Rheumatology 2015;54:139143 doi:10.1093/rheumatology/keu303 Advance Access publication 13 August 2014
RHEUMATOLOGY
Concise report Mortality in patients with giant cell arteritis Bo Baslund1, Marie Helleberg1, Mikkel Faurschou1 and Niels Obel1 Abstract Objective. The aim of this study was to examine whether GCA is associated with increased mortality.
Conclusion. GCA is associated with slightly increased early and late mortality. Key words: GCA, mortality, cardiovascular disease, aortic aneurysm, epidemiology, cancer.
Introduction GCA is the most frequently diagnosed vasculitis in adults. The presenting symptoms include new-onset headache, scalp tenderness and jaw claudication [1]. Although the disease has a predilection for the extra-cranial branches of the carotid artery, disease activity in the aorta is frequently present [1]. The proportion of patients with aortic involvement is not well established, with incidence estimates for aortic involvement ranging from 10 to 65% [26]. Patients with GCA have an increased risk of being diagnosed with aortic aneurysms and cardiovascular diseases [4, 7], which suggests that the mortality in this population might be increased. However, published data on mortality in patients with GCA are conflicting. Some studies have demonstrated mortality rates (MRs) comparable to those of the background population among GCA patients [812], while other investigations have shown increased [1315] or decreased mortality [16, 17]. In
1 Department of Infectious Disease and Rheumatology, Rigshospitalet, Copenhagen, Denmark
Submitted 11 December 2013; revised version accepted 9 June 2014. Correspondence to: Bo Baslund, Department of Infectious Disease and Rheumatology, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: [email protected]
some analyses, an increased rate of death was only found among patients with aortic involvement [5, 17]. However, most of these studies are hampered by small sample size, lack of well-matched comparison cohorts, inclusion of patients without biopsy-proven vasculitis and non-population-based study designs. To determine the relative risk of death and causes of death in patients with GCA, we conducted a populationbased, nationwide cohort study of the mortality in patients with biopsy-proven GCA.
Methods Denmark has a population of 5.5 million citizens, of whom 2.0 million are >50 years of age. We established a cohort that included all Danish citizens >50 years of age who were diagnosed with biopsy-proven GCA during the period 19932011 and an age- and sex-matched comparison cohort from the background population. In Denmark, patients with GCA are treated in hospital departments that specialize in rheumatology or internal medicine. Health care is funded through taxes and is therefore free of charge. We used the unique 10-digit civil registration number assigned to all individuals in Denmark at birth or upon immigration and stored in the Danish Civil Registration System to track patients and link
! The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
CLINICAL SCIENCE
Results. Compared with the general population, the relative risk (RR) of death in patients diagnosed with GCA was 1.17 (95% CI 1.01, 1.36) and 1.22 (95% CI 1.05, 1.41) 02 years and >10 years after diagnosis, respectively, whereas we observed no increased mortality during the follow-up period of 210 years [RR 0.96 (95% CI 0.88, 1.05)]. The increased mortality during the first 2 years of follow-up was mainly due to diseases of the circulatory system, including aortic aneurisms.
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Methods. We conducted a nationwide population-based cohort study including all individuals who between 1993 and 2011 were registered in the Danish National Hospital Register and the Danish Pathology Register with a biopsy-proven diagnosis of GCA (n = 1787). Through the Danish Civil Registration System we identified a comparison cohort of 33 953 persons from the background population, individually matched on age and sex. Data on causes of death were obtained from the Danish Registry of Causes of Death. We used Poisson regression to determine mortality rate ratios as estimates of relative risk of death and specific causes of death.
Bo Baslund et al.
