraperitoneálně pro léčbu indukovaného vazospazmu a byla hodnocena jeho účinnost. Závěr: Při porovnávání časů plaveb za 3 dny a ve všech směrech v kontrolní skupině a skupinách SAH a SAH-TAC bylo pozorováno snížení středních časů plaveb ve skupině, které byl po SAH podán takrolimus. V rámci analýzy rozptylu pomocí Kruskalova-Wallisova testu však nebyly v distribuci středních časů plaveb za tři dny pozorovány žádné signifikantní rozdíly mezi kontrolou a skupinami SAH a SAH-TAC na 95% intervalu spolehlivosti (p = 0,366).
Aim: The present study aims to demonstrate the efficacy of tacrolimus (TAC), an agent showing immunosuppressive effects through calcineurin inhibition, in the treatment of subarachnoid haemorrhage (SAH)-induced cerebral vasospasm in rat models. Material and Methods: The study, after gaining the approval of the ethics committee, included 18 male Sprague-Dawley rats which were allowed to swim in four directions within a Morris water maze until the cognitive function curves reached a plateau (4 days). After the retention swimming, four extremities were found while the rats were held in a prone position with the head at 20 degrees flexion under general anaesthesia. SAH was induced through the administration of 0.4 cc/ kg of autologous arterial blood into the cisterna magna. Tacrolimus (0.5 mg/ kg, 2 doses) was administered intraperitoneally for the treatment of the induced vasospasm, and its efficacy was investigated. Conclusion: When the three-day all-direction swimming times of the control, of SAH and SAH-TAC groups were compared, a decrease was noted in the mean times of swimming within the group administered with tacrolimus after SAH, although a Kruskal-Wallis variance analysis did not indicate any significant difference in the distribution of the mean three-day swimming times between control, SAH and SAH-TAC groups, at a 95% confidence interval (P = 0.366).
Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E-) were randomized to LI (n = 48) or SOC (n = 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E- (4/35 [13%] vs. 1/43 [2%], p = .15 and 12/48 [25%] vs. 6/53 [11.3%], p = .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocol analyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E- patients, notably E-/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p = .043). Eplet mismatch also predicted anti-class-I (p = .05) and anti-DQ (p < .001) de novo DSA. Adverse events were similar, but E-/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p = .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.
- MeSH
- imunosupresiva terapeutické užití MeSH
- imunosupresivní léčba MeSH
- lidé MeSH
- přežívání štěpu MeSH
- rejekce štěpu etiologie prevence a kontrola MeSH
- T-lymfocyty MeSH
- takrolimus * terapeutické užití MeSH
- testování histokompatibility MeSH
- transplantace ledvin * škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
