UBA1 gene mutation in giant cell arteritis

Clinical Rheumatology -     

Epidemiology of biopsy proven giant cell arteritis in northwestern Spain: trend over an 18 year period

OBJECTIVE: In Europe giant cell arteritis (GCA) is more common in Scandinavian countries than in southern regions. Epidemiological studies on GCA in other more distant countries have indicated a progressive increase in incidence. A regular cyclical pattern in incidence of GCA over 20 years has been reported in Olmsted County (Minnesota, USA). In contrast, no cyclical fluctuation has been recently reported in Sweden. To investigate further the epidemiology of GCA in southern Europe the trend in incidence and fluctuations of this vasculitis over 18 years in the Lugo region of northwestern Spain were examined. METHODS: A retrospective study of biopsy proven GCA diagnosed between 1 January 1981 and 31 December 1998 at a single hospital for a well defined population of almost 250 000 people. Annual incidence was calculated for the whole group of patients and for men and women separately. Monthly variations, annual peaks of incidence, and trend in the incidence of biopsy proven GCA with and without polymyalgia rheumatica (PMR) were also examined. RESULTS: One hundred and sixty one Lugo residents were diagnosed with biopsy proven GCA between 1981 and 1998. The average annual incidence for the population aged 50 and older was 10.24/100 000 (men 11.00/100 000, women 9.57/100 000). A progressive increase in the incidence in both men and women was seen. In men there was an annual increase of 8% (95% CI 4% to 13%; p<0.0001). In women the annual increase was 11% (95% CI 5% to 17%; p<0.0001). The overall annual increase for men and women was 10% (95% CI 6% to 14%; p<0.0001). No seasonal pattern or peaks in the incidence were seen. During the period 1981-94 GCA was more common in men than in women. In contrast, during the last years of study the increase in incidence was higher in women. In women the annual ratio of incidence of GCA with PMR/incidence of GCA without PMR was generally higher than 1. However, in men the annual ratio was initially 1 but decreased gradually, indicating a progressive decrease in the proportion of men with biopsy proven GCA associated with PMR. CONCLUSION: In northwestern Spain there has been a progressive increase in GCA incidence. As seen in other countries where GCA is more common, during the past few years the increase in incidence has been mainly due to a higher number of new cases in women.     

Temporal artery biopsy for giant cell arteritis

OBJECTIVE: To evaluate the influence of temporal artery biopsy (TAB) techniques on establishing a diagnosis of giant cell arteritis (GCA). METHODS: A retrospective review of 141 TAB pathology records from 1996 to 2002 was conducted. Histopathology slides on 136 TAB were reviewed by a single, independent, blinded pathologist. RESULTS: The population included 101 (71.6%) women, mean age 75.8 years (range 45-92), and 40 men, mean age 73.9 years (range 47-90). The mean length of a TAB sample after formalin fixation was 1.76 cm (range 0.1-5.3). Surgeons performing the TAB represented 6 disciplines. Ophthalmologists had the largest volume, at 78 biopsies (55.3%), and the longest segments of artery, with a mean length of 2.37 cm (range 0.4-5.3) (p < 0.001). Comparison of biopsy interpretation provided a kappa coefficient of 0.8 (95% CI 0.69, 0.91). The 38 (27%) positive biopsies had a mean length of 2.07 cm (SD 1.1), and the 98 negative biopsies a mean length of 1.69 cm (SD 1.04) (p = 0.058). Biopsies < 1.0 cm length (n = 35, 25.7%) were less likely to be positive than those > or = 1.0 cm (p = 0.037). No significant differences in surgical discipline, hospital site, number of slides, or cross-sections/cm artery were found between the positive and negative biopsies. CONCLUSION: Biopsy specimens reported positive for GCA tended to be longer than those reported as negative. A "threshold" size of 1.0 cm is associated with increased diagnostic yield. Lack of standardization of biopsy harvesting and processing techniques may contribute to variable sensitivity of TAB.     

Lack of association between intercellular adhesion molecule-1 gene polymorphisms and giant cell arteritis

