Jose A. Miranda-Filloy

Insulin resistance in rheumatoid arthritis: the impact of the anti‐TNF‐α therapy

Increased prevalence of insulin resistance has been observed in patients with rheumatoid arthritis (RA). High‐grade systemic inflammation is implicated in the development of insulin resistance in these patients. Tumor necrosis factor (TNF)‐α is a potent proinflammatory cytokine that plays a role in the initiation and progression of inflammation and the mechanisms associated with accelerated atherosclerosis in RA. In assessing data immediately prior to and after intravenous infusion of the anti‐TNF‐α monoclonal antibody‐infliximab in RA patients on period treatment with this drug attributable to disease refractory to conventional disease‐modifying antirheumatic drugs, a dramatic improvement of insulin resistance and insulin sensitivity was observed. A long‐term positive effect of TNF‐α antagonists infliximab and etanercept on insulin resistance in RA patients with severe disease was also reported. These results highlight the importance of therapies that act blocking TNF‐α function to reduce the mechanisms implicated in the development of the metabolic syndrome observed in RA.

The high prevalence of subclinical atherosclerosis in patients with ankylosing spondylitis without clinically evident cardiovascular disease.

We conducted the present study to determine whether subclinical macrovascular atherosclerotic disease was present in patients with ankylosing spondylitis (AS) without clinical history of cardiovascular disease. We also sought to establish whether demographic or clinical features of the disease may influence the development of subclinical atherosclerotic disease in a series of patients with AS seen at a community hospital. We recruited 64 patients who fulfilled the modified New York diagnostic criteria for AS from Hospital Xeral-Calde, Lugo, Spain. We excluded patients seen during the recruitment period who had cardiovascular disease or renal insufficiency. We also studied 64 matched controls. Carotid artery intima-media thickness (IMT) and carotid plaques were measured in the right common carotid artery. The study was performed using high-resolution B-mode ultrasound. Patients with AS exhibited greater carotid IMT than did matched controls (mean ± SD, 0.74 ± 0.21 mm vs. 0.67 ± 0.14 mm; p = 0.01; differences of means, 0.077; 95% confidence interval, 0.016-0.139). Carotid plaques were more commonly observed in patients with AS than in controls (19 [29.7%] vs. 6 [9.4%], respectively; p = 0.03). The best predictors for carotid plaques in patients with AS were erythrocyte sedimentation rate (ESR) at time of disease diagnosis (odds ratio [OR], 1.18; 95% confidence intervals [CI], 1.04-1.33; p = 0.01) and duration of disease (OR, 1.39; 95% CI, 1.01-1.92; p = 0.05). In contrast, there was no significant correlation between carotid IMT and either ESR or C-reactive protein in this study. Results of the present study show that patients with AS without clinically evident cardiovascular disease have a high prevalence of subclinical macrovascular disease in the form of increased carotid IMT and carotid plaques compared to matched controls. Abbreviations: AS = ankylosing spondylitis, BASDAI = Bath Ankylosing Spondylitis Disease Activity Index, BASFI = Bath Ankylosing Spondylitis Functional Index, CI = confidence intervals, CRP = C-reactive protein, ESR = erythrocyte sedimentation rate, IMT = intima-media thickness, IQ = interquartile, NSAID = nonsteroidal antiinflammatory drug, OR = odds ratio, RA = rheumatoid arthritis, SD = standard deviation, TNF = tumor necrosis factor.

Strokes at Time of Disease Diagnosis in a Series of 287 Patients With Biopsy-Proven Giant Cell Arteritis

