Biomedicines: Relapsing Polychondritis: An Updated Review
Biomedicines: Relapsing Polychondritis: An Updated Review
Biomedicines: Relapsing Polychondritis: An Updated Review
Review
Relapsing Polychondritis: An Updated Review
Francesco Borgia *, Roberta Giuffrida, Fabrizio Guarneri and Serafinella P. Cannavò
Department of Clinical and Experimental Medicine, Section of Dermatology, University of Messina,
98125 Messina, Italy; robgiuffrida@unime.it (R.G.); f.guarneri@tiscali.it (F.G.); cannavop@unime.it (S.P.C.)
* Correspondence: fborgia@unime.it; Tel.: +39-347-914347
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Received: 30 May 2018; Accepted: 25 July 2018; Published: 2 August 2018 !"#$%&'
1. Introduction
Relapsing polychondritis (RP) is an immune-mediated systemic disease characterized by recurrent
inflammatory episodes of cartilaginous and proteoglycan-rich tissues, including the elastic cartilage
of the ear and nose, the hyaline cartilage of peripheral joints, the fibrocartilage at axial sites and
the cartilage of the tracheobronchial tree, which result in progressive anatomical deformation and
functional impairment of the involved structures. In over 80% of patients, RP is disclosed by
auricular chondritis and polyarthritis, though many organs can be potentially involved. Its onset
is often insidious, with acute painful inflammatory crisis followed by spontaneous remission of
variable duration. This may render diagnosis very difficult at an early stage, with therapeutic delay
and consequent increased risk of permanent or life-threatening sequelae. Association with other
autoimmune disorders is found in 30% of all adult RP patients, rheumatoid arthritis (RA) being the
most common. In this review article we provide a comprehensive look into clinical presentation,
laboratory and instrumental investigations, diagnostic criteria, and therapeutic options, with a focus
on the role of biologics in the management of refractory patients.
51 years at the time of diagnosis [9]; however, RP can occur at any age. Pediatric RP represents <5%
of the reported cases, with age at onset varying from 1.7 months to 17 years; clinical presentation is
similar to adult RP [10]. Pregnancy does not influence the course of disease; no neonatal cases have
been described until now [11]. RP occurs with similar frequency in both genders, although a slight
female preponderance has been reported [12]. It affects all ethnic groups, with variability in clinical
presentation between Caucasian and Asian populations [13].
3. Pathogenesis
The exact pathogenesis of RP is not yet clearly defined. Genetic studies have identified HLA-DR4
as the major risk allele for RP, while a negative association exists between severity of organ involvement
and HLA-DR6 [14]; there is no evidence of familial transmission. RP is considered a complex
disorder targeting cartilaginous structures, with involvement of both humoral and cell-mediated
0
immune systems. Circulating autoantibodies against collagens II, IX and XI have been detected in
RP patients, suggesting that cartilage-specific autoimmunity may play a crucial role in the pathogenesis
of RP [15–17]. Type II collagen (CII) accounts for 95% of the total collagen content of the cartilage,
and may represent a primary target of autoimmunity. Circulating antibodies against CII have been,
in fact, detected in one third of RP patients with active disease, with a positive correlation between
serum titers and disease severity [15]. Other known target autoantigens are matrilin-1 and the
cartilage oligomeric matrix proteins (COMP). Matrilin-1 is a protein of the intercellular matrix, highly
expressed in tracheal, nasal, auricular, and chondro-sternal cartilages but not in normal adult joint
cartilage; COMP is predominantly found in the extracellular matrix of cartilage, ligaments, and tendons.
