eMedicine Specialties > Rheumatology > Vasculitis

Polychondritis

Nicholas Compton, MD, Staff Physician, Department of Medicine, Division of Dermatology, University of Washington Medical Center
Jane H Buckner, MD, Clinical Assistant Professor of Immunology, University of Washington; Director of Translation Research Program, Associate Member, Department of Immunology/Rheumatology, Benaroya Research Institute at Virginia Mason Research Center; Karin I Harp, MD, Consulting Staff, Department of Dermatology, Everett Clinic; Gregory J Raugi, MD, PhD, Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle

Updated: Jun 11, 2009

Introduction

Background

Relapsing polychondritis (RP) is a severe, episodic, and progressive inflammatory condition involving cartilaginous structures, predominantly those of the ears, nose, and laryngotracheobronchial tree. Other affected structures may include the eyes, cardiovascular system, peripheral joints, skin, middle and inner ear, and CNS. In 1923, Jaksch-Wartenhorst described a patient who experienced an 18-month course of progressive degeneration of the peripheral joints, external ears, nasal septum, external auditory canals, inner ear, and epiglottis. He termed this condition polychondropathia.¹

In 1960, Pearson, Kline, and Newcomer reviewed 12 cases and expanded the clinical spectrum of relapsing polychondritis to include nonconcurring inflammation of the auricles, nasal septum, peripheral joints, and larynx, with occasional involvement of the middle and inner ears, the eyes, costal cartilages, spine, trachea, bronchi, and epiglottis. They noted that, after a few episodes of inflammation, the cartilage was replaced by fibrous connective tissue. The term relapsing polychondritis was introduced in that review.²

Pathophysiology

The etiology of this rare disease is unknown; however, the pathogenesis is autoimmune. The evidence for an autoimmune etiology includes pathological findings of infiltrating T cells, the presence of antigen-antibody complexes in affected cartilage, cellular and humoral responses against collagen type II and other collagen antigens, and the observation that immunosuppressive regimens most often suppress the disease.

Humoral response

The specificity of autoimmune injury to cartilaginous tissues has led investigators to test the hypothesis that a cartilage-specific autoantibody is central to the pathogenesis of relapsing polychondritis. Various studies find circulating antibodies to cartilage-specific collagen types II, IX, and XI to be present in 30%-70% of patients with relapsing polychondritis. Researchers have found that antibodies to type II collagen are present during acute relapsing polychondritis episodes and that the levels correlate with the severity of the episode.³

Treatment with prednisone is associated with a decrease in antibody titers. Antibodies to collagen types I, II, and III are believed to result from cartilage destruction; it has been proposed that antibodies are formed as a primary event in relapsing polychondritis.³ However, anticollagen type II antibodies are not specific to relapsing polychondritis; they have been identified in other arthritides such as rheumatoid arthritis (RA). The epitope specificity of the antibodies in relapsing polychondritis differs from those in RA, suggesting different mechanisms for formation and pathophysiologic roles.

Autoantibodies to minor cartilage-specific collagens (ie, types IX and XI) have been described. They are more likely to be found in association with antibodies to type II collagen in patients with relapsing polychondritis. Furthermore, levels of antibodies to matrilin 1, an extracellular matrix protein predominantly expressed in tracheal cartilage, were significantly higher in patients with relapsing polychondritis, especially in those with respiratory symptoms, than in patients with Wegener granulomatosis, systemic lupus erythematosus, or RA and in healthy controls.⁴

Most patients with relapsing polychondritis had high titers of antifetal cartilage antibodies during the early acute phase. The antifetal cartilage antibodies were found in 6 of 9 patients and only 4 (1.5%) of 260 patients with RA, exclusively in long-standing disease.⁵ A report of relapsing polychondritis in the newborn of a mother with relapsing polychondritis suggests that antibodies crossing the placenta are necessary and sufficient to elicit the entire clinical syndrome.

Using proteomic surveillance to identify ubiquitous cellular proteins in patients with relapsing polychondritis, researchers identified 5 proteins that may be autoantigens. These include (1) tubulin-alpha ubiquitous/6, which, as a family, are main components in microtubules; (2) vimentin, an intermediate filament protein; (3) alpha-enolase; (4) calreticulin, a Ca²⁺ –binding chaperon indispensable for cardiac development; and (5) colligin-1/2. All but tubulin-alpha have been described as autoantigens in other autoimmune diseases (eg, RA, mixed connective-tissue disease, Behçet disease). Although autoantibodies to tubulin-alpha have been reported in other autoimmune conditions, immunoglobulin G (IgG) antibodies to tubulin-alpha chains are rarely reported and may have diagnostic value in persons with relapsing polychondritis.⁶

Cellular response

Although an inflammatory infiltrate of lymphocytes and neutrophils is the dominant histopathologic feature of relapsing polychondritis, little attention has been paid to the possible role of cellular immune responses in this condition. The association of relapsing polychondritis with HLA-DR4 also suggests an autoimmune pathogenesis. Individuals with HLA-DR4 were found to have a relative risk of 2 for developing relapsing polychondritis. The studies suggest the role of genetic factors in determining risk for developing relapsing polychondritis.

An elegant double-transgenic mouse model provides further evidence that HLA associations are important in the development of relapsing polychondritis. The model demonstrated that more than one HLA class II molecule might be required for expression of susceptibility. The model suggests an important role for cell-mediated immune responses and provides a means for acquiring a detailed understanding of its pathogenesis.

Natural killer T (NKT) cells, lymphocytes discrete from other T, B, and natural killer cells, come in two varieties: CD4⁺ and CD4^-/CD8^-. Antigen-presenting cells present antigen to the NKT cells via the major histocompatibility complex–like molecule CD1d. NKT cells are decreased in number and function in several other autoimmune diseases, including multiple sclerosis, RA, systemic lupus erythematosus, systemic sclerosis, and type 1 diabetes mellitus.

Researchers have quantified CD4^-/CD8^- and CD4⁺ V-alpha⁺ V-beta11⁺ NKT cells and found them decreased in patients with active or quiescent relapsing polychondritis compared with healthy controls. Analysis of the secreted cytokine profile and of binding of alpha-galactosylceramide–loaded CD1d to NKT cells suggests that CD4⁺ NKT cells play an important role in T1-helper responsiveness in patients with relapsing polychondritis.⁷

Serum levels of 17 cytokines from 22 patients with relapsing polychondritis experiencing a clinical flare were compared with those in age-matched controls. Three of the cytokines, interleukin 8, macrophage inflammatory protein 1-alpha, and monocyte chemoattractant protein-1, were found to be significantly elevated in patients with relapsing polychondritis. All 3 chemokines are proinflammatory and result in accumulation and activation of neutrophils, eosinophils, and monocytes/macrophages.⁸

Additionally, a group of researchers found T cells directed against collagen type II in one patient. A T-cell clone was identified and was found to be specific for a certain region of the collagen type II peptide. This research indicates that a T-cell response to collagen type II may play a role.⁹

Animal models

Mouse and rat models have been helpful in elucidating the autoimmune origin of relapsing polychondritis. Immunization of rats with native bovine type II collagen resulted in bilateral auricular chondritis, with histologic findings similar to the findings of human relapsing polychondritis in 12 of 88 (14%) rats. In addition, 8 of 12 rats developed arthritis. Severe auricular chondritis was accompanied by immunofluorescence positive for IgG and C3 in affected cartilage and by circulating IgG that was reactive against native bovine type II collagen.

