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1.
Artigo em Inglês | MEDLINE | ID: mdl-31310156

RESUMO

RATIONALE: Interstitial lung disease (ILD) represents a major challenge in systemic sclerosis (SSc), but there are no precise, population-based data on its overall impact, limiting opportunities for screening and management strategies. OBJECTIVE: Evaluate impact of ILD in a unique, nationwide, population based SSc cohort. METHODS: ILD was assessed prospectively in the Norwegian SSc cohort (Nor-SSc) including all 815 SSc patients resident in the country in 2000-2012. Lung HRCTs were available for fibrosis quantification at baseline (n=650, 80%) and follow-up. Pulmonary function tests were assessed at baseline (n=703, 86%) and follow-up. Vital status and standardized mortality rates (SMR) were estimated at study end (2018) in the 630 incident Nor-SSc cases and 15 individually matched controls. Cumulative survival rates were computed. MEASUREMENTS/MAIN RESULTS: At baseline, 50% of the SSc patients (n=324) had ILD by HRCT and 46% displayed pulmonary function declines consistent with ILD progression. Mortality correlated with extent of lung fibrosis as SMR increased from 2.2 with no fibrosis to 8.0 with >25% fibrosis. SMR was inversely related to baseline FVC% and increased at all FVC levels below 100%. In patients with normal range baseline FVC (80-100%) the 5- and 10-years survival rates correlated with presence or absence of lung fibrosis, being 83% and 80% with no fibrosis; and 69% and 56% with lung fibrosis (p=0.03). CONCLUSION: The mere presence of ILD at baseline appears to affect outcome in SSc, suggesting that all SSc patients should undergo baseline PFT and lung HRCT screening to diagnose ILD early and tailor further management.

2.
Arthritis Rheumatol ; 71(6): 972-982, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30624031

RESUMO

OBJECTIVE: Interstitial lung disease (ILD) in systemic sclerosis (SSc) runs a highly variable course, and prediction tools are highly desired. The aim of this study was to assess the diagnostic and prognostic performance of 4 candidate serum biomarkers for SSc-associated ILD. METHODS: Serum samples from a combined cohort of SSc patients (from Paris, France and Oslo, Norway; n = 427) were analyzed by enzyme-linked immunosorbent assay for concentrations of lung epithelial-derived surfactant protein D (SP-D), Krebs von den Lungen 6 glycoprotein (KL-6), CCL18, and OX40 ligand (OX40L). Lung fibrosis was measured by high-resolution computed tomography and pulmonary function tests. Associations of these candidate biomarkers with baseline disease involvement and prediction of disease progression over time (mean ± SD follow-up 3.2 ± 4.4 years) were investigated. RESULTS: In SSc patients at baseline, serum levels of KL-6 correlated with the forced vital capacity (FVC) (r = -0.317, P < 0.001), diffusing capacity for carbon monoxide (r = -0.335, P < 0.001), and extent of lung fibrosis (r = 0.551, P < 0.001). In multivariate analyses, serum levels of KL-6 and SP-D, but not CCL18 and OX40L, were associated with lung fibrosis (odds ratio [OR] 2.41, 95% confidence interval [95% CI] 1.43-4.07 [P = 0.001] and OR 3.15, 95% CI 1.81-5.48 [P < 0.001], respectively). In SSc patients with ILD at baseline, longitudinal, multivariate analyses showed that CCL18 serum levels were an independent predictor of a >10% decrease in the FVC (hazard ratio [HR] 2.90, 95% CI 1.25-6.73; P = 0.014) and de novo development of extensive disease (HR 3.71, 95% CI 1.02-13.52; P = 0.048). Matrix-based logistic regression models for the diagnosis and prognosis of SSc-associated ILD were constructed, and these models discriminated 3 groups of risk (mild, moderate, or high) for the diagnosis or worsening of lung fibrosis according to the serum levels of SP-D (for diagnosis) and serum levels of CCL18 (for progression of disease). CONCLUSION: These results show that SP-D is a relevant diagnostic biomarker for SSc-associated ILD, whereas KL-6 could be used to assess the severity of lung fibrosis. CCL18 appears to be a potential predictive marker for progression of ILD in SSc.

3.
PLoS One ; 13(11): e0206545, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30457999

RESUMO

BACKGROUND: Dysregulation of Fractalkine (CX3CL1) and its receptor CX3CR1 has been linked to the pathobiology of chronic inflammatory conditions. We explored CX3CL1 in systemic sclerosis (SSc) related progressive interstitial lung disease (ILD) and pulmonary hypertension (PH) in two different but complementary sources of biomaterial. METHODS: We collected lung tissue at the time of lung transplantation at UCLA from SSc-ILD patients (n = 12) and healthy donors (n = 12); and serum samples from the prospective Oslo University Hospital SSc cohort (n = 292) and healthy donors (n = 100). CX3CL1 was measured by ELISA. Cellular sources of CX3CL1/CX3CR1 in lung tissues were determined by immunohistochemistry and immunofluorescence. ILD progression and new onset PH endpoints were analysed. RESULTS: CX3CL1 concentrations were increased in SSc in lung tissue as well as in sera. In the UCLA cohort, CX3CL1 was highly correlated with DLCO. In the SSc-ILD lungs, CX3CL1 was identified in reactive type II pneumocytes and airway epithelial cells. CX3CR1 stained infiltrating interstitial mononuclear cells, especially plasma cells. In the Oslo cohort, CX3CL1 correlated with anti-Topoisomerase-I-antibody and lung fibrosis. CX3CL1 was associated with ILD progression in multivariable regression analysis but not PH. CONCLUSION: CX3CL1 is associated with progressive SSc-ILD but not SSc-PH. The CX3CR1/CX3CL1-biological axis may be involved in recruiting antibody secreting plasma cells to SSc lungs, thereby contributing to the immune-mediated pathobiology of SSc-ILD.