Abstract Patients with giant cell arteritis (GCA) generally present with cranial ischemic manifestations that are directly related to vascular involvement. They may also experience strokes in the territory of the carotid or the vertebrobasilar artery. We conducted the current study to assess the frequency and predictors of strokes in general, and of vertebrobasilar stroke in particular, at the time of diagnosis in a series of 287 consecutive patients with biopsy-proven GCA diagnosed over a 27-year period at the single hospital for a well-defined population of northwestern Spain. During the study period, 8 (2.8%) patients had strokes (1 in the carotid and 7 in the vertebrobasilar territory) between the onset of symptoms of the disease and 4 weeks after the onset of corticosteroid therapy. Six of the 7 patients with vertebrobasilar stroke were men. In most cases the vertebrobasilar stroke occurred after the onset of corticosteroid therapy. Smoking history was more common among patients with vertebrobasilar stroke (p = 0.01). Patients with vertebrobasilar stroke more commonly had permanent visual loss due to arteritic involvement of ophthalmic branches derived from the internal carotid (3/7; 42.9%) than the rest of GCA patients (33/280; 11.8%) (p = 0.05). Patients with strokes had higher hemoglobin values (13.2 ± 1.5 g/dL) than patients without (11.7 ± 1.6 g/dL) (p = 0.009). Moreover, only 1 (14.3%) of the 7 patients with vertebrobasilar stroke had anemia compared to 157 (56.1%) of the remaining 280 patients (p = 0.05). The best predictors of stroke were permanent visual loss (odds ratio [OR], 5.42) and arterial hypertension (OR, 5.06). In contrast, women (OR, 0.10) and patients with anemia at the time of disease diagnosis (OR, 0.11) had a significantly reduced risk of suffering strokes. Smoking history was the best positive predictor of vertebrobasilar stroke (OR, 5.22). In contrast, a reduced risk of suffering vertebrobasilar strokes was found in individuals who had anemia at the time of GCA diagnosis (OR, 0.13). Results of the current study show an increased risk of strokes, in the vertebrobasilar territory in particular, at the time of GCA diagnosis. Patients with biopsy-proven GCA and traditional cardiovascular risk factors or permanent visual loss have an increased risk of suffering strokes. Results also suggest a potential protective role of anemia against the development of these cerebrovascular complications. Abbreviations: CI = confidence intervals, CT = computed tomography, ESR = erythrocyte sedimentation rate, GCA = giant cell arteritis, IR = incidence ratio, MRI = magnetic resonance imaging, OR = odds ratio, PMR = polymyalgia rheumatica, RD = risk difference, TIA = transient ischemic attack, VEGF = vascular endothelial growth factor.

Giant cell arteritis in northwestern Spain: a 25-year epidemiologic study.

To continue our investigation of the epidemiology of giant cell arteritis (GCA) in southern Europe, we assessed the potential presence of trends, peaks, and fluctuations in the incidence of this vasculitis over a 25-year period in the Lugo region of northwestern Spain. We also sought to determine whether changes in the clinical spectrum of the disease existed. From 1981 to 2005, biopsy-proven GCA was diagnosed in 255 Lugo residents. The age- and sex-adjusted annual incidence rate was 10.13 (95% confidence interval [CI], 8.93-11.46) per 100,000 population aged 50 years and older. The mean age ± SD at the time of diagnosis was 75.0 ± 6.9 years. The annual incidence rate in women (10.23; 95% CI, 8.60-12.08) was slightly greater than that in men (9.92; 95% CI, 8.19-11.89) (p = 0.15). The annual incidence rate increased with advancing age up to a maximum of 23.16 (95% CI, 19.52-27.28) in the 70-79 year age-group. A progressive increase in the incidence was observed from 1981 through 2000 (p = 0.001). However, the age- and sex-adjusted incidence rate for biopsy-proven GCA in the Lugo region did not show peaks in the annual incidence of GCA. Likewise, we observed no seasonal pattern for the diagnosis of the disease. Visual ischemic manifestations and irreversible visual loss were observed in 57 (22.4%) and 32 (12.5%) of the 255 patients, respectively. A negative trend manifested by a progressive decline in the number of patients with visual ischemic manifestations (p = 0.021) or permanent visual loss (p = 0.018) was found over the 25-year period of study. The decline in the frequency of visual manifestations of GCA could not be attributed to a shorter delay to diagnosis, as no significant differences were observed when the delays to diagnosis in the 5 consecutive 5-year periods were compared. In conclusion, the current study confirms a progressive increase in the incidence of biopsy-proven GCA in northwestern Spain, and suggests that there has been a change in the clinical spectrum of the disease. Abbreviations: CI = confidence intervals, ESR = erythrocyte sedimentation rate, GCA = giant cell arteritis, OR = odds ratio, PMR = polymyalgia rheumatica, SD = standard deviation, TAB = temporal artery biopsy.

