27 research outputs found
Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy.
No full textGiant cell arteritis (GCA) and Takayasu’s arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P = 7.54E-07; ORGCA = 1.19, ORTAK = 1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA = 5.52E-04, ORGCA = 1.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus
Corrigendum: Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy.
No full textGiant cell arteritis (GCA) and Takayasu's arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P = 7.54E-07; ORGCA = 1.19, ORTAK = 1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA = 5.52E-04, ORGCA = 1.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus
Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: a phase III randomized study of the London Lung Cancer Group
No full textPurpose: This phase III randomized trial compared two chemotherapy regimens, gemcitabine plus carboplatin and mitomycin, ifosfamide, and cisplatin, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). The regimens were compared with regard to effects on survival, response rates, toxicity, and quality of life.Patients and Methods: Eligible patients had previously untreated stage IIIB or IV NSCLC suitable for cisplatin-based chemotherapy. Randomly assigned patients were to receive four cycles, each at 3-week intervals, of carboplatin area under the curve of 5 on day 1 plus gemcitabine 1,200 mg/m2 on days 1 and 8 (GCa) or mitomycin 6 mg/m2, ifosfamide 3g/m2, and cisplatin 50 mg/m2 on day 1 (MIC).Results: Between February 1999 and August 2001, 422 patients (GCa, n = 212; MIC, n = 210) were randomly assigned in the United Kingdom. The majority of patients received the intended four cycles (GCa, 64%; MIC, 61%). There was a significant survival advantage for GCa compared with MIC (hazard ratio, 0.76; 95% CI, 0.61 to 0. 93; P = .008). Median survival was 10 months with GCa and 7.6 months with MIC (difference, 2.4 months; 95% CI, 1.0 to 4.0), and 1-year survival was 40% with GCa and 30% with MIC (difference, 10%; 95% CI, 3% to 18%). Overall response rates were similar (42% for GCa v 41% for MIC; P = .84). More thrombocytopenia occurred with GCa (P = .03), but this was not associated with increased hospital admission or fatality. GCa caused less nausea, vomiting, constipation, and alopecia and was associated with fewer admissions for administration and better quality of life.Conclusion: In patients with advanced NSCLC, GCa chemotherapy was shown to be a better-tolerated treatment that conferred a survival advantage over MIC
Analysis of the common genetic component of large-vessel vasculitides through a meta-Immunochip strategy
No full textGiant cell arteritis (GCA) and Takayasu's arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P = 7.54E-07; ORGCA = 1.19, ORTAK = 1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA = 5.52E-04, ORGCA = 1.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus
Age at diagnosis influences the clinical phenotype, treatment strategies and outcomes in patients with giant cell arteritis: results from the observational GCAGE study on a large cohort of 1004 patients
No full textBackground: Immune and vascular ageing are proposed risk factors for giant cell arteritis (GCA). Data on the impact of age at diagnosis of GCA on the clinical presentation and course of the disease are scarce. Methods: Patients with GCA followed at referral centres within the Italian Society of Rheumatology Vasculitis Study Group were enrolled up to November 2021. Patients were grouped according to age at diagnosis: ≤64, 65-79 and ≥80 years old. Results: The study included 1004 patients, mean age 72.1±8.4, female 70.82%. Median follow-up duration was 49 (IQR 23-91) months. Patients in the oldest group (≥80 years) had significantly more cranial symptoms, ischaemic complications and risk for blindness compared with the groups 65-79 and ≤64 years (blindness: 36.98% vs 18.21% vs 6.19%; p<0.0001). Large-vessel-GCA was more frequent in the youngest group (65% of patients). Relapses occurred in 47% of patients. Age did not influence the time to first relapse, nor the number of relapses. Older age was negatively associated with the number of adjunctive immunosuppressants. Patients >65 years old had 2-3 fold increased risk for aortic aneurysm/dissection up to 60 months follow-up. Serious infections, but not other treatment-related complications (hypertension, diabetes, osteoporotic fractures), were significantly associated with older age. Mortality occurred in 5.8% of the population with age >65, cranial and systemic symptoms as independent risk factors. Conclusions: The highest risk of ischaemic complications, aneurysm development, serious infections and the possible undertreatment make of GCA a very challenging disease in the oldest patients
Trends in incidence of esophagus and gastric cancer in Italy by subsite and histology, 1986-97
No full textAbstract
OBJECTIVE: Population-based studies in Western countries suggest that the incidence of oesophageal adenocarcinoma (OA) and gastric cardia adenocarcinoma (GCA) is increasing, whereas the incidence of distal gastric carcinoma and oesophageal squamous cell carcinoma (OSCC) is declining. This is the first population-based study carried out in a southern European region to evaluate the time trends in incidence rates of oesophageal and gastric tumours according to subsite and histology over the period 1986-1997.
