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2.
Rev Med Suisse ; 18(793): 1588-1593, 2022 Aug 31.
Artigo em Francês | MEDLINE | ID: mdl-36047549

RESUMO

Azathioprine keeps an important place in the treatment of inflammatory bowel disease and autoimmune hepatitis. This molecule has a narrow therapeutic margin, associated with a risk of toxicity, particularly hematological and hepatic. Its complex metabolism is subject to genetic polymorphisms that are reflected in the inter-individual variability observed in the response to treatment and its tolerance profile. Hence, its use requires a good knowledge of this molecule. Treatment is initiated after a preliminary workup, followed by a progressive titration of the dosage while closely monitoring possible toxicities. Monitoring of blood levels of metabolites (including active ones) helps guide personalized dose adjustment.


L'azathioprine garde actuellement une place importante dans le traitement des maladies inflammatoires chroniques de l'intestin et de l'hépatite autoimmune. Il s'agit d'une molécule à marge thérapeutique étroite, associée à un risque de toxicité, notamment hématologique et hépatique. Son métabolisme complexe est influencé par des polymorphismes génétiques qui sont reflétés dans la variabilité interindividuelle observée dans la réponse au traitement et le profil de tolérance. Son utilisation nécessite donc une bonne connaissance de cette molécule. L'instauration du traitement se fait après un bilan préalable, puis une titration progressive des posologies, tout en surveillant étroitement les éventuelles toxicités. Le monitoring des concentrations sanguines des métabolites (notamment actifs) permet de guider l'adaptation personnalisée des posologies.


Assuntos
Gastroenterologia , Doenças Inflamatórias Intestinais , Azatioprina/metabolismo , Azatioprina/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico
3.
J Phys Chem B ; 126(36): 6936-6947, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36066119

RESUMO

Hemocompatibility is one of the major criteria for the successful cardiovascular applicability of novel biomaterials. In this context, monolayers of certain biomolecules can be used to improve surface biocompatibility. To this end, biocoatings incorporating a phospholipid (1,2-dioleoyl-sn-glycero-3-phosphocholine, DOPC), an immunosuppressant (cyclosporine A, CsA), and an antioxidant material (lauryl gallate, LG) were fabricated by depositing Langmuir films onto gold or mica substrates using the Langmuir-Blodgett (LB) technique. These LB monolayers were thoroughly characterized by means of quartz crystal microbalance (QCM), atomic force microscopy (AFM), cyclic voltammetry (CV), and contact angle (CA) measurements. The obtained results indicate that the properties of these LB films are modulated by the monolayer composition. The presence of LG in the three-component systems (DOPC-CsA-LG) increases the molecular packing and the surface coverage of the substrate, which affects the wettability of the biocoating. From the different compositions studied here, we conclude that DOPC-CsA-LG monolayers with a DOPC/CsA ratio of 1:1 and LG molar fractions of 0.50 and 0.75 exhibit improved surface biocompatible characteristics. These results open up new perspectives on our knowledge and better understanding of phenomena at the biomaterial/host interface.


Assuntos
Antioxidantes , Fosfolipídeos , Imunossupressores , Microscopia de Força Atômica , Fosfolipídeos/química , Propriedades de Superfície , Molhabilidade
4.
Cochrane Database Syst Rev ; 9: CD012854, 2022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-36094829

