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Background: Although, several studies have assessed the association of the phospholipase A2 receptor (PLA2R) and HLA-DQA1 SNPs with primary membranous nephropathy (PMN), results were inconsistent and between-studies heterogeneity needs to be investigated. Objectives: The aim of this review was to summarize existing data on the contribution of 10 SNPs in the PLA2R and HLA-DQA1 genes to PMN susceptibility and to investigate the between-studies heterogeneity by subgroup analyses and meta-regressions. Design: This study was performed according to the PRISMA guidelines for systematic reviews and meta-analyses. Data sources and methods: An electronic literature search for eligible studies among all papers published prior to January 10, 2024, was conducted through PubMed, EMBASE, Web of science and Scopus databases. Meta-analyses together with subgroup analyses and meta-regressions were performed for the 10 following SNPs: rs4664308, rs3749117, rs3749119, rs35771982, rs3828323, rs16844715, rs1511223, rs6757188, rs2715918, and rs2187668. Results: Combined analyses revealed a significant increase in PMN risk conferred by the following alleles: rs4664308*A, rs3749117*T, rs3749119*C, rs35771982*G, rs3828323*C, rs16844715*C, rs1511223*A, rs2715918*A, and rs2187668*A, all P-values < .001. Moreover, the PLA2R-rs4664308/HLA-DQA1-rs2187668 interaction was significantly associated with an increased PMN risk, P < .001. However, there was a substantial between-studies heterogeneity for some SNPs. Subgroup analyses by ethnicity for the 9 PLA2R SNPs did not show any cross-ethnic disparity. Inversely, the risk conferred by the HLA-DQA1 rs2187668*A allele was significantly higher in Caucasians (OR [95% CI] = 3.929 [3.251-4.748]) than in Asians (OR [95% CI] = 2.537 [1.94-3.318], P = .007. Besides, meta-regressions revealed for the majority of investigated SNPs significant correlations of the effect size with albumin, 24-hours proteinuria, serum creatinine, and eGFR levels. Hence, the influence on PMN risk conferred by the PLA2R and HLA-DQA1 SNPs was rather noted in patients with a severe disease. Conclusion: This meta-analysis showed that 9 out of the 10 investigated SNPs in PLA2R and HLA-DQA1 genes were associated with increased PMN risk. Heterogeneity could be due to disparate patient groups in terms of disease presentation for almost all SNPs, and ethnicity for the HLA-DQA1 rs2187668 SNP. Registration: This review has been registered on PROSPERO: CRD42024506729. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024506729.
Genetic factors in primary membranous nephritis Why was the study done? Primary membranous nephritis (PMN) is the most common etiology of adult-onset nephrotic syndrome. Understanding risk factors, particularly genetic ones, would provide a better understanding of its pathophysiological mechanisms in order to prevent and treat patients more effectively. What did the researchers do? The research team summarized published data on genetic factors associated with PMN including phospholipase A2 receptor (PLA2R) and HLA-DQA1 genes. What did the researchers find? The total number of included studies was 27. Nine out of ten genetic factors were found to be associated with PMN risk. Moreover, we noted significant interaction between PLA2R and HLA-DQA1 in potentializing PMN risk. Nevertheless, there was a significant between-studies heterogeneity which was found to be explained in part by disease severity. What do the findings mean? This study has identified some important some genetic factors associated with PMN together with confounding factors that could influence the aforementioned association.
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The impact of interleukin-10 (IL-10) gene promoter polymorphisms (SNPs) on treatment response in HCV patients was dissimilarly estimated. Hence, the aim of this meta-analysis was to robustly assess the effect of IL-10 SNPs on treatment response in HCV patients. An electronic literature search was carried out through PubMed, EMBASE, Web of science, and Scopus databases. Studies assessing the association between IL-10 polymorphisms and treatment response in HCV patients were included. Studies were excluded if genotype frequencies are not consistent with the Hardy-Weinberg Equilibrium (HWE) or in case of including patients with hepatitis B virus coinfection. Risk of bias in included studies was assessed using the Newcastle-Ottawa Scale. Meta-analyses were performed for the influence of IL-10 gene promoter SNPs (rs1800896 (-1082 A/G), rs1800871 (-819 C/T), and rs1800872 (-592 C/T)) and haplotypes on treatment response in HCV patients. Subgroup analyses, meta-regressions, publication bias assessment, and sensitivity analyses were also conducted. Overall, 32 studies with a total of 5943 HCV cases and 2697 controls were included in the present study. The -1082*G allele was significantly associated with increased risk of non-response (NR) to treatment, OR [95% CI] = 1.29 [1.1-1.51], p = .002. Besides, the rs1800872 -592*C allele was significantly associated with increased NR risk, OR [95% CI] = 1.22 [1.02-1.46], p = .03. Subgroup analysis showed that this association remained significant only in patients treated with PEG-IFN alone, p = .01. The -1082*G/-819*C/-592*C (GCC) haplotype was significantly associated with increased NR risk, OR [95% CI] = 1.62 [1.13-2.23], p = .009. Our results suggest that the IL-10 rs1800896 was associated with NR risk especially in North-African and Asian populations. Moreover, the IL-10 gene promoter -1082*G/-819*C/-592*C (GCC) haplotype which has been associated with higher production of IL-10, was significantly associated with increased NR risk.