In a case report, Saxne and Heinegard evidenced that serum levels of the two cartilage matrix proteins
varied inversely during monitoring of an RP patient. Raised matrilin-1 levels were measured in
the course of a flare-up, possibly reflecting an increased release from damaged cartilage; COMP
serum levels negatively correlated with disease activity, with a reduction in the acute phase and
a progressive increase in the course of clinical remission, suggesting that higher levels may reflect tissue
restoration and de novo synthesis of cartilage [18]. On the contrary, Kemta Lekpa et al. demonstrated,
in 21 RP patients, significantly higher COMP levels during the active phase than in the inactive
one [19]. Antibodies to matrilin-1, binding to tracheolaryngeal cartilage in vivo, were identified by
Hansson et al. in 13 out of 97 RP patients. Positive titers correlated with respiratory symptoms in 69%
of cases [20]. Interestingly, seven out of 97 RP patients showed concomitant presence of anti-matrilin-1
and anti-COMP antibodies, suggesting that immunization against COMP may be a consequence of the
matrilin-1 mediated process of cartilage destruction. Experimental studies in murine models confirmed
that immunization with extracellular matrix proteins can result in the development of a chondritis
closely resembling the clinical picture observed in human RP patients [21,22]. The role of cell-mediated
immune response in the pathophysiology of RP is supported by several data. Histopathological
examination of affected cartilages revealed inflammatory infiltrate composed by various proportions
of T-lymphocytes, mainly CD4 T-cells, macrophages, plasma cells, and immune deposits, restricted to
perichondrium at an early stage and, later, spreading to cartilage [23,24]. Chemokines consistent with
Th-1 profile, namely, interferon, interleukin (IL)-2, and IL-12, are released during this inflammatory
process [25]. Furthermore, T-cell response specific to peptides found in collagen type II or matrilin-1
was found in some patients [26]. With disease progression, high expression of proteolytic enzymes was
detected in perichondral cells and chondrocytes. Matrix metalloproteinase (MMP)-8, -9, and elastase
were expressed only in the perichondral granulation, whereas MMP-3 and cathepsin K and L were
detected in both chondrocytes and granulations. The strong correlation between the number of
apoptotic cells and the number of MMP-3-positive and cathepsin K-positive cells suggests that
cartilage destruction in RP can be sustained not only by perichondral inflammation, but also by
intrinsic factors, such as the aforementioned MMP-3 and cathepsin K and L, strongly expressed in
the chondrocytes of deteriorated cartilage and released from the same cells after apoptosis [27,28].
As suggested by Ouchi et al. [27], MMP-3 deteriorates many connective and plasma proteins, such
Biomedicines 2018, 6, 84 3 of 14
as proteoglycan, various type of collagen (IV, V, VII, IX and denatured type I), laminin, fibronectin,
elastin, alpha1-proteinase inhibitor, immunoglobulins, and substance P.
The above mentioned data allows us to hypothesize that yet unknown factors (maybe infectious
agents and/or mechanical and chemical aggressions) might cause protein degradation with consequent
release of cryptic cartilage antigens. In genetically predisposed subjects, immunization can occur
against these autoantigens, in part recognizable in CII, matrilin-1, and COMP. This may perpetuate, via
release of pro-inflammatory cytokines and recruitment of infiltrating cells in RP lesions, finally resulting
in cartilage destruction mediated by MMP released by chondrocytes undergoing apoptosis [28].
4. Clinical Manifestations
Chondritis and polyarthritis are the most common clinical features of RP but, since inflammation
of cartilaginous tissue potentially may occur at many anatomical districts, the disease often presents
with various combinations of heterogeneous, only apparently unrelated, signs and symptoms. RP can
also involve other proteoglycan-rich structures, such as the eye, heart valve, and blood vessels.
This makes diagnosis very difficult, especially when auricular and nasal involvement is not yet
come into view or when constitutional symptoms, including fever, weight loss, night sweats, fatigue,
and lympho-adenomegaly, anticipate the onset of characteristic manifestations [12,14].
4.1. Chondritis
Mono- or, more frequently, bilateral auricular chondritis is the most common feature of RP,
which is observed in up to 90% of patients during the course of the disease, and is the inaugural
symptom in 20% of cases [3,5,29]. The onset is abrupt, with painful red to violaceous erythema and
edema confined to the cartilaginous part of the ear, typically sparing the lobe, which lacks cartilage.
Acute inflammatory episodes tend to resolve spontaneously within few days or weeks, with recurrence
at
at variable intervals. As a long-term consequence of repeated flares, the cartilage matrix is severely
damaged and replaced by fibrous connective tissue. The ear progressively loses its normal morphology,
appearing nodular or verrucous, floppy or hardened for calcification. In a small percentage of patients,
the deformity of the pinna resembles the “cauliflower ear” of professional boxers [29]. Hearing loss,
which can be conductive or sensorineural, was demonstrated in as many as 46% of patients with RP,
and vestibular dysfunction was documented in 6%. Conductive hearing loss was reported secondary
to auricular cartilage collapse, edema of the canal, closure of the external auditory meatus leading to
serous otitis media, and stapedial foot plate fixation [30,31]; inflammation of the vestibular structures
or vasculitis of the internal auditory artery may cause sensorineural hearing loss [12,30]. Otitis externa,
chronic myringitis, and tinnitus were reported as well [32].
