Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 42
Filtrar
1.
Case Rep Rheumatol ; 2020: 8145790, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33204565

RESUMO

In this paper, we report a challenging case of a middle-age woman who developed antimelanoma differentiation-associated protein-5 dermatomyositis (anti-MDA5 DM) with interstitial lung disease (ILD) and was successfully treated with rituximab (RTX), after failure of a first-line therapy.

2.
Clin Exp Rheumatol ; 38(4): 748-753, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32723435

RESUMO

OBJECTIVES: Italy was one of the first countries significantly affected by the coronavirus disease 2019 (COVID-19) epidemic. The Italian Society for Rheumatology promptly launched a retrospective and anonymised data collection to monitor COVID-19 in patients with rheumatic and musculoskeletal diseases (RMDs), the CONTROL-19 surveillance database, which is part of the COVID-19 Global Rheumatology Alliance. METHODS: CONTROL-19 includes patients with RMDs and proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) updated until May 3rd 2020. In this analysis, only molecular diagnoses were included. The data collection covered demographic data, medical history (general and RMD-related), treatments and COVID-19 related features, treatments, and outcome. In this paper, we report the first descriptive data from the CONTROL-19 registry. RESULTS: The population of the first 232 patients (36% males) consisted mainly of elderly patients (mean age 62.2 years), who used corticosteroids (51.7%), and suffered from multi-morbidity (median comorbidities 2). Rheumatoid arthritis was the most frequent disease (34.1%), followed by spondyloarthritis (26.3%), connective tissue disease (21.1%) and vasculitis (11.2%). Most cases had an active disease (69.4%). Clinical presentation of COVID-19 was typical, with systemic symptoms (fever and asthenia) and respiratory symptoms. The overall outcome was severe, with high frequencies of hospitalisation (69.8%), respiratory support oxygen (55.7%), non-invasive ventilation (20.9%) or mechanical ventilation (7.5%), and 19% of deaths. Male patients typically manifested a worse prognosis. Immunomodulatory treatments were not significantly associated with an increased risk of intensive care unit admission/mechanical ventilation/death. CONCLUSIONS: Although the report mainly includes the most severe cases, its temporal and spatial trend supports the validity of the national surveillance system. More complete data are being acquired in order to both test the hypothesis that RMD patients may have a different outcome from that of the general population and determine the safety of immunomodulatory treatments.


Assuntos
Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Doenças Reumáticas/complicações , Reumatologia , Idoso , Betacoronavirus , Monitoramento Epidemiológico , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Pandemias , Sistema de Registros , Estudos Retrospectivos , Doenças Reumáticas/virologia
3.
Oncologist ; 25(6): e946-e954, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32181960

RESUMO

The safety and activity of immune checkpoint inhibitors have been characterized in interventional and observational studies. However, only small studies have specifically investigated these agents in patients who are excluded or underrepresented in clinical trials, frequently referred to as "special populations" or "underrepresented populations." These include older adults, those with dysregulated immune activation, patients with a compromised immune function, and those carrying major viral infections, lymphoproliferative diseases, and major organ dysfunctions. Therefore, there remains substantial uncertainty regarding the use of immune checkpoint inhibitors in these specific settings. The Network of Italian Supportive Care in Oncology has carried out a multidisciplinary project, with the contribution of oncologists and other specialists, to retrieve the existing evidence on the use of immunotherapy in patients with solid and hematological cancers with the final aim to provide an expert guidance. The results of this effort are presented in this article, which is focused on patients with major viral infections or those with immune dysregulation/autoimmune diseases, and could be useful to guide decisions in clinical practice and to design prospective clinical trials focusing on the use of immunotherapy in these populations. IMPLICATIONS FOR PRACTICE: Substantial uncertainty remains regarding the use of immune checkpoint inhibitors in "underrepresented" patients, such as older adults, those with dysregulated immune activation, and patients with a compromised immune function, major viral infections, lymphoproliferative diseases or major organ dysfunctions. The Network of Italian Supportive Care in Oncology has carried out a multidisciplinary project to retrieve the existing evidence on the use of immunotherapy in underrepresented patients with cancer in order provide an expert guidance. The results of this effort, with a focus on patients with major viral infections or those with immune dysregulation/autoimmune diseases, are presented in this article and could be useful to guide decisions both in clinical practice and to design clinical trials.

