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15 Biomarkers inVascular Disease
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357
observational data is probably the best hope in the hunt for biomarker patterns that
can truly inuence disease management.
15.10 Conclusion
Biomarkers are likely to have increased utility in the future of vascular surgery. To
date no biomarker for AAA or carotid stenosis has been translated into clinical practice. However, with advances in mass spectrometry and proteomic techniques combined with worldwide interest in this discovery science, a signicant discovery is
likely to not be far away. In the future, the decision to operate on a dilated aorta or
carotid stenosis may be guided by the presence of a specic protein in the patient’s
serum, and no longer simply the morphology of the lesion.
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Soluble CD36 in plasma is increased in patients with symptomatic atherosclerotic carotid
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A. Cadersa and I. M. Nordon
Further Reading
Golledge J, Tsao PS, Dalman RL, Norman PE.Circulating markers of abdominal aortic aneurysm
presence and progression. Circulation. 2008;118:2382–92.
Groeneveld ME, Meekel JP, Rubinstein SM, Merkestein LR, Tangelder GJ, Wisselink W, Truijers
M, Yeung KK.Systematic review of circulating, biomechanical, and genetic markers for the
prediction of abdominal aortic aneurysm growth and rupture. JAHA. 2018;7(13).
Hermus L, Lefrandt JD, Tio RA, Breek J-C, Zeebregts CJ.Carotid plaque formation and serum
biomarkers. Atherosclerosis. 2010;213:21–9.
Hlatky MA, Greenland P, Arnett DK, Ballantyne CM, Criqui MH, Elkind MSV, Go AS, Harrell
FE, Howard BV, Howard VJ, P.Y.H, Kramer CM, McConnell JP, Normand S-LP, O’Donnell
CJ, Smith SJ, Wilson PWF. Criteria for evaluation of novel markers of cardiovascular risk.
Circulation. 2009;119:2408–16.
Nordon IM, Brar R, Hinchliffe RJ, Cockerill GW, Loftus IM, Thompson MM.The role of pro-
teomic research in vascular disease. J Vasc Surg. 2009;49:1602–12.
Vasan RS. Biomarkers of vascular disease: Molecular basis and practical considerations.
Circulation. 2006;113:2335–62.
Chapter 16
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Pathophysiology andPrinciples
ofManagement ofVasculitis
andFibromuscular Dysplasia
MaureenRischmueller, SarahDownie-Doyle, andRobertFitridge
Key Learning Points
Early recognition and treatment of vasculitis leads to reduced morbidity and
•
mortality.
• Severity and prognosis of vasculitic conditions are dictated by the pathology,
size, and distribution of affected blood vessels.
•
Giant cell arteritis is characterised by a biphasic inammatory process, with the
glucocorticoid-responsive Th17 (IL-6/IL-17)-mediated pathway driving sys-
temic inammation in early disease, and poorly glucocorticoid-responsive Th1
(IL-12/IFNγ)-mediated mechanisms promoting chronicity of inammation in
blood vessel walls.
• Aortitis and retroperitoneal brosis are characteristic features of IgG4-related
disease.
M. Rischmueller (*)
Rheumatology Department, The Queen Elizabeth Hospital, Woodville, SA, Australia
Rheumatology Department, Royal Darwin Hospital, Darwin, NT, Australia
Discipline of Medicine, The University of Adelaide, Adelaide, SA, Australia
e-mail: Maureen.Rischmueller@sa.gov.au
S. Downie-Doyle
Rheumatology Department, The Queen Elizabeth Hospital, Woodville, SA, Australia
e-mail: Sarah.Downie-Doyle@sa.gov.au
R. Fitridge
Discipline of Surgery, The Queen Elizabeth Hospital, The University of Adelaide,
Woodville, SA, Australia
e-mail: robert.tridge@adelaide.edu.au
R. Fitridge (ed.), Mechanisms of Vascular Disease,
https://doi.org/10.1007/978-3-030-43683-4_16
361© Springer Nature Switzerland AG 2020
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• Cancer immunotherapy targeting immune checkpoints is a newly recognised
cause of vasculitis.
