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2.
PLoS One ; 14(2): e0213073, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30818333

RESUMO

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all non-redundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the meta-analysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPs.

3.
PLoS One ; 13(5): e0196793, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29734345

RESUMO

Genetic biomarkers are sought to personalize treatment of patients with rheumatoid arthritis (RA), given their variable response to TNF inhibitors (TNFi). However, no genetic biomaker is yet sufficiently validated. Here, we report a validation study of 18 previously reported genetic biomarkers, including 11 from GWAS of response to TNFi. The validation was attempted in 581 patients with RA that had not been treated with biologic antirheumatic drugs previously. Their response to TNFi was evaluated at 3, 6 and 12 months in two ways: change in the DAS28 measure of disease activity, and according to the EULAR criteria for response to antirheumatic drugs. Association of these parameters with the genotypes, obtained by PCR amplification followed by single-base extension, was tested with regression analysis. These analyses were adjusted for baseline DAS28, sex, and the specific TNFi. However, none of the proposed biomarkers was validated, as none showed association with response to TNFi in our study, even at the time of assessment and with the outcome that showed the most significant result in previous studies. These negative results are notable because this was the first independent validation study for 12 of the biomarkers, and because they indicate that prudence is needed in the interpretation of the proposed biomarkers of response to TNFi even when they are supported by very low p values. The results also emphasize the requirement of independent replication for validation, and the need to search protocols that could increase reproducibility of the biomarkers of response to TNFi.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Marcadores Genéticos/genética , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
4.
Rheumatology (Oxford) ; 56(8): 1407-1416, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28460084

RESUMO

Objective: The aim was to investigate the association between autoantibodies (autoAbs) and neuropsychiatric (NP) involvement in patients with SLE and to evaluate whether any autoAb or a combination of these autoAbs could indicate the underlying pathogenic process. Methods: Using a multiplexed protein array for 94 antigens, we compared the serum autoAb profiles of 69 NPSLE patients, 203 SLE patients without NP involvement (non-NPSLE) and 51 healthy controls. Furthermore, we compared the profiles of NPSLE patients with clinical inflammatory (n = 38) and ischaemic (n = 31) NP involvement. Results: In total, 75 IgG and 47 IgM autoAbs were associated with SLE patients in comparison with healthy controls. Comparing NPSLE with non-NPSLE and healthy control sera, 9 IgG (amyloid, cardiolipin, glycoprotein 2, glycoprotein 210, heparin, heparan sulphate, histone H2A, prothrombin protein and vimentin) and 12 IgM (amyloid, cardiolipin, centromere protein A, collagen II, histones H2A and H2B, heparan sulphate, heparin, mitochondrial 2, nuclear Mi-2, nucleoporin 62 and vimentin) autoAbs were present at significantly different levels in NPSLE. The combination of IgG autoAbs against heparan sulphate, histone H2B and vimentin could differentiate NPSLE from non-NPSLE (area under the curve 0.845, 99.97% CI: 0.756, 0.933; P < 0.0001). Compared with non-NPSLE, four IgG and seven IgM autoAbs were significantly associated with inflammatory NPSLE. In ischaemic NPSLE, three IgG and three IgM autoAbs were significantly different from non-NPSLE patients. Conclusion: In our cohort, the presence of high levels of anti-heparan sulphate and anti-histone H2B combined with low levels of anti-vimentin IgG autoAbs is highly suggestive of NPSLE. These results need to be validated in external cohorts.