METHODS: Cancer cases were drawn from seven registries of the Italian Network of Cancer Registries, which covers approximately 9% of the Italian population (annual average 5 027 944). Time trends in age and sex-standardized incidence rates were reported. Estimated annual percentage changes (EAPC) and related 95% confidence intervals (CI) were estimated by modelling age, sex, subsite and morphology-specific incidence rates through Poisson log-linear regression, and whenever necessary negative-binomial regression. Overall, 25 895 gastric and 2497 oesophageal carcinomas were examined.
RESULTS: On the whole, an increasing trend was observed for OA plus GCA. The increase was statistically significant in younger women (75 years: EAPC 4.0; 95% CI 1.2; 6.9). Similar trends were also observed in proximal gastric cancer (GCA plus fundus). A decline in the stomach subfundus incidence was observed in both sexes and in each age group. OSCC decreased significantly in men (EAPC-2.6; 95% CI-4.1;-0.9).
CONCLUSIONS: It is plausible that the different tendencies in oesophageal and proximal gastric cancer in men and women are attributable to heterogeneous distributions of risk factors by sex or age
Age at diagnosis influences the clinical phenotype, treatment strategies and outcomes in patients with giant cell arteritis: results from the observational GCAGE study on a large cohort of 1004 patients
No full textBackground Immune and vascular ageing are proposed risk factors for giant cell arteritis (GCA). Data on the impact of age at diagnosis of GCA on the clinical presentation and course of the disease are scarce. Methods Patients with GCA followed at referral centres within the Italian Society of Rheumatology Vasculitis Study Group were enrolled up to November 2021. Patients were grouped according to age at diagnosis: ≤64, 65-79 and ≥80 years old. Results The study included 1004 patients, mean age 72.1±8.4, female 70.82%. Median follow-up duration was 49 (IQR 23-91) months. Patients in the oldest group (≥80 years) had significantly more cranial symptoms, ischaemic complications and risk for blindness compared with the groups 65-79 and ≤64 years (blindness: 36.98% vs 18.21% vs 6.19%; p65 years old had 2-3 fold increased risk for aortic aneurysm/dissection up to 60 months follow-up. Serious infections, but not other treatment-related complications (hypertension, diabetes, osteoporotic fractures), were significantly associated with older age. Mortality occurred in 5.8% of the population with age >65, cranial and systemic symptoms as independent risk factors. Conclusions The highest risk of ischaemic complications, aneurysm development, serious infections and the possible undertreatment make of GCA a very challenging disease in the oldest patients
Complete nanopore repeat sequencing of SCA27B (GAA-FGF14 ataxia) in Japanese
No full textBackground Although pure GAA expansion is considered pathogenic in SCA27B, non-GAA repeat motif is mostly mixed into longer repeat sequences. This study aimed to unravel the complete sequencing of FGF14 repeat expansion to elucidate its repeat motifs and pathogenicity. Methods We screened FGF14 repeat expansion in a Japanese cohort of 460 molecularly undiagnosed adult-onset cerebellar ataxia patients and 1022 controls, together with 92 non-Japanese controls, and performed nanopore sequencing of FGF14 repeat expansion. Results In the Japanese population, the GCA motif was predominantly observed as the non-GAA motif, whereas the GGA motif was frequently detected in non-Japanese controls. The 5′-common flanking variant was observed in all Japanese GAA repeat alleles within normal length, demonstrating its meiotic stability against repeat expansion. In both patients and controls, pure GAA repeat was up to 400 units in length, whereas non-pathogenic GAA-GCA repeat was larger, up to 900 units, but they evolved from different haplotypes, as rs534066520, located just upstream of the repeat sequence, completely discriminated them. Both (GAA)≥250 and (GAA)≥200 were enriched in patients, whereas (GAA-GCA)≥200 was similarly observed in patients and controls, suggesting the pathogenic threshold of (GAA)≥200 for cerebellar ataxia. We identified 14 patients with SCA27B (3.0%), but their single-nucleotide polymorphism genotype indicated different founder alleles between Japanese and Caucasians. The low prevalence of SCA27B in Japanese may be due to the lower allele frequency of (GAA)≥250 in the Japanese population than in Caucasians (0.15% vs 0.32%–1.26%). Conclusions FGF14 repeat expansion has unique features of pathogenicity and allelic origin, as revealed by a single ethnic study