RESUMO

BACKGROUND: Non-adherence to immunosuppressant therapy is a significant concern following a solid organ transplant, given its association with graft failure. Adherence to immunosuppressant therapy is a modifiable patient behaviour, and different approaches to increasing adherence have emerged, including multi-component interventions. There has been limited exploration of the effectiveness of interventions to increase adherence to immunosuppressant therapy. OBJECTIVES: This review aimed to look at the benefits and harms of using interventions for increasing adherence to immunosuppressant therapies in solid organ transplant recipients, including adults and children with a heart, lung, kidney, liver and pancreas transplant. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 14 October 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs), quasi-RCTs, and cluster RCTs examining interventions to increase immunosuppressant adherence following a solid organ transplant (heart, lung, kidney, liver, pancreas) were included. There were no restrictions on language or publication type. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles and abstracts of identified records, evaluated study quality and assessed the quality of the evidence using the GRADE approach. The risk of bias was assessed using the Cochrane tool. The ABC taxonomy for measuring medication adherence provided the analysis framework, and the primary outcomes were immunosuppressant medication initiation, implementation (taking adherence, dosing adherence, timing adherence, drug holidays) and persistence. Secondary outcomes were surrogate markers of adherence, including self-reported adherence, trough concentration levels of immunosuppressant medication, acute graft rejection, graft loss, death, hospital readmission and health-related quality of life (HRQoL). Meta-analysis was conducted where possible, and narrative synthesis was carried out for the remainder of the results. MAIN RESULTS: Forty studies involving 3896 randomised participants (3718 adults and 178 adolescents) were included. Studies were heterogeneous in terms of the type of intervention and outcomes assessed. The majority of studies (80%) were conducted in kidney transplant recipients. Two studies examined paediatric solid organ transplant recipients. The risk of bias was generally high or unclear, leading to lower certainty in the results. Initiation of immunosuppression was not measured by the included studies. There is uncertain evidence of an association between immunosuppressant medication adherence interventions and the proportion of participants classified as adherent to taking immunosuppressant medication (4 studies, 445 participants: RR 1.09, 95% CI 0.95 to 1.20; I² = 78%). There was very marked heterogeneity in treatment effects between the four studies evaluating taking adherence, which may have been due to the different types of interventions used. There was evidence of increasing dosing adherence in the intervention group (8 studies, 713 participants: RR 1.14, 95% CI 1.03 to 1.26, I² = 61%).  There was very marked heterogeneity in treatment effects between the eight studies evaluating dosing adherence, which may have been due to the different types of interventions used. It was uncertain if an intervention to increase immunosuppressant adherence had an effect on timing adherence or drug holidays. There was limited evidence that an intervention to increase immunosuppressant adherence had an effect on persistence. There was limited evidence that an intervention to increase immunosuppressant adherence had an effect on secondary outcomes. For self-reported adherence, it is uncertain whether an intervention to increase adherence to immunosuppressant medication increases the proportion of participants classified as medically adherent to immunosuppressant therapy (9 studies, 755 participants: RR 1.21, 95% CI 0.99 to 1.49; I² = 74%; very low certainty evidence). Similarly, it is uncertain whether an intervention to increase adherence to immunosuppressant medication increases the mean adherence score on self-reported adherence measures (5 studies, 471 participants: SMD 0.65, 95% CI -0.31 to 1.60; I² = 96%; very low certainty evidence). For immunosuppressant trough concentration levels, it is uncertain whether an intervention to increase adherence to immunosuppressant medication increases the proportion of participants who reach target immunosuppressant trough concentration levels (4 studies, 348 participants: RR 0.98, 95% CI 0.68 to 1.40; I² = 40%; very low certainty evidence). It is uncertain whether an intervention to increase adherence to immunosuppressant medication may reduce hospitalisations (5 studies, 460 participants: RR 0.67, 95% CI 0.44 to 1.02; I² = 64%; low certainty evidence). There were limited, low certainty effects on patient-reported health outcomes such as HRQoL. There was no clear evidence to determine the effect of interventions on secondary outcomes, including acute graft rejection, graft loss and death. No harms from intervention participation were reported. AUTHORS' CONCLUSIONS: Interventions to increase taking and dosing adherence to immunosuppressant therapy may be effective; however, our findings suggest that current evidence in support of interventions to increase adherence to immunosuppressant therapy is overall of low methodological quality, attributable to small sample sizes, and heterogeneity identified for the types of interventions. Twenty-four studies are currently ongoing or awaiting assessment (3248 proposed participants); therefore, it is possible that findings may change with the inclusion of these large ongoing studies in future updates.


Assuntos
Imunossupressores , Transplante de Órgãos , Adolescente , Adulto , Criança , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Adesão à Medicação , Transplantados
5.
Front Immunol ; 13: 987841, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36110863

RESUMO

Objective: To explore the clinical features and prognoses of dermatomyositis (DM) associated with a double-positive anti-MDA5 and anti-aminoacyl-tRNA synthetase (anti-ARS) antibody presentation. Methods: We retrospectively analyzed 1280 consecutive patients with idiopathic inflammatory myopathy (IIM). Individuals with anti-MDA5 and anti-ARS antibodies (anti-MDA5+/ARS+) were compared to anti-MDA5-/ARS+ and anti-MDA5+/ARS- control individuals based on clinical, pulmonary radiological characteristics, treatment, and follow-up information. Results: Six individuals (0.47%) presented with anti-MDA5+/ARS+; of these, 2 (33.3%) were anti-PL-12+, 2 (33.3%) were anti-Jo-1+, 1 (16.7%) was anti-EJ+, and 1 (16.7%) was anti-PL-7+. Hallmark cutaneous manifestations, including Gottron's sign (100%), heliotrope rash (50%), mechanic's hand (66.7%), and skin ulcers (16.7%) were common. Anti-MDA5+/ARS+ patients tended to have higher ferritin levels (p = 0.038) than anti-MDA5-/ARS+ group, and higher CD4+ T-cell counts (p = 0.032) compared to the anti-MDA5+/ARS- group. Radiologically, NSIP with OP overlap was predominant (60%). Consolidation (60%), ground-glass attenuation (GGA) (80%), traction bronchiectasis (80%), and intralobular reticulation (100%) were common in anti-MDA5+/ARS+ individuals. All were diagnosed with ILD and 50% were categorized as RPILD. All patients received glucocorticoids combined with one or more immunosuppressants. Most (83.3%) had a good prognosis following treatment, but there was no difference in the survival rate between the three subgroups. Conclusion: Presentation with anti-MDA5+/ARS+ DM was rare. The clinical and radiological characteristics of anti-MDA5+/ARS+ DM combined the features of anti-MDA5+ and anti-ARS+ individuals. Individuals with anti-MDA5+/ARS+ antibodies may respond well to glucocorticoid therapy; glucocorticoids combined with one or more immunosuppressants may be considered a basic treatment approach.


