Efficacy of tocilizumab highlighted by FDG-PET/CT in a patient with relapsing polychondritis-associated aortitis

Abstract

Relapsing polychondritis (RP) is a rare systemic inflammatory disease primarily affecting the ears, nose and tracheobronchial tree cartilage, but also the cardiovascular system. Cardiovascular complications are the second cause of mortality in RP. We report the case of a woman with a corticosteroid-resistant RP-associated aortitis, who was successfully treated with tocilizumab (TCZ). The FDG-PET/CT was a useful tool for diagnosing aortitis and assessing the effect of biotherapy. We conducted a systematic literature review confirming this is the first case of rapid and sustained remission in a patient with corticosteroid-resistant RP-associated aortitis after TCZ treatment administered as a first-line immunotherapy. However, further studies are needed to confirm the beneficial effect of TCZ used in this life-threatening condition.

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Rheumatol Int
DOI 10.1007/s00296-017-3832-0
CASES WITHAMESSAGE
Efficacy oftocilizumab highlighted byFDG‑PET/CT inapatient
withrelapsing polychondritis‑associated aortitis
GhassanElourimi1· MichaelSoussan2· UrsulaWarzocha1· HélèneBugaud1·
RobinDhôte1· SébastienAbad1
Received: 15 May 2017 / Accepted: 21 September 2017
© Springer-Verlag GmbH Germany 2017
which is a life-threatening involvement of the disease [1]. If
corticosteroids remain the first-line treatment of RP-asso-
ciated aortitis, biologic agents have been shown to be an
alternative to conventional immunosuppressive drugs in case
of corticosteroid-resistant RP-associated aortitis [2].
According to the systematic literature review we con-
ducted, biologics, especially tocilizumab (TCZ), have been
successfully administered in patients with refractory RP-
associated aortitis, but always as salvage therapy.
We report herein the first case of a woman with a corticos-
teroid-resistant RP-associated aortitis, successfully treated
by TCZ used as first-line immunotherapy. The FDG-PET/CT
was a useful tool for both diagnosis of RP-associated aortitis
and evaluation of response to treatment with TCZ.
A systematic review of the literature was conducted
according to the published guidelines for narrative reviews
[3]. For PubMed search, a combination of MeSH terms
was used: “relapsing polychondritis”, “aortitis”, “bio-
logic agents” and “tocilizumab”. Preference was given to
the sources published within the 15–20 past years. After
searching, 13 occurrences were retrieved on Medline, 42
on Embase and 3 on Scopus. Case reports or case series
of RP with aortic involvement were excluded when follow-
up or therapeutic data were not available. Cases published
in the form of abstracts were not ruled out because of the
scarcity of the reported cases. Treatment regimen used in
our case report was approved by the ethics committee of
our institution “CLEA, Dr Coralie Bloch-Queyrat”. Consent
for the publication for this case report and any additional
related information were taken from the patient involved in
the study.
Abstract Relapsing polychondritis (RP) is a rare systemic
inflammatory disease primarily affecting the ears, nose and
tracheobronchial tree cartilage, but also the cardiovascular
system. Cardiovascular complications are the second cause
of mortality in RP. We report the case of a woman with a
corticosteroid-resistant RP-associated aortitis, who was suc-
cessfully treated with tocilizumab (TCZ). The FDG-PET/CT
was a useful tool for diagnosing aortitis and assessing the
effect of biotherapy. We conducted a systematic literature
review confirming this is the first case of rapid and sus-
tained remission in a patient with corticosteroid-resistant
RP-associated aortitis after TCZ treatment administered as
a first-line immunotherapy. However, further studies are
needed to confirm the beneficial effect of TCZ used in this
life-threatening condition.
