RESUMEN
Mutations in NFkB pathway genes can cause inborn errors of immunity (IEI), with NFKB1 haploinsufficiency being a significant etiology for common variable immunodeficiency (CVID). Indeed, mutations in NFKB1 are found in 4 to 5% of in European and United States CVID cohorts, respectively; CVID representing almost » of IEI patients in European countries registries. This case study presents a 49-year-old patient with respiratory infections, chronic diarrhea, immune thrombocytopenia, hypogammaglobulinemia, and secondary lymphoma. Comprehensive genetic analysis, including high-throughput sequencing of 300 IEI-related genes and copy number variation analysis, identified a critical 2.6-kb deletion spanning the first untranslated exon and its upstream region. The region's importance was confirmed through genetic markers indicative of enhancers and promoters. The deletion was also found in the patient's brother, who displayed similar but milder symptoms. Functional analysis supported haploinsufficiency with reduced mRNA and protein expression in both patients. This case underscores the significance of copy number variation (CNV) analysis and targeting noncoding exons within custom gene panels, emphasizing the broader genomic approaches needed in medical genetics.
Asunto(s)
Inmunodeficiencia Variable Común , Hermanos , Masculino , Adulto , Humanos , Persona de Mediana Edad , Haploinsuficiencia/genética , Variaciones en el Número de Copia de ADN , FN-kappa B/genética , Inmunodeficiencia Variable Común/genética , Secuencias Reguladoras de Ácidos Nucleicos , Subunidad p50 de NF-kappa B/genéticaRESUMEN
OBJECTIVE: While the incidence and type of blood malignancies are well documented amid primary Sjögren's syndrome patients (pSS), data focusing on solid neoplasms are more conflicting. We aimed to describe clinical, pathological, and immunological characteristics of pSS patients with cancers, along with the chronological interplay between the two conditions. METHODS: Outcomes concerning both pSS and cancer were retrospectively collected from Montpellier University Hospital (tertiary center) between 2019 and 2020. pSS characteristics were compared to a control group of pSS patients without cancer. RESULTS: A total of 165 patients with pSS were included: 55 patients with cancer (52 female, mean age 58.4 ± 10.4 years at pSS diagnosis; mean follow-up 10.5 ± 10.1 years, 12 patients had multiple cancers) and 110 controls without cancer. Characteristics of pSS patients with cancers were different from controls mostly for lymphoma prognosis factors. Among the 70 cancers, we recorded 55 solid neoplasms (whom 27 breast cancers and 8 lung cancers, and 82% of adenocarcinomas), with no evidence of disease at the end of follow-up in 85% of them. Among the 15 recorded blood malignancies, ten were lymphomas with an excellent prognosis. Regarding chronological interplay between cancer and pSS, most cancers (43%) were diagnosed close (± 5 years) to pSS diagnosis. Breast cancers were diagnosed before or close to pSS diagnosis (mean delay - 1.8 ± 13.0 years), at an early stage, with only two relapses (no cancer-related death), while lung cancers were diagnosed late after. CONCLUSIONS: The tight chronological interplay between breast cancer and pSS and the intriguing pathological and immunological pattern of pSS in these patients suggest a hypothesis of immune control of cancer.
Asunto(s)
Neoplasias Pulmonares , Linfoma , Síndrome de Sjögren , Humanos , Femenino , Persona de Mediana Edad , Anciano , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/diagnóstico , Estudios Retrospectivos , Recurrencia Local de Neoplasia , Linfoma/terapiaRESUMEN
OBJECTIVES: This study aimed to estimate the prevalence of ANCA-associated vasculitis (AAV), ie granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), in Southern France in 2018, and evaluate differences among Europeans and non-Europeans. METHODS: This population-based, cross-sectional study used four sources (hospitals, community-based physicians, laboratories, National Health Insurance) to identify adults ≥ 15 years diagnosed with GPA, MPA or EGPA, living in Hérault and Gard in 2018. Cases were defined using the ACR/EULAR classification criteria, and if necessary, the European Medicines Agency algorithm. Prevalence estimates were standardised to the world population and capture-recapture analysis was used to assess the comprehensiveness of the estimation. The influence of geographical origin was evaluated. RESULTS: 202 patients were selected, with 86 cases of GPA (42.6%), 85 cases of MPA (42.1%), and 31 cases of EGPA (15.3%). The standardised prevalence estimates per million inhabitants for 2018 were: 103 (95%CI 84 - 125) for AAV, 48 (95%CI 35 - 64) for GPA, 39 (95%CI 28 - 53) for MPA and 16 (95%CI 9 - 26) for EGPA, 36 (95%CI 25 - 50) for anti-PR3 positive AAV, 46 (95%CI 34 - 61) for anti-MPO positive AAV, and 16 (95%CI 9 - 26) for ANCA-negative AAV. The global estimation of comprehensiveness by capture-recapture analysis was 80.5%. The number of AAV cases was higher for non-European residents (P=0.001), particularly for MPA (P<0.0001). CONCLUSION: We provide a new estimate of AAV prevalence in France and show a higher prevalence of MPA in non-European patients.