4.
Clin Exp Rheumatol ; 38(5): 925-932, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31969225

RESUMO

OBJECTIVES: To compare the main characteristics of two inception cohorts (Italian [ITC] and Spanish [SPC]) cohorts of patients with systemic lupus erythematosus (SLE) at the time of diagnosis and at one year of follow-up. METHODS: Demographic, clinical and immunological characteristics, and treatments at SLE diagnosis and at 12 months of follow-up of ITC and SPC were compared. RESULTS: One hundred and sixty-four patients in the ITC and 231 patients in the SPC were compared. the patients from ITC were younger at SLE diagnosis (41.1±15.0 years vs. 46.4±15.6 years; p<0.001) and had a higher prevalence of arthritis (62.8% vs. 45.5%; p=0.001), serositis (25.6% vs. 16.0%; p=0.026), neurological involvement (7.9% vs. 1.7%; p=0.006), and immunological abnormalities (anti-dsDNA, anti-Sm, antiphospholipid antibodies) (93.9% vs. 77.8%; p<0.001). Conversely, photosensitivity (29.5% in ITC vs. 45.9% in SPC; p=0.001) and oral ulcers (12.4% vs. 30.3%; p<0.001) were more frequent at onset of SLE in the Spanish patients. At the first 12 months of follow-up, these differences were maintained. At SLE onset, more Italian patients received glucocorticoids (85.4% vs. 50.2%; p<0.001) and immunosuppressive agents. At 12 months of follow-up, more Spanish patients were treated with antimalarials (75.6% in ITC vs. 90.0% in SPC; p<0.001). Conversely, the use of glucocorticoids was lower in SPC (89.0% in ITC vs. 57.1% in SPC; p<0.001). CONCLUSIONS: These cohorts presented different profiles in terms of pattern of organ/system involvement and disease treatment, possibly as a consequence of patient selection or different disease management approaches between Italy and Spain.


Assuntos
Lúpus Eritematoso Sistêmico , Anticorpos Antifosfolipídeos , Humanos , Imunossupressores/uso terapêutico , Itália/epidemiologia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/epidemiologia , Espanha/epidemiologia
5.
Clin Exp Rheumatol ; 38(1): 88-93, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31140397

RESUMO

OBJECTIVES: Axial spondyloarthritides (axSpA) are a group of disorders that share similar pathogenetic mechanisms and clinical picture. The aim of this retrospective multicentric study was to evaluate demographic and clinical differences between ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA) patients. METHODS: Patients from 7 rheumatological centres in the Lazio region of Italy were included from January 1st, 2010 to April 1st, 2018, if they had undergone pelvic and/or spine radiographs or magnetic resonance imaging (MRI). Images were evaluated by one experienced radiologist in each centre who already had the clinical suspicion of axSpA. Clinical and therapeutic data were collected at the last observation visit. Categorical variables were presented with percentages and analysed by Chi squared test. Continuous variables were expressed as mean ± standard deviation and compared using the parametric unpaired t-test or the non-parametric Mann-Whitney U-test, when appropriate. p-values <0.05 were considered significant. RESULTS: 210 axSpA patients were included: 65.2% with AS and 34.7% with nr-axSpA. When comparing the two groups, AS patients had longer disease duration, were older, were more frequently males, had a greater diagnostic delay and a higher body mass index than the nr-axSpA patients (p<0.0001, p<0.0001, p=0.003 p=0.007, and p=0.04, respectively). The peripheral joints of the nr-axSpA patients were more frequently involved, had higher frequency of inflammatory bowel disease, higher C-reactive protein levels and lower frequency of HLA-B27 positivity (p=0.005, p=0.007, p=0.01, and p=0.01, respectively). TNF inhibitors were used in 87.8% patients with AS and 78.3% with nr-axSpA (p=0.04). More fat metaplasia was observed on MRI in the nr-axSpA group than in the AS group at sacroiliac joints (p=0.003), and more backfills were detected in the AS group on spine-MRI (p=0.003). Spine-bone marrow oedema was more prevalent in AS than in nr-axSpA (p=0.04), and more sclerosis and backfill were found in AS (p=0.003 and p=0.01, respectively). CONCLUSIONS: In clinical practice, distinctive features in AS and nr-axSpA patients emerged. Imaging is crucial in guiding the choice of treatment in order to control disease activity and inflammation.


