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M C Cénit, C P Simeón,
V Fonollosa,
G Espinosa,
E Beltrán,
L Sáez-Comet,
E Vicente-Rabaneda,
F J García-Hernández,
L Martínez-Estupiñán,
M Rodríguez-Carballeira, [......],
F J Narváez,
A Pros,
M Gallego,
R Ríos-Fernández,
M T Camps,
A Fernández-Nebro,
M V Egurbide,
P Carreira,
M A González-Gay,
J Martín
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ABSTRACT: Systemic sclerosis (SSc) is a complex autoimmune disease which genetic component has not been yet completely understood. IL6 encodes a cytokine with a crucial role in the development of autoimmunity and fibrosis and its actions mainly are controlled by IL-6 receptor (IL-6R). We aimed to investigate whether the functional genetic variants rs8192284 and rs2228044 previously associated with several autoimmune diseases, located within the IL-6 receptor (IL-6R) subunits IL6R and IL6ST genes, respectively, are involved in the susceptibility to SSc and/or its major clinical subphenotypes. A Spanish cohort including 1013 SSc patients and 1375 controls was genotyped using the TaqMan® allelic discrimination technology. SSc patients were subdivided according to the major clinical forms, autoantibody status and presence of fibrotic lung affection. Our data showed no influence of the selected variants in global SSc susceptibility (rs8192284: P=0.67, odds ratios (OR)=0.98; rs2228044: P=0.99, OR=1.00). Similarly, the clinical/autoantibody subphenotype analyses did not yielded significant results. Our data suggest that the analyzed polymorphisms may not play a significant role in the SSc susceptibility.
Tissue Antigens 06/2012; 80(3):254-8. · 2.59 Impact Factor
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J-E Martin,
F D Carmona,
J C A Broen, C P Simeón,
M C Vonk,
P Carreira,
R Ríos-Fernández,
G Espinosa,
E Vicente-Rabaneda,
C Tolosa, [......],
Ø Palm,
M M Chee,
J M van Laar,
C Denton,
A Herrick,
J Worthington,
B P C Koeleman,
T R D J Radstake,
C Fonseca,
J Martín
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ABSTRACT: Regulatory T cells (T(regs)) are crucial in the maintenance of the immune tolerance and seem to have an important role in systemic sclerosis (SSc). The interleukin 2 receptor α (IL2RA) is an important T(reg) marker, and polymorphisms of IL2RA gene are associated with a number of autoimmune diseases. Therefore, we aimed to investigate for the first time the association of the IL2RA locus in SSc. For this purpose, a total of 3023 SSc patients and 2735 matched healthy controls, from six European Caucasian cohorts, were genotyped for the IL2RA gene variants rs11594656, rs2104286 and rs12722495 using the TaqMan allelic discrimination technology. The overall meta-analysis reached statistical significance when the three polymorphisms were tested for association with SSc, the limited subtype (lcSSc) and anti-centromere auto-antibodies (ACAs). However, no significant P-values were obtained when the ACA-positive patients were removed from the SSc and lcSSc groups, suggesting that these associations rely on ACA positivity. The strongest association signal with ACA production was detected for rs2104286 (P(FDR)=2.07 × 10(-4), odds ratio=1.30 (1.14-1.47)). The associations of rs11594656 and rs12722495 were lost after conditioning to rs2104286, and allelic combination tests did not evidence a combined effect, indicating that rs2104286 best described the association between IL2RA and ACA presence in SSc.
Genes and immunity 02/2012; 13(2):191-6. · 4.22 Impact Factor
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J C A Broen,
L Bossini-Castillo,
L van Bon,
M C Vonk,
H Knaapen,
L Beretta,
B Rueda,
R Hesselstrand,
A Herrick,
J Worthington, [......],
G Riemekasten,
H P Kiener,
R Scorza, C P Simeón,
N Ortego-Centeno,
M A Gonzalez-Gay,
P Airò,
M J H Coenen,
J Martín,
T R D J Radstake
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ABSTRACT: To investigate whether polymorphisms in Toll-like receptor (TLR) genes, previously reported to be associated with immune-mediated diseases, are involved in systemic sclerosis (SSc).