Impact of Exposure to Environmental Particulate Matter on the Onset of Giant Cell Arteritis
No full textObjectiveThe aim of this study was to investigate the association between exposure to particulate matter with an aerodynamic diameter <= 10 mu m (PM10) and the development of giant cell arteritis (GCA) and its ischemic complications.MethodsThis was case-crossover study on consecutive patients who received a diagnosis of GCA in three hospitals in northern Italy between 2013 and 2021. The PM10 hourly and daily average concentrations, collected in the Italian monitoring network and archived by Istituto Superiore per la Protezione e la Ricerca Ambientale, were determined using European reference. We used a Bayesian hierarchical model to determine patients' daily exposures to them. We employed conditional logistic regression to estimate the effect of exposure on GCA symptoms onset or ischemic complications.ResultsWe included 232 patients. A positive association was observed between exposure to PM10 and GCA risk, with an incremental odd of 27.1% (95% confidence interval 5.8-52.6) for every 10-mu g/m3 increase in PM10 concentration within a 60-day period. We did not find any significant association for shorter periods or with ischemic complications. Subgroup analysis found a significantly higher incremental risk at a 60-day lag for patients >= 70 years old. Comparing patients who were chronically exposed to high PM10 levels (26.9 +/- 13.8 mu g/m3) to those who were not (11.9 +/- 7.9 mu g/m3) revealed that only in the former group was there an association between GCA onset and increased PM10 levels in the preceding 60 days.ConclusionExposure to environmental PM10 in the preceding 60 days seems to be associated with an increased risk of developing GCA, especially in older individuals with prolonged exposure to high levels of air pollution
Anxiety and depression in patients with giant cell arteritis
No full textPublisher Copyright: © The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.Objectives: To compare the prevalence of anxiety and depression in patients with GCA with that in the general population, using the Hospital Anxiety and Depression Scale (HADS), and to identify independent predictors of these psychiatric manifestations in patients with GCA. Methods: We conducted a cross-sectional study including all patients diagnosed with GCA followed during 1 year in a vasculitis outpatient clinic. The HADS and 36-item Short Form (SF-36) questionnaires were prospectively collected. Patients’ HADS results were compared with an age- and gender-matched control group. HADS anxiety (HADS-A) and HADS depression (HADS-D) scores between 8 and 10 defined possible anxiety and depression and ≥11 defined probable anxiety and depression, respectively. Results: We included 72 patients and 288 controls. Compared with controls, patients with GCA had a statistically significant higher prevalence of HADS-A ≥8 (48.6% vs 26.4%), HADS-A ≥11 (30.6% vs 12.2%) and HADS-D ≥11 (33.3% vs 18.1%). GCA was an independent predictor of HADS-A ≥8 [odds ratio (OR) 3.3 (95% CI 1.9, 5.9)], HADS-A ≥11 [OR 3.8 (95% CI 2.0, 7.4)] and HADS-D ≥11 [OR 2.6 (95% CI 1.4, 4.7)]. Among patients with GCA, a negative correlation was observed between HADS-A/D and SF-36 mental health scores (r = −0.780 and r = −0.742, respectively). Glucocorticoid therapy was a predictor of HADS-A ≥8 [OR 10.4 (95% CI 1.2, 94.2)] and older age of HADS-D ≥8 [OR 1.2 (95% CI 1.1, 1.3)] and HADS-D ≥11 [OR 1.1 (95% CI 1.0, 1.2)]. Conclusions: Compared with the general population, patients with GCA have a higher prevalence of anxiety and depression and GCA is an independent predictor of these symptoms. Glucocorticoid treatment and older age are predictors of anxiety and depression, respectively, in patients with GCA.publishersversionpublishe