Keywords Vasculitis· Aortitis· Relapsing
polychondritis· Tocilizumab· FDG-PET/CT
Introduction
Relapsing polychondritis (RP) is a rare systemic inflamma-
tory disease primarily affecting the ears, nose and tracheo-
bronchial tree cartilage. RP can affect large blood vessels,
Rheumatology
INTERNATIONAL
* Sébastien Abad
sebastien.abad@aphp.fr
1 Assistance Publique- Hôpitaux de Paris (AP-HP), Hôpital
Avicenne, Service de Médecine Interne, Université Paris
13,Sorbonne Paris Cité, Faculté de Médecine SMBH, 125
Route de Stalingrad, 93009BobignyCedex9, France
2 AP-HP, Hôpital Avicenne, Service de Médecine Nucléaire,
Université Paris 13, Sorbonne Paris Cité, Faculté de
Médecine SMBH, Bobigny, France

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Case presentation
A 59-year-old woman was hospitalized for prolonged
fever, bilateral knee arthritis, episcleritis, pericarditis and
increased C-reactive protein (420mg/l). Three weeks later,
she developed a bilateral auricular and nasal chondritis, sug-
gesting relapsing polychondritis. Oral prednisone, initiated
at 1mg/kg daily, led to complete regression of the systemic
manifestations. Corticosteroids were then tapered to 5mg
daily without any relapse of ocular or systemic manifesta-
tions after 48months of follow-up.
Six months after corticosteroids were stopped, the patient
presented with recurrence of fever, arthritis and auricular
chondritis. In addition, she had mouth ulcers. Laboratory
tests revealed marked neutrophilia (19.8 G/l) and elevated
C-reactive protein (511mg/l). Viral serologies and blood
cultures ruled out an infection. ANCA and ANA were nega-
tive. An FDG-PET/CT showed a vascular uptake of the tho-
racic ascending aorta, suggesting aortitis (Fig.1a). A tran-
sthoracic echocardiography showed no aortic abnormalities.
Inflammatory symptoms resolved after initiation of intra-
venous corticosteroids (methylprednisolone) at a dose of
500mg per day for 3days. Oral corticosteroids were then
started at 1mg/kg per day (i.e., 70mg/day). However, when
the corticosteroids were tapered to 50mg/day, chondritis and
episcleritis recurred. A course of TCZ (8mg/kg body weight
per month) was administered and resulted in the immediate
relief of discomfort and a prolonged decrease of the CRP.
During the 3-month follow-up period, corticosteroids were
gradually tapered to a minimal dose of 5mg daily. After
three courses of TCZ, complete response was achieved with
disappearance of clinical symptoms and normal inflamma-
tory parameters. A control FDG-PET/CT showed normal
aortic uptake (Fig.1b). One year later, the patient was still
receiving TCZ and had experienced neither recurrence of
inflammatory manifestations nor adverse events.
Discussion
RP is a rare disease with a recently estimated prevalence to
nine per million in the UK [4]. It is a chronic and potentially
fatal multisystem disorder, characterized by recurrent epi-
sode of inflammation of cartilaginous tissues [2]. All types
of cartilage may be involved, including cartilage of the ears
and nose, hyaline cartilage of the peripheral joints, cartilage
Fig. 1 FDG PET/ CT at diagnosis showing aortitis (a) and control at three month follow-up disclosing a normal arterial wall of aorta (b)

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Table 1 Efficacy of treatments in RP with corticosteroid-resistant aortitis (index case) and refractory aortitis (literature review)
CT corticosteroids, AZA azathioprine, CYC cyclophosphamide, MTX methotrexate, CICLO cyclosporine, LFN leflunomide, MRI magnetic resonance imaging, FDG-PET/CT positron emission
tomography/computerized tomography, NA not available
References Age (sex) Disease dura-
tion
Organ involve-
ment
Prior
treatment(s) in
addition to CT
Final treatment Outcome
criteria
Efficacy Onset of effi-
cacy
Duration of
follow-up
Adverse events
Elourimi etal.
2017
59years (F) 2years Aorta, ears,
nose
– Tocilizumab FDG-PET/CT Total recovery 1week 1year No
Salles etal.
