Case Report
Is Pre-Pulseless Takayasu’s Arteritis Always Treatable?
Vikas Agarwal1*, Latika Gupta1, Ramnath Misra1, Tushant Kumar2 and Paul Bacon3
1Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, India
2Department of Radiodiagnosis, Dr Ram Manohar Lohia Institute of Medical Sciences, India
3Rheumatology Research Group, University of Birmingham, United Kingdom
*Corresponding author: Vikas Agarwal, Professor, Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
Published: 17 Mar, 2017
Cite this article as: Agarwal V, Gupta L, Misra R, Kumar T,
Bacon P. Is Pre-Pulseless Takayasu’s
Arteritis Always Treatable?. Ann Clin
Case Rep. 2017; 2: 1307.
Abstract
TA is a rare large vessel vasculitis of unknown etiology, which is difficult to treat. Its natural history is marked by the absence of response to most therapies. The nonspecific nature of the symptoms at presentation and the absence of physical signs result in delayed diagnosis so that many cases progress to vessel stenosis before recognition. It is a common belief that early diagnosis, now possible with the development of PET scans, is imperative to limit inflammation before damage occurs in the form of pulse loss. The unique findings in our case challenge this common belief. We present a case diagnosed before any vascular deformation whose disease progressed despite aggressive therapy. TA is a rare large vessel vasculitis of unknown etiology; its natural history is marked by the absence of response to most therapies.
Introduction
The management of TA remains a complex clinical challenge from the onset. The nonspecific nature of the symptoms at presentation and the absence of physical signs result in delayed diagnosis in at least 20% of cases [1]. Once vessel stenosis occurs, abnormal hemodynamics from altered blood flow lead to further damage to the vessel wall. Damage begets more damage, which can eventually culminate in complete occlusion of the vessel due to fibrosis, intimal plaques and thrombi. A large majority of patients continue to remain minimally symptomatic; they manifest only when the precarious blood supply from collateral vessels is compromised due to dehydration or other factors. It is commonly believed that early diagnosis is essential to allow therapy to limit inflammation before damage occurs in the form of pulse loss [2]. The unique findings in our case challenge the concept that this is always successful.
Case Presentation
An 18-year-old boy presented to the Clinical Immunology department with complaints of
high-grade fever for past 2 months plus 14 kg weight loss. He had undergone extensive workup
elsewhere for pyrexia of unknown origin (PUO) without much avail. His investigations consistently
showed raised acute phase reactants (APR), with normal hemogram and serum chemistry. Cultures
and autoantibody screen were non-contributory. Meanwhile, he had been treated with various
antibiotics without relief. He also complained of new onset precordial pain, which was constricting
in nature, brought on by exertion and relieved with NSAIDs. Computerized Tomography (CT) of
the chest, embarked upon to find the causative focus of PUO, revealed thickening of the wall of the
arch and ascending aorta (Figure 1). This raised suspicion of an underlying large vessel vasculitis.
FDG PET scan confirmed diffuse uptake in the arch and ascending aorta, along with bilateral
common carotid arteries, more so on the left side (Figure 1c). The uptake was higher than the liver,
and amounted to SUVmax 2.3 in the ascending aorta. The absence of any mass or peri-aortic tissue
essentially ruled out IgG4 related disease.
Cardiovascular examination was reviewed again but was found to be normal. All peripheral
pulses were felt and no bruit could be appreciated. The boy, now three months into the illness, was
labeled with a diagnosis of ‘pre-pulseless’ Takayasu’s arteritis and initiated on 1 mg/kg Prednisolone
plus Azathioprine, to which the fever responded. He was also found to have hypertension at this
time, and ECG as well as Echocardiography bore the stigmata of this in the form of left ventricular
hypertrophy. Doppler scan of the renal arteries was normal.
