The systemic vasculitides are multisystem disorders characterised by the inflammation of blood vessels and tissue necrosis. Classified by the size of the vessels affected, the large vessel vasculitides include giant cell arteritis (GCA) and Takayasu’s arteritis (TA). These are anatomically, epidemiologically and clinically distinct conditions. They are often associated with considerable morbidity and mortality. The classification of vasculitis has been an area of controversy for many years and current classification criteria remain suboptimal. Although intensive efforts are under way to improve them, a further understanding of the aetiology and pathogenesis of these diseases is required to develop more sensitive and specific diagnostic tests. These efforts, however, have been hampered by the low prevalence of these diseases. The establishment of national and international registries is encouraged to enhance valuable data collection. These are anatomically, epidemiologically and clinically distinct conditions. This article summarises the current classification systems for systemic vasculitis and their limitations. We also review the presently known epidemiology, risk factors and morbidity and mortality associated with GCA and TA.
Descriptive epidemiology
Vasculitis is considered to be primary when there is no known underlying aetiology, and secondary, if associated with an infection (e.g., human immunodeficiency virus (HIV), hepatitis B or C) or an underlying connective tissue disease (e.g., systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA)). Histopathological examination is the main basis for diagnosing these diseases; however, often is not feasible. Hence, to classify diseases for research purposes, we must rely on other criteria as well.
Classification
The presently available classification systems for vasculitis remain suboptimal. Many attempts have been made to reclassify these diseases and currently, the two mostly widely used remain the 1990 American College of Rheumatology (ACR) criteria and the Chapel Hill Consensus conference (CHCC) criteria.
Looking back, in 1952, Pearl Zeek was the first to propose a classification system for primary vasculitis based predominantly on blood vessel size . She described five separate disorders including hypersensitivity angiitis, allergic granulomatous angiitis, rheumatic arteritis, periarteritis nodosa and temporal arteritis. Despite being described in 1948 , microscopic polyangiitis (MPA) was omitted from this early classification system. Wegener’s granulomatosis (WG) and Takayasu’s arteritis (TA) were likewise not included, being only described as a disease entity for the first time, a few years later Churg–Strauss syndrome (CSS) was not formally classified until 1984 and so was also absent . Nevertheless, with the lack of a detailed understanding of the pathogenesis of these diseases, Zeek’s framework has been the basis for later classification systems.
In the late 1980s, recognising that deficiencies of available classification systems were hampering epidemiological and clinical studies the ACR set about developing new classification criteria for the systemic vasculitides. In 1990, they published criteria classifying seven types of established vasculitis (giant cell arteritis (GCA), TA, WG, CSS, polyarteritis nodosa (PAN), Henoch–Schonlein purpura (HSP), and hypersensitivity vasculitis (HSV)) , with sensitivities ranging from 71.0% to 95.3% and specificities ranging from 78.7% to 99.7% . As classification, not diagnostic criteria however, their reliability in the specific diagnosis of patients with suspected vasculitis was poor.
Although a definitive step forward, the ACR criteria still had limitations. When developing these criteria histology was often lacking and it should ne noted that, the ‘gold standard’ for the vasculitic diagnosis was the judgement of the rheumatologists participating in the studies . In addition, MPA was still not a term commonly used and again, did not feature in the criteria. Developed just prior to their widespread introduction in clinical practice, there was also no reference to antineutrophil cytoplasmic autoantibodies (ANCAs), which now play a key role in the diagnosis of many patients with small vessel vasculitis. This new diagnostic test has also led to the emergence of “ANCA-associated vasculitis” (AAV) as a concept, which is now commonly used in clinical trials. Readers should also be aware that there may also be further changes to the individual disease names as it is likely that the ACR and the European League Against Rheumatism (EULAR) will recommend against the ongoing use of eponyms and rename WG in particular.
