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Risk of mortality in patients with giant cell arteritis: A systematic review and meta-analysis
Author’s Accepted Manuscript Risk of mortality in patients with giant cell arteritis: A systematic review and meta-analysis Catherine L. Hill, Rachel J. Black, Johannes Nossent, Carlee Ruediger, Leanne Nguyen, Jem Ninan, Susan Lester www.elsevier.com/locate/semarthrit
PII: DOI: Reference:
S0049-0172(16)30143-3 http://dx.doi.org/10.1016/j.semarthrit.2016.08.015 YSARH51100
To appear in: Seminars in Arthritis and Rheumatism Received date: 25 July 2016 Revised date: 23 August 2016 Accepted date: 23 August 2016 Cite this article as: Catherine L. Hill, Rachel J. Black, Johannes Nossent, Carlee Ruediger, Leanne Nguyen, Jem Ninan and Susan Lester, Risk of mortality in patients with giant cell arteritis: A systematic review and meta-analysis, Seminars in Arthritis and Rheumatism, http://dx.doi.org/10.1016/j.semarthrit.2016.08.015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Risk of Mortality in Patients with Giant Cell Arteritis: A Systematic Review and Meta-Analysis Catherine L Hill (1,2,3) Rachel J Black (2,3) Johannes Nossent (4) Carlee Ruediger (1,2) Leanne Nguyen (2) Jem Ninan (2,5) Susan Lester (1) (1) (2) (3) (4) (5) (6)
Rheumatology Unit, The Queen Elizabeth Hospital, Woodville, Australia Discipline of Medicine, University of Adelaide, Adelaide, Australia Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia Medicine, University of Western Australia, Australia Rheumatology Unit, Modbury Hospital, Modbury, Australia Basil Hetzel Institute, QEH, Woodville South, Australia
Corresponding Author: Professor Catherine L Hill Email: [email protected] Keywords: Giant Cell Arteritis Mortality Systematic Review Meta-analysis Source of Funding: Nil Disclosures: No conflicts of interest to declart
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ABSTRACT Background: Previous studies of mortality associated with GCA have shown conflicting results. We conducted a systematic review and meta-analysis to determine the mortality risk in GCA patients compared to the general population. Methods: We searched for published studies indexed in MEDLINE and EMBASE and the Cochrane database from inception to June 18, 2015 using the terms “giant cell arteritis” and “temporal arteritis” combined with the terms for death, mortality and survival. A manual search of citations from retrieved articles was also performed. The inclusion criteria were (1) observational studies of mortality in GCA (2) comparison of mortality to the general population. Studies published only in abstract form were excluded. Study eligibility and quality (Newcastle-Ottawa scale) were independently assessed by at least two investigators. Random effects meta-analysis of the mortality ratio (MR) was performed by the inverse variance method. Results: Out of 435 potentially relevant articles, 64 studies were reviewed, 19 studies were included in the review and 17 studies were included in the meta-analysis. Mortality was not increased in GCA patients ascertained from a population base (MR 1.03, 95% CI 0.96, 1.10), but was increased in patients ascertained from a hospital setting (MR 1.61, 95% CI 1.19, 2.19). There was no difference in MR by gender, and two studies provided evidence that mortality was increased in the early years following diagnosis. Conclusion: At a population level, long-term mortality is not increased in GCA. However, mortality risk may be increased in some patients, and may vary over time.
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INTRODUCTION Giant cell arteritis (GCA) is the commonest form of vasculitis in the elderly, which, untreated, can cause blindness and stroke [1]. The only known treatment currently demonstrated to avert the complications of GCA, such as blindness and stroke, are high dose corticosteroids [1]. However, high dose corticosteroids have significant and consistent adverse effects. Intuitively, it could be expected that GCA diagnosis would have an impact on mortality, given the complications of the disease and the necessary treatment, particularly in the elderly age group that are affected by GCA [2, 3]. However, previous studies of GCA have differed in the outcomes regarding mortality, in comparison with age- and sex-matched population controls. A previous expert review of the current literature related to impact of rheumatic diseases on mortality recommended a meta-analysis of mortality in GCA [4]. The aim of this study was to determine the relationship of GCA to mortality, using a systematic review and meta-analysis of cohort studies comparing mortality between patients with GCA and the general population.
METHODS Search Strategy The search strategy was developed and performed by a medical librarian (Supplementary File A). A search for published studies indexed in MEDLINE, EMBASE and the Cochrane database was carried out from inception to June 18, 2015 using the terms “giant cell arteritis” and “temporal arteritis” combined with terms for death, mortality and survival. A manual search of citations from retrieved articles was also performed. Conference abstracts and unpublished studies were not included. Inclusion Criteria The inclusion criteria were as follows: (1) published, peer-reviewed studies reporting mortality incidence in patients with GCA (2) statistical comparison of mortality in GCA patients to that of the general population. No language limitation was imposed, and translation from French, Dutch and
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Norwegian was performed by one of the authors (JN) as required. If a study contained patients that were included in a later analysis of the same cohort, the later report was used. Study eligibility was independently determined by three investigators (CH, RB, JN). Differing decisions were resolved by consensus with a fourth reviewer (SL). Quality Assessment The quality of each study was independently assessed by two investigators (CH, RB) using the Newcastle-Ottawa Quality Assessment Scale for the assessment of quality of non-randomised studies in meta-analysis [5]. This is an eight-item scale addressing selection and comparability of cases and controls, outcome assessment and follow-up. Each item was graded as low or uncertain risk, and results presented graphically. Data Extraction Two investigators (CH, SL) independently extracted data using a standardized data collection form. Data extracted included: first author, article title, publication year, country where the study was conducted, language, number of GCA patients, GCA diagnostic criteria used, verification of death, mean and maximum duration of follow-up, and reported mortality data. Statistical Analysis Studies were included in the quantitative synthesis if numerical data was extractable from the published paper. This included studies in which the standardized mortality ratio (SMR), relative risk (RR’s) or hazard ratio (HRs) were provided. Where necessary, the HR/SMR was imputed from published digitized survival curves or reported log-rank p values, assuming an exponential survival model (Supplementary File B). Random effects meta-analysis was performed using the natural logarithm of the SMR/HR/RR statistic using the generic inverse variance method. Estimation was performed by restricted maximum likelihood (REML), with the Knapp-Hartung adjustment [6]. Statistical heterogeneity was assessed using the I2 statistic, which quantifies the proportion of total variation across studies that is due to heterogeneity rather than chance. A value of I2 of 0-25% represents insignificant heterogeneity, 25-
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50% low heterogeneity, 50-75% moderate heterogeneity and 75-100% high heterogeneity. Prespecified moderator analysis to explore heterogeneity between studies, was performed by metaregression and consisted of study publication date, follow-up duration and data imputation. Pre-specified, within-study subgroup analyses for gender and time following GCA diagnosis were performed using multilevel mixed models. All analyses were performed using the R library metafor [7, 8].