Assuntos
Aminoacil-tRNA Sintetases , Dermatomiosite , Doenças Pulmonares Intersticiais , Autoanticorpos , Dermatomiosite/diagnóstico , Dermatomiosite/tratamento farmacológico , Ferritinas , Glucocorticoides , Humanos , Imunossupressores , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Prognóstico , Estudos Retrospectivos
6.
PLoS One ; 17(9): e0273720, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36067203

RESUMO

Myasthenia gravis (MG) is the most common autoimmune neuromuscular disorder, and is more common in women than in men. Anemia is also more common in women. The purpose of this study was to investigate factors associated with anemia and the negative impact of anemia in female MG patients. We investigated factors related to MG and anemia in 215 female patients with MG, who were attending the MG clinic of Keio Hospital between January and December 2021. We statistically evaluated clinical factors related to anemia in patients with and without anemia. Eighty-five patients (40%) had anemia in the past, and 130 patients did not have anemia in the past. There were no significant differences in age at study, age at MG onset, body mass index, or frequency of autoantibodies between the anemia and non-anemia groups. MG severity evaluated by the MG Foundation of America classification was greater in the anemia group than in the non-anemia group. History of anemia was associated with immunosuppressive treatment, such as prednisolone and calcineurin inhibitor treatment. There was a correlation between hemoglobin levels and the MG-quality of life score. Long term immunosuppressive therapy can cause anemia in female MG patients. Anemia may negatively affect the quality of life of female MG patients.


Assuntos
Anemia , Miastenia Gravis , Anemia/complicações , Anemia/tratamento farmacológico , Autoanticorpos , Inibidores de Calcineurina/uso terapêutico , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Miastenia Gravis/tratamento farmacológico , Qualidade de Vida
7.
BMJ Open ; 12(9): e061339, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36130755

RESUMO

INTRODUCTION: Both rituximab (RTX) and cyclophosphamide (CYC) are effectively used in combination with steroids as remission induction therapy for patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Several studies have shown that the effect on achieving (clinical) remission, frequency and severity of relapses is equivalent for both therapies, but there is accumulating data that the long-term safety profile of RTX might outperform CYC. Combination of RTX with low-dose CYC (LD-CYC) has been investigated in only a few uncontrolled cohort studies, in which clinical remission and a favourable immunological state with low relapse rates was quickly achieved. In this randomised controlled trial, we aim to investigate whether the combination treatment (RTX+LD CYC) is superior in comparison to standard care with RTX only. METHODS AND ANALYSIS: This study is an open-label, multicentre, 1:1 randomised, prospective study for patients with AAV with generalised disease, defined as involvement of major organs, that is, kidneys, lungs, heart and nervous system. In total, 100 patients will be randomised 1:1 to receive either remission induction therapy with standard of care (RTX) or combination treatment (RTX+LD CYC) in addition to steroids and both arms are followed by maintenance with RTX retreatments (tailored to B-cell and ANCA status). Our primary outcome is the number of retreatments needed to maintain clinical remission over 2 years. Secondary outcomes are relevant clinical endpoints, safety, quality of life and immunological responses. ETHICS AND DISSEMINATION: This study has received approval of the Medical Ethics Committee of the Leiden University Medical Center (P18.216, NL67515.058.18, date: 7 March 2019). The results of this trial (positive and negative) will be submitted for publication in relevant peer-reviewed publications and the key findings presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT03942887.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anticorpos Anticitoplasma de Neutrófilos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Estudos Multicêntricos como Assunto , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Rituximab , Resultado do Tratamento
8.
Trials ; 23(1): 780, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109788

RESUMO

Kidney transplant recipients are at an increased risk of severe COVID-19-associated hospitalisation and death. Vaccination has been a key public health strategy to reduce disease severity and infectivity, but the effectiveness of COVID vaccines is markedly reduced in kidney transplant recipients. Urgent strategies to enhance vaccine efficacy are needed. METHODS: RIVASTIM-rapamycin is a multicentre, randomised, controlled trial examining the effect of immunosuppression modification prior to a third dose of COVID-19 vaccine in kidney transplant recipients who have failed to develop protective immunity to a 2-dose COVID-19 vaccine schedule. Participants will be randomised 1:1 to either remain on standard of care immunosuppression with tacrolimus, mycophenolate, and prednisolone (control) or cease mycophenolate and commence sirolimus (intervention) for 4 weeks prior to and following vaccination. The primary outcome is the proportion of participants in each trial arm who develop protective serological neutralisation of live SARS-CoV-2 virus at 4-6 weeks following a third COVID-19 vaccination. Secondary outcomes include SARS-CoV-receptor binding domain IgG, vaccine-specific immune cell populations and responses, and the safety and tolerability of sirolimus switch. DISCUSSION: Immunosuppression modification strategies may improve immunological vaccine response. We hypothesise that substituting the mTOR inhibitor sirolimus for mycophenolate in a triple drug regimen will enhance humoral and cell-mediated responses to COVID vaccination for kidney transplant recipients. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12621001412820. Registered on 20 October 2021; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382891&isReview=true.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Imunossupressores , Transplante de Rim , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Humanos , Imunoglobulina G , Terapia de Imunossupressão , Imunossupressores/efeitos adversos , Inulina , Transplante de Rim/efeitos adversos , Estudos Multicêntricos como Assunto , Prednisolona , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Sirolimo/efeitos adversos , Serina-Treonina Quinases TOR , Tacrolimo
9.
Front Endocrinol (Lausanne) ; 13: 941215, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36111292

