Ali Hajeer

Visual manifestations of giant cell arteritis. Trends and clinical spectrum in 161 patients.

Giant cell (temporal) arteritis (GCA) is the most common systemic vasculitis in Western countries. It involves large and medium-sized vessels with predisposition to the cranial arteries in the elderly. Cranial ischemic complications, in particular permanent visual loss, constitute the most feared aspects of this vasculitis. Although the use of corticosteroids and a higher physician awareness may have contributed to a decrease in the frequency of severe ischemic complications, permanent visual loss is still present in 7%-14% of patients. To investigate further the incidence, trends, and clinical spectrum of visual manifestations in patients with GCA, we examined the features of patients with biopsy-proven GCA diagnosed at the single reference hospital for a defined population in northwestern Spain during an 18-year period. Predictive factors for the development of any visual manifestation, not only permanent visual loss, were also examined. Between 1981 and 1998, 161 patients were diagnosed with biopsy-proven GCA. Visual ischemic complications were observed in 42 (26.1%), and irreversible blindness, mainly due to anterior ischemic optic neuropathy and frequently preceded by amaurosis fugax, was found in 24 (14.9%). Despite a progressive increase in the number of new cases diagnosed, there was not a significant change in the proportion of patients with visual manifestations during the study period (p = 0.37). Patients with visual ischemic complications had lower clinical and laboratory biologic markers of inflammation. Indeed, during the last years of the study, anemia was associated with a very low risk of visual complications. Also, HLA-DRB1*04-positive patients had visual manifestations more commonly. Patients with other ischemic complications developed irreversible blindness more frequently. The best predictors of any visual complication were HLA-DRB1*04 phenotype (odds ratio [OR] 7.47) and the absence of anemia at the time of admission (OR for patients with anemia = 0.07). The best predictors of irreversible blindness (permanent visual loss) were amaurosis fugax (OR 12.63) and cerebrovascular accidents (OR 26.51). The present study supports the claim that ocular ischemic complications are still frequent in biopsy-proven GCA patients from southern Europe. The presence of other ischemic complications constitutes an alarm for the development of irreversible blindness. In contrast, a higher inflammatory response may be a protective factor against the development of cranial ischemic events.

Influence of TNFα gene polymorphisms on TNFα production and disease

Abstract Tumor necrosis factor α (TNFα) is a potent inflammatory cytokine. In human, the TNFα gene is located within the highly polymorphic major histocompatibility complex (MHC) region on chromosome 6p21.3. TNF gene cluster contains many polymorphisms including microsatellites and single nucleotide polymorphisms (SNPs). Many of these polymorphisms were found to be in linkage disequilibrium with HLA class I and II alleles. Some of the TNFα gene polymorphisms were found to influence TNFα production in vitro , for example the −308 SNP. Many studies have shown that this SNP and others within the TNFα gene associate with different inflammatory conditions. Whether this phenomenon is due to the direct influence of the SNP in question and/or due to linkage disequilibrium with other polymorphisms within the TNFα gene or the HLA system is still controversial.

TNF‐α gene polymorphism: Clinical and biological implications

TNF‐α is a proinflammatory cytokine that has been implicated in the severity of different immune‐regulated diseases including autoimmune diseases and transplantation. The gene for TNF‐α is located within the MHC region on chromosome 6p21.3. This is a highly polymorphic region, and the TNF‐α itself contains a large number of polymorphisms. Some of these polymorphisms form extended haplotypes with the HLA class I and II alleles. TNF polymorphisms have been investigated in different diseases and most often whenever there is an HLA association with the disease (for example IDDM and RA) association(s) with TNF polymorphisms has been described. There are many studies on the function of the TNF polymorphisms showing the influence of the different alleles on the in vitro and in vivo levels of TNF production. However, recent studies in animal models suggest that not only polymorphisms within the TNF cluster are important in the regulation of TNF production but also the receptors as well (TNF R). This suggests that investigating polymorphisms within the TNF cluster and TNF receptors will be important in understanding the role of TNF regulation in a given disease. Microsc. Res. Tech. 50:216–228, 2000.

Chemokine RANTES promoter polymorphism affects risk of both HIV infection and disease progression in the Multicenter AIDS Cohort Study.