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Hepatite C , Interleucina-10 , Humanos , Predisposição Genética para Doença , Genótipo , Hepatite C/tratamento farmacológico , Hepatite C/genética , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras GenéticasRESUMO
We present an overview of kidney transplantation activity in the Maghreb countries, based on data from the 9th Colloque France-Maghreb (Paris, May 20 and 21, 2022). For Algeria, Morocco and Tunisia, the incidence of end stage renal failure is respectively 120, 130 and 130 per million inhabitants, its prevalence 626, 900 and 833 per million inhabitants and the part of patients with a functional graft of 10.3, 1.8 et 8.5% with an annual number of transplants of 6.5, 0.8 and 8.7 per million inhabitants. Living donor transplants account for 99% of transplants in Algeria, 93% in Morocco and 80% in Tunisia. In conclusion, access to transplantation remains low in the Maghreb countries. All the modalities (living donor with enlargement of the circle of donors, deceased donors) must be further developed. Recommendations were issued to support activity.
Nous présentons un état des lieux de l'activité de transplantation rénale dans les pays du Maghreb à partir des données du 9e Colloque France-Maghreb (Paris, 20 et 21 mai 2022). Pour l'Algérie, le Maroc et la Tunisie, l'incidence de l'insuffisance rénale chronique terminale est respectivement de 120, 130 et 130 par million d'habitants, sa prévalence de 626, 900 et 833 par million d'habitants et la part des patients porteurs d'un greffon fonctionnel est de 10,3, 1,8 et 8,5 % avec un nombre annuel de transplantations de 6,5, 0,9 et 7,7 par million d'habitants. La transplantation avec donneur vivant représente 99 % des transplantations en Algérie, 93 % au Maroc et 80 % en Tunisie. En conclusion, l'accès à la transplantation reste faible dans les pays du Maghreb. Toutes les modalités (donneur vivant avec élargissement du cercle des donneurs, donneurs décédés) doivent être développées. Des recommandations ont été émises pour soutenir cette activité.
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Falência Renal Crônica , Transplante de Rim , Humanos , Argélia/epidemiologia , Tunísia/epidemiologia , Falência Renal Crônica/cirurgia , Falência Renal Crônica/epidemiologia , Doadores VivosRESUMO
OBJECTIVES: Attitudes and knowledge toward organ donation can influence a person's willingness to donate. The aim of this study was to assess attitudes and knowledge regarding organ donation among Tunisian adults. MATERIALS AND METHODS: We conducted a crosssectional survey at the national level from January 23 to February 15, 2017, among 1026 Tunisian adults. We used a standardized questionnaire to collect data by phone call. We performed statistical analyses with Stata software (version 11). RESULTS: The study included 495 male and 531 female participants. Forty-one percent of participants were 18 to 30 years old. In total, 81.7% had heard about organ donation. Fewer than half of respondents (47.8%) were aware that organ donation is regulated. In total, 80.7% accepted to donate their organs after death, and 32.2% had mentioned their opinion to relatives or friends. Only 1% had added their donor status on their national identity cards. CONCLUSIONS: Tunisian adults seem to have positive attitudes regarding organ donation. However, the proportion of respondents who included their donor status on their national identity cards was low. It is important to enhance information and education on organ donation in an effort to mitigate the shortage of organs.
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Transplante de Órgãos , Obtenção de Tecidos e Órgãos , Adulto , Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Doadores de Tecidos , Conhecimentos, Atitudes e Prática em Saúde , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: Single nucleotid polymorphisms (SNPs) of Fc-gamma receptors (FcgRs), by inducing a variation of their affinity to the Fc-region of immunoglobulins, might influence the efficacy of Fc-containing biologics prescribed in rheumatoid arthritis (RA). Our aim was to investigate associations of FCGR2A, FCGR3A and FCGR3B SNPs with TNF-inhibitors (TNFi)' response in Tunisian RA patients. METHODS: A cross-sectional, observational and analytic multicentric cohort study was conducted in a group of 47 Tunisian RA patients treated with (etanercept [ETA], adalimumab [ADL] and infliximab [IFX]). Treatment outcome was evaluated after 6 months. R131H-FCGR2A, F158V-FCGR3A and NA1/NA2-FCGR3B SNPs were genotyped. RESULTS: The analytic study including all types of TNFi showed that FCGR3A-F/F low-affinity receptor was associated with a greater decrease of DAS28, while FCGR3B-NA1/NA1 high-affinity receptor was associated with a lower decrease of DAS28 in ADL group. Furthermore, both of high affinity receptors FCGR3B-NA1/NA1 and FCGR3A-V/V were more prevalent in non-responders to ADL, according to EULAR criteria. CONCLUSIONS: Identifying reliable biomarkers of response to biologics in RA is necessary to improve responsiveness, preserve joints' functions and structure, and reduce treatment's cost. Our study showed that FCGR3A and FCGR3B polymorphisms might have an impact on TNFis' response in RA Tunisian patients since bad response was more frequent in homozygous carriers of high affinity alleles FCGR3A-V and FCGR3B-NA1.