Nasal chondritis is present at the time of diagnosis in 24% of patients, and develops subsequently
in 53% of cases [29]. The inflammatory process involves the nasal bridge, with acute redness,
tenderness, and pain, usually less marked than in the ears. It can be occasionally accompanied
by epistaxis [30]. Progressive destruction of nasal cartilage leads to the characteristic flattening of the
nasal bridge, finally resulting in the painless, irreversible “saddle nose” deformity, more frequently
observed in female patients and those under 50 years [7,12].
Laryngotracheobronchial involvement is seen at presentation in only 10% of cases, but it
eventually develops in half of all patients, more commonly in females [3,33]. When inflammation is
limited to the larynx, initial symptoms include pain and tenderness over the thyroid cartilage and
trachea, leading to laryngomalacia or permanent stenosis with hoarseness of voice, non-productive
cough, dyspnea, stridor, and wheezing, that may require emergency tracheotomy as a temporary or
permanent measure [3,7,34]. Tracheobronchial involvement has a poor prognosis, being the major cause
of morbidity and mortality [3]. The thickening of the tracheal wall with destruction of the cartilaginous
rings is characteristic. Tracheomalacia may be observed, with resultant airway collapse [35]. Fixed
narrowing and stenosis may develop from granulation tissue and peribronchial fibrosis. Strictures in
the airways from chronic inflammation, fixed or dynamic, might generate subglottic inflammation,
Biomedicines 2018, 6, 84 4 of 14
tracheal collapse, and secondary pulmonary infections [36]. Airway intervention is frequently required,
by means of balloon dilatation, stent placement, tracheotomy, or a combination of the above mentioned
techniques [35]. The involvement of costal cartilages occurs in 35% of patients, but it is rare at the
moment of diagnosis. It causes chest wall pain or swelling of the involved cartilages.
4.2. Arthropathy
This is the second most frequent symptom in RP and appears in approximately 50–85%
of patients during the disease, but in only 33% of these it is an initial feature [12,37]. The main
pattern of joint involvement is acute asymmetric intermittent polyarthritis or oligoarthritis affecting
metacarpophalangeal joints, proximal interphalangeal joints, knees, and, less commonly, ankle, wrists,
metatarsophalangeal joints, and elbows [37,38]. Usually, no erosions or deformities are observed,
although a few cases with joint destruction have been reported [39]. Axial involvement has rarely been
described, and tendinopathy and tenosynovitis are reported only in few cases [40].
related to concomitant vasculitis, usually considered as poorly specific. Recently, Tronquoy et al.
described the occurrence, in ten patients, of tense urticarial papules, frequently with annular shape,
predominantly located on the upper part of the trunk, shoulders, neck, and less frequently on the
proximal part of the limbs. Histologic examination consistently showed a lymphocytic vasculitis
with no leukocytoclastic vasculitis. Interestingly, in contrast with previous reports, skin lesions
occurred before the diagnosis of RP in seven of 10 cases, with a mean delay of RP of 23 months [56].
The concomitant presence of oral and genital aphtous ulcerations and chondritis has been first
described by Firestein, who coined the acronym MAGIC (mouth and genital ulcers with inflamed
cartilage) to indicate a syndrome which includes diagnostic criteria of RP and Behçet’s disease (BD).
Some Authors suggested the existence of a common autoimmune pathogenic mechanism [57], but the
pathogenic association between these three diseases is still unclear.
requiring no histologic confirmation [3]. These criteria were later modified by Damiani and Levine,
who expanded the spectrum of diagnostic criteria, adding the presence of at least one McAdam
criterion and positive histologic confirmation, or two McAdam criteria and positive response to
administration of corticosteroids or dapsone [4]. Another variant of McAdam criteria was proposed by
Michet et al. in 1986 [5]; according to the latter, the diagnosis of RP requires a confirmed inflammation
in two of three auricular, nasal or laryngotracheal cartilages, or else a proven inflammation in one of
the above cartilages and two other minor criteria among hearing loss, ocular inflammation, vestibulary
disfunction, seronegative arthritis.