4.
Artigo em Inglês | MEDLINE | ID: mdl-30281089

RESUMO

Objectives: Studies assessing relative mortality risks across the spectrum of systemic inflammatory rheumatic diseases are largely missing. In this study, we wanted to estimate standard mortality ratios (SMRs) and causes of death in an ethnically homogeneous cohort covering all major CTDs and primary systemic vasculitides (PSVs). Methods: We prospectively followed all incident CTD and PSV cases included in the Norwegian CTD and vasculitis registry (NOSVAR) between 1999 and 2015. Fifteen controls for each patient matched for sex and age were randomly drawn from the Norwegian National Population Registry. Causes of death were obtained from the National Cause of Death Register, death certificates and hospital charts. Results: The cohort included 2140 patients (1534 with CTD, 606 with PSV). During a mean follow-up time of 9 years, 279 of the patients (13%) died, compared with 2864 of 32 086 (9%) controls (P < 0.001). Ten years after diagnosis, the lowest survival was 60% in dcSSc, 73% in anti-synthetase syndrome (ASS) and 75% in lcSSc. In the CTD group, the highest SMRs were observed in dcSSc (SMR 5.8) and ASS (SMR 4.1). In the PSV group, Takayasu arteritis (SMR 2.5) and ANCA-associated vasculitis (SMR 1.5) had the highest SMRs. Major causes of death were cardiovascular disease (CTD 27%, PSV 28%), neoplasms (CTD 25%, PSV 27%), chronic respiratory disease (CTD 20%, PSV10%) and infections (CTD 9%, PSV 16%). Conclusion: We observed premature deaths across the spectrum of CTDs and PSVs, with highest SMRs in dcSSc and ASS. The overall mortality was highest in the CTD group.

5.
J Am Coll Cardiol ; 72(15): 1804-1813, 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30286924

RESUMO

BACKGROUND: Primary cardiac affection is common and is a major cause of death in systemic sclerosis (SSc), but there are knowledge gaps regarding the effect of cardiac dysfunction on mortality. OBJECTIVES: The purpose of this study was to evaluate diastolic function in a large, unselected SSc cohort and assess the effect of diastolic dysfunction (DD) on mortality. METHODS: SSc patients followed prospectively at the Oslo University Hospital from 2003 to 2016 with available echocardiographies and matched control subjects were included. DD was assessed by echocardiography according to the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. Pulmonary hypertension (PH) was diagnosed by right heart catheterization. Vital status was available for all patients. Cox regression analyses with hazards ratios (HRs) were conducted. RESULTS: Diastolic function was assessed in 275 SSc patients at baseline and in 186 patients at follow-up. At baseline, 46 of the 275 SSc patients (17%) were diagnosed with DD and 195 (71%) had normal diastolic function. After a median follow-up of 3.4 years (interquartile range: 1.6 to 6.2 years), the proportion of DD increased from 17% to 29%. During follow-up, 57% of patients with DD at baseline died, compared with 13% of patients with normal diastolic function. At baseline, 86 patients had performed right heart catheterization, and 43 were diagnosed with PH; of these 60% deceased. In multivariable Cox regression analyses, DD was a stronger predictor of death (HR: 3.7; 95% CI: 1.69 to 8.14; c-index 0.89) than PH (HR: 2.0; 95% CI: 1.1 to 3.9; c-index 0.84). CONCLUSIONS: DD is frequent in SSc, and the presence of DD is associated with high mortality. DD exceeds PH with respect to predicting mortality.