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Artrite Reumatoide , Inibidores do Fator de Necrose Tumoral , Humanos , Estudos de Coortes , Estudos Transversais , Polimorfismo Genético , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Receptores de IgG/genética , Proteínas Ligadas por GPI/genéticaRESUMO
Management of the COVID-19 pandemic relies on molecular diagnostic methods supported by serological tools. Herein, we developed S-RBD- and N- based ELISA assays useful for infection rate surveillance as well as the follow-up of acquired protective immunity against SARS-CoV-2. ELISA assays were optimized using COVID-19 Tunisian patients' sera and prepandemic controls. Assays were further validated in 3 African countries with variable endemic settings. The receiver operating curve was used to evaluate the assay performances. The N- and S-RBD-based ELISA assays performances, in Tunisia, were very high (AUC: 0.966 and 0.98, respectively, p < 0.0001). Cross-validation analysis showed similar performances in different settings. Cross-reactivity, with malaria infection, against viral antigens, was noticed. In head-to-head comparisons with different commercial assays, the developed assays showed high agreement. This study demonstrates, the added value of the developed serological assays in low-income countries, particularly in ethnically diverse populations with variable exposure to local endemic infectious diseases.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/diagnóstico , Pandemias , Ensaio de Imunoadsorção Enzimática , Tunísia/epidemiologia , Anticorpos AntiviraisRESUMO
AIMS: This study aims to determine whether a modification in Fc-γ receptors' (FcgRs) affinity to Fc portion, caused by single nucleotide polymorphisms such as rs1801274-R131H FcgRIIa, rs396991-F158V FcgRIIIa and NA1/NA2-FcgRIIIb, might impact clearance of therapeutic monoclonal antibodies and thus serum drug levels and the development of anti-drug antibodies. METHODS: A cross sectional, multicentral and noninterventional study was conducted in Tunisian RA patients treated with rituximab (RTX), etanercept (ETA), infliximab (IFX) and adalimumab (ADL). Serum drug level (SDL) of the different biologics and ADA against them were measured. All patients were genotyped for the 3 FcgR single nucleotide polymorphisms. RESULTS: A total of 81 patients were included: 47 were under tumour necrosis factor inhibitors (18 ETA, 13 ADL and 16 IFX), and 34 were under RTX. Regardless of the type of biotherapy, SDL was in therapeutic range, in 35 patients (43.2%), of whom only 1 was treated with RTX. Fourteen patients (22.2%) developed ADA, but none of the patients treated with ETA had detectable ADA levels. There was no association between SDL positivity and FcgR polymorphisms. However, the high affinity FcgR2A 131 H/H receptor was statistically more prevalent in patients with detectable ADA treated with ADL, IFX and RTX (P = .018). The same result was obtained in the monoclonal antibody tumour necrosis factor inhibitor subgroup (n = 29, P = .022) as well as in patients treated only with IFX (n = 16, P = .029). CONCLUSION: Our work supports the hypothesis of an impact of FcgR single nucleotide polymorphisms on biologics' immunogenicity, particularly FcgR R131H polymorphism, but further studies with larger cohorts need to be undertaken to confirm these results.
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Artrite Reumatoide , Produtos Biológicos , Humanos , Adalimumab/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Produtos Biológicos/uso terapêutico , Estudos Transversais , Etanercepte/uso terapêutico , Infliximab/uso terapêutico , Polimorfismo de Nucleotídeo Único , Rituximab/uso terapêuticoRESUMO
BACKGROUND: B cell activating factor (BAFF), a crucial factor for B cell survival and differentiation, has been linked to several autoimmune conditions. The aim of this study was to evaluate the association of BAFF gene's polymorphisms with its serum levels and to assess their effect on Graves' disease (GD) susceptibility and presentation. METHODS: Sixty-two GD patients and 152 healthy controls have been enrolled to investigate BAFF rs9514827 (-2841 T/C), rs1041569 (-2701 T/A) and rs9514828 (-871 C/T) gene's polymorphism by PCR-RFLP and serum BAFF level's kinetics under medical treatment by ELISA. RESULTS: Median serum BAFF level at baseline was significantly higher in GD patients (841.7 pg/ml [685.23-1058.32]) comparatively to controls (495.75 pg/ml [383.17-595.7]), p = 7.29 E-25. A ROC curve was used to assess BAFF performances in GD diagnosis and revealed an AUC of 94.9% [0.919-0.979], p = 7.29 E-25. At a cutoff value of 654.9 pg/ml of BAFF at baseline, the sensitivity and the specificity were, respectively, 83.9% and 90.8%. BAFF level was significantly increased in smoking patients (1079.55 pg/ml [875.35-1203]) comparatively to nonsmokers (746.95 pg/ml [643.2-915.7]), p = 3.1 E-5. While -2841 T/C and -2701 T/A genotypes and alleles frequencies were similar between patients and controls, the -871*T allele was significantly more prevalent in patients (0.613) than in controls (0.477); p = .01, OR [95% CI] = 1.73 [1.13-2.65]. The three studied polymorphisms were not associated with serum BAFF level at baseline. CONCLUSION: Serum BAFF level is significantly increased in GD especially in smoking patients. rs9514828 - 871*T allele might be a susceptibility variant for GD.
