pureheart

Relapsing Polychondritis
Posted 02/24/2004
Peter D. Kent; Clement J. Michet, Jr; Harvinder S. Luthra
Abstract and Introduction
Abstract

Relapsing polychondritis is a unique, rare autoimmune disorder in
which the cartilaginous tissues are the primary targets of destruction
but the immune damage can spread to involve noncartilaginous tissues
like the kidney, blood vessels, and so forth. The manifestations of
the disease can take many different forms and the pathogenesis is
still unclear. It may occur in a primary form or it may be associated
with other disease states. This article summarizes important aspects
of the disease with a focus on recent information regarding clinical
manifestations, disease associations, pathogenesis, and advances in
the****utics.

Introduction

Relapsing polychondritis was first described 80 years ago, and


observations have been well described, some of these reflect
manifestations of associated diseases. The pathogenesis remains
unknown, although immune abnormalities observed over the years led us
to classify it as an autoimmune disease. Some of the difficulties
involved in studying this disease relate to its rarity (making it
difficult to study patients with a similar phenotype), the lack of
appropriate animal models, and the lack of consistent laboratory
abnormalities, all of which lead to difficulty in developing a clear
working hypothesis. Ongoing efforts in this direction may soon produce
results. The lack of substantial populations in any one center's
the****utic studies leave us with generic approaches to treatment, as
is true of many immune-mediated inflammatory diseases. With the
advances in our ability to investigate molecular mechanisms of
diseases, and understanding the role of genomics and proteomics, we
anticipate major advances in our understanding of this syndrome in the
near future.

Clinical Features and Organ-Specific Special Investigations

Diagnostic criteria that distill the most common clinical features of
relapsing polychondritis were put forth in 1976 by McAdam et al.,[1]
but have since been modified. Currently, the diagnosis is usually made
on the basis of chondritis in two of three sites (auricular, nasal,
laryngotracheal) or one of those sites and two other features,
including ocular inflammation, audiovestibular damage, or seronegative
inflammatory arthritis.[2,3] A biopsy is unnecessary in most cases.
Clinical Manifestations

The reader is referred to several papers that review the literature on
relapsing polychondritis.[4,5*] The frequency of clinical
manifestations in relapsing polychondritis is shown in Table 1, which
combines data from three large studies involving 337 patients.[1,3,4]
Auricular chondritis is the most frequent and unique presenting sign,
causing subacute onset of pain, redness, and swelling of the ear,
sparing the lobule. Attacks often occur in a relapsing-remitting
pattern and may leave a floppy pinna or cauliflower deformity.
Conductive hearing loss can result from stenosis of the external
auditory c****, Eustachian tube chondritis, or serous otitis media.
Presumed vasculitis of the internal auditory artery may result in
acute sensorineural hearing loss with or without symptoms of
vestibular dysfunction.[6]
Musculoskeletal Manifestations

Arthritis is the second most common presenting symptom of relapsing
polychondritis and it eventually affects more than 70% of patients.
The arthritis of pure relapsing polychondritis is intermittent,
migratory, asymmetric, seronegative, and usually nonerosive.[7] Hand
and foot radiographs typically show joint space reduction and/or
osteopenia.[8] Relapsing polychondritis is often described in the
presence of other arthropathy-inducing diseases such as connective
tissue diseases, rheumatoid arthritis, and the
spondylarthropathies.[5*]
Ocular Manifestations

Although only approximately 18% of patients present with some evidence
of ocular inflammation, this eventually develops in nearly 60%.
Episcleritis and scleritis are the most common manifestations,
followed by keratoconjunctivitis sicca, iritis, retinopathy,
keratitis, optic neuritis, and corneal melt.[9] Inflammation external
to the globe can result in orbital pseudotumor, extraocular muscle
palsy, and lid edema.
Otorhinolaryngeal Manifestations

Nasal chondritis is painful, affects the distal part of the nasal
septum, and through recurrent episodes leads to a saddle nose
deformity. Chondritis of the laryngotracheal cartilages occurs in more
than half of patients, with a female preponderance, and may present
with anterior neck pain, hoarseness, cough, inspiratory obstruction
with choking, shortness of breath, or wheezing. Anatomically,
obstruction results from edema, vocal cord palsy,[10] fixed subglottic
or bronchial stenoses, and/or dynamic airway collapse.
Pulmonary Manifestations