In 1994, recognising that histological data was often not available, the CHCC produced revised definitions for systemic vasculitis . These, however, were not designed to be either classification nor diagnostic criteria. With the improvement in diagnostic tests available, the CHCC definitions allowed the further differentiation of immune-complex-mediated vasculidities such as Henoch Schonlein Purpura (HSP) and cryoglobulinaemic vasculitis. They also emphasised that WG, CSS and MPA were associated with ANCA; however, the presence of ANCA was not actually included in the definition of any of these diseases. A definition for MPA was included though, so for the first time it was able to be clearly distinguished from PAN. Consequently though, many cases formerly defined as PAN using the ACR criteria would now be reclassified as MPA, according to the Chapel Hill definitions. This should be taken into account when comparing data over different time periods.
A properly validated, revised, single classification system is still required and efforts are already under way to achieve this . However, until reliable gold standard tests are available, there is likely to be ongoing misclassification. Pending new criteria being available, it has been recommended that investigators report how many patients fulfil both the ACR and CHCC criteria . However, this should be done knowing that the ACR criteria and the Chapel Hill definitions for AAV and PAN are incompatible. To address this issue, a consensus method of applying the two systems to classify AAV for epidemiological studies has been developed by the European Medicines Agency (EMEA) . This algorithm incorporates MPA and ANCA, and has subsequently been validated , but remains untested in a clinical trial setting.
Classification
The presently available classification systems for vasculitis remain suboptimal. Many attempts have been made to reclassify these diseases and currently, the two mostly widely used remain the 1990 American College of Rheumatology (ACR) criteria and the Chapel Hill Consensus conference (CHCC) criteria.
Looking back, in 1952, Pearl Zeek was the first to propose a classification system for primary vasculitis based predominantly on blood vessel size . She described five separate disorders including hypersensitivity angiitis, allergic granulomatous angiitis, rheumatic arteritis, periarteritis nodosa and temporal arteritis. Despite being described in 1948 , microscopic polyangiitis (MPA) was omitted from this early classification system. Wegener’s granulomatosis (WG) and Takayasu’s arteritis (TA) were likewise not included, being only described as a disease entity for the first time, a few years later Churg–Strauss syndrome (CSS) was not formally classified until 1984 and so was also absent . Nevertheless, with the lack of a detailed understanding of the pathogenesis of these diseases, Zeek’s framework has been the basis for later classification systems.
In the late 1980s, recognising that deficiencies of available classification systems were hampering epidemiological and clinical studies the ACR set about developing new classification criteria for the systemic vasculitides. In 1990, they published criteria classifying seven types of established vasculitis (giant cell arteritis (GCA), TA, WG, CSS, polyarteritis nodosa (PAN), Henoch–Schonlein purpura (HSP), and hypersensitivity vasculitis (HSV)) , with sensitivities ranging from 71.0% to 95.3% and specificities ranging from 78.7% to 99.7% . As classification, not diagnostic criteria however, their reliability in the specific diagnosis of patients with suspected vasculitis was poor.
Although a definitive step forward, the ACR criteria still had limitations. When developing these criteria histology was often lacking and it should ne noted that, the ‘gold standard’ for the vasculitic diagnosis was the judgement of the rheumatologists participating in the studies . In addition, MPA was still not a term commonly used and again, did not feature in the criteria. Developed just prior to their widespread introduction in clinical practice, there was also no reference to antineutrophil cytoplasmic autoantibodies (ANCAs), which now play a key role in the diagnosis of many patients with small vessel vasculitis. This new diagnostic test has also led to the emergence of “ANCA-associated vasculitis” (AAV) as a concept, which is now commonly used in clinical trials. Readers should also be aware that there may also be further changes to the individual disease names as it is likely that the ACR and the European League Against Rheumatism (EULAR) will recommend against the ongoing use of eponyms and rename WG in particular.
