Non-Infectious Aortitis: a Report of 32 Cases from a Single Tertiary Centre in a 4-Year Period and Literature Review J

Non-infectious aortitis: a report of 32 cases from a single tertiary centre in a 4-year period and literature review J. Loricera1, R. Blanco1, J.L. Hernández2, J.M. Carril3, I. Martínez-Rodríguez3, A. Canga4, E. Peiró1, J. Alonso-Gutiérrez2, V. Calvo-Río1, F. Ortiz-Sanjuán1, C. Mata1, T. Pina1, M.C. González-Vela5, N. Martínez-Amador3, M.A. González-Gay1,6

Departments of 1Rheumatology, ABSTRACT mon condition. The diagnosis is often 2Internal Medicine, 3Nuclear Medicine, Objective. Non-infectious aortitis often delayed. Atypical PMR features, unex- 4 5 Radiology, and Pathology, Hospital presents with non-specific symptoms plained low back or limb pain, consti- Universitario Marqués de Valdecilla, leading to inappropriate diagnostic de- tutional symptoms along with increased IDIVAL, University of Cantabria, Santander, Spain; lay. We intend to describe the clinical acute phase reactants should be consid- 6University of the Witwatersrand, spectrum and outcome of patients with ered “red flags” to suspect the presence Johannesburg, South Africa. aortitis diagnosed at a single centre. of aortitis. Javier Loricera, MD Methods. We reviewed the clinical Ricardo Blanco, MD, PhD* charts of patients diagnosed with non- Introduction José L. Hernández, MD, PhD infectious aortitis between January Aortitis is the inflammation of the aor- José M. Carril, MD, PhD 2010 and December 2013 at the Rheu- tic wall (1, 2), and can be idiopathic or Isabel Martínez-Rodríguez, MD matology Division from a 1.000-bed associated with a cluster of infectious Ana Canga, MD tertiary teaching hospital from North- or non-infectious diseases (1-11). Gi- Enriqueta Peiró, MD Juan Alonso-Gutiérrez, MD ern Spain. The diagnosis of aortitis was ant cell arteritis (GCA) (12, 13) and Ta- Vanesa Calvo-Río, MD usually based on FDG-PET-CT scan, kayasu arteritis (TA) are the most com- Francisco Ortiz-Sanjuán, MD and also occasionally on CT or MRI mon underlying conditions associated Cristina Mata, MD angiography or helical CT-scan. with aortitis (14, 15), although it can be Trinitario Pina, MD Results. During the period of assess- a manifestation of other systemic dis- M. Carmen González-Vela, MD, PhD ment 32 patients (22 women and 10 eases (16-23). Néstor Martínez-Amador, MD men; mean age 68 years [range, 45– Non-infectious aortitis is often an un- Miguel A. González-Gay, MD, PhD* 87]) were diagnosed with aortitis. The derrecognised condition usually pre- *These authors share senior authorship. median interval from the onset of symp- senting with non-specific symptoms. Please address correspondence to: toms to the diagnosis was 21 months. Thus, high index of clinical suspicion Miguel A. González-Gay, MD, PhD, Department of Rheumatology, FDG-PET CT scan was the most com- is required (1, 2). Early diagnosis is Hospital Universitario Marqués mon tool used for the diagnosis of aor- of main importance to prevent serious de Valdecilla, IDIVAL, titis. The underlying conditions were complications, such as an aneurysmal Avenida de Valdecilla s/n, the following: giant cell arteritis (n=13 rupture or an aortic dissection (24). 39008 Santander, Spain. cases); isolated polymyalgia rheumati- Aortitis is a hystopathological term E-mail: [email protected] ca (PMR) (n=11); Sjögren’s syndrome (Fig. 1). However, in the clinical prac- Received on April 19, 2014; accepted in (n=2), Takayasu arteritis (n= 1); sar- tice, the diagnosis is based on imaging revised form on July 25, 2014. coidosis (n=1), ulcerative colitis (n=1), techniques (25, 26). Thus, the introduc- Clin Exp Rheumatol 2015; 33 (Suppl. 89): psoriatic arthritis (n=1), and large- tion in the last decade of 18F(fluoro)- S19-S31. vessel vasculitis that also involved the D-glucose (FDG) positron emission © Copyright Clinical and aorta (n=2). The most common clinical tomography (PET) computed tomo- Experimental Rheumatology 2015. manifestations at diagnosis were: PMR graphy scan (FDG-PET/CT scan) and features, often with atypical clinical contrast-enhanced magnetic resonance Key words: aortitis, giant cell presentation (n=23 patients, 72%); dif- imaging (MRI) (Fig. 2) has improved arteritis, polymyalgia rheumatica, fuse lower limb pain (n=16 patients, the diagnosis of large-vessel vascultides lower limb pain, PET/CT scan 50%); constitutional symptoms (n=12 (23, 26-30). patients, 37%), inflammatory low back In the present study we aimed to: a) an- Funding: This study was supported by pain (n=9 patients, 28%) and fever alyse the presenting features and clini- a grant from Fondo de Investigaciones (n=7 patients, 22%). Acute phase re- cal spectrum of patients with aortitis Sanitarias PI12/00193 (Spain). This work was also partially supported actants were increased in most cases diagnosed at a single centre, and b) es- by RETICS Programs, RD08/0075 (RIER) (median erythrocyte sedimentation rate tablish the clinical and laboratory data and RD12/0009/0013 from ‘Instituto de 46 mm/1st hour, and a median serum C- that may be considered as “red flags”, Salud Carlos III’ (ISCIII) (Spain). reactive protein 1.5 mg/dL). which may help to establish an early di- Competing interests: none declared. Conclusion. Aortitis is not an uncom- agnosis of aortitis.