Immunization of a different strain of rats with native chick type II collagen was associated with auricular chondritis, in addition to the intended collagen-induced arthritis. Biopsy studies showed that the few auricular lesions contained IgG and C3. Antibodies to native type II collagen were found in the sera of rats that developed auricular chondritis and in rats with collagen-induced arthritis.¹⁰

Although most data implicate cartilage collagens as the immunogens in relapsing polychondritis, immunization of rats with matrilin 1, a noncollagenous cartilage matrix protein, is associated with development of a clinical syndrome resembling relapsing polychondritis. The syndrome differed significantly from the collagen immunization disease model in that the trachea, nasal cartilages, and kidneys primarily were affected, and the joints and auricles were spared. Matrilin 1 is found in highest levels in the tracheal cartilage and in the nasal septum, likely explaining the observed clinical differences. Matrilin 1 is also found in adult auricular cartilage and costochondral cartilage and is absent in articular cartilage. The presence of both humoral and cellular responses to matrilin 1 has been detected in a patient with significant involvement of the auricular, nasal, and tracheobronchial cartilage and with little arthritis.¹¹

The same investigators demonstrated a crucial role for B cells and C5 in the induction of relapsing polychondritis–like symptoms. Additionally, pathogenicity of matrilin 1–specific antibodies in their matrilin 1–induced relapsing polychondritis mouse model was recently recognized. The authors note that further investigation is needed into the role of B cells, complement, and cell-mediated immunity to better understand this complex disease.¹¹

Recently, transgenic mice that expressed HLA-DQ6a8b developed spontaneous polychondritis in middle age. This condition is characterized by auricular and nasal chondritis with polyarthritis. As opposed to mice with collagen type II–induced polychondritis, mice with spontaneous polychondritis do not show the overwhelming collagen type II immune response and may serve as a better animal model of relapsing polychondritis.¹²

Other autoimmune disorders

The hypothesis of an autoimmune etiology for relapsing polychondritis is also supported by the high prevalence of other autoimmune disorders found in patients with relapsing polychondritis. McAdam et al reported that 25%-35% of patients with relapsing polychondritis had a concurrent autoimmune disease.¹³

Autoimmune Conditions Reported in Patients With Relapsing Polychondritis

*Individual patients may carry more than one autoimmune diagnosis.
†Reported as 13 (20%) of 66 prevalence by Trentham and Le without division by disease

In addition, several reports have linked relapsing polychondritis with internal malignancy. It is thought to be paraneoplastic in these cases. The underlying malignancy is most often hematological in nature, but solid tumors have also been described.²⁰

Frequency

United States

In clinical reports and reviews, relapsing polychondritis is reported to be a rare disease. By 1997, 600 cases had been reported worldwide. The annual incidence in Rochester, Minnesota, was noted to be 3.5 cases per million population.

International

The international incidence of relapsing polychondritis is unknown.

Mortality/Morbidity

In earlier studies, the 5-year survival rate associated with relapsing polychondritis was reported to be 66%-74% (45% if relapsing polychondritis occurs with systemic vasculitis), with a 10-year survival rate of 55%. More recently, a survival rate of 94% at 8 years has been reported.¹⁶ However, these data may represent relapsing polychondritis in patients with less severe disease than patients studied in earlier reports.

• The most frequent causes of death associated with relapsing polychondritis include infection secondary to corticosteroid treatment or respiratory compromise (10%-50% of deaths result from airway complications), systemic vasculitis, and malignancy unrelated to relapsing polychondritis.
• Although the life expectancy in all patients with relapsing polychondritis is decreased compared with age- and sex-matched healthy individuals, patients with renal involvement have a significantly lower age-adjusted life expectancy. Of those with renal disease, uremia is the third most frequent cause of death.
• Complications of relapsing polychondritis such as saddle-nose deformity (see Media File 9), systemic vasculitis, laryngotracheobronchial stricture, arthritis, and anemia in patients younger than 51 years portend a poorer prognosis than in age-matched patients with relapsing polychondritis without complications. Among patients older than 51 years, only anemia is associated with a poorer prognosis. Renal involvement is a poor prognostic factor at all ages.
  
  

  

  Saddle-nose deformity. Courtesy of the University of Washington, Division of Dermatology.

  
  
• Complications of relapsing polychondritis include vertigo, tinnitus, voice hoarseness, joint deformity, epiglottitis, scleritis, conjunctivitis, iritis, need for permanent tracheotomy (severe cases), severe pulmonary infection, blindness, frail chest wall, respiratory failure, aortic regurgitation, mitral regurgitation, aortic dissection, and glomerulonephritis-associated renal failure.

Race

Relapsing polychondritis is most common in whites. Although relapsing polychondritis has been found in persons of all races, little data are available for nonwhite persons.

Sex

Reviews from the 1970s and 1980s found that relapsing polychondritis has no sexual predilection. However, reviews in 1998 and 2002 suggested a slight female predominance.^21,16 Saddle-nose deformity and subglottic stricture are more common in females.

Age

Relapsing polychondritis may occur at any age; however, the disease usually has an onset during the fifth decade of life. No relationship exists between age of onset and sex.

Clinical

History

The array of possible presenting symptoms and the episodic nature of relapsing polychondritis (RP) may result in a significant delay in diagnosis. In a review of 66 patients, the elapsed time from patient presentation for medical care for a related symptom to diagnosis was reported to be 2.9 years.¹⁶ In fact, one third of patients with diagnosed relapsing polychondritis see 5 or more physicians before the correct diagnosis is made.

The affected systems and symptoms reported in patients with relapsing polychondritis before and after diagnosis include the following:

• General - Intermittent fever, weight loss, and skin rash (see Physical)
• Audiovestibular - Sudden ear pain (unilateral or bilateral), inability to sleep on affected side, floppy ear, suddenly diminished hearing, tinnitus (occasional or persistent), otitis media, ear drainage, vertigo (with or without nausea and vomiting), and unsteadiness
  
  

  

  Floppy ear. Courtesy of the University of Washington, Division of Dermatology.

  
  
• Musculoskeletal - Polyarthritis or monoarthritis, myalgias, back pain, rib pain, sternal pain, calf pain or claudication, and migratory or generalized arthralgias
• Respiratory - Dyspnea, wheezing, cough, exercise intolerance, hoarseness, and recurrent infection
• Gastrointestinal - Dysphagia
• Nasal - Feeling of fullness across nasal bridge, saddle-shaped nose, mild epistaxis, and painful, red, and swollen nose
• Ocular - Decreased visual acuity, conjunctivitis, episcleritis, scleritis, history of ocular inflammation, diplopia, and eyelid swelling
• Cardiovascular - Chest pain, abdominal pain, history of pericarditis, abnormal heart rate or rhythm, syncope, and history of subacute myocardial infarction (found on ECG)
• Central nervous system - Headache, ataxia, confusion, cranial nerve palsy, confusion, psychiatric signs, focal weakness/sensation changes, dementia, and seizures

Physical

McAdam et al criteria (3 of 6 clinical features necessary for diagnosis)

• Bilateral auricular chondritis
• Nonerosive seronegative inflammatory polyarthritis
• Nasal chondritis
• Ocular inflammation
• Respiratory tract chondritis
• Audiovestibular damage

Damiani and Levine criteria (1 of 3 conditions necessary for diagnosis)

• Three McAdam et al criteria
• One McAdam et al criterion plus positive histology results
• Two McAdam et al criteria plus therapeutic response to corticosteroid or dapsone therapy

Michet et al criteria (1 of 2 conditions necessary for diagnosis)

• Proven inflammation in 2 of 3 of the auricular, nasal, or laryngotracheal cartilages
• Proven inflammation in 1 of 3 of the auricular, nasal, or laryngotracheal cartilages plus 2 other signs including ocular inflammation, vestibular dysfunction, seronegative inflammatory arthritis, and hearing loss

Signs and symptoms of relapsing polychondritis include the following:

• Auricular chondritis
  • Of patients with relapsing polychondritis, 85%-95% develop auricular chondritis.
  • Unilateral or bilateral auricular pain, swelling, and redness develop suddenly but spare the lobules.
    
