Lack of association between interleukin-6 promoter polymorphism at position -174 and Henoch-Schönlein pur pura.

OBJECTIVE: To assess whether polymorphism of the interleukin (IL)-6 gene at the position -174 was implicated in the incidence of Henoch-Schönlein pur-pura (HSP). A further objective was to determine if any relationship existed with severe systemic complications of HSP, in particular with severe renal and gastrointestinal involvement. METHODS: Unselected patients from Northwest Spain with primary cutaneous vasculitis classified as HSP according to proposed criteria were studied. All patients included in the present study were required to have had at least 2 year's follow-up. Patients and controls were genotyped for a single biallelic (G/C) nucleotide polymorphism in the promoter region at the position -174 of the IL-6 gene by a polymerase reaction chain-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Forty-six Caucasian HSP patients and 124 healthy matched controls were studied. No allele or genotype differences between the whole group of HSP and controls were observed. This was also the case when HSP patients were stratified by the presence of gastrointestinal complications, nephritis, and permanent renal involvement (renal sequelae). CONCLUSION: The polymorphism in IL-6 gene promoter (-174 G/C) does not appear to be a genetic risk factor for HSP in Northwest Spain.

Contribution of MHC class I region to genetic susceptibility for giant cell arteritis.

OBJECTIVE: The aim of this study was to assess the potential contribution of HLA-class I MICA and HLA-B gene polymorphisms towards the pathogenesis of giant cell arteritis (GCA). METHODS: Ninety-eight biopsy-proven GCA patients and 225 ethnically matched controls from Lugo, Northwest Spain, were genotyped for the MICA-TM microsatellite polymorphism using a polymerase chain reaction (PCR)-based method. Genotyping of HLA-B was performed using PCR and detection with a reverse sequence-specific oligonucleotide (SSO) probes system. RESULTS: A significant difference in the distribution of the alleles of MICA between patient and control groups (P = 0.005) was found. This was due to an increased frequency of the MICA A5 allele in GCA patients compared with controls (26 vs 13.6%; P = 0.0001; P(C) = 0.0005; OR 2.2, 95% CI 1.4-3.4). In addition, the HLA-B*15 allele showed a higher frequency in GCA patients compared with controls (P = 0.004; P(C) = 0.04; OR 2.7, 95% CI 1.3-5.7). Interestingly, the association observed with the MICA A5 allele seems to be independent of linkage disequilibrium with HLA-B, as well as independent of that previously described with HLA-DRB1*04. Remarkably, simultaneous presence of MICA A5 and HLA-B*15 or HLA-DRB1*04 genetic markers leads to an increase in the OR obtained for each individual genetic marker (MICA A5 + B*15 OR 3.2; MICA A5 + DRB1*04 OR 5.8). CONCLUSIONS: Our results provide the first evidence that the MICA and HLA-B genes are independently associated with the genetic susceptibility to GCA, and suggest that several genes within the MHC might have independent effects in the susceptibility to this systemic vasculitis.

Influence of anti-TNF-alpha infliximab therapy on adhesion molecules associated with atherogenesis in patients with rheumatoid arthritis.

OBJECTIVE: Chronic systemic inflammation plays a pivotal role in the development of atherosclerosis in rheumatoid arthritis (RA). Soluble (s) adhesion molecules were found significantly increased in RA patients with active disease. Since increased levels of some adhesion molecules were closely linked to the development of endothelial dysfunction and atherosclerosis and administration of anti-TNF-alpha-infliximab resulted in a rapid and dramatic improvement of endothelial function in long-term infliximab treated RA patients, we assessed whether infusion of the chimeric anti-TNF-alpha infliximab might also yield a rapid and favorable effect on serum levels of soluble adhesion molecules in RA patients periodically treated with this drug because of severe disease. METHODS: We recruited patients with RA refractory to conventional therapy seen over a period of 2 months at Hospital Xeral-Calde, Lugo, Spain, who were on periodical treatment with infliximab for at least 14 weeks. Blood samples for determination of sICAM-1, sICAM-3, sVCAM-1, sE-selectin, and sP-selectin levels by ELISA were taken immediately before and after infliximab infusion. RESULTS: Thirty-four RA patients (25 women; mean age: 55.4 years; mean DAS28: 4.27) fulfilled the inclusion criteria. Following infliximab infusion a reduction of the overall mean values of the five adhesion molecules was observed. However, when a Wilcoxon signed-rank test was used, only significant differences for sICAM-3 and sP-selectin were observed. In this regard, sICAM-3 and sP-selectin levels fell in 26 (77%) and 28 (82%) of the 34 patients. CONCLUSION: Our study confirms a rapid and beneficial effect of infliximab infusion on expression of some adhesion molecules in RA patients treated periodically with this anti-TNF-alpha monoclonal antibody because of severe disease.

Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis.

OBJECTIVE: Systemic inflammation, insulin resistance, and endothelial dysfunction have been implicated in the development of cardiovascular disease in rheumatoid arthritis (RA). Since insulin resistance can promote endothelial dysfunction and anti-TNF-alpha blockade yield a rapid improvement of endothelial function, we have sought to assess whether TNF-alpha blockade may also result in a reduction of insulin serum levels and improvement of insulin resistance in RA patients who require this therapy because of severe and refractory disease. METHODS: We recruited patients with RA seen over a period of 1 month at Hospital Xeral-Calde, Lugo, Spain, that were on treatment with anti-TNF-alpha monoclonal antibody-infliximab. Patients with diabetes mellitus or plasma glucose > 110 mg/dl were excluded. Fasting blood samples were taken for determination of plasma glucose and serum insulin levels immediately prior to and after infliximab infusion. RESULTS: Twenty-seven RA patients (21 women; mean age: 57.1 years; mean DAS28: 4.43) fulfilled the inclusion criteria. Dramatic reduction in the serum insulin levels and insulin/glucose index was observed following infliximab infusion. Also, a significant improvement of insulin resistance and insulin sensitivity was found. CONCLUSION: Our study confirms a rapid beneficial effect of infliximab on insulin resistance and insulin sensitivity in RA patients treated periodically with this drug. It may support the long-term use of drugs that act blocking TNF-alpha function to reduce the mechanisms implicated in the development of atherosclerosis in patients with RA.

E-selectin polymorphism in erythema nodosum secondary to sarcoidosis.

OBJECTIVE: E-selectin is expressed on cytokine-stimulated endothelial cells and plays an important role in leukocyte-endothelium interactions and inflammatory cell recruitment. An A/C polymorphism at position +561 in the E-selectin gene, which yields an amino acid exchange from serine to arginine at position 128 in the epidermal growth factor-like domain, has been described. We have assessed whether this bi-allelic polymorphism may be implicated in the clinical expression of erythema nodosum (EN) secondary to sarcoidosis. METHODS: Thirty-one patients with biopsy-proven erythema nodosum (EN) associated with sarcoidosis, 68 patients with biopsy-proven EN related to other etiologies and 66 healthy matched controls from the Lugo region of Northwest Spain were studied. Patients and controls were genotyped for the A/C polymorphism gene by PCR-restriction fragment length polymorphism. RESULTS: A significantly reduced frequency of the C mutant allele was observed in patients with EN secondary to sarcoidosis compared to controls (p = 0.019) and also compared to patients with EN unrelated to sarcoidosis (p = 0.028). This was also the case when the distribution of genotypes in patients with sarcoidosis was compared with that observed in patients with EN due to other etiologies (p = 0.028) and controls (p = 0.037). This was due to an absence in both C/A heterozygotes and C/C homozygotes in patients with EN secondary to sarcoidosis. CONCLUSIONS: The present study constitutes the first attempt to assess the influence of E-selectin polymorphism at position +561 in the development of sarcoidosis. The C allele at the +561 position of the E-selectin gene is associated with significantly reduced risk of developing sarcoidosis in patients with EN.

Predictors of cerebrovascular accidents in giant cell arteritis in a defined population.