RESUMO

Diabetic kidney disease (DKD) combined with Membranous Nephropathy (MN) was observed in some patients with the increasing of Diabetic patients. However, no treatment guidelines are available for DKD combined with MN. In this study, we for the first time analyzed the safety and efficacy of leflunomide (LEF) combined with low-dose glucocorticoid methylprednisolone (MP) in the treatment of DKD with MN. We retrospectively collected the clinical data of patients with the highest number of DKD combined with MN diagnosed by renal biopsy between December 2016 and December 2020. The inclusion criteria were a history of diabetes for more than 20 months, no glucocorticoid therapy or immunosuppressant therapy for at least 6 months, urine protein level greater than 3.5 g, and a follow-up time of 16 months. In addition to conservative treatment, the patients received LEF monotherapy (LEF, n = 38) or LEF combined with low-dose methylprednisolone (LEF+MP, n = 26). After 16 months of treatment, the complete remission rate was 2.6%, and the remission rate was 15.8% in the LEF group; in the LEF+MP group, the complete remission rate and the remission rate were 23.1% and 34.6%, respectively. At month 16, the urine protein level was lower than the baseline value in both groups (p < 0.05) and was significantly lower in the LEF+MP group than in the LEF group (p < 0.05). Serum albumin levels were higher than the baseline value in both groups (p < 0.05), with no significant between-group difference (p > 0.05). No inter- or intragroup difference in serum creatinine or glycated hemoglobin was observed. During treatment, the relapse rate was lower in the LEF+MP group than in the LEF group (p < 0.05). No irreversible adverse events were observed. In summary, LEF+MP is more effective than LEF monotherapy for DKD combined with MN. Large, long-term, randomized, double-blind, controlled studies are needed to further validate the clinical efficacy of LEF+MP.


Assuntos
Nefropatias Diabéticas , Glomerulonefrite Membranosa , Leflunomida , Metilprednisolona , Creatinina , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/tratamento farmacológico , Quimioterapia Combinada/efeitos adversos , Glomerulonefrite Membranosa/complicações , Glomerulonefrite Membranosa/tratamento farmacológico , Hemoglobina A Glicada , Humanos , Imunossupressores/uso terapêutico , Leflunomida/uso terapêutico , Metilprednisolona/uso terapêutico , Estudos Retrospectivos , Albumina Sérica
10.
Orphanet J Rare Dis ; 17(1): 363, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36131317

RESUMO

BACKGROUND: Interleukin (IL)-6 is one of the key cytokines in the pathogenesis of secondary hemophagocytic lymphohistiocytosis (sHLH); however, the efficacy and safety of tocilizumab (TCZ), a monoclonal IL-6 receptor antibody, in patients with sHLH is uncertain. METHODS/RESULTS: This study included 64 adult patients who were diagnosed with sHLH based on the HLH-2004 criteria. Patients were classified into two groups based on treatment regimen at baseline: tocilizumab (TCZ group, n = 8) versus other treatments (control group), including HLH-2004 protocol (n = 35), chemotherapy (n = 7), glucocorticoid alone (n = 8), and with other immunosuppressants (n = 6). Primary outcome was overall 8-week survival. Baseline characteristics between the two groups were comparable. At day 56, one patient (12.5%) in the TCZ group and twenty-eight patients (51.9%) in the control group survived. Univariable and multivariable Cox proportional hazard analysis showed that TCZ significantly increased the risk of death (adjusted hazard ratio 5.55; 95% CI 2.13-14.49). The complete or partial response rate at day 14 was 44.6% in the control group, and nil in the TCZ group. In contrast, infectious complications occurred more frequently in the TCZ group than in the control group (14.3% vs. 50.0%). CONCLUSION: Our results suggest that tocilizumab has limited efficacy in treating adult patients with sHLH and could increase the risk of infectious complications compared to the conventional treatments.