Assuntos
Autoanticorpos/sangue , Vasculite Associada ao Lúpus do Sistema Nervoso Central/diagnóstico , Adulto , Autoanticorpos/imunologia , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Heparitina Sulfato/imunologia , Histonas/imunologia , Humanos , Imunoglobulina G/imunologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Masculino , Pessoa de Meia-Idade , Análise Serial de Proteínas , Vimentina/imunologia
5.
Rheumatology (Oxford) ; 56(10): 1676-1683, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28339952

RESUMO

Objective: To determine the contribution of reassessment in the attribution process of neuropsychiatric (NP) events to SLE or other aetiologies in a large, prospective and multidisciplinary assessed NPSLE cohort and to compare these results with other available attribution models for NP events occurring in SLE. Methods: Three hundred and four consecutive SLE patients presenting NP events were evaluated. All subjects underwent standardized multidisciplinary medical, neuropsychological, laboratory and radiological examination on the inclusion and reassessment dates. Diagnosis was always established by multidisciplinary consensus. The final diagnosis after reassessment also took into account disease course and response to treatment. These data were compared with currently available attribution models for NP events in SLE. Results: A total of 463 NP events were established. After reassessment, attribution to SLE was discordant in 64 (13.8%) NP events when compared with the first visit. We show that 14.5% of NP events previously attributed to SLE reclassified as non-NPSLE. In 86.4% of these patients immunosuppressive therapy was started after the first visit. When reassessment and available attribution models were compared, NPSLE cases overlapped considerably. Although specificity was high for all comparisons (0.81-0.95), an important variation in sensitivity (0.39-0.83) and agreement estimates (κ = 0.29-0.68) was observed. The Italian algorithm showed the highest sensitivity and specificity (>0.80) and moderate agreement (0.59-0.64). Conclusion: In clinical practice NP events presenting in SLE are too often attributed to an immune-mediated origin. Multidisciplinary reassessment avoids misclassification in NPSLE. Multidisciplinary reassessment is the reference standard in NP events presenting in SLE and cannot be replaced by available attribution models.


Assuntos
Lúpus Eritematoso Sistêmico/diagnóstico , Doenças do Sistema Nervoso/diagnóstico , Testes Neuropsicológicos , Equipe de Assistência ao Paciente , Avaliação de Sintomas/métodos , Adulto , Feminino , Humanos , Lúpus Eritematoso Sistêmico/psicologia , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/psicologia , Estudos Prospectivos
6.
Arthritis Res Ther ; 18(1): 289, 2016 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-27912793

RESUMO

BACKGROUND: Articular manifestations are common in systemic lupus erythematosus (SLE) whereas erosive disease is not. Antibodies to cyclic citrullinated peptide (anti-CCP) are citrulline-dependent in rheumatoid arthritis (RA), whereas the opposite is suggested in SLE, as reactivity with cyclic arginine peptide (CAP) is typically present. Antibodies targeting carbamylated proteins (anti-CarP) may occur in anti-CCP/rheumatoid factor (RF)-negative cases long before clinical onset of RA. We analysed these antibody specificities in sera from European patients with SLE in relation to phenotypes, smoking habits and imaging data. METHODS: Cases of SLE (n = 441) from Linköping, Sweden, and Leiden, the Netherlands, were classified according to American College of Rheumatology (ACR) and/or Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria. IgG anti-CCP, anti-CAP and anti-CarP were analysed by immunoassays. Radiographic data from 102 Swedish patients were available. RESULTS: There were 16 Linköping (6.8%) and 11 Leiden patients (5.4%) who were anti-CCP-positive, of whom approximately one third were citrulline-dependent: 40/441 (9.1%) were anti-CarP-positive, and 33% of the anti-CarP-positive patients were identified as anti-CCP-positive. No associations were found comparing anti-CCP or anti-CarP with ACR-defined phenotypes, immunologic abnormalities or smoking habits. Radiographically confirmed erosions were found in 10 patients, and were significantly associated with anti-CCP, anti-CarP and RF. Musculoskeletal ultrasonography scores were higher in anti-CCP-positive compared to anti-CCP-negative patients. CONCLUSIONS: In the hitherto largest anti-CarP study in SLE, we demonstrate that anti-CarP is more prevalent than anti-CCP and that the overlap is limited. We obtained some evidence that both autoantibodies seem to be associated with erosivity. Similar pathogenetic mechanisms to those seen in RA may be relevant in a subgroup of SLE cases with a phenotype dominated by arthritis.