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Fator Ativador de Células B , Doença de Graves , Humanos , Fator Ativador de Células B/sangue , Fator Ativador de Células B/genética , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Doença de Graves/sangue , Doença de Graves/tratamento farmacológico , Doença de Graves/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
AIMS: Interferon-beta (IFNß), the most widely prescribed medication for multiple sclerosis, is generally considered safe. Nevertheless, rare serious and/or life-threatening side effects have been reported such as thrombotic microangiopathy. A few mechanisms have been proposed to explain how interferon causes thrombotic microangiopathy, but immunological studies have been unable to pin this phenomenon down to a single pathophysiologic pathway. The aim of this article was to report a new mechanism explaining Interferon beta related thrombotic microangiopathy. METHODS: We report thrombotic microangiopathy in a 28-year-old male receiving interferon-beta treatment for multiple sclerosis. RESULTS: After three years of starting interferon beta therapy, the patient presented with malignant hypertension causing seizures, rapidly progressive renal failure requiring haemodialysis and haemolytic anaemia. Corticosteroid and plasma exchange sessions permitted haemolysis control. Nonetheless, the patient remained hemodialysis-dependent. Exploration of the complement system found a complement factor I deficiency whose activity normalized at the control carried out after 2 years. CONCLUSION: IFNß treatment may cause complement factor I deficit, which can lead to thrombotic microangiopathy and severe renal failure.
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Esclerose Múltipla , Insuficiência Renal , Microangiopatias Trombóticas , Masculino , Humanos , Adulto , Interferon beta/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Microangiopatias Trombóticas/induzido quimicamente , Insuficiência Renal/complicaçõesRESUMO
INTRODUCTION: Tacrolimus, exhibits interindividual pharmacokinetic variability and a narrow therapeutic index. The influence of the CYP3A5 6986A>G single nucleotide polymorphism (SNP) on this variability remains a topic of debate. AIM: To assess the impact of the aforementioned SNP on tacrolimus area under curve (AUC0-12h), adverse drug reactions (ADRs), and kidney graft outcomes. METHODS: Blood samples were collected from Tunisian kidney transplants over a five-year period during either the early (<3 months) or late (>3 months) post-transplant phases. Through blood concentration (C0) and AUC0-12h of tacrolimus were measured. Patients were prospectively followed to assess graft outcomes. Polymerase chain reaction of restriction fragment length polymorphism was used for CYP3A5 6986A>G genotyping. RESULTS: Fifty Tunisian kidney recipients receiving tacrolimus were enrolled in the study. Acute and chronic graft rejections were observed in eight and three patients, respectively. Twenty-one patients (42%) reported ADRs. C0 and AUC0-12h, showed a significant difference between CYP3A5*1 carriers (mean C0=4 ng.mL-1 and AUC0-12h=94.37 ng.h.mL-1) and CYP3A5*3/3 or poor metabolizers carriers (mean C0=7.45 ng.mL-1; AUC0-12h=151.27 ng.h.mL-1) (p=0.0001; p=0.003, respectively). Supratherapeutic tacrolimus levels were significantly more common in poor metabolizers (p=0.046; Odds-ratio =1.3; confidence interval 95% [1.12-1.66]). The impact of SNP was significant on C0, AUC0-12h, C0/Dose and AUC0-12h/Dose, only in the late phase (p=0.01, 0.002, 0.012, 0.003 respectively). CONCLUSION: CYP3A5*3 variant was significantly associated with tacrolimus pharmacokinetics but had no impact on graft outcomes.
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Transplante de Rim , Tacrolimo , Humanos , Tacrolimo/uso terapêutico , Imunossupressores/uso terapêutico , Citocromo P-450 CYP3A/genética , Polimorfismo de Nucleotídeo Único , GenótipoRESUMO
INTRODUCTION: Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive tryptophan-depleting enzyme expressed in nasopharyngeal carcinoma (NPC) tissue. However, IDO has not been reported in the peripheral blood of NPC patients. The aim of this study was to analyze, IDO1 and IDO2 messenger RNA (mRNA) expression, the kynurenine (Kyn) and tryptophan (Trp) plasma levels, their clinical values and their relationship with cytokine levels in NPC. METHODS: We evaluated IDO1 and IDO2 mRNA expression in peripheral blood mononuclear cells (PBMC) by quantitative real-time PCR, plasma Trp and Kyn levels by HPLC, and cytokine levels by ELISA in 75 NPC patients and 51 healthy controls. RESULTS: Compared to controls, IDO1 mRNA expression was significantly upregulated and IDO2 mRNA expression was significantly downregulated in PBMC of patients. Also compared to controls, plasma Kyn levels and Kyn/Trp ratio were significantly higher in patients. At the time of diagnosis, the plasma Kyn/Trp ratio was associated with advanced cancer status and was an independent prognostic factor for worse disease-specific survival. According to cancer stages, IDO1 mRNA expression was positively correlated with plasma Kyn/Trp ratio in patients with earlier stages (I-II-III) but negatively correlated in patients with the late-stage cancer (IV). Tumor necrosis factor-α, interleukin (IL)-6 and IL-10 levels were significantly higher in patients compared to controls. Moreover, and despite treatment, patients simultaneously carrying high plasma Kyn/Trp ratio and high plasma IL-6 and IL-10 levels at diagnosis died approximately 1 year after first diagnosis. CONCLUSION: Measuring blood IDO mRNA expression and Kyn/Trp ratio at diagnosis could be a potential marker to evaluate NPC progression and predict survival outcome.