Systemic Sclerosis in Northwestern Spain : A 19-year Epidemiologic Study

To investigate the epidemiology of systemic sclerosis (SSc) in southern Europe, we assessed the incidence, prevalence, clinical spectrum, and survival of patients diagnosed with SSc in the Lugo region of northwestern Spain. Between January 1988 and December 2006, SSc was diagnosed in 78 Lugo residents according to the criteria proposed by LeRoy and Medsger and/or the 1980 American College of Rheumatology (ACR) preliminary criteria for the classification of SSc. However, only 44 (56.4%) of the 78 patients fulfilled the 1980 ACR criteria for the classification of SSc. The mean age at the time of disease diagnosis was 59.8 ± 13.3 years. Twenty-three (29.5%) met definitions for diffuse SSc (dSSc), and 55 (70.5%) for limited SSc (lSSc). Patients with lSSc had a longer disease duration before the diagnosis (10.2 ± 12.0 yr) than those with dSSc (3.7 ± 3.2yr) (p < 0.001). Based on the criteria proposed by LeRoy and Medsger and/or the 1980 ACR criteria for the classification of SSc, the overall age- and sex-adjusted annual incidence rate over the 19-year study period was 2.3 (95% confidence interval [CI], 1.6-2.5) per 100,000 population aged 15 yr and older (women: 3.5 [95% CI, 2.3-3.9]; men: 1.0 [95% CI, 0.5-1.4]; p < 0.001). Using only the 1980 ACR criteria for SSc, the total annual-adjusted incidence rate was 1.2 (95% CI, 0.9-1.6) per 100,000 population aged 15 years and older (women: 1.8 [95% CI, 1.2-2.5]; men: 0.7 [95% CI, 0.3-1.2]; p < 0.001). The incidence increased significantly in individuals aged 45 years or older. The overall incidence rates of SSc increased over the length of the study (p for trend in the total incidence < 0.001). This was mainly due to a progressive increase of SSc in women between 1993 and 2002. By December 31, 2006, the overall age-adjusted SSc prevalence in the Lugo region of patients who met the criteria proposed by LeRoy and Medsger and/or the 1980 ACR criteria was 27.7 (95% CI, 21.1-35.84) per 100,000 population aged 15 years and older. Cardiopulmonary complications were the leading cause of death (13 of 20 cases). Compared with that in the general population, the probability of survival in patients with SSc was significantly reduced (p < 0.001). The current study establishes a baseline estimate of the incidence and clinical spectrum of SSc in northwestern Spain. According to our results, the incidence and prevalence of SSc in northwestern Spain are similar to those found in Greece and some regions of the United States. Our data confirm a reduced probability of survival in patients with SSc. Abbreviations: ACR = American College of Rheumatology, ANA = antinuclear antibodies, CI = confidence intervals, dSSc = diffuse systemic sclerosis, IIF = indirect immunofluorescence, lSSc = limited systemic sclerosis, lcSSc = limited cutaneous scleroderma, NDI = National Death Index, RP = Raynaud phenomenon, SD = standard deviation, SSc = systemic sclerosis.

A1298C polymorphism in the MTHFR gene predisposes to cardiovascular risk in rheumatoid arthritis

IntroductionWe determined the contribution of the methylene tetrahydrofolate reductase (MTHFR) 677 C>T and 1298 A>C gene polymorphisms to the susceptibility to rheumatoid arthritis (RA). We also assessed whether these two MTHFR gene polymorphisms may be implicated in the development of cardiovascular (CV) events and subclinical atherosclerosis manifested by the presence of endothelial dysfunction, in a series of Spanish patients with RA.MethodsSix hundred and twelve patients fulfilling the 1987 American College of Rheumatology classification criteria for RA, seen at the rheumatology outpatient clinics of Hospital Xeral-Calde, Lugo and Hospital San Carlos, Madrid, were studied. Patients and controls (n = 865) were genotyped using predesigned TaqMan SNP genotyping assays.ResultsNo significant differences in allele or genotype frequencies for the MTHFR gene polymorphisms between RA patients and controls were found. Also, no association between the MTHFR 677 C>T polymorphism and CV events or endothelial dysfunction was observed. However, the MTHFR 1298 allele C frequency was increased in patients with CV events after 5 years (38.7% versus 30.3%; odds ratio = 1.45; 95% confidence interval = 1.00 to 2.10; P = 0.04) and 10 years (42.2% versus 31.0%; odds ratio = 1.62; 95% confidence interval = 1.08 to 2.43; P = 0.01) follow up. Moreover, patients carrying the MTHFR 1298 AC and CC genotypes had a significantly decreased flow-mediated endothelium-dependent vasodilatation (4.3 ± 3.9%) compared with those carrying the MTHFR 1298 AA genotype (6.5 ± 4.4%) (P = 0.005).ConclusionsOur results show that the MTHFR 1298 A>C gene polymorphism confers an increased risk for subclinical atherosclerosis and CV events in patients with RA.