2014 [28]
30years (M) 7years Aorta, ears,
nose
MTX Tocilizumab Clinic, FDG-
PET/CT
Total recovery 1week 1year No
Stael etal. 2015
[29]
25years (M) 9years Aorta, skin,
eyes
CICLO, Inflixi-
mab
Tocilizumab Clinic, CRP Total recovery 1month 1year No
Narshi etal.
2002 [30]
43years (F) 16years Aorta, ears,
nose
Adalimumab Tocilizumab Clinic, CRP Total recovery 1week NA No
Loricera etal.
2014 [31]
50years (F) NA Aorta, ears,
nose
MTX, CYC,
LFN, CICLO,
Infliximab
Tocilizumab Clinic, CT Total recovery 3weeks NA No
Sugrue etal.
2014 [25]
51years (M) 1year Aorta, oral
ulceration
MTX Infliximab Clinic, FDG-
PET/CT
Mild impair-
ment
12months NA NA
Marie etal.
2009 [26]
38years (F) NA Aorta, ears,
nose, eyes
MTX, AZA,
CYC
Infliximab NA Total recovery 1year 3years No
Seymour etal.
2007 [27]
43years (F) 13years Aorta, ears,
nose
MTX, CYC Infliximab Clinic, CRP,
MRI
Total recovery NA NA NA
Selim etal.
2001 [20]
54years (F) 4years Aorta, aortic
regurgitation,
ears, nose
AZA, CYC Clinic, CRP Mild impair-
ment
NA No NA
Rho etal. 2005
[21]
51years (F) 1month Aorta, ears, MTX CYC NA Total recovery 1week NA No
Yung etal. 2000
[22]
30years (F) 20years Aorta, ears,
nose, aortic
valve
CYC, AZA AZA Clinic, MRI Total recovery 1week 10months No
Walker etal.
1998 [23]
28years (F) 1month Aorta, ears,
nose
CYC, CIClO,
MTX
AZA Clinic, MRI Mild impair-
ment
3months 6months NA
Walker etal.
1998 [23]
61years (M) 10months Aorta, ears,
nose
MTX, AZA AZA Clinic, MRI Total recovery 3weeks NA NA
Barreto etal.
2002 [24]
42years (M) 6years Aorta, aortic
valve, ears,
nose
MTX, CYC,
CICLO
Chlorambucil Clinic, CT Mild impair-
ment
1year 1year No

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of the tracheobronchial tree and also the artery wall. Diagno-
sis currently relies on the revised clinical criteria by Michet
etal. [5]. Cardiovascular complications can occur in as much
as 31% of cases in RP including aortic or mitral regurgita-
tion, aortic aneurysm and aortitis [6]. In a large recently
published series of 172 patients with RP, 11 (6.4%) had aor-
titis [1]. Cardiovascular complications represent the second
cause of mortality in RP [6–8].
Differential diagnosis of RP-associated aortitis must
be excluded since they have specific modalities of treat-
ment. In our patient, infectious aortitis, giant cell arteritis
or Takayasu’s arteritis was ruled out [9]. This 59-year-old
woman had no signs suggestive of such vasculitis and met
all required diagnostic criteria for RP.
Autoimmunity has been shown to be involved in the
pathogenesis of RP [10]. RP is characterized histopatho-
logically by a tissue infiltration of pleomorph cells including
macrophages, neutrophils, plasma cells and lymphocytes,
mainly of the CD4+T cell subset [11]. Also autoantigen
targets are still unknown, and there is evidence for a major
role of monocyte and macrophage activation in the course
of this Th1-mediated disease [12]. Indeed, IL-8, monocyte
chemoattractant protein 1 (MCP-1) and macrophage inflam-
matory protein 1beta (MIP-1beta) were found to be elevated
in the serum of patients with RP [12, 13]. IL-6, another
pro-inflammatory cytokine secreted by macrophages, has
been found to be highly increased in serum of patients with
active RP, making it a potential new promising therapeutic
target [14, 15].