RESULTS Included Studies The search strategy yielded 435 potentially relevant articles, 64 studies were assessed for eligibility (Supplementary file C, Table S1), and 45 studies were subsequently excluded (Figure 1). Although not formally included in the meta-analysis, six of these studies were identified as providing supplementary information relevant to causes and predictors of mortality in GCA [9-14]. Nineteen studies (18 published in English and one in Norwegian) were included in the systematic review [1533], with publication dates ranging from 1979-2015, and demographic data is presented in Table 1. In total, there were 4873 cases of GCA (study range 34-1787). The majority of studies were from Nordic countries (n=9), North America (3), France (2), UK (2), Spain (1), Israel (1) and Australia (1). The quality of the included studies was variable, although most studies were considered at low risk of bias in the majority of categories. (Figure 2). Combined Mortality Ratio in GCA patients The necessary mortality data could not be extracted from two studies, therefore the quantitative synthesis consisted of 17 studies [15-18, 20, 22-33], with a total of 4,733 GCA patients and 1,853 observed deaths. The overall analysis indicated a significant increase in mortality in GCA patients, with a combined Mortality Ratio (MR): 1.17 (95% CI 1.02, 1.35, p = 0.031), Figure 3. However, there was also evidence of substantial heterogeneity between studies (I2 = 76.5%), which makes the generalizability and
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interpretation of this result problematic. Although not a pre-specified analysis, patient ascertainment was identified as the major contributor to this between study heterogeneity. GCA cohorts were either ascertained through a population (n = 11) or hospital setting (n = 6), and subsequent subgroup analysis demonstrated a substantial reduction in overall heterogeneity when this was accounted for (I2 reduction from 76.5% to 36.8%), Figure 4. The 11 studies where GCA patients were ascertained from a population setting [15, 17, 20, 23-25, 28, 30-33] were remarkably homogeneous, and demonstrated no evidence of increased in mortality in GCA patients (MR: 1.03 (95% CI 0.96, 1.10), p = 0.35, I2 = 15.4%). In contrast, the six studies where GCA patients were recruited through a hospital setting [16, 18, 22, 26, 27, 29] were more heterogeneous, and there was an overall significant increase in mortality in these patients (MR: 1.61 (95% CI 1.19, 2.19), p = 0.010, I2 = 58.2%). This difference in mortality ratios between the two study subgroups was statistically significant (p = 0.001). Additional, pre-specified subgroup analyses indicated that publication year, maximum follow-up time, and data imputations did not impact substantively on results in terms of either heterogeneity or effect sizes. Of the two studies not included in the quantitative synthesis, the first was a Norwegian single centre study of 53 GCA patients followed up over to 15 years [19]. The authors reported no specific mortality data in the paper, other than stating that survival in GCA patients was comparable to that of the general population. The second study, Gouet 1985 [21], was a French single centre study of 87 GCA patients followed up to 12 years. Although an observed-expected survival curve was reported in the paper, this study was not included in the quantitative synthesis because there were clear violations of the constant hazards and proportional hazards assumptions required for imputation of the mortality ratio (Supplementary File B). Although the survival curve suggested some increased mortality in GCA patients, particularly over the first four years, the observed and expected proportions surviving at the end of the study were comparable. Change in Mortality Ratio over Time
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Although there was no evidence that differences in follow-up duration influenced between-study mortality ratio effect sizes (p = 0.41), the majority of these studies evaluated mortality after long term follow up (10 years or more). Therefore, the question remains as to whether mortality is specifically increased in the early years after initiation of high dose glucocorticoid therapy. Two recent, population-based Scandinavian studies, Baslund 2015 [15] (n = 1747) and Mohammad 2015 [28] (n = 840) were large enough to specifically address this question, and both reported a decline in the mortality ratio over time. Both studies reported a significantly increased mortality ratio at two years after treatment (combined estimate MR = 1.31 (95% CI 1.07, 1.61), p = 0.008) but no difference in mortality at a follow-up of more than 10 years (combined estimate MR = 0.98 (95% CI 0.83, 1.17), p = 0.80). The difference in mortality ratio between these two time points was statistically significant, p = 0.040 (within study comparison), however there was also evidence of considerable heterogeneity in the mortality ratios between the two studies (I2 = 74.8%). Differences in Mortality Ratios between Males and Females The breakdown of mortality by gender was available for 11 studies [15, 17, 20, 22-24, 27, 28, 30, 32, 33], which were predominantly population based GCA cohorts. There was no evidence of an increase in mortality in either males: Mortality ratio 0.98 (95% CI 0.91, 1.06, I2 = 0.0%), or females: MR: 1.07 (95% CI 0.97, 1.17, I2 =14.2%). The difference in mortality ratios between male and female GCA patients was not statistically significant (p = 0.20, within study comparison). Causes of death A subgroup of seven studies detailed the causes of death in GCA patients [17, 20-22, 27, 29, 30], which are tabulated in Table 2. This demonstrated that the leading causes of death were cardiovascular disease (39%) followed by cerebrovascular disease (14%), infection (13%) and malignancy (12%). However, differences in the methods used to code deaths between studies, make it difficult to directly compare.
