The value of duplex in systemic giant cell vasculitis

Giant cell vasculitis is a (medium) large vessels vasculitis. Most famous
within the giant cell vasculitis is the subgroup temporal arteritis. This
disorder was first described in 1890 by Hutchinson. The exact etiology of giant
cell vasculitis is unknown. Several hypotheses have been postulated, including
infectious (parvovirus B19), genetic (HLA-DRB1 and HLA-DR4), and auto-immuun.
The pathogenesis is a T-cell mediated vasculitis which is activated by the in
the adventitia located dendritic cells. On microscopic examination this is seen
as a transmural and segmental granulomatous (mononuclear) inflammatory
infiltrate consisting of such CD4 + T cells and giant cells. These giant cells
are not obligatory and are only found in about 50% of the patients.This leads
to intimahyperplasia, which ultimately can lead to stenosis and occludering
with ischemia. Last years there is a growing attention for the more systemic
'entity' , a form which is still unknown. It is unclear what the exact
relationship to the (typical) temporal artertitis is. Maybe in a few years will
be proven that the two separate entities are all one systemic disease. There is
growing evidence for the this. For more than 50% - 75% of the newly diagnosed
temporal arteritis there is any involvement of the great arteries and thus a
systemic reuscelvasculitis. In about 15% of the cases at diagnosis of a
temporal arteritis there is even a dilatation of the aorta. Besides the
involvement of vessels frequently described (as the aorta and extracranial
branches), almost all arteries can participate. But also conversely the
temporal artery can (asymptomatic) participate in systemic giant cell
vasculitis. How often the temporal artery is also involved and how often it is
possible with suspected systemic illness to use the temporal artery for
diagnostic use is unknown. Many other manifestations of giant cell vasculitis
have been described, from a mega-aortic syndrome to affected relatively small
arteries such as in the ovaries and cervix. But also hepatogenic involvement to
affected limbs or mammae. The incidence and prevalence of systemic giant cell
vasculitis is difficult to determine, particularly given that in the
literature, different names are used (arteritis and vasculitis, systemic and
extra-cranial), and therefore no distinction is made in how systemically the
disease is. Often prevalences expressed by the affected artery instead of each
individual. In addition, the disease may still be insufficiently recognized
(such as primary causes of aneurysms) or there are subclinical forms which we
at the moment even do not recognize yet. Given that systemic giant cell
vasculitis can be manifest on very many different locations, it also means that
the presentation of the disease is very atypical and varied. It is therefore
really the clinician whether and when there will be thought of a systemic giant
cell vasculation. In particular, also because there are no diagnostic criteria
for this entity. Many described symptoms including fatigue, (sub) febrile
temperature, weight loss, malaise and an elevated ESR. Less commonly, patients
present themselves with symptoms of claudication or ischemia. Given the fact
that there is no single presentation it will be interesting to (retrospective)
see the original presentation in this research. When in this patient population
then, after a reasonably exclution of infection, malignancy or other systemic
disease, a PET-CT is performed, there often seems to exist a giant cell
vasculitis. Sometimes only in a very late stage, while literature demonstrated
that the provision of early diagnosis of giant cell artiritis can influence the
prognosis. Most of the complications described in (late diagnosed) giant cell
vasculitis is blindness because of anterior ischemic optic neuropathy (AION)
(15-30%), transient ischemic attacks and stroke (3-4%), aneurysm formation and
dissection of the thoracic aorta (<15%). To influence the diagnostic process
and any late diagnosis, we need alternative accessible diagnostics which are
also less invasive and burdens

















ome for a patient. For the diagnosis of systemic giant cell vasculitis are no
existing diagnostic criteria. Today, the gold standard is still the 18F-FDG
PET-CT, regardless of what symptoms or abnormalities patient presents with.
Several studies show that a PET-CT appears useful as a diagnosticum a for giant
cell vasculitis but much less good at follow-up or relapse. Given that
diagnosis is based entirely on imaging, standardized guidelines or diagnostic
criteria seem essential for this. Even though several attempts have been made
to check out by means of scoring systems or comparisons of intensity with the
liver, there is still a need for a universal method. Besides the fact that
there is no uniformity in the diagnosis using PET, ther are other problems as
that sensitivity of PET scan for Giant Cell-arteritis depends on the degree of
inflammation, it's not possibel to check the PET involvement of the temporal
arteries due to the small diameter and its location next to the brains and
finally, the PET-CT is also another invasive, burdensome, not (very) accessible
and pretty expensive. Reason enough to investigate en develop alternative more
standardized research methods like an echo duplex, of which already good
results have been described, among other things, with 100% detection of
affected arteries in upper and / or lower extremities at this patientgroup.
There is increasing awareness about the additional value of duplex examination
of the temporal artery in the diagnosis of temporal arteritis. Duplex
examination can show halos, increase flow and stenoses and occlusions. In this
the halo is particularly important given that stenoses and occlusions of the
temporal artery are frequently seen in the elderly population, such as a sign
of atherosclerosis. Stenoses and occlusions of the temporal artery are
therefore not specific to the disease. These halos have a sensitivity ranging
from 40-86% and a specificity ranging from 78-100% in temporal arteritis, this
is a positive predictive value of 75-92% and a negative predictive value of
64-96%. About the applicability of a duplex in systemic giant cell vasculitis
is still very little known. As a relatively few invasive, accessible and
inexpensive available diagnostic tool, we want to try using this research to
gain more insight into the position of the duplex in the diagnosis, treatment
and follow-up of systemic giant cell vasculitis. It will also try to understand
which vessels most often affected and thus usefulness in the clinic. Partly
based on the fact that in 29% of patients with temporal arteritis duplex
examination also shows deviations from the larger vessels, including carotid
artery, subclavian artery and femoral artery, particularly vascular edema /
halos, indicating systemic vasculitis.View the fact that it is known that an
false-positive duplex can be seen in infection, malignancy, vasculitis, and
otherwise absent flow in the adjacent vein, it is important to use a control
group so clear conclusions can be drawn. In the follow-up phase, we try to make
use of the fact that there is an evolution in the degree of edema. Where we
must observe that a duplex may be false-negative in the early (with no vascular
edema) and in the late phase of inflammation (decrease edema vessel). The
literature has shown that duplex abnormalities are seen about 16 (7-56) days
after starting treatment with corticosteroids. We want to see if this applies
to all patients treated in our population and see what the average duration of
these duplexabnormalities is. We would also like to see what happens to the
duplex abnormalities during treatment or recurrent symptoms and if a decrease
or increase in bloodmarkers is correlated to the decrease or increase of the
vesseloedema. In addition to the PET-CT, the additional diagnosis tests of
laboratory tests, in which an increased ESR and CRP are most often used. The
ESR has a sensitivity of 76-82%, but only a specificity of 9%. 60% of patients
have a ESR> 100 mm / h, 89% ESR> 50mm/uur, 95% a ESR> 40 mm / hour. The CRP has
a sensitivity up to 97.5%.

