A recent study demonstrated the role of FDG-PET/CT
in the detection of chondritis and correlated morphological
findings with disease activity assessed by clinical symptoms
and laboratory data. The FDG uptake may be related to the
accumulation of the radiotracer in neutrophils, activated
lymphocytes and monocytes/macrophages. However, the
usefulness of FDG-PET/CT as a tool for detecting aortitis
in the course of RP has been poorly evaluated [16–18]. A
case series study suggested a role for FDG-PET/CT in the
diagnosis of aortitis in ANCA-associated vasculitis [19]. Our
case clearly showed the ability of FDG-PET/CT to detect a
potentially life-threatening complication with a typical FDG
accumulation in the aortic artery wall. Moreover, FDG-PET/
CT was useful in the follow-up of our patient, providing
evidence of a dramatic response to treatment.
A standardized therapeutic protocol for RP-associated
aortitis has not yet been established. The current therapy
is largely empirical and based on case reports or expert
recommendations. Corticosteroids or conventional immu-
nosuppressive drugs including methotrexate and cyclo-
phosphamide are usually proposed, but have been shown
to be ineffective in few cases of RP-associated aortitis.
The management of these patients considered as having
RP-associated refractory aortitis usually relies on a salvage
therapy, varying from a more aggressive conventional
immunosuppressive drug to off-label administration of
biologics (Table1). To date, of the 13 published cases of
such patients, 6 (mostly before the year 2000) reported that
salvage conventional immunosuppressive therapies led to
a total recovery in only half of the cases [20–24].
The efficacy of anti-TNF alpha and more recently of
TCZ, a humanized monoclonal antibody that blocks IL-6
signaling by binding to the alpha chain of the human IL-6
receptor, has been reported in RP with such “refractory”
aortitis. Of the 13 published case reports of RP with
refractory aortitis, 3 described anti-inflammatory effects of
infliximab, a chimeric (human and mouse) anti-TNF alpha
antibody, used as a salvage therapy. Infliximab induced
a partial response in one patient and a total recovery in
two others [25–27]. Total recovery after TCZ treatment in
RP-associated refractory aortitis has been reported in four
cases. However, in these cases TCZ was always adminis-
tered after either immunosuppressive therapy or anti-TNF
alpha [28–31].
In our patient, TCZ was used after corticosteroid treat-
ment failure. TCZ induced a complete response of RP-asso-
ciated aortitis after only three courses and enabled corticos-
teroid tapering to 5mg daily. In addition, complete response
was sustained without any recurrence after 1year of follow-
up. As shown by our clinical, biological and morphologi-
cal findings, TCZ used as a first-line immunotherapy was
a remarkably effective treatment of corticosteroid-resistant
RP-associated aortitis.
Of note, it has been recently shown in a patient with
Takayasu arteritis that TCZ could be an alternative treat-
ment to achieve a rapid control of a corticosteroid-resistant
disease [32].
To our knowledge, this is the first case report to show
the efficacy of TCZ used just after corticosteroids failure in
RP-associated aortitis. With a dramatic effect on vasculi-
tis, TCZ could prevent the onset of aortic dilatation, a life-
threatening cardiovascular complication of RP-associated
aortitis. In addition, TCZ seems to induce remission faster
and more efficiently than other biologics. A multicenter, ran-
domized, controlled study would be required to prove the
beneficial effect of TCZ in RP-associated aortitis, but would
be very difficult to conduct in this rare disease. However,
further studies are needed to evaluate the benefits of TCZ
in RP when used as a first-line immunotherapy after failure
of corticosteroids.
Acknowledgements We thank Dr Jonathan London (Department of
Internal Medicine, Hospital Cochin, Université Paris-5, Paris, France)
for his critical review of the manuscript.
Compliance with ethical standards
Conflict of interest The authors declare no conflict of interest.

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Financial support statement None.
