Microangiopatia em pacientes com esclerose sistêmica: estudo prospectivo em pacientes com doença precoce e estabelecida
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Data
2018-05-23
Autores
Camargo, Cintia Zumstein [UNIFESP]
Orientadores
Silva, Cristiane Kayser Veiga da [UNIFESP]
Tipo
Tese de doutorado
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Introdução: A Esclerose Sistêmica (ES) é uma doença autoimune crônica caracterizada por microangiopatia e fibrose da pele e órgãos internos, cujo diagnóstico em fases precoces permanece um desafio. Em 2001 LeRoy e Medsger propuseram critérios para ES precoce que incluem presença de fenômeno de Raynaud (FRy), capilaroscopia alterada e autoanticorpos específicos. Recentemente, foram propostos pelo ACR/EULAR novos critérios para a classificação da ES, que incluem manifestações presentes nos estágios precoce e tardio da doença. Apesar da importância do diagnóstico precoce da ES, poucos estudos avaliaram a incidência e fatores de risco associados ao desenvolvimento de ES estabelecida em pacientes com ES precoce e fatores de risco associados à progressão da ES em pacientes com doença estabelecida. A capilaroscopia periungueal (CPU) panorâmica e a videocapilaroscopia são métodos que avaliam alterações anatômicas da microcirculação em pacientes com FRy. Já o laser Doppler imaging (LDI) é um método de avaliação dinâmica do fluxo sanguíneo da microcirculação. Objetivos: Avaliação de fatores de risco clínicos e laboratoriais para evolução de pacientes com ES precoce para doença estabelecida, assim como para progressão de doença em pacientes com ES estabelecida em um seguimento de 3 anos. Adicionalmente, pretendemos avaliar de modo longitudinal as alterações na microcirculação periférica em pacientes com ES precoce e estabelecida.
Pacientes e métodos: Foi realizado estudo prospectivo no qual foram incluídos pacientes com ES estabelecida (n=80) (critérios do ACR/EULAR de 2013) e precoce (n=46) (critérios de LeRoy e Medsger de 2001) que realizaram avaliação no tempo 0 e após 3 anos de seguimento. Foram colhidos dados clínicos, de CPU panorâmica e videocapilaroscopia nas quais foram avaliadas o número de capilares/mm, número de capilares ectasiados, megacapilares, capilares ramificados, microhemorragias e grau de desvascularização, de avaliação de fluxo sanguíneo de polpas digitais mediante LDI (análise do fluxo antes e após estímulo frio), além de dosagem sérica de fator de von Willebrand (fvW). Foi considerada piora do número de megacapilares na CPU panorâmica ou videocapilaroscopia quando houve aumento maior ou igual a 0,1 na média do número de megacapilares para ES precoce e maior ou igual a 0,3 para ES estabelecida. Padrão SD (scleroderma pattern) foi subclassificado nos padrões precoce, ativo e tardio. Resultados: Ao final de três anos (38,4 ± 4,1 meses) foram reavaliados 60 pacientes com ES estabelecida (idade média 54 ± 14,2 anos) e 34 pacientes com ES precoce (idade média 53 ± 12,7 anos). Dos pacientes com ES precoce, 23,5% desenvolveram ES estabelecida. Ao final do acompanhamento, piora na CPU panorâmica e na videocapilaroscopia foi observada em 55,9% e 67,6% dos pacientes com ES precoce, respectivamente. Já nos pacientes com ES estabelecida foi observada piora em 91,7% na CPU panorâmica e 95% na videocapilaroscopia. Aumento do número de megacapilares e piora do grau de desvascularização foram mais frequentes nos pacientes que desenvolveram ES (p=0.02 e p=0.002 para CPU panorâmica). Utilizando análise multivariada, padrão ativo ou tardio na CPU na avaliação inicial (OR=30,0; p=0,01), foi fator preditor independente para desenvolvimento de ES estabelecida em pacientes com ES precoce. Aumento do número de megacapilares tanto na CPU panorâmica (OR=8,69; p=0,03) quanto na videocapilaroscopia (OR=6,92; p=0,049), sexo masculino (OR=40,55; p=0,01) e níveis elevados de fvW (OR= 1,03; p=0,03) foram fatores preditores independentes para desenvolvimento de novas úlceras digitais em pacientes com ES estabelecida. Progressão geral da doença na ES estabelecida foi associada a forma cutânea difusa (OR=3,00; p=0,048), menor fluxo sanguíneo de polpa digital (OR=0,99; p=0,03) e piora do número de capilares/mm avaliada pela CPU panorâmica (OR=3,48; p=0,04). Ao final do seguimento, houve aumento significativo no número de capilares ectasiados em pacientes com ES precoce e ES estabelecida, enquanto aumento do grau de desvascularização foi observado somente em pacientes com ES estabelecida.