Assuntos
Autoanticorpos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Peptídeos Cíclicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Autoantígenos/imunologia , Estudos de Coortes , Europa (Continente) , Feminino , Humanos , Imunoensaio , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Proteínas , Adulto Jovem
7.
Arthritis Rheumatol ; 68(9): 2338-44, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27111665

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy. METHODS: The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. RESULTS: This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P < 5 × 10(-6) ) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 × 10(-12) ). Analysis of the biologic relevance of the known SSc-RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. CONCLUSION: This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.


Assuntos
Artrite Reumatoide/genética , Estudo de Associação Genômica Ampla , Fatores Reguladores de Interferon/genética , Escleroderma Sistêmico/genética , Loci Gênicos , Predisposição Genética para Doença , Humanos , Fatores de Risco
8.
Brain ; 139(Pt 5): 1447-57, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26969685

RESUMO

Systemic lupus erythematosus is an inflammatory autoimmune disease with multi-organ involvement. Central nervous system involvement in systemic lupus erythematosus is common and results in several neurological and psychiatric symptoms that are poorly linked to standard magnetic resonance imaging outcome. Magnetic resonance imaging methods sensitive to tissue microstructural changes, such as diffusion tensor imaging and magnetization transfer imaging, show some correlation with neuropsychiatric systemic lupus erythematosus (NPSLE) symptoms. Histological examination of NPSLE brains reveals presence of cerebral oedema, loss of neurons and myelinated axons, microglial proliferation and reactive astrocytosis, microinfacrts and diffuse ischaemic changes, all of which can affect both diffusion tensor imaging and magnetization transfer imaging in a non-specific manner. Here we investigated the underlying cell-type specific microstructural alterations in the brain of patients with systemic lupus erythematosus with and without a history of central nervous system involvement. We did so combining diffusion tensor imaging with diffusion-weighted magnetic resonance spectroscopy, a powerful tool capable of characterizing cell-specific cytomorphological changes based on diffusion of intracellular metabolites. We used a 7 T magnetic resonance imaging scanner to acquire T1-weighted images, diffusion tensor imaging datasets, and single volume diffusion-weighted magnetic resonance spectroscopy data from the anterior body of the corpus callosum of 13 patients with systemic lupus erythematosus with past NPSLE, 16 patients with systemic lupus erythematosus without past NPSLE, and 19 healthy control subjects. Group comparisons were made between patients with systemic lupus erythematosus with/without past NPSLE and healthy controls on diffusion tensor imaging metrics and on diffusion coefficients of three brain metabolites: the exclusively neuronal/axonal N-acetylaspartate, and the predominantly glial creatine + phosphocreatine and choline compounds. In patients with systemic lupus erythematosus with past NPSLE, significantly higher diffusion tensor imaging mean and radial diffusivities were accompanied by a significantly higher intracellular diffusion of total creatine (0.202 ± 0.032 µm(2)/ms, P = 0.018) and total choline (0.142 ± 0.031 µm(2)/ms, P = 0.044) compared to healthy controls (0.171 ± 0.024 µm(2)/ms, 0.124 ± 0.018 µm(2)/ms, respectively). Total N-acetylaspartate, total creatine and total choline diffusion values from all patients with systemic lupus erythematosus correlated positively with systemic lupus erythematosus disease activity index score (P = 0.033, P = 0.040, P = 0.008, respectively). Our results indicate that intracellular alterations, and in particular changes in glia, as evidenced by increase in the average diffusivities of total choline and total creatine, correlate with systemic lupus erythematosus activity. The higher diffusivity of total creatine and total choline in patients with NPSLE, as well as the positive correlation of these diffusivities with the systemic lupus erythematosus disease activity index are in line with cytomorphological changes in reactive glia, suggesting that the diffusivities of choline compounds and of total creatine are potentially unique markers for glial reactivity in response to inflammation.