Assuntos
Espondilartrite/fisiopatologia , Espondilite Anquilosante/fisiopatologia , Diagnóstico Tardio , Demografia , Feminino , Humanos , Itália , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Espondilartrite/diagnóstico , Espondilite Anquilosante/diagnóstico
6.
Arthritis Care Res (Hoboken) ; 72(12): 1820-1826, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31560454

RESUMO

OBJECTIVE: A project aimed at developing new classification criteria for systemic lupus erythematosus (SLE) is based on weighted criteria that include both laboratory and clinical items. Combinations of certain symptoms may occur commonly in SLE, which provides an argument against independently counting these items. The current study was undertaken to evaluate the interrelationship between candidate criteria items in the International Early SLE cohort and in the Euro-Lupus cohort. METHODS: The International Early SLE cohort included 389 patients, who were diagnosed within 3 years prior to the study. Data on the ACR's 1997 update of the SLE revised criteria, the Systemic Lupus International Collaborating Clinics 2012 criteria, and on 30 additional items were collected. To evaluate the interrelationship of the criteria, a tetrachoric correlation was used to assess the degree of association between different manifestations in the same organ system. The correlations identified in the International Early SLE cohort were validated in the Euro-Lupus cohort. RESULTS: A few relevant correlations were observed among specific clinical cutaneous manifestations (in particular, malar rash correlated with photosensitivity, alopecia, and oral ulcers) and serologic manifestations (anti-Sm and anti-double-stranded DNA and anti-RNA polymerase, anti-Ro and anti-La, and antiphospholipid antibodies), and these results were validated in the Euro-Lupus cohort. The associations within the mucocutaneous domain, hematologic and the specific autoantibodies suggest that within a single domain only the highest ranking item should be counted to avoid overrepresentation. CONCLUSION: Some of the candidate SLE criteria cluster within domains. Given these interrelationships, multiple criteria within a domain should not be independently counted. These results are important to consider for the structure of new SLE classification criteria.

7.
Rheumatology (Oxford) ; 59(9): 2272-2281, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31840179

RESUMO

OBJECTIVE: To investigate risk factors for damage development in a prospective inception cohort of early diagnosed SLE patients. METHODS: The Early Lupus Project recruited an inception cohort of patients within 12 months of SLE classification (1997 ACR criteria). At enrolment and every 6 months thereafter, the SLICC/ACR Damage Index was recorded. The contribution of baseline and time-varying covariates to the development of damage, defined as any SLICC/ACR Damage Index increase from 0 to ≥1, was assessed using univariate analysis. Forward-backward Cox regression models were fitted with covariates with P < 0.05 to identify factors independently associated with the risk of damage development. RESULTS: Overall, 230 patients with a mean (s.d.) age of 36.5 (14.4) years were eligible for this study; the mean number of visits per patient was 5.3 (2.7). There were 51 (22.2%) patients with SLICC/ACR Damage Index ≥1 after 12 months, 59 (25.6%) after 24 months and 67 (29.1%) after 36 months. Dyslipidaemia [P = 0.001; hazard ratio (HR) 2.9; 95% CI 1.5, 5.6], older age (P = 0.001; HR 3.0; 95% CI 1.6, 5.5), number of organs/systems involved (P = 0.002; HR 1.4; 95% CI 1.1, 1.8) and cardiorespiratory involvement (P = 0.041; HR 1.9; 95% CI 1.0, 3.7) were independently associated with an increased risk of developing damage. Risk profiles for damage development differed for glucocorticoid-related and -unrelated damage. HCQ use (P = 0.005; HR 0.4; 95% CI 0.2, 0.8) reduced the risk of glucocorticoid-unrelated damage. CONCLUSION: We identified risk factors of damage development, but little effect of glucocorticoids, in this early SLE cohort. Addressing modifiable risk factors from the time of SLE diagnosis might improve patient outcomes.