We genotyped 14 polymorphisms in the genes for TLRs 2, 4, 7, 8, and 9 in a discovery cohort comprising 452 SSc patients and 537 controls and a replication cohort consisting of 1,170 SSc patients and 925 controls. In addition, we analyzed 15-year followup data on 964 patients to assess the potential association of TLR variants with the development of disease complications. We analyzed the functional impact of the associated polymorphism on monocyte-derived dendritic cells.
In the discovery cohort, we observed that a rare functional polymorphism in TLR2 (Pro631His) was associated with antitopoisomerase (antitopo) positivity (odds ratio 2.24 [95% confidence interval 1.24-4.04], P=0.003). This observation was validated in the replication cohort (odds ratio 2.73 [95% confidence interval 1.85-4.04], P=0.0001). In addition, in the replication cohort the TLR2 variant was associated with the diffuse subtype of the disease (P=0.02) and with the development of pulmonary arterial hypertension (PAH) (Cox proportional hazards ratio 5.61 [95% confidence interval 1.53-20.58], P=0.003 by log rank test). Functional analysis revealed that monocyte-derived dendritic cells carrying the Pro63His variant produced increased levels of inflammatory mediators (tumor necrosis factor α and interleukin-6) upon TLR-2-mediated stimulation (both P<0.0001).
Among patients with SSc, the rare TLR2 Pro631His variant is robustly associated with antitopoisomerase positivity, the diffuse form of the disease, and the development of PAH. In addition, this variant influences TLR-2-mediated cell responses. Further research is needed to elucidate the precise role of TLR-2 in the pathogenesis of SSc.
Arthritis & Rheumatism 09/2011; 64(1):264-71. · 7.87 Impact Factor
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B Rueda,
P Gourh,
J Broen,
S K Agarwal, C Simeon,
N Ortego-Centeno,
M C Vonk,
M Coenen,
G Riemekasten,
N Hunzelmann, [......],
T Nearney,
D Hilda,
M A Gónzalez-Gay,
P Airo,
L Beretta,
R Scorza,
T R D J Radstake,
M D Mayes,
F C Arnett,
J Martin
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ABSTRACT: To investigate the possible association of the BANK1 gene with genetic susceptibility to systemic sclerosis (SSc) and its subphenotypes.
A large multicentre case-control association study including 2380 patients with SSc and 3270 healthy controls from six independent case-control sets of Caucasian ancestry (American, Spanish, Dutch, German, Swedish and Italian) was conducted. Three putative functional BANK1 polymorphisms (rs17266594 T/C, rs10516487 G/A, rs3733197 G/A) were selected as genetic markers and genotyped by Taqman 5 allelic discrimination assay.
A significant association of the rs10516487 G and rs17266594 T alleles with SSc susceptibility was observed (pooled OR=1.12, 95% CI 1.03 to 1.22; p=0.01 and pooled OR=1.14, 95% CI 1.05 to 1.25; p=0.003, respectively), whereas the rs3733197 genetic variant showed no statistically significant deviation. Stratification for cutaneous SSc phenotype showed that the BANK1 rs10516487 G, rs17266594 T and rs3733197 G alleles were strongly associated with susceptibility to diffuse SSc (dcSSc) (pooled OR=1.20, 95% CI 1.05 to 1.37, p=0.005; pooled OR=1.23, 95% CI 1.08 to 1.41, p=0.001; pooled OR=1.15, 95% CI 1.02 to 1.31, p=0.02, respectively). Similarly, stratification for specific SSc autoantibodies showed that the association of BANK1 rs10516487, rs17266594 and rs3733197 polymorphisms was restricted to the subgroup of patients carrying anti-topoisomerase I antibodies (pooled OR=1.20, 95% CI 1.02 to 1.41, p=0.03; pooled OR=1.24, 95% CI 1.05 to 1.46, p=0.01; pooled OR=1.26, 95% CI 1.07 to 1.47, p=0.004, respectively).
The results suggest that the BANK1 gene confers susceptibility to SSc in general, and specifically to the dcSSc and anti-topoisomerase I antibody subsets.
Annals of the rheumatic diseases 10/2009; 69(4):700-5. · 8.11 Impact Factor
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ABSTRACT: To determine survival and mortality in a cohort of Spanish patients with scleroderma (systemic sclerosis, SSc) and to analyse whether survival is influenced by demographic, clinical or immunological variables or the extent of skin involvement.