    

    

    Auricular edema and erythema sparing the lobule. Courtesy of Gregory J. Raugi, MD, PhD.

    
    
  • The pain and redness usually resolve within 2-4 weeks but may recur.
  • The ear cartilage softens and collapses forward. The external auditory canal can collapse after 1 or more episodes.
    
    

    

    Forward listing ear. Courtesy of the University of Washington, Division of Dermatology.

    
    
    
    

    

    Bilateral inflammation and structural collapse of the auricles in a patient found to have aortic dissection. Courtesy of the University of Washington, Division of Dermatology.

    
    
  • Nodularity of the auricle may develop.
  • Calcification occurs in 40% of patients.
• Nonerosive seronegative inflammatory polyarthritis
  • A seronegative nonnodular arthritis develops in 52%-85% of patients. The acute onset of an inflamed joint may mimic a crystal arthropathy.
  • Most commonly, the arthritis is asymmetric, oligoarticular or polyarticular, nondeforming, and nonerosive. One case of arthritis mutilans has been reported.²²
  • The ankles, elbow, wrists, proximal interphalangeal joints, metacarpophalangeal joints, and metatarsophalangeal joints are often involved, although any joint may be affected.
  • The costochondral, sternoclavicular, and sternomanubrial joints may be involved.
  • The forefeet are usually spared.
  • Effusions may accompany arthritis and may be noninflammatory or mildly inflammatory.
• Nasal chondritis
  • Nasal chondritis occurs in 48%-72% of patients with relapsing polychondritis.
  • The nasal chondritis is acute and painful and accompanied by a feeling of fullness over the nasal bridge.
  • Mild epistaxis may be present.
  • A saddle-nose deformity may develop in longstanding disease (Media File 9).
    
    

    

    Saddle-nose deformity. Courtesy of the University of Washington, Division of Dermatology.

    
    
• Ocular inflammation
  • Collagen types II, IX, and XI are found in the cornea and sclera. Autoantibodies to these collagens, which are found in patients with relapsing polychondritis, may be responsible for direct harm to the eyes.
  • Of patients with relapsing polychondritis, 50%-65% develop ocular sequelae related to episodic inflammation of the uveal tract, conjunctivae, sclerae, and/or corneas.
  • The most common conditions are episcleritis (39%) and scleritis (14%).
    
    

    

    Unilateral episcleritis. Courtesy of Gregory J. Raugi, MD, PhD.

    
    
  • Eyelid edema, iritis, and retinopathy are found in 9% of patients, and 5% of patients have ocular muscle paresis or optic neuritis.
  • Peripheral ulcerative keratitis is found in 4% of patients and has been associated with perforation, endophthalmitis, and bilateral enucleation.
  • Papilledema, visual field defects, ptosis, lid retraction, proptosis, and cataracts may also be found on examination.
• Respiratory tract chondritis
  • Respiratory tract involvement affects 40%-56% of patients with relapsing polychondritis and may involve any portion of the respiratory tree, including the distal bronchi.
  • Tenderness to palpation may occur over the anterior trachea or thyroid cartilage.
  • Chondritis weakens the tracheal cartilage rings, resulting in wheezing, dyspnea, cough, and hoarseness.
  • The upper airways can eventually become stenosed and are replaced by collapsible fibrotic tissue. Airways superior to the thoracic inlet collapse upon inspiration, and airways below the thoracic inlet collapse upon expiration; therefore, both inspiratory stridor and expiratory wheezing may be noted on auscultation.
  • Inflammation and swelling of the glottis, larynx, and subglottic tissues may require tracheostomy.
  • Acute inflammation of the distal airways can lead to obstruction and recurrent pneumonia.
• Audiovestibular damage
  • Audiovestibular derangements are experienced by 46%-50% of patients, usually those with concomitant auricular chondritis.
  • Sudden loss of hearing is usually permanent, while tinnitus, nausea, vomiting, nystagmus, and vertigo may subside. In some patients, hearing loss is attributed to vasculitic damage to the eighth cranial nerve.
• Cardiovascular disease
  • Relapsing polychondritis has been reported to affect the cardiovascular system in 24% of patients.
  • Aortic and mitral valve regurgitation, aortic aneurysm, aortitis, aortic thrombosis, pericarditis, first- to third-degree heart block, and myocardial infarction, at times mediated through ostial stenosis of a coronary artery or arteries, have been reported.
  • Relapsing polychondritis aortitis exhibits inflammation in the media, resulting in loss of glycosaminoglycans and elastic tissue.
    • Any region of the aorta and more than one region simultaneously may be affected. In descending order of frequency, they include the ascending aorta, aortic ring, descending thoracic portion, and abdominal aorta, potentially existing silently rupture and death.
    • The most common clinical presentations include aortic arch syndrome, abdominal aortic aneurysm, and aortic regurgitation.
    • The clinical presentation of aortic regurgitation (resulting from ascending aorta involvement) may include left ventricular failure. Aortic regurgitation may result from damage to the aortic cusps or from annular dilatation due to destruction of supporting tissues.
• Skin disease
  • Skin lesions are found in 17%-39% of patients with relapsing polychondritis.
  • Specific lesions are limited to erythema and edema overlying the inflamed cartilaginous structures.
    
    

    

    Severe auricular edema and inflammation. Courtesy of the University of Washington, Division of Dermatology.

    
    