Laboratory findings may be suggestive of inflammation and sometimes organ damage, but there
are not specific laboratory tests for the diagnosis of RP. The levels of C-reactive protein and erythrocyte
sedimentation rate are usually raised during the inflammatory crisis, but findings of normal values
during the remission phase do not allow exclusion of the diagnosis. Blood exams may reveal anemia,
leukocytosis, thrombocytosis, polyclonal hyper-gammaglobulinemia; serum creatinine and urinalysis
are useful to detect renal function impairment [29]. Other laboratory investigations, such as rheumatoid
factor, antinuclear antibody (ANA), anti-phospholipid antibodies, and complement levels, can be
useful to evidence the presence of concomitant diseases [14]. The prevalence of ANA observed in RP
is low, and the finding of a significant titre of ANA in a patient with RP strongly suggests the presence
of an associated disorder [67]. Anti-neutrophil cytoplasmic antibodies (ANCA) can be present in up to
25% of patients with RP and concomitant ANCA-associated vasculitis [68], but they may also be an
isolated finding in RP or precede the onset of vasculitis [53,69].
Identification of anti-type II collagen antibodies in the acute phase of RP represents another low
specificity-finding [70], whereas their serum levels seem to correlate with disease severity [15].
A positive correlation between raised serum levels of anti-matrilin-1 antibodies and the presence
of respiratory symptoms has been reported by Hansson et al. [20]. Even COMP levels may be high
in the active phase of the disease [19]. Histology does not add weighty diagnostic information and
biopsy of the cartilage is not routinely performed, with the exception of atypical clinical presentation.
The detection of basophilic staining of the cartilage matrix, perichondral round-cell infiltration or
cartilage destruction with fibrous replacement can be of diagnostic value [12]. X-ray examination may
be helpful to evidence calcification of auricolar, nasal, tracheal, and articular cartilage, which may
be found in chronic RP. The sensitivity of conventional chest radiography is not sufficient for
accurate visualization of RP. Early identification of airway involvement is mandatory for prompt
diagnosis and aggressive treatment, which may prevent a potentially fatal outcome. The CT findings
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in patients with RP consisted mainly of airway wall thickening, airway stenosis, airway malacia,
airway wall calcification, and air trapping [71]. Expiratory CT abnormalities are present in the
majority of RP patients, yet only half of patients demonstrated abnormalities on routine inspiratory
CT scans. According to Lee et al., dynamic expiratory CT should be considered a routine diagnostic
component if there is clinical suspicion of airway involvement [72]. However, stenosis may not
improve after suppression of inflammation, making CT assessment following therapy difficult in
some cases. MRI plays a major role in the diagnosis of RP by demonstrating a unique pattern of
inflammation and enhancement, that preferentially involves the perichondrium and chondroepiphysis,
even in the early phases of the disease. Recently, encouraging results have been reported with
fluorodeoxyglucose (FDG)-PET/CT, that promises to be a useful tool for both diagnosis and evaluation
of disease activity [73]. Bronchoscopy is accompanied by an elevated risk of exacerbation of airway
inflammation and may induce potentially fatal respiratory distress, so its use is limited to selected
cases [35]. Echocardiography is used to assess cardiac valves and aortic root in RP patients with
suspected cardiovascular involvement. A recent report highlights the utility of PET-CT in detecting
aortic root dilatation secondary to aortitis with critical coronary artery stenosis [74]. Bone scintigraphy
using 99mTc-methylene diphosphonate and gallium-67 citrate has been reported to demonstrate
inflammatory cartilage and joints and may be employed for evaluating inflammatory activity and
monitoring treatment responses in RP patients [75,76].
A specific disease activity score, called the Relapsing Polychondritis Disease Activity Index
(RPDAI), has been developed by a panel of RP experts in 2012 in order to standardize the evaluation
of patients and to monitor response to treatment [77]. The RPDAI score is made up of 27 items with
individual weights ranging from 1 to 24 and a maximum theoretical RPDAI score of 265, taking into
account disease manifestations in a 28-day period (online scoring at www.RPDAI.org). Preliminary
results of RPDAI application seem to confirm the potential utility of this tool in monitoring the clinical
course of the disease [78].
Survival rates have increased from 70% after five years to 94% after eight years, and 91% after
10 years in a recent large single-center study [40]. These improvements can be explained in the light of
improved diagnostic ability, with detection of the disease at an early stage, and availability of new
drugs. Causes of death in RP include disease-dependent direct organic damage, concomitant diseases,
and infections, which may be an undesired consequence of immunosuppressive treatments [79].