Pulmonary function tests, including inspiratory and expiratory flow
volume curves, should be performed in all patients with relapsing
polychondritis to detect occult airway disease.[11,12] In the presence
of respiratory symptoms or pulmonary function test abnormalities, CT
of the chest should be performed. Findings may include tracheal and
bronchial stenoses, thickening and calcifications of the airway walls,
obstructive bronchiectasis, and dynamic tracheal/bronchial
collapse.[13,14] Bronchoscopy is not routinely used because it poses a
risk of respiratory decompensation to the patient, but it may help
distinguish postinflammatory from active inflammatory lesions.
Costochondritis and inflammation of the manubriosternal joint may also
compromise respiration.
Renal Manifestations

Urinalysis should be obtained with follow-up visits because
approximately 22% of patients with relapsing polychondritis develop
some type of renal lesion do***ented by microhematuria, proteinuria,
or abnormal kidney biopsy.[15] Renal involvement is associated with a
higher incidence of extrarenal vasculitis, arthritis, and a worse
survival. Renal pathology has included mesangial expansion, IgA
nephropathy,[16] tubulointerstitial nephritis, and segmental
necrotizing crescentic glomerulonephritis.[15] Some renal lesions may
be associated with coexisting diseases such as systemic lupus
erythematosus.
Dermatologic Manifestations

A recent study of 200 cases of relapsing polychondritis found that 73
patients (37%) had at least one associated disease that could cause a
skin condition.[17] Of the remaining 127 patients with pure relapsing
polychondritis, 45 (35%) had dermatologic involvement during the
course of follow-up. Oral aphthous ulcers were the most frequent
manifestation, followed by nodules on the limbs with an erythema
nodosum appearance (15%), purpura, sterile pustules, superficial
phlebitis, and livedo reticularis. Limb ulcerations, urticarial
papules, bluish red papules, distal necrosis, and erythema elevatum
diutinum were each seen in less then 5% of patients. Although seven
patients had both oral and genital aphthae in the absence of other
diseases, none had uveitis and they were not classified under the
MAGIC syndrome (mouth and genital ulcers with inflamed cartilage).[18]
Leukocytoclastic vasculitis was the most frequent biopsy diagnosis,
with other causes including septal panniculitis, neutrophilic
dermatoses, and thrombotic occlusion of dermal vessels. Of patients
with a myelodysplastic syndrome and relapsing polychondritis, 91% had
dermatologic involvement, and the mean age at first chondritis was 63
years compared with 41 years in patients without an associated
disease. The coexistence of skin manifestations and relapsing
polychondritis in the elderly warrants vigilance for the development
of a myelodysplastic syndrome.
Cardiovascular Manifestations

The spectrum of cardiovascular disease manifestations of relapsing
polychondritis includes aortitis,[19] thoracic and abdominal aortic
aneurysms,[20] Takayasu-like aortic arch syndrome,[21] aortic and/or
mitral regurgitation,[22] impairment of the conduction system,[23]
pericarditis,[24] medium- and large-vessel (including coronary)
vasculitis,[25] thrombophlebitis,[26] and arterial thrombosis.[27*]
Some, but not all thrombotic complications have been linked to
antiphospholipid syndrome.[28] Aortic regurgitation is the most
prevalent cardiovascular complication, occurring in approximately 4 to
10% of patients.[19,24] These complications tend to occur after
several years of smoldering and often occult disease, and they may
develop in the presence of ongoing immunosuppressive therapy.[27*] In
the patient with a murmur or unexplained dyspnea, electrocardiography
and echocardiography should be performed. CT, magnetic resonance
angiography,[29] ultrasound, and conventional angiography can be used
to evaluate for aneurysms, vasculitis, or thromboses.
Neurologic Manifestations

Central and peripheral nervous system involvement in relapsing
polychondritis occurs in approximately 3% of patients.[30] The cranial
nerves are most frequently involved,[31] but seizures, cerebral
dysfunction, confusion,[32] headaches, cerebral aneurysm,[33] and
rhomboencephalitis[34] have been described. The pathogenesis of these
symptoms is presumed to be vasculitic, but definite central nervous
system vasculitis is rarely do***ented.[35] MRI of the brain may show
multifocal areas of enhancement consistent with cerebral
vasculitis.[36] Cerebrospinal fluid may be normal, may show a
lymphocytic pleocytosis, and may mimic bacterial infection.[34,37,38]

