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1.
Rheumatology (Oxford) ; 55(12): 2148-2155, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27593964

RESUMO

OBJECTIVE: To determine if ischaemia is a causal factor in the development of calcinosis in SSc. METHODS: Patients with SSc were assessed yearly. Physicians reported the presence of calcinosis, digital ischaemia (digital ulcers, digital necrosis/gangrene, loss of digital pulp on any digits and/or auto- or surgical digital amputation) and nailfold capillary dropout assessed using a dermatoscope. The number of digits with digital ischaemia was used as an assessment of the severity of digital ischaemia. SSc specific antibodies were detected with a line immunoassay. Multiple logistic regression and Cox proportional hazards models were generated to determine associations between calcinosis, digital ischaemia and capillary dropout. RESULTS: One thousand three hundred and five patients were included in this study, of whom 300 (23.0%) had calcinosis at study entry. In a cross-sectional multivariate analysis, at baseline, calcinosis was associated with digital ischaemia (odds ratio (OR) = 2.37, 95% CI: 1.66, 3.39), severity of ischaemia (OR = 1.12, 95% CI: 1.06, 1.18), capillary dropout (OR = 1.41, 95% CI: 1.05, 1.89), ACAs (OR = 1.68, 95% CI: 1.17, 2.43) and anti-RNA polymerase III antibodies (OR = 1.77, 95% CI: 1.08, 2.89). Current use of calcium channel blockers was inversely associated with the presence of calcinosis (OR = 0.70, 95% CI: 0.52, 0.96). Of the 805 patients with no calcinosis at study entry and at least one follow-up visit, 215 (26.7%) developed calcinosis during follow-up. Significant baseline predictors of the development of calcinosis in follow-up were digital ischaemia (hazard ratio (HR) = 1.82, 95% CI: 1.30, 2.54), capillary dropout (HR = 1.46, 95% CI: 1.08, 1.99), dcSSc (HR = 1.57, 95% CI: 1.11, 2.21), ACA (HR = 2.18, 95% CI: 1.50, 3.17) and anti-RNA polymerase III antibodies (HR = 2.58, 95% CI: 1.65, 4.04). CONCLUSION: Ischaemia may play a role in the development of calcinosis in SSc.


Assuntos
Calcinose/etiologia , Dedos/irrigação sanguínea , Isquemia/complicações , Escleroderma Sistêmico/complicações , Calcinose/prevenção & controle , Bloqueadores dos Canais de Cálcio/uso terapêutico , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Tempo
2.
Arthritis Care Res (Hoboken) ; 67(4): 582-7, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25233870

RESUMO

OBJECTIVE: The goal of this study was to determine the sensitivity of the new 2013 classification criteria for systemic sclerosis (SSc; scleroderma) in an independent cohort of SSc subjects and to assess the contribution of individual items of the criteria to the overall sensitivity. METHODS: SSc subjects from the Canadian Scleroderma Research Group cohort were assessed. Sensitivity was determined in several subgroups of patients. In patients without the criterion of skin thickening proximal to the metacarpophalangeal (MCP) joints, we recalculated sensitivity after removing the individual criterion. RESULTS: A total of 724 SSc patients were included. Most were women (86%), mean age was 55.8 years, mean disease duration was 10.9 years, and 59% had limited cutaneous SSc (lcSSc). Overall, the sensitivity of the 2013 criteria was 98.3% compared to 88.3% for the 1980 criteria. This pattern was consistent among those with lcSSc (98.8% versus 85.6%), anticentromere antibodies (98.9% versus 79.8%), disease duration ≤3 years (98.7% versus 84.7%), and no skin involvement proximal to the MCP joints (97% versus 60%). In the latter subgroup, removing Raynaud's phenomenon and sclerodactyly from the criteria reduced the sensitivity to 77% and 79%, respectively. Removing both sclerodactyly and puffy fingers reduced the sensitivity to 62%. CONCLUSION: The 2013 SSc classification criteria classify more SSc patients than the 1980 criteria. The improvement in sensitivity is most striking in those with lcSSc, especially those without skin involvement proximal to the MCP joints. The addition of Raynaud's phenomenon and puffy fingers to the 2013 criteria accounts for important gains in sensitivity.