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Fig. 1. A. Microscopic panoramic view of the aortic wall showing medial necrosis with inflammatory response (H&E, original magnification x25). Fig. 2. Coronal MRA of the abdominal aorta. B. Microscopic higher power view showing inflammatory infiltrate with lymphocytes and a Langhans Irregular lumen stenosis of the infrarenal ab- type giant cell (H&E, original magnification x200). dominal aorta.

Patients and methods whether patients with PMR features ful- mg/dL in all the patients. Whole-body Patient population filled the classification criteria proposed FDG-PET uptake was assessed 180 We reviewed the clinical charts of pa- by EULAR/ACR 2012 (34). minutes after injection of 7 MBq/kg of tients diagnosed with non-infectious Sjögren’s syndrome was diagnosed 18F-FDG, using a Biograph LSO Pico aortitis between January 2010 and De- according to the European-American 3D from Siemens Healthcare Molecular cember 2013 at the Rheumatology Di- classification criteria (35), and psoriat- Imaging (Hoffman Estates, IL, USA). A vision from a 1.000-bed tertiary teach- ic arthritis was diagnosed on the basis low dose CT scan for attenuation cor- ing hospital from Northern Spain. The of CASPAR criteria (36). rection and anatomic localisation was diagnosis of aortitis was usually based first obtained, followed by a FDG-PET on FDG-PET-CT scan, and also occa- Data collection and clinical scan (acquiring 250 s/bed position). Im- sionally on CT or MRI angiography or definitions ages were reconstructed using the or- helical CT-scan. In all the cases clinical Clinical and laboratory data were re- dered subsets-expectation maximisation features and/or laboratory abnormali- trieved according to a pre-established (OSEM) algorithm (2 iterations, 8 sub- ties were also present. research protocol. To minimise entry sets). Images were visually evaluated GCA (31) and TA (32) were diagnosed error, all the data were double-checked. by two experienced nuclear medicine according to the American College of Fever was defined as a temperature specialists according to the intensity of Rheumatology classification criteria. >38ºC. Constitutional symptoms were the 18F-FDG uptake by the vessel wall Under the term “polymyalgia rheumat- asthenia, anorexia or weight loss at the supraaortic trunks, thoracic aorta, ica” (PMR) we included patients with greater than 5% of the normal body abdominal aorta, iliac arteries and femo- typical and atypical polymyalgia fea- weight. Lower limb pain was defined ral/tibioperoneal arteries. tures. Typical PMR was defined when as a diffuse pain involving the thighs. the patient fulfilled the PMR criteria Inflammatory low back pain was diag- Statistical analysis proposed by Chuang et al. (33). On the nosed according to the Assessment of Results were expressed as mean ± other hand, we defined atypical PMR Spondyloarthritis International Society standard deviation (SD) or as median, when patients did not fulfill the crite- (ASAS) (37). ESR was considered in- range and/or interquartile range (IQR) ria for PMR shown above (33). These creased when it was higher than 20 or as appropriate. Analysis was performed patients had aches and pain resembling 25 mm/1st hour for men or women, re- with the STATISTICA software pack- PMR and at least one of the following spectively. Serum CRP levels above 0.5 age (Statsoft Inc. Tulsa, OK, USA). features: a) inflammatory low back pain, mg/dL were considered as high values. b) diffuse pain in the lower limbs, c) Results persistent fever, d) constitutional symp- FDG-PET CT scan acquisition and Overall results toms and/or e) lack of improvement of image analysis We studied 32 patients (22 women/10 PMR with low-medium dose oral cor- Patients had to be in fasting state for at men) with non-infectious aortitis. The ticosteroids (in all cases prednisone least 6 hours before the examination. mean age±SD at the time of diagnosis range: 10–15 mg/day). We also assessed Serum glucose level was lower than 160 was 68±11 years (range 45–87 years).

S-20 Non-infectious aortitis / J. Loricera et al. arteries supraaortic vessels, thoracic and abdominal aorta iliac arteries PET-CT: ascending and descending aorta aortic arch PET-CT: ascending and descending thoracic aorta, aortic arch, supraaortic vessels PET-CT: PET-CT: large arteries of lower limbs large PET-CT: thoracic and abdominal aorta, supraaortic vessels iliac arteries PET-CT: PET-CT: aorta, supraaortic vessels and both common iliac arteries PET-CT: vessels of lower limbs thoracic aorta, supraaortic vessels, medium and large PET-CT: descending thoracic aorta and abdominal PET-CT: ascending and descending aorta, aortic arch, supraaortic vessels, iliac PET-CT: aortic arch, thoracic and abdominal aorta PET-CT: ascending aorta, aortic arch, thoraco-abdominal supraaortic vessels, PET-CT: vessels, including supraaortic, thoracic and large PET-CT: thoracic aorta and supraaortic vessels PET-CT: ascending aorta, aortic arch, femoral and popliteal arteries PET-CT: aortic arch PET-CT: supraaortic vessels and thoracic aorta PET-CT: thoracic aorta and femoral tibial arteries PET-CT: PET-CT: supraaortic vessels, left common iliac artery, femoral and tibial arteries supraaortic vessels, left common iliac artery, PET-CT: supraaortic vessels and subclavian arteries PET-CT: Scintigraphy: uptake along the venous-arterial route of both popliteal fossas aorta, supraaortical vessels, subclavian arteries and both common carotid PET-CT: femoral arteries femoral, popliteal and tibial arteries abdominal aorta and bifurcation of iliac femoral arteries thoracic aorta and supraaortic vessels PET-CT: thoracic aorta and supraaortic vessels PET-CT: thoracic aorta, supraaortic vessels and pulmonary artery trunk PET-CT: thoracic aorta PET-CT: thoracic aorta PET-CT: thoracic aorta PET-CT: descending aorta and aortic arch. PET-CT: MRA: aortic elongation and thickening of descending aorta. thoracic aorta PET-CT: without inflammatory activity PET-CT: wall thickening of both common and external carotid. Carotid Doppler-ultrasound: MRA: decreased caliber of the infrarenal abdominal aorta. Lower limb arteriography: decreased caliber of the infrarenal a bdominal aorta and stenosis. Stenosis of left subclavian artery vessels of lower limbs thoracic aorta, supraaortic vessels and large PET-CT: atherosclerosis with aortocoronary calcification and elongated aorta CT: Imaging technique and result thoracic aorta and supraaortic vessels PET-CT: PET-CT: ascending and descending aorta, aortic arch, femoral tibial arteries PET-CT:

artery biopsy NP Positive Positive Positive Negative Negative Negative Positive Positive Positive Positive Negative NP NP NP NP NP NP Positive Positive NP NP NP NP NP Negative Negative NP Negative Negative NP Negative Temporal

4/0.1 46/NP 27/1.2 126/28.2 104/12.6 67/13.4 78/3.3 4/0.16 10/0.15 32/1.2 43/0.2 119/1.6 53/0.9 2/0.1 46/0.4 25/1.5 12/<0.1 75/NP 101/11.75 12/0.9 25/0.1 70/7.7 65/5.5 28/2.6 110/12.4 43/NP 62/2.1 33/0.6 78/2.1 92/4 111/0.99 33/2.1 diagnosis of aortitis ESR/CRP at the time No No No Atypical No Typical Typical Typical Typical Typical Atypical Typical Atypical Atypical Typical Typical Atypical Typical No Typical Atypical Typical Typical No No Atypical Atypical Typical Typical No No Typical PMR No No No No No No No No No No No No No No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes pain pain limb Lower No No No No No No No No No No No No No No No No No No No No No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes matory Inflam- low back

No No No No No No No No No No No No No No No No No No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes tional Constitu- symptoms

No No No No No No No No No No No No No No No No No No No No No No No No No Yes Yes Yes Yes Yes Yes Yes Fever

0 5 0 0 0 8 2 6 0 0 8 0 0 2 1 9 0 99 72 15 30 23 17 19 71 26 39 24 ND 119 136 170 From first of aortitis (months)

Delay to the diagnosis 4 6 2 8 9 3 2 2 4 11 36 77 18 31 47 27 10 21 14 27 13 69 44 26 0.3 ND 100 120 142 180 156 156 initial physician From the symptom consultation hour); CRP: C-reactive protein (mg/dL). st

Associated disease GCA, PMR GCA, PMR GCA GCA, PMR GCA, PMR GCA, PMR GCA, PMR GCA, PMR GCA GCA, PMR GCA, PMR GCA, PMR GCA Isolated atypical PMR Isolated atypical PMR Isolated atypical PMR Isolated atypical PMR Isolated atypical PMR Isolated typical PMR Isolated PMR Isolated PMR Isolated PMR Isolated typical PMR Isolated PMR syndrome Sjögren’s syndrome Sjögren’s TA Sarcoidosis, PMR Ulcerative colitis, PMR Psoriatic arthritis Idiopathic Idiopathic Main features of 32 patients finally diagnosed as having aortit is. sex 56/F 59/M 68/M 69/F 70/F 63/F 65/F 72/F 73/F 79/F 81/F 82/M 85/F 52/F 56/F 63/F 68/M 76/M 53/F 62/M 65/F 79/F 79/F 81/F 71/F 79/F 48/F 56/M 69/F 45/M 64/M 87/M Age/ Table I. Table Case 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 ESR: performed; Not NP: tomography. emission positron 18FDG PET: angiography; resonance magnetic MRA: tomography; computed CT: arteritis; Takayasu TA: rheumatica; polymyalgia PMR: arteritis; cell giant GCA: female; F: male; M: Erythrocyte sedimentation rate (mm/1

S-21 Non-infectious aortitis / J. Loricera et al.

CclinR, CclinR, CclinR, CclinR, CclinR, ClabR PlabR CclinR, ClabR ClabR ClabR. ClabR CclinR, ClabR ClabR PlabR PlabR Outcome CclinR, ClabR ClabR CclinR, ClabR CclinR, CclinR, CclinR, CclinR, CclinR,

7 3 6 7 5 36 20 36 15 24 66 36 34 (months) Follow-up

------mg/w mg/w mg/w mg/w Other therapy MTX 10 MTX 15 MTX 15 MTX 15 in follow-up Aortitis: therapy and outcome at 1 month dose) and other Initial prednisone therapy / response (8 mg/kg/m)/ PclinR, ClabR ClabR ClabR PclinR, ClabR CclinR, CclinR, PlabR // CclinR, PlabR PclinR, - TCZ (8mg/k/m)// 25+TCZ 40//CclinR, ClabR 10+ MTX 7.5// - - - - 7.5+MTX (25 mg/w)// 45/CclinR, ClabR 20+ MTX10// 7.5+MTX (12.5mg/w)

6 8 99 30 19 72 17 35 aortitis GCA to GCA (months) diagnosis Time from Time Synchronous Synchronous Synchronous Synchronous Synchronous