  • Various nonspecific skin lesions have been reported.
    • Aphthous ulcers are the most common.
    • Limb nodules, purpura, papules, sterile pustules, superficial phlebitis, livedo reticularis, limb ulceration, and distal necrosis have been reported.
    • Rarer findings include Sweet syndrome, urticarial vasculitis, and Kaposi sarcoma.
    • Some findings likely represent the skin manifestations of the many conditions associated with relapsing polychondritis rather than specific manifestations of relapsing polychondritis itself.
  • Cutaneous vasculitis: The prevalence of biopsy-proven cutaneous (small vessel) leukocytoclastic vasculitis is approximately 10%, while the prevalence of systemic (including skin) medium-to-large vessel vasculitis ranges from 11%-56%. It may appear as in its typical form of palpable purpura or as hemorrhagic bullae, typically on the lower extremities or other dependent areas.
  • Erythema elevatum diutinum: This has been described in 2 patients with relapsing polychondritis.^23,24
  • Cutaneous polyarteritis nodosa: A patient with relapsing polychondritis presented with relapsing painful red nodules from 1-3 cm in size, occurring on the entire skin and accompanied by arthralgias and myalgias.
  • Other cutaneous lesions reported in patients with relapsing polychondritis and vasculitis included the following:
    • Palpable purpura
    • Acute febrile neutrophilic dermatosis (Sweet syndrome)
    • Subcutaneous inflammatory nodules resembling erythema nodosum
    • Localized ulcerating neutrophilic conditions resembling pustules, furuncles, abscesses, and ulcerating abscesses
  • Panniculitis: This is characterized by 5- to 10-cm tender erythematous nodules showing septal and lobular inflammation.²⁵
  • Other skin conditions: Isolated case reports of other cutaneous manifestations of relapsing polychondritis include the following:
    • Hyperpigmentation
    • Pustular psoriasis
    • Macular purpura of the palms, soles, lower limbs, and buttocks
    • Erythematous papular plaques of the face, upper and lower extremities, and thorax
    • Alopecia universalis
    • Actinic granulomas
    • Urticaria
    • Angioedema
    • Livedo reticularis
    • Erythema multiforme
  • Mouth and genital ulcers with inflamed cartilage (MAGIC syndrome): MAGIC syndrome is characterized by an overlap of relapsing polychondritis with Behçet disease. Firestein et al proposed this condition in 1985 in a report of 5 patients.²⁶ The two types of MAGIC syndrome are as follows:²⁷
    • The more common type begins with the oral and genital ulcers of Behçet disease.
    • The second, less common, type is the polychondritis type, in which genital ulcers or erythema nodosum follows the initial presentation of oral ulcers and polychondritis.
• Central nervous system
  • CNS manifestations of relapsing polychondritis are rare and can vary.
  • It is believed that vasculitis of the small and/or medium sized arteries is the underlying etiology.²⁸ Neurologic symptoms may present before other more frequent manifestations of relapsing polychondritis.
  • Patients may present with seizures, memory loss, delusions, limb weakness, paresthesias or gait disturbances, or other cerebellar symptoms.
  • Cranial nerve damage is common in relapsing polychondritis-associated CNS vasculitis and most often affects the second cranial nerve, followed less commonly by the sixth, seventh, and eighth cranial nerves.
  • Limbic encephalitis has been reported associated with relapsing polychondritis.^29,30
  • Aseptic meningitis has been reported infrequently in relapsing polychondritis.³¹
  • Clinical neurologic assessment is an important aspect of the physical examination of patients with relapsing polychondritis.
• Renal
  • From 1943-1980, 129 patients with relapsing polychondritis were seen at the Mayo Clinic, of whom 29 (22%) had evidence of glomerulonephritis based on a diagnostic renal biopsy or the presence of microhematuria and proteinuria.³²
  • Patients with renal damage are older and more likely to have extrarenal vasculitis and arthritis.
  • A proposed mechanism in the pathogenesis of renal involvement in relapsing polychondritis derives from the deposition of immune complexes leading to glomerular damage.³²
  • Pathological biopsy findings include segmental necrotizing glomerulonephritis with or without crescents, interstitial lymphocytic infiltrates, interstitial fibrosis, active tubulitis, and glomerulosclerosis.
  • The response to treatment varies from stabilization of renal function to renal failure.
• Other conditions
  • Relapsing polychondritis has been seen in patients with underlying myelodysplastic syndrome and, less often, lymphoma. These cases may be paraneoplastic in nature.
  • Acute mastitis may be found in relapsing polychondritis.¹⁹
  • Thromboembolism has been reported.

Causes

The cause of relapsing polychondritis is not known. Familial clustering has not been observed. Susceptibility for developing relapsing polychondritis is increased slightly by the HLA-DR4 haplotype.

Three intriguing case reports suggest that hormonal influences may be important in relapsing polychondritis. Two men have developed relapsing polychondritis after receiving injections of luteinizing hormone-releasing hormone, and a woman with arthritis mutilans had a sudden exacerbation of her condition and new onset of atrophy of the auricular cartilage, nasal septum, weight loss, and deafness after receiving an injection of chorionic gonadotropin.³³

Differential Diagnoses

Other Problems to Be Considered

Rheumatoid arthritis
Polyarteritis nodosa
Cogan syndrome
Infectious perichondritis
MAGIC syndrome (relapsing polychondritis [RP] plus Behçet disease)
Trauma (especially in boxers and wrestlers)
Congenital syphilis
Chronic external otitis
Auricular calcification (secondary to other conditions, eg, trauma, Addison disease, diabetes, hyperthyroidism)

Auricular chondritis

Infectious perichondritis (commonly due to Pseudomonas aeruginosa infection); also, fungal infection, tuberculosis, syphilis, and leprosy
Chronic external otitis
Trauma
Frostbite
Calcification of the pinna resulting from Addison disease, ochronosis, acromegaly, essential hypertension, diabetes mellitus, and familial cold hypersensitivity
Complication of mastoid surgery
Benign nodular deformity, ie, chondrodermatitis nodularis chronica helicis

Inflammatory arthritis

Rheumatoid arthritis (adult or juvenile)
Reactive arthritis
Acute gonococcal arthropathy
Rheumatic fever
Wegener granulomatosis
Polyarteritis nodosa
Systemic lupus erythematosus and other collagen-vascular disorders

Nasal chondritis/saddle-nose deformity

Infectious perichondritis
Wegener granulomatosis
Congenital syphilis
Nasal NK/peripheral T-cell lymphoma (formerly known as angiocentric lymphoma)

Ocular inflammation

Reactive arthritis (ie, conjunctivitis plus arthritis plus urethritis)
Rheumatoid arthritis, Behçet disease, enteropathic arthritis, or Still disease (ie, iritis or chorioretinitis plus arthritis)
Polyarteritis nodosa or Wegener granulomatosis (ie, scleritis or episcleritis plus arthritis)
Sjögren syndrome (ie, keratoconjunctivitis sicca plus arthritis)
Cogan syndrome (ie, intersitial keratitis plus cochlear and vestibular damage)
Arteriosclerosis, syphilis, collagen vascular disease, herpes zoster, sickle cell disease, migraine, coagulation disorders (ie, ischemic optic neuropathy)

Tracheal obstruction

Trauma (eg, strangulation)
Prolonged intubation
Sarcoidosis
Wegener granulomatosis
Endoluminal malignancy
Tuberculosis/sarcoidosis webs

Respiratory tree chondritis

Perichondritis of the larynx resulting from herpes, syphilis, erysipelas, tonsillitis, peritonsillar abscess, tuberculosis, measles, diphtheria, scarlet fever, avitaminosis, blastomycosis, actinomycosis, Wegener granulomatosis, xanthoma, typhus, Vincent infection, anthrax, or smallpox

CNS alterations

Septic meningitis (fungal, bacterial, mycobacterial)
Aseptic meningitis unrelated to relapsing polychondritis, ie, viral
Ménière disease
Temporal arteritis
Malignancy
Drug toxicity
Encephalitis or meningoencephalitis
Other causes of cerebral vasculitis
Other causes of seizure disorder
Leprosy

Aortitis

Erdheim cystic medial necrosis
Marfan syndrome
Syphilitic aortitis
Giant cell arteritis

