Relapsing Polychondritis following Treatment with Secukinumab for Ankylosing Spondylitis: Case Report and Review of the Literature

Abstract

Relapsing polychondritis (RP) is an autoimmune disorder that often occurs concomitantly with other autoimmune diseases, though RP has been infrequently associated with ankylosing spondylitis (AS). There is a small, but growing, body of the literature demonstrating case reports describing RP secondary to AS in patients treated with tumor necrosis alpha inhibitors (TNFi’s). We present the first case in which RP developed in AS while treated with an interleukin 17A inhibitor (IL-17Ai), secukinumab. With this case report, we hope to raise physician awareness of the possible autoimmune disorders that may arise subsequent to novel immunomodulation therapies, particularly that RP may develop subsequent to inhibition of IL-17A.

Full text

Case Report
Relapsing Polychondritis following Treatment with
Secukinumab for Ankylosing Spondylitis: Case Report and
Review of the Literature
Alexander Zheutlin and Elena Schiopu
University of Michigan Medical School, Ann Arbor, MI, USA
Correspondence should be addressed to Alexander Zheutlin; zheutlin@umich.edu
Received 23 March 2018; Accepted 19 June 2018; Published 2 July 2018
Academic Editor: Mehmet Soy
Copyright ©2018 Alexander Zheutlin and Elena Schiopu. is is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Relapsing polychondritis (RP) is an autoimmune disorder that often occurs concomitantly with other autoimmune diseases,
though RP has been infrequently associated with ankylosing spondylitis (AS). ere is a small, but growing, body of the literature
demonstrating case reports describing RP secondary to AS in patients treated with tumor necrosis alpha inhibitors (TNFi’s). We
present the first case in which RP developed in AS while treated with an interleukin 17A inhibitor (IL-17Ai), secukinumab. With
this case report, we hope to raise physician awareness of the possible autoimmune disorders that may arise subsequent to novel
immunomodulation therapies, particularly that RP may develop subsequent to inhibition of IL-17A.
1. Introduction
Relapsing polychondritis (RP) is classified as a rare disease
by the National Organization for Rare Disorders, with an
incidence of 3.5 per 1,000,000 and has a paucity of research
elucidating a clear etiology [1]. RP is an autoimmune disease,
which targets the cartilaginous framework in multiple organ
systems, but demonstrates a predilection for the ears, nose,
and larynx [2]. RP is documented in patients with other
autoimmune diseases as frequently as 30–37% of the time [3].
e association between RP and AS has been reported in only
few cases over the many decades of study. However, recent
work estimates that as many of 12% of patients with AS have
concomitant RP, with a risk of lifetime comorbidity risk of
67% to develop RP [4]. Historical treatment of AS focused on
nonsteroidal anti-inflammatory drugs (NSAIDs), with more
recent therapeutic regimens including TNFi. Recently, a hu-
man monoclonal antibody targeting IL-17A, secukinumab,
has demonstrated efficacy in AS patients who failed a trial of
TNF-alpha inhibitors, and for those who have never utilized
any other biologic drugs [5]. Of the major clinical trials
examining secukinumab, side effects were found to be similar
to the placebo group, with nasopharyngitis and inflammatory
bowel disease (IBD) being the most common adverse event
[5]. Given the recent availability of secukinumab, no research
has yet associated with antibody formation and newly de-
veloped autoimmune disease with the IL-17A inhibitors. e
current case is the first report of RP development secondary to
the use of an IL-17Ai for treatment of AS.
2. Case Report
Our patient, M.J., is a 56-year-old male, who has had in-
flammatory back pain since his twenties, but was diagnosed
with AS at 53 years while hospitalized for small bowel
obstruction. He was found to have sacroiliitis, enthesitis,
inflammatory arthritis, positive HLA-B27, and elevated
C-reactive protein (CRP) at 2.1mg/dl (normal <0.6 mg/dl).
At the time of diagnosis, M.J. was started on adalimumab
40 mg subcutaneously once every 14 days and celecoxib as
needed. Despite an initial positive symptomatic response, his
axial manifestations persisted, and he developed peripheral
inflammatory arthritis in ankles, feet, wrists, and meta-
carpophalangeal (MCP) joints. At 18 months after initiation
of adalimumab, the patient developed leukopenia and
neutropenia, associated with mild infections such as cellulitis
Hindawi
Case Reports in Rheumatology
Volume 2018, Article ID 6760806, 4 pages
https://doi.org/10.1155/2018/6760806

