Chapter 159. Relapsing Polychondritis

The incidence of RP has been estimated to be 3.5/million in Rochester, Minnesota.1 The peak age for disease onset is the fifth decade; however, development of the disease may occur in young children and in the elderly.2 The male to female ratio has been estimated from 1.1 to 1.3.3 Although most cases have been reported in Caucasians, there is no evidence supporting the role of ethnic or geographical factors.

Several lines of evidence have been accumulated that suggest the role of autoimmunity in RP. More than 30% of patients have an associated disease, mainly of autoimmune origin.

The role of the humoral immune response was based on the presence of antibodies to collagen type II in the acute phase of RP. Antibody titers seemed to correlate with the severity of symptoms. Other antibodies were secondarily detected in patients with RP: antibodies to collagen type IX and type XI, minor collagens which represent 5–10% of cartilage collagens, antibodies to matrilin-1, an extracellular matrix protein, predominantly expressed in upper respiratory tract cartilage, and antibodies to cartilage oligomeric matrix protein, other cartilage proteins expressed in auricular, tracheal and nasal cartilage. Several animal models have been published in which immunization with these various cartilage proteins induced a variety of chondritis manifestations that mimic those seen in patients.4 A role for immune complexes and subsequent activation of the complement system is suggested by examination of tissue lesions that usually show the presence of granular deposits of immunglobulins and the C3 component of complement associated with CD4+ lymphocytes and plasma cells. The influence of T cells in RP pathogenesis, although less investigated, has also been demonstrated in patients and in animal models with specificity against the same cartilage proteins. T-cell clones isolated from an RP patient were found to be specific for a peptide corresponding to residues 261–273 of the type II collagen and were restricted to either the DRBI*0101 or the DRBI*0401 allele.5 A significant near two fold increase in DR4 antigen frequency was found in RP patients as compared to that in healthy controls, but the genotyping of DR-4 positive patients and controls did not show a predominance of any DR4 subtype. Genetic susceptibility was also confirmed by animal models.6

Disease onset is usually sudden with characteristic chondritis, and/or less frequently arthritis or ocular inflammation. Nonspecific initial symptoms such as fever or weight loss are rare.

Attacks of chondritis usually occur in a relapsing and remitting pattern. Inflammatory episodes generally last a few days or weeks and may subside spontaneously or after treatment is initiated; recurrences after weeks or months occur and result subsequently in cartilage destruction. Auricular chondritis is the most frequent (85%), causing pain, redness, and swelling of the cartilaginous portion of the pinna, sparing the noncartilaginous lobe (Fig. 159-1). Biopsy of the auricular cartilage is not usually necessary to make a diagnosis. The histology shows perichondrial inflammation and the loss of the normal cartilaginous basophilia. After several attacks, the pinna may become soft and floppy with a cauliflower appearance (Fig. 159-2); sometimes it is stiff due to calcifications. Nasal chondritis (65%) is less inflammatory, presenting with nasal pain, stuffiness, rhinorrhea, and sometimes epistaxis. The characteristic saddle-nose deformity (Fig. 159-3) may appear secondarily or without previous inflammatory episodes. Respiratory tract chondritis, though uncommon at presentation, occurs in up to 50% of patients, and may be lethal. This results in complaints of hoarseness, nonproductive persistent cough, dyspnea, wheezing. Complications include upper airway collapse, obstructive respiratory insufficiency and secondary infections. Costochondritis (35%) induces parietal pains, which may also compromise respiration.

Joint pain is a common presenting feature (30%). Large and small joints of the peripheral or axial skeleton may all be affected (>70%). Arthritis is intermittent, migratory, asymmetric, seronegative, and usually nonerosive.

Nearly 60% of patients develop ocular inflammation. Episcleritis and scleritis (see eFig. 159-3.1) are the most common manifestations, followed by keratoconjunctivitis sicca, iritis, retinopathy, keratitis. Rarely corneal perforation, retinal vasculitis, and optic neuritis lead to blindness.