Assuntos
Doenças Reumáticas/classificação , Reumatologia/classificação , Esclerodermia Localizada/classificação , Escleroderma Sistêmico/classificação , Sociedades Médicas/normas , Adulto , Idoso , Canadá/epidemiologia , Estudos de Coortes , Estudos Transversais , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/epidemiologia , Reumatologia/normas , Esclerodermia Localizada/diagnóstico , Esclerodermia Localizada/epidemiologia , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/epidemiologia , Estados Unidos/epidemiologia , Adulto Jovem
3.
Medicine (Baltimore) ; 93(24): 318-32, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25500701

RESUMO

Dermatomyositis (DM) is a major clinical subset of autoimmune myositis (AIM). The characteristic DM rash (Gottron papules, heliotrope rash) and perifascicular atrophy at skeletal muscle biopsy are regarded as specific features for this diagnosis. However, new concepts are challenging the current definition of DM. A modified Bohan and Peter classification of AIM was proposed in which the core concept was the inclusion of the diagnostic significance of overlap connective tissue disease features. In this clinical classification, a DM rash in association with myositis in the absence of overlap features indicates a diagnosis of pure DM. However, overlap features in association with myositis allow a diagnosis of overlap myositis (OM), irrespective of the presence or absence of the DM rash. Perifascicular atrophy may be present in both pure DM and OM. Recently, the presence of perifascicular atrophy in myositis without a DM rash was proposed as diagnostic of a novel entity, adermatopathic DM. We conducted the present study to evaluate these new concepts to further differentiate pure DM from OM.Using the modified Bohan and Peter classification, we performed a follow-up study of a longitudinal cohort of 100 consecutive adult French Canadian patients with AIM, including 44 patients with a DM phenotype, defined as a DM rash, and/or DM-type calcinosis, and/or the presence of perifascicular atrophy on muscle biopsy. A detailed evaluation was performed for overlap features, the extent and natural history of the DM rash, adermatopathic DM, DM-specific and overlap autoantibodies by protein A immunoprecipitation on coded serum samples, and associations with cancer and survival.Two distinct subsets were identified in patients with a DM phenotype: pure DM (n = 24) and OM with DM features, or OMDM (n = 20). In pure DM, the DM rash was a dominant finding. It was the first disease manifestation, was always present at the time of myositis diagnosis, and was associated with a high cutaneous score and chronicity. Concurrent heliotrope rash and Gottron papules (positive predictive value [PPV] 91%), as well as the V-sign and/or shawl sign (PPV 100%), were diagnostic of pure DM. Anti-Mi-2, anti-MJ, and anti-p155 autoantibodies were present in 50% of pure DM patients and were restricted to this subset (PPV 100%). Cancer was present in 21% of pure DM patients. The 15-year survival was excellent (92%).In contrast, in patients with OMDM, the first manifestation was proximal muscle weakness or other skeletal muscle-related complaints. The DM rash appeared at diagnosis or at follow-up, was associated with a low cutaneous extent score and was transient. Adermatopathic DM, which was absent in pure DM, was highly predictive (PPV 100%) of OMDM. Overlap autoantibodies (including anti-Jo-1, anti-PL-7, anti-PM-Scl, anti-U1RNP, and/or anti-U5-RNP) were found in 70% of OMDM patients. OMDM was not associated with cancer, but the 15-year survival was significantly decreased (65%).Perifascicular atrophy occurred as commonly in OMDM (n = 6/20, 30%) as in pure DM (n = 4/24, 17%) patients. These 6 OMDM patients had adermatopathic DM at myositis diagnosis, and only 1 of them developed a DM rash at follow-up, emphasizing the lack of specificity of perifascicular atrophy for pure DM.In conclusion, using the modified Bohan and Peter classification of AIM allowed identification of OMDM, a new clinical subset of OM. Furthermore, identification of OMDM allowed recognition of pure DM as a new entity that was distinct from OMDM or from OM without DM features. However, the absolute specificity of a DM rash and perifascicular muscle atrophy for the diagnosis of pure DM was lost. The distinctive clinical manifestations and autoantibody profiles presented are proposed as diagnostic criteria to differentiate pure DM from OMDM.


Assuntos
Dermatomiosite/diagnóstico , Miosite/diagnóstico , Adolescente , Adulto , Idoso , Atrofia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Dermatomiosite/patologia , Diagnóstico Diferencial , Exantema/diagnóstico , Exantema/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miosite/patologia , Pele/patologia , Adulto Jovem
4.
J Cell Physiol ; 226(7): 1907-14, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21506121

