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Relapsing polychondritis: a new adverse event secondary to the use of tumour

necrosis factor antagonists?

Article  in  Rheumatology (Oxford, England) · May 2011

DOI: 10.1093/rheumatology/ker144 · Source: PubMed

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FIG. 1 CT angiogram with 3D reconstruction showing
obstruction of the right subclavian artery.
Our patient presented with scleroderma 5 years after
the onset of membranous nephropathy. It may represent
a coincidental occurrence; however, in view of the previ-
ous reports, an association (albeit rare) between the dis-
eases cannot be ruled out. Narrowing of medium-sized
vessels has been noted in scleroderma; however, ob-
struction of a major arterial trunk may be due to throm-
bosis [10], which may occur in the setting of nephrotic
syndrome. The onset of membranous nephropathy was
at the age of 12 years; thus she is one of the youngest
(among the patients in literature) to present with this
combination of diseases.
Rheumatology key message
. Severe SSc, with vascular occlusion, may develop
in longstanding membranous nephropathy.
Disclosure statement: The authors have declared no
conflicts of interest.
Dipankar Sarkar1, Geetabali Sircar2,
Rajesh Waikhom1, Arpita Raychowdhury1,
Rajendra Pandey3 and Alakendu Ghosh2
1
Department of Nephrology and 2Department of
Rheumatology, Institute of Postgraduate Medical Education
and Research, Kolkata, West Bengal, India.
Accepted 25 March 2011
Correspondence to: Dipankar Sarkar, Department of
Nephrology, Institute of Postgraduate Medical Education and
Research, Kolkata, West Bengal, 700060, India. E-mail:
deepsircar@gmail.com
www.rheumatology.oxfordjournals.org
Letters to the Editor
References
1 Janson WR, Arend WP. Renal disorders associated with
systemic sclerosis. In: Schrier RW, ed. Diseases of the
kidney. 8th edition. Lippincott: Williams & Wilkins,
2007:1701–15.
2 Karpinski J, Jothy S, Radoux V et al.
D-penicillamine-induced crescentic glomerulonephritis
and antimyeloperoxidase antibodies in a patient with
scleroderma. Case report and review of the literature.
Am J Nephrol 1997;17:528–32.
3 Maes B, Van Mieghem A, Messiaen T et al. Limited
cutaneous systemic sclerosis associated with
MPO-ANCA positive renal small vessel vasculitis of
the microscopic polyangiitis type. Am J Kidney Dis 2000;
36:E16.
4 Nepal M, Mainali R, Schworer CM et al. Nephrotic range
proteinuria: rare manifestation of scleroderma renal crisis.
Ann Clin Lab Sci 2008;38:163–7.
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5 Hirohata S, Ohse T, Takeuchi A et al. Systemic
sclerosis complicated with nephrotic syndrome: relevance
with antiribosomal P antibody. Rheumatol Int 2001;21:
40–3.
6 Pamuk GE, Pamuk ON, Altiparmak MR et al. Secondary
amyloidosis in progressive systemic sclerosis. Clin
Rheumatol 2001;20:285–7.
7 Eiser AR, Zilversmit R, Neff MS et al. Progressive systemic
sclerosis with the nephrotic syndrome and acquired factor
X deficiency. Am J Nephrol 1986;6:61–5.
8 Nunez S, Konstantinov KN, Servilla KS. Association
between scleroderma, renal cell carcinoma
and membranous nephropathy. Clin Nephrol 2009;71:
63–8.
9 Wielosz E, Majdan M, Suszek D et al. Nephrotic syndrome
as a clinical manifestation of systemic sclerosis.
Rheumatol Int 2007;27:1087–9.
10 Lwai S, Schmid FR, Jaffari M. Thrombotic occlusion of
large arteries in scleroderma. Proc Inst Med Chic 1967;26:
232–4.
Rheumatology 2011;50:1523–1525
doi:10.1093/rheumatology/ker144
Advance Access publication 18 May 2011
Relapsing polychondritis: a new adverse event
secondary to the use of tumour necrosis
factor antagonists?
SIR, Biologic therapies have proved their efficacy in sev-
eral rheumatic diseases in recent years, although various
related adverse events have been described [1]. We de-
scribe two cases of relapsing polychondritis (RP) during
TNF-blocker therapy in patients with undifferentiated SpA
and AS, respectively. To our knowledge, these are the first
reported cases of polychondritis induced by biological
therapy.
A 45-year-old man was diagnosed with HLA-B27-
positive SpA in 1996 due to polyarthritis and enthesopathy
in both feet. Initially, he was treated with NSAIDs; MTX
20 mg/week/s.c. and methylprednisolone 4 mg/day was
added later due to lack of response. In spite of therapy,
1523
Letters to the Editor

