Download 3. Pathogenesis of giant cell arteritis

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GCA is a large vessel vasculitis of unknown aetiology characterized by
the presence of giant cells in biopsy specimens from large arteries.
GCA shows a striking age tropism with a marked increase in incidence
with age over 50 years. GCA is classified using the ACR criteria,
developed in 1990 [1].
Prospective studies from Scandinavia report annual incidence
figures for biopsy-proven GCA of 15–35 per 100 000 individuals aged
over 50 years, similar rates have been reported from Olmsted County
(Minnesota, USA) and in a UK community based study (reviewed in [2]).
The incidence increases with age, peaking aged 80 years or older; very
few cases occur aged less than 50 years. Most series from Northern
Europe report a greater incidence in women, with a female to male
ratio of around 2.5:1; the female excess is lower in southern European
countries and Israel whilst in Northwest Spain, India and Turkey the
ratio is equal.
In Olmsted County between 1950–54 and 1980–84 there was an
increase from 6.7/100 000 to 28.5/100 000 in persons aged >50 years.
The rate then stabilized and has not risen further. A similar increase in
incidence has been documented in Göteborg, Sweden between 1976
and 1995 from 16.8/100 000 to 30.1/100 000 persons aged >50 years.
GCA appears to be more common in Caucasian populations
compared with non-Caucasians, however, there are few studies
directly comparing different populations [2]. The incidence is highest
in Scandinavians and in populations descended from them. The Viking
heritage of the UK might be responsible for the relatively high
frequency of GCA seen in the UKGPRD study; the incidence is highest
in East Anglia, an area with marked Viking ancestry [3]. GCA is much
less common in southern European populations, which have a different
genetic background [4]. The Olmsted county population is descended
from Scandinavian migrants to the USA. Studies from Tennesse and
Texas have reported a much lower incidence in African-Americans
and Hispanics. There is a low prevalence in Japan compared with
Europe [5].
The epidemiology of a rare disease such as GCA poses challenges
to epidemiologists. One difficulty is case definition. The ACR (1990)
criteria for GCA are sensitive and specific and have been used in most
recent studies. The age criterion (age >50 years) means that patients
presenting with a large vessel vasculitis below 50 years of age are
often considered not to have GCA. The ACR did not mandate a biopsy.
Many studies have been hospital based and only include biopsy
proven cases. Many cases are managed solely in the community
without a biopsy leading to uncertainty as to the veracity of the
diagnosis. The UKGPRD study only validated a small sample (50) of
cases of which only five had a biopsy and two were positive [3]. Novel
techniques for diagnosis such as temporal artery ultrasound, large
vessel angiography of FDG-PET imaging are not considered in the
current classification schemes.
A further difficulty is case capture. GCA is rare, occurs in the elderly
and therefore a large elderly population is required to determine the
incidence and prevalence, and this poses questions of feasibility. A
large population increases the risk of incomplete case detection but
permits a reasonable number of cases to be collected in a practicable
time frame; whereas a smaller population requires a much longer time
frame to collect the necessary cases, which also may not be feasible.
Statistical methods of capture–recapture analysis enable estimates to
be made of the number of missing cases.
The existing literature on the epidemiology of GCA contains a
number of deficiencies. Many of the existing studies only report biopsy
positive cases and this leads to an underestimate of the number of
cases. The biopsy rate varies between centres. The histological
detection of vasculitis is dependent on an adequate length specimen
and examination of several sections. Furthermore skip lesions occur
so that even if the above conditions are met, evidence of vasculitis
may not be seen. A number of the earlier studies were hospital based
and GCA is often managed in the community. A number were
conducted retrospectively again leading to potential bias. There have
been several community based studies (e.g. UKGPRD and Thin
databases), however, it is unclear how robust was the case definition.
There have been very few studies conducted since 2000.
There is therefore an urgent need for a large-scale prospective
community based study with robust methods of diagnosis and
classification, and appropriate statistical power.
References
1. Hunder GG, Arend WP, Bloch DA et al. The American College of
Rheumatology 1990 criteria for the classification of vasculitis.
Introduction. Arthritis Rheum 1990;33:1065–7.
2. Watts RA, Scott DGI. Epidemiology of vasculitis. In: Bridges L,
Ball S, Fessler B, eds. Epidemiology of vasculitisOxford Textbook
of Vasculitis. 3rd edn. Oxford: Oxford University Press, 2014.