8.
Autoimmun Rev ; 18(9): 102352, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31323355

RESUMO

Studies on last genetic and epigenetic predisposition to APS are summarized. It is well known that genetic predisposition is in HLA system (DR4 and DRw53) and that lupus anticoagulant (LA) and anticardiolipin antibodies (aCL) are both associated with the same HLA antigens. Other genes, outside the MHC, give their contribution to the development of this autoimmune syndrome, such as IRF5, STAT4 and those related to inherited thrombophilia - factor V Leiden and G20210A prothrombin polymorphisms. Finally, post-transcriptional modifications of anti-beta2GPI antibodies could be implicated too. The most important discovery of last years is that altered microRNAs' expression is linked to autoimmunity, thrombosis, early atherosclerosis, and oxidative stress in APS.


Assuntos
Síndrome Antifosfolipídica/genética , Epigênese Genética/fisiologia , Antígenos HLA/genética , Resistência à Proteína C Ativada/sangue , Resistência à Proteína C Ativada/genética , Resistência à Proteína C Ativada/imunologia , Anticorpos Anticardiolipina/sangue , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Predisposição Genética para Doença , Genótipo , Humanos , Inibidor de Coagulação do Lúpus/sangue , Polimorfismo Genético , Trombose/complicações , Trombose/genética , Trombose/imunologia , beta 2-Glicoproteína I/imunologia
9.
Autoimmun Rev ; 18(8): 805-813, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31176871

RESUMO

Immune checkpoints are small molecules expressed by immune cells that play critical roles in maintaining immune homeostasis. Immune checkpoint inhibitors (ICPIs) are new cancer drugs that target self-tolerance pathways exploited by tumors to escape immune destruction, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or its ligand (PD-L1). Several ICPIs have been approved by Food and Drug Administration, increasing overall survival with different cancers. However, their use can determine development of many different inflammatory side effects, that are defined immune-related adverse effects (irAEs); among others, rheumatological irAEs can develop in these patients. Currently, we have limited data about these adverse effects; particularly, few evidence come from clinical trials about patients with pre-existing autoimmune diseases because they were excluded from them. Therefore we analysed the existing scientific literature dealing with this issue, in order to answer to different clinical questions. According to all reviewed data, rheumatological irAEs are not infrequent, in both previously diseased and undiseased patients, but they are often mild and reversible. Close monitoring and interdisciplinary management and monitoring is necessary in order to ensure best care. Many questions remain unanswered or not completely answered; further data are necessary to implement our knowledge in this field and to standardize and optimize clinical practice.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Imunoterapia/efeitos adversos , Neoplasias/tratamento farmacológico , Doenças Reumáticas/induzido quimicamente , Humanos , Neoplasias/imunologia
10.
Autoimmun Rev ; 18(2): 164-176, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30572134

RESUMO

Pregnancy requires a special management in women with inflammatory rheumatic diseases (RDs), with the aim of controlling maternal disease activity and avoiding fetal complications. Despite the heterogeneous course of RDs during pregnancy, their impact on pregnancy largely relates to the extent of active inflammation at the time of conception. Therefore, accurate evaluation of disease activity is crucial for the best management of pregnant patients. Nevertheless, there are limitations in using conventional measures of disease activity in pregnancy, as some items included in these instruments can be biased by symptoms or by physiological changes related to pregnancy and the pregnancy itself may influence laboratory parameters used to assess disease activity. This article aims to summarize the current literature about the available instruments to measure disease activity during pregnancy in RDs. Systemic lupus erythematosus is the only disease with instruments that have been modified to account for several adaptations which might interfere with the attribution of signs or symptoms to disease activity during pregnancy. No modified-pregnancy indices exist for women affected by other RDs, but standard indices have been applied to pregnant patients. The current body of knowledge shows that the physiologic changes that occur during pregnancy need to be either adapted from existing instruments or developed to improve the management of pregnant women with RDs. Standardized instruments to assess disease activity during pregnancy would be helpful not only for clinical practice but also for research purposes.