In 1994, recognising that histological data was often not available, the CHCC produced revised definitions for systemic vasculitis . These, however, were not designed to be either classification nor diagnostic criteria. With the improvement in diagnostic tests available, the CHCC definitions allowed the further differentiation of immune-complex-mediated vasculidities such as Henoch Schonlein Purpura (HSP) and cryoglobulinaemic vasculitis. They also emphasised that WG, CSS and MPA were associated with ANCA; however, the presence of ANCA was not actually included in the definition of any of these diseases. A definition for MPA was included though, so for the first time it was able to be clearly distinguished from PAN. Consequently though, many cases formerly defined as PAN using the ACR criteria would now be reclassified as MPA, according to the Chapel Hill definitions. This should be taken into account when comparing data over different time periods.
A properly validated, revised, single classification system is still required and efforts are already under way to achieve this . However, until reliable gold standard tests are available, there is likely to be ongoing misclassification. Pending new criteria being available, it has been recommended that investigators report how many patients fulfil both the ACR and CHCC criteria . However, this should be done knowing that the ACR criteria and the Chapel Hill definitions for AAV and PAN are incompatible. To address this issue, a consensus method of applying the two systems to classify AAV for epidemiological studies has been developed by the European Medicines Agency (EMEA) . This algorithm incorporates MPA and ANCA, and has subsequently been validated , but remains untested in a clinical trial setting.
Case definitions
To allow comparisons and simplify the epidemiological analysis, the vasculidities are subdivided into primary (if there is no associated underlying disease) and secondary (a well-defined associated disease is present). The primary vasculidities are further classified into the size of the blood vessels predominantly involved. We will focus on adult large-vessel vasculitis using the generally accepted ACR criteria, Chapel Hill consensus definitions and the more recent attempt to merge them . Both have a high specificity and sensitivity for the large-vessel vasculidities. The main discrepancy in the definitions is for TA where the age cut-off in the ACR criteria is 40 years, whereas in the CHCC it is 50 years. This should be taken into account when comparing studies using the different classification systems.
Incidence and prevalence
Large-vessel vasculitis
Giant cell arteritis (GCA) is also known as temporal arteritis and preferentially affects medium-and large-sized arteries in the elderly. It is the most common primary systemic vasculitis in adults and, by definition, occurs in those over the age of 50 years. In Europe and North America, the estimated prevalence is 200 per 100 000 and the incidence is 20–30 per 100 000 . Although the condition had been considered less common among Hispanics, recent evidence has challenged this notion. Latitude is an important risk factor, with a prevalence in Sweden twice that of Spain or Italy.
TA is a chronic inflammatory arteritis affecting large vessels, predominantly the aorta and its main branches of young women. It produces a variety of ischaemic symptoms due to stenosis and thrombosis of major arteries. It is far less common with reported worldwide incidence rates of only 1–2 per million. Epidemiological studies are therefore difficult and there is a paucity of data available overall.
Geographical variation
There appears to be a clear geographical gradient of frequencies in GCA, with a statistically significant increase in both incidence and prevalence of the disorder with increasing northerly latitudes. The highest worldwide incidence is reported to be in southern Norway with 32.8 per 100 000 people over the age of 50 years affected. Other Scandinavian countries including Denmark , Finland , Iceland and Sweden have also shown a high incidence, ranging between 20 and 27 per 100 000 for the population older than 50 years. Interestingly, the incidence reported in Olmsted County, Minnesota in the United States, was similar to that found in the Scandinavian countries (18.8 per 100 000 individuals over the age of 50 years) , and likely reflects the prevalent Scandinavian background in the region.
Moving further down to southern Europe, studies report a much lower incidence rate with northern Italy 6.9 per 100 000 and northwest Spain 10.2 per 100 000 . Similarly, in Saskatoon, Saskatchewan, Canada, approximately 9.4 per 100 000 are affected each year.