References
1. Le Besnerais M, Arnaud L, Boutémy J etal (2017) Aortic involve-
ment in relapsing polychondritis. Jt Bone Spine Rev Rhum.
doi:10.1016/j.jbspin.2017.05.009
2. Mathian A, Miyara M, Cohen-Aubart F etal (2016) Relapsing
polychondritis: a 2016 update on clinical features, diagnostic tools,
treatment and biological drug use. Best Pract Res Clin Rheumatol
30:316–333. doi:10.1016/j.berh.2016.08.001
3. Gasparyan AY, Ayvazyan L, Blackmore H, Kitas GD (2011) Writ-
ing a narrative biomedical review: considerations for authors, peer
reviewers, and editors. Rheumatol Int 31:1409–1417. doi:10.1007/
s00296-011-1999-3
4. Hazra N, Dregan A, Charlton J etal (2015) Incidence and mortality
of relapsing polychondritis in the UK: a population-based cohort
study. Rheumatology 54:2181–2187. doi:10.1093/rheumatology/
kev240
5. Michet CJ, McKenna CH, Luthra HS, O’Fallon WM (1986) Relaps-
ing polychondritis. Survival and predictive role of early disease
manifestations. Ann Intern Med 104:74–78
6. Del Rosso A, Petix NR, Pratesi M, Bini A (1997) Cardiovascular
involvement in relapsing polychondritis. Semin Arthritis Rheum
26:840–844
7. Surgical treatment of the cardiac manifestations of relapsing poly-
chondritis: overview of 33 patients identified through literature
review and the mayo clinic records - Mayo Clinic Proceedings. http://
www.mayoclinicproceedings.org/article/S0025-6196(11)61731-X/
pdf. Accessed 24 July 2017
8. Shimizu J, Oka H, Yamano Y etal (2016) Cardiac involvement in
relapsing polychondritis in Japan. Rheumatol Oxf Engl 55:583–584.
doi:10.1093/rheumatology/kev320
9. Rousselin C, Pontana F, Puech P, Lambert M (2016) Differential
diagnosis of aortitis. Rev Med Int 37:256–263. doi:10.1016/j.
revmed.2016.02.002
10. Arnaud L, Mathian A, Haroche J etal (2014) Pathogenesis of relaps-
ing polychondritis: a 2013 update. Autoimmun Rev 13:90–95.
doi:10.1016/j.autrev.2013.07.005
11. Ouchi N, Uzuki M, Kamataki A etal (2011) Cartilage destruction
is partly induced by the internal proteolytic enzymes and apoptotic
phenomenon of chondrocytes in relapsing polychondritis. J Rheu-
matol. doi:10.3899/jrheum.101044
12. Stabler T, Piette J-C, Chevalier X etal (2004) Serum cytokine pro-
files in relapsing polychondritis suggest monocyte/macrophage acti-
vation. Arthritis Rheum 50:3663–3667. doi:10.1002/art.20613
13. Ohwatari R, Fukuda S, Iwabuchi K etal (2001) Serum level of mac-
rophage migration inhibitory factor as a useful parameter of clini-
cal course in patients with Wegener’s granulomatosis and relaps-
ing polychondritis. Ann Otol Rhinol Laryngol 110:1035–1040.
doi:10.1177/000348940111001108
14. Wallace ZS, Stone JH (2013) Refractory relapsing polychondritis
treated with serial success with interleukin 6 receptor blockade. J
Rheumatol 40:100–101. doi:10.3899/jrheum.120381
15. Kawai M, Hagihara K, Hirano T etal (2009) Sustained response
to tocilizumab, anti-interleukin-6 receptor antibody, in two patients
with refractory relapsing polychondritis. Rheumatol Oxf Engl
48:318–319. doi:10.1093/rheumatology/ken468
16. Yamashita H, Takahashi H, Kubota K etal (2014) Utility of fluoro-
deoxyglucose positron emission tomography/computed tomography
for early diagnosis and evaluation of disease activity of relapsing
polychondritis: a case series and literature review. Rheumatology
53:1482–1490. doi:10.1093/rheumatology/keu147
17. Lei W, Zeng H, Zeng D-X etal (2016) (18)F-FDG PET-CT: a pow-
erful tool for the diagnosis and treatment of relapsing polychondritis.