the patient continued to present bilateral Achilles tendon- FIG. 1 Acute auricular chondritis involving the
itis and left knee arthritis, and biological therapy with eta- cartilaginous part of the left ear (Patient 2).
nercept 25 mg twice weekly (July 2005) together with
isoniazid 300 mg/day for chemoprophylaxis of latent
tuberculosis, was initiated, with a favourable, early re-
sponse, achieving remission. Treatment with methylpred-
nisolone was stopped. In October 2007, the patient
complained of bilateral pain, erythema and swelling of
the auricle, ocular symptoms (red, itchy eyes), neck
pain, irritative cough and chest pain. Polychondritis was
diagnosed based on the clinical manifestations, and eta-
nercept was stopped. Treatment with prednisone
15 mg/day was started with partial improvement. A
chest scan showed discrete bronchial stasis; spirometry
and echocardiography were normal. The prednisone dose
was increased to 20 mg/day in November 2007 with im-
provement. The prednisone dose was slowly tapered in
December 2007, when the joint pain resumed and the

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on February 20, 2013

patient decided to re-start etanercept treatment on his
own initiative, with early improvement. At an outpatient
visit in February 2008, the patient was asymptomatic for
joint, ocular, auricular and chest symptoms. Treatment
with etanercept 50 mg/week was continued. After a
follow-up of 34 months, the patient remains asymptomatic,
with no recurrence of polychondritis or spondylitis.
A 49-year-old male was diagnosed with HLA-B27-
positive AS at 21 years of age and treated with NSAIDs
as needed. The patient has been followed up at our
rheumatology clinic for 4 years: in the first visit he com-
plained of inflammatory lumbar pain, arthralgia and recurrent
episodes of uveitis. Tests showed elevated acute-phase
reactants. Treatment with infliximab 5 mg/kg was initiated
with good response and tolerability. In March 2010,
developed RP after starting biological therapy and im-
the patient presented with acute ocular symptoms
proved after it was withdrawn suggest that the symptoms
(redness and soreness), erythema and swelling of both
may be related to the therapy rather than to the coexist-
auricles (Fig. 1). After discarding other causes, polychon-
dritis was diagnosed. Anti-TNF treatment was stopped ence of two rheumatic diseases. The traditional treatment
and prednisone 1 mg/kg was started. The patient’s con- of RP includes glucocorticoids and immunosuppressive
dition resolved slowly but favourably. Four months later, agents [2, 3], but recently, treatment with biologic
axial and joint symptoms recurred and treatment with agents, mostly anti-TNF, has been described [6–8]. Most
adalimumab 40 mg every 2 weeks was started, with an reports are of small series or isolated cases, frequently
early response. Currently, the patient remains asymptom- with a favourable outcome. However, no cases of RP
atic for spondylitis and polychondritis and is still receiving induced by biological therapy have been described until
adalimumab. now. The fact that biological therapy may induce the
RP is a rare autoimmune disease of unknown aetiology development of other diseases, such as new-onset
in which the cartilaginous tissues, especially of the ears, psoriasis or uveitis, in which it has also been shown to
nose, joints and tracheobronchial tree, are the target for be effective therapy, may be suggestive of a paradoxical
inflammation and progressive destruction [2, 3]. Although reaction [9], and this might also occur with RP. In addition,
our patients did not develop recurrent episodes of poly- some cases of the development of autoantibodies or
chondritis, other causes of chondritis were ruled out. In autoimmune diseases, frequently with good prognosis
addition, the involvement of other areas frequently after therapy discontinuation have been described with
involved in RP, such as the ocular region or the respiratory biological therapy [10], suggesting an autoimmune mech-
tract, suggests the diagnosis of RP based on its charac- anism. In our cases, determination of anti-type II collagen
teristic clinical manifestations. In around one-third of RP antibodies, which have been found in some RP cases [3],
patients, an association with other diseases has been could unfortunately not be performed to check this hy-
found [2, 3], but the association of RP with SpA is ex- pothesis. In conclusion, we describe the first cases
tremely unusual and there are only a few reported cases of RP induced by biological therapy, which evolved
[4, 5]. This feature, together with the fact that our patients favourably after treatment discontinuation.