and gastroenteritis. Adalimumab was held for 6 months, and
etanercept was initiated due to AS flares. After 3 months of
symptomatic relief and adequate disease control, he developed
leukopenia and etanercept was subsequently discontinued.
At the time the leukopenia occurred, the patient did not
have clinical manifestations of drug-induced SLE (rash,
arthritis, hypocomplementemia, or proteinuria/hematuria);
he was found to have +ANA (1 :160, homogeneous pattern)
and negative double-stranded DNA. A thorough hemato-
logical workup ruled out any other causes of leukopenia, and
a decision was made to avoid TNFi’s and to start the patient on
secukinumab (complete clinical course is shown in Figure 1).
Secukinumab was started with an initial loading dose of
150 mg subcutaneously weekly for five weeks, followed by
monthly doses. Following the last loading dose, the patient
had an episode of gastroenteritis which was treated with 7
days of ciprofloxacin, and developed swelling, erythema, and
throbbing pain of his bilateral ears and tip of the nose. He
started a 17-day course of intravenous daptomycin and
ertapenem, as his symptoms were thought to be secondary to
a neutropenic infection. However, his symptoms did not
abate. e patient developed periorbital edema and uveitis,
which resolved with topical steroids. Additionally, he was
started on 60 mg of daily prednisone by his primary care
provider, tapered to 20 mg daily within a week, with reso-
lution of his swelling and pain.
Upon physical examination in our rheumatology clinic
(four days after the steroids were stopped), there was nasal
erythema diffusely, with mild tenderness to palpation. Bi-
lateral auricular chondritis was present, with moderate
hyperemia of the right ear (Figure 2). Some cartilaginous
collapse was noted as well. Additionally, the patient had mild
anterior uveitis present on the lateral aspect. At this time, the
patient had a positive Schober’s test of 13.5 centimeters, and
no synovitis of the appendicular joints was noted. Based
upon the presence of bilateral auricular chondritis, nasal
chondritis, and recent ocular inflammation, RP was diagnosed
based upon clinical presentation and history.
e patient was started on oral prednisone 20 mg for
seven days, with a reduction of 5 mg per week as tolerated,
along with 20 mg of methotrexate once a week, with a folic
acid supplement of 1 mg. Following initiation of prednisone,
there was resolution of the clinical manifestation of RP (auricular
and nasal hyperemia and chondritis, as well as uveitis) along
with improvement in the inflammatory markers.
3. Discussion
e Assessment of Spondyloarthritis treatment guidelines
include a trial of NSAIDs for four weeks, following by TNFi’s
in the event NSAIDs do not provide clinical improvement
[6]. However, numerous patients do not achieve remission
with initial TNFi therapy [7]. is poses a problem in
treatment, as a trial of a different TNFi is suggested following
the failure of a first TNFi. Recent clinical trials examining
Adalimumab Discontinued DiscontinuedEtanercept
DiscontinuedStart: secukinumab
Start: methotrexate
Month 0 Month 16 Month 20 Month 22 Month 25 Month 27
2.6 2.2 5.7 2-2.5 5.9 6.0
WBC
(thousands/μl)
erapy
M.J.
clinical
course
Ankylosing spondylitis
diagnosed Axial symptom progression Steroid responsive
inammation of right ear
and nose, uveitis
Leukopenia and
neutropenia; recurrent
cellulitis
Cellulitis, Streptococcus pneumoniae
pharyngitis, C. difficile
Relapsing polychondritis
diagnosed
Figure 1: Clinical course of patient, M.J. e three timelines overlap laboratory findings with therapeutic regimen and clinical course.
(a)
(c)
(b)
Figure 2: Panel image demonstrating new-onset auricular chon-
dritis and hyperemia in the above two panels, with nasal chondritis
visualized in the bottom panel.
2Case Reports in Rheumatology