TABLE 1 Characteristics of the study population
Number Total follow-up time, years Follow-up time, median (IQR), years Deaths, n Age at diagnosis/index date, median (IQR), years Female, n (%)
GCA patients
Background population controls
1787 12 649 6.6 (3.110.5) 846 74 (6979) 1298 (72.6)
33 953 243 862 6.5 (3.110.7) 15,484 74 (6979) 24 662 (72.6)
IQR: interquartile range.
of the patients to whom they were matched. Observation time was calculated from the index date to the date of emigration, death or 6 November 2011, whichever came first. MRs with 95% CIs were calculated as the number of deaths per 1000 person-years (PY) under the assumption of a Poisson distribution. We used Poisson regression analyses to calculate MR ratios (MRRs) as estimates of RR. Age (in 10-year intervals) and calendar year (in 5-year intervals) were included as time-updated variables. Analyses were stratified by sex, age, time since index date and calendar year of index date. The study was approved by the Danish Data Protection Agency. SPSS version 15.0 (SPSS, Chicago, IL, USA) and Stata version 8.0 (StataCorp, College Station, TX, USA) were used for data analysis.
Results Patients We identified 1787 patients with a biopsy-proven diagnosis of GCA, of whom 72.6% were females. The median follow-up time was 6.6 years [interquartile range (IQR) 3.110.5] for patients and 6.5 years (IQR 3.110.7) for population controls (Table 1). Median age at time of diagnosis was 74 years (IQR 66.679.1). The number of individuals diagnosed per year was evenly distributed in the study period [98 individuals/yr (IQR 83114)]. Mortality During the first 2 years following diagnosis, patients with GCA had a slightly increased mortality rate compared with population controls [MRR 1.17 (95% CI 1.01, 1.36)] (Table 2). During the period 210 years after the vasculitis diagnosis we observed no difference in mortality between patients and population controls, whereas mortality was slightly increased >10 years after the diagnosis [MRR 1.22 (95% CI 1.05, 1.41)]. The RR of death did not differ substantially by sex, age or calendar year of diagnosis (Table 2).
Statistics
Causes of death
The index date was defined as the date of diagnosis of GCA for the patients. For the population controls, the index date was defined as the date of vasculitis diagnosis
The risk of death due to diseases of the circulatory system was increased among patients compared with population controls during the period 02 years and >10 years after
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data from various Danish national registries. From the Danish National Patient Registry, which collects information on dates and diagnoses of all in- and outpatient admissions in Denmark, we identified all individuals >50 years of age who between 1993 and 2011 were registered with a clinical diagnosis of GCA [International Classification of Diseases, 10th revision (ICD-10): M35.5]. By linkage with the Danish Pathology Registry, which includes information on all pathology specimens from Danish pathology departments, we subsequently identified the subgroup of patients for whom the diagnosis of GCA had been proved by a biopsy from the temporal artery showing giant cell inflammation (Snomed classification: T45270, M40160) within 4 weeks of the clinical diagnosis. A comparison cohort of persons from the Danish background population individually matched on sex and date of birth was established by means of the Danish Civil Registration System. This cohort included 19 population controls randomly selected for each patient with GCA. We used the Danish Civil Registration System and the Danish Register of Causes of Death to obtain data on emigrations, deaths and causes of death. Study outcomes were time to death and to cause-specific death. Causes of death were classified according to the ICD-10. Deaths caused by respiratory tract infections (ICD-10: J00J22, J85J86) and genitourinary tract infections (ICD-10: N10N12, N70N74) were classified as infections rather than diseases in the respiratory or genitourinary system, respectively. We analysed death and causes of death in three time periods: 02, 210 and >10 years. This subdivision was based on the clinical course of GCA, which usually remits within 624 months of disease onset [18] and may have late involvement of the large vessels [17]. We further analysed the risk of death due to diseases affecting the arteries/circulatory system: ischaemic heart disease (ICD10: I20I25), aortic aneurism (ICD10: I71) and stroke (ICD10: I60I69).
Poisson regression analyses adjusted for sex, age, time since diagnosis and calendar year of diagnosis. MR: mortality rate; MRR: mortality rate ratio; PY: person-years.