Workup

Laboratory Studies

• No laboratory findings are specific for relapsing polychondritis (RP).
• Anemia, if present, is typically normochromic and normocytic and is associated with a poor prognosis.
• Nonspecific indicators of inflammation (eg, elevated erythrocyte sedimentation rate, elevated levels of C-reactive protein) are often present.
• Mild leukocytosis may be detected.
• Because relapsing polychondritis is associated with many multisystemic diseases, a laboratory evaluation commensurate with the spectrum of reported symptoms is indicated to ascertain the presence of complicating conditions.
• Use antinuclear antibody reflexive panel, rheumatoid factor, and antiphospholipid antibodies (if history of thrombosis is found) to evaluate for other autoimmune connective-tissue diseases.
• For a vasculitis workup, perform a CBC count with differential; metabolic panel; creatinine, liver transaminase, and serum alkaline phosphatase studies; urinalysis dipstick and microscopic evaluation of sediment; cryoglobulins; viral hepatitis panel; antinuclear antibody (ANA); and antineutrophil cytoplasmic antibody (ANCA) tests.
• Use the purified protein derivative test to evaluate for exposure to tuberculosis. (Tuberculosis is often overlooked as an infectious cause of perichondritis.)
• Use serologic tests for syphilis if it is suspected, including rapid plasma reagent or VDRL testing. Saddle-nose deformity is a clinical manifestation of congenital syphilis and can go undiagnosed into adulthood; however, it can also be a consequence of gumma formation in adulthood.
• Cultures may be indicated, depending on the clinical presentation.
  • Sputum cultures for bacteria and acid-fast bacilli may be needed in patients with respiratory symptoms.
  • Bacterial, acid-fast bacilli, and fungal cultures may be appropriate for cartilage biopsy samples, especially from the respiratory tree.
  • Blood cultures may be useful in the assessment of febrile episodes that are combined with nausea, vertigo, and/or muscle weakness.
  • Bacterial and viral cultures of the cerebrospinal fluid may be indicated to exclude meningitis or to help exclude aseptic meningitis or CNS vasculitis.

Imaging Studies

• Chest radiography (posteroanterior [PA] and lateral views)
  • Tracheal stenosis may be observed on plain radiographs.
    
    

    

    Tracheal stenosis on chest x-ray film. Courtesy of Julie E. Takasugi, MD.

    
    
  • Calcification of cartilaginous structures supports the diagnosis of relapsing polychondritis.
  • Coexisting systemic vasculitis may be suggested by the presence of pulmonary parenchymal infiltrates.
• Spiral CT scanning (without contrast)
  • Spiral CT scanning (without contrast), from the superior trachea to the lower lobe bronchi, is advised in patients with relapsing polychondritis and respiratory symptoms.
  • Spiral CT scanning is a noninvasive test that readily identifies tracheal and bronchial thickening, stenosis, and calcification. Smooth anterior and lateral wall thickening with sparing of the posterior wall of the trachea and mainstem bronchi is virtually pathognomonic for relapsing polychondritis.
  • High-resolution CT scanning can reveal air trapping and diffuse or focal thickening of the airways. Expiratory CT scanning can be used to evaluate for air trapping and malacia of the airways. A series of 18 patients with relapsing polychondritis and pulmonary symptoms revealed that 94% had airway malacia and air trapping on dynamic expiratory CT scans.³⁴ The authors suggest that this modality should be used in all patients with relapsing polychondritis to allow for early detection of airway compromise. However, they did not provide the duration of disease in the study population, nor did they correlate the findings with those of pulmonary function tests. The benefit of dynamic expiratory CT scanning is unproven but may provide more information in difficult cases.
  • CT scanning results correlate well with pulmonary function tests, identifying obstructive patterns. CT scanning is not only safer but is also more sensitive and specific than bronchoscopy.
• MRI
  • MRI has been a useful adjunct in the clinical diagnosis of relapsing polychondritis
  • MRI is better able to distinguish between edema, fibrosis, and inflammation than is CT scanning.
  • T1-weighted images, T2-weighted images, and T1-weighted images with gadolinium contrast provide characterization of relapsing polychondritis-related changes in cartilaginous tissues.
  • MRI also reveals thickening of the thoracic aorta before dilatation occurs.
  • MRI may be useful for monitoring the effects of treatment.
• Posteroanterior and lateral dye contrast pharyngotracheogram
  • PA and lateral dye contrast pharyngotracheogram may be helpful if tracheal narrowing or edema is suggested.
  • Both views are required to avoid underestimating the severity of stenosis or swelling.
• Scintigraphy
  • Scintigraphy may prove helpful for identifying potential sites for biopsy to aid the histologic diagnosis when the clinical diagnosis is in doubt (ie, because of unfulfilled diagnostic criteria).
  • Technetium Tc 99m methylene diphosphonate bone scintigraphy has been used in the evaluation of chest pain, allowing identification of possible sites for biopsy in costochondral tissues.
  • Gallium Ga 67 citrate scintigraphy has also been found to show increased uptake in affected areas.

Other Tests

• Pulmonary function testing with flow-volume loop studies
  • Pulmonary function testing (PFT) with flow-volume loops is strongly recommended in patients who present with respiratory symptoms, since PFT may assist in the differential diagnoses and provide information about severity of the disease. This may also be used to monitor patients' disease activity.
  • PFT in patients with relapsing polychondritis who have respiratory involvement demonstrates a nonreversible obstructive pattern with collapse and stenosis of the airways. The decrease in forced expiratory volume in 1 second correlates with the degree of dyspnea.
• Electrocardiography
  • Perform ECG to assess patients with relapsing polychondritis who demonstrate signs of vasculitis.
  • Also, perform ECG to monitor these patients, since they may incur silent ischemia if vasculitis has developed.
• Echocardiography: Echocardiogram may be needed to assess aortic root dilatation and degree of aortic regurgitation.

Procedures

• Intubation may be dangerous and futile.
• Tracheostomy is usually the best method for providing an airway in patients with relapsing polychondritis in acute respiratory distress (because of the high likelihood of tracheal or bronchial stenosis or edema).
• Biopsy of the cartilage is a potential source of infection and cosmetic damage. Perform biopsy on cartilage only if histopathological data are required to meet the diagnostic criteria for relapsing polychondritis.
• Biopsy of skin lesions (nonadjacent to cartilage) may provide useful adjunctive information.

Histologic Findings

Biopsy of cartilage in patients with relapsing polychondritis demonstrates chondrolysis, chondritis, and perichondritis. The cartilage loses its basophilia, probably by release of sulfated proteoglycans from the matrix, and the chondrocytes are decreased in number and may appear pyknotic. Early relapsing polychondritis is characterized by a mixed inflammatory infiltrate of lymphocytes, neutrophils, and plasma cells in the perichondrium. As the cartilage degenerates, mononuclear cells and macrophages infiltrate the matrix. The cartilage matrix is eventually destroyed and replaced by fibrous connective tissue. Despite the presence of clinical erythema, overlying skin is normal.

Distant lesions with the clinical appearance of vasculitis have histologic features consistent with the clinical syndrome, including leukocytoclastic or granulomatous vascular injury.

Treatment

Medical Care

No controlled trials of therapy for relapsing polychondritis (RP) have been published. The goal of treatment is to abate current symptoms and to preserve the integrity of cartilaginous structures.

• The mainstay of treatment is systemic corticosteroid therapy. Prednisone (20-60 mg/d) is administered in the acute phase and is tapered to 5-25 mg/d for maintenance. Severe flares may require 80-100 mg/d. Most patients require a low daily dose of prednisone for maintenance; however, intermittent administration of high doses during only flares of the condition is successful in rare cases. McAdam et al found that continuous prednisone decreased the severity, frequency, and duration of relapses.
  
  

  

  Same patient as in Image 5 after 4-6 weeks of steroid treatment. Note resolution of auricular inflammation with nodularity and forward listing of the ears. Courtesy of the University of Washington, Division of Dermatology.

  
  
  
  

  

  Close-up view of same patient as in Image 6. Forward flopping of ear with nodularity after steroid treatment. Courtesy of the University of Washington, Division of Dermatology.