DISCUSSION
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In this first meta-analysis and systematic review of mortality in GCA compared to the general population, long-term mortality, at a population level, was not increased (MR 1.03, 95% CI 0.96, 1.10) and no difference in mortality between males (MR 0.98, 95% CI 0.91, 1.06) and females (MR 1.07, 95% CI 0.97, 1.17) was seen. These results are reassuring given that untreated, GCA is a disease with serious, life threatening sequelae and high-dose glucocorticoid treatment is associated with significant concomitant risk, particularly in elderly patients. However, the finding that GCA is not associated with excess mortality requires qualification. Firstly, there is evidence that GCA mortality may be specifically increased within the first two years following diagnosis and initiation of treatment, although only two studies specifically examined this [15, 28]. Secondly, mortality is increased in GCA patients recruited through a hospital setting (MR 1.61, 95% CI 1.19, 2.19). This finding, although not a pre-specified subgroup analysis, is neither unexpected nor surprising. Reported prognostic factors for increased mortality in GCA patients include comorbid disease [9, 26], visual loss [11, 12] and higher maintenance glucocorticoid doses [11-13, 33]. It is likely that comorbid conditions and more severe, difficult to control disease contribute to the higher mortality observed in GCA patients ascertained through a hospital setting. When reported, the most frequent causes of death, were cardiovascular disease (CVD) (39%) followed by cerebrovascular disease (14%), infection (13%) and malignancy (12%). Stroke is a known complication of untreated GCA, yet there does not appear to be an increased risk of death in GCA patients due to cerebrovascular disease [15, 20, 24], which may be interpreted as a measure of treatment success. Similarly, there are no reports of an increased, cause-specific, risk of death in GCA patients due to malignancy [9, 15, 20, 25, 31]. While two studies reported no cause-specific increase in mortality in GCA patients due to infections, [15, 25], a disproportionate contribution of infections to deaths in the first year has also been identified [29, 30], which may possibly be attributable to immunosuppression following treatment initiation. The evidence in relation to CVD is more variable, and may be in part due to difficulties in distinguishing between atherosclerotic disease and the vasculitic vessel wall changes that can be
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seen in GCA. Several studies have reported that mortality is increased in GCA patients with CVD compared to GCA patients without CVD [10, 13, 20, 26, 32]. Other studies have been unable to demonstrate a cause-specific increased risk of death due to CVD in GCA patients compared to the general population [10, 20, 24, 25]. The presence of traditional cardiovascular disease risk factors at the time of disease diagnosis, in particular hypertension, has been found to increase the risk of cerebrovascular accidents in biopsy proven-GCA patients [34], and there may in fact be an increased risk of death due to CVD in the first one to two years following GCA diagnosis [15]. In contrast GCA patients, who were currently off glucocorticoid therapy and had at least 3 years of follow-up, showed less carotid intima-media thickness compared to matched controls and did not have higher subclinical macrovascular atherosclerotic disease [35], an unexpected finding given that glucocorticoid treatment is known to increase cardiovascular disease risk. More recently, attention has focused on a subgroup of GCA patients with aortic involvement (aneurysm and/or dissection), in whom mortality appears to be increased [15, 25]. Deaths attributed to gastrointestinal (GI) problems comprised 4% of the deaths tabulated in this review. Increased mortality due to both vascular and GI (ulcer/hemorrhagic) bleeding has also been reported [15, 25]. Strengths of this study include its systematic and rigorous methodology with multiple investigators involved in the assessment for eligibility, data extraction and quality assessment. In addition, it is a relatively large systematic review, despite eligibility criteria that selected studies with a low risk of bias, as indicated by the quality assessment. It also did not exclude studies on the basis of language. A limitation of this review is that no markers of disease severity, glucocorticoid dose or toxicity could be included. Few studies reported on the cause of mortality in GCA and specific causes could therefore not be quantified. Further there was limited data addressing increased mortality in the first one to two years following diagnosis, and there may have been incomplete capture of late complications (such as aortic aneurysm/dissection) due to the variable length of follow-up in the included studies.
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The main conclusions of this study, which are well supported by the available data are that (1) at a population level, there is no long term mortality associated with GCA and (2) the mortality ratio does not differ according to gender. However, patients diagnosed and treated in the hospital setting may be at higher mortality risk compared to GCA patients in the population as a whole. This potentially reflects that hospital patients have more severe, difficult to control disease and possibly more complicated disease due to the effects of comorbidities further research is required to evaluate the prognosis of such patients, in particular, those with more widespread aortic involvement. Further consideration of the potential contribution to mortality of glucocorticoid side effects, such as infections, and gastrointestinal bleeding is also warranted.
ACKNOWLEDGEMENTS We would like to acknowledge the input of Anna Holasek, Medical Librarian, Central Adelaide Local Health Network, with the literature search and strategy.
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22. Graham E, Holland A, Avery A, Russell RW. Prognosis in giant-cell arteritis. Br Med J (Clin Res Ed). 1981 Jan 24; 282(6260):269-271. 23. Gran JT, Myklebust G, Wilsgaard T, Jacobsen BK. Survival in polymyalgia rheumatica and temporal arteritis: a study of 398 cases and matched population controls. Rheumatology (Oxford). 2001 Nov; 40(11):1238-1242. 24. Jonasson F, Cullen JF, Elton RA. Temporal arteritis. A 14-year epidemiological, clinical and prognostic study. Scott Med J. 1979 Apr; 24(2):111-117. 25. Kermani TA, Warrington KJ, Crowson CS, Ytterberg SR, Hunder GG, Gabriel SE, et al. Largevessel involvement in giant cell arteritis: a population-based cohort study of the incidence-trends and prognosis. Ann Rheum Dis. 2013 Dec; 72(12):1989-1994. 26. Le Page L, Duhaut P, Seydoux D, Bosshard S, Ecochard R, Abbas F, et al. [Incidence of cardiovascular events in giant cell arteritis: preliminary results of a prospective double cohort study (GRACG)]. Rev Med Interne. 2006 Feb; 27(2):98-105. 27. 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 Feb; 100(2):193-196. 28. Mohammad AJ, Nilsson JA, Jacobsson LT, Merkel PA, Turesson C. Incidence and mortality rates of biopsy-proven giant cell arteritis in southern Sweden. Ann Rheum Dis. 2015 Jun; 74(6):993997. 29. Nesher G, Sonnenblick M, Friedlander Y. Analysis of steroid related complications and mortality in temporal arteritis: a 15-year survey of 43 patients. J Rheumatol. 1994 Jul; 21(7):12831286. 30. Ninan J, Nguyen AM, Cole A, Rischmueller M, Dodd T, Roberts-Thomson P, et al. Mortality in patients with biopsy-proven giant cell arteritis: a South Australian population-based study. J Rheumatol. 2011 Oct; 38(10):2215-2217. 31. Nordborg E, Bengtsson BA. Death rates and causes of death in 284 consecutive patients with giant cell arteritis confirmed by biopsy. BMJ. 1989 Aug 26; 299(6698):549-550. 32. Rajala SA, Ahvenainen JE, Mattila KJ, Saarni MI. Incidence and survival rate in cases of biopsyproven temporal arteritis. Scand J Rheumatol. 1993; 22(6):289-291. 33. Uddhammar A, Eriksson AL, Nystrom L, Stenling R, Rantapaa-Dahlqvist S. Increased mortality due to cardiovascular disease in patients with giant cell arteritis in northern Sweden. J Rheumatol. 2002 Apr; 29(4):737-742. 34. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Gomez-Acebo I, Pego-Reigosa R, Lopez-Diaz MJ, Vazquez-Trinanes MC, et al. Strokes at time of disease diagnosis in a series of 287 patients with biopsy-proven giant cell arteritis. Medicine (Baltimore). 2009 Jul; 88(4):227-235. 35. Gonzalez-Juanatey C, Lopez-Diaz MJ, Martin J, Llorca J, Gonzalez-Gay MA. Atherosclerosis in patients with biopsy-proven giant cell arteritis. Arthritis Rheum. 2007 Dec 15; 57(8):1481-1486.
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FIGURES
Figure 1. Flow diagram for included studies
PMR = Polymyalgia Rheumatica
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Figure 2. Quality assessment of included studies (Newcastle-Ottawa assessment tool [5])
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Figure 3. Random effects meta-analysis of the mortality ratio in Giant Cell Arteritis (GCA) patients compared to age and gender matched population controls. Seventeen studies were included in the meta-analysis. There was substantial heterogeneity between studies which could largely be attributed to whether patients were ascertained from a population base (n = 11) or a hospital setting (n = 6), which resulted in a reduction in I2 from 76.5% to 36.8%. In contrast to GCA patients ascertained from a hospital setting, there was no excess in long-term mortality in GCA patients ascertained from a population base.
n.GCA = number of GCA patients in the study; n.Deaths = number of deaths in GCA patients; F/up = maximum duration of follow-up; RE = Random Effects
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Figure 4. Random effects meta-analysis of the mortality ratio in male and female patients with Giant Cell Arteritis (GCA) compared to age and gender matched population controls. Mortality data for both males and females was available for a subgroup of 11 studies, which were predominantly population based cohorts. There was no excess mortality in either males or females, and no evidence of a difference in mortality ratios between males and females.
n.GCA = number of GCA patients in the study; n. Deaths = number of deaths in GCA patients; Cohort = whether patients were ascertained from a population or hospital setting; RE = Random Effects
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Table 1. Characteristics of included studies.
Study
Jonasson , 1979 [24]
Cou ntry
Scotl and
Area
Lothian region
ACR crit eria
FollowUp
Controls
Relevant Outcomes
Quantitative Synthesis
1
Biop sy Prov en
74 %
7 3
100 %
NR
~ 50 months (mean)
Population mortality rates
Observed/Expected deaths (graph format)
Yes
100 %
NR
60 months (mean)
Population mortality rates
Observed/Expected survival curves & p values (by gender), GCA deaths
Yes (imputed)
NR
15 years (maxim um)
Population mortality rates
GCA deaths only; no expected data reported
No. Insufficient data
Population mortality rates
Observed/Expected survival curve, GCA deaths
No. Data unsuitable for imputation.
Lan gua ge
%F em ale
Eng lish
A g e
Graham, 1981 [22]
UK
3 centres, London
Eng lish
71 %
5 5 8 8
Fjermest ad, 1983 [19]
Nor way
Single centre, Trondheim
Nor weg ian
57 %
7 1
100 %
Gouet, 1985 [21]
Fran ce
Single centre, Poitiers
Eng lish
60 %
7 3
100 %
NR
60 months (mean)
Boesen, 1987 [17]
Den mar k
Ribe County
Eng lish
83 %
7 0
33%
100 %
3 year (maxim um)
Population mortality rates
Observed/Expected deaths
Yes
Nordbor g, 1989 [31]
Swe den
Goteborg
Eng lish
NR
N R
100 %
NR
> 10 year (maxim um)
Population mortality rates
Observed/Expected deaths
Yes
Bisgard, 1991 [16]
Den mar k
Single centre, Holstebro Hospital
Eng lish
NR
7 1
100 %
NR
13 year maximu m
Population mortality rates
Standardised Mortality Ratio
Yes
Rajala, 1993 [32]
Finl and
Tampere
Eng lish
74 %
7 2
100 %
NR
NR
Population mortality rates
Relative survival, GCA survival at 5 & 10 years, GCA deaths
Yes (imputed)
Nesher, 1994 [29]
Isra el
Single centre, Jerusalem
Eng lish
65 %
7 6
91%
100 %
36 months (mean)
Population mortality rates
Standardised Mortality Ratio
Yes
Matteso n, 1996 [27]
USA / Cana da
Rheumatolo gy Centres (28)
Eng lish
75 %
N R
NR
100 %
85 months (mean)
Population mortality rates
Standardised Mortality Ratio
Yes
Gonzalez -Gay, 1997[20 ]
Spai n
NW Spain
Eng lish
46 %
7 4
100 %
NR
54 months (median )
Population mortality rates
Standardised Mortality Ratio
Yes
Gran, 2001 [23]
Nor way
Aust Agder county
Eng lish
77 %
N R
100 %
100 %
64 months (mean)
Population controls (4:1)
Relative Risk
Yes
Uddham mar, 2002
Swe den
Västerbotte n, Northern Sweden
Eng lish
NR
7 1
100 %
100 %
10 year (median )
Population mortality rates
Observed/Expected deaths
Yes
17
Study
Cou ntry
Area
Lan gua ge
%F em ale
A g e 1
Biop sy Prov en
ACR crit eria
FollowUp
Controls
Relevant Outcomes
Quantitative Synthesis
Population controls (n=483)
Relative Risk
Yes
[33]
Le Page, 2006 [26]
Fran ce
Multicentre, CRAGC cohort
Fre nch
72 %
7 5
70%
NR
24 months (maxim um)
Crow, 2009 [18]
USA
Utah, single centre
Eng lish
86 %
7 7
100 %
NR
5 year (maxim um)
Population controls (100:1)
Case-control survival curves, p value, GCA deaths
Yes (imputed)
Ninan, 2011 [30]
Aust ralia
South Australia
Eng lish
72 %
7 8
100 %
NR
66 months (mean)
Population mortality rates
Standardised Mortality Ratio
Yes
Minnesota
Eng lish
80 %
7 6
87%
100 %
8.8 years (median )
Population mortality rates
Standardised Mortality Ratio
Yes
73 %
7 4
100 %
NR
6.6 years (median )
Population controls (n=33,953)
Mortality rates and ratios at discrete time intervals
Yes (weighted cumulative estimates)
75 %
7 6
100 %
NR
62 months (median )
Population mortality rates
Standardised Mortality Ratio
Yes
Kermani , 2013 [25]
USA
Baslund, 2015 [15]
Den mar k
Denmark
Eng lish
Moham mad, 2015 [28]
Swe den
Skane county
Eng lish
1Age
at diagnosis
18
Table 2. Causes of death in patients with Giant Cell Arteritis. Only seven studies reported causes of deaths in similar categories necessary to enable tabulation. The most frequent causes of death are similar between these studies.
Graham 1981 [22] 32
Gouet 1985 [21] 24
Boesen 1987 [17] 5
Nesher 1994 [29] 19
Matteson 1996 [27] 49
Gonzalez Gay 1997 [20] 22
Ninan 2011* [30] 71
14
7
2
7
24
7
25
5
6
1
6
6
6
Infection
5
1
3
2
12
Malignancy
3
1
6
5
12
Total deaths Cardiovascul ar Cerebrovasc ular
Gastrointest inal Aortic aneurysm
6
2 1
1 1
4
Pulmonary Pulmonary embolus
5
1 2
1
Renal
1
Other/Not specified
6
2
2
3 2 3
5
5
3
Total (%) 222 86 (39%) 30 (14%) 29 (13%) 27 (12%) 8 (4%) 6 (3%) 6 (3%) 7 (3%) 4 (2%) 19 (9%)
* Data was recoded by the authors, as cardiovascular and cerebrovascular deaths were originally combined within one group.
19
PII: DOI: Reference:
S0049-0172(16)30143-3 http://dx.doi.org/10.1016/j.semarthrit.2016.08.015 YSARH51100
To appear in: Seminars in Arthritis and Rheumatism Received date: 25 July 2016 Revised date: 23 August 2016 Accepted date: 23 August 2016 Cite this article as: Catherine L. Hill, Rachel J. Black, Johannes Nossent, Carlee Ruediger, Leanne Nguyen, Jem Ninan and Susan Lester, Risk of mortality in patients with giant cell arteritis: A systematic review and meta-analysis, Seminars in Arthritis and Rheumatism, http://dx.doi.org/10.1016/j.semarthrit.2016.08.015 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Title: Risk of Mortality in Patients with Giant Cell Arteritis: A Systematic Review and Meta-Analysis Catherine L Hill (1,2,3) Rachel J Black (2,3) Johannes Nossent (4) Carlee Ruediger (1,2) Leanne Nguyen (2) Jem Ninan (2,5) Susan Lester (1) (1) (2) (3) (4) (5) (6)
Rheumatology Unit, The Queen Elizabeth Hospital, Woodville, Australia Discipline of Medicine, University of Adelaide, Adelaide, Australia Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia Medicine, University of Western Australia, Australia Rheumatology Unit, Modbury Hospital, Modbury, Australia Basil Hetzel Institute, QEH, Woodville South, Australia
Corresponding Author: Professor Catherine L Hill Email: [email protected] Keywords: Giant Cell Arteritis Mortality Systematic Review Meta-analysis Source of Funding: Nil Disclosures: No conflicts of interest to declart
1
ABSTRACT Background: Previous studies of mortality associated with GCA have shown conflicting results. We conducted a systematic review and meta-analysis to determine the mortality risk in GCA patients compared to the general population. Methods: We searched for published studies indexed in MEDLINE and EMBASE and the Cochrane database from inception to June 18, 2015 using the terms “giant cell arteritis” and “temporal arteritis” combined with the terms for death, mortality and survival. A manual search of citations from retrieved articles was also performed. The inclusion criteria were (1) observational studies of mortality in GCA (2) comparison of mortality to the general population. Studies published only in abstract form were excluded. Study eligibility and quality (Newcastle-Ottawa scale) were independently assessed by at least two investigators. Random effects meta-analysis of the mortality ratio (MR) was performed by the inverse variance method. Results: Out of 435 potentially relevant articles, 64 studies were reviewed, 19 studies were included in the review and 17 studies were included in the meta-analysis. Mortality was not increased in GCA patients ascertained from a population base (MR 1.03, 95% CI 0.96, 1.10), but was increased in patients ascertained from a hospital setting (MR 1.61, 95% CI 1.19, 2.19). There was no difference in MR by gender, and two studies provided evidence that mortality was increased in the early years following diagnosis. Conclusion: At a population level, long-term mortality is not increased in GCA. However, mortality risk may be increased in some patients, and may vary over time.
2
INTRODUCTION Giant cell arteritis (GCA) is the commonest form of vasculitis in the elderly, which, untreated, can cause blindness and stroke [1]. The only known treatment currently demonstrated to avert the complications of GCA, such as blindness and stroke, are high dose corticosteroids [1]. However, high dose corticosteroids have significant and consistent adverse effects. Intuitively, it could be expected that GCA diagnosis would have an impact on mortality, given the complications of the disease and the necessary treatment, particularly in the elderly age group that are affected by GCA [2, 3]. However, previous studies of GCA have differed in the outcomes regarding mortality, in comparison with age- and sex-matched population controls. A previous expert review of the current literature related to impact of rheumatic diseases on mortality recommended a meta-analysis of mortality in GCA [4]. The aim of this study was to determine the relationship of GCA to mortality, using a systematic review and meta-analysis of cohort studies comparing mortality between patients with GCA and the general population.
METHODS Search Strategy The search strategy was developed and performed by a medical librarian (Supplementary File A). A search for published studies indexed in MEDLINE, EMBASE and the Cochrane database was carried out from inception to June 18, 2015 using the terms “giant cell arteritis” and “temporal arteritis” combined with terms for death, mortality and survival. A manual search of citations from retrieved articles was also performed. Conference abstracts and unpublished studies were not included. Inclusion Criteria The inclusion criteria were as follows: (1) published, peer-reviewed studies reporting mortality incidence in patients with GCA (2) statistical comparison of mortality in GCA patients to that of the general population. No language limitation was imposed, and translation from French, Dutch and
3
Norwegian was performed by one of the authors (JN) as required. If a study contained patients that were included in a later analysis of the same cohort, the later report was used. Study eligibility was independently determined by three investigators (CH, RB, JN). Differing decisions were resolved by consensus with a fourth reviewer (SL). Quality Assessment The quality of each study was independently assessed by two investigators (CH, RB) using the Newcastle-Ottawa Quality Assessment Scale for the assessment of quality of non-randomised studies in meta-analysis [5]. This is an eight-item scale addressing selection and comparability of cases and controls, outcome assessment and follow-up. Each item was graded as low or uncertain risk, and results presented graphically. Data Extraction Two investigators (CH, SL) independently extracted data using a standardized data collection form. Data extracted included: first author, article title, publication year, country where the study was conducted, language, number of GCA patients, GCA diagnostic criteria used, verification of death, mean and maximum duration of follow-up, and reported mortality data. Statistical Analysis Studies were included in the quantitative synthesis if numerical data was extractable from the published paper. This included studies in which the standardized mortality ratio (SMR), relative risk (RR’s) or hazard ratio (HRs) were provided. Where necessary, the HR/SMR was imputed from published digitized survival curves or reported log-rank p values, assuming an exponential survival model (Supplementary File B). Random effects meta-analysis was performed using the natural logarithm of the SMR/HR/RR statistic using the generic inverse variance method. Estimation was performed by restricted maximum likelihood (REML), with the Knapp-Hartung adjustment [6]. Statistical heterogeneity was assessed using the I2 statistic, which quantifies the proportion of total variation across studies that is due to heterogeneity rather than chance. A value of I2 of 0-25% represents insignificant heterogeneity, 25-
4
50% low heterogeneity, 50-75% moderate heterogeneity and 75-100% high heterogeneity. Prespecified moderator analysis to explore heterogeneity between studies, was performed by metaregression and consisted of study publication date, follow-up duration and data imputation. Pre-specified, within-study subgroup analyses for gender and time following GCA diagnosis were performed using multilevel mixed models. All analyses were performed using the R library metafor [7, 8].
RESULTS Included Studies The search strategy yielded 435 potentially relevant articles, 64 studies were assessed for eligibility (Supplementary file C, Table S1), and 45 studies were subsequently excluded (Figure 1). Although not formally included in the meta-analysis, six of these studies were identified as providing supplementary information relevant to causes and predictors of mortality in GCA [9-14]. Nineteen studies (18 published in English and one in Norwegian) were included in the systematic review [1533], with publication dates ranging from 1979-2015, and demographic data is presented in Table 1. In total, there were 4873 cases of GCA (study range 34-1787). The majority of studies were from Nordic countries (n=9), North America (3), France (2), UK (2), Spain (1), Israel (1) and Australia (1). The quality of the included studies was variable, although most studies were considered at low risk of bias in the majority of categories. (Figure 2). Combined Mortality Ratio in GCA patients The necessary mortality data could not be extracted from two studies, therefore the quantitative synthesis consisted of 17 studies [15-18, 20, 22-33], with a total of 4,733 GCA patients and 1,853 observed deaths. The overall analysis indicated a significant increase in mortality in GCA patients, with a combined Mortality Ratio (MR): 1.17 (95% CI 1.02, 1.35, p = 0.031), Figure 3. However, there was also evidence of substantial heterogeneity between studies (I2 = 76.5%), which makes the generalizability and
5
interpretation of this result problematic. Although not a pre-specified analysis, patient ascertainment was identified as the major contributor to this between study heterogeneity. GCA cohorts were either ascertained through a population (n = 11) or hospital setting (n = 6), and subsequent subgroup analysis demonstrated a substantial reduction in overall heterogeneity when this was accounted for (I2 reduction from 76.5% to 36.8%), Figure 4. The 11 studies where GCA patients were ascertained from a population setting [15, 17, 20, 23-25, 28, 30-33] were remarkably homogeneous, and demonstrated no evidence of increased in mortality in GCA patients (MR: 1.03 (95% CI 0.96, 1.10), p = 0.35, I2 = 15.4%). In contrast, the six studies where GCA patients were recruited through a hospital setting [16, 18, 22, 26, 27, 29] were more heterogeneous, and there was an overall significant increase in mortality in these patients (MR: 1.61 (95% CI 1.19, 2.19), p = 0.010, I2 = 58.2%). This difference in mortality ratios between the two study subgroups was statistically significant (p = 0.001). Additional, pre-specified subgroup analyses indicated that publication year, maximum follow-up time, and data imputations did not impact substantively on results in terms of either heterogeneity or effect sizes. Of the two studies not included in the quantitative synthesis, the first was a Norwegian single centre study of 53 GCA patients followed up over to 15 years [19]. The authors reported no specific mortality data in the paper, other than stating that survival in GCA patients was comparable to that of the general population. The second study, Gouet 1985 [21], was a French single centre study of 87 GCA patients followed up to 12 years. Although an observed-expected survival curve was reported in the paper, this study was not included in the quantitative synthesis because there were clear violations of the constant hazards and proportional hazards assumptions required for imputation of the mortality ratio (Supplementary File B). Although the survival curve suggested some increased mortality in GCA patients, particularly over the first four years, the observed and expected proportions surviving at the end of the study were comparable. Change in Mortality Ratio over Time
6
Although there was no evidence that differences in follow-up duration influenced between-study mortality ratio effect sizes (p = 0.41), the majority of these studies evaluated mortality after long term follow up (10 years or more). Therefore, the question remains as to whether mortality is specifically increased in the early years after initiation of high dose glucocorticoid therapy. Two recent, population-based Scandinavian studies, Baslund 2015 [15] (n = 1747) and Mohammad 2015 [28] (n = 840) were large enough to specifically address this question, and both reported a decline in the mortality ratio over time. Both studies reported a significantly increased mortality ratio at two years after treatment (combined estimate MR = 1.31 (95% CI 1.07, 1.61), p = 0.008) but no difference in mortality at a follow-up of more than 10 years (combined estimate MR = 0.98 (95% CI 0.83, 1.17), p = 0.80). The difference in mortality ratio between these two time points was statistically significant, p = 0.040 (within study comparison), however there was also evidence of considerable heterogeneity in the mortality ratios between the two studies (I2 = 74.8%). Differences in Mortality Ratios between Males and Females The breakdown of mortality by gender was available for 11 studies [15, 17, 20, 22-24, 27, 28, 30, 32, 33], which were predominantly population based GCA cohorts. There was no evidence of an increase in mortality in either males: Mortality ratio 0.98 (95% CI 0.91, 1.06, I2 = 0.0%), or females: MR: 1.07 (95% CI 0.97, 1.17, I2 =14.2%). The difference in mortality ratios between male and female GCA patients was not statistically significant (p = 0.20, within study comparison). Causes of death A subgroup of seven studies detailed the causes of death in GCA patients [17, 20-22, 27, 29, 30], which are tabulated in Table 2. This demonstrated that the leading causes of death were cardiovascular disease (39%) followed by cerebrovascular disease (14%), infection (13%) and malignancy (12%). However, differences in the methods used to code deaths between studies, make it difficult to directly compare.
DISCUSSION
7
In this first meta-analysis and systematic review of mortality in GCA compared to the general population, long-term mortality, at a population level, was not increased (MR 1.03, 95% CI 0.96, 1.10) and no difference in mortality between males (MR 0.98, 95% CI 0.91, 1.06) and females (MR 1.07, 95% CI 0.97, 1.17) was seen. These results are reassuring given that untreated, GCA is a disease with serious, life threatening sequelae and high-dose glucocorticoid treatment is associated with significant concomitant risk, particularly in elderly patients. However, the finding that GCA is not associated with excess mortality requires qualification. Firstly, there is evidence that GCA mortality may be specifically increased within the first two years following diagnosis and initiation of treatment, although only two studies specifically examined this [15, 28]. Secondly, mortality is increased in GCA patients recruited through a hospital setting (MR 1.61, 95% CI 1.19, 2.19). This finding, although not a pre-specified subgroup analysis, is neither unexpected nor surprising. Reported prognostic factors for increased mortality in GCA patients include comorbid disease [9, 26], visual loss [11, 12] and higher maintenance glucocorticoid doses [11-13, 33]. It is likely that comorbid conditions and more severe, difficult to control disease contribute to the higher mortality observed in GCA patients ascertained through a hospital setting. When reported, the most frequent causes of death, were cardiovascular disease (CVD) (39%) followed by cerebrovascular disease (14%), infection (13%) and malignancy (12%). Stroke is a known complication of untreated GCA, yet there does not appear to be an increased risk of death in GCA patients due to cerebrovascular disease [15, 20, 24], which may be interpreted as a measure of treatment success. Similarly, there are no reports of an increased, cause-specific, risk of death in GCA patients due to malignancy [9, 15, 20, 25, 31]. While two studies reported no cause-specific increase in mortality in GCA patients due to infections, [15, 25], a disproportionate contribution of infections to deaths in the first year has also been identified [29, 30], which may possibly be attributable to immunosuppression following treatment initiation. The evidence in relation to CVD is more variable, and may be in part due to difficulties in distinguishing between atherosclerotic disease and the vasculitic vessel wall changes that can be
8
seen in GCA. Several studies have reported that mortality is increased in GCA patients with CVD compared to GCA patients without CVD [10, 13, 20, 26, 32]. Other studies have been unable to demonstrate a cause-specific increased risk of death due to CVD in GCA patients compared to the general population [10, 20, 24, 25]. The presence of traditional cardiovascular disease risk factors at the time of disease diagnosis, in particular hypertension, has been found to increase the risk of cerebrovascular accidents in biopsy proven-GCA patients [34], and there may in fact be an increased risk of death due to CVD in the first one to two years following GCA diagnosis [15]. In contrast GCA patients, who were currently off glucocorticoid therapy and had at least 3 years of follow-up, showed less carotid intima-media thickness compared to matched controls and did not have higher subclinical macrovascular atherosclerotic disease [35], an unexpected finding given that glucocorticoid treatment is known to increase cardiovascular disease risk. More recently, attention has focused on a subgroup of GCA patients with aortic involvement (aneurysm and/or dissection), in whom mortality appears to be increased [15, 25]. Deaths attributed to gastrointestinal (GI) problems comprised 4% of the deaths tabulated in this review. Increased mortality due to both vascular and GI (ulcer/hemorrhagic) bleeding has also been reported [15, 25]. Strengths of this study include its systematic and rigorous methodology with multiple investigators involved in the assessment for eligibility, data extraction and quality assessment. In addition, it is a relatively large systematic review, despite eligibility criteria that selected studies with a low risk of bias, as indicated by the quality assessment. It also did not exclude studies on the basis of language. A limitation of this review is that no markers of disease severity, glucocorticoid dose or toxicity could be included. Few studies reported on the cause of mortality in GCA and specific causes could therefore not be quantified. Further there was limited data addressing increased mortality in the first one to two years following diagnosis, and there may have been incomplete capture of late complications (such as aortic aneurysm/dissection) due to the variable length of follow-up in the included studies.
9
The main conclusions of this study, which are well supported by the available data are that (1) at a population level, there is no long term mortality associated with GCA and (2) the mortality ratio does not differ according to gender. However, patients diagnosed and treated in the hospital setting may be at higher mortality risk compared to GCA patients in the population as a whole. This potentially reflects that hospital patients have more severe, difficult to control disease and possibly more complicated disease due to the effects of comorbidities further research is required to evaluate the prognosis of such patients, in particular, those with more widespread aortic involvement. Further consideration of the potential contribution to mortality of glucocorticoid side effects, such as infections, and gastrointestinal bleeding is also warranted.
ACKNOWLEDGEMENTS We would like to acknowledge the input of Anna Holasek, Medical Librarian, Central Adelaide Local Health Network, with the literature search and strategy.
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22. Graham E, Holland A, Avery A, Russell RW. Prognosis in giant-cell arteritis. Br Med J (Clin Res Ed). 1981 Jan 24; 282(6260):269-271. 23. Gran JT, Myklebust G, Wilsgaard T, Jacobsen BK. Survival in polymyalgia rheumatica and temporal arteritis: a study of 398 cases and matched population controls. Rheumatology (Oxford). 2001 Nov; 40(11):1238-1242. 24. Jonasson F, Cullen JF, Elton RA. Temporal arteritis. A 14-year epidemiological, clinical and prognostic study. Scott Med J. 1979 Apr; 24(2):111-117. 25. Kermani TA, Warrington KJ, Crowson CS, Ytterberg SR, Hunder GG, Gabriel SE, et al. Largevessel involvement in giant cell arteritis: a population-based cohort study of the incidence-trends and prognosis. Ann Rheum Dis. 2013 Dec; 72(12):1989-1994. 26. Le Page L, Duhaut P, Seydoux D, Bosshard S, Ecochard R, Abbas F, et al. [Incidence of cardiovascular events in giant cell arteritis: preliminary results of a prospective double cohort study (GRACG)]. Rev Med Interne. 2006 Feb; 27(2):98-105. 27. 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 Feb; 100(2):193-196. 28. Mohammad AJ, Nilsson JA, Jacobsson LT, Merkel PA, Turesson C. Incidence and mortality rates of biopsy-proven giant cell arteritis in southern Sweden. Ann Rheum Dis. 2015 Jun; 74(6):993997. 29. Nesher G, Sonnenblick M, Friedlander Y. Analysis of steroid related complications and mortality in temporal arteritis: a 15-year survey of 43 patients. J Rheumatol. 1994 Jul; 21(7):12831286. 30. Ninan J, Nguyen AM, Cole A, Rischmueller M, Dodd T, Roberts-Thomson P, et al. Mortality in patients with biopsy-proven giant cell arteritis: a South Australian population-based study. J Rheumatol. 2011 Oct; 38(10):2215-2217. 31. Nordborg E, Bengtsson BA. Death rates and causes of death in 284 consecutive patients with giant cell arteritis confirmed by biopsy. BMJ. 1989 Aug 26; 299(6698):549-550. 32. Rajala SA, Ahvenainen JE, Mattila KJ, Saarni MI. Incidence and survival rate in cases of biopsyproven temporal arteritis. Scand J Rheumatol. 1993; 22(6):289-291. 33. Uddhammar A, Eriksson AL, Nystrom L, Stenling R, Rantapaa-Dahlqvist S. Increased mortality due to cardiovascular disease in patients with giant cell arteritis in northern Sweden. J Rheumatol. 2002 Apr; 29(4):737-742. 34. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Gomez-Acebo I, Pego-Reigosa R, Lopez-Diaz MJ, Vazquez-Trinanes MC, et al. Strokes at time of disease diagnosis in a series of 287 patients with biopsy-proven giant cell arteritis. Medicine (Baltimore). 2009 Jul; 88(4):227-235. 35. Gonzalez-Juanatey C, Lopez-Diaz MJ, Martin J, Llorca J, Gonzalez-Gay MA. Atherosclerosis in patients with biopsy-proven giant cell arteritis. Arthritis Rheum. 2007 Dec 15; 57(8):1481-1486.