1.41) 1.53) 1.58) 1.47) 1.78) 1.41) (1.05, (0.85, (1.13, (1.00, (1.14, (1.05, 1.22 1.15 1.33 1.21 1.42 1.22 (97.3, 129.7) (81.5, 146.2) (96.1, 133.7) (64.5, 94.6) (209.2, 323.4) (97.3, 129.7) 112.4 109.2 113.4 78.1 260.1 112.4 186 45 141 105 81 186 1.05) 1.09) 1.09) 1.17) 1.05) 1.10) 1.12) (0.88, (0.77, (0.88, (0.86, (0.84, (0.90, (0.72, 0.96 0.92 0.98 1.00 0.94 0.99 0.90 67.4) 77.9) 66.9) 42.5) 112.8) 71.4) 62.3) (56.3, (55.2, (54.2, (31.5, (90.2, (58.6, (40.5, 61.6 65.6 60.2 36.6 100.9 64.7 50.2 477 130 347 173 304 394 83 1.36) 1.50) 1.41) 1.47) 1.42) 1.39) 1.49) (1.01, (0.89, (0.98, (0.81, (1.01, (0.95, (0.91, 1.17 1.15 1.17 1.09 1.20 1.15 1.17 65.1) 88.0) 62.0) 34.8) 109.0) 68.7) 69.4) (48.7, (52.8, (43.6, (19.5, (78.0, (47.7, (43.0, 56.3 68.2 52.0 26.1 92.2 57.3 54.6 183 59 124 46 137 116 67 All Male Female Age 75 years 19932002 20032011
MR/1000 PY (95% CI) MRR (95% CI) MR/1000 PY (95% CI) MR/1000 PY (95% CI) Deaths, n
02 years
MRR (95% CI)
Deaths, n
210 years
Time since diagnosis/index date
TABLE 2 MRs and MRRs among patients with GCA
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diagnosis of GCA [MRR 1.32 (95% CI 1.04, 1.68) and 1.47 (95% CI 1.10, 1.95)]. Within the category of diseases of the circulatory system, the risk of death due to ischaemic heart disease was increased during the period 02 years after diagnosis [MRR 1.39 (95% CI 0.97, 1.98)], although not statistically significant, whereas the risk of death caused by stroke did not differ between patients and population controls (data not shown). We did find an increased rate of death due to diseases of the digestive system, with an MRR of 2.48 (95% CI 1.79, 3.43) for 02 years and 1.64 (95% CI 1.31, 2.07) for 210 years. In the period >10 years after the diagnosis, no difference could be detected between the two groups. The rates of death due to aortic aneurism were low, but higher among patients than controls [MRR 3.69 (95% CI 1.27, 10.75)] during the first 2 years after diagnosis, but no differences could demonstrated after this period. Patients had a significantly lower risk of death due to cancer than controls in the periods 02 and 210 years after diagnosis [MRR 0.47 (95% CI 0.29, 0.75) and 0.68 (95% CI 0.53, 0.87), respectively]. We did not find any increased risk of death among the following disease groups: infections, endocrine, nervous, respiratory or genitourinary systems. In all time periods the risk of death due to diseases in the musculoskeletal system and connective tissue was substantially increased in patients diagnosed with GCA.
Discussion In this large, population-based, nationwide cohort study we demonstrated increased risk of death in patients with biopsy-proven GCA during the first 2 years and >10 years after the diagnosis of vasculitis. The increase in mortality was small and mainly due to diseases of the circulatory system. Although the observed increase in mortality was modest, the large size of our patient population allowed us to assess mortality during different follow-up periods with a high degree of statistical precision. Furthermore, the fact that the GCA diagnosis was histologically proved in all cases minimizes the risk of misclassification, which could potentially have led to an overestimation of MRs. We had access to national registers that allowed us to perform analyses with long-term tracking of study subjects and negligible loss to follow-up. Importantly, data on causes of death were obtained from the same data source for GCA patients and population controls, so any potential misclassification bias would be non-differential and as such would have no impact on the estimates of RR of death. We observed high mortality due to musculoskeletal diseases in the GCA cohort, whereas almost none from the control cohort were registered as having died from musculoskeletal diseases. We presume that the increased risk of death due to musculoskeletal diseases in the GCA cohort may be a result of classification according to the underlying disease by the attending physician, who would typically be aware of the GCA diagnosis of the deceased. Incorrect listing cannot be excluded.
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Deaths, n
>10 years
MRR (95% CI)
Mortality in patients with GCA
Bo Baslund et al.
Rheumatology key messages . .
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GCA is associated with slightly increased mortality. The increased mortality was seen early (02 years) and late (>10 years) after GCA diagnosis.