  
  
• Other medications reported to control symptoms and, perhaps, progression of the disease, include dapsone (25-200 mg/d), azathioprine, methotrexate (MTX; 7.5-22.5 mg/wk), cyclophosphamide, and cyclosporin A. MTX has been administered beginning at 7.5 mg/wk, increasing up to 22.5 mg/wk in conjunction with steroid administration and has been found to significantly decrease corticosteroid requirements while controlling symptoms.
• Biologics: Case reports have described successful treatment with anti–tumor necrosis factor-alpha inhibitors infliximab, etanercept, and adalimumab. Anakinra, an interleukin 1 receptor antagonist; leflunomide, which inhibits pyrimidine synthesis; and rituximab, an anti-CD20 chimeric antibody, have also shown benefit.^35,36,37,38
• Oral administration of nonsteroidal anti-inflammatory drugs (NSAIDs) has not been effective.
• Medical care must include assessment for and treatment of other confounding or concurrent autoimmune disorders.

Surgical Care

Surgeries encountered in the care of patients with relapsing polychondritis may include tracheostomy, permanent tracheotomy placement, tracheal stent placement, aortic aneurysm repair, cardiac valve replacement, and saddle-nose deformity repair. The benefits of any proposed surgery must be weighed adequately against the patient's risk for infection, especially in the event of acute relapse, since patients are at an increased risk of infection whether or not they are using corticosteroids.

Additionally, patients with relapsing polychondritis and tracheal disease may be at particular risk regarding complications resulting from tracheal intubation and extubation.

Consultations

Relapsing polychondritis is a complex condition that requires a team approach for patient care.

• Dermatologists or specialists in infectious diseases are often involved early in the course of the disease to evaluate the patient for infectious causes of cellulitis or perichondritis.
• Rheumatologists usually become the primary care provider and should be involved early in patient care.
• Ophthalmologists should also be involved early to diagnose, monitor, and treat the potentially devastating ocular complications.
• Cardiologists, neurologists, nephrologists, and otolaryngologists may be asked to manage other aspects of relapsing polychondritis.
• Plastic surgeons can aid in nasal reconstruction if saddle-nose deformity is present.

Diet

No special recommendations have been noted.

Activity

No special recommendations have been noted.

Medication

Prednisone is the drug of choice for relapsing polychondritis (RP) and is used in acute flares and for long-term suppression of inflammation. Continuous treatment with prednisone decreases severity, duration, and frequency of relapses. In patients who require higher maintenance doses of prednisone, MTX is often administered as an adjuvant treatment. MTX is used with prednisone to reduce the overall steroid requirement for disease control; however, some patients may eventually be maintained with MTX alone. Dapsone has been beneficial in some patients with mild relapsing polychondritis, although more current clinical experience has found dapsone to be less useful.

Corticosteroids

These agents are the mainstay of therapy. They have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Orasone, Meticorten)

McAdam et al found that continuous use of prednisone decreased severity, frequency, and duration of relapses. Some patients may use reduced prednisone doses or remain steroid free with use of MTX.
For the acute phase, administer 20-60 mg/d and taper to 5-25 mg/d for maintenance. Severe flares may require 80-100 mg/d. Most patients require low daily dose for maintenance; however, rarely, some patients can be treated successfully by intermittent administration of high doses during flares of the condition. In acute airway obstruction, IV pulse steroids are necessary.

Dosing

Adult

Acute flares: 20-100 mg/d PO
Chronic suppression: 5-25 mg/d PO; average qd
Maintenance: 25 mg/d PO, although some patients with less severe disease may use 15 mg/d or less
Adjust dose to minimum required to maintain control of inflammation; current clinical average is 10 mg/d; if >10 mg/d required, MTX commonly is added to reduce total prednisone requirement

Pediatric

0.05-2 mg/kg/d PO qd or divided bid/qid
Acute therapy for respiratory distress depends on age and ranges from 10-40 mg PO q12h (as used in acute asthma therapy)

Interactions

Ketoconazole, erythromycin, clarithromycin, estrogens, and birth control pills increase levels; aminoglutethimide, phenytoin, PB, rifampin, cholestyramine, and ephedrine decrease levels
Increased drug levels occur with potassium-depleting diuretics (potentiates potassium loss and digitalis toxicity) and cyclosporine; decreased drug levels occur with isoniazid, insulin (resistance is induced), and salicylates
Monitor anticoagulant therapy and theophylline levels

Contraindications

Absolute: systemic fungal infection, herpes simplex keratitis, hypersensitivity (usually with corticotropin; occasionally noted with IV preparations)
Relative: hypertension, active TB, CHF, prior psychosis, positive for IPPD, glaucoma, severe depression, diabetes mellitus, active PUD, cataracts, osteoporosis, recent bowel anastomosis, pregnancy

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur (consider Pneumocystis carinii prophylaxis); does not cross placenta; use lower dose in hypothyroidism, liver disease, obesity (decrease cortisol-binding globulin and increase free fraction of steroid); cortisol-binding globulin may increase with pregnancy, hyperthyroidism and concurrent estrogen therapy

Disease-modifying antirheumatic agents

These agents inhibit cell growth and proliferation.

Methotrexate (Folex, Rheumatrex)

Unknown mechanism of action in treatment of inflammatory reactions; may affect immune function. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness).
Effective steroid-sparing treatment for relapsing polychondritis. Adjust dose gradually to attain satisfactory response.

Dosing

Adult

7.5 mg/wk PO; increase to goal 22.5 mg/wk PO as tolerated

Pediatric

Not established

Interactions

Salicylates, NSAIDs, dipyridamole, probenecid, retinoids, ethanol, triamterene, pyrimethamine, sulfonamides, TCN, chloramphenicol, penicillin or other broad-spectrum antibiotics, trimethoprim, dapsone, theophylline, phenytoin, phenothiazines, barbiturates and nitrofurantoin (impair folic acid absorption), ascorbic acid, phenylbutazone, cyclosporin, and aminoglycosides

Contraindications

Absolute: Pregnancy or desire to get pregnant, active PUD, alcoholism, primary/secondary immunodeficiency, blood dyscrasias, active hepatitis, cirrhosis, chronic renal failure, active infections, and documented hypersensitivity
Relative: History of excessive alcohol intake, history of substance abuse, increased LFT results, recent hepatitis, diabetes, obesity, history of heritable liver disease, unreliable patient, CrCl <50 mL/min, male contemplating conception (must discontinue for 3 mo)

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Mucositis and myelosuppression are dose-limiting factors; possible hepatotoxicity with duration of treatment and total dose; risk of hepatic fibrosis increases after total dose of 1.5 g (monitor LFT results monthly), some recommend biopsy after receiving 1.5-2 g total, others biopsy after 3 consecutive elevated liver function panels in same year (must monitor AST, ALT, and albumin monthly)

Anakinra (Kineret)

Recombinant interleukin 1 receptor antagonist expressed from Escherichia coli. Natural interleukin 1 receptor antagonist produced by macrophages/activated monocytes blocking effects of interleukin 1.

Dosing

Adult

100 mg/d SC

Pediatric

Safety and effectiveness have not been established

Interactions

Abatacept, adalimumab, etanercept, and infliximab increase risk of serious infection

Contraindications

Documented hypersensitivity to anakinra or E coli–derived products

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Live vaccine administration; stop drug for active infection; preexisting neutropenia; chronic infection

Anti-inflammatory agents

These agents possibly inhibit lysosomal enzyme activity, which in turn may reduce inflammation.