- - - - - CRP 12/0.9 27/1.2 4/0.16 43/0.2 32/1.2 ESR / 46/ND 119/1.6 10/0.15 of  Features at aortitis diagnosis Fever, ILBP, ConsS ILBP, Fever, pain in lower limbs diffuse when prednisone is tapered below of 25 mg/d guirdle when prednisone is tapered below 10 mg/d Asymptomatic but Clinical features Headache and loss of weight Asthenia Fever, pain in thighs, Fever, Headache, pain in scapular and lower limbs pain ILBP Fever, sweating, ConsS Fever, sweating, Malaise, fever, ConsS Chest pain Asymptomatic ConsS, PMR, headache,

at first month dose / response 50/CclinR, PlabR 45/ PclinR, PlabR 50/ PclinR, PlabR 20 /PclinR, PlabR 40/ PclinR, ClabR 40/ PclinR, ClabR Initial prednisone 10/ CclinR, ClabR 30/ CclinR, ClabR 40/ CclinR, ClabR 45/ CclinR, ClabR 40/ CclinR, ClabR 30/ CclinR, ClabR 45/ CclinR, ClabR

artery Negative Positive Positive NP Positive Positive Positive Positive Negative Positive Negative Positive Positive biopsy Temporal

CRP ESR / 49/5.5 85/4.6 46/1.9 78/3.3 75/ND 84/ND 131/24 113/1.4 67/13.4 76/2.92 108/13.2 126/28.2 101/11.75

No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Abnormal exploration temporal artery No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes PMR hour); CRP: C-reactive protein (mg/dL); NP: Not performed. hour); CRP: C-reactive protein (mg/dL); st No No No No No No No No No No Yes Yes Yes Features at GCA diagnosis Features at GCA Visual symptoms No No No No No No No No No Yes Yes Yes Yes Jaw cation claudi- No No No No No Yes Yes Yes Yes Yes Yes Yes Yes Headache*

56/F 69/F 70/F 63/F 65/F 72/F 73/F 79/F 81/F 85/F 59/M 68/M 82/M /sex Main features of 13 patients with giant cell arteritis (GCA) a nd aortitis. Age (yrs) (at aortitis diagnosis) Case 1 2 3 4 ConsS 5 6 7 8 9 10 reactants 11 asthenia 12 phase 13 acute from usual. *Headache: recent onset or different constitutional ConsS: pain; back low inflammatory ILBP: metothrexate; MTX: response; laboratory partial PlabR: response; laboratory complete ClabR: response; clinical partial PclinR: response; clinical complete CclinR; male; M: female; F: symptoms; ESR: Erythrocyte sedimentation rate (mm/1 Table II. Table

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Fig. 3. An 81-year-old woman (case 11 in Tables I and II) with GCA confirmed by temporal artery biopsy. FDG-PET CT scan was perfomed. Sagittal (A) and coronal (B) PET images showed an intense and well defined FDG lineal uptake along the thoracic and abdominal aortic wall. Axial view through the aortic arch (C) revealed intense FDG uptake by the arterial wall. Maximum intensity projection image of the lower extremities (D) also showed an intense lineal FDG uptake along the femoral and tibioperoneal arteries.

The median interval from the onset of isolated PMR. Noteworthy, patients in which TA was diagnosed on the ba- the symptoms to the diagnosis of aorti- with atypical PMR experienced, more sis of raised acute phase reactants and tis was 21 (IQR: 6–69) (range 0.3–180) commonly, symptoms such as thigh an arteriography with high-grade ste- months. Table I summarises the main pain, low back pain or lower limb pain, nosis in the infrarenal aorta, dilation features of the patients included in our and they had a poor response to low- of the arc of Riolan and 50% left sub- series. medium doses of prednisone (10–15 clavian artery stenosis. She was started mg/day). Besides, none of the 5 pa- on prednisone (30 mg/day) and MTX Clinical subtypes of aortitis tients with isolated atypical PMR ful- (15 mg/week). Normalisation of acute – Giant cell arteritis and aortitis filled the ACR/EULAR criteria (34). phase reactants and resolution of asthe- We diagnosed 13 patients (10 women/3 nia was achieved 2 months later. Then, men) with aortitis associated with GCA. – Sjögren’s syndrome and aortitis prednisone was tapered until complete The mean age±SD was 71±9 years Two patients were diagnosed with discontinuation one year later. (range 56–85 years). GCA was histo- Sjögren’s syndrome and aortitis. The Sarcoidosis and ulcerative colitis associ- logically confirmed in 9 of 13 cases. The first one was a 71-year-old woman di- ated with aortitis was diagnosed in two main clinical and laboratory character- agnosed with Sjögren’s syndrome in patients previously reported (16, 17). istics of these patients are summarised 1997. Aortitis was suspected because Finally, a 45-year-old man with psori- in Table II. Of note, in 8 cases initially persistently high ESR levels despite atic arthritis and aortitis was diagnosed diagnosed of GCA, the diagnosis of aor- treatment with low-dose corticoster- in our centre. He suffered a stroke and titis was made later (median [IQR]: 24.5 oids. A FDG-PET CT scan showed in- then began with diffuse pain in lower (8–72) months; range 6–99 months). creased vascular uptake with a typical limbs. Because of the lower limb pain pattern suggestive of aortitis. Rituxi- and the previous history of stroke, a – Typical and atypical polymyalgia mab (375 mg/m2 weekly for 4 weeks) large-vessel vasculitis was suspected rheumatica associated with aortitis was added with an excellent clinical and confirmed by increased FDG up- Twenty-three patients had PMR (typi- response at 3 months. take in the ascending and descending cal in 15 cases). It was isolated in 11 The second patient was a 79-year-old thoracic aorta, aortic arch and supraaor- (typical in 6 cases and atypical in 5), woman diagnosed with Sjögren’s syn- tic vessels. Successful response to adal- and associated with other conditions in drome with persistently elevated ESR imumab (40 mg every other week sub- the remaining (10 cases with GCA, 1 and anaemia. The patient underwent a cutaneously) in combination with MTX with sarcoidosis and 1 with ulcerative FDG-PET CT scan that disclosed an (15 mg/week) was achieved. colitis). increased FDG uptake in the thoracic Patients (8 women and 3 men) with aortic wall consistent with aortitis. – Large-vessel vasculitis that also isolated PMR had a mean age of 67±10 involved the aorta years (range 52–81 years). Table III – Aortitis related to other diseases Two cases of large-vessel vasculitis shows the main clinical features and We found a patient with Leriche syn- that also involved the aorta were in- laboratory parameters of patients with drome and exertional angina pectoris cluded in this series. The first one was