3. Smeeth L, Cook C, Hall AJ. Incidence of diagnosed polymyalgia
rheumatica and temporal arteritis in the United Kingdom, 1990–
2001. Ann Rheum Dis 2006;65:1093–8.
4. Tian C, Kosoy R, Nassir R et al. European population genetic
substructure: further definition of ancestry informative markers for
distinguishing among diverse European ethnic groups. Mol Med
2009;15:371–83.
5. Kobayashi S, Yano T, Matsumoto Y et al. Clinical and epidemiologic analysis of giant cell (temporal) arteritis from a nationwide
survey in 1998 in Japan: the first government-supported nationwide
survey. Arthritis Rheum 2003;49:594–8.
3. PATHOGENESIS OF GIANT CELL ARTERITIS
Maria C. Cid1,*
1
Department of Autoimmune Diseases, Hospital Clı́nic, University of
Barcelona, IDIBAPS, Barcelona, Spain
*Correspondence to Maria C. Cid. E-mail: [email protected]
GCA is an immune-mediated chronic inflammatory disease of large
vessels. The pathogenesis of GCA is poorly understood. The
epidemiology of GCA strongly indicates that genetic background,
ageing and gender undoubtedly play a role. Various polymorphisms
have been associated with increased risk of GCA but the strongest
association appears to be with variants in the class II major
histocompatibility complex reinforcing the concept that GCA is an
antigen-driven disease [1]. However, the nature of the triggering
agent(s) has not been identified. Activated dendritic cells are present in
lesions and are thought to play an important role in T-cell activation [2,
3]. GCA is characterized by a prominent Th1-mediated immune
response with vigorous expression of IFNg and IFNg- induced
products in lesions in accordance with the granulomatous nature of
lesions [2, 3]. In recent years it has become apparent that a Th17mediated immune response also contributes to GCA and that patient
with prominent Th17 response respond better to glucocorticoid
treatment [4, 5].
Amplification cascades following these inititating events are
seminal in the development and perpetuation of GCA lesions. IFNg is
a potent activator of macrophages which maintain inflammatory
cascades and participate in vascular injury. Macrophages produce
pro-inflammatory cytokines IL-1, TNFa and IL-6 among many others
which correlate with the intensity of the systemic inflammatory
response, typical of the disease [6]. Tissue expression and serum
concentrations of TNFa and IL-6 correlate with disease persistence [6].
Chemokines, endothelial adhesion molecules and colony-stimulating
factors are also produced in lesions and reinforce inflammatory loops
by recruiting and expanding the half-life of additional inflammatory
cells [6, 7]. Angiogenic factors are produced in lesions and promote
neovascularization providing new entries for infiltrating leucocytes [8].
Activated macrophages produce reactive oxygen species which
contribute to oxidative damage and vessel wall injury [9]. Matrix
metalloprotease (MMP-9 and MMP-2) expression, activation and
proteolytic activity have been detected in lesions and, given their
elastinolytic activity, are probably contributing to disruption of elastic
fibres and abnormal vascular remodelling [10].
Currently the treatment of GCA mainly relies on glucocorticoids
with induce a rapid relief of symptoms but are unable to induce
sustained remission in 60–70% of patients. Understanding the
pathogenic mechanisms leading to GCA may lead to the identification
of better therapeutic agents. The association between increased
expression of TNFa and persistent disease activity provided support to
the performance of clinical trials blocking TNF with infliximab,
etanercept or adalimumab which, unfortunately, have proved insufficient to abrogate disease activity and maintain remission, presumably
due to redundancy in inflammatory pathways [11, 12]. Currently,
blocking the IL-6 receptor with tocilizumab is being tested in an
international multicentre trial. IL-6 is a multifunctional cytokine involved
not only in inducing the acute phase response and ensuing systemic
symptoms but also in maintaining the Th17 pathway. Interfering with
CD28-mediated T-cell co-stimulation with abatacept, presumably
during antigen presentation, is also currently being tested in a
multicentre trial.
Growth factors produced by activated macrophages or by injured
vascular smooth muscle cells drive a vascular remodelling programme
leading to myofibroblast differentiation of smooth muscle cells,
migration towards the intimal layer and deposition of extra cellular
matrix proteins. This leads to intimal hyperplasia and vessel occlusion,
source of the ischaemic complications of GCA patients. Several
factors including PDGFs, TGFb and endothelin-1, may contribute to
myofibroblast activation and production of matrix, eventually leading
Friday 22 November 2013
to vascular occlusion [13, 14]. Their expression in lesions is not downregulated by glucocorticoids suggesting that mechanisms of vessel
occlusion may require a specific approach in large-vessel vasculitis
[15, 16].