Assuntos
Ácido Aspártico/análogos & derivados , Axônios/metabolismo , Colina/metabolismo , Creatina/metabolismo , Vasculite Associada ao Lúpus do Sistema Nervoso Central/metabolismo , Neuroglia/metabolismo , Fosfocreatina/metabolismo , Adulto , Ácido Aspártico/metabolismo , Estudos de Casos e Controles , Corpo Caloso/metabolismo , Imagem de Tensor de Difusão , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade
9.
Arthritis Rheumatol ; 68(8): 1945-54, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26894522

RESUMO

OBJECTIVE: To assess white matter (WM) and gray matter (GM) magnetization transfer ratio histogram peak heights (MTR-HPHs) in different subsets of patients with neuropsychiatric systemic lupus erythematosus (NPSLE) who have unremarkable findings on 3T magnetic resonance imaging of the brain and to evaluate whether these values could be used to highlight different clinically suspected underlying pathogenic processes or identify the clinical NPSLE status or whether they could be associated with a specific NPSLE syndrome. METHODS: Sixty-four SLE patients with neuropsychiatric symptoms were included. The initial NPSLE diagnosis and suspected underlying pathogenic process were established by multidisciplinary evaluation. The final diagnosis was made after also considering the disease course 6-18 months later. Thirty-three patients with central nervous system (CNS) NPSLE and 31 SLE patients with neuropsychiatric symptoms unrelated to SLE (non-SLE-related NP) were included. Twenty SLE patients without neuropsychiatric symptoms and 36 healthy control subjects were included for comparison. Differences in the WM and GM mean MTR-HPHs and between the different NPSLE subgroups (CNS NPSLE diagnosis, NPSLE phenotype [inflammatory or ischemic], and clinical changes after treatment) and the relationship to NPSLE syndromes were evaluated. RESULTS: Patients with inflammatory NPSLE had significantly lower WM MTR-HPHs than did the healthy controls, the SLE patients, and the non-SLE-related NP patients. Cognitive disorder, mood disorder, and psychosis were related to lower WM MTR-HPH values and cerebrovascular symptoms to higher values. Furthermore, the mean MTR-HPHs in the WM increased when the clinical status of the NPSLE patients improved. CONCLUSION: Measurement of MTR-HPH of the WM has the potential to identify inflammatory NPSLE with CNS involvement. This finding underscores the usefulness of this technique for the detection of cerebral changes in NPSLE patients and for the assessment of clinical changes after treatment.


Assuntos
Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/diagnóstico por imagem , Vasculite Associada ao Lúpus do Sistema Nervoso Central/etiologia , Imagem por Ressonância Magnética , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto , Feminino , Humanos , Masculino , Estudos Prospectivos
10.
Drugs ; 76(4): 459-83, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26809245

RESUMO

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a generic definition referring to a series of neurological and psychiatric symptoms directly related to systemic lupus erythematosus (SLE). NPSLE includes heterogeneous and rare neuropsychiatric (NP) manifestations involving both the central and peripheral nervous system. Due to the lack of a gold standard, the attribution of NP symptoms to SLE represents a clinical challenge that obligates the strict exclusion of any other potential cause. In the acute setting, management of these patients does not differ from other non-SLE subjects presenting with the same NP manifestation. Afterwards, an individualized therapeutic strategy, depending on the presenting manifestation and severity of symptoms, must be started. Clinical trials in NPSLE are scarce and most of the data are extracted from case series and case reports. High-dose glucocorticoids and intravenous cyclophosphamide remain the cornerstone for patients with severe symptoms that are thought to reflect inflammation or an underlying autoimmune process. Rituximab, intravenous immunoglobulins, or plasmapheresis may be used if response is not achieved. When patients present with mild to moderate NP manifestations, or when maintenance therapy is warranted, azathioprine and mycophenolate may be considered. When symptoms are thought to reflect a thrombotic underlying process, anticoagulation and antiplatelet agents are the mainstay of therapy, especially if antiphospholipid antibodies or antiphospholipid syndrome are present. Recent trials on SLE using new biologicals, based on newly understood SLE mechanisms, have shown promising results. Based on what we currently know about its pathogenesis, it is tempting to speculate how these new therapies may affect the management of NPSLE patients. This article provides a comprehensive and critical review of the literature on the epidemiology, pathophysiology, diagnosis, and management of NPSLE. We describe the most common pharmacological treatments used in NPSLE, based on both a literature search and our expert opinion. The extent to which new drugs in the advanced development of SLE, or the blockade of new targets, may impact future treatment of NPSLE will also be discussed.