Funding: None. Disclosure statement: The authors have declared no conflicts of interest.
References 1 Salvarani C, Cantini F, Boiardi L, Hunder GG. Polymyalgia rheumatica and giant cell arteritis. N Engl J Med 2002;347: 26171. 2 Espitia O, Neel A, Leux C et al. Giant cell arteritis with or without aortitis at diagnosis. A retrospective study of 22 patients with longterm followup. J Rheumatol 2012;39: 215762. 3 Prieto-Gonzalez S, Arguis P, Garcia-Martinez A et al. Large vessel involvement in biopsy-proven giant cell arteritis: prospective study in 40 newly diagnosed patients using CT angiography. Ann Rheum Dis 2012;71: 11706. 4 Evans JM, O’Fallon WM, Hunder GG. Increased incidence of aortic aneurysm and dissection in giant cell (temporal) arteritis: a population-based study. Ann Intern Med 1995; 122:5027. 5 Nuenninghoff DM, Hunder GG, Christianson TJH, McClelland RL, Matteson EL. Mortality of large-artery complication (aortic aneurysm, aortic dissection, and/or large-artery stenosis) in patients with giant cell arteritis: a population-based study over 50 years. Arthritis Rheum 2003;48:35327. 6 Gonzalez-Gay MA, Garcia-Porrua C, Pin˜eiro A et al. Aortic aneurysm and dissection in patients with biopsy-proven giant cell arteritis from northwestern Spain: a populationbased study. Medicine 2004;83:33541. 7 Gonzalez-Gay MA, Vazquez-Rodriguez TR, GomezAcebo I et al. Strokes at time of disease diagnosis in a series of 287 patients with biopsy-proven giant cell arteritis. Medicine 2009;88:22735. 8 Nordborg E, Bengtsson BA. Death rates and causes of death in 284 consecutive patients with giant cell arteritis confirmed by biopsy. BMJ 1989;299:54950. 9 Matteson EL, Gold KN, Bloch DA, Hunder GG. Long-term survival of patients with giant cell arteritis in the American College of Rheumatology giant cell arteritis classification criteria cohort. Am J Med 1996;100:1936. 10 Rajala SA, Ahvenainen JE, Mattila KJ, Saarni MI. Incidence and survival rate in cases of biopsy-proven temporal arteritis. Scand J Rheumatol 1993;22:28991. 11 Gonza´lez-Gay MA, Blanco R, Abraira V et al. Giant cell arteritis in Lugo, Spain, is associated with low longterm mortality. J Rheumatol 1997;24:21716. 12 Gran JT, Myklebust G, Wilsgaard T et al. Survival in polymyalgia rheumatica and temporal arteritis: a study of 398 cases and matched population controls. Rheumatology 2001;40:123842. 13 Bisga˚rd C, Sloth H, Keiding N, Juel K. Excess mortality in giant cell arteritis. J Intern Med 1991;230: 11923. 14 Uddhammar A, Eriksson A-L, Nystro¨m L, Stenling R, Rantapa¨a¨-Dahlqvist S. Increased mortality due to
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We observed an increased risk of death due to diseases of the circulatory system, which is in accordance with a concept of GCA as a disease affecting the aorta and its larger branches. The pathogenic events underlying the increased risk of cardiovascular deaths in the present cohort cannot be determined from our data. It is tempting to speculate that inflammation in the larger arteries may be of importance for the increased mortality observed in the first 2 years after GCA diagnosis, while relapsing or persistent vasculitis activity may have contributed pathogenically to the increased number of deaths from diseases of the circulatory system observed after prolonged follow-up. Several case series have suggested that patients with GCA are at higher risk of developing cancer. Subsequent larger studies have not been able to confirm these observations [19], and in accordance with the latter investigations we observed a decreased risk of deaths due to cancer in the GCA patients compared with the control cohort. Our findings do not substantiate that patients with GCA have an increased risk of stroke (haemorrhagic and ischaemic) [7]. Our study is limited by the lack of access to clinical information on cardiovascular risk factors, including smoking habits, pre-existing atherosclerotic disease, blood pressure levels and lipid profiles. Furthermore, due to the lack of laboratory results we could not determine potential differences in mortality between patients with high and low inflammatory response. We cannot exclude that the vasculitis diagnosis might have been overlooked in GCA patients with life-threatening cardiovascular manifestations at disease onset. We presume that the impact from such misclassification on our estimates is minor, but would lead to an underestimation of risk of death in the GCA population. Patients with GCA who have large vessel involvement less frequently have a positive temporal artery biopsy. By including only biopsyproven cases, we cannot exclude that the MR could be higher, as aortic aneurysm/dissection is associated with increased mortality in GCA [17]. Corticosteroids are very effective for the treatment of GCA, but therapy with these agents may cause serious side effects [14], including an increased risk of systemic infections during the first months of therapy [20]. We observed increased mortality from diseases of the circulatory system during early follow-up, while the risk of death due to infectious diseases was not increased in the initial period after the diagnosis of GCA. Our study demonstrates that the increased risk of death in GCA patients is minimal. Therefore patients can be reassured that their prognosis concerning risk of death is good.