Epidemiology

The incidence of relapsing polychondritis has been estimated to be 3.5
cases per million in Rochester, Minnesota.[39,40] Using the data from
three large studies, the female-to-male ratio is equal and the mean
age at diagnosis is 47 years.[1,3,4] Most cases occur in whites. Both
pediatric and elderly cases have been described with an age range of 6
to 87 years.[17] Pregnancy does not seem to influence the disease
course, and 72% of pregnancies in one series were successful.[41]

Disease Associations

As many as 37% of patients with relapsing polychondritis have an
associated hematologic disorder, connective tissue disease,
vasculitis, dermatologic disorder, or other autoimmune disease[5*,17]:

* Systemic vasculitis
* Leukocytoclastic vasculitis
* Connective tissue diseases
* Behçet disease
* Rheumatoid arthritis
* Juvenile chronic arthritis
* Spondylarthropathies
* Myelodysplastic syndromes
* Hematologic malignancies
* Cryoglobulinemia
* Thymoma
* Retroperitoneal fibrosis
* Familial Mediterranean fever
* Inflammatory bowel disease
* Pernicious anemia
* Primary biliary cirrhosis
* Panniculitis
* Psoriasis
* Dermatitis herpetiformis
* Vitiligo
* Atopic dermatitis
* Lichen planus
* Autoimmune thyroid disease
* Myasthenia gravis
* Diabetes mellitus
* Glomerulonephritis[3,4,5*]

A case of relapsing polychondritis was recently described in a patient
with both HIV infection and sarcoidosis.[42*] Because of the myriad of
disease associations, it has been proposed that relapsing
polychondritis be thought of as a syndrome, which can be primary or
secondary,[43] akin to antiphospholipid syndrome.

Pathogenesis, Laboratory Studies, and Histopathologic Findings

The pathogenesis of relapsing polychondritis is not known. There is a
significant increase in the frequency of human leukocyte antigen
(HLA)-DR4 in patients, and the disease is associated negatively with
HLA-DR6.[30,44] Oligonucleotide-based genotyping, however, failed to
show any predominant HLA-DR4 subtype.[44] HLA-DQ6/8 transgenic mice
develop auricular chondritis after immunization with type II
collagen.[45] Antibodies to type II collagen, as well as types IX and
XI have been described, but they lack sensitivity and
specificity.[46-49] Cell-mediated immunity is important in the
pathogenesis of relapsing polychondritis.[50] Levels of macrophage
inhibitory factor are significantly higher in patients than in control
subjects.[51] Furthermore, one patient has been characterized with
T-cell clones specific for a type II collagen epitope.[52*] Rarely,
there may be a mechanical insult to cartilage such as ear piercing of
the cartilaginous portion, which is temporally correlated with the
development of relapsing polychondritis.[53]

Nonspecific markers of an inflammatory state may be present with
active relapsing polychondritis. Other serologic tests are of little
value, other than to suggest associated diseases. Antineutrophil
cytoplasmic antibodies have been found in some patients with relapsing
polychondritis.[54] These may be nonspecific or may be associated with
overlap syndromes.

Histopathology of involved cartilage specimens in relapsing
polychondritis reveals loss of normal cartilage basophilia with
hematoxylin-eosin staining and inflammation of the perichondrium with
neutrophils, eosinophils, lymphocytes, and plasma cells. Later,
cartilage is replaced by granulation tissue and fibrosis.[55]
Immunofluorescence studies may show the presence of immunoglobulin and
C3 complement deposits along the chondrofibrous junction and in
perichondral vessel walls.[56]

Differential Diagnosis

Because of its rarity and attribution of symptoms to other coexistent
disease, 1 or 2 years may elapse before the diagnosis is made.
Auricular chondritis is relatively unique to relapsing polychondritis
and eventually occurs in nearly 90% of cases. However, necrotizing
external otitis resulting from Pseudomonas aeruginosa should always be
considered in the patient with a unilateral inflamed ear.[57]

Various diseases can cause inflammatory or granulomatous lesions of
the larynx and subglottic region, including Wegener granulomatosis,
sarcoidosis, tuberculosis, amyloidosis, and rheumatoid
arthritis.[58,59] The differential diagnosis of a saddle nose
deformity includes Wegener granulomatosis, relapsing polychondritis,
and rarely syphilis or leprosy