Relapses and Recurrences in Giant Cell Arteritis: A Population-based Study of Patients With Biopsy-proven Disease From Northwestern Spain

We conducted the present study to determine the incidence of disease flares (relapses and recurrences) in a series of patients with biopsy-proven giant cell arteritis (GCA). We assessed a series of 174 patients who were diagnosed with biopsy-proven GCA, uniformly treated, and followed at the rheumatology division of Hospital Xeral-Calde (Lugo, Spain), the single rheumatology division for a well-defined population. All of them were followed for at least 1 year after the disease diagnosis. Seventy-one (40.8%) experienced relapses or recurrences of the disease. Patients who had relapses or recurrences did not show clinical differences when compared with the remaining biopsy-proven GCA patients. However, the total duration of corticosteroid therapy was significantly longer in those patients who had relapses or recurrences of the disease. The median dose of prednisone and the median duration of corticosteroid treatment at the time of the first relapse were 5 mg/d and 16 months, respectively. Headache (52%) was the most common feature at the time of the first relapse. Polymyalgia rheumatica manifestations occurred in 30% of the patients at that time. However, none of them developed visual loss. Thirty-two patients experienced recurrences of the disease when prednisone dose had been discontinued. The median time from the disease diagnosis to the time of the recurrence was 23 months. The presence of anemia (hemoglobin <12 g/dL) at the time of disease diagnosis was the best predictor of relapses or recurrences of GCA (odds ratio, 2.17; 95% confidence interval, 1.02-4.62; p = 0.04). The results from the present study confirm that relapses and recurrences are frequent in homogenously treated patients with biopsy-proven GCA. A chronic inflammatory response manifested by anemia at the time of disease diagnosis may predict the development of disease flares.Abbreviations: CI = confidence interval, ESR = erythrocyte sedimentation rate, GCA = giant cell arteritis, IL = interleukin, IQR = interquartile range, OR = odds ratio, PMR = polymyalgia rheumatica, SD = standard deviation.

NFKB1-94ATTG ins/del polymorphism (rs28362491) is associated with cardiovascular disease in patients with rheumatoid arthritis

INTRODUCTION Rheumatoid arthritis (RA) is an inflammatory disease associated with increased cardiovascular (CV) mortality. A recent study has disclosed association between NFKB1-94ATTG ins/del polymorphism and higher risk of coronary heart disease in healthy Caucasians. Because of that, we assessed the influence of this polymorphism in the risk of CV disease in RA patients. MATERIAL AND METHODS 1437 Spanish patients with RA were genotyped for the NFKB1-94ATTG ins/del polymorphism. Two hundred and seventy-one of them (18.8%) had experienced CV events. RESULTS After adjusting for sex, age at RA diagnosis and traditional CV risk factors RA patients carrying the NFKB1 del/del genotype had higher risk of CV events than those with ins/ins genotype (Hazard ratio [HR] = 1.76, 95% CI: 1.05-2.97, p = 0.03), while heterozygous patients had an intermediate (but non-significant) risk (HR = 1.31, 95% CI: 0.90-1.92, p = 0.16). CONCLUSION Our results suggest that NFKB1-94ATTG ins/del polymorphism is associated with CV disease in patients with RA.

Systemic lupus erythematosus in northwestern Spain: a 20-year epidemiologic study.