The study included 79 patients diagnosed with SSc and taking part in a study to determine the extent of sclerosis, visceral involvement and immunological alterations. We studied the number of observed and expected deaths (the expected number being based on age- and sex-specific rates in the background population) and derived standardized mortality ratios with their 95% confidence intervals (CI). Cumulative survival after onset of the first symptom was estimated according to the Kaplan-Meier method. The Cox method was used to identify the prognostic factors.
The mortality rate was 0.0249 deaths per person-year. Survival at 15 yr was 0.62 (95% CI 0.410-0.778). The standardized mortality ratio was 429.4% (95% CI 222-750). On crude analysis, lung involvement [forced vital capacity (FVC) <70%, pulmonary hypertension], SSc renal crisis, an active capillaroscopic pattern, pericardial effusion and age over 60 yr at diagnosis were associated with shorter survival. On multivariate analysis, only age at diagnosis over 60 yr, FVC <70% and SSc renal crisis were independent prognostic factors.
The mortality rate associated with SSc showed a four-fold increase compared with the background population. Lung involvement and sclerodermal renal crisis were found to be independently associated with reduced survival.
Rheumatology 01/2003; 42(1):71-5. · 4.06 Impact Factor
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ABSTRACT: The objective of this study was to investigate the presence of nailfold capillary abnormalities and extrahepatic signs of connective tissue disease in patients with primary biliary cirrhosis (PBC), as compared to patients with other chronic liver diseases. We evaluated 22 patients with PBC and 15 patients with other chronic liver diseases as a control group. Nailfold capillaroscopy was performed by two observers blinded to clinical findings using a Wild M3 stereomicroscope with an Intralux 5000 Volpi cold light lamp. We detected nailfold capillary abnormalities in 20 out of 22 (91%) PBC patients. Twelve of these 20 patients (54%) showed capillary alterations characteristic of systemic sclerosis. In the control group only two out of 15 patients (13%) presented alterations and in both cases they were a non-specific type. The presence of nailfold capillary abnormalities was significantly greater in PBC patients than in the control group (P < 0.001). Eleven out of the 22 PBC patients (50%) had extrahepatic signs of connective tissue disease and most of them were related to systemic sclerosis; patients with other chronic liver diseases did not present rheumatic manifestations (P < 0.001). In PBC patients there was a significant association between systemic sclerosis capillary pattern and rheumatic manifestations (P < 0.03). The high prevalence of nailfold capillary abnormalities characteristic of systemic sclerosis in patients with PBC and the correlation with sclerodermal manifestations suggests that this capillaroscopic finding could be a useful indicator to investigate rheumatic manifestations in these patients.
Lupus 02/2001; 10(9):628-31. · 2.34 Impact Factor
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ABSTRACT: To describe the outcome of the pregnancy in patients with scleroderma.
Patients with scleroderma and control group were included in this retrospective study. Two groups were different in pregnant patients with scleroderma: pregnancy before scleroderma (A1) and pregnancy after scleroderma (A2). The presence of clinical problems during pregnancy and the outcome of scleroderma were collected in a questionnaire. Differences in the frequencies of complications were analyzed using the U Mann-Whitney, the chi-square or Fisher's exact test when necessary.
The frequency of global fetal complications was increased in patients group, but there was no significantly increased frequency when variables were analyzed independently: number of births, miscarriages, fetal deaths, preterm births and low weight full term babies. There was no increased frequency of renal crisis, hypertension or eclampsia. Differences between diffuse and limited subsets were no observed. Improvement of scleroderma was seen in only 3 patients and worsening of skin thickening was experienced by 2 patients.
The pregnant scleroderma patients are a group with high risk pregnancies and therefore well-supervised pregnancies are necessary.
Medicina Clínica 01/2000; 113(20):761-4. · 1.38 Impact Factor
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British journal of rheumatology 10/1996; 35(9):910-1.
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ABSTRACT: To assess cardiovascular abnormalities in patients with limited systemic sclerosis (SSc), using noninvasive cardiac techniques.
Sixty-three patients with limited SSc were prospectively evaluated with Doppler echocardiography and thallium-201 perfusion scintigraphy after a cold-stress test and radionuclide ventriculography.
In the patients with limited SSc, there was a significantly high prevalence of abnormal left- and right-diastolic function parameters (P = 0.001 and P = 0.0002, respectively), thickening of papillary muscles (46%; P = 0.003), and mild mitral regurgitation (49%; P < 0.0001), compared with controls. Systolic pulmonary arterial hypertension was detected in 9 patients (14%), and pericardial effusion in 11 patients (18%). In 64% of patients with limited SSc, an ischemic response was detected on the thallium cold-stress scan; similarly, an ischemic response was detected in 57% of patients with primary Raynaud's phenomenon (P < 0.0001 versus controls).