RESUMEN
OBJECTIVES: Systemic sclerosis (SSc) can cause malnutrition due to frequent gastrointestinal involvement. However, prevalence of malnutrition in SSc is poorly known. The aim of this study was to evaluate the prevalence of malnutrition in SSc and its potential associations with disease features in patients from a tertiary referral center. METHODS: All patients meeting American College of Rheumatology/European Alliance of Associations for Rheumatology criteria for SSc followed between January 1, 1985, and January 1, 2019, at the Department of Internal Medicine, Saint Eloi University Hospital, were included. Malnutrition was assessed using the 2020 French recommendations for SSc and the malnutrition universal screening tool score. Severe malnutrition was defined via the French Haute Autorité de Santé (National Health Authority) 2007 criteria. RESULTS: A total of 120 patients were included, with mean age 64 (± 15) y and a female-to-male sex ratio of 5:1. According to 2020 French recommendations, 71 patients (59.2%) were malnourished and 30 (25%) had at least one criterion of severe malnutrition. With the malnutrition universal screening tool score, 41.7%, 20%, and 38.3%, respectively, had low, medium, and high risk of malnutrition. Multivariate analysis revealed the following results: 1) malnutrition was associated with cardiac involvement (P < 0.01); 2) a high malnutrition universal screening tool score was also associated with specific cardiac involvement (P < 0.01); and 3) severe malnutrition was strongly correlated with interincisal distance <35 mm (P = 0.02). CONCLUSIONS: Malnutrition affects more than half of SSc patients and is associated with specific cardiac involvement. Interincisal distance <35 mm could be a red flag for severe malnutrition in SSc.
Asunto(s)
Desnutrición , Esclerodermia Sistémica , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Prevalencia , Desnutrición/epidemiología , Desnutrición/etiología , Desnutrición/diagnóstico , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/epidemiología , Análisis MultivarianteRESUMEN
BACKGROUND: Bevacizumab-a humanized monoclonal antibody-has been widely used to treat patients with hereditary hemorrhagic telangiectasia (HHT), but no randomized trial has yet been conducted. METHODS: This study is a double-blind multicenter randomized phase 2 trial with a 1:1 active-treatment-to-placebo ratio. We included patients over the age of 18 with a confirmed diagnosis and the need for at least four red blood cell (RBC) units transfused in the 3 months before study enrollment. Bevacizumab was administered at a dose of 5 mg/kg every 14 days with a total of six injections. The primary efficacy criterion was a decrease of at least 50% in the cumulative number of RBC units transfused in a 3-month period before and after treatment. RESULTS: A total of 24 patients (12 in each group) were included and randomized at 4 different centers. In intention-to-treat analysis, 63.6% of patients (7/11) in the bevacizumab group versus 33.3% of patients (4/12) in the placebo group decreased the number of blood transfusions by at least 50% (p = 0.22). Hemoglobin levels significantly improved at 6 months in the bevacizumab versus placebo group (p = 0.02). The pharmacokinetics study revealed that patients with high exposure to bevacizumab had a significant decrease in RBC transfusions (p = 0.03). Fifty-nine adverse events were observed, 34 in the placebo arm versus 25 in the bevacizumab arm. CONCLUSION: Though the present trial was underpowered, patients with HHT receiving bevacizumab required numerically fewer red blood cell transfusions than those receiving placebo, particularly those with high exposure.