The lowest incidence rates of GCA reported are 1.58 per 100 000 in Tennessee , 1.3 per 100 000 in Scotland , 1 per 100 000 in the native Alaskan population and 0.2 per 100 000 in Jerusalem . Few studies have looked at incidence in the Asian populations, which have recently been estimated to be between 0.09 and 1.5 per 100 000 . In China, several larger epidemiological studies on rheumatic diseases have not identified any cases of GCA . However, seven biopsy-proven cases of GCA have been reported from Singapore, with all seven patients being of Chinese origin . Although thought to be low, there have also been limited population-based studies undertaken in the Middle-Eastern countries. The true incidence of GCA in the Arab population is difficult to estimate, but recent retrospective data from one tertiary referral centre in Riyadh, Saudi Arabia reports this to be very low with only 7/102 (6.8%) positive biopsies over a 22-year period .
With evidence of northerly latitude being a risk factor for GCA, others have examined the role of altitude . In northwest Spain, the authors found no difference in GCA incidence in 210 patients residing at different altitudes. Larger prospective studies with a greater variation in altitude are needed to better address this association.
TA is thought to be more prevalent in Asian countries; however, it has been described at similar rates in most parts of the world. The incidence in the USA (Olmsted County, Minnesota, USA) is 2.6 per million , Sweden 0.8–1.2 per million , Kuwait 2.2 per million , Japan 1–2 per million, Germany 1 per million and the UK 0.8 per million . One large retrospective multicentre cohort study of Italian patients has helped to profile the disease in Western Europe ; however, the incidence rates were not reported. Further studies are required to better define the incidence of this condition around the world, and given the small number of cases, national registries may be useful to enable this.
Prevalence
Only a small number of studies have reported the prevalence of GCA, and all have focussed on individuals older than 50 years of age. In Olmsted County, prevalence was estimated from cumulative incidence rates to be 278 per 100 000 (95% confidence interval (CI) 192–268), and was again higher in women than men and increased dramatically with age . Using these Olmsted County prevalence rates, and the corresponding 2005 US population estimates from the Census Bureau, 228 000 Americans were estimated to have GCA . In northern Germany, the prevalence of GCA was 24.0 per 100 000, and in southern Germany it was 30.0 per 100 000 . Although contrary to the data suggesting an increased incidence of GCA with more northerly latitudes, these results were believed to reflect the higher prevalence of GCA in urban compared with rural populations. In Tunisia, a recent retrospective study estimates the prevalence of GCA to be 7 per 100 000 , which is higher than expected from other data from Arab countries. The lowest prevalence was reported in Japan with 1·47 per 100 000 population affected .
Occurring so infrequently, there is only limited data available regarding TA prevalence. Reports are sparse, often from single centres or involving few patients, and are thus not representative of a whole country. In Japan, it is estimated to be 40 per million . In the UK primary care cohort, the prevalence was only 4.7 per million . Subclinical disease, however, may be missed, underestimating the actual prevalence. This was highlighted in an autopsy series in Japan where the prevalence was reported to be as high as 1 in 3000 cases .
What are the time trends?
There is currently conflicting data as to whether there is an overall increase in the incidence and prevalence of GCA. A recent, 25-year epidemiologic study in northwestern Spain demonstrated a statistically significant increase in the incidence of GCA when comparing rates over five consecutive time periods from 1981 to 2005. The highest annual incidence rate in those over 50 years of age occurred between 1996 and 2000 . Similar results were seen in studies in Olmsted County and Sweden where the annual incidence of GCA increased from 16.8 per 100 000 in 1973–1975 to 18.3 per 100 000 in 1977–1986 and 22.2 per 100 000 in 1976–1995 .
Improved awareness of the condition and new diagnostic modalities (e.g. positron emission tomography (PET), magnetic resonance angiography (MRA) and computed tomography (CT) angiography) is likely to have contributed to some of the reported increased incidence. Differences in the catchment areas of the populations studied, and a shift in the design (retrospective to prospective) and quality of the studies may also have confounded this finding.
Whether this increased incidence is also simply a reflection of an ageing population structure was addressed and refuted by Nordborg et al. . After adjusting for the increase in age of their Swedish population over time, they found that the incidence of biopsy-proven GCA was still significantly increasing. This was despite the immigration of individuals from southern Europe and northern Africa to the region during their years of observation, which should have reduced the incidence. Other regions, such as south Norway , the Gulf Coast , and Jerusalem , did not see any change in the incidence rate during the duration of their studies.