6.
Arthritis Rheumatol ; 70(10): 1644-1653, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29687634

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) is a major cause of pulmonary arterial hypertension (PAH). Murine models indicate key roles for chemokines CCL19 and CCL21 and their receptor CCR7 in lung inflammation leading to PAH. The objective of this study was to assess the chemokine CCL19-CCL21 axis in patients with SSc-related PAH. METHODS: Serum samples obtained from 2 independent prospective SSc cohorts (n = 326), patients with idiopathic PAH (n = 12), and healthy control subjects (n = 100) were analyzed for CCL19/CCL21 levels, by enzyme-linked immunosorbent assay. The levels were defined as either high or low, using the mean + 2 SD value in controls as the cutoff value. Risk stratification at the time of PAH diagnosis and PAH-related events were performed. Descriptive and Cox regression analyses were conducted. RESULTS: CCL21 levels were higher in patients with SSc compared with controls and were elevated prior to the diagnosis of PAH. PAH was more frequent in patients with high CCL21 levels (≥0.4 ng/ml) than in those with low CCL21 levels (33.3% versus 5.3% [P < 0.001]). In multivariate analyses, CCL21 was associated with PAH (hazard ratio [HR] 5.1, 95% CI 2.39-10.76 [P < 0.001]) and occurrence of PAH-related events (HR 4.7, 95% CI 2.12-10.46, P < 0.001). Risk stratification at the time of PAH diagnosis alone did not predict PAH-related events. However, when risk at diagnosis was combined with high or low CCL21 level, there was a significant predictive effect (HR 1.3, 95% CI 1.03-1.60 [P = 0.027]). A high CCL21 level was associated with decreased survival (P < 0.001). CONCLUSION: CCL21 appears to be a promising marker for predicting the risk of SSc-related PAH and PAH progression. CCL21 may be part of a dysregulated immune pathway linked to the development of lung vascular damage in SSc.

7.
Rheumatology (Oxford) ; 57(3): 480-487, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29237073

RESUMO

Objective: The DETECT algorithm was developed for screening patients with SSc at high risk of pulmonary arterial hypertension (PAH). We evaluated the impact of this algorithm in a SSc population. Methods: Patients from the unselected, prospective Oslo University Hospital SSc study were divided into the Early and DETECT cohorts, respectively, depending on whether an incident right heart catheterization (RHC) was performed before (2009-13) or after (2014-17) the DETECT algorithm was instituted. A PAH diagnosis and patient risk stratification (low, intermediate and high risk) were performed according to 2015 European Society of Cardiology guidelines. Results: At the time of the incident RHC, PAH frequency was similar between the DETECT (15/84 with PAH; 18%) and Early (16/77; 21%) cohorts, but more patients had borderline pulmonary hypertension (PH) in the DETECT (31%) than in the Early (17%) cohort. PAH risk levels were distributed differently. In the DETECT cohort, 27% and 27% were at low and high risk, respectively, at the time of PAH diagnosis. In the Early cohort, 19 and 44% were at low and high risk, respectively. A follow-up RHC, performed after [mean (SD)] 2.4 (1.8) years, showed that 39% of patients with borderline PH in the Early cohort had developed PAH. Conclusion: The DETECT algorithm did not alter PAH incidence in this unselected SSc population. However, it appeared to affect the risk distribution at the time of PAH diagnosis and increased the frequency of borderline PH cases. These findings may translate into novel opportunities for earlier PAH treatment and, possibly, prevention.


Assuntos
Algoritmos , Cateterismo Cardíaco/estatística & dados numéricos , Hipertensão Pulmonar/epidemiologia , Programas de Rastreamento/estatística & dados numéricos , Escleroderma Sistêmico/complicações , Idoso , Cateterismo Cardíaco/métodos , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Incidência , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Noruega/epidemiologia , Estudos Prospectivos , Medição de Risco/métodos , Fatores de Tempo
8.
Arthritis Res Ther ; 19(1): 17, 2017 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28122635

RESUMO

BACKGROUND: Magnetic resonance imaging (MRI) of thigh muscles is increasingly used to assess disease activity and damage extent in chronic myositis, but the validity of the findings is not clear. Here, the primary aim was to compare thigh MRI findings in patients having chronic myositis associated with anti-synthetase syndrome (ASS) and in matched healthy controls. METHODS: Cross-sectional analyses of thigh muscle MRI, muscular function and creatinine kinase (CK) were performed in 68 ASS patients (median disease duration 71 months) and 67 controls matched for age and gender. MRI changes associated with disease activity (edema in muscles and fascia) and damage (fatty replacement and muscle volume reduction) were assessed semiquantitatively, giving a total MRI score of 0-78 (total edema 0-42 and total damage 0-36). RESULTS: ASS patients had higher total MRI score than the matched controls (14.1 versus 3.0; p < 0.001) and less muscle strength (p < 0.001). Muscle edema was more frequent in ASS patients than controls (38% versus 12%), as was fatty replacement (42% versus 4%). In ASS patients, we found that the total edema score correlated with CK, but 23% of the patients with normal CK had score > 18. Muscle compartment analyses in ASS patients showed that muscle edema was most pronounced anteriorly, while fatty replacement dominated posteriorly. CONCLUSIONS: This study showed, for the first time, the magnitude of difference in muscle MRI findings between chronic myositis cases and matched controls. In ASS patients, muscle MRI appeared to provide useful complementary information to muscle strength and CK levels in the assessment of myositis.