Management

Because of its rarity, treatment for relapsing polychondritis is based
more on case series than on quality clinical trials. Traditional
therapy is with oral corticosteroids, in doses of 10 to 20 mg daily
for mild to moderate auricular and nasal chondritis or arthritis,
whereas doses of 1 mg/kg/day are used for sensorineural hearing loss,
vestibular symptoms, ocular involvement, respiratory compromise, and
vascular and renal complications. Pulse intravenous steroids (1 g/day
for 3 days) and nebulized racemic ephedrine may be helpful for acute
airway obstruction, allowing tracheostomy to be performed electively
instead of emergently.[60,61]

Nonsteroidal antiinflammatory drugs may be useful for arthralgias and
mild arthritis. Colchicine (0.6 mg twice daily) is of reported benefit
particularly for auricular chondritis, for which its effects are noted
within days.[62,63] Dapsone (50 to 200 mg/day) may also be of use in
milder disease, but side effects are common.[64,65]

One recent report describes a child successfully treated with daily
oral fetal bovine type II collagen. There was also a dramatic change
in the pre- and posttreatment T-cell cytokine profile. Although little
can be gleaned from this single report, the favorable side effect
profile oral type II collagen makes it deserving of further
study.[66**]

Methotrexate and azathioprine have been used with some success as
disease-modifying and steroid-sparing agents.[4,67] Treatment with
oral (1 to 2 mg/kg/day) or pulse intravenous (0.6 g/m2)
cyclophosphamide is used for organ-threatening pulmonary, cardiac, or
renal disease.[68,69] Cyclosporine A, in doses of 5 to 15 mg/kg/day
has helped in several cases that were refractory to other
agents.[70,71]

Several biologic therapies have been tried in relapsing
polychondritis. An anti-CD4 chimeric monoclonal antibody has been
successful as a salvage therapy.[72] Infliximab has been reported to
induce remission in one patient,[73] but another diabetic patient with
relapsing polychondritis developed severe septicemia, a parasternal
abscess, and died after initiating infliximab therapy.[74] When other
treatments fail, autologous stem cell transplantation may induce
complete remission in relapsing polychondritis.[75]

Adjuncts to medication therapy may be required. Continuous positive
airway pressure can provide symptomatic benefit, particularly at
night, in patients with tracheo- and bronchomalacia.[76] Tracheostomy
may be required in the setting of respiratory distress and localized
subglottic involvement.[77] Metallic stent placement can provide
immediate improvement in airflow dynamics, but complications plague
their use.[77,78*,79,80] In extreme cases, surgeries to splint open
externally or reconstruct the airway have been tried, but results are
mediocre at best.[77]

Prophylactic complete replacement of the ascending aorta with a graft
that includes the aortic valve should be performed in patients with
severe aortic insufficiency to limit the postoperative risk of
periprosthetic leak and aneurysm formation.[81] Patients diagnosed
with thoracic aneurysms should be screened for abdominal and iliac
aneurysms that may be asymptomatic until they rupture.[20] Permanent
pacemaker placement is indicated for complete heart block.[23]

All patients undergoing surgery should have preoperative pulmonary
function tests and, if abnormal, CT of the chest to screen for airway
involvement. A small endotracheal tube placed over a bronchoscope may
limit traumatic intubation or respiratory decompensation. Continuous
positive airway pressure can be administered if necessary. Whenever
the procedure allows, intubation should be avoided, using local or
regional anesthesia.[82]

Prognostic Factors

Airway involvement, infection, and cardiovascular complications
including vasculitis are the leading causes of death in relapsing
polychondritis.[3] Factors that negatively impact survival at the time
of diagnosis include old age, anemia, and laryngotracheal stricture.
Saddle nose deformity, arthritis, vasculitis, and anemia may be more
important variables among patients younger than 50 years of age.[3]
The 10-year survival rate reported in one series from 1986 was 55%,
whereas in 1998, another series found that 94% of patients were alive
after 8 years.[3,4]

Conclusion

Relapsing polychondritis is a rare autoimmune disorder diagnosed on
the basis of its clinical features. Awareness of the possible
manifestations, complications, and expansion of the treatment options
will hopefully continue to improve the prognosis and quality of life
for affected patients.

Reprint Address

Correspondence to Harvinder S. Luthra, MD, Division of Rheumatology,
Department of Internal Medicine, Mayo Clinic, 200 1st Street SW,
Rochester, MN 59905, USA Tel: 507 284 3389; fax: 507 284 0564; e-mail:
luthra@mayo.edu
Abbreviation Notes

HLA, human leukocyte antigen

Curr Opin Rheumatol 16(1):56-61, 2004. © 2004 Lippincott Williams &
Wilkins

http://www.medscape.com/viewarticle/467034?mpid=25517