ObjectiveTo examine whether polymorphism in the RANTES gene is associated with HIV disease outcome. DesignRANTES, a ligand of the major HIV co-receptor, CCR5, is known to block HIV-CCR5 interactions. Recently, two single nucleotide polymorphisms in the RANTES gene promoter region, designated −403G/A and −28C/G, have been described. Both polymorphisms can affect in-vitro promoter activity, and the RANTES −403A, −28G haplotype has been associated with a slower CD4 cell count decline rate in a Japanese cohort. MethodsWe compared RANTES compound genotype frequencies between HIV-positive and exposed-uninfected participants of the Multicenter AIDS Cohort Study (MACS) and rates of progression to AIDS for MACS seroconverters. ResultsWe found that the two most common RANTES promoter compound genotypes, G1 (−403G/G, −28C/C) found in 67% of Caucasians, and G4 (−403G/A, −28C/C) found in 23% of Caucasians, were associated with altered risk of HIV transmission and progression, particularly in individuals who lacked the protective CCR5 mutation, CCR5Δ32. In this study, individuals with a G4 compound genotype were more likely to acquire HIV than individuals with a G1 compound genotype (OR 1.72, P = 0.016) and the risk increased when individuals possessing CCR5Δ32 were omitted from consideration (OR 2.13, P = 0.005). Among seroconverters lacking CCR5Δ32, those who had the G4 compound genotype progressed significantly slower to AIDS-1993 than those with the G1 compound genotype (median time to AIDS 7.6 versus 5.4 years; RH 0.65;P = 0.007). ConclusionsThese data implicate the RANTES-403A allele as a risk factor for HIV transmission and as a protective factor for HIV progression.

Weak association between subjective symptoms of and objective testing for dry eyes and dry mouth: results from a population based study

OBJECTIVES To determine associations between symptoms of dry eyes and dry mouth and objective evidence of lacrimal and salivary gland dysfunction in a population based sample. To determine associations between these elements and the presence of autoantibodies. METHODS A cross sectional population based survey. Subjects were interviewed and examined (Schirmer-1 test and unstimulated salivary flow) for the presence of dry eyes and mouth. Antibodies (anti-Ro [SS-A], anti-La [SS-B], rheumatoid factor, antinuclear antibody) were measured. RESULTS 341 subjects were examined. Twenty four per cent had dry eye symptoms, 29% dry mouth symptoms, and 14% both. There was only a weak association between the presence of oral or ocular symptoms and their respective test results. Associations were strongest between dry mouth symptoms and positive test results, and in subjects under 55 years of age. There was no association between the presence of autoantibodies and either symptoms or signs of dry eyes or dry mouth. CONCLUSION Only weak associations were found between self reported symptoms of dry eyes and dry mouth and objective measures said to define Sjögrens syndrome in the general population. The clinical significance of these symptoms in the community needs reappraisal.

HLA-DRB1 status affects endothelial function in treated patients with rheumatoid arthritis.

PURPOSE To examine endothelial function in rheumatoid arthritis patients and to assess whether clinical or genetic factors affect the development of endothelial dysfunction. METHODS Fifty-five patients fulfilling the 1987 American College of Rheumatology classification criteria for rheumatoid arthritis were recruited from Hospital Xeral-Calde, Lugo, Spain. Patients were required to have been treated for at least 5 years, including current treatment with one or more disease-modifying antirheumatic drugs. Patients with diabetes mellitus, renal insufficiency, or cardiovascular disease were excluded. Thirty-one age-, sex-, and ethnically matched controls were also studied. Endothelium-dependent (postischemia) and -independent (postnitroglycerin) vasodilatation were measured by brachial ultrasonography. Patients were genotyped for human leukocyte antigen (HLA)-DRB1. RESULTS Patients had decreased endothelium-dependent vasodilatation (mean [+/- SD], 3.8% +/- 4.9%) compared with controls (8.0% +/- 4.5%; P <0.001). There were no differences in endothelium-independent vasodilatation. Clinical features were not associated with endothelial dysfunction. Endothelium-dependent vasodilatation was lower in the 30 rheumatoid arthritis patients with the HLA-DRB1*04 shared epitope alleles (2.4% +/- 4.1%) than in the remaining patients (5.5% +/- 5.3%; P = 0.01). Similar results were seen for patients with the HLA-DRB1*0404 shared epitope allele (-0.4% +/- 2.5%) compared with other patients (4.4% +/- 4.9%; P = 0.01). CONCLUSION Patients with chronically treated rheumatoid arthritis had evidence of endothelial dysfunction, especially those with certain HLA-DRB1 genotypes. If confirmed, our results suggest that HLA-DRB1 status may be a predictor of cardiovascular risk in these patients.

IL-10 gene promoter polymorphisms in rheumatoid arthritis

IL-10 is an anti-inflammatory cytokine which may modulate disease expression in RA. Three dimorphic polymorphisms within the IL-10 gene promoter have recently been identified and appear to influence regulation of its expression. The 1082*A allele has been associated with low and the 1082*G allele with high in vitro IL-10 production. We have analysed 117 unrelated Caucasoid RA patients and 119 ethnically matched controls. No significant differences in the allele frequencies of the three polymorphisms were found between controls and RA patients. In contrast, a significant association between the 1082*A allele and the (-1082*A/-819*C/-592*C) haplotype and IgA RF+ve/IgG RF-ve patients was observed. The association of genotypes encoding low IL-10 production with IgA RF in RA is incompatible with its suggested role in antibody isotype switching. IgA RF has been associated with severe RA and may thus be indirectly correlated with a genotype encoding low IL-10 production.