Assuntos
Imagem por Ressonância Magnética/métodos , Força Muscular , Músculo Esquelético/diagnóstico por imagem , Miosite/diagnóstico por imagem , Adulto , Creatina Quinase/sangue , Creatina Quinase/metabolismo , Creatinina/sangue , Creatinina/metabolismo , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/enzimologia , Músculo Esquelético/fisiopatologia , Miosite/enzimologia , Miosite/fisiopatologia
9.
J Rheumatol ; 44(4): 459-465, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28089974

RESUMO

OBJECTIVE: Extensive skin disease and renal crisis are hallmarks of anti-RNA polymerase III (RNAP)-positive systemic sclerosis (SSc), while lung and heart involvement data are conflicting. Here, the aims were to perform time-course analyses of interstitial lung disease (ILD) and pulmonary hypertension (PH) in the RNAP subset of a prospective unselected SSc cohort and to use the other autoantibody subsets as comparators. METHODS: The study cohort included 279 patients with SSc from the observational Oslo University Hospital cohort with complete data on (1) SSc-related autoantibodies, (2) paired, serial analyses of lung function and fibrosis by computed tomography, and (3) PH verified by right heart catheterization. RESULTS: RNAP was positive in 33 patients (12%), 79% of which had diffuse cutaneous SSc. Pulmonary findings were heterogeneous; 49% had no signs of fibrosis while 18% had > 20% fibrosis at followup. Forced vital capacity at followup was < 80% in 39% of the RNAP subset, comparable to the antitopoisomerase subset (ATA; 47%), but higher than anticentromere (ACA; 13%). Accumulated frequency of PH in the RNAP subset (12%) was lower than in ACA (18%). At 93% and 78%, the 5- and 10-year survival rates in RNAP were comparable to the ATA and ACA subsets. CONCLUSION: In this cohort, the RNAP subset was marked by cardiopulmonary heterogeneity, ranging from mild ILD to development of severe ILD in 18%, and PH development in 12%. These data indicate that cardiopulmonary risk stratification early in the disease course is particularly important in RNAP-positive SSc.


Assuntos
Autoanticorpos/imunologia , Doenças Cardiovasculares/complicações , Pneumopatias/complicações , RNA Polimerase III/imunologia , Escleroderma Sistêmico/complicações , Adulto , Idoso , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Pneumopatias/diagnóstico por imagem , Pneumopatias/imunologia , Pneumopatias/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Escleroderma Sistêmico/diagnóstico por imagem , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/mortalidade , Índice de Gravidade de Doença , Taxa de Sobrevida , Tomografia Computadorizada por Raios X
10.
Arthritis Care Res (Hoboken) ; 69(2): 278-285, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27159262

RESUMO

OBJECTIVE: To study the epidemiology and clinical characteristics of Takayasu arteritis (TAK) in southeast Norway (population 2.8 million). METHODS: All study area hospital databases were screened to capture every potential TAK case between 1999 and 2012. These cases were manually chart reviewed, and only patients fulfilling either the 1990 American College of Rheumatology classification or the 1995 Ishikawa diagnostic criteria were included. RESULTS: Inclusion criteria were met by 78 patients (68 female, 10 male). Point prevalence (by 2012) segregated by ethnic origin was 22.0 per 106 (95% confidence interval [95% CI] 17-29) in northern Europeans compared to 78.1 (95% CI 38-152) in Asian whites and 108.3 (95% CI 46-254) in Africans (P < 0.001). The incidence rate increased from 1 to 2 per 106 in the first to last 5-year period of the study (P = 0.03). Northern Europeans were mean age 32.3 years at onset, and 47% had involvement confined to aortic arch branches (angiographic type I), while 24% had extensive type V disease. Mean onset age in Asian and African cases was 20.3 years and 47% had type V disease. Coexisting inflammatory bowel disease was observed in 8% and ankylosing spondylitis in 7%. CONCLUSION: We report 2-4 times higher population prevalence than previously observed, and the highest prevalence ever found in Norwegians of Asian and African descent. The results support the idea that TAK in northern Europeans is marked by limited arterial involvement and older age at onset.


Assuntos
Arterite de Takayasu/epidemiologia , Arterite de Takayasu/patologia , Adulto , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Noruega/epidemiologia , Prevalência
11.
Arthritis Care Res (Hoboken) ; 69(9): 1384-1390, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-27813289

RESUMO

OBJECTIVE: To assess pregnancy outcomes in an unselected Takayasu arteritis (TAK) cohort, and identify pregnancy-related concerns. METHODS: Consenting female patients with TAK were predominantly recruited from a population-based southeast Norway TAK cohort. Additional cases (n = 8) were recruited at Oslo University Hospital. Data on the number of pregnancies, births, and pregnancy outcomes before and after disease onset were retrieved from medical charts, patient questionnaires, and the Medical Birth Registry of Norway (MBRN). Data on pregnancy-related concerns were gathered from patient questionnaires. RESULTS: Altogether, the 58 women in the TAK study cohort had been through 110 pregnancies, 73 (in 33 patients) before disease onset and 37 (in 23 patients) after onset. The frequencies of miscarriages, induced abortions, and maternal complications did not differ between pregnancies occurring before and after TAK onset. Pregnancy-related hypertension was seen in 4.2% of the patients, compared to 1.5% (P = 0.37) in the reference cohort from MBRN, and preeclampsia/eclampsia in 4.5% compared to 3% (P = 0.2). The mean gestational age at delivery in pregnancies after TAK onset was 37.5 weeks, compared to 39.5 weeks in the MBRN references (P < 0.001). Cesarean sections were more frequent in deliveries after TAK onset (42%) than in MRBN controls (11%) (P < 0.001). Pregnancy-related concerns were recorded in 80% of the TAK cohort, with 60% expressing concerns about passing the disease to offspring. CONCLUSION: In this population-based TAK cohort, the maternal and fetal outcomes were favorable. This study reveals a high prevalence of pregnancy-related concerns in TAK patients.