Assuntos
Lúpus Eritematoso Sistêmico/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Ciclofosfamida/uso terapêutico , Gerenciamento Clínico , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Plasmaferese/métodos , Rituximab/uso terapêutico
11.
Front Immunol ; 7: 647, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28082982

RESUMO

C1q deficiency is a rare immunodeficiency, which is strongly associated with the development of systemic lupus erythematosus (SLE). A mutation in one of the C1q genes can either lead to complete deficiency or to low C1q levels with C1q polypeptide in the form of low-molecular weight (LMW) C1q. Patients with C1q deficiency mainly present with cutaneous and renal involvement. Although less frequent, neuropsychiatric (NP) involvement has also been reported in 20% of the C1q-deficient patients. This involvement appears to be absent in other deficiencies of early components of the complement classical pathway (CP) (C1r/C1s, C2, or C4 deficiencies). We describe a new case with C1q deficiency with a homozygous G34R mutation in C1qC-producing LMW-C1q presenting with a severe SLE flare with NP involvement. The serum of this patient contained very low levels of a LMW variant of C1q polypeptides. Cell lysates contained the three chains of C1q, but no intact C1q was detected, consistent with the hypothesis of the existence of a LMW-C1q. Furthermore, we provide a literature overview of NP-SLE in C1q deficiency and hypothesize about the potential role of C1q in the pathogenesis of NP involvement in these patients. The onset of NP-SLE in C1q-deficient individuals is more severe when compared with complement competent NP-SLE patients. An important number of cases present with seizures and the most frequent findings in neuroimaging are changes in basal ganglia and cerebral vasculitis. A defective CP, because of non-functional C1q, does not protect against NP involvement in SLE. The absence of C1q and, subsequently, some of its biological functions may be associated with more severe NP-SLE.

12.
Neuroimage Clin ; 8: 337-44, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26106559

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement and results in neurological and psychiatric (NP) symptoms in up to 40% of the patients. To date, the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) poses a challenge due to the lack of neuroradiological gold standards. In this study, we aimed to better localize and characterize normal appearing white matter (NAWM) changes in NPSLE by combining data from two quantitative MRI techniques, diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI). 9 active NPSLE patients (37 ± 13 years, all females), 9 SLE patients without NP symptoms (44 ± 11 years, all females), and 14 healthy controls (HC) (40 ± 9 years, all females) were included in the study. MTI, DTI and fluid attenuated inversion recovery (FLAIR) images were collected from all subjects on a 3 T MRI scanner. Magnetization transfer ratio (MTR), mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) maps and white matter lesion maps based on the FLAIR images were created for each subject. MTR and DTI data were then co-analyzed using tract-based spatial statistics and a cumulative lesion map to exclude lesions. Significantly lower MTR and FA and significantly higher AD, RD and MD were found in NPSLE compared to HC in NAWM regions. The differences in DTI measures and in MTR, however, were only moderately co-localized. Additionally, significant differences in DTI measures, but not in MTR, were found between NPSLE and SLE patients, suggesting that the underlying microstructural changes detected by MD are linked to the onset of NPSLE. The co-analysis of the anatomical distribution of MTI and DTI measures can potentially improve the diagnosis of NPSLE and contribute to the understanding of the underlying microstructural damage.