Br J Radiol 89:20150695. doi:10.1259/bjr.20150695
18. Wang J, Li S, Zeng Y etal (2014) 18F-FDG PET/CT is a valu-
able tool for relapsing polychondritis diagnose and therapeutic
response monitoring. Ann Nucl Med 28:276–284. doi:10.1007/
s12149-014-0805-1
19. Soussan M, Abisror N, Abad S etal (2014) FDG-PET/CT in patients
with ANCA-associated vasculitis: case-series and literature review.
Autoimmun Rev 13:125–131. doi:10.1016/j.autrev.2013.09.009
20. Selim AG, Fulford LG, Mohiaddin RH, Sheppard MN (2001) Active
aortitis in relapsing polychondritis. J Clin Pathol 54:890–892
21. Rho YH, Choi SJ, Choi YS etal (2005) Relapsing polychondritis
with aortitis without valvular involvement. J Rheumatol 32:954–956
22. Yung A, Charleson HA, Ullal R, Doube A (2000) A case of relaps-
ing polychondritis with coronary ostial stenosis and severe aortic
incompetence. Semin Arthritis Rheum 30:144–146
23. Walker UA, Weiner SM, Vaith P etal (1998) Aortitis in relapsing
polychondritis. Br J Rheumatol 37:1359–1361
24. Barretto SN, Oliveira GH, Michet CJ etal (2002) Multiple cardio-
vascular complications in a patient with relapsing polychondritis.
Mayo Clin Proc 77:971–974. doi:10.4065/77.9.971
25. Sugrue G, Durcan L, Bell L etal (2014) Unsuspected cardiovas-
cular involvement in relapsing polychondritis: a case of aortitis
with critical coronary artery stenosis secondary to relapsing poly-
chondritis. Circ Cardiovasc Imaging 7:409–411. doi:10.1161/
CIRCIMAGING.113.001290
26. Marie I, Lahaxe L, Josse S, Levesque H (2009) Sustained response
to infliximab in a patient with relapsing polychondritis with aor-
tic involvement. Rheumatology 48:1328–1329. doi:10.1093/
rheumatology/kep224
27. Seymour MW, Home DM, Williams RO, Allard SA (2007) Pro-
longed response to anti-tumour necrosis factor treatment with
adalimumab (Humira) in relapsing polychondritis complicated by
aortitis. Rheumatology 46:1738–1739. doi:10.1093/rheumatology/
kem229
28. Sallés M, Mínguez S, Ros S etal (2017) Sustained response to toci-
lizumab in a patient with relapsing polychondritis complicated by
aortitis. Clin Exp Rheumatol 35(Suppl 103):223
29. Stael R, Smith V, Wittoek R etal (2015) Sustained response to
tocilizumab in a patient with relapsing polychondritis with aortic
involvement: a case based review. Clin Rheumatol 34:189–193.
doi:10.1007/s10067-014-2670-7
30. Narshi CB, Allard SA (2012) Sustained response to tocilizumab,
anti-IL-6 antibody, following anti-TNF-α failure in a patient with
relapsing polychondritis complicated by aortitis. Rheumatology
51:952–953. doi:10.1093/rheumatology/ker451
31. Loricera J, Blanco R, Castañeda S et al (2014) Tocilizumab in
refractory aortitis: study on 16 patients and literature review. Clin
Exp Rheumatol 32:S79–S89
32. Risse J, Mandry D, Settembre N etal (2016) Dramatic Response
to Tocilizumab Before Emergency Surgery in Severe Active
Takayasu Disease. Circ Cardiovasc Imaging. doi:10.1161/
CIRCIMAGING.116.004819