S-23 Non-infectious aortitis / J. Loricera et al. PlabR Exitus Exitus Outcome CclinR and CclinR and PclinR, PlabR PclinR, PlabR PclinR, PlabR PclinR, PlabR PclinR, ClabR PclinR, ClabR CclinR, PlabR CclinR, PlabR CclinR, ClabR CclinR, ClabR CClinR, PlabR CClinR, PlabR CclinR, PclinR

8 8 3 6 3 2 1 0 15 16 16 (months) Follow-up

------in the follow-up HQ 300 mg/d Other therapy MTX 20 mg/w MTX 10 mg/w MTX 10 mg/w, MTX 10 mg/w, Aortitis: therapy and outcome

side effects other therapy / 5/PclinR, PlabR discontinued the 20/PclinR, PlabR 20/PclinR, PlabR 30/CclinR, PlabR 10/CclinR, PlabR 20/PclinR, ClabR 30/PclinR, ClabR 5/PCclinR, PlabR 40/CclinR, ClabR 40//CclinR, ClabR because the patient because the patient Predisone dose and 6.25/PclinR, PlabR. treatment for fear of treatment for fear of Response at 1 month

2 6 2 8 26 119 136 PMR aortitis (months) diagnosis Time from Time diagnosis to Synchronous Synchronous Synchronous Synchronous

CRP CRP 2/0.1 ESR/ 43/NP 62/2.1 25/0.1 53/0.9 46/0.4 70/7.7 33/0.6 78/2.1 25/1.5 65/5.5

ILBP girdle ConsS and arms is tapered Pain in thighs Pain in thighs Features at the time of aortitis diagnosis Clinical features and pelvic girdles Reactivation of the and abdominal pain Pain in thighs, ILBP Shivering, shore throat Asthenia, pain in thighs Pain in cervical, shoulder Pain in thighs, lower limbs Pain in thighs and shoulder symptoms when prednisone symptoms when prednisone

10/ No clinical 1 month and PlabR improvement improvement 5/PclinR, PlabR No improvement 10/PclinR, PlabR Initial prednisone dose / response at 10/CclinR, ClabR 10/CclinR, ClabR 20/ PclinR, PlabR 20/ PclinR, ClabR 10/ CclinR, ClabR 30/ CclinR, ClabR 10/C clinR, ClabR No corticosteroids// hour); CRP: C-reactive protein (mg/dL); Prednisone dose: mg/day ; NP: Not performed. PMR Typical Typical Typical Typical Typical Typical st atypical Atypical Atypical Atypical Atypical Atypical Typical or Typical

CRP CRP ESR / 10/0.1 62/2.1 87/1.1 98/0.1 59/2.9 70/7.7 33/0.6 30/1.0 28/2.2 65/5.5 33/ND

- - pain ILBP ILBP throat ConsS ConsS Features at PMR diagnosis Headache Pain in thighs Other features Pain in thighs, Asthenia, pain and lower limbs Shivering, shore Lower limbs pain in thighs, headache No No Yes Yes Yes Yes Yes Yes Yes Yes Yes pain Pelvic No No No No No Yes Yes Yes Yes Yes Yes pain Scapular No No No No No No No No Yes Yes Yes pain Cervical

Main features of 11 patients with isolated typical and atypical polymyalgia rheumatica (PMR) aortitis. Main features of 11 sex 52/F 56/F 63/F 53/F 65/F 79/F 79/F 81/F 68/M 76/M 62/M Age (yrs)/ Table III. Table Case* 14 15 16 17 18 19 20 21 22 23 24 I. Table * Related to case number from constitutional ConsS: pain; back low inflammatory ILBP: metothrexate; MTX: response; laboratory partial PlabR: response; laboratory complete ClabR: response; clinical partial PclinR: response; clinical complete CclinR: male; M: female; F: symptoms. HQ: hidroxichloroquine; ESR: Erythrocyte sedimentatio n rate (mm/1

S-24 Non-infectious aortitis / J. Loricera et al.