OBJECTIVE: To examine the frequency and predictors of cerebrovascular accidents (CVA) in giant cell arteritis (GCA) patients from a defined population. METHODS: Retrospective study of biopsy-proven GCA patients diagnosed from 1981 through 2001 at the single hospital for the population of Lugo (Northwest Spain). RESULTS: Thirty (14.3%) of the 210 biopsy-proven GCA patients had CVA, 5 of them (16.7%) involving the vertebrobasilar territory. Five patients (4 of them involving the carotid territory) had CVA within the 2 years prior to the onset of GCA symptoms. Four patients had CVA within the first month after the diagnosis of the disease. Of these, 3 involved the vertebrobasilar territory. Another 5 patients suffered carotid stroke between the 4th and the 12th month after the disease diagnosis. The remaining 16 GCA patients had CVA (all but one involving the carotid territory) at least 1 year after the diagnosis of vasculitis. No differences in the clinical and laboratory features at the time of diagnosis between patients who had CVA and the rest of the biopsy-proven GCA patients were observed. However, hypertension and hyperlipidemia at the time of diagnosis of GCA were associated with the development of CVA (p < 0.05 for both). Also, anemia at the time of diagnosis (hemoglobin < 12 g/dL) [hazard ratio = 0.34 (95% CI 0.12 - 1.00; p = 0.05)] was negatively associated with CVA within the first 10 years after the diagnosis of the disease. Mortality in GCA patients with CVA was not significantly higher than that in patients without CVA (hazard ratio = 1.53; p = 0.14). CONCLUSION: The present study confirms that CVA may occur in GCA. Vertebrobasilar accidents are more common than carotid accidents at the time of diagnosis of the disease. Vascular risk factors should be carefully controlled in the follow-up of GCA patients.

Interferon-gamma gene microsatellite polymorphisms in patients with biopsy-proven giant cell arteritis and isolated polymyalgia rheumatica.

OBJECTIVES: Inflammatory cytokines are implicated in the pathogenesis of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). In this study we have examined the potential association of a CA repeat polymorphism in the first intron of the interferon gamma (IFN-gamma) gene with disease susceptibility and clinical expression of these conditions. METHODS: Seventy-nine patients with isolated PMR, 59 biopsy-proven GCA patients and 129 ethnically matched controls from Lugo (NW Spain) were studied. Patients and controls were genotyped by molecular methods for the microsatellite dinucleotide (CA) repeat within the first intron of IFN-gamma gene. RESULTS: No significant differences in the distribution of alleles for the IFN-gamma gene polymorphism between GCA and isolated PMR patients and controls were found. However, the frequency of IFN-gamma allele *4 (128 bp) was reduced in GCA patients (33.1%) compared with isolated PMR patients (46.2%). Also, GCA patients with visual ischemic manifestations exhibited a significantly reduced frequency of IFN-gamma allele *4 compared with those without visual manifestations (17.9% versus 42.5%; p = 0.05 [OR: 0.36, 95% CI: 0.13-1.00]). Moreover, allele *3 (126 bp) was over-represented in the GCA patients with visual ischemic manifestations (71.4% versus 44.4% in the remaining GCA patients; p = 0.01 [OR = 3.13, 95% CI: 1.27-7.68]). CONCLUSIONS: In GCA, IFN-gamma functional polymorphisms are associated with clinical manifestations of severity rather than susceptibility to this vasculitis.

Tuberculous spondylitis: epidemiologic and clinical study in non-HIV patients from northwest Spain.

OBJECTIVES: To study the epidemiology, clinical features, and outcome of non-human immunodeficiency virus (HIV) patients diagnosed with tuberculous spondylitis (TS) in a well-defined region of northwestern Spain. METHODS: Retrospective chart review of patients older than 14 years of age diagnosed with TS at two contiguous areas between 1986 and 1999. RESULTS: Thirty-seven patients (19 men; mean age 60.3 years) were diagnosed with TS. The average annual incidence rate of TS was 0.55/100,000 population 15 years of age and older. The thoracic and lumbar regions were affected in most cases. The mean duration of symptoms before diagnosis was 28 weeks (range 3-129). Active or healed pulmonary tuberculosis was observed in only 30%. The tuberculin skin test was negative in 24%. The most common findings at the time of diagnosis were back pain and elevated ESR (either 89%). Of note, only 19% had fever. On admission plain radiographs disclosed the presence of spondylitis in 84% of the patients. Computed tomography scan and magnetic resonance imaging yielded conclusive diagnostic data in the cases with normal radiographs, and were very useful in the visualization of abscesses and intraspinal compression. Cultures of material from percutaneous needle aspiration and open bone biopsy were positive for Mycobacterium tuberculosis in 79% and 77% of the cases, respectively. Antituberculous therapy was given to all patients (mean duration of treatment 44 weeks). Surgical procedures were performed in 12 cases, in 7 of them to remove paraspinal and/or epidural abscesses, and in 5 because of neurological complications. Local pain and neurological deficits were the mostfrequent sequelae (16 and 8 cases, respectively). One patient died during the course of treatment due to a co-morbid disease. None of the patients had relapses of tuberculosis. CONCLUSION: TS is a major cause of morbidity. There is a long delay to the diagnosis in most patients. Awareness of its clinical features and early therapy are required to reduce severe complications.