• Fibromuscular disease is a non-atherosclerotic arterial disease which pre-
dominantly affects women aged from 45 to 55 at time of diagnosis. FMD may
be asymptomatic or cause thrombosis, aneurysm development and/or
dissection.
• Fibromuscular disease most frequently affects the renal and cerebrovascular
arteries. FMD lesions should be classied according to appearance on angiogra-
phy as focal or multifocal FMD.
M. Rischmueller et al.
16.1 Introduction
Vasculitis covers a broad array of clinicopathological diseases, from transient
localised cutaneous reactions, to clinical manifestations of systemic diseases, to
fulminant life-threatening diseases dominated by widespread inammation,
occlusion and rupture of blood vessels. There is great diversity in pathophysiology, clinical presentation, diagnosis and management. Cutaneous lesions such as
petechiae, livedo reticularis, purpura, nodules and ulcers raise the suspicion of
vasculitis, which also commonly affects organs and tissues including lungs, kidneys, peripheral nerves, muscles, and the gastrointestinal tract. Patients are often
systemically unwell with malaise, fever, weight loss, arthralgia, normochromic
normocytic anaemia and have raised inammatory markers. History is important
and should include the onset and evolution of symptoms, systems review, preceding infections, exposure to drugs and toxins, and relevant family history. Full
blood count, electrolytes, renal and hepatic function, C reactive protein (CRP),
erythrocyte sedimentation rate (ESR) and, where relevant, viral titres, autoantibodies, and cryoglobulins should be measured. Urinalysis is important to identify
renal involvement, typied by red cells, casts, or proteinuria, as prompt treatment
may avert irreversible renal failure. Biopsy remains the gold standard for histopathological conrmation of vasculitis, and in addition to formalin xation, a
fresh sample should be provided for immunouorescent labelling of immune
complexes and complement if small vessel vasculitis is suspected. Imaging is
paramount when a biopsy is unobtainable and, in large vessel vasculitis, is useful
to determine the extent of disease.
Comorbidities are common, including treatment-related toxicities such as
corticosteroid- induced obesity, mood disorders, skin fragility, bruising, osteoporotic fractures, peptic ulcer disease, diabetes, dyslipidaemia, hypertension, accelerated atherosclerosis, cataracts, glaucoma, and immunosuppression predisposing
individuals to common and opportunistic infections. Vaccination against inuenza,
pneumococcus, and pertussis should be up to date, and prophylaxis against
16 Pathophysiology andPrinciples ofManagement ofVasculitis andFibromuscular…
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pneumocystis jiroveci pneumonia should be prescribed for patients taking high
doses of glucocorticoids. It should be noted that vaccination with live vaccines such
as Zostavax (attenuated varicella-zoster virus vaccine) are contraindicated in the
setting of immunosuppression because of the risk of disseminated viral disease.
Baseline assessment of bone mineral density, and treatment to prevent or manage
steroid-induced osteoporosis is standard of care. Small and large vessel vasculitis is
associated with an increased risk of contemporaneous malignancy, particularly in
elderly patients, and clinical examination supplemented by relevant investigations
should be undertaken.
The aetiology of most vasculitides is unknown, with management directed
towards the prevention and treatment of organ damage, maintenance of a low
inflammatory state, titration of therapy according to clinical, serologic and
imaging parameters, management of comorbidities, and prevention and management of treatment-related side effects. This chapter will outline the main
types of vasculitis encountered in clinical practice, describe known pathogenetic mechanisms, and present management strategies. In addition to vasculitis,
Raynaud’s phenomenon, thromboangiitis obliterans and fibromuscular dysplasia will be discussed.
363
16.2 Primary Versus Secondary Vasculitis
Vasculitis is caused by immune-mediated inammation of blood vessels. In most
cases the underlying cause of this reaction is unknown, and the term “primary”
is often applied, whereas in a subset of cases the vasculitis is triggered by a
known drug or virus or is a manifestation of an underlying systemic disease and
is thus termed “secondary”. Categorization into primary versus secondary vasculitis becomes problematic, however, as more aetiologies are discovered.