References
1. Carmona FD, González-Gay MA, Martı́n J. Genetic component of
giant cell arteritis. Rheumatology 2014;53:6–18.
2. Cid MC, Campo E, Ercilla G et al. Immunohistochemical analysis
of lymphoid and macrophage cell subsets and their immunologic
activation markers in temporal arteritis. Influence of corticosteroid
treatment. Arthritis Rheum 1989;32:884–93.
3. Weyand CM, Goronzy JJ. Immune mechanisms in medium and
large-vessel vasculitis. Nat Rev Rheumatol 2013;9:731–40.
4. Espı́gol-Frigolé G, Corbera-Bellalta M, Planas-Rigol E et al.
Increased IL-17A expression in temporal artery lesions is a
predictor of sustained response to glucocorticoid treatment in
patients with giant-cell arteritis. Ann Rheum Dis 2013;72:1481–7.
5. Terrier B, Geri G, Chaara W et al. Interleukin-21 modulates Th1
and Th17 responses in giant cell arteritis. Arthritis Rheum
2012;64:2001–11.
6. Hernández-Rodrı́guez J, Segarra M, Vilardell C et al. Tissue
production of pro-inflammatory cytokines (IL-1beta, TNFalpha and
IL-6) correlates with the intensity of the systemic inflammatory
response and with corticosteroid requirements in giant-cell
arteritis. Rheumatology 2004;43:294–301.
7. Cid MC, Hoffman MP, Hernández-Rodrı́guez J et al. Association
between increased CCL2 (MCP-1) expression in lesions and
persistence of disease activity in giant-cell arteritis. Rheumatology
2006;45:1356–63.
8. Cid MC, Hernández-Rodrı́guez J, Esteban MJ et al. Tissue and
serum angiogenic activity is associated with low prevalence of
ischemic complications in patients with giant-cell arteritis.
Circulation 2002;106:1664–71.
9. Rittner HL, Kaiser M, Brack A, Szweda LI, Goronzy JJ,
Weyand CM. Tissue-destructive macrophages in giant cell
arteritis. Circ Res 1999;84:1050–8.
10. Segarra M, Garcı́a-Martı́nez A, Sánchez M et al. Gelatinase
expression and proteolytic activity in giant-cell arteritis. Ann
Rheum Dis 2007;66:1429–35.
11. Hoffman GS, Cid MC, Rendt-Zagar KE et al. Infliximab-GCA Study
Group. Infliximab for maintenance of glucocorticosteroid-induced
remission of giant cell arteritis: a randomized trial. Ann Intern Med
2007;146:621–30.
12. Seror R, Baron G, Hachulla E et al. Adalimumab for steroid sparing
in patients with giant-cell arteritis: results of a multicentre
randomised controlled trial. Ann Rheum Dis 2013 doi: 10.1136/
annrheumdis-2013-203586 [Epub ahead of print].
13. Lozano E, Segarra M, Corbera-Bellalta M et al. Increased
expression of the endothelin system in arterial lesions from
patients with giant-cell arteritis: association between elevated
plasma endothelin levels and the development of ischaemic
events. Ann Rheum Dis 2010;69:434–42.
14. Lozano E, Segarra M, Garcı́a-Martı́nez A, Hernández-Rodrı́guez J,
Cid MC. Imatinib mesylate inhibits in vitro and ex vivo biological
responses related to vascular occlusion in giant cell arteritis. Ann
Rheum Dis 2008;67:1581–8.
15. Visvanathan S, Rahman MU, Hoffman GS et al. Tissue and serum
markers of inflammation during the follow-up of patients with
giant-cell arteritis–a prospective longitudinal study. Rheumatology
2011;50:2061–70.
16. Corbera-Bellalta M, Garcı́a-Martı́nez A, Lozano E et al. Changes in
biomarkers after therapeutic intervention in temporal arteries
cultured in Matrigel: a new model for preclinical studies in giantcell arteritis. Ann Rheum Dis 2013 Apr 27 [Epub ahead of print].