Mortality in patients with GCA
cardiovascular disease in patients with giant cell arteritis in northern Sweden. J Rheumatol 2002;29:73742.
population-based cohort study of the incidence-trends and prognosis. Ann Rheum Dis 2012;72:198994.
15 Crow RW, Katz BJ, Warner JEA et al. Giant cell arteritis and mortality. J Gerontol A Biol Sci Med Sci 2009;64A: 3659.
18 Salvarani C, Pipitone N, Versari A, Hunder GG. Clinical features of polymyalgia rheumatica and giant cell arteritis. Nat Rev Rheumatol 2012;8:50921.
16 Bengtsson BA, Malmvall BE. Prognosis of giant cell arteritis including temporal arteritis and polymyalgia rheumatica. A follow-up study on ninety patients treated with corticosteroids. Acta Med Scand 1981;209:33745.
19 Kermani TA, Scha¨fer VS, Crowson CS et al. Malignancy risk in patients with giant cell arteritis: a population-based cohort study. Arthritis Care Res 2010;62:14954.
17 Kermani TA, Warrington KJ, Crowson CS et al. Large-vessel involvement in giant cell arteritis: a
20 Durand M, Thomas SL. Incidence of infections in patients with giant cell arteritis: a cohort study. Arthritis Care Res 2012;64:5818.
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RHEUMATOLOGY
Concise report Mortality in patients with giant cell arteritis Bo Baslund1, Marie Helleberg1, Mikkel Faurschou1 and Niels Obel1 Abstract Objective. The aim of this study was to examine whether GCA is associated with increased mortality.
Conclusion. GCA is associated with slightly increased early and late mortality. Key words: GCA, mortality, cardiovascular disease, aortic aneurysm, epidemiology, cancer.
Introduction GCA is the most frequently diagnosed vasculitis in adults. The presenting symptoms include new-onset headache, scalp tenderness and jaw claudication [1]. Although the disease has a predilection for the extra-cranial branches of the carotid artery, disease activity in the aorta is frequently present [1]. The proportion of patients with aortic involvement is not well established, with incidence estimates for aortic involvement ranging from 10 to 65% [26]. Patients with GCA have an increased risk of being diagnosed with aortic aneurysms and cardiovascular diseases [4, 7], which suggests that the mortality in this population might be increased. However, published data on mortality in patients with GCA are conflicting. Some studies have demonstrated mortality rates (MRs) comparable to those of the background population among GCA patients [812], while other investigations have shown increased [1315] or decreased mortality [16, 17]. In
1 Department of Infectious Disease and Rheumatology, Rigshospitalet, Copenhagen, Denmark
Submitted 11 December 2013; revised version accepted 9 June 2014. Correspondence to: Bo Baslund, Department of Infectious Disease and Rheumatology, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: [email protected]
some analyses, an increased rate of death was only found among patients with aortic involvement [5, 17]. However, most of these studies are hampered by small sample size, lack of well-matched comparison cohorts, inclusion of patients without biopsy-proven vasculitis and non-population-based study designs. To determine the relative risk of death and causes of death in patients with GCA, we conducted a populationbased, nationwide cohort study of the mortality in patients with biopsy-proven GCA.