Despite the initial good response, the systemic symptoms resurfaced over the next month, and
the patient developed a bruit in the left Subclavian Artery (SCA). CT angiography showed new
involvement of the left SCA, seen as thickening of the vessel wall at the ostium. It also confirmed the previous findings of isolated wall thickening at the ascending
aorta and the arch, plus the right Common Carotid Artery (CCA)
just distal to the origin.
Cyclophosphamide monthly infusions were then initiated
but were halted after three doses when the patient developed lowgrade
fever with pleural thickening, which was initially attributed to
tuberculosis. When all workup was negative, the fever was deemed
to be due to Takayasu arteritis activity and he was pulsed with three
doses of 1gram methyl prednisolone. This time the patient chose to
take Methotrexate (MTX) instead, although fever persisted for three
months despite full dose (25 mg/week) of MTX and split prednisolone
dosing (15 and 5 mg respectively). APRs were elevated and repeat
PET scan showed uptake as before (Figure 2a).
He was subsequently treated with Mycophenolate Mofetil 3
grams per day, plus prednisolone 20 mg per day, for 3 months before
it was stopped due to diarrhoea and rash. He was subsequently given
tocilizumab monthly infusions (8 mg/kg) for 8 months, to which he
responded briefly, with negative APRs for the first time in the course of
his illness. At that time, however, PET scan continued to show disease
activity. This follow up PET scan revealed new focus of uptake in the descending aorta as well (SUVmax 4.1), although previous foci had
become inactive (Figure 2b), and soon thereafter his clinical disease
resurfaced despite ongoing therapy. He had accrued damage in the
form of left subclavian stenosis and symptoms of vertebro-basilar
insufficiency. He also sustained a Transient Ischemic Attack (TIA)
due to hypoperfusion in the left MCA territory from his underlying
carotid disease. He was then switched to tacrolimus (TAC) (1 mg/
day) and prednisolone (15 mg per day) with clinical benefit. The
last PET scan while on TAC was negative (Figure 2c), even though
stenosis in the carotids has been progressive on follow up CTA. He
has bilateral CCA and left SCA long segment stenosis (5 and 7 cm
long respectively) along with intramural plaques visualised in the
entire upper aorta and descending arta close to the renal arteries on
MRI (Figure 3).
After 6 months of tacrolimus, he again had precordial pain and accelerated hypertension. He did not have fever this time, although
CRP was elevated but PET scan continued to be negative. Trough
serum Tacrolimus levels were normal so MTX was added, but the
symptoms subsided within a month’s time.
Figure 1
Figure 1
(a) CT Angiogram at 3 months of symptoms: Axial image shows
diffuse circumferential wall thickening of the arch of aorta (thick white arrow).
(b) Coronal image at the same time shows diffuse circumferential wall
thickening of bilateral common carotid artery (red arrow) without significant
luminal narrowing. (c) 18FDG PET image at 3 months of symptom onset
shows circumferential and linear uptake (thin white arrow) in these areas
suggestive of inflammatory process involving the large vessel walls possibly
large vessel vasculitis; CT- Computerized tomography, FDG PET- fluoro-Dglucose
positron emission tomography.
Figure 2
Figure 2
(a) 18FDG PET scan one year later, after Cyclophosphamide and
Methotrexate trial shows persistent uptake in the arch, descending aorta and
bilateral common carotid artery (thick white arrow) (b) New focus of uptake
is seen in descending abdominal aorta (black arrow) after eight months of
monthly Tocilizumab infusion (c) No uptake is seen in subsequent scan done
after four years of the illness (suggesting lack of active disease); FDG PETfluoro-
D-glucose positron emission tomography.
Figure 3
Figure 3
MR angiogram after three years into the disease, shows moderate
narrowing of the left CCA (white arrow) and mild narrowing of right CCA & left
SCA (white arrowhead), suggestive of damage; MR- Magnetic resonance,
CCA- common carotid artery, SCA- subclavian artery.