GIANT CELL ARTERITIS
4. GENETICS OF GCA: GWAS
Javier Martin1,*
1
Instituto de Parasitologı́a y Biomedicina López Neyra, Granada,
Spain
*Correspondence to Javier Martin. E-mail: [email protected]
i3
GCA is considered a complex disease with a poorly known genetic
component. Genetic studies in GCA clearly pointed to genes located in
the MHC region being strongly associated with GCA. Moreover, recent
studies have indicated that other key members of the immune and
inflammatory response are crucial players in the development and
progression of GCA.
In particular, we have recently identified NLRP1 and PTPN22 as
novel GCA susceptibility genes, adding other pieces of the genetic
puzzle underlying the pathogenesis of this complex disease.
An important step forward has been made in recent years towards
the understanding of the genetic basis of immune-mediated diseases
due to the use of high-through put genotyping platforms such as
genome-wide association study (GWAS) and the Immunochip (IChip)
custom SNP array. At present, we are applying these new technologies—GWAS and IChip—to the identification of novel genetic factors
involved in GCA.
5. BIOMARKERS IN PMR, GCA AND OTHER LARGE VESSEL
ARTERITIDES
Michael Schirmer1,*
Innsbruck Medical University, Innsbruck, Austria
*Correspondence to Michael Schirmer. E-mail:
[email protected]
1
Introduction: Chen et al. [1] state that biomarkers can be classified
into five categories based on their application in different disease
stages: antecedent biomarkers to identify the risk of developing an
illness; screening biomarkers to screen for subclinical disease;
diagnostic biomarkers to recognize overt disease; staging biomarkers
to categorize disease severity, and prognostic biomarkers to predict
future disease course, including recurrence, response to therapy, and
monitoring efficacy of therapy. Interestingly an expert at the National
Institutes of Health (NIH) has defined a biomarker as ‘a characteristic
that is objectively measured and evaluated as an indicator of normal
biological processes, pathogenic processes, or pharmacological
responses to a therapeutic intervention’ [2]. According to this
definition, biomarkers include not only laboratory tests but also
function testing, electrocardiographic testing and imaging depending
on the underlying disease. The clinical value of biomarkers has to be
studied in prospective clinical trials with standardized treatment and
clear outcome parameters and depends on their sensitivity/specificity
and reliability. Also many biomarkers have both prognostic and
predictive features. Here we summarize the use of biomarkers in
PMR, GCA and other large vessel vasculitides including Takayasu
arteritis (TA), isolated aortitis (as a single organ vasculitis) and Behcet’s
disease (BD, as a variable vessel vasculitis).
Methods: Currently available international diagnostic and classification criteria were screened for the recommended use of laboratory and
imaging biomarkers. For PMR, preliminary results from the ongoing
EULAR/ACR project for the assessment of management recommendations (under the guidance of B Dasgupta and E Matteson) and data
from a review on remission and relapse of the diseases are
summarized [3].
Results: Beside ESR and CRP, no validated laboratory biomarkers have
been established for PMR, GCA and other large vessel arteritides,
although several candidate biomarkers have been identified so far. As a
diagnostic biomarker to recognize overt disease, ELISAs using the
human ferritin peptide revealed a positivity of IgG antibodies against
ferritin of 92% in GCA and/or PMR patients, with a false positive rate of
29% in systemic lupus erythematosus, 3% in RA, 0% in late onset RA
and 1% in blood donors [4]. For the detection of response to treatment in
active PMR, for example, receiver operating curves analyses of
fibrinogen showed higher specificity than either ESR or CRP, with an
overall sensitivity and specificity of 92% and 96% [5]. Another group
found that plasma IL-6 was more sensitive than ESR for indicating
disease activity in untreated and treated GCA patients [6]. These authors
pointed out that smouldering disease activity might expose GCA
patients to the risk of progressive vascular disease (e.g. formation of
aortic aneurysms) and chronic systemic complications such as IL-6mediated osteopenia. Also persistent elevation of von Wilebrand factor
during early remission of GCA was considered as a marker for an
endothelial activation status induced by a remaining inflammatory
microenvironment [7]. Interestingly, optic nerve ischaemia has been
associated with increased levels of circulating vascular endothelial
growth factor in another Spanish study [8]. As imaging biomarkers,
sonography has now been introduced in the 2012 provisional EULAR/
ACR classification criteria for PMR, leading to an increased specificity of