Although the frequency of cardiovascular symptoms was low in patients with limited SSc, a significant rate of cardiovascular abnormalities was found by noninvasive cardiac techniques.
Arthritis & Rheumatism 08/1996; 39(7):1138-45. · 7.87 Impact Factor
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The American Journal of Gastroenterology 05/1996; 91(4):826-7. · 7.28 Impact Factor
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ABSTRACT: The presence of anticardiolipin antibodies (aCL), von Willebrand factor activity and platelet function was studied in 35 patients with systemic sclerosis (SSc) scleroderma and 22 healthy controls. aCL positivity was observed in no patient with SSc or controls, whereas beta-thromboglobulin and platelet factor 4 levels were significantly higher in patients with SSc (p less than 0.001 and p less than 0.002, respectively). Furthermore, plasma from patients with SSc had a greater degree of aggregation to adenosine diphosphate 1 microM (p less than 0.05) but not to collagen or arachidonic acid. The plasma of patients with scleroderma also had increased von Willebrand factor activity compared with controls (p less than 0.001). We conclude that aCL appears not to play a central role in the pathogenesis of vascular and hemostatic alterations in SSc.
The Journal of Rheumatology 01/1992; 18(12):1833-6. · 3.69 Impact Factor
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ABSTRACT: The changes of nailfold capillaries detected by capillary microscopy is a characteristic frequently observed in systemic sclerosis. The relationship between the different capillary microscopic changes and clinical manifestation, organic disease and disease progression were studied.
Sixty-three patients were studied in whom capillary microscopy was performed and organic disease was determined by analytical and morphological examination. The presence of association between the capillary microscopic signs and clinical manifestation and disease progression were investigated by the chi-square and Fisher tests.
Capillary microscopic alterations were found in 95% of the patients. The extense capillary loss was associated as statistically significant to the diffuse form of scleroderma. Statistically significant associations were not found between the different capillary microscopic signs and disease progression and organic disease (global and individual per each organ).
Although capillary microscopic changes are present in most scleroderma patients they are not useful in the evaluation of organ involvement of the disease. The presence of extense capillary loss is linked to worse prognosis in its association to the diffuse form of scleroderma.
Medicina Clínica 12/1991; 97(15):561-4. · 1.38 Impact Factor
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ABSTRACT: We evaluated platelet function in 59 patients with Raynaud's phenomenon (RP): 24 had primary RP (PRP) and in 35 RP was associated with diffuse scleroderma (DS). In the group with PRP there were 10 males and 14 females, with a mean age of 43 +/- 12 years and a time of evolution of 5 +/- 5 years. In the group with RP associated with DS there were 31 females and 4 males with a mean age of 53 +/- 12 years and a time of evolution of 9 +/- 7 years. The control group consisted of 20 healthy individuals (14 males and 6 females with a mean age of 40 +/- 12 years). In all patients and controls beta-thromboglobulin (BTG) and platelet factor 4 (PF4) levels were measured in plasma, and platelet aggregation was evaluated in the presence of adenosine diphosphate (ADP), collagen and arachidonic acid. The patients with RP associated with DS had BTG and PF4 higher than those with PRP and controls (p less than 0.02). The BTG/PF4 ratio was also significantly greater in patients with DS (p less than 0.005). The platelets from patients with DS had a greater aggregation with ADP (1 microM and 0.5 microM) than those from PRP (p less than 0.03). We concluded that patients with RP associated with DS had in vivo activation and a greater aggregation of platelets, in contrast with the absence of these findings in the group with PRP and in controls.
Medicina Clínica 01/1991; 95(20):761-3. · 1.38 Impact Factor
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Medicina Clínica 12/1990; 95(15):598. · 1.38 Impact Factor
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Medicina Clínica 08/1990; 95(6):234. · 1.38 Impact Factor
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Medicina Clínica 06/1990; 94(18):719. · 1.38 Impact Factor
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Medicina Clínica 03/1990; 94(4):158-9. · 1.38 Impact Factor
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Clinical and experimental rheumatology 14(2):222. · 2.15 Impact Factor