new IL-17Ai have demonstrated their utility in achieving
clinically significant improvement in patients with AS and
were approved by the FDA in January of 2016 [8, 9]. IL-17Ai
has good tolerability, with a side effect distribution similar to
the effect of placebo. Notable side effects found in the
MEASURE 1 and MEASURE 2 trials were nasopharyngitis,
headache, viral infection, dyslipidemia, nausea, influenza,
and mouth ulcers [5].
RP is considered an autoimmune disease with a reaction
to endogenous type II collagen [10]. Chondrocytes are tar-
geted by antibodies becoming necrotic before being replaced
with fibrotic cell lineages [11]. e current paradigm for the
pathogenesis of RP involves cytokine-mediated immunologic
activity via IL-17A and TNF-alpha leading to matrix-degrading
proteinases production from chondrocytes [12]. Additionally,
antibodies to type II collagen and CD4+ cells have been
implicated in the disease pathogenesis, though the exact re-
lationship is not clearly known [13]. ese underlying bio-
chemical processes lead to the clinical manifestations of auricular
chondritis, nasal chondritis, laryngeal chondritis, nondeforming
or erosive arthritis, and various ocular manifestations, including
uveitis.
Various treatment modalities have been found to be
effective in treating RP. Patients with mild inflammation can
be treated with NSAIDs and low-dose prednisone. Dapsone
or higher prednisone doses can be utilized in patients with
more severe symptoms. In patients for whom an effective
dose of steroids is not an option, methotrexate or azathi-
oprine may be used to reduce the necessary burden of steroid
therapy [2].
RP has been sparingly diagnosed in the context of TNFi
therapy for patients with AS. In 2014, Azevedo et al. described
a case of etanercept-induced RP in the treatment of an adult
man with AS. e patient was HLA-B27 positive and was
diagnosed based upon clinical suspicion two months after
initiating etanercept therapy. is patient was taken off the
TNF-alpha inhibitor and with the addition of corticosteroids
saw improvement in his RP within five months [14]. Two
similar cases were described by Hern´
andez et al. in 2011, in
which two HLA-B27 were diagnosed with newly developed
RP as consequence of TNA-alpha inhibitor therapy [15].
ese cases similarly presented with RP after approximately
two months on TNFi. Steroids were started in each patient in
combination with TNFi cessation, with resolution of symp-
toms after five to six months. TNFi’s were successfully
restarted without documented recurrence of RP [14, 15].
To our knowledge, this is the first described case of RP
induced by IL-17Ai therapy. Our patient never presented
with symptoms of RP prior to initiation of the IL-17Ai.
ough a different agent, the clinical course is similar to
cases in the literature documenting RP following TNF-alpha
inhibitors. Autoantibody development seen in patients
treated with TNF-alpha inhibitors may follow a similar
pathogenesis as the clinical case documented in the current
report. TNF-alpha and IL-17A are proinflammatory cyto-
kines involved in the same pathway [16]. is pathway is
a particularly exciting target for AS treatment. When
compared to healthy controls, patients diagnosed with AS
exhibit significantly higher levels of serum IL-17A [17].
Designing therapies to inhibit IL-17A may be of even more
benefit in HLA-B27-positive patients. Misfolded HLA-B27
has been introduced as an important factor in upregulation
of 17 cytokines, including IL-17A [18].
e expression of IL-17A in a pathogenic context arises
predominantly from a subset of  cells, 17. ese cells
also express TNF [19]. IL-17A and TNF have been suggested
as synergistic inflammatory factors [20]. e dual effect of
these cytokines can cause damage particularly to cartilage
and bone [21]. ese two cytokines augment inflammation
via an increase in endothelial selectins for neutrophil che-
motaxis as well as expression of neutrophil chemokines [22].
e balance of these cytokines is altered by biologic drugs.
Patients who respond to TNFi decrease endogenous levels of
IL-17A and TNF-alpha. However, in nonresponders to
TNFi, there is a paradoxical elevation of 17 and IL-17 [23].
e novel therapeutic targeting of IL-17A is attractive
due to the relationship between AS and poorly modulated
IL-17A production, and the ability of IL-17 inhibitors to
diminish overexpression of IL-17 [8]. Additionally, the ef-
fectiveness as studied in the MEASURE 1 and 2 trials
demonstrates the powerful utility of this class of drugs in
achieving clinical remission [5]. e development of RP and
paradoxical increase in inflammation of cartilage secondary
to IL-17A inhibitors is likely the result of a disturbance in the
equilibrium of these cytokines. Blocking IL-17A cytokines
allows for the potential of increasing other inflammatory
cytokines, such as IL-17F, which can act at the same re-
ceptor, and TNF-alpha [24]. ere is still an incom-
prehensive understanding of the causal relationship between
TNFi’s and IL-17A inhibitors with RP development, ne-
cessitating further study to elucidate the relationship.
4. Conclusion
is is the first reported case of RP following treatment with
an IL-17A inhibitor, adding to a growing body of evidence
emphasizing new onset of autoimmune diseases in a subset
of patients. Prior cases have been found subsequent to TNFi
use and have increased clinician awareness of the potential
development of RP in patients with AS. e clinical di-
agnosis of RP in the current case is supported by clinical
evidence of polychondritis and elevated inflammatory
markers, as well as symptom resolution following the dis-
continuation of secukinumab and initiation of prednisone
therapy. Given the novelty of IL-17Ai and restricted treat-
ment options of AS, it is important that physicians are wary
of the potential development of RP following IL-17Ai use in
patients with AS.
Conflicts of Interest
e authors declare that they have no conflicts of interest.
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4Case Reports in Rheumatology