Conclusões: Neste estudo prospectivo no qual foram avaliados tanto pacientes com ES precoce quanto pacientes com ES estabelecida, padrão ativo ou tardio na capilaroscopia foi fator independente para o desenvolvimento de ES estabelecida em pacientes com ES precoce. Piora de parâmetros da capilaroscopia apresentou influência sobre o desenvolvimento de novas úlceras digitais e progressão geral da doença em pacientes com ES estabelecida.
Introduction: Systemic Sclerosis (SSc) is a chronic autoimmune disease, characterized by microangiopathy and fibrosis of the skin and internal organs, whose diagnosis in early stages remains a challenge. In 2001 LeRoy and Medsger proposed criteria for the classification of early SSc defined by the presence of Raynaud's phenomenon (RP), capillaroscopy abnormalities and specific autoantibodies. Recently, new criteria for the classification of SSc have been proposed by the ACR/EULAR, which include manifestations present in the early and late stages of the disease. Despite the importance of the early diagnosis of SSc, few studies have evaluated the incidence and risk factors associated with the development of definite SSc in patients with early SSc, as well as the risk factors associated with disease progression in patients with definite disease. Widefield nailfold capillaroscopy (NFC) and videocapillaroscopy are methods that evaluate anatomical changes of the microcirculation in patients with RP. Laser Doppler imaging (LDI) is a method of measurement of superficial microvascular blood flow. Objective: Evaluation of clinical and laboratorial risk factors for progression to definite disease in early SSc patients, as well for disease progression in patients with definite disease in a follow up of 3 years. In addition, the longitudinal abnormalities in the microcirculation were evaluated in patients with definite and early SSc. Patients and methods: In this prospective study, patients with definite SSc (n=80) (ACR/EULAR 2013 criteria) and patients with early SSc (n=46) (LeRoy and Medsger 2001 criteria) were evaluated at baseline and after 3 years of follow-up. Clinical data, widefield NFC and videcapillaroscopy (parameters evaluated: number of capillaries / mm, number of enlarged capillaries, giant capillaries, ramified capillaries, microhaemorrhages and avascular score) were collected in all subjects at baseline and at the end of the follow-up. The mean finger blood flow (FBF) measured by LDI (before and after cold stimulus), and serum levels of von Willebrand factor were also evaluated. Worsening of the number of giant capillaries was considered when there was an increase in the mean number of giant capillaries greater or equivalent to 0.1 for early SSc and greater or equivalent to 0.3 for definite SSc. The scleroderma pattern was classified as early, active and late. Results: At the end of 3 years (38.4 ± 4.1 months), 60 patients with definite SSc (mean age 54 ± 14.2 years) and 34 patients with early SSc (mean age 53 ± 12.7 years) were reevaluated. Of the patients with early SSc, 23.5% developed definite SSc. Any worsening in widefield NFC and videocapillaroscopy was observed in 55.9% and 67.6% of the patients with early SSc, respectively. In patients with definite SSc, worsening was observed in 91.7% in widefield NFC and 95% in videocapillaroscopy. An increase in the number of giant capillaries and worsening in the avascular score were more frequent in patients who developed SSc (p=0.02 and p=0.002 in widefield NFC, respectively). By multivariate analysis, an active or late pattern in NFC at baseline (OR = 30.0, p = 0.01), was an independent predictor for the development of definite SSc in patients with early SSc. On the other hand, worsening of the number of giant capillaries in both widefield NFC (OR = 8.69, p = 0.03) and videocapillaroscopy (OR = 6.92, p = 0.05), male sex (OR = 40.55, p = 0.01) and elevated vWF levels (OR = 1.03, p = 0.03) were independent predictors for the development of new digital ulcers in patients with definite SSc. Overall disease progression in patients with definite SSc was associated with diffuse cutaneous form (OR = 3.00; p=0.048), lower fingertip blood flow (OR = 0.99, p=0.03) and worsening of number of capillaries/mm in widefield NFC (OR=3.48, p=0.04). At the end of follow-up, there was a significant increase in the number of enlarged capillaries in patients with early SSc and definite SSc, while an increase in the avascular score was observed only in patients with definite SSc. Conclusions: In this prospective study in which both patients with early SSc and patients with defined SSc were evaluated, active or late pattern in capillaroscopy was an independent risk factor for the development of definite SSc in patients with early SSc. Worsening of capillaroscopy parameters influenced the development of new digital ulcers and overall disease progression in patients with definite SSc.