Asunto(s)
Hemorragia , Telangiectasia Hemorrágica Hereditaria , Adulto , Humanos , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/efectos adversos , Bevacizumab/efectos adversos , Hemorragia/tratamiento farmacológico , Telangiectasia Hemorrágica Hereditaria/complicaciones , Telangiectasia Hemorrágica Hereditaria/tratamiento farmacológico , Resultado del Tratamiento , Método Doble CiegoRESUMEN
OBJECTIVE: The aim of this study was to compare safety and efficacy of long-term home parenteral nutrition between patients with systemic sclerosis and intestinal failure (IF) and controls with IF from another etiology. METHODS: A retrospective study was conducted in a referral center for systemic sclerosis (SSc) in Montpellier, France. Patients followed between 1985 and 2020 with SSc-related IF were included and compared with control patients with IF from another etiology. The patients included had to be treated for ≥4 wk by home parenteral nutrition (HPN). Primary outcome was occurrence of HPN-related complications. Secondary outcomes included duration of parenteral nutrition, body mass index at 12 mo, and survival. RESULTS: Cumulative duration of HPN was 23 397 catheter days. HPN resulted in body mass index increase in both groups. There was no statistical difference regarding catheter-related bloodstream infections and thrombosis between the groups, despite use of immunosuppressive drugs and autologous hematopoietic stem cell transplantation in patients with SSc. However, the patients with SSc had significantly more HPN-related cardiac overload than the controls (P < 0.0001). Overloads occurred in SSc patients with and without cardiac disease, arguing for comprehensive hemodynamic screening in this condition. CONCLUSION: Long-term HPN in SSc-related IF is feasible but unveils occult cardiac disease.
Asunto(s)
Infecciones Relacionadas con Catéteres , Cardiopatías , Enfermedades Intestinales , Insuficiencia Intestinal , Nutrición Parenteral en el Domicilio , Esclerodermia Sistémica , Humanos , Estudios Retrospectivos , Nutrición Parenteral en el Domicilio/efectos adversos , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/terapia , Infecciones Relacionadas con Catéteres/epidemiología , Infecciones Relacionadas con Catéteres/etiología , Cardiopatías/etiología , Cardiopatías/terapia , Enfermedades Intestinales/etiología , Enfermedades Intestinales/terapiaRESUMEN
BACKGROUND: EPHB4 loss of function is associated with type 2 capillary malformation-arteriovenous malformation syndrome, an autosomal dominant vascular disorder. The phenotype partially overlaps with hereditary haemorrhagic telangiectasia (HHT) due to epistaxis, telangiectases and cerebral arteriovenous malformations, but a similar liver involvement has never been described. METHODS: Members of the French HHT network reported their cases of EPHB4 mutation identified after an initial suspicion of HHT. Clinical, radiological and genetic characteristics were analysed. RESULTS: Among 21 patients with EPHB4, 15 had a liver imaging, including 7 with HHT-like abnormalities (2 female patients and 5 male patients, ages 43-69 years). Atypical epistaxis and telangiectases were noted in two cases each. They were significantly older than the eight patients with normal imaging (median: 51 vs 20 years, p<0.0006).The main hepatic artery was dilated in all the cases (diameter: 8-11 mm). Six patients had hepatic telangiectases. All kind of shunts were described (arteriosystemic: five patients, arterioportal: two patients, portosystemic: three patients). The overall liver appearance was considered as typical of HHT in six cases.Six EPHB4 variants were classified as pathogenic and one as likely pathogenic, with no specific hot spot. CONCLUSION: EPHB4 loss-of-function variants can be associated with HHT-like hepatic abnormalities and should be tested for atypical HHT presentations.