Assuntos
Linfo-Histiocitose Hemofagocítica , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Interleucina-6 , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Receptores de Interleucina-6 , Estudos Retrospectivos
11.
Ther Drug Monit ; 44(5): 615-624, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36101928

RESUMO

BACKGROUND: The study aimed to establish a population pharmacokinetic (PPK) model of tacrolimus for Chinese patients with nephrotic syndrome using the patient's genotype and Wuzhi capsule dosage as the main test factors. METHODS: Ninety-six adult patients with nephrotic syndrome, who were receiving tacrolimus treatment, were enrolled. A nonlinear mixed-effects model was used to determine the influencing factors of interindividual tacrolimus metabolism variation and establish a PPK model. To optimize the tacrolimus dosage, 10,000 Monte Carlo simulations were performed. RESULTS: The 1-chamber model of first-order absorption and elimination was the most suitable model for the data in this study. The typical population tacrolimus clearance (CL/F) value was 16.9 L/h. The percent relative standard error (RSE%) of CL/F was 12%. Increased Wuzhi capsule and albumin doses both decreased the tacrolimus CL/F. In CYP3A5 homozygous mutation carriers, the CL/F was 39% lower than that of carriers of the wild-type and heterozygous mutation. The tacrolimus CL/F in patients who were coadministered glucocorticoids was 1.23-fold higher than that of the control. According to the patient genotype and combined use of glucocorticoids, 26 combinations of Wuzhi capsule and tacrolimus doses were matched. The Monte Carlo simulation identified the most suitable combination scheme. CONCLUSIONS: An improved tacrolimus PPK model for patients with nephrotic syndrome was established, and the most suitable combination of Wuzhi capsule and tacrolimus doses was identified, thus, facilitating the selection of a more economical and safe administration regimen.


Assuntos
Síndrome Nefrótica , Tacrolimo , Adulto , China , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/farmacocinética , Modelos Biológicos , Método de Monte Carlo , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/genética , Tacrolimo/farmacocinética
12.
Orphanet J Rare Dis ; 17(1): 355, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36104799

RESUMO

BACKGROUND: Facial angiofibroma is the most predominant cutaneous manifestation of tuberous sclerosis complex (TSC), a rare autosomal dominant genetic disorder impacting the mechanistic target of rapamycin (mTOR). Facial angiofibroma can bleed spontaneously, impair eyesight, and cause aesthetic disfiguration causing psychological and social stress. To date, there is little or no evidence on the demographics, and other TSC features associated with facial angiofibroma or the use of mTOR inhibitor for the management of facial angiofibroma. This is a retrospective study of TSC Alliance's Natural History Database aimed to characterize facial angiofibroma and to evaluate features associated with a higher risk of facial angiofibroma or the use of topical mTOR inhibitors for the management of facial angiofibroma. Data in the NHD was obtained from 18 clinical sites in the US since 2006. RESULTS: Of the 2240 patients, 2088 patients were enrolled in the US and data from 2057 patients were included in this analysis. The mean (median) age of overall TSC patients was 22.4 (19.0) years. A total of 69 patients were ≤ 5 years of age. Facial angiofibroma was noted in 1329 (64.6%) patients with TSC. Patients with facial angiofibroma were older on average (Mean: 25.9 [median, 23.0] vs. 16.0 [12.4 years] years, p < 0.0001). In patients with vs. without facial angiofibroma, TSC2 mutation (38.9% vs. 34.8%) was more common than TSC1 mutation (12.3% vs. 18.1%), and the incidence rate of most of the other TSC-related manifestations was significantly higher in patients with facial angiofibroma. Majority of patients had focal seizures (72.8% vs. 60.7%), followed by angiomyolipoma (63.7% vs. 21.8%) and renal cysts (59.4% vs. 33.5%). The age groups, 11-17 (odds ratio [OR], 2.53) and 18-45 years (5.98), TSC2 mutation (1.31), focal seizures (1.50), ADHD (1.47) angiomyolipoma (2.79), and renal cysts (2.63) were significantly associated with a higher risk of facial angiofibroma based on multivariate logistic regression. Abrasive or laser therapy was used by 17.1% and 2.6% patients, respectively. Topical mTOR inhibitor use was noted for 329 (24.8%) patients with facial angiofibroma. Overall systemic mTOR inhibitor use was observed in 399 (30.0%) patients for management of one or more TSC manifestations. Use of systemic mTOR inhibitor for facial angiofibroma was noted for 163 (12.3%) patients, among whom only 9 (0.7%) patients used exclusively for the management of facial angiofibroma. Of the patients with facial angiofibroma, 44.6% did not receive any treatment. Significantly higher use of topical mTOR inhibitor was associated with the 11-17 years age group (OR, 1.67), anxiety (1.57), angiomyolipoma (1.51), and renal cysts (1.33). CONCLUSIONS: The presence of TSC2 mutations and most other TSC-related manifestations was significantly higher in patients with facial angiofibroma. About one-fourth of patients with facial angiofibroma used a topical mTOR inhibitor and use of systemic mTOR inhibitor for the management of facial angiofibroma or for the other manifestations was noted for 30.0%. About 44.6% of patients did not receive any treatment for the management of facial angiofibroma.