Fig. 4. Suggested work- ommended in patients in whom close up in patients presenting follow-up is needed as this technique with an autoimmune or inflammatory condition is very useful to assess wall thickening to determine the pres- and wall oedema, and to determine the ence of aortitis. presence of specific lesions such as the presence of aneurysms or thrombus, (1, 41, 42, 46). In recent years, however, FDG-PET CT scan has gained consid- erable acceptability as a non-invasive tool potentially useful for the diagnosis and management of patients with large-vessel vasculitis by providing a metabolic functional image of the vessel wall inflammation before structural changes are seen (47-52). This technique is especially helpful in atypical presentations of vasculitis (17, 53). Previous studies have shown good results evaluating the aortic involvement in patients with large-vessel vasculitis (28). GCA is more common in Caucasian individuals older than 50 years (54-57), and may affect the aorta and its major a 64-year-old man presented with high- Discussion branches (12, 13, 29, 58-63). Table IV grade fever and dyspnea. He had mild We describe a series of 32 patients di- summarises the main series on patients leucocytosis, ESR 104 mm/1st hour and agnosed with aortitis at a single tertiary with GCA and aortic involvement. serum CRP 12.6 mg/dL. Complete mi- hospital from Northern Spain over a The use of new imaging techniques crobiological studies were all negative. 4-year period. As expected, aortitis was has disclosed that extracranial large- Temporal artery biopsy was normal. mainly observed in the setting of GCA vessel involvement in GCA is more A body CT-scan disclosed sligthy en- and PMR. common than initially thought (26). larged left paratracheal lymph nodes, Non-infectious aortic disease presents Aortitis in the setting of GCA is a po- and a biopsy showed reactive lym- with a wide range of symptoms. Apart tentially serious and usually underdiag- phadenitis. A 18F-FDG PET/CT scan from fever, headache, back pain, and nosed complication (64). A prospective revealed an increased uptake in the tho- PMR manifestations (38), severe aor- study using CT-scan within the month racic and abdominal aorta, supraaortic tic insufficiency, aortic aneurysms and after GCA diagnosis showed that aor- vessels and iliac arteries. The patient rarely, aortic disection and rupture tic thickening occurs frequently at the started on prednisone (40 mg/day) and have been described at the time of dis- time of diagnosis of GCA, and that this MTX (10 mg/week) reaching complete ease diagnosis (1, 13, 39, 40). In our condition predominantly affects the clinical remission. series, the most common clinical mani- ascending aorta (65). In keeping with The second patient was an 87-year-old festations of aortitis were PMR, diffuse these observations, using CT angiogra- man who was sent to the hospital be- lower limb pain, constitutional symp- phy Prieto-González et al. found aorti- cause of chest wall pain and inflamma- toms, inflammatory low back pain, and tis in 67% of 40 newly diagnosed GCA tory low back pain as well as asthenia, fever. Most of these manifestations are patients (66). Histopathology studies anorexia and weight loss of 3 months´ non-specific. Therefore, a high index of disclosed ascending aorta involvement duration. The ESR was 110 mm/1st hour suspicion for aortitis is needed. Thus, in 8–13% of GCA patients (13, 61, 62). and serum CRP 12.4 mg/dL. A body- in patients with chronic or relapsing in- Aortitis in patients with GCA may lead CT scan showed diffuse atherosclerosis flammatory diseases, these clinical fea- to aortic aneurysms. The risk of aneu- with aortocoronary calcification and an tures along with elevated acute phase rysmal rupture and aortic dissection is elongated aorta. A 18F-FDG PET/CT reactants should be considered as “red increased in patients with GCA. They scan revealed homogeneous and diffuse flags” to suspect the presence of aortitis occur mostly in the ascending thoracic increased FDG uptake in the thoracic (Fig. 4). aorta. Comparing with people of the aorta, supraaortic vessels and large ves- Regarding imaging techniques, angio- same age and sex, Evans et al. reported sels of lower extremities. Prednisone graphy has been replaced by angioCT- that patients with GCA had a 17-fold (30 mg/day) was initiated with complete scan and MRI in the diagnosis and increased risk of thoracic aortic aneu- resolution of the symptoms and normal- assessment of distribution and activ- rysm and a 2.4-fold increased risk of isation of the acute phase reactants. ity of aortitis (23, 41-43). MRI is rec- abdominal aortic aneurysm (39). Simi-

S-25 Non-infectious aortitis / J. Loricera et al. our). h st hour); CRP: hour); CRP: st Outcome Imaging techniques Rapid resolution Rapid resolution Rapid resolution dissecting aortic aneu aortic dissecting rysm, recovering without complications Treatment failure Treatment failure Treatment required surgery for a required surgery 6 months later the patient 6 months later the patient Relapse Relapse

Angiography MRI Angiography Angiography CT, angiography, CT, Angiography, CT, MRI, CT, Angiography, MRI, CT, Angiography, US US CDS, PET Angiography, CT, CT, Angiography, echocardiogram MRI, US

4 9 33 67 36 27 17 20 Positive biopsy (n) Response to temporal artery temporal artery (initial dose) (initial corticosteroids Yes (methyl- Yes Yes (prednisolone, Yes prednisolone, 500 mg/day/3 days) Yes(prednisone, (prednisone, Yes 30 mg/day). 15 mg/day) 40 mg/day) 20 mg/day) 20 mg/day) Yes (prednisolone, Yes Yes (prednisolone, Yes

ESR Mean: 61 Mean: 56±25 Mean: 96 Median: 104 (range 40–139) Median: 81.5 Median: 79 [IQR 58–97] [IQR 64–116] Mean: 90±20 Mean: 101±21

9 4 6 2 3 NA NA NA (n) rasonography; NA: not available. ESR: erythrocyte sedimentation rate (mm/1 rate sedimentation erythrocyte ESR: available. not NA: rasonography; Visual Imaging technique manifestations

6 2 14 15 12 NA NA NA (n) Jaw CT: aortic wall thickening CT: CT and MRA: thickening of aortic arch its CT MRI: vessel wall thickening, edema, MRI: vessel wall thickening, edema, branches, descending and abdominal aorta FDG uptake in aortic arch branches, thoracic PET: and abdominal aorta. abdominal aorta and mild stenosis of the right internal carotid artery. thoracic aorta. increased mural contrast enhancement, stenosis of left subclavian artery. increased mural contrast enhancement. CT: soft tissue thickening of the descending CT: CT and MRA: thickening of thoracic CT claudication

40 19 NA 12.6 6.01 CRP 11.57

25 14 NA NA NA NA NA NA 82 42 90 NA 120 105 ESR exam (n) artery on physical Abnormal temporal