Dapsone (Avlosulfon)

Bactericidal and bacteriostatic against mycobacteria; mechanism of action is similar to that of sulfonamides in which competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. Used in some patients in whom prednisone did not control symptoms. Successes and failures have been reported; therefore, prednisone remains the DOC.

Dosing

Adult

25-200 mg/d PO

Pediatric

Not established; suggested dose is <100 mg/d PO

Interactions

Trimethoprim, probenecid, folic acid antagonists (eg, pyrimethamine, MTX) increase levels; activated charcoal, PABA, and rifampin decrease levels; hemolysis may be increased with sulfonamides and hydroxychloroquine

Contraindications

Absolute: Documented hypersensitivity
Relative: G-6-PD deficiency (especially in African Americans, Middle Eastern heritage, Asians), significant cardiopulmonary disease, significant hematologic disease, sulfa allergy (cautious use in patients with sulfa allergy may be attempted; cross-reactivity is relatively rare and mild)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Perform weekly blood counts (first month), then perform WBC counts monthly (6 mo), then semiannually; discontinue if significant reduction in platelets or leukocytes or if hematopoiesis is observed; caution in methemoglobin reductase deficiency, G-6-PD deficiency (patients receiving >200 mg/d), or hemoglobin M because of high risk for hemolysis; caution in patients exposed to other agents or conditions (eg, infection, diabetic ketosis) capable of producing hemolysis; peripheral motor neuropathy can occur (rare); phototoxicity may occur when exposed to UV light; breastfeeding unsafe (significant excretion in breast milk results in risk of hemolytic anemia in infants who are breastfed); hypoxia from methemoglobinemia

Monoclonal antibodies - Antitumor necrosis factor-alpha inhibitors

These agents inhibit action of TNF-alpha, an inflammatory cytokine implicated for its contribution to rheumatic disease and cancer cachexia. Use described only in case reports.

Infliximab (Remicade)

Chimeric human-murine IgG1-kappa monoclonal antibody that binds to TNF-alpha. Binds both soluble and transmembrane forms and inhibits its binding to its receptors. Cells with transmembrane TNF-alpha bound to infliximab appear to be lysed with complement.

Dosing

Adult

Not established but extrapolation from other uses: 3 or 5 mg/kg IV over 2 h on weeks 0, 2, and 6 and then q8wk

Pediatric

Not established

Interactions

Risk of serious infections may increase when used in combination with anakinra; abciximab may increase risk of hypersensitivity reactions, increase risk of thrombocytopenia, and reduce effects of infliximab when used in combination with infliximab; infliximab may enhance toxicity/adverse effects of abatacept

Contraindications

Documented hypersensitivity to infliximab, its components, or murine products; moderate-to-severe CHF

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Black box warning: tuberculosis, invasive fungal infections, and other opportunistic infections have occurred in patients taking infliximab; all patients should be screened and treated for latent tuberculosis prior to initiation of infliximab; medication should be stopped during active infection; risk of reactivation of hepatitis B; hematologic abnormalities; mild CHF; seizure disorder may be worsened; monitor liver function tests for liver failure; serum-sickness reactions have occurred with reinstitution; may form autoantibodies causing a lupuslike syndrome

Etanercept (Enbrel)

Soluble, dimeric recombinant TNF receptor fused to the Fc fragment of human IgG1. This binds to TNF and inhibits its activities.

Dosing

Adult

50 mg/wk SC; Carter (2005) used 25 mg SC twice/wk

Pediatric

Safety and effectiveness have not been established

Interactions

Anakinra, abatacept, live virus vaccines, and live BCG vaccine; cyclophosphamide

Contraindications

Sepsis; documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May exacerbated CNS demyelinating disease; active infection (chronic or localized); stop drug if serious infection or sepsis occurs; may form autoantibodies causing a lupuslike syndrome; risk of reactivation of hepatitis B; pancytopenia; needle cover contains latex; may increase risk of malignancy; caution in poorly controlled diabetes mellitus

Adalimumab (HUMIRA)

Recombinant fully-human IgG1 anti-tumor necrosis factor monoclonal antibody. It binds to TNF-alpha and reduces it ability to effect its biological activities.

Dosing

Adult

40 mg SC q2wk

Pediatric

Wt based dosing: ages 4-17
15-30 Kg: 20 mg SC q2wk
30 Kg or more: 40 mg SC q2wk

Interactions

May interfere with immune response to live virus vaccine (eg, MMR) and reduce efficacy; methotrexate (MTX) decreases clearance (available data do not support adjusting dose of either adalimumab or MTX); coadministration with anakinra (an interleukin-1 antagonist that also blocks TNF) may cause additive adverse effects, particularly development of serious infections; rilonacept; abatacept

Contraindications

Documented hypersensitivity; active infection

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Causes immunosuppression; may be associated with serious infections (some fatal) including reactivation of tuberculosis, sepsis, or opportunistic infections, discontinue if serious infection occurs; increases risk for lymphoma development; associated with CNS demyelination (rare); autoantibody development may occur causing lupuslike syndrome; may cause hypersensitivity reactions including anaphylaxis and hematologic adverse effects (ie, pancytopenia, aplastic anemia); exacerbation of CHF or new onset CHF has been observed with TNF-blocking agents

Anti-CD20 antigen on B lymphocytes

CD20 is a B-lymphocyte antigen that regulates cell cycle initiation. Use described in one case report.

Rituximab (Rituxan)

Murine/Human chimeric anti-CD20 monoclonal antibody. CD20 is expressed early in pre-B cell development. Binding induces complement-dependent B-cell cytotoxicity along with antibody-dependent cellular toxicity.

Dosing

Adult

1 g IV days 1 and 15 when dosing in combination with MTX
375 mg/m² IV qwk x 4 (single agent therapy)

Pediatric

Not established

Interactions

Coadministration with cisplatin is known to cause severe renal toxicity including acute renal failure; may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 months of vaccine); abciximab, antihypertensives, echinacea

Contraindications

Documented hypersensitivity; IgE-mediated reaction to murine proteins

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use with caution in patients with dormant infections such as hepatitis B, hepatitis C, or CMV due to risk of reactivation; hypotension, bronchospasm, and angioedema may occur, premedication with acetaminophen and diphenhydramine may decrease incidence; discontinue treatment if life-threatening cardiac arrhythmias occur; must administer by slow IV infusion, do not administer IV push or bolus
Infusion reaction; preexisting cardiac/pulmonary condition; progressive multifocal leukoencephalopathy (PML); bowel obstruction/perforation; cytopenias; renal impairment

Interleukin-1 receptor antagonists

These agents have anti-inflammatory characteristics.

Leflunomide (Arava)

Isoxazole immunomodulatory agent with anti-inflammatory characteristics. Mechanism of action is through the inhibition of dihydroorotate dehydrogenase, which leads to a decrease in proliferative activity.
Although not entirely elucidated, it is thought to inhibit de novo pyrimidine synthesis. It inhibits proliferation of immune cells.

Dosing

Adult

100 mg PO qd for 3 d, initially, followed by a maintenance dose of 20 mg PO qd

Pediatric

Not established

Interactions

Cholestyramine and charcoal reduce effects; concomitant administration with rifampin increases toxicity; methotrexate, cholestyramine, rifapentine, warfarin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Serious adverse reactions include hepatotoxicity and immunosuppression; other reactions include nausea, diarrhea, abdominal pain, rash, bronchitis, headache, hypertension, dizziness, and alopecia; caution if impaired liver or renal function or if immunodeficient

Follow-up

Complications

• Complications of relapsing polychondritis (RP) include vertigo, tinnitus, voice hoarseness, joint deformity, epiglottitis, scleritis, conjunctivitis, iritis, need for permanent tracheotomy (severe cases), severe pulmonary infection, blindness, frail chest wall, respiratory failure, aortic regurgitation, mitral regurgitation, aortic dissection, and glomerulonephritis-associated renal failure.