Methods Denmark has a population of 5.5 million citizens, of whom 2.0 million are >50 years of age. We established a cohort that included all Danish citizens >50 years of age who were diagnosed with biopsy-proven GCA during the period 19932011 and an age- and sex-matched comparison cohort from the background population. In Denmark, patients with GCA are treated in hospital departments that specialize in rheumatology or internal medicine. Health care is funded through taxes and is therefore free of charge. We used the unique 10-digit civil registration number assigned to all individuals in Denmark at birth or upon immigration and stored in the Danish Civil Registration System to track patients and link
! The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
CLINICAL SCIENCE
Results. Compared with the general population, the relative risk (RR) of death in patients diagnosed with GCA was 1.17 (95% CI 1.01, 1.36) and 1.22 (95% CI 1.05, 1.41) 02 years and >10 years after diagnosis, respectively, whereas we observed no increased mortality during the follow-up period of 210 years [RR 0.96 (95% CI 0.88, 1.05)]. The increased mortality during the first 2 years of follow-up was mainly due to diseases of the circulatory system, including aortic aneurisms.
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Methods. We conducted a nationwide population-based cohort study including all individuals who between 1993 and 2011 were registered in the Danish National Hospital Register and the Danish Pathology Register with a biopsy-proven diagnosis of GCA (n = 1787). Through the Danish Civil Registration System we identified a comparison cohort of 33 953 persons from the background population, individually matched on age and sex. Data on causes of death were obtained from the Danish Registry of Causes of Death. We used Poisson regression to determine mortality rate ratios as estimates of relative risk of death and specific causes of death.
Bo Baslund et al.
TABLE 1 Characteristics of the study population
Number Total follow-up time, years Follow-up time, median (IQR), years Deaths, n Age at diagnosis/index date, median (IQR), years Female, n (%)
GCA patients
Background population controls
1787 12 649 6.6 (3.110.5) 846 74 (6979) 1298 (72.6)
33 953 243 862 6.5 (3.110.7) 15,484 74 (6979) 24 662 (72.6)
IQR: interquartile range.
of the patients to whom they were matched. Observation time was calculated from the index date to the date of emigration, death or 6 November 2011, whichever came first. MRs with 95% CIs were calculated as the number of deaths per 1000 person-years (PY) under the assumption of a Poisson distribution. We used Poisson regression analyses to calculate MR ratios (MRRs) as estimates of RR. Age (in 10-year intervals) and calendar year (in 5-year intervals) were included as time-updated variables. Analyses were stratified by sex, age, time since index date and calendar year of index date. The study was approved by the Danish Data Protection Agency. SPSS version 15.0 (SPSS, Chicago, IL, USA) and Stata version 8.0 (StataCorp, College Station, TX, USA) were used for data analysis.
Results Patients We identified 1787 patients with a biopsy-proven diagnosis of GCA, of whom 72.6% were females. The median follow-up time was 6.6 years [interquartile range (IQR) 3.110.5] for patients and 6.5 years (IQR 3.110.7) for population controls (Table 1). Median age at time of diagnosis was 74 years (IQR 66.679.1). The number of individuals diagnosed per year was evenly distributed in the study period [98 individuals/yr (IQR 83114)]. Mortality During the first 2 years following diagnosis, patients with GCA had a slightly increased mortality rate compared with population controls [MRR 1.17 (95% CI 1.01, 1.36)] (Table 2). During the period 210 years after the vasculitis diagnosis we observed no difference in mortality between patients and population controls, whereas mortality was slightly increased >10 years after the diagnosis [MRR 1.22 (95% CI 1.05, 1.41)]. The RR of death did not differ substantially by sex, age or calendar year of diagnosis (Table 2).