Vasculitis has more recently been divided according to the size and type of blood
vessel involved, which has merit given that similar organs and tissues are
affected. The discovery of anti-neutrophil cytoplasmic antibodies (ANCAs)
associated with a subset of patients with small vessel vasculitis, causative viruses
and gene mutations in a subset of patients previously diagnosed with polyarteritis nodosa, and the evolution of modern imaging techniques such as magnetic
resonance imaging/angiography (MRI/MRA) and positron emission tomography
(PET), has led to further subclassication of vasculitis. Table 16.1 shows the
names for vasculitides adopted by the 2012 International Chapel Hill Consensus
Conference of the nomenclature of vasculitides [1]. Technology-led advances in
our understanding of mechanisms of disease initiation and progression, as well
as insights emerging from empiric trials of targeted biologic therapies, will continue to inform this area.
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Table 16.1
vasculitides adopted by the
2012 International Chapel
Hill Consensus Conference
on the Nomenclature of
Vasculitides [
Names for
1]
Large vessel vasculitis (LVV)
Takayasu arteritis (TAK)
Giant cell arteritis (GCA)
Medium vessel vasculitis (MVV)
Polyarteritis nodosa (PAN)
Kawasaki disease (KD)
Small vessel vasculitis (SVV)
Antineutrophil cytoplasmic antibody (ANCA)-associated
vasculitis (AAV)
Microscopic polyangiitis (MPA)
Granulomatosis with polyangiitis (Wegener’s) (GPA)
Eosinophilic granulomatosis with polyangiitis (Churg-
Strauss) (EGPA)
Immune complex SVV
Anti-glomerular basement membrane (anti-GBM)
disease
Cryoglobulinemic vasculitis (CV)
IgA vasculitis (Henoch-Schönlein) (IgAV)
Hypocomplementemic urticarial vasculitis (HUV)
(anti-C1q vasculitis)
Variable vessel vasculitis (VVV)
Behcet’s disease (BD)
Cogan’s syndrome (CS)
Single-organ vasculitis (SOV)
Cutaneous leukocytoclastic angiitis
Cutaneous arteritis
Primary central nervous system vasculitis
Isolated aortitis
Others
Vasculitis associated with systemic disease
Lupus vasculitis
Rheumatoid vasculitis
Sarcoid vasculitis
Others
Vasculitis associated with probable aetiology
Hepatitis C virus-associated cryoglobulinemic vasculitis
Hepatitis B virus-associated vasculitis
Syphilis-associated aortitis
Drug-associated immune complex vasculitis
Drug-associated ANCA-associated vasculitis
Cancer-associated vasculitis
Others
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365
16.3 Large Vessel Vasculitis
16.3.1 Giant Cell Arteritis (Temporal Arteritis)
Giant cell arteritis (GCA) is a granulomatous vasculitis principally involving
medium- and large-calibre branches of the aorta, which left untreated, can lead to
permanent blindness. It is the commonest form of vasculitis, occurring in patients
over the age of 50, and mainly affects people of northern European and Scandinavian
descent. There is a female preponderance and a worldwide incidence between 1 and
30 per 100,000. The strongest genetic association is with human leucocyte antigen
class II gene loci DRB1∗04, DQA1∗03 and DQB1∗03 [2].
GCA is a T cell driven disease characterised by the formation of vessel wall granulomas, intimal hyperplasia and end-organ ischaemia. T helper cell 1 (Th1) and
Th17 pathways and innate immunity appear to be central in its pathogenesis.
Activation and maturation of immature vascular dendritic cells (vasDCs) within the
normally immunoprivileged arterial wall leads to recruitment and activation of local
innate immune cells such as monocytes and broblasts, as well as naive CD4 T cells.
Adventitial vasa vasora critically control vessel wall access and drive differentiation
of tissue-invasive T cells, which establish tissue residency within autonomous
inammatory lesions [3]. Antigens have been suspected to drive the local activation
of vasculitogenic CD4 T cells, but recent data suggest a more generalized defect in
their threshold setting. In health, immune checkpoints provide a physiological brake
on T cell activation to curb inammation-associated tissue destruction. This mechanism has been shown to be disrupted in GCA, as vasDCs fail to express the immunoinhibitory programmed cell death ligand-1 (PD-L1), leaving lesional T cells
unchecked. Consequently, programmed cell death protein-1 (PD-1)-positive CD4 T
cells can enter the vessel wall, where they produce a broad spectrum of inammatory
cytokines including interferon-gamma (IFN-γ), interleukin-17 (IL-17) and IL-21,
and have a direct role in driving intimal hyperplasia and intramural neoangiogenesis.