No No NA NA NA Yes pain 7 9 Thighs 25 24 15 18 NA NA (n) Headache

No No No NA NA NA Pelvic

8 1 4 22 21 10 13 (n) ND PMR

NA NA NA Yes Yes Yes

Shoulder 17 16 NA NA NA NA NA NA

symptoms (n) Constitutional No NA NA NA Yes Yes pain

Cervical

1 6 5 14 NA NA NA NA (n) Fever

NA NA NA Yes Yes Yes Stiffness

No NA NA NA Yes Yes Age (years) Fever Median:67 Mean: 71±11 Mean: 66 Mean 77±7 Mean: 71.1±6.4 Median: 74.7 Median: 75.2 Median: 69 (range 54–92) (range 52–88) [70.7–83.1] [68.8–80.9] 61 64 73 67 63 66 Age (years)

n/sex

1/F 1/F 1/F 1/F 1/F 1/M n/sex 41(31F/10M) 15 (15 F) 74 (65F/9M) 4(3F/1M) 20 (12F/8M); all with 30 (24F/6M); all with or dissection 21 (17F/4M); all with 72 (51F/21M) aortic aneurysm aortic aneurysm and/ artery stenosis large (29) (76) (74) (74) (29) (29) Former series describing the main features of GCA patients with aortic and/or its major branches involvement. Former series describing the main features of GCA (60) (59) (58) (75) Review of published cases polymyalgia rheumatica and involv ement the aorta and/or its major branches. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. (13) (52) (13) erence Table IV. IV. Table Reference Ghinoi González-Gay et al. Nuenninghoff et al. Nuenninghoff et al. Brack Narváez Lie (63) Evans ult US: tomography; emission positron PET: imaging; resonance magnetic MRI: tomography; computed CT: sonography; Doppler colour CDS: female; F: male; M: V. Table Ref Kataoka Kataoka Koga Narváez Narváez Milchert M: male; F: computed female; tomography; CT: MRA: magnetic resonance angiography; MRI: magnetic resonance positron imaging; emission PET: tomography; NA: not available. ESR: erythrocyte sedimentation rate (mm/1 C-reactive protein (mg/dL)

S-26 Non-infectious aortitis / J. Loricera et al.

lar data have been reported in biopsy- proven GCA patients from Northwest

hour); CRP: hour); CRP: Spain (61). Of note, Liozon et al. indi- st cated that the presence of classic cra- Doppler-US angiography Angiography Angiography Angiography

CTA, PET, US, PET, CTA, nial features of GCA at the time of dis- Imaging technique Aortography, DSA, Aortography, ease diagnosis may be a negative pre- dictor of an aortic complication (67).

Overall, patients with large-vessel in- NA NA NA CRP

(Median) volvement in the setting of GCA are younger than patients with classic cra- 3.75 [IQR: 0.7–9.5] nial temporal arteritis (66 vs. 72 years) and most of them are women (83% vs.

66%). Moreover, the time between the 88 NA NA ESR

(Median) onset of symptoms and the diagnosis of

(range 30–125) the disease is usually longer in patients 45 [IQR: 17.5–96.5] with aortitis (7 months vs. 2 months) (26).

Patients with large-vessel GCA may (n) Bruits present with typical cranial temporal arteritis or PMR, but they may also pre- Subclavian: 13 Subclavian: 121 Carotid: 7 Abdominal: 6 Femoral: 3 Carotid: 60/121 Abdominal: 44/122 Femoral: 17/120 Carotid: 146 Abdominal: 55 Femoral: 24 Carotid: 42 Abdominal: 17 Femoral: 2 Subclavian: 60/121 Subclavian: 13 sent with non-specific symptoms such as fever, sweating, malaise, anorexia,

13 37 weight loss, fatigue, lower extremity ND n (%) (87%) (40%) (62%) 50/125 claudication or arthralgias (26, 42, 68). Upper limb claudication Therefore, in many GCA patients the diagnosis of aortitis may be extremely

8 20

106 difficult, leading to a long diagnos- n (%) (53%) (38%) (43%) (33%) 41/109 tic delay. Thus, in a series of biopsy- (new-onset), Hypertension proven GCA patients from Northwest Spain, the mean time between the diag-

3 9

62 nosis of GCA and the diagnosis of aor- n (%) (20%) (36%) (25%) (15%) 37/104,

Weight loss Weight tic involvement was 57 months (61). Similar results have been reported in other studies (29, 58).

4 18 Joint 116 n (%) Aortic complications may be the cause (27%) (35%) (47%) (30%) 36/103

manifestations of death in 3–12% of patients with large-vessel GCA (13). A recent epide-

20 miologic study on large-vessel involve- 139 n (%) (47%) (54%) (56%) (33%) 58/107 Fatigue/ malaise ment in GCA patients from Olmsted County (MN) has shown that incidence

of any large-vessel event is high within

68 10 16 n (%) Fever (67%) (29%) (27%) (27%) 30/103 the first year of GCA diagnosis. The incidence of aortic aneurysm/dissection is also increased 5 years after GCA di-

agnosis (69). Survival of GCA patients with aortic aneurysm or dissection was Age (years) Mean: 33.1±12 (range 19–51) Median: 31.5 [IQR: 22.9–39.8] (range 7–64) Median: 36 Median: 25 found decreased (standardised mortal- ity ratio, 2.63; 95%CI 1.78–3.73) (69). PMR is also a common disorder in individuals older than 50 years from n (Sex) Western countries (55, 56). This may 248 (221F/27M) M) 126 (115F/11 15 (11F/4M) 60 (58F/2/M) appear as an isolated disease or associated with ischemic features of GCA (82) (86) (85) Reported series on main features of patients with Takayasu arteritis. Takayasu Reported series on main features of patients with (70, 71). In the literature a handful of et al. (83)

et al. case reports emphasise the presence of et al.

et al. aortitis in patients with PMR (29, 57,

Table VI. Table Reference Noosin Schmidt Bicakcigil Kerr M: male; F: female; computed CTA: tomography angiography; DSA: digital subtraction angiography; positron PET: emission tomography; US: ultrasonography; NA: not available. ESR: erythrocyte sedimentation rate (mm/1 C-reactive protein (mg/dL) 70, 72-76). Table V summarises the lit-