Prognosis

• In earlier studies, the 5-year survival rate associated with relapsing polychondritis was reported to be 66%-74% (45% if relapsing polychondritis occurs with systemic vasculitis), with a 10-year survival rate of 55%. More recently, Trentham and Le found a survival rate of 94% at 8 years.¹⁶ However, these data may represent relapsing polychondritis in patients with less severe disease than patients studied in earlier reports.
• The most common causes of relapsing polychondritis–related death include infection secondary to corticosteroid treatment or respiratory compromise (10%-50% of deaths result from airway complications), systemic vasculitis, and malignancy unrelated to relapsing polychondritis.
• Complications of relapsing polychondritis such as saddle-nose deformity, systemic vasculitis, laryngotracheobronchial stricture, arthritis, and anemia in patients younger than 51 years portend a poorer prognosis than in age-matched patients with relapsing polychondritis without complications. Among patients older than 51 years, only anemia is associated with a poorer prognosis. Renal involvement is a poor prognostic factor at all ages.

Patient Education

• Internet support sites exist for patients with relapsing polychondritis and their friends and family. Although the author accepts no responsibility for quality, the following sites may be helpful:
  • Polychondritis Educational Society, Ltd
  • Relapsing Polychondritis

Miscellaneous

Medicolegal Pitfalls

• Delay in diagnosis of relapsing polychondritis (RP) is common. Intubation can be difficult in patients with relapsing polychondritis, and an ear, nose, and throat evaluation may be indicated prior to elective intubation in any patient with a history of tracheal symptoms.

Special Concerns

• Pregnant patients with relapsing polychondritis or patients who develop relapsing polychondritis during pregnancy fare well overall. Of relapsing polychondritis cases diagnosed during pregnancy, 26% were diagnosed at a mean gestational age of 20 weeks. Disease flares occur in 30% of pregnancies in patients with relapsing polychondritis, and only 30% of the patients require changes in medication. Of 24 pregnancies observed in patients with relapsing polychondritis, fetal loss was uncommon (3 of 21 nonectopic pregnancies). Of the 18 live births, 15 mature and 3 premature babies were delivered without evidence of neonatal inflammatory disease.
  • The presence of accompanying systemic diseases in pregnancy and in relapsing polychondritis is often disconcerting to practitioners and to patients. One study reported a concurrent prevalence of other inflammatory disorders to occur in 45% of patients with relapsing polychondritis, including RA, systemic lupus erythematosus with antiphospholipid syndrome, Takayasu arteritis, and ankylosing spondylitis. Patients who are severely affected by relapsing polychondritis are advised against pregnancy; however, analysis of 25 pregnancies did not find a difference in pregnancy outcome in patients with concurrent systemic disease and relapsing polychondritis.
  • Systemic administration of prednisone is the treatment of choice in pregnant patients with relapsing polychondritis. NSAIDs have been used but are not effective and must be withdrawn 8 weeks prior to delivery because of the risk of problems in the neonate and/or mother, such as "delayed onset or increased duration of labor, constriction of the ductus arteriosus in utero, and persistent pulmonary hypertension in the neonate".^39,40
  • Dapsone has not been reported to be embryotoxic and has been found to be safe in clinical experience with pregnant patients treated for leprosy and Hansen disease. Cyclophosphamide is toxic in the first trimester of pregnancy, and MTX is also toxic in early pregnancy.

Multimedia

Media file 1: Auricular edema and erythema sparing the lobule. Courtesy of Gregory J. Raugi, MD, PhD.

Media file 2: Severe auricular edema and inflammation. Courtesy of the University of Washington, Division of Dermatology.

Media file 3: Forward listing ear. Courtesy of the University of Washington, Division of Dermatology.

Media file 4: Floppy ear. Courtesy of the University of Washington, Division of Dermatology.

Media file 5: Bilateral inflammation and structural collapse of the auricles in a patient found to have aortic dissection. Courtesy of the University of Washington, Division of Dermatology.

Media file 6: Same patient as in Image 5 after 4-6 weeks of steroid treatment. Note resolution of auricular inflammation with nodularity and forward listing of the ears. Courtesy of the University of Washington, Division of Dermatology.

Media file 7: Close-up view of same patient as in Image 6. Forward flopping of ear with nodularity after steroid treatment. Courtesy of the University of Washington, Division of Dermatology.

Media file 8: Unilateral episcleritis. Courtesy of Gregory J. Raugi, MD, PhD.

Media file 9: Saddle-nose deformity. Courtesy of the University of Washington, Division of Dermatology.

Media file 10: Tracheal stenosis on chest x-ray film. Courtesy of Julie E. Takasugi, MD.

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Keywords

relapsing polychondritis, RP, cartilaginous inflammation, cartilage inflammation, inflamed cartilage, inflamed ear, ear inflammation, inflamed nose, nose inflammation, inflamed laryngotracheobronchial tree, laryngotracheobronchial tree inflammation, airway chondritis, infection secondary to corticosteroid treatment, respiratory compromise, systemic vasculitis, auricular chondritis, seronegative arthritis, non-nodular arthritis, nonnodular arthritis, respiratory tract chondritis, audiovestibular damage, audio-vestibular damage, aortic arch syndrome, abdominal aortic aneurysm, aortic regurgitation, chondrolysis, chondritis, perichondritis

Contributor Information and Disclosures

Author

Nicholas Compton, MD, Staff Physician, Department of Medicine, Division of Dermatology, University of Washington Medical Center
Nicholas Compton, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Medical Dermatology Society
Disclosure: Nothing to disclose.

Coauthor(s)

Jane H Buckner, MD, Clinical Assistant Professor of Immunology, University of Washington; Director of Translation Research Program, Associate Member, Department of Immunology/Rheumatology, Benaroya Research Institute at Virginia Mason Research Center
Jane H Buckner, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, Phi Beta Kappa, and Sigma Xi
Disclosure: Nothing to disclose.

Karin I Harp, MD, Consulting Staff, Department of Dermatology, Everett Clinic
Karin I Harp, MD is a member of the following medical societies: Alpha Omega Alpha
Disclosure: Nothing to disclose.

Gregory J Raugi, MD, PhD, Professor, Department of Internal Medicine, Division of Dermatology, University of Washington at Seattle; Chief, Dermatology Section, Primary and Specialty Care Service, Veterans Administration Medical Center of Seattle
Gregory J Raugi, MD, PhD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Medical Editor

Bryan L Martin, DO, Chief, Allergy Immunology Department, Walter Reed Army Medical Center; Associate Professor of Medicine and Pediatrics, Uniformed Services University of the Health Sciences; United States Army Consultant in Allergy Immunology and Immunizations
Bryan L Martin, DO is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Osteopathic Internists, American College of Physicians, American Medical Association, and American Osteopathic Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Elliot Goldberg, MD, Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine
Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Professor of Medicine, Temple University School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital
Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa
Disclosure: medifocus Honoraria Review panel membership; health dialogs Honoraria Consulting; West Penn Allegheny Health System None Board membership

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