AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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.

In 1960, Pearson, Kline, and Newcomer reviewed 12 cases and expanded the clinical spectrum of RP to include nonconcurrent 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.

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 RP. Various studies find circulating antibodies to cartilage-specific collagen types II, IX, and XI to be present in 30-70% of patients with RP. Buckner et al have found the antibodies in 50% of a panel of more than 100 patients. Foidart et al found that antibodies to type II collagen are present during acute RP episodes and that the levels correlate with the severity of the episode.

Treatment with prednisone is associated with a decrease in antibody titers. No antibody can be detected in the serum of healthy patients or patients with other arthritides not associated with RP. Noting the reports of antibodies to collagen types I, II, and III believed to result from cartilage destruction, Foidart et al proposed that antibodies are formed as a primary event in RP. The epitope specificity of anticollagen type II antibodies differs between RP and rheumatoid arthritis (RA), suggesting different mechanisms for formation and pathophysiologic roles.

Autoantibodies to minor cartilage-specific collagens (ie, types IX and XI) have been described and reported more likely to be found in association with antibodies to type II collagen in patients with RP. Furthermore Hannson et al found that levels of antibodies to matrilin 1, an extracellular matrix protein predominantly expressed in tracheal cartilage, were significantly higher in patients with RP, especially if respiratory symptoms were present, when compared with patients with Wegener granulomatosis, systemic lupus erythematosus, RA, and normal controls.

Ebringer et al found that high titers of antifetal cartilage antibodies were present in most patients with RP during the early acute phase. Patients who lacked detectable antibody had RP for at least a few years, suggesting the disease had run its course. Ebringer et al found antifetal cartilage antibodies in 6 of 9 patients. Antifetal cartilage antibodies were found in only 4 (1.5%) of 260 patients with RA and only when patients had long-standing disease. One report of RP occurring in the newborn of a mother with RP suggests that antibodies crossing the placenta are necessary and sufficient to elicit the entire clinical syndrome.

To determine whether the autoimmunity in RP is directed exclusively at cartilage proteins, Tanaka et al used proteomic surveillance to ubiquitous cellular proteins in patients with RP. They 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 RP.

Cellular response

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

Further evidence that HLA associations are important in the development of RP is provided by an elegant double-transgenic mouse model for RP. The model demonstrated that more than one HLA class II molecule may 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, novel lymphocytes discrete from other T, B, and natural killer cells, come in 2 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.

Takagi et al quantitated CD4^-/CD8^-and CD4⁺V-alpha⁺V-beta11⁺ NKT cells and found them decreased in patients with active or quiescent RP 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 RP patients. Levels of 17 cytokines in serum from 22 RP patients experiencing a clinical flare were compared with age-matched controls. Levels of 3 cytokines were significantly elevated in RP patients; these were interleukin 8, macrophage inflammatory protein 1-alpha, and monocyte chemoattractant protein-1. All 3 chemokines are proinflammatory and result in accumulation and activation of neutrophils, eosinophils, and monocytes/macrophages.

Animal models

Mouse and rat models have been helpful in elucidating the autoimmune origin of RP. Immunization of rats with native bovine type II collagen resulted in bilateral auricular chondritis, with histology findings similar to RP findings in humans in 12 of 88 (14%) rats. In addition, 8 of 12 rats developed arthritis. Severe auricular chondritis was accompanied by positive immunofluorescence to 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 serendipitously lead McCune et al to find auricular chondritis in rats with the intended collagen-induced arthritis. IgG and C3 were found in the few lesions on which biopsy was performed. Antibodies to native type II collagen were found in the sera of rats that developed auricular chondritis and in rats with collagen-induced arthritis only.

Immunization with bovine type II collagen of transgenic mice lacking in endogenous class II expression resulted in the development of auricular chondritis and severe arthritis. Sensitized mice also exhibited significant humoral and cellular responses against type II collagen.

Although most data implicate cartilage collagens as the immunogens in RP, immunization of rats with matrilin 1, a noncollagenous cartilage matrix protein, is associated with development of a clinical syndrome resembling RP. 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, which probably explains the observed clinical differences. Matrilin 1 also is 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.

The same investigators demonstrated a crucial role for B cells and C5 in the induction of RP-like symptoms. Additionally, pathogenicity of matrilin-1–specific antibodies in their matrilin-1–induced RC 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.