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Cinurenina , Neoplasias Nasofaríngeas , Citocinas/genética , Expressão Gênica , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Interleucina-10/genética , Interleucina-6/genética , Cinurenina/metabolismo , Leucócitos Mononucleares/metabolismo , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/genética , RNA Mensageiro/genética , Triptofano/metabolismoRESUMO
BACKGROUND: To overcome the COVID-19 pandemic, serology assays are needed to identify past and ongoing infections. In this context, we evaluated the diagnostic performance of 6 immunoassays on samples from hospitalized patients for moderate to critical COVID-19. METHODS: 701 serum samples obtained from 443 COVID-19 patients (G1: 356 positive RT-PCR patients and G2: 87 negative RT-PCR cases) and 108 pre-pandemic sera from blood donors were tested with 6 commercial immunoassays: (1) Elecsys Anti-SARS-CoV-2, Roche (Nucleocapsid, N), (2) Elecsys Anti-SARS-CoV-2 S, Roche (Spike, S), (3) Vidas SARS-COV-2 IgM/IgG, BioMérieux (S), (4) SARS-CoV-2 IgG, Abbott (N), (5) Access SARS-CoV-2 IgG, Beckman Coulter (Receptor Binding Domain), and (6) Standard F COVID-19 IgM/IgG Combo FIA, SD Biosensor (N). RESULTS: Global sensitivities of the evaluated assays were as follows: (1) Roche anti-N = 74.5% [69.6-79.3], (2) Roche anti-S = 92.7% [84.7-100], (3) Vidas IgM = 74.9% [68.6-81.2], (4) Vidas IgG = 73.9% [67.6-80.1], (5) Abbott = 78.6% [63.4-93.8], (6) Beckman Coulter = 74.5% [62-86.9], (7) SD Biosensor IgM = 73.1% [61-85.1], and (8) SD Biosensor IgG = 76.9% [65.4-88.4]. Sensitivities increased gradually from week 1 to week 3 as follow: (1) Roche anti-N: 63.3%, 81% and 82.1%; (2) Vidas IgM: 68.2%, 83.2% and 85.9%; and (3) Vidas IgG: 66.7%, 79.1% and 86.6%. All immunoassays showed a specificity of 100%. Seropositivity was significantly associated with a higher frequency of critical COVID-19 (50.8% vs. 38.2%), p = 0.018, OR [95% CI] = 1.668 [1.09-2.553]. Inversely, death occurred more frequently in seronegative patients (28.7% vs. 13.6%), p=3.02 E-4, OR [95% CI] = 0.392 [0.233-0.658]. CONCLUSION: Evaluated serology assays exhibited good sensitivities and excellent specificities. Sensitivities increased gradually after symptoms onset. Even if seropositivity is more frequent in patients with critical COVID-19, it may predict a recovery outcome.
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Anticorpos Antivirais/sangue , Teste Sorológico para COVID-19 , COVID-19/diagnóstico , SARS-CoV-2/crescimento & desenvolvimento , Adulto , Idoso , Biomarcadores/sangue , COVID-19/sangue , COVID-19/imunologia , COVID-19/virologia , Estudos de Casos e Controles , Feminino , Hospitalização , Interações Hospedeiro-Patógeno , Humanos , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença , Fatores de TempoRESUMO
Objectives To evaluate the serum dosage of the biomedicine (DBM) and the incidence of antidrug antibody (ADA) against antitumor necrosis factor (TNF) in spondyloarthritis, and to demonstrate the influence of these parameters on the clinical efficiency. Methods We conducted a cross-sectional multicentric study including patients with spondylarthritis (SpA) under antiTNF (infliximab [INF], etanercept [ETA] and adalimumab [ADL]) for at least 6 months. A dosage of the ADA and DBM were practiced by the immuno-enzymatic essay. Result Seventy one patients were recruited. Disease modifying antirheumatic drugs (DMARDs) were associated with anti-TNF in 30%. ADA was positive in 54% for INF, 33% for ADL and 0% for ETA with a significant difference(p<0.0001). Immunogenicity was correlated to a bad therapeutic response (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]≥4)(p=0.04). The DBM was inversely correlated with the rate of ADA for patients treated with INF(p<0.0001) and ADL(p<0.0001). The DBM was also inversely correlated with BASDAI of INF(p=0.03) and ADL (p=0.01). ADA was significantly associated with an anterior switch of anti TNF(p=0.04), the use of INF(p=0.002), presence of coxitis(p=0.01) and higher body mass index (BMI)(p=0.007). DMARDs associated with anti TNF were not a protective factor for positive ADA. In a multivariate study, only INF and BMI were independent factors of positive ADA. Conclusion The ADA formation lowered the DBM and favored the therapeutic failure.