Asunto(s)
Malformaciones Arteriovenosas Intracraneales , Telangiectasia Hemorrágica Hereditaria , Masculino , Humanos , Femenino , Telangiectasia Hemorrágica Hereditaria/complicaciones , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Telangiectasia Hemorrágica Hereditaria/genética , Epistaxis/complicaciones , Hígado , MutaciónRESUMEN
BACKGROUND: The systemic capillary leak syndrome (SCLS), also known as Clarkson disease, is a very rare condition characterized by recurrent life-threatening episodes of vascular hyperpermeability in the presence of a monoclonal gammopathy. Extended intravenous immunoglobulin (IVIG) treatment is associated with fewer recurrences and improved survival, but the optimal treatment dosage and duration remain unknown. OBJECTIVE: We aim to evaluate the safety of IVIG tapering and withdrawal in patients with SCLS. METHODS: We conducted a retrospective multicenter study including all adult patients with monoclonal gammopathy-associated SCLS from the EurêClark registry who received at least 1 course of IVIG. The primary end point was overall survival according to IVIG withdrawal. RESULTS: Fifty-nine patients of mean ± SD age 51 ± 13 years were included. Overall cumulative probabilities of 2-, 5-, 10- and 15-year survival were 100%, 85%, 72%, 44%, respectively. The IVIG was withdrawn at least once in 18 patients (31%; W+ group) and never in 41 patients (69%; W- group). Cumulative probabilities of 10-year survival in W+ versus W- groups were 50% and 83% (log rank test, P = .02), respectively. Relapse rate and the median number of relapses in the W+ versus the W- groups were 72% versus 58% (P = 0.3) and 2.5 (0.3-4) versus 1 (0-2) (P = .03), respectively. The IVIG tapering was not statistically associated with increased person-year incidence of attacks using a mixed linear model. CONCLUSIONS: The IVIG withdrawal was associated with increased mortality and higher rate of recurrence in SCLS patients. The IVIG tapering might be cautiously considered in stable SCLS patients.
Asunto(s)
Síndrome de Fuga Capilar , Paraproteinemias , Adulto , Humanos , Persona de Mediana Edad , Síndrome de Fuga Capilar/tratamiento farmacológico , Inmunoglobulinas Intravenosas/uso terapéutico , Paraproteinemias/complicaciones , Estudios Retrospectivos , IncidenciaRESUMEN
BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) disease is a rare genetic disorder with symptoms and complications that can significantly affect patients' daily lives. To date, no scale has been validated to assess the specific symptoms of this disease on the quality of life (QOL) of HHT patients. This makes it difficult for clinicians to accurately measure the quality of life of patients with HHT. The present study aims to develop and validate a QOL measurement tool specific to HHT disease: the QOL questionnaire in HHT (QoL-HHT). METHODS: A quantitative, non-interventional, multi-center study involving HHT patients in twenty French HHT expert centers was conducted. A calibration sample of 415 HHT patients and a validation sample of 228 HHT patients voluntarily participated in the study. Data were analyzed using exploratory factor analysis (EFA), confirmatory factor analysis (CFA), Exploratory Structural Equation Modeling (ESEM) analyses, reliability analyses, and correlational analyses. RESULTS: The EFA, CFA and ESEM results allowed us to provide evidence of the factorial structure of a questionnaire composed of 24 items measuring 6 domains of QOL: Physical limitations, social relationships, concern about bleeding, relationship with the medical profession, experience of symptoms, and concern about the evolution of the disease. Cronbach's alpha coefficients (> 0.70) demonstrated reliable internal consistency of all the QoL-HHT scores (dimensions). The results of the test-retest provided further evidence of the reliability of the QOL-HHT scores over time. Correlational analyses provided evidence for the convergent validity of the QoL-HHT scores. CONCLUSIONS: We developed a simple and quick self-assessment tool to measure quality of life specific to HHT disease. This study demonstrated reliability and validity of our QoL-HHT scores. It is a very promising tool to evaluate the impact of HHT disease on all aspects of the quality of life of HHT patients in order to offer them individualized medico-psycho-social support. TRIAL REGISTRATION: ClinicalTrials, NCT03695874. Registered 04 October 2018, https://www. CLINICALTRIALS: gov/ct2/show/NCT03695874.