The limited data available in TA suggest that the incidence rates have remained fairly stable over time, but, with low case numbers, larger prospective studies are still required.
Morbidity and mortality
The spectrum of clinical manifestations associated with GCA ranges from nonspecific complaints such as headache and myalgias to specific organ dysfunction such as visual loss, arm claudication or stroke. The major morbidity is related to both ischaemic complications of the disease and the immunosuppressive treatment. Partial or complete loss of vision occurs in 15–20% of patients in most series, whilst cerebrovascular ischaemic events affect 3–4% and thoracic artery aneurysms 7% of cases. Ruptured aortic aneurysms are fatal in around 80% compared with 65–75% mortality from ruptured aortic aneurysms from all other causes. Considering the advanced age of the patient population, their associated co-morbidities and the secondary complications of long-term steroid treatment, the overall prognosis of patients with GCA is good. In fact, a study comparing patients with GCA to age-matched controls found no difference in mortality .
TA is a chronic, relapsing illness associated with considerable morbidity. Less than 20% will have a self-limiting illness or a course of disease that resolves after a short period of therapy. Affecting a younger generation, disease-associated morbidities frequently impair the patients’ abilities to perform routine daily activities and to maintain employment. The site of the lesions and the degree of involvement determine the extent and the clinical severity. In the National Institutes of Health study, 74% were functionally affected by their disease and 47% of these patients were fully disabled . Overall, around 60% have vascular claudication that impairs the ability to perform routine daily activities and, unfortunately, sustained vascular patency by angioplasty is relatively unsuccessful in most populations with adequate follow-up.
In 1977, Lupi-Herrera and colleagues reported a 15% mortality rate among patients who had TA in whom long-term follow-up data were available . Approximately half of the deaths in the cohort resulted from congestive cardiac failure (CCF). Among a cohort of 88 patients from India who had TA, there was a 5-year survival rate of 91% and a 10-year survival rate of 84%. Forty percent of deaths in the Indian cohort were also the result of CCF . In the US, there have been two large cohort studies. Data from the Cleveland Clinic Foundation showed a mortality rate of 4% at 3 years . In this cohort, morbidity was also substantial. More than two-thirds of patients had difficulty performing routine daily activities, and approximately 25% of patients were unable to work. In France, the estimated 5-year and 10-year survival rates were 95.2% and 90.8%, respectively . As this is a relatively young population affected, and the follow-up period of the trials is generally short, the true disease- and treatment-related morbidity and mortality are likely to be underestimated.
Risk factors
What are the relevant risk factors for the occurrence of the condition?
Gender
As in the majority of auto-immune diseases, GCA affects women 2–3 times more commonly than men. This difference appears to be more marked in the northern parts of Europe. Only in one earlier Spanish study and a more recent study from Tunisia were males reported to be predominant in GCA. However, a more recent analysis of extended data from the same Spanish population shows that the incidence of GCA was actually slightly higher in women, but not statistically significant .
In TA, there is a marked predominance of the disease in female patients (at least 85% women in most series). In the largest study from Japan, the female to male ratio was eight to one . Similar ratios were seen in Mexico (6.9:1) and France (4.8:1); however, this female predominance was not seen in Israel (1.2:1) and India where men and women were equally represented . The female:male sex ratio was also reported to decrease with westerly latitudes, suggesting a possible genetic predisposition . However, this East-to-West sex ratio has been contradicted by a recent Italian study .
Race
GCA primarily affects whites, specifically those of northern European descent. Few studies have addressed the prevalence or incidence of GCA in minority populations. As described above, Scandinavians have the highest prevalence, and GCA is rare in African Americans . Although the condition was thought to be less common among Hispanic persons, recent evidence from Miami has challenged this notion. They found the prevalence and clinical course of GCA to be similar in Hispanic and non-Hispanic patients .