Introduction: Systemic Sclerosis (SSc) is a chronic autoimmune disease, characterized by microangiopathy and fibrosis of the skin and internal organs, whose diagnosis in early stages remains a challenge. In 2001 LeRoy and Medsger proposed criteria for the classification of early SSc defined by the presence of Raynaud's phenomenon (RP), capillaroscopy abnormalities and specific autoantibodies. Recently, new criteria for the classification of SSc have been proposed by the ACR/EULAR, which include manifestations present in the early and late stages of the disease. Despite the importance of the early diagnosis of SSc, few studies have evaluated the incidence and risk factors associated with the development of definite SSc in patients with early SSc, as well as the risk factors associated with disease progression in patients with definite disease. Widefield nailfold capillaroscopy (NFC) and videocapillaroscopy are methods that evaluate anatomical changes of the microcirculation in patients with RP. Laser Doppler imaging (LDI) is a method of measurement of superficial microvascular blood flow. Objective: Evaluation of clinical and laboratorial risk factors for progression to definite disease in early SSc patients, as well for disease progression in patients with definite disease in a follow up of 3 years. In addition, the longitudinal abnormalities in the microcirculation were evaluated in patients with definite and early SSc. Patients and methods: In this prospective study, patients with definite SSc (n=80) (ACR/EULAR 2013 criteria) and patients with early SSc (n=46) (LeRoy and Medsger 2001 criteria) were evaluated at baseline and after 3 years of follow-up. Clinical data, widefield NFC and videcapillaroscopy (parameters evaluated: number of capillaries / mm, number of enlarged capillaries, giant capillaries, ramified capillaries, microhaemorrhages and avascular score) were collected in all subjects at baseline and at the end of the follow-up. The mean finger blood flow (FBF) measured by LDI (before and after cold stimulus), and serum levels of von Willebrand factor were also evaluated. Worsening of the number of giant capillaries was considered when there was an increase in the mean number of giant capillaries greater or equivalent to 0.1 for early SSc and greater or equivalent to 0.3 for definite SSc. The scleroderma pattern was classified as early, active and late. Results: At the end of 3 years (38.4 ± 4.1 months), 60 patients with definite SSc (mean age 54 ± 14.2 years) and 34 patients with early SSc (mean age 53 ± 12.7 years) were reevaluated. Of the patients with early SSc, 23.5% developed definite SSc. Any worsening in widefield NFC and videocapillaroscopy was observed in 55.9% and 67.6% of the patients with early SSc, respectively. In patients with definite SSc, worsening was observed in 91.7% in widefield NFC and 95% in videocapillaroscopy. An increase in the number of giant capillaries and worsening in the avascular score were more frequent in patients who developed SSc (p=0.02 and p=0.002 in widefield NFC, respectively). By multivariate analysis, an active or late pattern in NFC at baseline (OR = 30.0, p = 0.01), was an independent predictor for the development of definite SSc in patients with early SSc. On the other hand, worsening of the number of giant capillaries in both widefield NFC (OR = 8.69, p = 0.03) and videocapillaroscopy (OR = 6.92, p = 0.05), male sex (OR = 40.55, p = 0.01) and elevated vWF levels (OR = 1.03, p = 0.03) were independent predictors for the development of new digital ulcers in patients with definite SSc. Overall disease progression in patients with definite SSc was associated with diffuse cutaneous form (OR = 3.00; p=0.048), lower fingertip blood flow (OR = 0.99, p=0.03) and worsening of number of capillaries/mm in widefield NFC (OR=3.48, p=0.04). At the end of follow-up, there was a significant increase in the number of enlarged capillaries in patients with early SSc and definite SSc, while an increase in the avascular score was observed only in patients with definite SSc. Conclusions: In this prospective study in which both patients with early SSc and patients with defined SSc were evaluated, active or late pattern in capillaroscopy was an independent risk factor for the development of definite SSc in patients with early SSc. Worsening of capillaroscopy parameters influenced the development of new digital ulcers and overall disease progression in patients with definite SSc.
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Citação
CAMARGO, Cintia Zumstein. Microangiopatia em pacientes com esclerose sistêmica: estudo prospectivo em pacientes com doença precoce e estabelecida. São Paulo, 2018. 88 f. Tese (Doutorado em Ciências da Saúde Aplicadas à Reumatologia) - Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 2018.