Assuntos
Complicações na Gravidez/fisiopatologia , Doenças Reumáticas/fisiopatologia , Feminino , Humanos , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/patologia , Doenças Reumáticas/patologia
11.
Arthritis Rheumatol ; 71(1): 91-98, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30035365

RESUMO

OBJECTIVE: Systemic lupus erythematosus (SLE) presents with nonspecific signs and symptoms that are also found in other conditions. This study aimed to evaluate manifestations at disease onset and to compare early SLE manifestations to those of diseases mimicking SLE. METHODS: Academic lupus centers in Asia, Europe, North America, and South America collected baseline data on patients who were referred to them during the previous 3 years for possible SLE and who had a symptom duration of <1 year. Clinical and serologic manifestations were compared between patients diagnosed as having SLE and those diagnosed as having SLE-mimicking conditions. Diagnostic performance of the 1997 American College of Rheumatology (ACR) SLE classification criteria and the 2012 Systemic Lupus International Collaborating Clinics (SLICC) SLE classification criteria was tested. RESULTS: Data were collected on 389 patients with early SLE and 227 patients with SLE-mimicking conditions. Unexplained fever was more common in early SLE than in SLE-mimicking conditions (34.5% versus 13.7%, respectively; P < 0.001). Features less common in early SLE included Raynaud's phenomenon (22.1% versus 48.5%; P < 0.001), sicca symptoms (4.4% versus 34.4%; P < 0.001), dysphagia (0.3% versus 6.2%; P < 0.001), and fatigue (28.3% versus 37.0%; P = 0.024). Anti-double-stranded DNA, anti-ß2 -glycoprotein I antibodies, positive Coombs' test results, autoimmune hemolytic anemia, hypocomplementemia, and leukopenia were more common in early SLE than in SLE-mimicking conditions. Symptoms detailed in the ACR and SLICC classification criteria were significantly more frequent among those with early SLE. Fewer patients with early SLE were not identified as having early SLE with use of the SLICC criteria compared to the ACR criteria (16.5% versus 33.9%), but the ACR criteria demonstrated higher specificity than the SLICC criteria (91.6% versus 82.4%). CONCLUSION: In this multicenter cohort, clinical manifestations that could help to distinguish early SLE from SLE-mimicking conditions were identified. These findings may aid in earlier SLE diagnosis and provide information for ongoing initiatives to revise SLE classification criteria.


Assuntos
Doenças Autoimunes/diagnóstico , Lúpus Eritematoso Sistêmico/diagnóstico , Síndrome de Sjogren/diagnóstico , Adulto , Anemia Hemolítica Autoimune/etiologia , Anticorpos Antinucleares , Síndrome Antifosfolipídica/diagnóstico , Artrite Reumatoide/diagnóstico , Autoanticorpos/imunologia , Estudos de Coortes , Proteínas do Sistema Complemento/imunologia , Teste de Coombs , DNA/imunologia , Transtornos de Deglutição/etiologia , Diagnóstico Diferencial , Feminino , Febre de Causa Desconhecida/etiologia , Hepatite Autoimune/diagnóstico , Humanos , Leucopenia/etiologia , Doenças Pulmonares Intersticiais/diagnóstico , Lúpus Eritematoso Sistêmico/classificação , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Doença Mista do Tecido Conjuntivo/diagnóstico , Doença de Raynaud/etiologia , Escleroderma Sistêmico/diagnóstico , Síndrome de Sjogren/etiologia , Tireoidite Autoimune/diagnóstico , Doenças do Tecido Conjuntivo Indiferenciado/diagnóstico , Adulto Jovem , beta 2-Glicoproteína I/imunologia
12.
Lupus Sci Med ; 3(1): e000163, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27651920

RESUMO

OBJECTIVES: Rituximab (RTX) is a biological treatment used off-label in patients with systemic lupus erythematosus (SLE). This survey aimed to investigate the off-label use of RTX in Europe and compare the characteristics of patients receiving RTX with those receiving conventional therapy. METHODS: Data on patients with SLE receiving RTX were taken from the International Registry for Biologics in SLE retrospective registry and complemented with data on patients with SLE treated with conventional therapy. For nationwide estimates of RTX use in patients with SLE, investigators were asked to provide data through case report forms (CRFs). Countries for which no data were submitted through CRFs, published literature and/or personal communication were used, and for European countries where no data were available, estimates were made on the assumption of similarities with neighbouring countries. RESULTS: The estimated off-label use of RTX in Europe was 0.5%-1.5% of all patients with SLE. In comparison with patients with SLE on conventional therapy, patients treated with RTX had longer disease duration, higher disease activity and were more often treated with immunosuppressives. The most frequent organ manifestations for which either RTX or conventional therapy was initiated were lupus nephritis followed by musculoskeletal and haematological. The reason for treatment was, besides disease control, corticosteroid-sparing for patients treated with conventional therapy. CONCLUSIONS: RTX use for SLE in Europe is restrictive and appears to be used as a last resort in patients for whom other reasonable options have been exhausted.