Asunto(s)
Calidad de Vida , Telangiectasia Hemorrágica Hereditaria , Humanos , Psicometría/métodos , Enfermedades Raras/complicaciones , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Telangiectasia Hemorrágica Hereditaria/complicacionesRESUMEN
BACKGROUND: In patients with acute intermittent porphyria (AIP), induction of delta aminolevulinic acid synthase 1 (ALAS1) leads to haem precursor accumulation that may cause recurring acute attacks. In a recent phase III trial, givosiran significantly reduced the attack rate in severe AIP patients. Frequent adverse events were injection-site reaction, fatigue, nausea, chronic kidney disease and increased alanine aminotransferase. OBJECTIVES: To describe the efficacy and safety of givosiran based on a personalized medical approach. METHODS: We conducted a retrospective patient file study in 25 severe AIP patients treated with givosiran in France. We collected data on clinical and biochemical efficacy along with reports of adverse events. RESULTS: Givosiran drastically reduced the attack rate in our cohort, as 96% were attack-free at the time of the study. The sustained efficacy of givosiran in most patients allowed us to personalize dosing frequency. In 42%, givosiran was only given when haem precursor levels were increasing. Our data suggest that givosiran is most effective when given early in the disease course. We confirmed a high prevalence of adverse events. One patient discontinued treatment due to acute pancreatitis. All patients had hyperhomocysteinemia, and all patients with initial homocysteine levels available showed an increase under treatment. In this context, one patient was diagnosed with pulmonary embolism. CONCLUSION: The sustained effect of givosiran allowed a decrease in dosing frequency without compromising treatment efficacy. The high prevalence of adverse events emphasizes the importance of restricting the treatment to severe AIP and administering the minimum effective dose for each patient.
Asunto(s)
Pancreatitis , Porfiria Intermitente Aguda , Acetilgalactosamina/análogos & derivados , Enfermedad Aguda , Hemo , Humanos , Pancreatitis/tratamiento farmacológico , Porfiria Intermitente Aguda/tratamiento farmacológico , Medicina de Precisión , Pirrolidinas , Estudios RetrospectivosAsunto(s)
COVID-19 , Neuromielitis Óptica , Acuaporina 4 , Autoanticuerpos , Humanos , Neuromielitis Óptica/complicacionesRESUMEN
BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare genetic disease characterized by a deregulated neo-angiogenesis. Besides a mainly vascular phenotype (muco-cutaneous telangiectases, arteriovenous malformations), a specific risk of infection is suggested by case series of severe and atypical infections as well as by reports of decreased T and natural killer (NK) lymphocyte counts. As some evidence supports a dysregulation of the CXCR4/CXCL12 chemotactic axis of HHT endothelial cells, we hypothesized that a similar phenomenon could occur on lymphocytes. METHODS: Eighteen HHT patients with history of severe infection (HSI) were matched in age and sex with 18 HHT without HSI and 18 healthy control subjects (HC). We assessed the cell count and the surface expression of CXCR4 and CD26 (CXCL12 inactivating peptidase) of circulating T-helper and T-cytotoxic lymphocytes (including naive, memory and activated subsets) and NK cells. RESULTS: The overall HHT group of 36 patients exhibited a reduction of circulating T-helper lymphocytes compared to HC (median: 517 vs. 1026 cells/mm3, p < 0.0001), correlated with age (r = - 0.46, p = 0.005), requirement of intravenous iron or blood transfusions (median: 291 vs. 627 cells/mm3, p = 0.03) and CXCR4 surface expression (r = 0.353, p = 0.0345). CXCR4 and CD26 membrane expression were both decreased on HHT T-helper lymphocytes (median MFI ratio: 4.49 vs. 5.74 for CXCR4 and 3.21 vs. 4.33 for CD26, p = 0.03 and 0.0018 respectively) with an unchanged CXCR4/CD26 ratio. The HHT group with HSI had a higher CXCR4/CD26 ratio on the total T-lymphocyte population, as well as on the T-helper population and its naive subset (median on naive T-helper cells: 2.34 vs. 1.32, p = 0.0002). CONCLUSIONS: Our findings support a dysregulation of the CXCL12/CXCR4 chemotaxis of T-helper lymphocytes in HHT patients, potentially linked to their T-helper lymphopenia and susceptibility to infection.