Although predominantly described in the Asian population, there does not appear to be any significant ethnic predisposition to TA. Few studies have examined heterogeneous populations. In a study from France with 20% black, 20% North African and 40% white patients, the proportion who had onset of TA after 40 years of age was noted to be significantly higher in white than in non-white patients . This may have been due to poorer socioeconomic status.
Age
As defined by the ACR criteria, GCA affects individuals older than 50 years of age. To test whether GCA can occur in younger patients, Smetana and Shmerling identified 26 studies that provided the age of the patients with biopsy-proven GCA. Of the 1435 patients with biopsy-proven GCA, only two were younger than 50 years .
The risk of developing GCA has been shown to increase with advancing age, being 20 times higher after 90 years than between 50 and 60 years of age . From a population-based study in the UK, the incidence rate of GCA increased markedly to 60 per 100 000, when only persons aged 80 years or older were considered . Multiple studies have had similar conclusions, including those from southern Norway , Italy and Jerusalem .
The mean age of onset of symptoms appears to occur between the low- to mid-70s but has been reported to be increasing. Kermani et al. . studied the mean age at onset of GCA over a 55-year period in the Olmsted County population. They concluded that the average age at onset had increased from 74.7 years in the first decade (1950–1959) of study to 79.2 years in later years (1999–2004). Analysis of these incidence rates showed that this increase in age at diagnosis was related to an increase in the incidence of GCA in patients older than 70 years. There was no increase in the incidence of GCA in younger individuals. There was also no evidence that the increase in age over time was different in men compared with women. Using light and electron microscopy, tiny calcifications have been shown to occur in the arterial internal elastic lamina of the general population in an age and sex distribution similar to that of GCA. It has been suggested that the inflammatory process of GCA may start with the formation of giant cells that attack these micro-calcifications , which are more common in elderly female patients.
TA is generally considered to be a disease of younger people, with age below 40 years being one of the ACR (1990) classification criteria for the condition. The peak onset of disease is during the second or third decades of life. However, there are multiple reports of the occurrence of TA in patients over 50 years or even after 60 years of age. In the Italian Takayasu’s Arteritis (ITAKA) Study Group, the median age at onset was more than 40 years in 17.5% and more than 50 years of age in 10.7% of patients. In a recent French study , 32% of patients had disease onset after the age of 40 years, 18.3% after the age of 50 years and 4.9% after age 60 years of age. There are also reports of TA onset in children as young as 24 months .
Environmental
Infection
Cyclical fluctuations in the incidence of GCA and the presence of activated antigen-presenting dendritic cells in temporal arteries have suggested a role of infectious agents in the pathogenesis of GCA. This is also supported by data suggesting that the prevalence of recent or current infections is three times higher in patients with GCA than matched controls . Seasonal clustering of the incidence of GCA in late spring and early summer has been reported by several groups. In Jerusalem, the onset of GCA symptoms appeared to peak between May and June with twice as many patients being diagnosed during this period than expected . Likewise in Sweden, peaks in positive temporal artery biopsies were also seen during late winter and autumn . Cyclical patterns in the incidence rate of GCA were also shown in Minnesota with a peak every 6–7 years . However, other studies have refuted these findings .
Various organisms have been postulated to trigger GCA; however, to date no infectious aetiology has been confirmed to have a direct causative effect. Those most commonly studied include Chlamydia pneumoniae , Mycoplasma pneumoniae , varicella zoster virus, human parvovirus B19 and human parainfluenza virus type 1 . One Danish study reported clustering of GCA in relation to two epidemics of M. pneumoniae and two major outbreaks of human parvovirus B19 and C. pneumonia . Dahaut et al. reported that reinfection with human parainfluenza virus type I was associated with the development of GCA. Studies have, however, also refuted these findings .