13.
Autoimmun Rev ; 15(5): 433-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26804759

RESUMO

Studies on the immunogenetic predisposition to antiphospholipid syndrome (APS) and on other non-genetic and epigenetic factors are summarised and discussed. Family studies suggest a genetic predisposition to APS. It appears that this genetic predisposition is in part accounted for by the HLA system, the most consistent associations being those with DR4 and DRw53. Furthermore, it appears that lupus anticoagulant (LA) and anticardiolipin (aCL) antibodies are both associated with the same HLA antigens. Population studies suggest that HLA genes have a role in conferring susceptibility to develop primary APS, with some differences in different ethnic groups. Other genes, outside the MHC, give their contribution to the development of this autoimmune syndrome, such as IRF5, STAT4 and those related to inherited thrombophilia--factor V Leiden and G20210A prothrombin polymorphisms. Finally, post-transcriptional modifications of anti-beta2GPI antibodies could be implicated too.


Assuntos
Síndrome Antifosfolipídica/genética , Animais , Anticorpos/imunologia , Síndrome Antifosfolipídica/imunologia , Predisposição Genética para Doença , Humanos , Polimorfismo Genético , Processamento de Proteína Pós-Traducional
14.
Ann Rheum Dis ; 74(3): e14, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24534757

RESUMO

OBJECTIVES: To perform fine mapping of the PXK locus associated with systemic lupus erythematosus (SLE) and study functional effects that lead to susceptibility to the disease. METHODS: Linkage disequilibrium (LD) mapping was conducted by using 1251 SNPs (single nucleotide polymorphism) covering a 862 kb genomic region on 3p14.3 comprising the PXK locus in 1467 SLE patients and 2377 controls of European origin. Tag SNPs and genotypes imputed with IMPUTE2 were tested for association by using SNPTEST and PLINK. The expression QTLs data included three independent datasets for lymphoblastoid cells of European donors: HapMap3, MuTHER and the cross-platform eQTL catalogue. Correlation analysis of eQTLs was performed using Vassarstats. Alternative splicing for the PXK gene was analysed on mRNA from PBMCs. RESULTS: Fine mapping revealed long-range LD (>200 kb) extended over the ABHD6, RPP14, PXK, and PDHB genes on 3p14.3. The highly correlated variants tagged an SLE-associated haplotype that was less frequent in the patients compared with the controls (OR=0.89, p=0.00684). A robust correlation between the association with SLE and enhanced expression of ABHD6 gene was revealed, while neither expression, nor splicing alterations associated with SLE susceptibility were detected for PXK. The SNP allele frequencies as well as eQTL pattern analysed in the CEU and CHB HapMap3 populations indicate that the SLE association and the effect on ABHD6 expression are specific to Europeans. CONCLUSIONS: These results confirm the genetic association of the locus 3p14.3 with SLE in Europeans and point to the ABHD6 and not PXK, as the major susceptibility gene in the region. We suggest a pathogenic mechanism mediated by the upregulation of ABHD6 in individuals carrying the SLE-risk variants.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/genética , Desequilíbrio de Ligação/genética , Lúpus Eritematoso Sistêmico/genética , Monoacilglicerol Lipases/genética , Proteínas do Tecido Nervoso/genética , Proteínas Serina-Treonina Quinases/genética , RNA Mensageiro/genética , Processamento Alternativo , Estudos de Casos e Controles , Mapeamento Cromossômico , Cromossomos Humanos 1-3 , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único
15.
Arthritis Res Ther ; 16(3): R128, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-24946689