Statistics
Causes of death
The index date was defined as the date of diagnosis of GCA for the patients. For the population controls, the index date was defined as the date of vasculitis diagnosis
The risk of death due to diseases of the circulatory system was increased among patients compared with population controls during the period 02 years and >10 years after
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data from various Danish national registries. From the Danish National Patient Registry, which collects information on dates and diagnoses of all in- and outpatient admissions in Denmark, we identified all individuals >50 years of age who between 1993 and 2011 were registered with a clinical diagnosis of GCA [International Classification of Diseases, 10th revision (ICD-10): M35.5]. By linkage with the Danish Pathology Registry, which includes information on all pathology specimens from Danish pathology departments, we subsequently identified the subgroup of patients for whom the diagnosis of GCA had been proved by a biopsy from the temporal artery showing giant cell inflammation (Snomed classification: T45270, M40160) within 4 weeks of the clinical diagnosis. A comparison cohort of persons from the Danish background population individually matched on sex and date of birth was established by means of the Danish Civil Registration System. This cohort included 19 population controls randomly selected for each patient with GCA. We used the Danish Civil Registration System and the Danish Register of Causes of Death to obtain data on emigrations, deaths and causes of death. Study outcomes were time to death and to cause-specific death. Causes of death were classified according to the ICD-10. Deaths caused by respiratory tract infections (ICD-10: J00J22, J85J86) and genitourinary tract infections (ICD-10: N10N12, N70N74) were classified as infections rather than diseases in the respiratory or genitourinary system, respectively. We analysed death and causes of death in three time periods: 02, 210 and >10 years. This subdivision was based on the clinical course of GCA, which usually remits within 624 months of disease onset [18] and may have late involvement of the large vessels [17]. We further analysed the risk of death due to diseases affecting the arteries/circulatory system: ischaemic heart disease (ICD10: I20I25), aortic aneurism (ICD10: I71) and stroke (ICD10: I60I69).
Poisson regression analyses adjusted for sex, age, time since diagnosis and calendar year of diagnosis. MR: mortality rate; MRR: mortality rate ratio; PY: person-years.
1.41) 1.53) 1.58) 1.47) 1.78) 1.41) (1.05, (0.85, (1.13, (1.00, (1.14, (1.05, 1.22 1.15 1.33 1.21 1.42 1.22 (97.3, 129.7) (81.5, 146.2) (96.1, 133.7) (64.5, 94.6) (209.2, 323.4) (97.3, 129.7) 112.4 109.2 113.4 78.1 260.1 112.4 186 45 141 105 81 186 1.05) 1.09) 1.09) 1.17) 1.05) 1.10) 1.12) (0.88, (0.77, (0.88, (0.86, (0.84, (0.90, (0.72, 0.96 0.92 0.98 1.00 0.94 0.99 0.90 67.4) 77.9) 66.9) 42.5) 112.8) 71.4) 62.3) (56.3, (55.2, (54.2, (31.5, (90.2, (58.6, (40.5, 61.6 65.6 60.2 36.6 100.9 64.7 50.2 477 130 347 173 304 394 83 1.36) 1.50) 1.41) 1.47) 1.42) 1.39) 1.49) (1.01, (0.89, (0.98, (0.81, (1.01, (0.95, (0.91, 1.17 1.15 1.17 1.09 1.20 1.15 1.17 65.1) 88.0) 62.0) 34.8) 109.0) 68.7) 69.4) (48.7, (52.8, (43.6, (19.5, (78.0, (47.7, (43.0, 56.3 68.2 52.0 26.1 92.2 57.3 54.6 183 59 124 46 137 116 67 All Male Female Age 75 years 19932002 20032011
MR/1000 PY (95% CI) MRR (95% CI) MR/1000 PY (95% CI) MR/1000 PY (95% CI) Deaths, n
02 years
MRR (95% CI)
Deaths, n
210 years
Time since diagnosis/index date
TABLE 2 MRs and MRRs among patients with GCA
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diagnosis of GCA [MRR 1.32 (95% CI 1.04, 1.68) and 1.47 (95% CI 1.10, 1.95)]. Within the category of diseases of the circulatory system, the risk of death due to ischaemic heart disease was increased during the period 02 years after diagnosis [MRR 1.39 (95% CI 0.97, 1.98)], although not statistically significant, whereas the risk of death caused by stroke did not differ between patients and population controls (data not shown). We did find an increased rate of death due to diseases of the digestive system, with an MRR of 2.48 (95% CI 1.79, 3.43) for 02 years and 1.64 (95% CI 1.31, 2.07) for 210 years. In the period >10 years after the diagnosis, no difference could be detected between the two groups. The rates of death due to aortic aneurism were low, but higher among patients than controls [MRR 3.69 (95% CI 1.27, 10.75)] during the first 2 years after diagnosis, but no differences could demonstrated after this period. Patients had a significantly lower risk of death due to cancer than controls in the periods 02 and 210 years after diagnosis [MRR 0.47 (95% CI 0.29, 0.75) and 0.68 (95% CI 0.53, 0.87), respectively]. We did not find any increased risk of death among the following disease groups: infections, endocrine, nervous, respiratory or genitourinary systems. In all time periods the risk of death due to diseases in the musculoskeletal system and connective tissue was substantially increased in patients diagnosed with GCA.