Assuntos
Complicações Cardiovasculares na Gravidez/etiologia , Arterite de Takayasu/complicações , Adolescente , Adulto , Idade de Início , Cesárea/estatística & dados numéricos , Criança , Parto Obstétrico/estatística & dados numéricos , Feminino , Idade Gestacional , Humanos , Hipertensão Induzida pela Gravidez/epidemiologia , Hipertensão Induzida pela Gravidez/etiologia , Recém-Nascido , Pessoa de Meia-Idade , Noruega/epidemiologia , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/etiologia , Gravidez , Resultado da Gravidez , Prevalência , Sistema de Registros , Inquéritos e Questionários , Adulto Jovem
12.
Clin Exp Rheumatol ; 34(4): 690-3, 2016 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27214260

RESUMO

OBJECTIVES: To investigate serum levels of endostatin in a well characterised cohort of patients with primary Sjögren's syndrome (pSS) and healthy controls (HC) and assess associations between these mediators and clinical parameters. METHODS: All patients (n=144) were recruited from the Norwegian systemic connective tissue disease and vasculitis registry (NOSVAR) and fulfilled American-European classification criteria for pSS. Pulmonary involvement was based on clinical symptoms and abnormal findings on high-resolution computed tomography of the lungs. The controls were 100 healthy blood donors. Serum levels of endostatin was determined by enzyme immunoassay. RESULTS: We found higher mean levels of serum endostatin in patients with pSS compared with the controls (p<0.001). The patients with interstitial lung disease (ILD) had higher levels compared with those without pulmonary involvement. CONCLUSIONS: Our results indicate that endostatin is increased in patients with pSS and particularly in those with ILD.


Assuntos
Endostatinas/sangue , Doenças Pulmonares Intersticiais/sangue , Síndrome de Sjogren/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/imunologia , Masculino , Pessoa de Meia-Idade , Noruega , Sistema de Registros , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologia , Tomografia Computadorizada por Raios X , Regulação para Cima
13.
J Rheumatol ; 43(6): 1107-13, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27036381

RESUMO

OBJECTIVE: Interstitial lung disease (ILD) is a major component of the antisynthetase syndrome, but quantitative data on longterm pulmonary outcome in antisynthetase syndrome are limited. In this study, the main aims were to compare pulmonary function tests (PFT) and the 6-min walking distance (6MWD) between patients with antisynthetase syndrome and healthy sex- and age-matched controls, to evaluate the extent of ILD by lung high-resolution computed tomography (HRCT), and to assess correlations between PFT measures and ILD extent. METHODS: Concurrent PFT and 6MWD were performed in 68 patients with antisynthetase syndrome and their individually matched controls. Additionally, in the patients, the extent of ILD was determined in 10 HRCT sections, expressed as percentage of total lung volumes. RESULTS: Median disease duration in the antisynthetase syndrome cohort was 71 months. Compared with the matched controls, the patients with antisynthetase syndrome had mean 28%, 27%, and 53% lower absolute values of forced vital capacity (FVC), forced expiratory volume in 1 s, and DLCO (p < 0.001). Mean difference in 6MWD between patients and controls was 116 m (p < 0.001). Median extent of ILD by HRCT was 20% (range 0-73) and correlated with FVC and DLCO. Pulmonary outcome did not differ between Jo1 and non-Jo1 subsets. CONCLUSION: To our knowledge, this study is the first to demonstrate a highly significant difference in PFT between patients with antisynthetase syndrome with 6 years of followup and healthy controls. DLCO displayed the highest difference with mean 53% lower value in the patients. FVC and DLCO correlated significantly with ILD extent, indicating these variables as appropriate outcome measures in antisynthetase syndrome-associated ILD.


Assuntos
Doenças Pulmonares Intersticiais/complicações , Pulmão/fisiopatologia , Miosite/complicações , Adulto , Estudos Transversais , Feminino , Humanos , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Miosite/diagnóstico por imagem , Miosite/fisiopatologia , Testes de Função Respiratória , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
14.
Chest ; 150(2): 299-306, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26997242