RESUMO

INTRODUCTION: We aimed to replicate a recent study which showed higher genetic risk load at 15 loci in men than in women with systemic lupus erythematosus (SLE). This difference was very significant, and it was interpreted as indicating that men require more genetic susceptibility than women to develop SLE. METHODS: Nineteen SLE-associated loci (thirteen of which are shared with the previous study) were analyzed in 1,457 SLE patients and 1,728 healthy controls of European ancestry. Genetic risk load was calculated as sex-specific sum genetic risk scores (GRS(s)). RESULTS: Our results did not replicate those of the previous study at either the level of individual loci or the global level of GRS(s). GRS(s) were larger in women than in men (4.20 ± 1.07 in women vs. 3.27 ± 0.98 in men). This very significant difference (P < 10(-16)) was more dependent on the six new loci not included in the previous study (59% of the difference) than on the thirteen loci that are shared (the remaining 41%). However, the 13 shared loci also showed a higher genetic risk load in women than in men in our study (P = 6.6 × 10(-7)), suggesting that heterogeneity of participants, in addition to different loci, contributed to the opposite results. CONCLUSION: Our results show the lack of a clear trend toward higher genetic risk in one of the sexes for the analyzed SLE loci. They also highlight several limitations of assessments of genetic risk load, including the possibility of ascertainment bias with loci discovered in studies that have included mainly women.


Assuntos
Carga Genética , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos , Alelos , Estudos de Casos e Controles , Europa (Continente) , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Humanos , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Razão de Chances , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Fatores Sexuais
16.
Clin Vaccine Immunol ; 20(5): 761-4, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23467774
17.
PLoS One ; 7(9): e45356, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23049788

RESUMO

INTRODUCTION: Systemic Lupus Erythematosus (SLE) shows a spectrum of clinical manifestations that complicate its diagnosis, treatment and research. This variability is likely related with environmental exposures and genetic factors among which known SLE susceptibility loci are prime candidates. The first published analyses seem to indicate that this is the case for some of them, but results are still inconclusive and we aimed to further explore this question. METHODS: European SLE patients, 1444, recruited at 17 centres from 10 countries were analyzed. Genotypes for 26 SLE associated SNPs were compared between patients with and without each of 11 clinical features: ten of the American College of Rheumatology (ACR) classification criteria (except ANAs) and age of disease onset. These analyses were adjusted for centre of recruitment, top ancestry informative markers, gender and time of follow-up. Overlap of samples with previous studies was excluded for assessing replication. RESULTS: THERE WERE THREE NEW ASSOCIATIONS: the SNPs in XKR6 and in FAM167A-BLK were associated with lupus nephritis (OR=0.76 and 1.30, P(corr) =0.007 and 0.03, respectively) and the SNP of MECP2, which is in chromosome X, with earlier age of disease onset in men. The previously reported association of STAT4 with early age of disease onset was replicated. Some other results were suggestive of the presence of additional associations. Together, the association signals provided support to some previous findings and to the characterization of lupus nephritis, autoantibodies and age of disease onset as the clinical features more associated with SLE loci. CONCLUSION: Some of the SLE loci shape the disease phenotype in addition to increase susceptibility to SLE. This influence is more prominent for some clinical features than for others. However, results are only partially consistent between studies and subphenotype specific GWAS are needed to unravel their genetic component.


Assuntos
Grupo com Ancestrais do Continente Europeu , Loci Gênicos , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idade de Início , Autoanticorpos/imunologia , Europa (Continente)/epidemiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/imunologia , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/imunologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Fenótipo , Fator de Transcrição STAT4/genética , Fator de Transcrição STAT4/imunologia
18.
Clin Exp Rheumatol ; 30(6): 939-42, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22992305

RESUMO

OBJECTIVES: Several single nucleotide polymorphisms (SNPs) have been associated with rheumatoid arthritis (RA) such as peptidylarginine deiminase-4 (PADI4), osteopontin (OPN), and perforin (PRF1) genes. Thus, we aimed at analysing the influence of eight SNPs in these candidate genes on RA susceptibility and their association with laboratory and clinical features in terms of response to anti-TNF therapy. METHODS: We performed a case-control study on 377 Caucasian RA patients and 391 healthy, ethnicity-matched, population-based controls. All subjects were genotyped for PADI4_89/94, PADI4_92, PADI4_104, PADI4_100 in PADI4; -156G/GG and +1239A/C in OPN and A91V and N252S in PRF1 genes. The patients were stratified for shared epitope (SE) HLA-DRB1. rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) were analysed. The patients started anti-TNF treatment and they were evaluated at baseline and after 12 weeks. Disease activity was evaluated with DAS28 and response to treatment with EULAR criteria. RESULTS: A statistically significant association between RA and OPN -156G/GG was found (p=0.023). SE was firmly confirmed to be associated with RA (OR=3.68; p<10-10). No other statistically significant association with clinical and laboratory features were observed. CONCLUSIONS: For the first time, in an Italian cohort, we report the association between -156G/GG in OPN gene and RA susceptibility. Short-term response to anti-TNF therapy was not influenced by the genetic variants studied.