Discussion In this large, population-based, nationwide cohort study we demonstrated increased risk of death in patients with biopsy-proven GCA during the first 2 years and >10 years after the diagnosis of vasculitis. The increase in mortality was small and mainly due to diseases of the circulatory system. Although the observed increase in mortality was modest, the large size of our patient population allowed us to assess mortality during different follow-up periods with a high degree of statistical precision. Furthermore, the fact that the GCA diagnosis was histologically proved in all cases minimizes the risk of misclassification, which could potentially have led to an overestimation of MRs. We had access to national registers that allowed us to perform analyses with long-term tracking of study subjects and negligible loss to follow-up. Importantly, data on causes of death were obtained from the same data source for GCA patients and population controls, so any potential misclassification bias would be non-differential and as such would have no impact on the estimates of RR of death. We observed high mortality due to musculoskeletal diseases in the GCA cohort, whereas almost none from the control cohort were registered as having died from musculoskeletal diseases. We presume that the increased risk of death due to musculoskeletal diseases in the GCA cohort may be a result of classification according to the underlying disease by the attending physician, who would typically be aware of the GCA diagnosis of the deceased. Incorrect listing cannot be excluded.
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GCA is associated with slightly increased mortality. The increased mortality was seen early (02 years) and late (>10 years) after GCA diagnosis.
Funding: None. Disclosure statement: The authors have declared no conflicts of interest.
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We observed an increased risk of death due to diseases of the circulatory system, which is in accordance with a concept of GCA as a disease affecting the aorta and its larger branches. The pathogenic events underlying the increased risk of cardiovascular deaths in the present cohort cannot be determined from our data. It is tempting to speculate that inflammation in the larger arteries may be of importance for the increased mortality observed in the first 2 years after GCA diagnosis, while relapsing or persistent vasculitis activity may have contributed pathogenically to the increased number of deaths from diseases of the circulatory system observed after prolonged follow-up. Several case series have suggested that patients with GCA are at higher risk of developing cancer. Subsequent larger studies have not been able to confirm these observations [19], and in accordance with the latter investigations we observed a decreased risk of deaths due to cancer in the GCA patients compared with the control cohort. Our findings do not substantiate that patients with GCA have an increased risk of stroke (haemorrhagic and ischaemic) [7]. Our study is limited by the lack of access to clinical information on cardiovascular risk factors, including smoking habits, pre-existing atherosclerotic disease, blood pressure levels and lipid profiles. Furthermore, due to the lack of laboratory results we could not determine potential differences in mortality between patients with high and low inflammatory response. We cannot exclude that the vasculitis diagnosis might have been overlooked in GCA patients with life-threatening cardiovascular manifestations at disease onset. We presume that the impact from such misclassification on our estimates is minor, but would lead to an underestimation of risk of death in the GCA population. Patients with GCA who have large vessel involvement less frequently have a positive temporal artery biopsy. By including only biopsyproven cases, we cannot exclude that the MR could be higher, as aortic aneurysm/dissection is associated with increased mortality in GCA [17]. Corticosteroids are very effective for the treatment of GCA, but therapy with these agents may cause serious side effects [14], including an increased risk of systemic infections during the first months of therapy [20]. We observed increased mortality from diseases of the circulatory system during early follow-up, while the risk of death due to infectious diseases was not increased in the initial period after the diagnosis of GCA. Our study demonstrates that the increased risk of death in GCA patients is minimal. Therefore patients can be reassured that their prognosis concerning risk of death is good.
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