Assuntos
Angiomiolipoma , Doenças Renais Císticas , Neoplasias Renais , Esclerose Tuberosa , Adulto , Angiomiolipoma/tratamento farmacológico , Carotenoides , Humanos , Imunossupressores/uso terapêutico , Neoplasias Renais/complicações , Inibidores MTOR , Estudos Retrospectivos , Convulsões/tratamento farmacológico , Sirolimo/uso terapêutico , Esclerose Tuberosa/complicações , Esclerose Tuberosa/tratamento farmacológico , Esclerose Tuberosa/genética , Estados Unidos , Vitamina A/análogos & derivados , Adulto Jovem
13.
Front Cell Infect Microbiol ; 12: 931635, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36118020

RESUMO

Malaria is one of the most prevalent infectious diseases posing a serious challenge over the years, mainly owing to the emergence of drug-resistant strains, sparking a need to explore and identify novel protein targets. It is a well-known practice to adopt a chemo-genomics approach towards identifying targets for known drugs, which can unravel a novel mechanism of action to aid in better drug targeting proficiency. Immunosuppressive drugs cyclosporin A, FK506 and rapamycin, were demonstrated to inhibit the growth of the malarial parasite, Plasmodium falciparum. Peptidyl prolyl cis/trans isomerases (PPIases), comprising cylcophilins and FK506-binding proteins (FKBPs), the specific target of these drugs, were identified in the Plasmodium parasite and proposed as an antimalarial drug target. We previously attempted to decipher the structure of these proteins and target them with non-immunosuppressive drugs, predominantly on FKBP35. This review summarizes the structural insights on Plasmodium PPIases, their inhibitor complexes and perspectives on drug discovery.


Assuntos
Antimaláricos , Tacrolimo , Antimaláricos/farmacologia , Ciclosporina/metabolismo , Ciclosporina/farmacologia , Imunossupressores/metabolismo , Peptidilprolil Isomerase/metabolismo , Plasmodium falciparum/genética , Sirolimo/farmacologia , Tacrolimo/química , Tacrolimo/metabolismo , Tacrolimo/farmacologia , Proteínas de Ligação a Tacrolimo/química , Proteínas de Ligação a Tacrolimo/metabolismo
14.
J Immunol Res ; 2022: 3129389, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36118414

RESUMO

Background: Tacrolimus has unpredictable pharmacokinetic (PK) characteristics, which are partially attributed to CYP3A5 polymorphism. The potential effects of clinical factors in the postoperative period of transplantation on tacrolimus PK and those of early tacrolimus PK variability on clinical outcomes are yet to be clarified. Methods: We examined the genetic and clinical factors affecting early tacrolimus PK variability in 256 kidney transplant recipients. The relationships among tacrolimus exposure, graft function delay (DGF), and acute rejection (AR) were further explored. Findings. The CYP3A5 genotype were strongly associated with tacrolimus concentration/dose ratio (C 0/D). Additionally, ABCB1 (rs1045642 and rs2032582) and ABCC2 (rs3740066) were found to have potential independent effects on early tacrolimus C 0/D in multivariate analysis. Red blood counts and albumin level were the most significant clinical factors associated with tacrolimus C 0/D. Wuzhi capsule also exerted an effect on tacrolimus PK. A model combined with pharmacogenetic and clinical factors explained 43.4% tacrolimus PK variability compared with 16.3% on the basis of CYP3A5 genotype only. Notably, increasing tacrolimus concentrations in the early postoperative stage were associated with AR, but not DGF. Conclusions: Combined analysis of genotype and specific clinical factors is important for the formulation of precise tacrolimus dose regimens in the early stage after kidney transplantation.


Assuntos
Transplante de Rim , Tacrolimo , Albuminas , Citocromo P-450 CYP3A/genética , Humanos , Imunossupressores/uso terapêutico , Período Perioperatório , Tacrolimo/farmacocinética , Tacrolimo/uso terapêutico
15.
Open Vet J ; 12(4): 578-583, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36118717

RESUMO

Background: No specific study on concurrent nephropathy has been conducted in dogs with chronic enteropathy (CE), except for soft-coated Wheaten Terriers. Moreover, limited information exists regarding the urinary profile in dogs with CE. Aim: To describe, compare, and discuss the alterations in selected serum biochemical and urinary parameters in dogs with CE. Methods: Multicentric retrospective study on dogs with CE diagnosed after exclusion of extra-gastrointestinal diseases. In addition, dogs with azotemia and lower urinary tract diseases were excluded. Information on canine chronic enteropathy clinical activity index (CCECAI) score, muscular condition score (MCS), presence of glycosuria, proteinuria [urine protein-to-creatinine (UPC) ratio > 0.5], and/or cylindruria (>1-2 casts/hpf) at diagnosis were gleaned from the medical records. Dogs were retrospectively classified as food-responsive enteropathy, immunosuppressant-responsive enteropathy, or nonresponsive enteropathy based on the presence of gastrointestinal histological inflammation and the treatment response. In addition, based on the serum albumin concentration (ALB), dogs were classified as having protein-losing enteropathy (PLE). Results: Ninety CE dogs were included. Fifty-two dogs had mild-to-severely decreased MCS and 38 dogs showed altered urinary parameters. No significant associations were found between CCECAI and altered urinary parameters. No significant association was found between PLE dogs and altered urinary parameters. PLE dogs showed higher prevalence of proteinuria than non-PLE dogs (p = 0.03; OR = 2.8; 95% CI = 1-6.8). Conclusion: Despite the presence of altered urinary profile in dogs with CE, further studies are needed to explore a possible link between gastrointestinal and renal inflammation.