RESUMO

Our hypothesis is that the development of lesional areas of skin in patients with systemic sclerosis (SSc) originates from the selection of profibrotic cell subpopulations within their non-lesional skin areas, due to their greater resistance to apoptosis. Sensitivity to apoptosis of early-stage or late-stage SSc fibroblasts as well as of healthy cells was compared using extrinsic or intrinsic apoptotic pathway-inducers. Subpopulations of non-lesional SSc cells and healthy cells obtained after repeated Fas-induced apoptosis were compared with respect to their fibrotic parameters such as collagen and MMP secretion. Only late-stage lesional SSc cells were more resistant to Fas-induced apoptosis than their non-lesional counterparts isolated from the same patient. This result correlated with an increase in the levels of the anti-apoptotic proteins cFLIPs and cIAP in lesional cells compared to non-lesional cells. Healthy and non-lesional cell populations could be selected to generate a subpopulation that was more resistant to apoptosis. However, only the late-stage non-lesional SSc fibroblast populations showed a significant decrease in MMP secretion, one of parameters of the fibrosis. Our results show that resistance to apoptosis is an important characteristic of the late-stage lesional SSc fibroblast phenotype. We thus hypothesized that a selection of specific fibroblast subpopulations from late-stage non-lesional SSc skin areas could be at the origin of lesional populations. These cells should become independent of any exogenous stimuli and can induce or maintain SSc skin lesions.


Assuntos
Apoptose , Proteína Ligante Fas/metabolismo , Fibroblastos/enzimologia , Metaloproteinases da Matriz Secretadas/metabolismo , Esclerodermia Difusa/enzimologia , Transdução de Sinais , Pele/enzimologia , Adulto , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Regulação para Baixo , Fibroblastos/patologia , Fibrose , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Pessoa de Meia-Idade , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Esclerodermia Difusa/diagnóstico , Esclerodermia Difusa/patologia , Pele/patologia , Receptor fas/metabolismo
5.
J Pathol ; 217(4): 534-42, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19086038

RESUMO

We set out to examine the pathophysiological mechanisms of fibrosis in diffuse systemic sclerosis (SSc) using a tissue engineering approach. Skin fibroblasts were isolated from lesional skin of SSc patients with a disease duration of less than 1 year (early-stage SSc) or more than 10 years (late-stage SSc). Fibroblasts were also isolated from non-lesional skin and compared with normal fibroblasts isolated from healthy adults. Cells were cultured using a tissue engineering method to reconstruct a human dermis, and histologically observed. Dermal thickness was measured, as it reflects the global and intrinsic capacity of cells to reconstitute matrix. Collagen I, MMP-1, and MMP activity were evaluated. Cells were treated with TGFbeta1 or CTGF during dermis formation to study their fibrogenic role. Clinical severity of skin involvement was measured by a modified Rodnan score. Thickness of the dermis generated with non-lesional early-stage SSc fibroblasts was similar to normal cells. In contrast, reconstructed dermis from lesional early-stage SSc fibroblasts and non-lesional late-stage SSc cells was thinner, while lesional late-stage SSc fibroblasts made a thicker dermis. Dermis was always thicker when produced with TGFbeta1-treated cells, except when lesional late-stage SSc fibroblasts from patients with high Rodnan skin scores were used. CTGF did not affect dermal thickness. Measurements of collagen I and collagenases in the culture medium of the various reconstructed dermis could explain some of the changes observed. We conclude that the fibrotic phenotype of SSc fibroblasts varies with disease duration and with severity of skin involvement, and this is clearly visualized during in vitro dermis reconstruction.


Assuntos
Escleroderma Sistêmico/patologia , Pele/patologia , Adulto , Idoso , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Colágeno Tipo I/análise , Colágeno Tipo I/metabolismo , Fator de Crescimento do Tecido Conjuntivo/farmacologia , Progressão da Doença , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Humanos , Masculino , Metaloproteinase 1 da Matriz/análise , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinases da Matriz/análise , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , Fenótipo , Escleroderma Sistêmico/metabolismo , Pele/metabolismo , Engenharia Tecidual/métodos , Fator de Crescimento Transformador beta1/farmacologia
6.
Arthritis Rheum ; 58(12): 3902-12, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19035499

RESUMO

OBJECTIVE: To identify in patients with Raynaud's phenomenon (RP) independent markers that predict progression to definite systemic sclerosis (SSc) and to determine in patients with progression to SSc the type and sequence of microvascular damage and its relationship to SSc-specific autoantibodies. METHODS: Consecutive patients referred for evaluation of RP who had no definite connective tissue disease were evaluated for microvascular damage by nailfold capillary microscopy (NCM) and for anticentromere (anti-CENP-B), anti-Th/To, anti-topoisomerase I, and anti-RNA polymerase III (anti-RNAP III) autoantibodies by specific assays. Patients were studied prospectively. RESULTS: Of the 586 patients who were followed up for 3,197 person-years, 74 (12.6%) developed definite SSc. A characteristic sequence of microvascular damage was identified, starting with enlarged capillaries, followed by capillary loss, and then by capillary telangiectases. Definite SSc was diagnosed in close temporal relationship to capillary loss. Enlarged capillaries, capillary loss, and SSc-specific autoantibodies independently predicted definite SSc. Anti-CENP-B and anti-Th/To antibodies predicted enlarged capillaries; these autoantibodies and anti-RNAP III predicted capillary loss. Each autoantibody was associated with a distinct time course of microvascular damage. At followup, 79.5% of patients with 1 of these autoantibodies and abnormal findings on NCM at baseline had developed definite SSc. Patients with both baseline predictors were 60 times more likely to develop definite SSc. The data validated the proposed criteria for early SSc. CONCLUSION: In RP evolving to definite SSc, microvascular damage is dynamic and sequential, while SSc-specific autoantibodies are associated with the course and type of capillary abnormalities. Abnormal findings on NCM at baseline together with an SSc-specific autoantibody indicate a very high probability of developing definite SSc, whereas their absence rules out this outcome.