Assuntos
Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Osteopontina/genética , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/etnologia , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Humanos , Hidrolases/genética , Itália/epidemiologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Peptídeos Cíclicos/imunologia , Perforina , Fenótipo , Proteínas Citotóxicas Formadoras de Poros/genética , Proteína-Arginina Desiminase do Tipo 4 , Desiminases de Arginina em Proteínas , Fator Reumatoide/sangue , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
19.
Ann Rheum Dis ; 71(7): 1219-26, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22696686

RESUMO

OBJECTIVES: To perform fine mapping of the autoimmunity susceptibility gene BLK and identify functional variants involved in systemic lupus erythematosus (SLE). METHODS: Genotyping of 1163 European SLE patients and 1482 controls and imputation were performed covering the BLK gene with 158 single-nucleotide polymorphisms. Logistic regression analysis was done using PLINK and conditional analyses using GENABEL's test score. Transfections of BLK constructs on HEK293 cells containing the novel mutation or the wild type form were analysed for their effect on protein half-life using a protein stability assay, cycloheximide and western blot. CHiP-qPCR for detection of nuclear factor κ B (NFkB) binding. RESULTS: Fine mapping of BLK identified two independent genetic effects with functional consequences: one represented by two tightly linked associated haplotype blocks significantly enriched for NFκB-binding sites and numerous putative regulatory variants whose risk alleles correlated with low BLK mRNA levels. Binding of NFkBp50 and p65 to an associated 1.2 Kb haplotype segment was confirmed. A second independent genetic effect was represented by an Ala71Thr, low-frequency missense substitution with an OR=2.31 (95% CI 1.38 to 3.86). The 71Thr decreased BLK protein half-life. CONCLUSIONS: These results show that rare and common regulatory variants in BLK are involved in disease susceptibility and both, albeit independently, lead to reduced levels of BLK protein.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Mutação , Polimorfismo de Nucleotídeo Único , Quinases da Família src/genética , Biomarcadores/metabolismo , Mapeamento Cromossômico , Regulação Enzimológica da Expressão Gênica , Marcadores Genéticos/genética , Genótipo , Células HEK293 , Meia-Vida , Humanos , NF-kappa B/metabolismo , Ligação Proteica , Estabilidade Proteica , Transfecção , Quinases da Família src/metabolismo
20.
Arthritis Res Ther ; 14(2): R94, 2012 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-22541939

RESUMO

INTRODUCTION: We aimed to investigate whether the effect size of the systemic lupus erythematosus (SLE) risk alleles varies across European subpopulations. METHODS: European SLE patients (n = 1,742) and ethnically matched healthy controls (n = 2,101) were recruited at 17 centres from 10 different countries. Only individuals with self-reported ancestry from the country of origin were included. In addition, participants were genotyped for top ancestry informative markers and for 25 SLE associated SNPs. The results were used to compare effect sizes between the Central Eureopan and Southern European subgroups. RESULTS: Twenty of the 25 SNPs showed independent association with SLE, These SNPs showed a significant bias to larger effect sizes in the Southern subgroup, with 15/20 showing this trend (P = 0.019) and a larger mean odds ratio of the 20 SNPs (1.46 vs. 1.34, P = 0.02) as well as a larger difference in the number of risk alleles (2.06 vs. 1.63, P = 0.027) between SLE patients and controls than for Central Europeans. This bias was reflected in a very significant difference in the cumulative genetic risk score (4.31 vs. 3.48, P = 1.8 × 10-32). Effect size bias was accompanied by a lower number of SLE risk alleles in the Southern subjects, both patients and controls, the difference being more marked between the controls (P = 1.1 × 10-8) than between the Southern and Central European patients (P = 0.016). Seven of these SNPs showed significant allele frequency clines. CONCLUSION: Our findings showed a bias to larger effect sizes of SLE loci in the Southern Europeans relative to the Central Europeans together with clines of SLE risk allele frequencies. These results indicate the need to study risk allele clines and the implications of the polygenic model of inheritance in SLE.


Assuntos
Alelos , Loci Gênicos/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Viés , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA