takayasu arteritis in infancy
TRANSCRIPT
have been paid into institutional research funds. All other
authors have declared no conflicts of interest.
Andreas Goebel1,2, Siraj Misbah3, Kate MacIver1,Louise Haynes2, Janet Burton3, Ceri Philips4,Bernhard Frank2 and Helen Poole5
1Department of Translational Medicine, Pain Research
Institute, Liverpool University, 2Department of Pain Medicine,
Walton Centre NHS Foundation Trust, Liverpool,3Department of Clinical Immunology, Oxford University
Hospitals NHS Foundation Trust, Oxford, 4Swansea Centre
for Health Economics, Swansea University, Swansea and5School of Natural Sciences and Psychology,Liverpool John Moore’s University, Liverpool, UK.
Accepted 12 July 2013
Correspondence to: Andreas Goebel, Department ofTranslational Medicine, Pain Research Institute, Liverpool
University, Lower Lane, Fazakerley, Liverpool L9 7AL, UK.
E-mail: [email protected]
References
1 Kohr D, Singh P, Tschernatsch M et al. Autoimmunity
against the beta(2) adrenergic receptor and muscarinic-2
receptor in complex regional pain syndrome. Pain 2011;
152:2690�700.
2 Goebel A, Stock M, Deacon R et al. Intravenous
immunoglobulin response and evidence for pathogenic
antibodies in a case of complex regional pain syndrome 1.
Ann Neurol 2005;57:463�4.
3 Goebel A, Baranowski AP, Maurer K et al. Intravenous im-
munoglobulin treatment of complex regional pain syn-
drome: a randomized trial. Ann Intern Med 2010;152:152�8.
4 Dworkin RH, Turk DC, Farrar JT et al. Core outcome
measures for chronic pain clinical trials: IMMPACT
recommendations. Pain 2005;113:9�19.
5 Harden RN, Bruehl S, Perez RS et al. Validation of pro-
posed diagnostic criteria (the ‘‘Budapest Criteria’’) for
complex regional pain syndrome. Pain 2010;150:268�74.
6 Lucas M, Hugh-Jones K, Welby A et al.
Immunomodulatory therapy to achieve maximum efficacy:
doses, monitoring, compliance and self-infusion at home.
J Clin Immunol 2010;30(Suppl 1):S84�9.
7 Turner-Stokes L, Goebel A. Complex regional pain syn-
drome: concise guidance. Clin Med 2011;11:596�600.
Rheumatology 2013;52:2093�2095
doi:10.1093/rheumatology/ket109
Advance Access publication 12 April 2013
Takayasu arteritis in infancy
SIR, A 14-month-old girl was admitted acutely to the
cardiac intensive care unit with pulmonary oedema
secondary to severe acute aortic regurgitation and mitral
regurgitation. She had complaints of persistent cough in
the preceding 6 months, but had normal development and
growth, including normal ophthalmological assessment,
hearing and balance. Echocardiography indicated an
inflammatory process, with initial suspicion of aortic root
abscess. Urgent cardiac surgery was performed which
involved mitral valve repair, aortic root homograft replace-
ment and reimplantation of the left coronary artery. There
was no frank pus around the aortic root. Blood cultures
were sterile, the CRP was 27 mg/l (reference range
<20 mg/l) and the ESR 35 mm/h (reference range
<10 mm/h). Extensive infectious workup including syphilis
serology and tuberculosis was negative. Histology of the
aortic root revealed an inflammatory reaction with plasma
cell infiltrate affecting the adventitia (Fig. 1A). The mitral
valve leaflet demonstrated fragmented elastic laminae,
fibroblast proliferation, increased vascularity and neovas-
cularization with small blood vessels and mixed eosino-
philic and plasma cell infiltrate. There was no histological
evidence of acute bacterial endocarditis. Magnetic reson-
ance angiography (MRA) and cardiac MRI confirmed the
presence of large-vessel vasculitis affecting much of the
aortic arch and its major branches, with arterial wall
thickening and gadolinium uptake, luminal irregularity
and patchy fusiform dilatation extending to the iliac bifur-
cation (Fig. 1B), confirming the diagnosis of Takayasu
arteritis (TA). She was treated with daily oral prednisolone
(2 mg/kg per day; with planned taper to 0.2 mg/kg over
4�6 months pending response), weekly s.c. MTX (15 mg/
m2 per week) and 5 mg/kg per day of aspirin as antiplate-
let therapy. She made an excellent clinical recovery fol-
lowing her cardiac surgery and had prompt and complete
normalization of her acute phase reactants. Three months
later, she attended a routine outpatient appointment and
was clinically in remission, with normal ESR and CRP.
Two days later, however, she had an out-of-hospital car-
diac arrest, requiring cardiopulmonary resuscitation for 30
min. She was transferred back to the cardiac intensive
care unit, with recurrent episodes of unstable angina
(severe pain and ST depression associated with bradycar-
dia and apnoea). Emergency cardiac catheterization re-
vealed severe stenosis of the reimplanted left coronary
artery. Infliximab (6 mg/kg, at weeks 0, 2, 6 and four
weekly thereafter) was added to her immunosuppressive
therapy, and she received continuous i.v. unfractionated
heparin, later converted to clopidogrel. One month after
her cardiac arrest, she underwent successful left internal
mammary artery bypass graft for stenotic left coronary
artery disease. Again she made an excellent and rapid
recovery. Five months later, however, she re-presented
with transient ischaemic attacks with intermittent weak-
ness affecting her right leg related to an occluded left
carotid artery, which was not amenable to angioplasty
or stenting. Warfarin was then added in place of clopido-
grel, aiming for a therapeutic international normalized ratio
of 2�3. MRA 22 months from initial presentation revealed a
slender left common carotid and left subclavian artery, but
no discrete focal narrowing. There was tapering of the
infrarenal abdominal aorta and some stenosis of the su-
perior mesenteric artery, although there were no areas of
late gadolinium enhancement, and the aortic wall thicken-
ing had resolved. Twenty-four months from her initial
presentation, she has been successfully weaned off
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daily prednisolone and is maintained on weekly s.c. MTX,
adalimumab 24 mg/m2 every 2 weeks, warfarin and as-
pirin. She remains asymptomatic, although her develop-
ment is still not yet back to the expected level for her age.
TA is a non-specific large-vessel vasculitis of unknown
origin, with possible genetic contribution [1]. To the best of
our knowledge, this is the first report of an acute cardiac
presentation of TA in an infant. TA is exceedingly rare in
pre-school children, and cardiac involvement is
under-recognized in paediatric patients although it is
described (rarely) in infantile TA [2�5]. Coronary arteritis
resulting in stenoses and aneurysms, cardiac valvular le-
sions and ventricular aneurysm are among the various
cardiac manifestations reported in children with TA [6].
Prior to our case, the youngest patient reported with pri-
mary involvement of aortic and mitral valves in TA was 3
years old [7]. Early diagnosis of large-vessel vasculitis and
institution of immunosuppressive therapy is essential to
avoid complications resulting from stenotic disease. It is
likely that delayed diagnosis (often several years [8]) in the
paediatric population contributes to the high frequency
(80%) of patients who require surgery for stenotic/
occlusive lesions [9]. Granulomas are a major feature of
the histopathology; however, this may not be the case in
children in the early phase of the disease where mononu-
clear infiltration of the adventitia with perivascular cuffing
of the vasa vasorum occurs early [10]. Thus, in the early
phase of the disease, histopathological findings may only
reveal rather bland lymphocytic inflammation with some
neovascularization as in our case. Once considered, the
diagnosis of TA can be confirmed by angiography; MRA is
advocated as it avoids radiation, provides adequate lume-
nography for large arteries and detects arterial intramural
inflammatory changes including increased wall thickness
and late gadolinium enhancement that may be used to
monitor disease activity/progression. In conclusion, we
wish to raise awareness of the occurrence of TA in infancy
and emphasize that cardiac involvement can be feature of
large-vessel vasculitis in children and adults.
Rheumatology key message
. TA can occur in very young children, who maypresent with acute cardiac valve involvement.
FIG. 1 Histopathology and cardiac MRI findings.
(A) Aortic valve revealing florid inflammatory infiltrate composed of plasma cells, lymphocytes and eosinophils,
revascularization and fibrosis. (B) Black-blood (turbo spin echo) MRI showing the aortic arch in a skewed sagittal plane,
after the aortic root replacement. The image shows aortic wall thickening, luminal irregularity and patchy fusiform
dilatation.
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Disclosure statement: The authors have declared no
conflicts of interest.
Nilima Singh1, Marina Hughes1, Neil Sebire1 andPaul Brogan1,2
1Rheumatology Department, Great Ormond Street Hospital
for Children NHS Foundation Trust and 2RheumatologyDepartment, UCL/Institute of Child Health, London, UK.
Accepted 4 February 2013
Correspondence to: Nilima Singh, Rheumatology
Department, Great Ormond Street Hospital, Great OrmondStreet, London WC1N 3JH, UK.
E-mail: [email protected]
References
1 Morishita KA, Rosendahl K, Brogan PA. Familial Takayasu
arteritis—a pediatric case and a review of the literature.
Pediatr Rheumatol Online J 2011;9:6.
2 Vos GD, van der Blij JF, van Leeuwen TM et al. Takayasu’s
disease as the cause of myocardial infarct in an infant.
Ned Tijdschr Geneeskd 1987;131:1355�7.
3 Eke F, Balfe JW, Hardy BE. Three patients with arteritis.
Arch Dis Child 1984;59:877�83.
4 Kierzkowska B, Lipinska J, Baranska D et al. Takayasu’s
arteritis mimicking Kawasaki disease in 7-month-old infant,
successfully treated with glucocorticosteroids and intra-
venous immunoglobulins. Rheumatol Int 2012;32:3655�9.
5 Campos LM, Castellanos AL, Afiune JY et al. Takayasu’s
arteritis with aortic aneurysm associated with Sweet’s
syndrome in childhood. Ann Rheum Dis 2005;64:168�9.
6 Matsubara O, Kuwata T, Nemoto T et al. Coronary artery
lesions in Takayasu arteritis: pathological considerations.
Heart Vessels Suppl 1992;7:26�31.
7 Bernstein HS, Ursell PC, Teitel DF. Primary involvement of
the mitral and aortic valves in Takayasu’s arteritis. Cardiol
Young 1997;7:228�31.
8 Ozen S, Pistorio A, Iusan SM et al. EULAR/PRINTO/PRES
criteria for Henoch-Schonlein purpura, childhood
polyarteritis nodosa, childhood Wegener granulomatosis
and childhood Takayasu arteritis: Ankara 2008. Part II: Final
classification criteria. Ann Rheum Dis 2010;69:798�806.
9 Kalangos A, Christenson JT, Cikirikcioglu M et al. Long-
term outcome after surgical intervention and interventional
procedures for the management of Takayasu’s arteritis in
children. J Thorac Cardiovasc Surg 2006;132:656�64.
10 Gulati A, Bagga A. Large vessel vasculitis. Pediatr Nephrol
2010;25:1037�48.
Rheumatology 2013;52:2095�2097
doi:10.1093/rheumatology/ket143
Advance Access publication 12 April 2013
Distal lower extremity swelling as a prominentphenotype of NOD2-associated autoinflammatorydisease
SIR, We previously reported an autoinflammatory disease
associated with nucleotide-binding oligomerization
domain containing protein 2 (NOD2) gene mutations,
designated as NOD2-associated autoinflammatory dis-
ease (NAID) [1, 2]. Herein we report the presence of
distal lower extremity (ankle and foot) swelling as a prom-
inent phenotype of this disease.
Five patients were recruited as they met diagnostic cri-
teria for NAID [2] and had a clinical commonality: distal
lower extremity swelling/pain. The consent of the patients
was obtained and the study was approved by the
Institutional Review Board of the Cleveland Clinic.
Patient 1, a 64-year-old white woman, presented with
intermittent fever with maximum temperature of 39.4�C
and each episode typically lasted 2 days followed by ab-
dominal erythematous patches. These symptoms had
recurred every 4 weeks during the previous 5 years, with
each episode lasting for several days. A skin biopsy
showed dermatitis. There was also intermittent
polyarthralgia, with notable left ankle and foot swelling;
US examination excluded deep vein thrombosis
(Fig. 1A); radiographic examination was unremarkable.
Oesophagogastroduodenoscopy (EGD) and colonoscopy
with biopsy were performed for heartburn, but the results
were unremarkable.
Patient 2, a 47-year-old white woman, had intermittent
erythematous patches and plaques on the face and neck.
They had recurred every 6 weeks for the past 3 years, and
each episode lasted for 5�7 days. A skin biopsy showed
spongiotic dermatitis. She also had intermittent polyarth-
ralgia, particularly unilateral ankle and foot swelling, on
both physical and radiographic examination. A workup
for mild diarrhoea, including EGD, colonoscopy and CT
enterography, was unremarkable.
Patient 3, a 49-year-old white woman, presented with
intermittent erythematous rash on her extremities over the
past 6 years. She also had intermittent polyarthralgia, with
notable ankle and foot swelling with unremarkable radio-
graph, and each episode of the articular presentation lasted
for a few hours to 3 days. Besides low-grade fever, she also
had intermittent moderate left upper quadrant pain, which
prompted a workup including chest radiograph, EGD and
CT scan of the abdomen and pelvis. The results were
normal as were her serum lipase and amylase levels.
Patient 4, a 29-year-old white man, presented with mul-
tiple episodes of bloody stools and abdominal pain of
1 month duration. His father had been diagnosed with
colitis but did not have any known NOD2 mutations. A
colonoscopic examination with biopsy showed non-spe-
cific pancolitis with normal terminal ileum and the absence
of granulomas. The patient reported left lower chest pain,
and a chest radiograph and CT revealed left lower lobe
infiltrate with a small pleural effusion, which resolved with
several days of high-dose prednisone. He also had right
foot/ankle redness and swelling (Fig. 1B) and transient
freckle-like rash on the extremity. A skin biopsy showed
leucocytoclastic vasculitis (LCV).
Patient 5, a 52-year-old white woman, reported high
fever of 3 years’ duration; it recurred every 10 days, and
each episode lasted for several hours. She also had inter-
mittent polyarthralgia with notable ankle swelling and pain
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