1524 www.rheumatology.oxfordjournals.org

Rheumatology key message
. Biological therapy with anti-TNF could induce RP.
Disclosure statement: The authors have declared no
conflicts of interest.
Maria Victoria Hernández1, Virginia Ruiz-Esquide1,
Maria Eugenia Gómez-Caballero1,
Jose A. Gómez-Puerta1, Juan D. Cañete1 and
Raimon Sanmartı́1
1
Rheumatology Department, Arthritis Unit, Hospital Clı́nic,
University of Barcelona, Barcelona, Spain
Accepted 11 March 2011
Correspondence to: Maria Victoria Hernández, Rheumatology
Department, Arthritis Unit, Hospital Clı́nic, University of
Barcelona, 08036 Barcelona, Spain.
E-mail: mvhernan@clinic.ub.es
References
1 Alonso-Ruiz A, Pijoan JI, Ansuategui E, Urkaregi A,
Calabozo M, Quintana A. Tumor necrosis factor alpha
drugs in rheumatoid arthritis: systematic review and
metaanalysis of efficacy and safety. BMC Musculoskelet
Disord 2008;9:52.
2 Lahmer T, Treiber M, von Werder A et al. Relapsing
polychondritis: an autoimmune disease with many faces.
Autoimmun Rev 2010;9:540–6.
3 Gergely P, Poór P. Relapsing polychondritis. Best Pract
Res Clin Rheumatol 2004;18:723–38.
4 Pazirandeh M, Ziran BH, Khandelwal BK, Reynolds TL,
Khan MA. Relapsing polychondritis and spondyloarthro-
pathies. J Rheumatol 1988;15:630–2.
5 Bahiri R, Bzami F, Benbouazza K, Saoud B,
Hajjaj-Hassouni N. Relapsing polychondritis and ankylos-
ing spondylitis in the same patient. Joint Bone Spine 2006;
73:474–83.
6 Marie I, Lahaxe L, Josse S, Levesque H. Sustained
response to infliximab in a patient with relapsing
polychondritis with aortic involvement. Rheumatology
2009;48:1328–9.
7 Subrahmanyam P, Balakrishnan C, Dasgupta B.
Sustained response to etanercept after failing infliximab, in
a patient with relapsing polychondritis with tracheomala-
cia. Scand J Rheumatol 2008;37:239–40.
8 Lahmer T, Knopf A, Treiber M, Heemann U, Thuermel K.
Treatment of relapsing polychondritis with the TNF-alpha
antagonist adalimumab. Clin Rheumatol 2010;29:1331–4.
9 Fouache D, Goëb V, Massy-Guillemant N et al.
Paradoxical adverse events of anti-tumour necrosis factor
therapy for spondyloarthropathies: a retrospective study.
Rheumatology 2009;48:761–4.
10 Bacquet-Deschryver H, Jouen F, Quillard M et al. Impact
of three anti-TNFalpha biologics on existing and emergent
autoimmunity in rheumatoid arthritis and spondylarthro-
pathy patients. J Clin Immunol 2008;28:445–55.
www.rheumatology.oxfordjournals.org
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Letters to the Editor
Rheumatology 2011;50:1525–1526
doi:10.1093/rheumatology/ker145
Advance Access publication 14 June 2011
Comment on: Low TNF-induced NF-B and p38
phosphorylation levels in leucocytes in tumour
necrosis factor receptor-associated periodic
syndrome
SIR, We read with great interest the recent article by
Stjernberg-Salmela et al. [1], advocating low TNF receptor-
induced nuclear factor-kappaB (NF-B) signalling in TNF
receptor-associated periodic syndrome (TRAPS). In
many, although not all, instances, TRAPS patients have
been found to have a reduced level of circulating soluble
tumor necrosis factor receptor 1 (TNFR1) (sTNFR), and it
is thought that this reduction in sTNFR compromises the
natural ability to buffer TNF activity, thereby rendering
these individuals susceptible to harmful spontaneous
Downloaded from http://rheumatology.oxfordjournals.org/ by guest on February 20, 2013
bouts of fever resulting from TNF-induced bursts of pyro-
genic cytokine release. Consistent with this model of
TNF-induced inflammation, the majority of researchers
investigating TRAPS pathophysiology have similarly re-
ported that TNFR1 mutations are associated with elevated
NF-B signalling activity in TRAPS patients. Importantly,
the authors of the current manuscript have also published
research articles showing that patients with the C73R mu-
tation in TNFR1 have low sTNFR1 between attacks [2], as
well as showing (through collaboration with our two re-
spective groups) increased cell surface TNFR1 and ele-
vated NF-B activity [3], which leads to the secretion of
pyrogenic cytokines [4].
How might one reconcile the above publications with
the current findings [1]? The authors try to rationalize
this by suggesting that our previous investigations [3]
induced an artefactual activation of NF-B through cellular
stress response to sample handling. Artefactual activation
is highly unlikely, however, as the cells in this study were
allowed a 4-h recovery time post-isolation. In addition, all
cells from controls and TRAPS mutations were isolated in
parallel, as well as being incubated both identically and
simultaneously to the C73R cells. Crucially, the only cells
in this study to show an increased cell surface expression
of TNFR1 and significantly increased p65 NF-B subunit
activity were those with the C73R mutation.
As the discrepancy in the NF-B findings is not due to
handling artefacts in the Nedjai et al. study [3], what else
might explain these differences? Whole-cell studies can
be problematic when studying transcription factors. While
NF-B p65 subunit phosphorylation is indeed one of the
triggers for activation of this molecule, nevertheless it is
only once inside the nucleus that DNA-binding can occur.
Therefore, it is essential to study NF-B. This is not
the case with the current methodologies utilized by
Stjernberg-Salmela et al. [1], raising the possibility of
signal interference from cytoplasmic NF-B. Furthermore,
as the authors themselves openly acknowledge, they are
hostage to the unknown extent of membrane permeabil-
ization in their cells. For instance, were TNF to sensitize
1525