Despite an initial study reporting high prevalence of C. pneumoniae in GCA patients using immunocytochemistry and polymerase chain reaction (PCR) techniques , subsequent studies have not confirmed this finding . Further, against this is the low rate of C. pneumoniae seroprevalence found in Denmark and Norway where the incidence of GCA is high. In a small series of patients, no increase in seroprevalence was found for influenza A and B, mumps, adenovirus, enterovirus, rotavirus, Q-fever, leptospirosis, M. pneumoniae and Chlamydia .
The concept of infection as a trigger for TA is supported by immunopathological analyses showing an increased expression of the 65-kDa heat shock protein, as well as human leucocyte antigen (HLA) I and II in TA, lesions suggesting a pathogenic role of CD4 and CD8 T-cells. Tuberculosis was originally implicated in view of the high prevalence of infection in East Asia, as well as the granulomatous nature of the disease. However, the lack of response to anti-tuberculous treatment, and the absence of DNA in lesions have not substantiated this association. Incidence rates have now been shown to be similar in several parts of the world with high and low prevalence of tuberculosis.
Overall, to date there is no convincing evidence today that GCA or TA is an infectious vasculitis.
Non-infective
Non-infective environmental agents have also been linked to the development of GCA. In Germany, Reinhold-Keller et al. described a 2.25-fold increased risk of GCA in people living in urban areas compared with those living in rural ones . A similar finding was reported in Denmark, where the incidence of GCA was also higher in areas with a more dense population . The possibility of a lower ascertainment of GCA in rural regions however, was not able to be excluded as a cause of the differences in either study. With regard to cardiovascular risk factors, case-control studies have reported an increased risk of GCA in heavy smokers and in patients with previous atherosclerotic disease .
Genetics
A genetic predisposition has also been suspected from reports of increased prevalence among first-degree relatives as well as familial forms of the disease . A similar incidence of GCA is seen in populations living in different geographical areas giving credence to this hypothesis.
Following on from the possibility that infections may be the instigators of GCA, genetic studies have focussed on HLA class I molecules that are known to be presenters of peptide molecules. To date, GCA disease susceptibility has been associated with an increased frequency of HLA-DR4 and HLA-DRB1 ∗ 04 . The HLA-DRB1 ∗ 0401 and HLA-DRB1 ∗ 0404 alleles (components of the DR4 gene) have been shown to be less frequent in the Japanese population . This may contribute to the low GCA incidence seen in this patient group. Interestingly, GCA susceptibility in populations also shows important immunogenetic differences with the strength of the HLA-DRB1 association with GCA varying between different populations. For example, in Spain, GCA in Lugo is associated with HLA-DRB1 ∗ 04 alleles , whereas this is not the case for Reggio Emilia patients .
Apart from HLA class I and II genes, it is likely that other genetic factors may contribute to the susceptibility to these conditions, particularly those factors involved in inflammation. Although beyond the scope of this article, many studies have shown the implication of genetic variants in key components of immune and inflammatory pathways in GCA susceptibility . Polymorphisms relating to the expression of tumour necrosis factor (TNF) α, intercellular adhesion molecule 1 (ICAM-1) and interleukin 1 receptor antagonist (IL-1Ra) also are associated with increased susceptibility to GCA . In northwest Spain, GCA was independently associated with different TNF microsatellite polymorphisms as well as the major histocompatibility complex (MHC) class I chain-related gene A ( MICA ) and HLA-B genes .
TA has been described in monozygotic twins, suggesting the involvement of genetic factors in the aetiopathogenesis of the disease . In Japan, there is a clear association with the HLA-B52 and B39 alleles , whereas, in Mexican and Colombian patients, there is a higher incidence of the HLA-DRB1 ∗ 1301 and HLA-DRB1 ∗ 1602 alleles . In a study from the National Institutes of Arteritis Health including predominantly non-Asians, HLA-DR4 was most closely associated with TA .
What are the relevant risk factors for the outcome of the condition?