Asunto(s)
Telangiectasia Hemorrágica Hereditaria , Dipeptidil Peptidasa 4/metabolismo , Células Endoteliales , Humanos , Células Asesinas Naturales/metabolismo , Receptores CXCR4 , Linfocitos T Colaboradores-Inductores/metabolismo , Telangiectasia Hemorrágica Hereditaria/epidemiologíaRESUMEN
BACKGROUND: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in the ENG (HHT1), ACVRL1 (HHT2) and, to a lesser extent MADH4 and GDF2, which encode proteins involved in the TGF-ß/BMP9 signaling pathway. Common visceral complications of HHT are caused by pulmonary, cerebral, or hepatic arteriovenous malformations (HAVMs). There is large intrafamilial variability in the severity of visceral involvement, suggesting a role for modifier genes. The objective of the present study was to investigate the potential role of ENG, ACVRL1, and of other candidate genes belonging to the same biological pathway in the development of HAVMs. METHODS: We selected 354 patients from the French HHT patient database who had one disease causing variant in either ENG or ACVRL1 and who underwent hepatic exploration. We first compared the distribution of the different types of variants with the occurrence of HAVMs. Then, we genotyped 51 Tag-SNPs from the Hap Map database located in 8 genes that encode proteins belonging to the TGF-ß/BMP9 pathway (ACVRL1, ENG, GDF2, MADH4, SMAD1, SMAD5, TGFB1, TGFBR1), as well as in two additional candidate genes (PTPN14 and ADAM17). We addressed the question of a possible genetic association with the occurrence of HAVMs. RESULTS: The proportion of patients with germline ACVRL1 variants and the proportion of women were significantly higher in HHT patients with HAVMs. In the HHT2 group, HAVMs were more frequent in patients with truncating variants. Six SNPs (3 in ACVRL1, 1 in ENG, 1 in SMAD5, and 1 in ADAM17) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383). CONCLUSIONS: In this large association study, we confirmed the strong relationship between ACVRL1 and the development of HAVMs. Common polymorphisms of ACVRL1 may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants.
Asunto(s)
Receptores de Activinas Tipo II , Hígado , Enfermedades Pulmonares , Telangiectasia Hemorrágica Hereditaria , Enfermedades Vasculares , Receptores de Activinas Tipo II/genética , Endoglina/genética , Femenino , Genotipo , Humanos , Hígado/irrigación sanguínea , Mutación , Telangiectasia Hemorrágica Hereditaria/genética , Enfermedades Vasculares/genéticaRESUMEN
Hereditary hemorrhagic telangiectasia is a rare but ubiquitous genetic disease. Epistaxis is the most frequent and life-threatening manifestation and tacrolimus, an immunosuppressive agent, appears to be an interesting new treatment option because of its anti-angiogenic properties. Our objective was to evaluate, six weeks after the end of the treatment, the efficacy on the duration of nosebleeds of tacrolimus nasal ointment, administered for six weeks to patients with hereditary hemorrhagic telangiectasia complicated by nosebleeds, and we performed a prospective, multicenter, randomized, placebo-controlled, double-blinded, ratio 1:1 phase II study. Patients were recruited from three French Hereditary Hemorrhagic Telangiectasia (HHT) centers between May 2017 and August 2018, with a six-week follow-up, and we included people aged over 18 years, diagnosed with hereditary hemorrhagic telangiectasia and epistaxis (total duration > 30 min/6 weeks prior to inclusion). Tacrolimus ointment 0.1% was self-administered by the patients twice daily. About 0.1 g of product was to be administered in each nostril with a cotton swab. A total of 50 patients was randomized and treated. Mean epistaxis duration before and after treatment in the tacrolimus group were 324.64 and 249.14 min, respectively, and in the placebo group 224.69 and 188.14 min, respectively. Epistaxis duration improved in both groups, with no significant difference in our main objective comparing epistaxis before and after treatment (p = 0.77); however, there was a significant difference in evolution when comparing epistaxis before and during treatment (p = 0.04). Toxicity was low and no severe adverse events were reported. In conclusion, tacrolimus nasal ointment, administered for six weeks, did not improve epistaxis in HHT patients after the end of the treatment. However, the good tolerance, associated with a significant improvement in epistaxis duration during treatment, encouraged us to perform a phase 3 trial on a larger patient population with a main outcome of epistaxis duration during treatment and a longer treatment time.