Assuntos
Autoanticorpos/sangue , Microvasos/imunologia , Doença de Raynaud/imunologia , Doença de Raynaud/patologia , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Adulto , Especificidade de Anticorpos , Árvores de Decisões , Progressão da Doença , Diagnóstico Precoce , Feminino , Seguimentos , Humanos , Incidência , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Doença de Raynaud/classificação , Doença de Raynaud/epidemiologia , Escleroderma Sistêmico/classificação , Escleroderma Sistêmico/epidemiologia , Estudos Soroepidemiológicos , Adulto Jovem
7.
Arthritis Rheum ; 57(1): 64-70, 2007 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-17266095

RESUMO

OBJECTIVE: We previously reported that patients with systemic lupus erythematosus (SLE) in the US incurred approximately 19% and 12% higher direct medical costs than patients in Canada and the UK, respectively, without experiencing superior outcomes expressed as disease damage or quality of life. In the present study, we compared cumulative indirect costs over 4 years in these patients. METHODS: A total of 715 patients with SLE (269 US, 231 Canada, 215 UK) were surveyed semiannually for 4 years on employment status and time lost from labor and nonlabor market activities. Cross-country comparisons of indirect costs were performed. RESULTS: In the US, Canada, and the UK, mean 4-year cumulative indirect costs (95% confidence interval [95% CI]) due to diminished labor market activity were $56,745 ($49,919, $63,571), $38,642 ($32,785, $44,500), and $42,213 ($35,859, $48,567), respectively, and cumulative indirect costs due to diminished nonlabor market activity were $5,249 ($2,766, $7,732), $5,455 ($3,290, $7,620), and $8,572 ($5,626, $11,518), respectively. Regression results showed that cumulative indirect costs (95% CI) due to diminished labor market activity in the US were $6,750 ($580, $12,910) greater than in Canada and $10,430 ($4,050, $16,800) greater than in the UK. Indirect costs due to diminished nonlabor market activity in the US were $280 (-$2,950, $3,520) less than in Canada and $2,010 (-$1,490, $5,510) less than in the UK, both results insignificant due to wide CIs. CONCLUSION: Despite American patients incurring greater direct medical costs than Canadian and British patients, they do not experience superior health outcomes in terms of less productivity loss in either labor market or nonlabor market activities.


Assuntos
Efeitos Psicossociais da Doença , Custos de Cuidados de Saúde/estatística & dados numéricos , Lúpus Eritematoso Sistêmico/economia , Canadá , Eficiência , Humanos , Análise de Regressão , Fatores de Tempo , Reino Unido , Estados Unidos
8.
Mt Sinai J Med ; 69(4): 208-19, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12357262

RESUMO

Apoptosis is a physiological process of cell death that normally occurs when cells are damaged or no longer needed. One of its major roles is the maintenance of peripheral immune tolerance, by eliminating activated T and B cells beyond the course of an infection, and thus terminating immune responses. When apoptosis becomes dysfunctional, either being "too much" or "too little," a variety of different disease states may be triggered. For example, insufficient apoptosis of activated immune cells is the basis of the Canale Smith Syndrome /ALPS, whereas excessive apoptosis of ~ islet cells of the pancreas is involved in the pathogenesis of autoimmune diabetes mellitus. In this review, we explain the fundamental aspects and molecular mechanisms of apoptosis and their relevance to several important human autoimmune diseases.


Assuntos
Apoptose/fisiologia , Doenças Autoimunes/fisiopatologia , Animais , Apoptose/imunologia , Autoimunidade/fisiologia , Caspases/fisiologia , Proteína Ligante Fas , Genes Supressores de Tumor/fisiologia , Humanos , Glicoproteínas de Membrana/fisiologia , Mitocôndrias/fisiologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Receptores do Fator de Necrose Tumoral/fisiologia , Transdução de Sinais/fisiologia
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