The -403 G-->A promoter polymorphism in the RANTES gene is associated with atopy and asthma.

Asthma is a complex inflammatory condition often associated with bronchial hyperreactivity and atopy. Genetic and environmental factors are implicated and several candidate genes have been implicated. Of these, the chemokine RANTES is responsible for the recruitment of inflammatory cells such as eosinophils and T-lymphocytes. We have recently identified a polymorphism within the RANTES promoter (−403 G→A) and have examined its role, using a PCR-RFLP assay, in the development of atopy and asthma in 201 Caucasian subjects. Atopic status was determined using skin prick testing and serum IgE levels. Severity of airway dysfunction was assessed using spirometric measurement (FEV1) and methacholine challenge (PC20). The −403 A allele was associated with an increased susceptibility to both atopy and asthma. Thus, the proportion of subjects carrying this allele was higher in each of atopic non-asthmatics, non-atopic asthmatics and atopic asthmatics compared with non-atopic, non-asthmatic controls. In particular, this allele was associated with skin test positivity but not IgE level. Homozygosity for the −403 A allele conferred a 6.5-fold increased risk of moderate/severe airway obstruction (FEV1 ⩽80% predicted), a marker for established asthma. Our data, whilst preliminary, indicate that the association of RANTES genotype with both atopy and asthma reflect independent effects, suggesting different mechanisms for the role of this chemokine in atopy and development of airway obstruction.

Association of giant cell arteritis and polymyalgia rheumatica with different tumor necrosis factor microsatellite polymorphisms

OBJECTIVE To determine whether giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are associated with different tumor necrosis factor (TNF) microsatellite polymorphisms. METHODS Typing of TNF microsatellite polymorphisms was carried out by molecular-based techniques on DNA obtained from a population sample of residents from Lugo, northwestern Spain. A case-control approach was used to compare 136 patients with GCA and/or PMR with 147 ethnically matched controls. The association of disease with TNF microsatellite polymorphisms was investigated using chi-square tests and multivariate logistic regression analyses. RESULTS Different TNF microsatellite associations were found with GCA and PMR. In patients with isolated GCA, the primary association was with TNFa2, which was independent of the GCA associations with HLA-DRB1*0401 and *0101. A negative association was found with TNFa10. In patients with isolated PMR, there was a positive association with TNFb3. This was found to be independent of the HLA-DRB1*13/*14 association in isolated PMR. TNFd4 was negatively associated with isolated PMR. Forward stepwise logistic regression analyses indicated that the strongest association with GCA was provided by the TNFa2 allele, although DRB1*0401 and *0101 were still associated. PMR was primarily associated with TNFb3. A direct comparison of TNF allele frequencies between isolated GCA and isolated PMR indicated that the main difference between these conditions occurred in the frequency of TNFa10. CONCLUSION GCA and PMR in individuals from northwestern Spain are associated with different TNF microsatellite polymorphisms. The primary TNF associations (TNFa2 and TNFb3) appear to influence susceptibility to these conditions independent of any HLA-DRB1 association.

Association of IL-10 genotype with sudden infant death syndrome.

Sudden infant death syndrome (SIDS) is a major cause of infant death of unknown etiology. We propose that SIDS results from a genetically determined imbalance in the production of inflammatory and anti-inflammatory cytokines in response to the infants microbial flora. We were especially interested to know the relationship between SIDS and genetically determined higher or lower production of IL-10, an anti-inflammatory cytokine. Biallelic polymorphisms in the promoter region of the IL-10 gene associated with higher or lower production of IL-10 were determined in a SIDS and in a control group using a sequence-specific oligonucleotide approach. One particular allele of the IL-10 gene, the IL-10-592*A allele, was significantly associated with SIDS. Indeed, 70% of the SIDS babies carried the IL-10-592*A allele (p = 0.007 compared with control). In addition, there was a significant reduction in the frequency of homozygosity for the allele IL-10-592*C (p = 0.001 compared with control). Carrying the A allele (either A/A or A/C) had an odds ratio of 3.3 (95% confidence interval 1.4-8.0). In the same patients there was no association with other IL-10 gene polymorphisms nor with other cytokine (TNF-alpha, TGF-beta 1) genotypes, emphasizing the particular relationship between SIDS and the IL-10-592*A allele.