RESUMO

OBJECTIVE: Markers for early identification of progressive interstitial lung disease (ILD) in systemic sclerosis (SSc) are in demand. Chemokine CCL18, which has been linked to pulmonary inflammation, is an interesting candidate, but data have not been consistent. We aimed to assess CCL18 levels in a large, prospective, unselected SSc cohort with longitudinal, paired data sets on pulmonary function and lung fibrosis. METHODS: Sera from the Oslo University Hospital SSc cohort (n = 298) and healthy control subjects (n = 100) were analyzed for CCL18 by enzyme immunoassay. High CCL18 (>53 ng/mL) was defined using the mean value plus 2 SD in sera obtained from healthy control subjects as the cutoff. RESULTS: High serum CCL18 was identified in 35% (105 of 298). Annual decline in FVC differed significantly between high and low CCL18 subsets (13.3% and 4.7%; P = .016), as did the annual progression rate of lung fibrosis (0.9% [SD, 2.9] and 0.2% [SD, 1.9]). Highest rates of annual FVC decline > 10% (21%) and annual fibrosis progression (1.2%) were seen in patients with high CCL18 and early disease (< 3 years). In multivariate analyses, CCL18 was associated with annual FVC decline > 10% (OR, 1.1; 95% CI, 1.01-1.11) and FVC < 70% at follow-up (OR, 3.1; 95% CI, 1.08-8.83). Survival analyses showed that patients with high CCL18 had reduced 5- and 10-year cumulative survival compared with patients with low CCL18 (85% and 74%, compared with 97% and 89%, respectively; P = .001). CONCLUSIONS: The results from this prospective cohort reinforce the notion that high CCL18 may serve as a marker for early identification of progressive ILD in SSc.


Assuntos
Quimiocinas CC/imunologia , Fibrose Pulmonar/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Noruega , Prognóstico , Estudos Prospectivos , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/mortalidade , Fibrose Pulmonar/fisiopatologia , Testes de Função Respiratória , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/mortalidade , Escleroderma Sistêmico/fisiopatologia , Taxa de Sobrevida , Capacidade Vital
15.
Rheumatology (Oxford) ; 55(1): 103-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26320136

RESUMO

OBJECTIVE: MCTD is a chronic, immune-mediated disorder defined by the combined presence of serum anti-RNP antibodies and distinct clinical features, including progressive lung fibrosis. The aim of the study was to evaluate the potential impact of anti-SSA (i.e. Ro52 and Ro60) and anti-SSB autoantibodies as markers for disease outcomes in MCTD. METHODS: Stored serum samples from 113 patients included in the cross-sectional, nationwide Norwegian MCTD cohort were screened for the presence of anti-Ro52, anti-Ro60 and anti-SSB by a commercial line immunoassay. Correlation analyses were carried out with clinical parameters, including quantitative lung fibrosis scores by high-resolution CT. Lung fibrosis was defined by reticular pattern changes according to the Fleischner Society CT criteria for interstitial lung disease. RESULTS: Anti-Ro52 antibodies were present in 29%, anti-Ro60 in 19% and anti-SSB in 6% of the MCTD sera. High-resolution CT scoring identified lung fibrosis in 38 of 113 (34%) MCTD patients. Anti-Ro52 antibodies were detected in 50% (19 of 38) of the MCTD patients with lung fibrosis and in 19% (14 of 75) without lung fibrosis (P < 0.001). The odds ratio for the presence of anti-Ro52 antibodies in lung fibrosis was 4.4 (95% CI 1.8, 10.3). Anti-Ro52 antibodies were equally frequent in patients with mild to moderate (eight of 17; 44%) and severe fibrosis (11 of 21; 52%). Anti-Ro52 was not associated with any of the other clinical parameters assessed, nor was anti-Ro60 or anti-SSB. CONCLUSION: Our cross-sectional data suggest that anti-Ro52 antibodies may serve as a potential marker for lung fibrosis in MCTD.


Assuntos
Anticorpos Antinucleares/imunologia , Doença Mista do Tecido Conjuntivo/imunologia , Fibrose Pulmonar/imunologia , Ribonucleoproteínas/imunologia , Adulto , Anticorpos Antinucleares/sangue , Doença Crônica , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Mista do Tecido Conjuntivo/sangue , Doença Mista do Tecido Conjuntivo/complicações , Fibrose Pulmonar/sangue , Fibrose Pulmonar/etiologia , Estudos Retrospectivos
16.
Arthritis Res Ther ; 17: 231, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26315510