Assuntos
Vasculite Associada ao Lúpus do Sistema Nervoso Central/patologia , Imagem por Ressonância Magnética/métodos , Substância Branca/patologia , Adulto , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Imagem Multimodal
14.
Rheumatology (Oxford) ; 54(8): 1459-63, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25767155

RESUMO

OBJECTIVE: To assess drug survival and the reasons for switching anti-TNF-α therapy in SpA patients in a Spanish nationwide study. METHODS: A cross-sectional study was performed. Sample size was calculated to represent all regions and hospitals throughout the country. Demographic data, patient characteristics and disease activity parameters were obtained. Drug survival and reasons for switching anti-TNF therapy were also recorded. RESULTS: A total of 467 SpA patients receiving at least one anti-TNF agent were identified. Among patients who received a first, second and third anti-TNF course, 39.4%, 37.4% and 23.1% discontinued treatment, respectively. The main reasons for switching anti-TNF agents in the first course were lack or loss of efficacy (LOE) and adverse events (AEs) in 40% and 30% of switchers, respectively. Similarly, reasons for switching during the second anti-TNF course were LOE in 48% and AEs in 28% of switchers. Of the 467 SpA patients starting anti-TNF therapy, 28% switched to a second and 8% switched to a third therapy. Mean drug survival for the first, second and third anti-TNF courses were 84.4 (95% CI 78.4, 90.5), 70.2 (95% CI 61.6, 78.9) and 64.8 (95% CI 51.1, 78.5) months, respectively (P = 0.315). CONCLUSION: Twenty-eight per cent of SpA patients starting anti-TNF therapy switched to a second anti-TNF agent. Drug survival did not differ among anti-TNF courses. The main reason for switching anti-TNF therapy was LOE. Switchers were more frequently women and had higher disease activity parameters at the time of the study than non-switchers.


Assuntos
Antirreumáticos/uso terapêutico , Substituição de Medicamentos/estatística & dados numéricos , Espondiloartropatias/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores Sexuais , Espanha/epidemiologia , Espondiloartropatias/diagnóstico , Espondiloartropatias/epidemiologia , Resultado do Tratamento
15.
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
17.
Open Access Rheumatol ; 6: 39-47, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-27790033

RESUMO

Calcium pyrophosphate dihydrate crystal deposition disease (CPPD) is an inflammatory arthritis produced by the deposition of calcium pyrophosphate (CPP) crystals in the synovium and periarticular soft tissues. It is the third most common inflammatory arthritis. Diagnosis is suspected on the basis of the clinical picture and radiographic/laboratory findings. The reference standard for the diagnosis of CPPD is based on the identification of CPP crystals in synovial fluid by light microscopy, compensated polarized light microscopy, or phase contrast microscopy. Most treatment approaches for CPPD are based upon clinical experience and not upon controlled trials. They range - depending on the subtype and the characteristics of symptoms - from no treatment to interleukin-1 blockade antibodies or specific therapy for an underlying disease. This review summarizes all we know so far about the diagnosis and management of CPPD.

18.
Eur J Dermatol ; 24(1): 53-62, 2014 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24509438

RESUMO

BACKGROUND: Psoriasis has been associated with vitamin D insufficiency and cardiovascular risk factors. Reports show that serum 25-hydroxyvitamin D (25-OHD) levels are inversely associated with chronic inflammatory systemic diseases, cardiovascular risk factors and cardiovascular outcomes. OBJECTIVE: To analyze the association between 25-hydroxyvitamin D serum levels and subclinical carotid atherosclerosis (maximal intima-media thickness (MIMT)) in psoriasis patients and controls. MIMT was compared and associated factors were analyzed. PATIENTS AND METHOD: This was a case-control study with 44 psoriatic patients without arthritis from a Dermatology outpatient clinic in Granada (Spain) and 44 controls. Confounding factors related to 25-OHD serum levels and cardiovascular risk factors were also analyzed. RESULTS: 25-OHD levels were significantly lower in the psoriatic than in the control group (29.20 vs. 38.00 ng/mL p<0.0001) and a significant negative correlation was found between serum 25-OHD levels and the MIMT (rs=-0.678, p<0.0001) in psoriatic patients. No correlation was found in healthy controls. This association remained after adjusting for confounders. Serum 25-OHD levels were significantly lower (p=0.003) in psoriatic patients with carotid atheromatous plaque (22.38±10.23 ng/mL) than in those without (31.74±8.62 ng/mL). Patients with a longer history of psoriasis presented significantly higher MIMT than controls (638.70±76.21 vs 594.67±80.20 µm; p=0.026 for ≥6 yrs with psoriasis). CONCLUSIONS: In psoriasis patients, lower serum 25-OHD levels were associated with higher MIMT after adjusting for selected confounding factors. The MIMT risk increases with a longer history of psoriasis, regardless of the patient's age.