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BACKGROUND: Primary membranous nephritis (PMN) is an autoimmune disease induced by the deposit of antibodies (Ab) to the phospholipase receptor A2 receptor (PLA2R) on podocytes. In this context, we aimed to assess the relationships between anti-PLA2R Ab, PLA2R rs4664308 SNP, PLA2R mRNA levels and PMN susceptibility and outcome. METHODS: Sixty-eight PMN patients, 30 systemic lupus erythematosus (SLE) patients with secondary MN and 30 healthy control subjects served for anti-PLA2R Ab measurement by ELISA and PLA2R rs4664308 SNP genotyping by a commercial real-time PCR. Twenty patients with tubulo-interstitial nephritis (TIN) were used as controls for renal PLA2R mRNA quantification in PMN patients from kidney biopsies. PLA2R mRNA quantification was carried-out by real-time PCR after RNA extraction. RESULTS: Forty-three (63.2%) PMN patients received initial therapy consisting of alternating monthly cycles of corticosteroids and cyclophosphamide. Twelve (17.6%) patients had resistant PMN to initial therapy and were consecutively treated by cyclosporine or tacrolimus. Anti-PLA2R Ab were positive in 54 (79.4%) PMN patients, while all SLE patients and controls were negative, p<0.0001. Moreover, anti-PLA2R Ab levels were significantly higher in PMN patients (134.85 [41.25-256.97] RU/ml) than in SLE patients (3.35 [2.3-4.35] RU/ml) and controls (2 [2-2.3]), p<0.0001. Consequently, a ROC curve showed for 100% specificity a sensitivity of 94.1% at a threshold of 2.6 RU/ml. Besides, Anti-PLA2R antibodies levels were significantly associated to non-remission; p = 0.002. The rs4664308*A wild-type allele was significantly more frequent in PMN patients (0.809) than in controls (0.633) and SLE patients (0.65); p = 0.008, OR [95% CI] = 2.44 [1.24-4.82] and p = 0.016, OR [95% CI] = 2.27 [1.15-4.5], respectively. Renal PLA2R mRNA levels were significantly higher in PMN patients (218.29 [66.05-486.07]) than in TIN patients (22.09 [13.62-43.34]), p<0.0001. Moreover, PLA2R mRNA levels were significantly higher in non-remission patients (fold-factor vs. partial remission = 2.46 and fold-factor vs. complete remission = 12.25); p = 1.56 10E-8. In addition, PLA2R mRNA and anti-PLA2R Ab levels were significantly correlated, Spearman Rho = 0.958, p<0.0001. CONCLUSION: Anti-PLA2R Ab and renal PLA2R mRNA could be useful markers for PMN outcome predicting. The PLA2R rs6446308 SNP is associated with PMN susceptibility in Tunisians.
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Autoanticorpos/sangue , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/imunologia , Polimorfismo de Nucleotídeo Único , Receptores da Fosfolipase A2/genética , Receptores da Fosfolipase A2/imunologia , Autoanticorpos/imunologia , Biópsia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/patologia , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , TunísiaRESUMO
INTRODUCTION: Axial spondyloarthritis (SpA) is a common inflammatory arthritis characterized by axial skeletal inflammation, enthesitis, and association with HLA-B27. Pro-inflammatory cytokines play important roles in the regulation of inflammatory response and seem to be good candidates involved in the development of this pathology. AIM: To assess the influence of the functional polymorphisms of single nucleotide polymorphims (SNPs) of IL-1 and IL-1 Ra in SpA susceptibility Tunisian patients. METHODS AND RESULTS: One hundred and one patients and 100 ethnic-matched healthy controls were genotyped. Susceptibility to SpA was showed with SNP's: C/T of IL-1α (-889) (p=0.0001) and 1/1 of IL-1Ra (p<10-3). Analysis of SpA patients according to clinical behavior of the disease reveled the influence of these polymorphisms in SpA course. Indeed, individuals carrying the allele T (+3954) of IL-1ß and allele 1 of IL-1Ra had an increased risk of peripheral arthritis (p=0.047, p=0.05, respectively). Also the 1/1 genotype of IL-1Ra was significantly decreased in SpA patients having an active disease (BASDAI>4) (p=0.033). CONCLUSION: Genetic polymorphisms of pro-inflammatory IL-1/IL-1Ra cytokines seem to be involved in susceptibility and clinical course of SpA in Tunisian patients.