OBJECTIVE: Studies have shown an association between HLA-DRB1*04 and giant cell arteritis (GCA). Intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms were reported to contribute susceptibility to GCA in Italian patients where susceptibility to GCA is not associated with HLA-DRB1*04 alleles. ICAM-1 is also highly expressed within inflammatory infiltrates of the blood vessels of GCA patients. To investigate the clinical implications of ICAM-1 polymorphisms in GCA, we examined their potential association and influence in the development of visual ischemic complications in a series of patients with GCA from Northwest Spain where GCA susceptibility is associated with HLA-DRB1*04. METHODS: Fifty-eight biopsy proven GCA and 129 ethnically matched controls were studied. Patients and controls were genotyped for ICAM-1 polymorphism at codons 241 and 469 by PCR-RFLP. RESULTS: The distribution of the alleles and genotypes for each ICAM- polymorphism did not show significant differences between GCA patients and controls. Although visual manifestations were significantly more likely to occur in men than women (OR 5.2, p = 0.018), allele and genotype frequencies of ICAM-1 polymorphisms in patients with GCA were not associated with development of visual complications or anemia. Visual complications in GCA were primarily associated with carriage of an HLA-DRB1*04 allele. No evidence was found for interaction between HLA-DRB1*04 and ICAM-1 polymorphism. CONCLUSION: ICAM-1 polymorphisms are not genetic risk factors for the susceptibility and severity of GCA in Northwest Spain.     

Atherosclerosis in patients with biopsy‐proven giant cell arteritis

Objective

To examine the presence of atherosclerosis in a series of giant cell arteritis (GCA) patients attended to in a community hospital and to determine whether clinical features or steroid therapy might be associated with the development of atherosclerotic disease.

Methods

Forty consecutive patients diagnosed with biopsy‐proven GCA, periodically followed at the rheumatology outpatient clinic of Hospital Xeral‐Calde, Lugo (Spain), who had ended steroid therapy and had at least 3 years of followup were assessed for the presence of atherosclerosis by determination of the carotid intima‐media thickness (IMT) and carotid plaques using high‐resolution B‐mode ultrasound. Forty matched controls were also studied.

Results

GCA patients exhibited less carotid artery IMT than did matched controls (mean ± SD 1.01 ± 0.16 mm versus 1.13 ± 0.20 mm; P = 0.005; difference in means 0.12, 95% confidence interval 0.04–0.20). Patients who required steroid therapy for >2 years had greater mean ± SD carotid IMT (1.04 ± 0.17 mm versus 0.95 ± 0.15 mm) but the difference was not statistically significant (P = 0.10). A positive correlation between age at the time of the study and the carotid artery IMT in GCA patients was observed (r = 0.673, P < 0.001). However, adjusting for age, sex, and classic atherosclerosis risk factors, no significant correlation between carotid IMT and the routine laboratory markers of inflammation assessed at the time of disease diagnosis, disease duration, or cumulative prednisone dose was found.

Conclusion

The present study demonstrates that atherosclerotic macrovascular disease is not increased in patients with GCA.     

Endothelial nitric oxide synthase haplotype associations in biopsy-proven giant cell arteritis

OBJECTIVE: To assess the influence of endothelial nitric oxide synthase (eNOS) polymorphisms in the susceptibility to giant cell arteritis (GCA). METHODS: We studied 57 patients with biopsy-proven GCA diagnosed at the Rheumatology Division of Hospital Xeral-Calde and 117 ethnically matched controls. Patients and controls were genotyped by PCR for a variable number tandem repeat polymorphism in intron 4, a T/C polymorphism at position -786 in the promoter region, and a polymorphism in exon 7 (298Glu/Asp or 5557G/T) of the eNOS gene. RESULTS: No differences in allele or genotype frequencies for individual polymorphisms were observed between patients with GCA and controls. However, when haplotype frequencies for the combination of the 3 eNOS polymorphisms were estimated, a significant increase in the frequency of haplotype C/1/T and a significant decrease in the frequency of haplotype C/1/G were observed in GCA patients compared to controls (p = 0.04, OR 1.8, 95% CI 1.0-3.3; p = 0.02, OR 0.3, 95% CI 0.1-0.8, respectively). CONCLUSION: Significant differences in eNOS haplotype frequencies between GCA patients and controls may indicate a role for these polymorphisms in the susceptibility to this condition.     

Ischemic heart disease in patients from Northwest Spain with biopsy proven giant cell arteritis. A population based study

OBJECTIVE: To assess the incidence, mortality, and predictors of ischemic heart disease (IHD) in patients from the Lugo region of Northwest Spain with biopsy-proven giant cell arteritis (GCA). METHODS: Retrospective study of patients with biopsy-proven GCA diagnosed from 1981 to 2001 at the single hospital for a population of 250,000 people. A survival analysis was performed. Hazard ratios and standardized mortality ratio (SMR) as well as predictors of IHD in patients with biopsy-proven GCA were also assessed. RESULTS: Nineteen (9%) of the 210 patients with biopsy-proven GCA diagnosed during the period of study had IHD. The incidence of IHD in patients with GCA was 12.6/1000 person-years at risk (95% CI 6.9-21.0). During the study period 1981-2000 the population aged > or = 50 years in Lugo was roughly 100,000, and the mortality rate due to IHD in patients with GCA for that population was 8/100,000. The SMR in patients with GCA due to IHD was 1.62 (95% CI 0.70-3.20). Mortality in patients with GCA who had IHD was higher than in those patients without IHD (age and sex adjusted hazard ratio 2.81, 95% CI 1.51-5.21; p = 0.001). Age (hazard ratio 1.15), hypertension (hazard ratio 2.51), and abnormal temporal artery on physical examination (hazard ratio 0.36) at the time of diagnosis of GCA were the best predictors of IHD over the followup period in patients with biopsy-proven GCA. CONCLUSION: Our observations suggest that mortality due to IHD in patients from Lugo with GCA is not much higher than that reported in the Spanish population aged 50 years and older. However, mortality in patients with GCA with IHD is higher than in GCA patients without IHD.     