S-27 Non-infectious aortitis / J. Loricera et al. erature cases of PMR with involvement small-vessel vasculitis (90). Sarcoidosis titis. Forty-five percent of the patients of aorta and/or its major branches. has also been associated with Wegener’s had aneurysm-related symptoms, 33% The diagnosis of PMR is very straight- granulomatosis, microscopic polyangii- were asymptomatic, 12.5% had consti- forward when typical features, such as tis, polyarteritis nodosa and TA (19, 90, tutional symptoms, 9.4% polymyalgia pain in the neck, and shoulder and pel- 96). Association of sarcoidosis with aor- and 4.7% suffered symptoms related vic girdles are present (77, 78). titis and Crohn’s disease has also been to the involvement of cranial arteries. However, the presence of atypical described (97). Seventy-two per cent of patients had symptoms or a poor response to corti- Inflammatory bowel disease is -char additional vascular imaging abnormali- costeroids should be considered warn- acterised by diarrhoea with blood and ties (109). Miller et al. found isolated ing signs for the presence of a condition mucus, and may be accompanied by ex- aortitis in 47% of patients from a series mimicking this disease but different traintestinal symptoms. Although aorti- of 45 patients who underwent an as- from isolated and typical PMR (79). tis has been reported in patients with cending aortic resection (112). It was also the case for some of our Crohn’s disease (98-100), large-vessel Patients with retroperitoneal fibrosis, patients diagnosed with aortitis. Com- involvement in ulcerative colitis is very inflammatory abdominal aortic -aneu pared to the vast majority of patients uncommon (83, 101, 102). rysms or perianeurysmal aortitis may with PMR reported in clinical studies, Sjögren’s syndrome is a heterogeneous develop constitutional symptoms, ab- complications of large-vessel vasculitis systemic autoimmune disease char- dominal or back pain, fever, fatigue, in PMR patients are extremely rare. A acterised by keratoconjuctivitis sicca, night sweats and elevated inflammatory search for aortitis should only be un- xerostomy and a wide spectrum of sys- markers (1, 4, 5, 9, 113-117). In patients dertaken in PMR under special circum- temic symptoms and signs. Although with retroperitoneal fibrosis, ureteral stances. This may be the case if atypical vascular involvement is very uncom- obstruction and renal failure have been findings such as low back pain or pain mon, in the present study we described reported (1, 5); and sometimes blood involving mainly the legs associated to two cases associated with aortitis. We and lymphatic vessels may be also in- elevation of acute phase reactants are also reported a patient with aortitis and volved (116, 118). present. psoriatic arthritis. This association has There are other diseases that may be TA is a large-vessel vasculitis uncom- previously been reported as single case also included under the term “idiopath- mon in Western countries (54). Howev- reports (103-106). ic aortitis”. This is the case of Erdheim- er, it has been widely described in peo- In our series, we described two patients Chester disease and immunoglobulin ple from Asia, Africa and Latin Amer- with large-vessel vasculitis that also G4-related disease. Erdheim-Chester ica (80). TA affects commonly young involved the aorta. The main features disease is a rare systemic disease char- people (81). The aorta, carotid and sub- were unexplained fever along with high acterised hystopathologically by histi- clavian are the arteries most frequently ESR in one patient and low back pain ocytosis of no-Langerhans cells. It may involved (82, 83). The development of in the other. present with retroperitoneal infiltration arterial stenosis and aneurysms leads Idiopathic aortitis is an uncommon dis- and cardiovascular involvement. When to claudication, bruits, limb pain, and order characterised by giant cells or the aorta is affected, the periaortic tis- diminished or even absent pulses (84). lymphoplasmacytic inflammation of sue is infiltrated circumferentially from Sometimes patients may also complain the aorta (107). Female gender, smok- ascending aorta to the iliac bifurcation of visual loss or stroke, constitutional ing, and older age are risk factors for (7, 42, 119, 120). Immunoglobulin G4- symptoms, fever, malaise, weight loss the disease (108-111). Two related related disease encompasses a broad or anorexia (84). Table VI shows a set entities have been proposed: isolated spectrum of disorders presenting with of series of patients with TA in which idiopathic thoracic aortitis, and chronic fibrosis of several organs, increase of information on major branch involve- periaortitis, that encompass idiopathic serum IgG and IgG4 and autoantibod- ment is described (82, 83, 85, 86). retroperitoneal fibrosis, inflammatory ies. The aorta and its major branches In our study, we only disclosed one abdominal aortic aneurysm, perianeu- show a lymphoplasmacytic infiltration patient with multiple arterial stenosis rysmal aortitis and idiopathic isolated and irregular fibrosis in the adventitial features and complications related to abdominal periaortitis (1). Isolated aor- layer (42, 121). In this entity, chronic severe vascular involvement in the set- titis usually manifests as an aneurysm periaortitis is more frequent than aor- ting of a delayed diagnosis of TA. of the ascending aorta, and is often titis. Differences between isolated aor- Aortitis may be associated with other an incidental finding during the histo- titis and GCA have recently been de- diseases. It may occur in the setting of pathological study of the aortic wall scribed by Talarico et al. (122). sarcoidosis, a multisystemic disease that after thoracic surgery (107). Neverthe- In conclusion, aortitis is not an uncom- involves the lungs, eyes and skin (87). less, sometimes it may present with mon entity. However, the search for Sarocidosis may coexist with rheu- symptoms related to aortic inflamma- aortitis should only be undertaken in matic diseases including PMR (16, 88). tion. Liang et al. published 64 patients patients presenting with typical PMR Although uncommonly reported (89), who underwent an aortic aneurysm dis- under special circumstances. It may be sarcoidosis may be associated with vas- section at Mayo Clinic. Most of them the case in the evaluation of corticos- cular involvement (90-96), mostly with (81%) were classified as isolated - aor teroid-resistant PMR patients (123).

S-28 Non-infectious aortitis / J. Loricera et al.

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