Assuntos
Doenças do Cão , Doenças Inflamatórias Intestinais , Nefropatias , Enteropatias Perdedoras de Proteínas , Animais , Creatinina , Doenças do Cão/patologia , Cães , Imunossupressores , Inflamação/veterinária , Doenças Inflamatórias Intestinais/veterinária , Nefropatias/veterinária , Enteropatias Perdedoras de Proteínas/patologia , Enteropatias Perdedoras de Proteínas/veterinária , Proteinúria/veterinária , Estudos Retrospectivos , Albumina Sérica
16.
Front Immunol ; 13: 978429, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119045

RESUMO

Objective: To examine the efficacy of tacrolimus on top of glucocorticoids (GCs) in the management of idiopathic inflammatory myopathies-associated interstitial lung disease (IIM-ILD) and further assess the therapeutic benefit and safety of low-dose pirfenidone followed above treatments. Methods: The retrospective study comprised 250 patients with IIM-ILD hospitalized in Tongji Hospital from 2014 to 2020. Demographic data, survival outcomes, and recurrence rates over the 1-year follow-up period were retrospectively analyzed. These patients were divided into two groups based on treatment with tacrolimus alone or other conventional immunosuppressants. Endpoints were compared by adjusted Cox regression model using inverse probability of treatment weighting to minimize treatment bias and potential confounders. For the prospective study, IIM-ILD patients treated with tacrolimus alone or tacrolimus combined with low-dose pirfenidone were enrolled from 2018 to 2020. Clinical characteristics, survival outcomes and multifarious assessment scales were followed up at baseline, 3, 6 and 12 months. The primary endpoint was 12-month survival rate and the secondary endpoints included respiratory-related events, adverse events, exacerbation in HRCT findings and laboratory parameters during therapy courses, and changes in respiratory function. Results: For the retrospective study, tacrolimus group (n=93) had a significantly higher survival rate (weighted HR=0.330, p=0.002) and a lower relapse rate (weighted HR=0.548, p=0.003) compared with patients treated with other types of immunosuppressant (n=157) after adjustment. The prospectively enrolled 34 IIM-ILD patients were treated with tacrolimus (n=12) or tacrolimus combined with low-dose pirfenidone (n=22). After 12 months of treatment with tacrolimus, patients in the prospective cohort showed significant improvements in cardio-pulmonary function, disease activity, muscle strength, and mental scale from baseline. Subgroup analysis indicated that patients with tacrolimus and pirfenidone combination therapy showed lower chest HRCT scores (p=0.021) and lower respiratory-related relapse rates than those in tacrolimus monotherapy group (log-rank p=0.0029). The incidence rate of drug-associated adverse events (AEs) was comparable between two groups and none of the patients discontinued the treatment due to severe AEs. Conclusion: Tacrolimus is well-tolerated and effective in the treatment of IIM-ILD. Furthermore, low-dose pirfenidone add-on treatment seems result in favorable improvements in pulmonary involvements for IIM-ILD patients. Clinical Trial Registration: http://www.chictr.org.cn, identifier ChiCTR2100043595.


Assuntos
Doenças Pulmonares Intersticiais , Tacrolimo , Glucocorticoides/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Doenças Pulmonares Intersticiais/etiologia , Estudos Prospectivos , Recidiva , Estudos Retrospectivos , Tacrolimo/efeitos adversos
17.
Front Immunol ; 13: 991832, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119036

RESUMO

Recombinant adeno-associated virus (AAV) is a promising delivery vehicle for in vivo gene therapy and has been widely used in >200 clinical trials globally. There are already several approved gene therapy products, e.g., Luxturna and Zolgensma, highlighting the remarkable potential of AAV delivery. In the past, AAV has been seen as a relatively non-immunogenic vector associated with low risk of toxicity. However, an increasing number of recent studies indicate that immune responses against AAV and transgene products could be the bottleneck of AAV gene therapy. In clinical studies, pre-existing antibodies against AAV capsids exclude many patients from receiving the treatment as there is high prevalence of antibodies among humans. Moreover, immune response could lead to loss of efficacy over time and severe toxicity, manifested as liver enzyme elevations, kidney injury, and thrombocytopenia, resulting in deaths of non-human primates and patients. Therefore, extensive efforts have been attempted to address these issues, including capsid engineering, plasmapheresis, IgG proteases, CpG depletion, empty capsid decoy, exosome encapsulation, capsid variant switch, induction of regulatory T cells, and immunosuppressants. This review will discuss these methods in detail and highlight important milestones along the way.