RESUMEN
Cancer among patients with systemic sclerosis (SSc) would appear to be more prevalent than in the general population. Pathophysiological hypotheses are multiple, involving intertwined factors such as immune system antitumoral response, oxygen species dysregulation, and immunosuppressive treatments. We aimed to identify SSc patients with cancer monitored at our center, describing their clinical and immunological characteristics, such as cancer-specific outcomes. We focused in particular on the temporal relationships between cancer onset and SSc diagnosis. A retrospective study was conducted on SSc patients from Montpellier University Hospital from 2003 to 2018. Clinical characteristics and outcomes of each SSc patient with cancer were recorded. Fifty-five patients with SSc and at least one cancer was included (median age 56 years (47-66)), with a median follow-up time of 11 years (4-15). Sixty-four metachronous malignancies were identified (12 patients had two cancers). Among them, early-onset cancer occurrences (±5 years from SSc diagnosis) included 23 cancers (39% breast cancers, 13% lung cancers, and 13% gastro-intestinal tract cancers). Twenty-two cancers occurred 10 years (±5 years) after SSc diagnosis (14% breast cancers, 23% gastrointestinal (GI) tract cancers, and 18% lung cancers). Patients without any of the two autoantibodies (anti-centromere (ACA) and anti-topoisomerase (ATA-scl70) antibodies) were more prevalent in the early-onset cancer subgroup (14 vs. 6, p = 0.02). This study brought to light two peaks of cancer occurrence in SSc patients. Early-onset cancers were associated with SSc with a specific immunological signature. Late-onset cancers might be the consequence of a subtle interplay between repeated target organ inflammation, immunosuppressant use, mesenchymal cell dysfunction and subsequent genetic alterations.
RESUMEN
OBJECTIVE: The randomized, controlled MAINRITSAN2 trial was designed to compare the capacity of an individually tailored therapy [randomization day 0 (D0)], with reinfusion only when CD19+ lymphocytes or ANCA had reappeared, or if the latter's titre rose markedly, with that of five fixed-schedule 500-mg rituximab infusions [D0 + D14, then months (M) 6, 12 and 18] to maintain ANCA-associated vasculitis (AAV) remissions. Relapse rates did not differ at M28. This ancillary study was undertaken to evaluate the effect of omitting the D14 rituximab infusion on AAV relapse rates at M12. METHODS: MAINRITSAN2 trial data were subjected to post-hoc analyses of M3, M6, M9 and M12 relapse-free survival rates in each arm as primary end points. Exploratory subgroup analyses were run according to CYC or rituximab induction and newly diagnosed or relapsing AAV. RESULTS: At M3, M6, M9 and M12, respectively, among the 161 patients included, 79/80 (98.8%), 76/80 (95%), 74/80 (92.5%) and 73/80 (91.3%) from D0, and 80/81 (98.8%), 78/81 (96.3%), 76/81 (93.8%) and 76/81 (93.8%) from D0+D14 groups were alive and relapse-free. No between-group differences were observed. Results were not affected by CYC or rituximab induction, or newly diagnosed or relapsing AAV. CONCLUSIONS: We were not able to detect a difference between the relapse-free survival rates for up to M12 for the D0 and D0+D14 rituximab-infusion groups, which could suggest that omitting the D14 rituximab remission-maintenance dose did not modify the short-term relapse-free rate. Nevertheless, results at M12 may also have been influenced by the rituximab-infusion strategies for both groups.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Antirreumáticos/administración & dosificación , Quimioterapia de Mantención/métodos , Rituximab/administración & dosificación , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Antígenos CD19 , Supervivencia sin Enfermedad , Esquema de Medicación , HumanosRESUMEN
MAIN OBJECTIVE: To prospectively assess the cost-consequence of a standardized diagnostic strategy as to compared to an open one for the etiological diagnosis of uveitis. DESIGN: This was a prospective, non-inferiority, multicentre, randomized controlled trial. METHODS: We included all consecutive patients with uveitis who had visited at least one of the Departments of Ophthalmology. In the standardized group, patients had a minimal work-up regardless of the type of uveitis (including evaluation of the CBC, ESR, C-reactive protein, tuberculin skin test, syphilis serology and chest X-ray). Depending on ophthalmological findings, further investigations could be performed. In the open strategy, ophthalmologists were free to order any kind of investigation. The main outcome was the mean cost per patient of each strategy. RESULTS: 903 uveitis patients were included from January, 2010 to May, 2013. The mean cost per patient of the standardized strategy was 182.97 euros [CI 95% (173.14; 192.80)], and the mean cost per patient of the open strategy was 251.75 euros [CI 95% (229.24; 274.25)]. Therefore, the mean cost per patient of the standardized strategy was significantly lower than the mean cost per patient of the open strategy (p<0.001). There were significantly fewer visits (p<0.001), fewer radiological procedures (p<0.004) and fewer laboratory investigations (p<0.001) in the standardized group. CONCLUSION: A standardized strategy is a cost-saving approach for the etiological diagnosis of uveitis.