Other autoimmune disorders

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

Autoimmune Conditions Reported in Patients With RP

*Individual patients may carry more than one autoimmune diagnosis

†Reported as 13 (20%) of 66 prevalence by Trentham and Le without division by disease

Frequency

United States

RP is referred to in clinical reports and reviews as an uncommon and 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. Buckner noted an incidence of 4 cases per million in the Pacific Northwest.

International

International incidence is unknown.

Mortality/Morbidity

In earlier studies, the 5-year survival rate for RP was reported to be 66-74% (45% if RP occurs with systemic vasculitis) with a 10-year survival rate of 55%. More recently, Trentham and Le reported a survival rate of 94% at 8 years. This data may represent RP in patients with less severe disease than patients studied in earlier reports.

• The most frequent causes of death include infection secondary to corticosteroid treatment or respiratory compromise (10-50% of deaths result from airway complications), systemic vasculitis, and malignancy unrelated to RP.
• The presence of complications of RP, including saddle-nose deformity (see Media File 9), systemic vasculitis, laryngotracheobronchial stricture, arthritis, and anemia in patients younger than 51 years, portends a poorer prognosis than in age-matched patients with RP 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.
• Complications of 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.

Race

The preponderant group affected is the white population. Although RP has been found in persons of all races, very little data are available for nonwhite persons.

Sex

Reviews from the 1970s and 1980s found no sex distribution difference among patients with RP.

• In 1998, 1 report of only 66 patients found 3 times as many female as male patients affected. Although this can be consistent with the proposed autoimmune etiology of RP, it is the only such report in the literature, and selection bias or another confounding factor may have been present.
• Saddle-nose deformity and subglottic stricture occur more frequently in female patients; however, this distinction may result from differences in the amount and shape of cartilage in female structures.

Age

RP may occur at any age; however, it most commonly is found in the fifth decade of life. No relationship exists between age of onset and sex.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

The array of possible presenting complaints and the episodic nature of 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. In fact, one third of patients have seen 5 or more physicians before the RP diagnosis is made.

The affected systems and complaints reported in patients with RP before and after diagnosis are as follows:

• 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
• 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, 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, and seizures

Physical

Diagnostic criteria for RP first were proposed by McAdam et al and have been modified several times. Perform biopsy only if clinical criteria are in question.

McAdam et al criteria (3 of 6 clinical features are present)

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

Damiani and Levine criteria (1 of 3 conditions is met)

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

Michet et al criteria (1 of 2 conditions is met)

• 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 RP include the following:

• Auricular chondritis: Of patients with RP, 85-95% develop auricular chondritis, typically with the sudden onset of unilateral or bilateral ear (auricle) pain, swelling, and redness, sparing the lobules. 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. If the damage is less, 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. Most commonly, the arthritis is asymmetric, oligoarticular or polyarticular, nondeforming, and nonerosive. Although any joint may be affected, the ankles, elbow, wrists, proximal interphalangeal joints, metacarpophalangeal joints, and metatarsal phalangeal joints are often involved. 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. Acute onset of an inflamed joint occasionally may mimic a crystal arthropathy. Although RP-associated arthritis usually is nonerosive, at least 1 case of arthritis mutilans has been reported in association with RP.
• Nasal chondritis: Nasal chondritis occurs in 48-72% of patients with RP. Typically, the onset of nasal chondritis is acute, painful, and accompanied by a feeling of fullness over the nasal bridge. Mild epistaxis may be present. One may see saddle-nose deformity if the disease has been present for sometime (Media File 9).
• Ocular inflammation
• • Of patients with RP, 50-65% develop ocular sequelae related to episodic inflammation of the uveal tract, conjunctivae, sclerae, and/or corneae.
  • The most common conditions are episcleritis (39%) and scleritis (14%).
  • 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 also may be found on examination.
  • Collagen types II, IX, and XI, which are present in cartilage, also are found in the cornea and sclera. Autoantibodies to these collagens, which are found in patients with RP, may be responsible for direct harm to the eyes.
• Respiratory tract chondritis: Respiratory tract involvement affects 40-56% of patients 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 on inspiration, and airways below the thoracic inlet collapse on expiration; therefore, both inspiratory stridor and expiratory wheezing may be noted on auscultation. Presentations with 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 usually is 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: RP has been found to affect the cardiovascular system in 24% of patients, with resulting aortic and mitral valve regurgitation, aortic aneurysm, aortitis, aortic thrombosis, pericarditis, first- to third-degree heart block, and myocardial infarction.
• • RP aortitis exhibits inflammation in the media of any portion of the aorta and is accompanied by loss of glycosaminoglycans and elastic tissue.
  • Affected areas, in descending order of frequency, include the ascending aorta, aortic ring, descending thoracic portion, and abdominal aorta.
  • The most common clinical presentations include aortic arch syndrome, abdominal aortic aneurysm, and aortic regurgitation.
  • Lesions may be multiple.
  • Clinical presentation of aortic regurgitation (resulting from ascending aorta involvement) may include left ventricular failure, but abdominal aortic aneurysm is likely to be silent and may result in rupture and death. Aortic regurgitation may result from damage to the aortic cusps or to annular dilatation because of destruction of supporting tissues.
• Skin disease: Skin lesions are found in 17-39% of patients with RP. Specific lesions are limited to erythema and edema overlying the inflamed cartilaginous structures. A variety of nonspecific skin lesions have been reported, with aphthous ulcers being most common, followed by limb nodules, purpura, papules, sterile pustules, superficial phlebitis, livedo reticularis, limb ulceration, and distal necrosis. Rarer findings include Sweet syndrome and urticarial vasculitis (Serratrice, 2005) and Kaposi sarcoma (Manghani, 2004). Some findings likely represent the skin manifestations of the many conditions associated with RP rather than specific manifestations of RP.
• Cutaneous vasculitis: Cutaneous vasculitis has been reported by Hager and Moore (1 case), McAdam et al (3 of 23 patients in their series, plus 3 of 136 in a review of pre-1976 literature), Michet et al (5% of 112 patients at Mayo Clinic), Pierard et al (1 case), Rauh et al (1 case), and Stewart et al (1 case with CNS vasculitis). True prevalence of vasculitis in patients with RP is difficult to determine because of selection and reporting bias and inconsistencies in defining cutaneous vasculitis. Michet's 1990 review places the prevalence of biopsy-proven cutaneous (small vessel) leukocytoclastic vasculitis at approximately 10% and the prevalence of systemic (including skin) medium-to-large vessel vasculitis at 11-56%.
• • Erythema elevatum diutinum: A vasculitic syndrome resembling erythema elevatum diutinum has been described in 2 patients with RP.
  • • A 50-year-old woman with sequelae of RP was found to have nonpurpuric, raised, tender, inflammatory nodules on both lower extremities. Skin biopsy revealed invasion of the reticular dermal vessels with mononuclear cells and eosinophils.
    • A 69-year-old man was described with "numerous firm, erythematous, occasionally hemorrhagic, confluent papules, pink or yellow with a xanthoma-like appearance, distributed symmetrically on the dorsum of the hands" (Weinberger, 1979). Biopsy of an early lesion revealed "a dense dermal infiltrate of polymorphonuclear leukocytes, nuclear dust, some lymphocytes, and histiocytes around the vessels of the mid and papillary dermis, and endothelial wall swelling [with] fibrinoid necrosis both within vessel walls and dermis" (Weinberger, 1979). Biopsy of a late lesion found polymorphonuclear leukocyte infiltrate to be less dense and vessel fibrosis to be increasing. IgG and immunoglobulin A deposits were found along the dermal-epidermal junction on direct immunofluorescence.
  • Other possible cutaneous vasculitis syndromes
  • • Small vessel leukocytoclastic vasculitis also has been described as a bullous vasculitic rash of the legs and as hemorrhagic bullae.