Assuntos
Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1/genética , Interleucina-1alfa/genética , Espondilartrite/genética , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Estudos Transversais , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Interleucina-1beta/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Espondilartrite/fisiopatologia , Tunísia , Adulto JovemRESUMO
Infliximab (IFX) is a chimeric monoclonal antibody which has proven its efficacy in the treatment of inflammatory diseases. However, its efficacy can be limited by the development of anti-IFX antibodies (ATI) resulting in a therapeutic failure of IFX. ATI plasmatic monitoring is then indicated to optimize IFX treatment. The aim of this study was to validate an ELISA (enzyme linked immuno sorbent assay) method of ATI plasmatic monitoring. METHODS: Assessment of performance was based on the study of correlation and concordance (Bland Altman method) of the absorbances measured by the two readers. ELISA kit validation was made by calculating the accuracy and the exactitude. RESULTS: We collected 23 samples. Their mean age was 46 years and sex ratio M/W was 0.92. In nine cases, plasmatic AIT were positive and in 14 cases, they were not detected. Correlation between the two readers showed a correlation coefficient r2 of 99.95%. Concordance limits of the confidence interval 95% were [-112.768%-41.425%] with a bias of -35.671%. Repeatability and reproductibility were checked by a positive control and coefficients of variation were respectively of 5.574% and 14.184%. Limits of detection and quantification were respectively of 0.046 and 0.086. The positive predictive value was 0.5 and the negative predictive value was 1. The sensitivity was 100% and the specificity was 83%. CONCLUSION: The assessment of the performance of the tested microplate reader and the validation of the tested ELISA kit showed good results allowing ATI routine measurement to optimize therapeutic management of patients treated by IFX.
Assuntos
Anticorpos Monoclonais/sangue , Infliximab/imunologia , Kit de Reagentes para Diagnóstico , Testes Sorológicos/métodos , Adulto , Anticorpos Monoclonais/análise , Monitoramento de Medicamentos/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Kit de Reagentes para Diagnóstico/normas , Doenças Reumáticas/sangue , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/tratamento farmacológico , Sensibilidade e Especificidade , Espondilite Anquilosante/sangue , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/tratamento farmacológicoRESUMO
Despite the current availability of more potent drugs, hepatitis C virus (HCV) infection is still treated with a combination of IFN-α and ribavirin in many countries. Interferon/ribavirin therapy can induce the appearance of autoantibodies to Rods and Rings (anti-RR), which have been associated to a poorer prognosis. The aim of this study was to investigate the prevalence of anti-RR antibodies before and after ribavirin therapy and to look for a possible association with HCV infection outcome. In this context, anti-RR antibodies were detected by IFI on HEp-2 cells in 142 patients under ribavirin therapy (G1: 74 patients with a positive posttreatment HCV-PCR and G2: 68 patients with a negative posttreatment HCV-PCR, matched in age and gender), 84 kidney transplant recipients (KTRs) under mycophenolate and 158 controls (30 with systemic lupus erythematosus, 37 with rheumatoid arthritis, and 91 healthy blood donors). No patient had anti-RR antibody before IFN-α/ribavirin therapy, while 27 (19%) developed the anti-RR pattern under treatment. The anti-RR antibody was absent in all KTRs and the 158 controls. The frequency of anti-RR antibody was significantly higher in G1 (27; 36.48%) than in G2 (0), p < 0.001. Moreover, and in G1, anti-RR antibody was more frequent in nonresponders (NR) patients (23, 56.1%) than in relapsers (REL) (4, 12.1%); p < 0.001, OR [95%CI] = 9.26 [2.75-31.18]. Moreover, anti-RR antibody titer was significantly higher in NR patients (3,200 [1,600-6,400]) comparatively to REL patients (800 [500-1,400]), p = 0.002. Likewise, log of viral load postribavirin therapy was significantly higher in anti-RR positive patients (6.24 ± 0.64) than in anti-RR negative (4.69 ± 1.06), p < 0.001. Based on these findings, ribavirin-induced anti-RR autoantibody seems to be associated with a more frequent nonresponse to IFN-α/ribavirin therapy with a significant higher HCV viral load.
Assuntos
Antivirais/uso terapêutico , Autoanticorpos/sangue , Hepatite C/imunologia , Ribavirina/uso terapêutico , Carga Viral , Adulto , Autoanticorpos/imunologia , Feminino , Hepacivirus , Hepatite C/tratamento farmacológico , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Testes Sorológicos , Resultado do Tratamento , Adulto JovemRESUMO
AIM: The aim of the present study was to characterize the molecular basis of complement factor I deficiency in Tunisian atypical haemolytic and uremic syndrome patients with low factor I levels. METHODS: Six adults and seven children were enrolled in this study. Complement factor I levels were assessed by a homemade sandwich ELISA and ranged between 12.5% and 60%. Genomic DNA was amplified by way of a polymerase chain reaction using intronic primers flanking the 13 coding exons. Sequencing of amplified products was carried out by the dye terminator sequencing method. Molecular study was performed on parental samples for three dead paediatric patients. The control group consisted of 100 healthy Tunisian donors. RESULTS: We identified a total of 13 substitutions and one insertion: seven in introns, four in exons and three in UTR. The new mutations were c.-132G > C, c.71 + 181 T > A in 5'UTR and intron 1, respectively. Three intronic polymorphisms were predicted to have impact on splicing events: c.482 + 6C > T, c.884-42_884-41insTTAAA (rs34422850) and c.1429 + 33 A > G (rs9998151). They were three missense mutations leading to a p.Ile 357Met, p.Ile416Leu and p.GLu548Gln. p.Ile 357Met was found in two patients and one relative. Half of the patients had associated mutation and/or polymorphisms. CONCLUSION: This is the first genetic study in Tunisian and Maghrebin atypical haemolytic and uraemic syndrome patients. The high occurrence of Ile357Met mutation may reflect a founding effect. Functional impact of the two new mutations c.-132G > C and c.71 + 181A > T have to be studied. Association of simultaneous genetic abnormalities may explain the variability of atypical haemolytic and uraemic syndrome, penetrance and disease phenotype.