Assuntos
Dependovirus , Vetores Genéticos , Animais , Dependovirus/genética , Vetores Genéticos/genética , Humanos , Imunoglobulina G/genética , Imunossupressores , Peptídeo Hidrolases/genética
18.
Front Immunol ; 13: 994064, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119082

RESUMO

Immune checkpoint inhibitors (ICIs) have demonstrated promising therapeutic outcomes in treating a variety of malignancies, but immune-related adverse events (irAE) may develop. Among all the irAE, immune-related pneumonitis was relatively common and life-threatening. High-dose corticosteroid was recommended for the initial management, but a part of patients developed steroid-refractory pneumonitis. Other immunosuppressants were recommended, but the optimal treatment is still controversial. Here, we report two cases of steroid-refractory immune-related pneumonitis who were successfully treated with pulse corticosteroid therapy. Case 1 was hepatocellular carcinoma treated with nivolumab for 5 months. She developed acute respiratory distress syndrome due to grade 4 immune-related pneumonitis that was refractory to intravenous methylprednisolone 2 mg/kg/day treatment. Methylprednisolone 500 mg for 3 days followed by 2 mg/kg/day steroid as maintenance therapy was given. Subsequently, her pneumonitis was regressed, and the endotracheal tube was successfully removed on day 9 after the start of pulse therapy. Case 2 presented with grade 4 immune-related pneumonitis in spite the use of methylprednisolone 1 mg/kg for his skin rash. Pulse corticosteroid therapy was prescribed, then his pneumonitis was completely regressed on day 12. In this report, we demonstrated the potential role of pulse corticosteroid therapy for steroid-refractory pneumonitis.


Assuntos
Antineoplásicos Imunológicos , Pneumonia , Corticosteroides/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunossupressores/uso terapêutico , Metilprednisolona/uso terapêutico , Nivolumabe/efeitos adversos , Pneumonia/induzido quimicamente , Pneumonia/diagnóstico , Pneumonia/tratamento farmacológico
19.
Medicine (Baltimore) ; 101(37): e30750, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36123864

RESUMO

RATIONALE: Kimura disease (KD) is a rare, chronic inflammatory disease characterized by painless subcutaneous nodules predominantly located in the head and neck regions. Orbital KD, which intrudes into the intraconal space and results in compressive optic neuropathy, is rare and has not been previously reported. PATIENT CONCERNS: A 68-year-old man presented with blurred vision and progressive proptosis in the left eye that had been present for 2 years. DIAGNOSIS: Magnetic resonance imaging of the brain revealed soft tissue lesions with contrast enhancement and restricted diffusion involving the bilateral eyelids, orbits, and intraconal region; those on the left side were more prominent than those on the right side. The lesion encased the left optic nerve. Laboratory test results revealed elevated serum immunoglobulin E level and peripheral eosinophilia. An orbital mass biopsy demonstrated hyperplastic lymphoid follicles with germinal centers in the subcutaneous area and abundant mononuclear and binuclear eosinophils infiltrating the interfollicular area. A pathological diagnosis of KD was made based on the blood test results. INTERVENTIONS: Orbital decompression and debulking surgery of the orbital tumor in the left eye were performed to treat the compressive optic neuropathy. OUTCOMES: After systemic oral steroid and immunosuppressive agent therapies, the patient's visual acuity in the left eye improved, and the KD activity was stable. CONCLUSIONS: We present a rare case of orbital KD-associated optic neuropathy, wherein early diagnosis and treatment preserved the patient's vision. This complication should be considered in patients with a history of compressive optic neuropathy during the differential diagnosis.


Assuntos
Doença de Kimura , Doenças do Nervo Óptico , Idoso , Humanos , Imunoglobulina E , Imunossupressores , Masculino , Nervo Óptico/patologia , Doenças do Nervo Óptico/diagnóstico
20.
Clin Appl Thromb Hemost ; 28: 10760296221125785, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36124377

RESUMO

The introduction Caplacizumab in the management of Immune thrombotic thrombocytopenic purpura (iTTP) has raised different questions, considering its cost-efficacy and the optimal immunosuppressive treatment (IST) to associate. A retrospective multicenter collection of 42 first iTTP cases was conducted to identify variables associated with a higher burden of care and necessity of an implemented IST with early Rituximab (RTX) rescue. A significant correlation resulted between ADAMTS13 inhibitors (ADAMTS13inh) at diagnosis with total plasma exchange (PEXtot) and PEX needed to achieve clinical response (PEXtoCR, r = 0.46; r = 0.48), along with age (r = - 0.31; r = -0.35), platelet count (r = -0.30; r = -0.30), LDH (r = 0.44; r = 0.41) and total bilirubin (r = 0.54; r = 0.35). ADAMTS13inh also correlated with number of days of hospitalization (DoH, r = 0.44). A significant difference was observed in terms of median ADAMTS13inh titer at diagnosis in patient treated with RTX rescue and those responding to only steroid treatment. Thus, ADAMTS13inh titer resulted a marker of iTTP burden of care, associated with higher number of PEXtot, PEXtoCR, DoH and higher probability of needing RTX rescue to achieve clinical response and could be a useful tool for management of new iTTP cases and an interesting variable to optimize iTTP cases stratification in future Caplacizumab cost-efficacy analysis.


Assuntos
Púrpura Trombocitopênica Idiopática , Púrpura Trombocitopênica Trombótica , Trombose , Proteína ADAMTS13 , Autoanticorpos , Bilirrubina , Humanos , Imunossupressores , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Trombótica/tratamento farmacológico , Rituximab/uso terapêutico , Esteroides/uso terapêutico , Trombose/tratamento farmacológico
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