Assuntos
Espessura Intima-Media Carotídea , Psoríase/complicações , Deficiência de Vitamina D/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/sangue , Fatores de Risco , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/sangue
19.
Acta Derm Venereol ; 94(2): 142-5, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23995104

RESUMO

Vitamin D deficiency is associated with higher cardiovascular risk and metabolic syndrome (MeS) criteria. The main objective of this study was to analyse the association of 25-hydroxyvitamin D (25-OHD) serum levels with MeS (National Cholesterol Education Program-Adult Treatment Panel-III criteria) in 46 Spanish patients with psoriasis, but without arthritis and systemic treatment, and 46 control subjects, matched by sex and age. The patients with psoriasis showed significantly lower level of 25-OHD than controls (30.5 vs. 38.3 ng/ml; p = 0.0001). Patients with MeS had significantly lower serum levels of 25-OHD than those without MeS (24.1 ± 7.5 vs. 32.8 ± 8.9, p = 0.007), and a negative correlation was found between 25-OHD and waist circumference, diastolic blood pressure, fasting glucose, and triglyceridaemia. In the control group no significant correlation between 25-OHD and MeS was found. Al-though the sample was small, our results suggest a potential protective role for 25-OHD in the metabolic profile of patients with psoriasis without arthritis.


Assuntos
Síndrome Metabólica/sangue , Psoríase/sangue , Deficiência de Vitamina D/diagnóstico , Vitamina D/análogos & derivados , Pressão Sanguínea , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Masculino , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Psoríase/complicações , Luz Solar , Vitamina D/sangue , Deficiência de Vitamina D/sangue
20.
Joint Bone Spine ; 81(2): 164-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23932927

RESUMO

OBJECTIVE: To assess cardiovascular (CV) risk in psoriatic arthritis (PsA) patients without clinically evident CV disease or classic atherosclerosis risk factors according to the SCORE chart following the EULAR recommendations. METHODS: Eighty PsA patients without previous CV events or atherosclerosis risk factors and eighty matched controls were included. Information on demographic, anthropometric and clinical-serological data of disease was assessed. The national calibrated Systematic Coronary Risk Evaluation (SCORE) index was calculated and the association between this SCORE and clinical-serological data of these patients was analyzed. RESULTS: PsA patients had higher acute phase reactants as well as higher SCORE mean values than healthy controls (1.99±3.52 vs. 1.0±1.74; P=0.028). According to SCORE definitions, 71 (89%) patients had low-intermediate CV risk and 9 (11%) were above the threshold of high risk. In the control group, 76 (95%) had low-intermediate risk and four (5%) had high CV risk. However, there were no differences in CV risk stratification between both groups (P=0.148). PsA patients with high-very high CV risk had longer disease duration (P=0.001) and higher levels of triglycerides (P=0.009). PsA patients showed a significant correlation between SCORE values and disease duration (ß=0.185; P=0.0001) and the average annual levels of C reactive protein (CRPa), ß=2.38; P=0.014. CONCLUSION: CV risk assessment in PsA patients without clinically evident CV disease or classic atherosclerosis risk factors may be underestimated by using only the SCORE chart. In these patients, disease duration and the CRPa may help to establish a better stratification of the actual CV risk.


Assuntos
Artrite Psoriásica/epidemiologia , Doenças Cardiovasculares/epidemiologia , Adulto , Aterosclerose/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco
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