The deciency of the PD-1 immune checkpoint in GCA, promoting unopposed T
cell immunity, contrasts with checkpoint hyperactivity in cancer patients in whom
excessive PD-L1 expression paralyses the function of antitumor T cells [
Diverse macrophage subsets, secreting matrix metalloproteinases which degrade
the internal elastic lamina, and smooth muscle cells within the media, promote the
migration and proliferation of myobroblasts into and within the intima, ultimately
inducing wall capillarisation and intimal hyperplasia, leading to luminal compromise [3]. Macrophages release IL-6 and IL-1β, potent cytokines required for differentiation of Th17 effector cells; levels of circulating IL-6 correlate with the
severity of the acute inammatory response in GCA, and uctuate in line with disease activity. Th1 cells differentiate in the presence of IL-12, thought to be produced
by activated vasDCs, and these effector T cells are responsible for the secretion of
IFN-γ, a potent activator of macrophages and heavily implicated in promoting
4].
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M. Rischmueller et al.
mural inltration, as well as giant cell and granuloma formation. In contrast to IL-6
and IL-17, which appear to wax and wane with disease activity and are highly
responsive to glucocorticoids, elevated levels of IL-12 and IFN-γ persist within the
serum of patients and within temporal artery samples despite months of glucocorticoid treatment, and higher levels of these cytokines correlate with ischaemic
complications.
16.3.1.1 Biphasic Inammatory Response inGCA
It has been proposed that there is a biphasic inammatory process, where the Th17
(IL-6/IL-17)-mediated pathway, which is glucocorticoid-responsive, drives systemic inammation in early GCA, while Th1 (IL-12/IFN-γ)-mediated mechanisms
promote chronicity and are poorly steroid responsive. This might explain the disconnect between early control of systemic inammation and suboptimal numbers of
patients achieving long-term remission, with late development of aortic aneurysms
[2]. A recent study of patients who had serial temporal artery biopsies (TAB) before
and 3–12months after initiation of therapy revealed that vascular inammation persisted in most patients, despite normalisation of CRP and ESR [3].
GCA may occur de novo, or in patients with known polymyalgia rheumatica
(PMR), a related inammatory condition characterised by pain and stiffness of the
shoulder and hip girdles. The most common presenting features of GCA are of
occlusive cranial arteritis, such as temporal headache, jaw claudication, facial pain,
amaurosis fugax, diplopia, cerebrovascular accident (particularly of the vertebral
circulation) and unheralded unilateral or bilateral blindness, which occurs in up to
20% of patients. Limb claudication due to large vessel vasculitis in the absence of
cranial arteritis may be the presenting feature of GCA, and some patients present
with generalised lethargy, malaise, unexplained weight loss, or pyrexia of unknown
origin. Physical signs may be minimal, but include scalp tenderness, nodularity/
decreased pulsation of the temporal artery, and in patients with visual symptoms,
fundoscopic changes of anterior ischaemic optic neuropathy, retinal arterial occlusions or choroidal infarction. Presenting features with the highest positive predictive
value for GCA include jaw claudication and/or scalp tenderness [
2]. Depending on
disease duration, normocytic anaemia, thrombocytosis and/or leukocytosis may be
evident, and signicant elevation of the ESR and/or CRP is characteristic, although
occasionally absent. The American College of Rheumatology classication criteria
for GCA are shown in Table16.2 [5].
GCA is considered a medical emergency because of the high risk of irreversible
blindness or stroke if treatment is delayed. In patients sustaining monocular blindness, there is a 50% risk of visual loss in the contralateral eye within 2weeks.
Histopathology of a temporal artery biopsy (TAB) is the gold standard for diagnosis, but treatment should not be delayed, as pre-TAB glucocorticoid exposure
does not affect the yield for up to 6weeks and beyond [6]. The sensitivity of TAB
for the diagnosis of GCA varies between 39 and 91% because of skip lesions, and
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