6. Therapy
There are no evidence-based guidelines for the treatment of RP. Available therapeutic options are
summarized in Table 2. The goal of therapy is the control of the inflammatory crisis and the long-term
suppression of the immune-mediated pathogenetic mechanisms. The ideal therapy should allow the
achievement of rapid relief of symptoms and the prevention of multi-organ effects on cartilaginous
structures, with the fewest side effects, taking into consideration the need for chronic administration.
Non-steroidal anti-inflammatory drugs (NSAIDs) may be used for pain control and inflammation
in non-severe forms of RP, characterized by involvement of nose, external ear, or joints only [80,81].
Mild manifestations can be also managed with dapsone (50–100 mg, once daily; maximum dose of
200 mg, once daily) or colchicine (0.6 mg 2–4 times daily) [82–84]. In the case of NSAIDs resistance
or in severe forms including ocular, laryngotracheal, or cardiac involvement, systemic vasculitis and
severe polychondritis, systemic corticosteroids are considered the treatment of choice [85,86]. Oral
prednisone is usually started with a dose ranging from 0.25 to 1 mg/kg daily, reducing the dose,
if possible, during the course of the disease [80,86]. If a rapid effect is necessary, intravenous pulse
methylprednisolone (500–1000 mg/day) can be helpful [86].
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six patients, and not effective in 28 patients. In particular, the use of infliximab (3–10 mg/kg every
6–8 weeks) [89] induced complete or partial remission of inflammatory signs and complications
in 18 out of 31 RP patients treated. The efficacy of etanercept (50 mg/week) and adalimumab
(40 mg/2 weeks) was tested respectively in eight and four patients; the first was effective in five patients,
while the last in two. The efficacy of rituximab is still debated, with some authors who reported
improvement [91,92] of the clinical course of the disease and others who found the drug ineffective [86].
Anakinra (100 mg/day) has been used in a small amount of patients, particularly after a lack of
efficacy of other biologics [86,93,94]. Promising results have been documented with tocilizumab
(8 mg/kg/month), with serial MRI imaging showing response to treatment in progressive RP with
visceral involvement [90]. Abatacept was used successfully (750 mg/month) in three patients with RP
by Moulis et al. [95,96]. Peng et al. tested abatacept in four patients at the dose of 125 mg/week for
24 weeks. In two cases the treatment was discontinued early for worsening of organ disease. However,
chondritis improved in three out of four cases [97]. In general, data show that biologics may help
and lead to improvements in cases of RP refractory to conventional therapy. However, randomized
controlled trials, although not easy to perform due to the rarity of the disease, are needed to assure
efficacy and safety of biologics in RP.
Limited experiences with other treatments, such as 6-mercaptopurine, plasmapheresis, anti-CD4
monoclonal antibody, penicillamine, minocycline, high-dose intravenous immunoglobulins and
leflunomide, have been reported in literature, with mixed results [86,98–100].
In selected cases, complicated by severe bronchial stenosis or intractable cardiac failure because of
valve regurgitation, and in the event of aortic aneurysms, surgical or interventional procedures could
be necessary [80].
7. Conclusions
RP is a rare and potentially fatal multisystemic autoimmune disease of unknown etiology, affecting
primarily cartilagineous and proteoglycan-rich structures. Patients present with a wide spectrum of
clinical manifestations that allow diagnosis to be made. To date, therapy of RP is still empiric, due to
the lack of standardized guidelines on treatment, and is defined on the basis of disease activity and
severity of organ involvement. Mild forms are treated with NSAIDs, colchicine, dapsone, and low-dose
corticosteroids. Life-threatening or organ-threatening complications require high-dose corticosteroids
and immunosuppressants. Biologics are a new weapon in the war against autoimmune diseases,
such as RP. However, the number of patients treated are still limited, and the majority of studies is
heterogeneous and with different outcomes. Moreover, little laboratory and clinical research has been
conducted on human RP recently, as demonstrated by the limited number of papers published in the
last years. For these reasons, clinical trials are needed and biologics should be used after the failure of
conventional immunosuppressive treatments.
Author Contributions: F.B. and S.P.C. designed the manuscript; F.B. and R.G. wrote the manuscript; F.G. created
the tables and cured the bibliographical references; S.P.C. revised critically the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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