Also, anemia, thrombocytopenia and elevation of liver enzymes are seen
(20-30%) .Despite the relatively high sensitivity, better serum markers are
highly desirable, both as a diagnostic (hopefully with better specificity) and
at follow-up. From the pathophysiology of giant cell vasculitis it is now known
that the activation of dendritic cells release inflammatory cytokines such as
IL6 and IL8, which then stimulates the activation of the T cells and
inflammation again. In addition, macrophages also release cytokines IL1 and
IL6, which contribute to the systemic features of temporal arteritis. Precisely
these cytokines seem to play an important role in the pathogenesis of giant
cell vasculitis. Something recent therapeutic studies, with the so-called IL6
inhibitors, already seem to support. In addition to IL-6, there is also
evidence that other serum markers may be useful in giant cell arteritis. One of
the larger studies on this part shows that a significant elevation of titer of
ESR, CRP, intercellular adhesion molecule (ICAM) -1 and PDGF between patients
with relapse and other control patients without relapse. When looking within 1
patient between the time of relapse and stable disease, the following markers
are rise significant: BSE (77 vs 20 mm / h), CRP (1.90 vs 0.5 mg / dl), ICAM-1
(298.33 vs. 235.70 ng / ml), TNF-a (10.95 vs 2.45 pg / ml) and IL-12p40 (60.06
vs 7.80 pg / ml). This study was unable to demonstrate significant increase of
IL-6, as opposed to in another study, in which IL-6, was possibly even more
sensitive than ESR. Finally, there are indications that anti-cardiolipin
antibodies may be a good marker. All in all, untill now there is no consensus
on any new (and better) markers and enough research in this area is desired.
Reason enough involve these new serum markers in this study.

This research aims the usefullness of duplex mapping in systemic giant cell
vasculitis. In determing the diagnosis, the duplex will be compared with the
current gold standard, the 18F-FDG PET-CT, looking at the sensitivity and
specificity of the duplex compared to the control group without systemic giant
cell vasculitis. Efforts will be made to further specify the subgroups of
vessels where this is going to be possible. Furthermore, the value of duplex
during follow-up period will be examined as well. Particular we will try to
evaluate the usefullness of decrease / increase of edema and to assess if this
corresponds respectively to a restoring or a exacerbation of the vasculitis,
where an increase in ESR has to be the control, as we use this at the moment.
It is interesting therefore to infer whether it should be possible to adapt
this treatment sooner and perhaps to reduce with prednisolone. Finally, we will
evaluate how systemic reuscelvasculitiden most often are and will check for new
serum markers.

Primary Objective:
• Sensitivity and specificity of the duplex examination at systemic giant cell
vasculitis as compared to the current gold standard (18F-FDG PET-CT)
• Value of duplex during follow-up
o Increase edema = exacerbation vasculitis?
o Decrease edema = healing vasculitis? (And affected therapy?)

Secondary Objective (s):
• Specifying sensitivity and specificity of duplex to affected vessels
• How systemic is the vasculitis?
• Role of new serum markers in the diagnosis of systemic giant cell vasculitis
and the temporal arteritis.
• Duration that duplex abnormalities persist after initiation of therapy with
corticosteroids
• Retrospective initial presentation of systemic giant cell vasculitis

In this prospective, cohort study, all patients with 18F-FDG PET-CT proved
giant cell vasculitis wil be investigated. Only patients seen within the St.
Elisabeth Hospital or the TweeSteden Hospital in Tilburg by a neurologist,
internist, rheumatologist or ophthalmologist are included.

Flowchart:
1. All patients with 18F-FDG PET-CT proved giant cell vasculitis, seen by a
neurologist, internist, rheumatologist or ophthalmologist.
*
2. Duplex examination and blood tests according to protocol
*
3. Treatment and follow-up according to the guidelines
*
4. When the first duplex was abnormal with the presence of halos, a control
duplex wil be performed 4 weeks and 8 weeks (and every 8 weeks later with still
persisting abnormalities) after initiation of therapy with corticosteroids. If
an exacerbation of the vasculitisis suspected (increased symptoms or increased
blood disorders), a control duplex is performed as well.
*
5. Outpatient control after last duplex, further follow up according to the
guidelines
*
6. Analysis results in termination research

The burden exist of extra duplex investigations and once an extra tube of blood
during.