Lack of association between macrophage migration inhibitory factor gene polymorphism and giant cell arteritis

OBJECTIVE: To investigate the role of macrophage migration inhibitory factor (MIF) gene polymorphism in giant cell arteritis (GCA). METHODS: Eighty-three patients with biopsy-proven GCA, 20 of them with visual ischemic complications, and 122 healthy matched controls from the Lugo region of Northwest Spain were studied. Patients and controls were genotyped for a single nucleotide polymorphism in the 5'-flanking region at position -173 of the MIF gene, using SNapshot ddNTP primer extension, followed by capillary electrophoresis (ABI 3100). RESULTS: No significant differences in MIF gene polymorphism were observed in patients with biopsy-proven GCA compared to controls. This was also the case when GCA patients with or without visual ischemic complications were compared. CONCLUSION: Polymorphism in MIF gene promoter -173 G/C does not appear to be a genetic risk factor for GCA in Northwest Spain.     

Visual hallucinations in giant cell arteritis: association with visual loss

OBJECTIVE: To evaluate the frequency and characteristics of visual hallucinations (VH) in patients with giant cell arteritis (GCA) and to determine their relationship to other visual phenomena. METHODS: This prospective study included 31 consecutive patients with GCA. All were asked whether they had experienced recent visual phenomena. Patients with visual symptoms underwent a comprehensive ophthalmologic examination. When unusual visual phenomena were reported, patients were asked to describe their nature, duration, and frequency of occurrence. RESULTS: Visual symptoms occurred in 6 patients: permanent visual loss in 5 and amaurosis fugax in one. In 4 of the 5 patients with permanent visual loss, it was preceded by intermittent VH over a period of 1-10 days. Patients were aware of the unreal nature of the visions. Hallucinations disappeared within 2 weeks, but in one patient, recurred 6 months later in association with further visual deterioration. CONCLUSION: The occurrence of visual hallucinations in patients with GCA-associated visual loss is more common than previously appreciated. As hallucinations preceded permanent loss of vision, this phenomenon may serve as a harbinger of imminent visual loss.     

Combined temporal arteriography and selective biopsy in suspected giant cell arteritis.

Superficial temporal arteriography was studied by selective biopsy of abnormal arterial segments and random biopsy of the main stem in 33 patients with clinically supected giant cell arteritis. Of the total of 33 temporal arteriograms 9 showed definite abnormalities (7 in the periphery and 2 in the main stem). Selective biopsy of the 7 peripheral abnormal segments showed arteritis in only 2, narrowing of the vessels in the remainder being due to atheroma (3) and fibrointimal thickening (2)--that is, 5 'false positives' for temporal arteritis on arteriography. Histological evidence of arteritis was found in 9 patients, only 5 of whom had clearly abnormal arteriograms--that is, 4 'false negatives'. Thus temporal arteriography appears to have low sensitivity for identifying arteritic lesions and also frequently gives 'false positive' results. It is concluded that temporal arteriography is not a satisfactory alternative to biopsy, and that its value as an adjunct to selective biopsy is limited because of its frequent failure to detect lesions found histologically.     

Supraorbital nodule biopsy leading to the diagnosis of giant cell arteritis

Giant cell arteritis is a systemic vasculitis which usually involves the cranial arteries. We report the case of a 57‐year‐old patient presenting with headache and painful subcutaneous supraorbital nodule. A subsequent biopsy of a supraorbital nodule led to the diagnosis of giant cell arteritis.     