Asunto(s)
Oftalmología/normas , Uveítis/diagnóstico , Uveítis/economía , Adulto , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Oftalmólogos , Oftalmología/economía , Pautas de la Práctica en Medicina/economía , Pautas de la Práctica en Medicina/normas , Estudios Prospectivos , Uveítis/etiologíaRESUMEN
OBJECTIVE: To compare individually tailored, based on trimestrial biological parameter monitoring, to fixed-schedule rituximab reinfusion for remission maintenance of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAVs). METHODS: Patients with newly diagnosed or relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in complete remission after induction therapy were included in an open-label, multicentre, randomised controlled trial. All tailored-arm patients received a 500 mg rituximab infusion at randomisation, with rituximab reinfusion only when CD19+B lymphocytes or ANCA had reappeared or ANCA titre rose markedly based on trimestrial testing until month 18. Controls received a fixed 500 mg rituximab infusion on days 0 and 14 postrandomisation, then 6, 12 and 18 months after the first infusion. The primary endpoint was the number of relapses (new or reappearing symptom(s) or worsening disease with Birmingham Vasculitis Activity Score (BVAS)>0) at month 28 evaluated by an independent Adjudication Committee blinded to treatment group. RESULTS: Among the 162 patients (mean age: 60 years; 42% women) included, 117 (72.2%) had GPA and 45 (27.8%) had MPA. Preinclusion induction therapy included cyclophosphamide for 100 (61.7%), rituximab for 61 (37.6%) and methotrexate for 1 (0.6%). At month 28, 21 patients had suffered 22 relapses: 14/81 (17.3%) in 13 tailored-infusion recipients and 8/81 (9.9%) in 8 fixed-schedule patients (p=0.22). The tailored-infusion versus fixed-schedule group, respectively, received 248 vs 381 infusions, with medians (IQR) of 3 (2-4) vs 5 (5-5) administrations. CONCLUSION: AAV relapse rates did not differ significantly between individually tailored and fixed-schedule rituximab regimens. Individually tailored-arm patients received fewer rituximab infusions. TRIAL REGISTRATION NUMBER: NCT01731561; Results.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Antirreumáticos/administración & dosificación , Rituximab/administración & dosificación , Adulto , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Antirreumáticos/efectos adversos , Antirreumáticos/uso terapéutico , Subgrupos de Linfocitos B/efectos de los fármacos , Biomarcadores/sangre , Esquema de Medicación , Monitoreo de Drogas/métodos , Femenino , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Medicina de Precisión/métodos , Recurrencia , Inducción de Remisión/métodos , Rituximab/efectos adversos , Rituximab/uso terapéutico , Índice de Severidad de la EnfermedadRESUMEN
INTRODUCTION: Ovarian cancer is mostly diagnosed at advanced stage. Better survival is achieved through complete debulking surgery and chemotherapy. Historically, neoadjuvant chemotherapy (NAC) has been introduced for unresectable disease to decrease tumor load and perform a unique complete surgery. Four randomized control trials have compared primary debulking surgery to NAC, but there is still controversy about the use of neoadjuvant chemotherapy and questions about its modalities. Areas covered: We made a review of knowledge on benefits of NAC compared to primary debulking chemotherapy, in terms of survival and morbidity, methods of administration, new drugs in early and late phase trials, the selection of patients. Similar survival was observed after NAC and interval debulking surgery or primary debulking surgery. Morbidity of surgery was decreased after interval debulking compared primary debulking surgery. Conventional drugs are carboplatin and paclitaxel. Safety of bevacizumab was evaluated in phase 2 trials associated with conventional drugs. Immunotherapy trials are enrolling patients in phase 1 study. Expert commentary: NAC followed by debulking surgery is the best treatment for patients with advanced ovarian cancer.