Corticotropin releasing hormone promoter polymorphisms in giant cell arteritis and polymyalgia rheumatica.

OBJECTIVE: Giant cell (temporal) arteritis (GCA) and polymyalgia rheumatica (PMR) are different but overlapping diseases of unknown etiology affecting the elderly. Corticotropin-releasing hormone (CRH) helps to regulate the immune response and maintain homeostasis during inflammatory stress. CRH promoter region polymorphisms in the 5'regulatory region of the CRH gene have been described. To investigate the possible implications of the CRH promoter polymorphisms in PMR and GCA susceptibility we have examined a series of patients with these conditions. METHODS: Sixty-two patients with biopsy-proven GCA, 86 patients with isolated PMR and 147 ethnically matched controls from the Lugo region of Northwest Spain were included in this study. Patients and controls were genotyped for CRH polymorphism in the 5' regulatory region of the gene at position 1273 (alleles A1 andA2) and at position 225 (alleles B1 and B2) by PCR-restriction fragment length polymorphism. Allele frequencies and genotype distribution were evaluated by the chi-square test. RESULTS: When GCA and PMR patients were examined for alleles and genotypes for each CRH polymorphism no significant differences in frequency were found compared with controls. A higher CRH-A2 allele frequency was observed in GCA patients with visual complications (21.4%) compared with controls (9.2%) and GCA cases without eye involvement [6.3%; p= 0.017, Pcorr = 0.034, O.R: 4.1 (95% CI 1.2- 13.9)], although this was based on a small sample of patients with ischemic visual complications (n = 14) and should be interpreted with caution. No differences in CRH allele or genotype frequencies were observed in isolated PMR patients stratified by relapses and recurrence of disease symptoms. CONCLUSION: Polymorphisms in the CRH gene regulatory region do not appear to be associated with increased susceptibility to PMR or GCA. The CRH-A2 allele may encode risk for the development of visual complications in GCA, although further studies to confirm this will be required.

IL-6 promoter polymorphism at position -174 modulates the phenotypic expression of polymyalgia rheumatica in biopsy-proven giant cell arteritis.

OBJECTIVES: Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are related diseases in which diverse genetic and environmental factors are implicated. Both GCA and PMR are characterized by an intense acute phase reaction. In these sYndromes the increased production of IL-6 has been observed. To investigate further the genetic influence of IL-6 in GCA and PMR we have examined the IL-6 promoter polymorphism (G to C) at position -174 in the 5' region in a series of patients from Northwest Spain diagnosed with GCA and/or PMR. METHODS: Sixtxy-two biopsy-proven GCA patients (30 of them with associated PMR) and 84 patients with isolated PMR were studied. Patients and ethnically matched controls (n = 124) were from the Lugo region (Galicia, Northwest Spain). Patients and controls were genotyped for HLA-DRB1 and IL-6 polymorphism at position -174 by molecular methods. RESULTS: IL-6-174 allele C was marginally increased infrequency in GCA patients with PMR manifestations compared with isolated GCA (Pcorr 0.06; OR = 2.3). The increase in the frequency of the CC genotype in GCA patients with PMR versus those with isolated GCA was statistically significant (Pcorr 0.02). The increased frequency of allele C in GCA patients with PMR was more commonly observed in HLA-DRBI *04 negative patients. However, this polymorphism was not associated with a higher risk of ischemic events in GCA or with relapses in PMR. CONCLUSION: Allele C at position -174 in the 5' promoter region of the IL-6 gene may be associated with PMR in biopsy-proven GCA patients not carrying HLA-DRBI *04 alleles.