Intercellular adhesion molecule 1 gene polymorphisms in polymyalgia rheumatica/giant cell arteritis: association with disease risk and severity

OBJECTIVE: Intercellular adhesion molecule 1 (ICAM-1) is widely distributed in shoulder synovial membrane of active polymyalgia rheumatica (PMR) and strongly expressed in granulomatous inflammatory infiltrate of the temporal artery in giant cell arteritis (GCA). ICAM-1 genes may contribute to the inflammatory PMR/GCA processes. We examined potential associations of ICAM-1 gene polymorphisms with PMR/GCA susceptibility and severity. METHODS: We enrolled 121 consecutive patients with "pure" PMR and 56 patients with biopsy positive GCA residing in Reggio Emilia, Italy. Among patients with PMR, 91 had a followup duration of at least one year. Selected as control subjects were 228 healthy blood donors, 75 patients with nonarteritic central retinal artery occlusion, and 116 cataract surgery patients from the same geographic area. All PMR/GCA patients and controls were genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for ICAM-1 polymorphism at codon 241 (exon 4) and codon 469 (exon 6). RESULTS: The frequency of R241 was significantly higher in PMR/GCA patients [p = 0.00001, odds ratio (OR) 5.0 (95% confidence intervals, CI 2.6-9.6) ], in pure PMR patients [p = 0.00001, OR 5.0 (95% CI 2.5-10.0)], and in GCA patients [p = 0.00005; OR 5.0 (95% CI 2.2-11.5)] compared to the healthy controls. The frequency of R241 was significantly higher in total PMR/GCA patients compared to patients with nonarteritic central retinal artery occlusion [p = 0.0007; OR 5.3 (95% CI 1.8-15.5)] and cataract surgery patients [p = 0.0003; OR 4.1 (95% CI 1.8-9.0)]. The distribution of E/K 469 genotype was similar in PMR/GCA patients and in the 3 control groups. Cox proportional hazards modeling identified 2 variables that independently increased the risk of PMR relapse/recurrence: erythrocyte sedimentation rate at diagnosis > 72 mm/h [relative risk 1.6 (95% CI 1.1-2.3)] and the presence of R241 allele [relative risk 1.6 (95% CI 1.1-2.4)]. CONCLUSION: Our findings show that G/R 241 polymorphism of ICAM-1 is associated with PMR/GCA susceptibility and confers an increased risk of relapse/recurrence in PMR.     

Fever in biopsy‐proven giant cell arteritis: Clinical implications in a defined population

Objective

To assess the frequency and clinical features of biopsy‐proven giant cell arteritis (GCA) patients who had fever at the time of diagnosis of the disease, and the relationship between fever, ischemic complications, and the systemic inflammatory response in GCA.

Methods

A retrospective study of biopsy‐proven GCA patients diagnosed between 1981 and 2001 was performed at the single referral hospital for a well‐defined population in the Lugo region of northwest Spain. Patients were considered as having fever if the axillary temperature at the time of admission or during the followup prior to the onset of corticosteroid therapy was ≥38°C.

Results

During the period of study, 21 (10%) of the 210 biopsy‐proven GCA patients had fever. Two of them fulfilled criteria for fever of unknown origin. Patients with fever had a lower frequency of severe ischemic manifestations than the rest of biopsy‐proven GCA patients. They also exhibited a more severe inflammatory disease, with significant abnormality in most laboratory variables, including higher elevation of erythrocyte sedimentation rate, lower values of hemoglobin, and higher proportion of patients with increased alkaline phosphatase. By logistic regression analysis, we observed that patients with fever had an increased risk of developing anemia (odds ratio [OR] 12.24). In contrast, a negative association between severe ischemic manifestations and fever was found (OR 0.41).

Conclusion

Biopsy‐proven GCA patients with fever constitute a subgroup of patients with more severe inflammatory response and less ischemic disease.

     

Endothelial nitric oxide synthase gene polymorphisms in giant cell arteritis

OBJECTIVE: To examine potential associations of the Glu/Asp(298) polymorphism in exon 7 and the 4a/b polymorphism in intron 4 of the endothelial nitric oxide synthase (eNOS) gene with susceptibility to and clinical expression of giant cell arteritis (GCA), particularly in patients with versus those without ischemic complications. METHODS: Ninety-one consecutive patients with biopsy-proven GCA, who were residents of Reggio Emilia, Italy, and 133 population-based controls from the same geographic area were genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for eNOS polymorphisms in exon 7 and intron 4. The patients were separated into 2 subgroups according to the presence or absence of ischemic complications (visual loss and/or jaw claudication and/or aortic arch syndrome). RESULTS: The distribution of the Glu/Asp(298) genotype differed significantly between GCA patients and controls (corrected P [P(corr)] = 0.003). Carriers of the Asp(298) allele (Asp/Asp or Glu/Asp) were significantly more frequent among the GCA patients than among the controls (P(corr) = 0.0002, odds ratio 3.3, 95% confidence interval 1.7-6.3). The distribution of the 4a/b genotype was similar in GCA patients and controls. No significant associations were found when GCA patients with and without ischemic complications were compared. CONCLUSION: Our findings show that the Glu/Asp(298) polymorphism of the eNOS gene is associated with GCA susceptibility.