RESUMO

INTRODUCTION: Systemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are chronic immune-mediated disorders complicated by vascular organ damage. The aim of this study was to examine the serum levels of the markers of neoangiogenesis: endostatin and vascular endothelial growth factor (VEGF), in our unselected cohorts of SSc and MCTD. METHODS: Sera of SSc patients (N = 298) and MCTD patients (N = 162) from two longitudinal Norwegian cohorts were included. Blood donors were included as controls (N = 100). Circulating VEGF and endostatin were analyzed by enzyme immunoassay. RESULTS: Mean endostatin levels were increased in SSc patients 93.7 (37) ng/ml (P < .001) and MCTD patients 83.2 (25) ng/ml (P < .001) compared to controls 65.1 (12) ng/ml. Median VEGF levels were elevated in SSc patients 209.0 (202) pg/ml compared to MCTD patients 181.3 (175) pg/ml (P = .017) and controls 150.0 (145) pg/ml (P < .001). Multivariable analysis of SSc subsets showed that pulmonary arterial hypertension (coefficient 15.7, 95 % CI: 2.2-29.2, P = .023) and scleroderma renal crisis (coefficient 77.6, 95 % CI: 59.3-100.0, P < .001) were associated with elevated endostatin levels. Multivariable analyses of MCTD subsets showed that digital ulcers were associated with elevated endostatin levels (coefficient 10.5, 95 % CI: 3.2-17.8, P = .005). The risk of death increased by 1.6 per SD endostatin increase (95 % CI: 1.2-2.1, P = .001) in the SSc cohort and by 1.6 per SD endostatin increase (95 % CI: 1.0-2.4, P = .041) in the MCTD cohort after adjustments to known risk factors. CONCLUSIONS: Endostatin levels were elevated in patients with SSc and MCTD, particularly SSc patients with pulmonary arterial hypertension and scleroderma renal crisis, and MCTD patients with digital ulcers. Elevated endostatin levels were also associated with increased all-cause mortality during follow-up in both groups of patients. We propose that endostatin might indicate the degree of vascular injury in SSc and MCTD patients.


Assuntos
Endostatinas/sangue , Doença Mista do Tecido Conjuntivo/sangue , Escleroderma Sistêmico/sangue , Doenças Vasculares/sangue , Adulto , Biomarcadores/sangue , Vasos Sanguíneos/patologia , Causas de Morte , Estudos de Coortes , Feminino , Humanos , Hipertensão Pulmonar/sangue , Estimativa de Kaplan-Meier , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Doença Mista do Tecido Conjuntivo/mortalidade , Análise Multivariada , Taxa de Sobrevida , Úlcera/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto Jovem
17.
Semin Arthritis Rheum ; 45(3): 301-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26190563

RESUMO

OBJECTIVE: To utilise an exposed/unexposed cohort strategy for mortality and cancer analyses across unselected and complete cohorts of patients with idiopathic inflammatory myopathy (IIM) resident in south-east Norway (denominator population 2.6 million), between 2003 and 2012. METHOD: IIM cases were identified by comprehensive searches through patient administrative databases followed by manual chart review. Polymyositis (PM) and dermatomyositis (DM) cases were classified by the Peter and Bohan and/or Targoff diagnostic criteria and sporadic inclusion body myositis (sIBM) by the European NeuroMuscular Centre (ENMC) criteria from 1997 and/or 2011. Every patient was matched for sex, age and residential area with 15 unexposed/non-IIM individuals drawn from the national population registry. RESULTS: Total mortality in the IIM cohort was 27% (87/326). Standardized mortality rate (SMR) was higher in DM (2.6) than PM (2.4) and sIBM (1.7). IIM-related causes of death were frequent (64%) and included cancer (all IIM subsets), aspiration (sIBM), pulmonary complications (PM/DM) and infections (PM/DM). Multivariate analyses identified age at diagnosis (PM and sIBM), positive anti-SSA (PM), cancer (DM), and DLCO < 60% (DM) as independent mortality risk factors. Cancer risk was increased in DM (standard incidence rate 2.0) and PM (SIR = 1.3), but not in sIBM (SIR = 0.9). Ovarian cancer was more prevalent in DM than in the general population (8.3% vs 1.1%). CONCLUSION: Our results suggest that mortality rates and cancer risk remain elevated in DM, and to a lesser degree also in PM. Mortality rate was also increased in sIBM, but some deaths appeared to be due to potentially preventable causes.


Assuntos
Miosite/epidemiologia , Neoplasias/epidemiologia , Idoso , Bases de Dados Factuais , Dermatomiosite/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Miosite/mortalidade , Neoplasias/mortalidade , Noruega/epidemiologia , Polimiosite/epidemiologia , Risco , Taxa de Sobrevida
18.
Arthritis Rheumatol ; 67(8): 2205-12, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25916462

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) carries a high risk of progressive interstitial lung disease (ILD), but tools for stratifying individual risk are scarce. The purpose of this study was to assess detailed data from serial lung fibrosis measurements and paired pulmonary function tests (PFTs) as outcome prediction tools in a prospective cohort of SSc patients. METHODS: Paired PFTs and high-resolution computed tomography (HRCT) scans were obtained at baseline and at followup in 305 SSc patients who met the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria. The extent of fibrosis was scored on 10 sections from every HRCT scan and expressed as the percentage of the total lung volume. RESULTS: Baseline HRCT analyses revealed 3 SSc subgroups: those with >20% lung fibrosis (n = 40), those with 1-20% fibrosis (n = 157), and those with no fibrosis (n = 108). At followup HRCT (mean of 3.1 years later), all 108 group 3 patients were still free of fibrosis. In group 2 patients, 146 continued to have 1-20% fibrosis (group 2a), whereas 11 (marked by short disease duration of 1.3 years) had experienced progression to >20% fibrosis (group 2b). The annual fibrosis progression rate differed across the 4 groups: 0.9% in group 1, 0.7% in group 2a, 5.9% in group 2b, and 0% in group 3. The annual fibrosis progression rate correlated with the total decline in the forced vital capacity (FVC) (7.1%, 5.7%, 8.7%, and 2.9% in groups 1, 2a, 2b, and 3, respectively), but not the diffusing capacity for carbon monoxide (DLco) (8.4%, 7.7%, 7.7%, and 8.6%, respectively). Multivariate analyses identified anticentromere antibodies (odds ratio [OR] 4.7) and baseline DLco (OR 1.04) as predictors of no fibrosis at followup and baseline fibrosis (OR 1.3) and FVC (OR 0.96) as predictors of >20% fibrosis at followup. CONCLUSION: These prospective cohort data suggest that HRCT performed at baseline predicts the development of fibrosis, the rate of progression of fibrosis, and the decline in pulmonary function in SSc.