Figure 4
Discussion
The need for early diagnosis of Takayasu’s arteritis is widely
accepted among rheumatologists and cardiologists alike. Novel
imaging methods such as 18F-FDG-PET, Doppler US, or MR
angiography can identify early vessel wall inflammation before stenosis
occurs. The era of FDG PET in the workup of PUO has improved case
detection rates [2]. Its impact on the survival rates in TA are not clear
[3] but it is believed that early diagnosis and institution of treatment
can prevent damage accrual. Our case highlights the shortcoming of
the present immunosuppressive therapy (including biologics such as
Tocilizumab), in preventing vascular obstruction even if instituted at
the pre-pulseless stage.
This case defines clearly the natural history of the disease. The
patient manifested with systemic symptoms with elevated APRs plus
positive vessel inflammation on PET and only later went on to vessel
stenosis with claudication. This highlights the sensitivity of FDG PET
in early diagnosis, before changes are appreciated on angiography.
Interestingly, the patient developed progressive disease despite
initiation of therapy - including steroids, immunosuppressants and
biologics - early in the course (Figure 4). The failure to respond to
multiple therapies is even more surprising. The patient had high
disease activity as scored on ITAS.A at symptoms onset, though
scores were much lower on follow up as persistent disease is not
recorded PET findings often remain positive even after initiation
of treatment [4]. The lack of a comparative clinical gold standard of
disease activity makes it difficult to comment on the utility of PET in
the follow up of patients [2]. However, persistent PET positivity while
on treatment is consistent with findings of persistent inflammation in
post mortem studies on patients without clinical symptoms of activity
[5]. It is known that Th17 responses dominate in the active phase of
the disease before autonomous activity from vascular smooth muscle
cells is triggered [6]. It is not very clear, though, as to how late in the
disease pathogenesis, these changes occur.
The findings from this case may lead us to believe that the
autonomous activity is triggered as early as 3 months into the disease.
This indicates that we need to think about disease progression as a
much more complex process than current dogma about the benefits
of early diagnosis suggests. The role of immunosuppression in
altering the disease course remains dubious at best. Restenosis after
intervention is the best model for treatment efficacy in Takayasu’s.
It has been clearly shown that restenosis rates are lower in cases that
undergo intervention only after receiving immuno-suppressants
[7]. However attempts to control systemic as well as vascular
inflammation in this patient failed miserably at all times.
The only time our patient felt clinically better was while on
Tocilizumab, but never-the-less vascular progression continued.
The patient did stabilize eventually on Tacrolimus (clinically and on
PET scan), which suggests that T cell responses are important in the
pathogenesis. TA is a granulomatous inflammatory disease and T cells
are important for granuloma formation; hence there is rationale for
using T-cell directed therapies in TA. However, the reported failure
of other T cell targeted therapies like abatacept in TA may lead us to
think otherwise [8]. Failure of Cyclosporine in Takayasu’s has been reported in previous studies, though two Japanese cases benefitted with
Tacrolimus [9-11]. Although both TAC and cyclosporine antagonize
calcineurin and cytokine production, the former in addition inhibits
the expression of high affinity IL-7 receptor on immune cells. It also
prevents IL-2 mediated IL-5 production by CD4+T cells [12]. Thus
it is more efficacious at reducing IL-2 producing T cells in renal
transplant patients. It is plausible to suggest that such additional
immunosuppressive actions of Tacrolimus have a role to play in as
yet undiscovered pathogenic pathways of this intriguing disease.
Fever and chest pain in the last episode subsided within a month
of adding MTX to TAC, when drug effectiveness was not expected
to take over. Similarly, in clinical practice, it is not unusual to find
patients who present with stenosis without ever having had systemic
symptoms of the pre-pulse less phase. This could possibly suggest
that intermittent inflammation in TA starts and ceases on its own,
consequent to factors that are still unknown. The course of TA is
highly variable from being a monophasic inflammatory illness in
some but a progressive obstructive vascular lesion at one or more sites
in others. Our case illustrates the substantial problems in controlling
such progressive disease despite early diagnosis with initiation of
active therapy in the pre-pulseless phase.
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