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FIGURES
Figure 1. Flow diagram for included studies
PMR = Polymyalgia Rheumatica
13
Figure 2. Quality assessment of included studies (Newcastle-Ottawa assessment tool [5])
14
Figure 3. Random effects meta-analysis of the mortality ratio in Giant Cell Arteritis (GCA) patients compared to age and gender matched population controls. Seventeen studies were included in the meta-analysis. There was substantial heterogeneity between studies which could largely be attributed to whether patients were ascertained from a population base (n = 11) or a hospital setting (n = 6), which resulted in a reduction in I2 from 76.5% to 36.8%. In contrast to GCA patients ascertained from a hospital setting, there was no excess in long-term mortality in GCA patients ascertained from a population base.
n.GCA = number of GCA patients in the study; n.Deaths = number of deaths in GCA patients; F/up = maximum duration of follow-up; RE = Random Effects
15
Figure 4. Random effects meta-analysis of the mortality ratio in male and female patients with Giant Cell Arteritis (GCA) compared to age and gender matched population controls. Mortality data for both males and females was available for a subgroup of 11 studies, which were predominantly population based cohorts. There was no excess mortality in either males or females, and no evidence of a difference in mortality ratios between males and females.
n.GCA = number of GCA patients in the study; n. Deaths = number of deaths in GCA patients; Cohort = whether patients were ascertained from a population or hospital setting; RE = Random Effects
16
Table 1. Characteristics of included studies.
Study
Jonasson , 1979 [24]
Cou ntry
Scotl and
Area
Lothian region
ACR crit eria
FollowUp
Controls
Relevant Outcomes
Quantitative Synthesis
1
Biop sy Prov en
74 %
7 3
100 %
NR
~ 50 months (mean)
Population mortality rates
Observed/Expected deaths (graph format)
Yes
100 %
NR
60 months (mean)
Population mortality rates
Observed/Expected survival curves & p values (by gender), GCA deaths
Yes (imputed)
NR
15 years (maxim um)
Population mortality rates
GCA deaths only; no expected data reported
No. Insufficient data
Population mortality rates
Observed/Expected survival curve, GCA deaths
No. Data unsuitable for imputation.
Lan gua ge
%F em ale
Eng lish
A g e
Graham, 1981 [22]
UK
3 centres, London
Eng lish
71 %
5 5 8 8
Fjermest ad, 1983 [19]
Nor way
Single centre, Trondheim
Nor weg ian
57 %
7 1
100 %
Gouet, 1985 [21]
Fran ce
Single centre, Poitiers
Eng lish
60 %
7 3
100 %
NR
60 months (mean)
Boesen, 1987 [17]
Den mar k
Ribe County
Eng lish
83 %
7 0
33%
100 %
3 year (maxim um)
Population mortality rates
Observed/Expected deaths
Yes
Nordbor g, 1989 [31]
Swe den
Goteborg
Eng lish
NR
N R
100 %
NR
> 10 year (maxim um)
Population mortality rates
Observed/Expected deaths
Yes
Bisgard, 1991 [16]
Den mar k
Single centre, Holstebro Hospital
Eng lish
NR
7 1
100 %
NR
13 year maximu m
Population mortality rates
Standardised Mortality Ratio
Yes
Rajala, 1993 [32]
Finl and
Tampere
Eng lish
74 %
7 2
100 %
NR
NR
Population mortality rates
Relative survival, GCA survival at 5 & 10 years, GCA deaths
Yes (imputed)
Nesher, 1994 [29]
Isra el
Single centre, Jerusalem
Eng lish
65 %
7 6
91%
100 %
36 months (mean)
Population mortality rates
Standardised Mortality Ratio
Yes
Matteso n, 1996 [27]
USA / Cana da
Rheumatolo gy Centres (28)
Eng lish
75 %
N R
NR
100 %
85 months (mean)
Population mortality rates
Standardised Mortality Ratio
Yes
Gonzalez -Gay, 1997[20 ]
Spai n
NW Spain
Eng lish
46 %
7 4
100 %
NR
54 months (median )
Population mortality rates
Standardised Mortality Ratio
Yes
Gran, 2001 [23]
Nor way
Aust Agder county
Eng lish
77 %
N R
100 %
100 %
64 months (mean)
Population controls (4:1)
Relative Risk
Yes
Uddham mar, 2002
Swe den
Västerbotte n, Northern Sweden
Eng lish
NR
7 1
100 %
100 %
10 year (median )
Population mortality rates
Observed/Expected deaths
Yes
17
Study
Cou ntry
Area
Lan gua ge
%F em ale
A g e 1
Biop sy Prov en
ACR crit eria
FollowUp
Controls
Relevant Outcomes
Quantitative Synthesis
Population controls (n=483)
Relative Risk
Yes
[33]
Le Page, 2006 [26]
Fran ce
Multicentre, CRAGC cohort
Fre nch
72 %
7 5
70%
NR
24 months (maxim um)
Crow, 2009 [18]
USA
Utah, single centre
Eng lish
86 %
7 7
100 %
NR
5 year (maxim um)
Population controls (100:1)
Case-control survival curves, p value, GCA deaths
Yes (imputed)
Ninan, 2011 [30]
Aust ralia
South Australia
Eng lish
72 %
7 8
100 %
NR
66 months (mean)
Population mortality rates
Standardised Mortality Ratio
Yes
Minnesota
Eng lish
80 %
7 6
87%
100 %
8.8 years (median )
Population mortality rates
Standardised Mortality Ratio
Yes
73 %
7 4
100 %
NR
6.6 years (median )
Population controls (n=33,953)
Mortality rates and ratios at discrete time intervals
Yes (weighted cumulative estimates)
75 %
7 6
100 %
NR
62 months (median )
Population mortality rates
Standardised Mortality Ratio
Yes
Kermani , 2013 [25]
USA
Baslund, 2015 [15]
Den mar k
Denmark
Eng lish
Moham mad, 2015 [28]
Swe den
Skane county
Eng lish
1Age
at diagnosis
18
Table 2. Causes of death in patients with Giant Cell Arteritis. Only seven studies reported causes of deaths in similar categories necessary to enable tabulation. The most frequent causes of death are similar between these studies.
Graham 1981 [22] 32
Gouet 1985 [21] 24
Boesen 1987 [17] 5
Nesher 1994 [29] 19
Matteson 1996 [27] 49
Gonzalez Gay 1997 [20] 22
Ninan 2011* [30] 71
14
7
2
7
24
7
25
5
6
1
6
6
6
Infection
5
1
3
2
12
Malignancy
3
1
6
5
12
Total deaths Cardiovascul ar Cerebrovasc ular
Gastrointest inal Aortic aneurysm
6
2 1
1 1
4
Pulmonary Pulmonary embolus
5
1 2
1
Renal
1
Other/Not specified
6
2
2
3 2 3
5
5
3
Total (%) 222 86 (39%) 30 (14%) 29 (13%) 27 (12%) 8 (4%) 6 (3%) 6 (3%) 7 (3%) 4 (2%) 19 (9%)
* Data was recoded by the authors, as cardiovascular and cerebrovascular deaths were originally combined within one group.
19