Assuntos
Pulmão/fisiopatologia , Fibrose Pulmonar/fisiopatologia , Escleroderma Sistêmico/fisiopatologia , Adulto , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Capacidade de Difusão Pulmonar , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/etiologia , Testes de Função Respiratória , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Capacidade Vital
19.
Rheumatology (Oxford) ; 54(8): 1420-8, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25740830

RESUMO

OBJECTIVE: To retrospectively evaluate the efficacy and safety of rituximab (Rtx) treatment in patients with anti-synthetase syndrome (ASS) and severe interstitial lung disease (ILD). METHODS: Patients with severe ILD and >12 months follow-up post-Rtx were identified from the Oslo University Hospital ASS cohort (n = 112). Clinical data, including pulmonary function tests (PFTs), were retrospectively collected from medical reports. Extent of ILD pre-, and post-Rtx was scored on thin-section high-resolution CT (HRCT) images and expressed as a percentage of total lung volume. Muscle strength was evaluated by manual muscle testing of eight muscle groups (MMT8). RESULTS: Altogether, 34/112 ASS patients had received Rtx; 24/34 had severe ILD and >12 months follow-up post-Rtx (median 52 months). In these 24 patients, the median percentage of predicted forced vital capacity, forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) increased by 24%, 22% and 17%, respectively, post-Rtx. Seven patients (all with disease duration <12 months and/or acute onset/exacerbation of ILD) had >30% improvement in all three PFTs. HRCT analysis showed a median 34% reduction in ILD extent post-Rtx. MMT8 score increased post-Rtx. During follow-up, 7/34 (21%) Rtx-treated ASS patients died; 6/7 deaths were related to infections. The mortality rate in the Rtx-treated group was comparable to that of the remaining ASS cohort (25/78 deceased; 32%). CONCLUSION: This study, which included 24 Rtx-treated ASS patients with severe ILD, reports improved PFTs after a median 52 months follow-up post-Rtx. The best outcome was observed in patients with a disease duration <12 months and/or acute onset/exacerbation of ILD. The study indicates that Rtx could be a treatment option for selected ASS patients, but infections should be given attention.


Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Antirreumáticos/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/etiologia , Miosite/complicações , Adulto , Idoso , Estudos de Coortes , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Força Muscular/fisiologia , Miosite/fisiopatologia , Testes de Função Respiratória , Estudos Retrospectivos , Rituximab , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X , Resultado do Tratamento
20.
Ann Rheum Dis ; 74(8): 1551-6, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24695011

RESUMO

OBJECTIVES: The occurrence of polymyositis (PM) and dermatomyositis (DM) in the general population is largely unknown and unbiased data on clinical and laboratory features in PM/DM are missing. Here, we aim to identify and characterise every PM/DM patient living in southeast Norway (denominator population 2.64 million), 2003-2012. METHOD: Due to the structure of the Norwegian health system, all patients with PM/DM are followed at public hospitals. Hence, all public hospital databases in southeast Norway were screened for patients having ICD-10 codes compatible with myositis. Manual chart review was then performed to identify all cases meeting the Peter & Bohan and/or Targoff classification criteria for PM/DM. RESULTS: The ICD-10 search identified 3160 potential myositis patients, but only 208/3160 patients met the Peter & Bohan criteria and 230 the Targoff criteria (100 PM, 130 DM). With 56 deaths during the observation period, point prevalence of PM/DM was calculated to 8.7/100 000. Estimated annual incidences ranged from 6 to 10 /1 000 000, with peak incidences at 50-59 (DM) and 60-69 years (PM). Myositis specific antibodies (Jo-1, PL-7, PL-12, signal recognition particle (SRP) and Mi-2) were present in 53% (109/204), while 137/163 (87%) had pathological muscle MRI. Frequent clinical features included myalgia (75%), arthritis (41%) dyspnoea (62%) and dysphagia (58%). Positive anti-Jo-1, present in 39% of DM and 22% of PM cases, was associated with dyspnoea, arthritis and mechanic hands. CONCLUSIONS: Our data indicate that the population prevalence of PM/DM in Caucasians is quite low, but underscores the complexity and severity of the disorders.


Assuntos
Dermatomiosite/epidemiologia , Polimiosite/epidemiologia , Adulto , Dermatomiosite/diagnóstico , Humanos , Noruega/epidemiologia , Polimiosite/diagnóstico , Prevalência
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