To further investigate the epidemiology of systemic lupus erythematosus (SLE) in southern Europe, we assessed the incidence, prevalence, clinical spectrum of the disease, flares, and survival of patients diagnosed with SLE in the Lugo region of northwestern Spain. Between January 1987 and December 2006, 150 Lugo residents were diagnosed as having SLE according to the 1982 American College of Rheumatology criteria for the classification of SLE. Women outnumbered men (127 [84.7%] vs. 23 [15.3%]). The mean age at the time of disease diagnosis was 46.1 ± 19.6 years. The mean follow-up from the time of disease diagnosis was 7.8 ± 4.5 years. The age- and sex-adjusted annual incidence rate over the 20-year study period was 3.6 (95% confidence interval [CI], 3.0-4.2) per 100,000 population aged 15 years and older. The overall annual incidence rate over the 20-year study period in women (5.9/100,000 population aged ≥15 yr; 95% CI, 4.9-7.0) was higher than in men (1.1/100,000 population aged ≥15 yr; 95% CI, 0.7-1.7) (p < 0.001). By December 31, 2006, the overall age-adjusted SLE prevalence in the Lugo region for patients who fulfilled at least 4 of 1982 American College of Rheumatology criteria was 17.5 per 100,000 population aged 15 years and older (95% CI, 12.6-24.1). Prevalence in women (29.2/100,000 population aged ≥15 yr; 95% CI, 20.0-40.7) was higher than in men (5.8/100,000 population aged ≥15 yr; 95% CI, 2.0-12.0).The most frequent clinical manifestation was arthritis. As reported in population-based studies on SLE patients of European descent, renal disease was observed in only 27.3% of the patients. The rate of flares was 0.084/year. A younger age and the presence of nephritis at the time of disease diagnosis were associated with the development of flares during the follow-up of Lugo patients. Compared with the general population the probability of survival in patients with SLE was significantly reduced (p = 0.04).In conclusion, the present study establishes a baseline estimate of the incidence and clinical spectrum of SLE in northwestern Spain. According to our results, the incidence of SLE in northwestern Spain is slightly higher than that reported in most European regions. Patients with SLE from northwestern Spain have a later average age onset and a lower frequency of nephritis than in the African-American population. However, our data show a reduced probability of survival in Spanish patients with SLE.Abbreviations: ACR = American College of Rheumatology, ANA = antinuclear antibody, CI = confidence interval, IIF = indirect immunofluorescence, OR = odds ratio, SD = standard deviation, SLE = systemic lupus erythematosus.

Asymptomatic Hyperuricemia and Serum Uric Acid Concentration Correlate with Subclinical Atherosclerosis in Psoriatic Arthritis Patients Without Clinically Evident Cardiovascular Disease

OBJECTIVE To establish whether serum uric acid concentration correlates with carotid intima-media wall thickness (IMT) in a cohort of psoriatic arthritis (PsA) patients without overt cardiovascular (CV) disease or classic CV risk factors who attended a community hospital. METHODS A series of 52 PsA patients were assessed by carotid ultrasonography. Carotid IMT and carotid plaques were measured in the right common carotid artery. A correlation between serum uric acid concentration and carotid IMT was assessed and receiver operating characteristic curves to evaluate the ability of serum uric acid to predict carotid IMT > 0.90 mm and carotid plaques were performed. RESULTS PsA patients with hyperuricemia (n = 6 [11.5%]) had greater carotid IMT (mean +/- standard deviation: 0.89 +/- 0.20 mm) than those without hyperuricemia (n = 46 [89%]; 0.67 +/- 0.16 mm) (P = 0.01). Patients with carotid IMT < 0.60 mm had lower mean serum uric acid levels (4.7 +/- 1.2 mg/dL) than those with greater carotid IMT (5.3 +/- 1.7 mg/dL for patients with carotid IMT 0.76-0.90 mm and 6.4 +/- 1.3 mg/dL for those with carotid IMT > 0.90 mm; P for trend = 0.02). A significant correlation between carotid IMT and serum uric acid concentration was observed (r = 0.337; P = 0.01). High serum uric acid levels were associated with an increased risk of having carotid IMT > 0.90 mm (Odds ratio = 2.66 [95% confidence interval: 1.08-6.53], P = 0.03, area under receiver operating characteristic curve: 0.80) or with the presence of carotid plaques (Odds ratio = 1.85 [95%; confidence interval: 1.01-3.38], P = 0.05, area under receiver operating characteristic curve: 0.72). CONCLUSIONS In PsA patients without clinically evident CV disease there is a correlation between serum uric acid concentration and subclinical atherosclerosis.