Anterior ischaemic optic neuropathies (AIONs) with resultant vision loss and ischaemic stroke are feared complications of GCA. However, identifying patients at risk for severe ischaemic events remains an unresolved issue. Patients originating from North Africa reportedly have more frequent occurrence of ischaemic stroke (25% vs. 5%, p = 0.03) than white patients . The presence of traditional atherosclerosis risk factors (hypercholesterolemia, hypertension, diabetes mellitus, and smoking) at the time of diagnosis has been associated with the development of severe ischaemic manifestations in patients with this vasculitis . Older age, a past history of ischaemic heart disease, a low systemic inflammatory response and the absence of constitutional symptoms have also been suggested as independent risk factors for cranial ischaemic events . Ischaemic complications have also been associated with genes encoding vascular endothelial growth factor (VEGF), interferon-c and platelet glycoprotein receptor .
A recent Swiss cohort study addressed the question of whether the absence of pre-existing anti-platelet therapy, platelet count and platelet size were risk factors for developing ischaemic stroke and permanent visual loss in patients with GCA. They reported that ischaemic events still occurred despite established platelet inhibition and neither platelet count nor size was associated with the risk of severe ischaemic events. No positive impact of anti-platelet therapy on the risk of severe ischaemic complications has also been confirmed in more recent studies . In a cohort from Spain, coronary event rates were not significantly different between patients with GCA and controls, but coronary events were more likely to be fatal in patients with GCA .
Permanent partial or complete loss of vision in one or both eyes occurs in less than 20% of patients, and is often an early manifestation. An elevated platelet count , jaw claudication , amaurosis fugax and HLA-DRB1 ∗ 04 alleles have been reported by others to be risk factors for permanent visual loss. Late recurrence of visual loss is also associated with female sex, older age, worse initial visual acuity, oral (vs. intravenous) initial steroid treatment and higher erythrocyte sedimentation rate (ESR). HLA-DRB1 alleles have been associated with progressive symptoms. Interestingly, constitutional symptoms and elevated liver enzymes are associated with a lower risk of visual loss . This may be related to the fact that these patients are more likely to seek medical attention and be treated earlier. The means of identifying the patients at greatest risk of vision loss and the question of whether or not some patients are relatively protected against this complication remain unresolved.
Aortic involvement may include aortic aneurysms, aortic valve insufficiency, aortic dissection and large artery stenosis of the arms, legs or the cervical arteries. Occurring in about 10–15% of patients, they are usually late complications of GCA. Thoracic aortic aneurysms are reported to be 17 times more frequent in patients with GCA than in non-affected people .
Despite early case-control studies suggesting an increased risk of malignancy in patients with biopsy-proven GCA , more recent prospective studies have concluded that there does not appear to be an increased risk of first cancer after diagnosis . No consistently reliable predictors of relapsing disease in GCA have been found.
Data predicting the outcome of patients with TA is limited. A small number of patients will experience a self-limiting inflammatory episode, which does not require chronic immunosuppressive therapy and does not progress to the occlusive stage . Predicting this subset of patients is not currently possible and there remain no sensitive or specific biological markers for the diagnosis or monitoring of disease activity. Visual disturbances, such as blurring or amaurosis fugax, occur in 8–13%, whilst permanent loss of vision is unusual. Stroke and transient ischaemic attacks can result from progressive arterial stenosis or from uncontrolled hypertension (HTN), and may occur in 5% and 20% of cases, respectively . Risk factors for developing these complications have not been identified. Correlation between the levels of acute phase reactants and diagnostic imaging is also often poor in TA and cannot be relied upon to predict such complications. In terms of the site of disease activity, Japanese patients have more frequent lesions at the aortic arch and its branches , while lesions in Korean and Indian patients were more commonly found in the abdominal aorta . Age at disease onset, sex, clinical manifestations, laboratory findings, total number of lines of treatments and history of vascular surgery have been shown not to be significant markers of prognosis Arnaud et al. . The presence of valvular heart disease, cerebrovascular accidents, congestive heart failure, ischaemic heart disease, retinopathy and renovascular hypertension have all been associated with a poorer outcome Part et al. .
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