Assuntos
Síndrome Hemolítico-Urêmica Atípica , Complemento C3/deficiência , Fator I do Complemento , Doenças Genéticas Inatas , Adulto , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/epidemiologia , Síndrome Hemolítico-Urêmica Atípica/genética , Criança , Pré-Escolar , Estudos de Coortes , Complemento C3/genética , Fator I do Complemento/análise , Fator I do Complemento/genética , Feminino , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Doenças da Deficiência Hereditária de Complemento , Humanos , Lactente , Masculino , Mutação , Polimorfismo Genético , Tunísia/epidemiologiaRESUMO
INTRODUCTION: Clopidogrel (clopi) is a prodrug widely prescribed in the management of coronary artery disease and requires the intervention of hepatic cytochrome P450 2C19 (CYP2C19) for its activation. However, there is interindividual variability in response to clopi despite the use of recommended doses. Thus, the studies have highlighted the effect of the CYP2C19 gene polymorphism or Cyp2C19 gene on the response to clopi and particularly Cyp2C19 * 2 which may be associated with an increased risk of major cardiovascular events or MACE. OBJECTIVE: To evaluate the effect of Cyp2C19 * 2 polymorphism on MACE occurrence and hemorrhagic complications in patients treated with clopi. METHODS: We carried out a descriptive longitudinal study including 71 patients placed under clopi for a minimum duration of one month. Genotyping of the Cyp2C19 allele was performed by conventional polymerase chain reaction (PCR). After a follow-up period of 495 ± 183 days, we performed a statistical analysis to evaluate the association between the Cyp2C19 * 2 polymorphism and the occurrence of MACE or hemorrhagic complications. RESULTS: Among our patients, 51% had an angioplasty, 42% medical treatment and 7% a coronary artery bypass surgery. In our study population, 52% were heterozygous (HTZ), 28% homozygous (HMZ) healthy * 1 / * 1 and 20% HMZ had the loss of function allele * 2 / * 2. The allelic frequency of Cyp2C19 * 2 was 46%. Follow-up mean duration was of 495 ± 183 days. During this period, the prevalence of MACE was 11% and that of hemorrhagic complications was 13%. In our study, we did not observe a significant association between the occurrence of MACE or hemorrhagic complications with the genotype carrying the Cyp2C19 * 2 allele. CONCLUSION: Among patients treated with clopi, wearing a Cyp2C19 * 2 function loss allele didn't seem to be associated with a significantly higher risk of MACE, nor a significantly lower risk of hemorragic complications. This suggests the necessity of larger studies.
Assuntos
Clopidogrel/uso terapêutico , Citocromo P-450 CYP2C19/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Clopidogrel/farmacocinética , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Técnicas de Genotipagem , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Heterozigoto , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Polimorfismo Genético , Tunísia/epidemiologiaRESUMO
Th17 cell subset has been implicated in autoimmune diseases, tumor immunity and, transplant rejection. In order to investigate the role of IL-17/IL-23 pathway in allograft outcome, intragraft expression of IL-17 mRNA and single nucleotide polymorphisms (SNPs) of IL-17A, IL-17F, IL-17RC, and IL23R genes were evaluated with a quantification of IL-17A, IL-17F, and IL-23 plasma levels. This study revealed that recipients with acute rejection (AR) had a significant increase in IL-17A mRNA expression levels after transplantation compared to controls (P = 0.037). Moreover, IL-17A plasma levels were significantly higher in AR group; pretransplantation (Day-1 [D-1]): P = 0.00022 and posttransplantation (Day 7 [D7]): P < 10-14 . IL-17F and IL-23 plasma levels were significantly higher in AR at D7 only (47.86 vs. 22.99 pg/ml; and 33.82 vs. 18.811 pg/ml; P = 0.015 and P < 10-17 , respectively). Using receiver-operating characteristic curves, D7 IL-17A and IL-23 plasma levels exhibited excellent sensitivities and specificities for predicting AR. Genetic study revealed no association between IL-17A, IL-17F, IL-17RC, and IL23R studied SNPs and AR. Nevertheless, a significant improvement of graft survival was found in kidney transplant recipients carrying IL-17F-rs763780*A/A, IL-17RC*G/G, and *G/A genotypes. Besides, IL-17A mRNA levels were significantly higher in patients carrying the IL-23R*G/G genotype comparatively to those with *G/A genotype. Based on these findings, significant increase of IL-17A mRNA and protein levels in AR recipients that are genetically controlled highlights the role of this cytokine that can be a useful clinical biomarker to predict early acute renal allograft rejection.