Conductive hearing loss is secondary to stenosis of the external auditory canal, Eustachian tube chondritis or serous otitis media while perception hearing loss may occur as a consequence of sensorineural involvement. Symptoms of vestibular dysfunction such as dizziness, ataxia, nausea, and vomiting are usually acute and improve with time.

The spectrum of cardiovascular manifestations is wide including different cardiac tissues (aortic and/or mitral regurgitation, impairment of the conduction system, pericarditis) and all types of vessels (thoracic and abdominal aortitis leading to aneurysms, Takayasu-like aortic arch syndrome, medium and large vessels vasculitis, leukocytoclastic vasculitis, thrombophlebitis). Lesions are inflammatory and/or thrombotic. Some but not all thrombotic manifestations have been linked to antiphospholipid syndrome. Large vessel vasculitis tends to occur after several years of smoldering and often occult disease, despite immunosuppressive therapy.

Dermatologic manifestations are sometimes the presenting feature of RP (12%), and become apparent in more than one-third of patients of a large series.7 They are nonspecific including nodules on the limbs (see eFig. 159-3.2), annular eruptions, purpura (see eFig. 159-3.3), oral or complex aphthosis (see eFig. 159-3.4), papules, sterile pustules (see eFig. 159-3.5), superficial phlebitis, livedo reticularis, ulcerations on the limbs, distal necrosis (see eFig. 159-3.6). They appear concomitantly or independent of attacks of chondritis. Pathological features include inflammatory or thrombotic vascular lesions, neutrophil infiltrates as in neutrophilic dermatoses, and inflammation of the dermis or subcutis. Patients with and without dermatologic manifestations have similar clinical manifestations of RP. However, the frequency of dermatologic manifestations (>90%), age at first chondritis and male/female ratio seems higher when RP is associated with myelodysplasia7; so, their presence in an old man warrants repeated blood counts to detect a smoldering myelodysplasia.

Laboratory findings in RP are nonspecific, consistent with acute or chronic inflammation. Urinalysis may be abnormal in the presence of renal involvement (mesangial expansion, IgA nephropathy, tubulointerstitial nephritis, or necrotizing glomerulonephritis).

Pulmonary function tests, including inspiratory and expiratory flow volume curves, should be performed systematically to detect occult pulmonary involvement, which may be confirmed by computed tomography of the respiratory tract. Three-dimensional or spiral magnetic resonance imaging may provide better resolution. Although not routinely available, autoantibodies to collagen type II, IX, XI and to matrilin I can be found in patients with RP. Urinary type II collagen neoepitope measurement may be a useful tool to follow evolution of disease.8

(Box 159-1)

(Box 159-2)

The clinical course of RP is progressive with intermittent flares. The number of different organ manifestations, their severity, and the response to treatment are unpredictable. Common causes of death are respiratory or cardiovascular complications and secondary infections. Patients have an increased risk of developing lethal myelodysplastic malignancies.

Because of the highly variable course of relapsing polychondritis, individualized therapy is the key to optimum management. General therapeutic guidelines are based on retrospective analyses of series of patients or isolated case reports. Nonsteroidal anti-inflammatory drugs, colchicine or dapsone may be useful for patients with mild auricular or nasal chondritis, arthralgia or mild arthritis. More serious manifestations require oral corticosteroids in a dose of 0.3–1 mg/kg of body weight according to severity. Pulse intravenous steroids are prescribed for acute airway obstruction, sudden hearing loss and/or before surgical intervention (tracheostomy, aortic aneurysm repair, cardiac valve replacement). Long-term corticosteroids decrease the frequency and severity of recurrences although it has no preventive effect of vital organ involvement. Many kinds of immunosuppressants have been used with some success as disease-modifying and steroid-sparing agents. Methotrexate, azathioprine, cyclophosphamide, and cyclosporine A are the more commonly used. The beneficial effects of new biological therapies such as antitumor necrosis factor agents, anti-interleukin-1 or -6 receptor, and of autologous stem cell transplantation have been reported in isolated cases.