    • A patient with RP presenting with cutaneous polyarteritis nodosa was reported by Rauh et al. The lesions presented as relapsing painful red nodules from 1-3 cm in size, occurring on the entire skin and accompanied by arthralgias and myalgias.
    • Serratrice et al report a patient who presented w/ an urticarial eruption on her arms, thorax and legs, no biopsy was performed. She had associated hypocomplementemia and was later diagnosed with RP and hypocomplementemic urticarial vasculitis.
    • Other cutaneous lesions reported in patients with RP and vasculitis included palpable purpura, inflammatory infiltrating neutrophilic conditions resembling erythema elevatum diutinum or acute febrile neutrophilic dermatosis (Sweet syndrome), subcutaneous inflammatory nodules resembling erythema nodosum or polyarteritis nodosa, and localized ulcerating neutrophilic conditions resembling pustules, furuncles, abscesses, and ulcerating abscesses.
  • Panniculitis: Disdier et al reported 2 cases of cutaneous panniculitis with RP. The lesions were described as recurrent "large dermohypodermal nodules (5-10 cm) [of the buttocks and thighs] leading to large atrophic scars." One case also involved the lower back region and was mistaken for morpheae. Biopsy specimens revealed normal epidermis, "dermal edema, [and] hypodermal septal and lobular infiltration with polyclonal inflammatory cells [and lipophagia]" (Disdier, 1996). Biopsy performed in 1 patient found the inflammatory infiltrate to be composed of lymphocytes and plasma cells. In the other patient, polymorphonuclear leukocytes and mononuclear cells were found in the biopsy specimen. No necrosis was noted.
  • Other conditions: Isolated case reports of other possible cutaneous manifestations of RP include hyperpigmentation; pustular psoriasis; macular purpura of the palms, soles, lower limbs, and buttocks; purpura; erythematous papular plaques of the face, upper and lower extremities, and thorax; alopecia universalis; actinic granulomas; "recurrent crops of elevated erythematous and vesicular skin nodules on the limbs...trunk...and even gums" with ulceration of some nodules (Pearson, 1960); urticaria; and angioedema, livedo reticularis, erythema nodosum, and erythema multiforme.
  • Mouth and genital ulcers with inflamed cartilage (MAGIC syndrome): MAGIC syndrome describes the overlap (in individual patients) of RP with Behçet disease. This condition was proposed by Firestein et al in 1985 in a report of 5 patients. In 1997, Imai et al analyzed the 8 reported cases and found 2 types of MAGIC syndrome. 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 the initial presentation of oral ulcers and polychondritis is followed by genital ulcers or erythema nodosum.
• Central nervous system: CNS manifestations of RP are rare and can be varied. It is believed that vasculitis is the underlying etiology. The first case of CNS vasculitis was reported in 1988 by Stewart et al and was confirmed microscopically on autopsy as resulting from diffuse small-artery and medium-artery vasculitis of the brain.
• • Since the neurologic sequelae of RP are diverse, patients may present with seizures, limb weakness, paresthesias or gait disturbances, or other cerebellar symptoms.
  • Neurologic symptoms may present before other more frequent manifestations of RP.
  • Marie et al reported a case of diplopia as the first presenting manifestation of RP, which led to the finding that the patient had a right sixth cranial nerve palsy because of CNS vasculitis. McAdam et al reported a case of left seventh cranial nerve palsy in RP. Cranial nerve damage is common in RP-associated CNS vasculitis and most often affects the second cranial nerve, followed less commonly by the sixth, seventh, and eighth cranial nerves.
  • Ohta et al reported on case and Fujiki et al reported 2 cases of limbic encephalitis associated with RP. The patients presented with (1) amnesic syndrome with depression and memory impairment and (2) psychiatric features of euphoria and hyperactive behavior, respectively.
  • Marie et al reported a case of bilateral facial diplegia preceding the diagnosis of RP. The patient was treated with corticosteroids and had complete resolution of her bilateral seventh nerve palsy.
  • Aseptic meningitis has been reported infrequently in RP.
  • Sato et al report a case of a 51-year-old man with headache and nasal congestion who was found to have a meningeal plasma cell granuloma invading into the adjacent skull. During his evaluation, he demonstrated features of RP. Similarly, Shinkeigaku et al reported a case of intracranial inflammatory granuloma in a 67-year-old man with RP.
  • Clinical neurologic assessment is an important aspect of the physical examination of patients with RP.
• Renal: From 1943-1980, 129 patients with RP were seen at the Mayo Clinic, of which 29 (22%) had evidence of glomerulonephritis based on a diagnostic renal biopsy or the presence of microhematuria and proteinuria (with results of at least 2+ on urinalysis in 1 patient).
• • Biopsies showed segmental necrotizing glomerulonephritis or renal vasculitis.
  • Patients with renal damage were older and more likely to have extrarenal vasculitis and arthritis.
  • Although all patients with RP had a decreased observed survival rate compared to expected rates for their age and gender, patients with renal involvement had a significantly lower age-adjusted life expectancy.
  • When presence of renal involvement, age, vasculitis, and arthritis were evaluated together, only advancing age adversely affected outcome. When each variable was considered independently, renal involvement, age, and vasculitis each were associated with decreased survival. Of the 47 (36%) patients who died, 18 (62% of the RP plus renal group) had renal involvement and 29 (29% of the RP-only group) did not have renal involvement.
  • The top 3 causes of death, in descending order, for patients without renal involvement included infection, vasculitis, and cardiovascular involvement. The corresponding list for patients with renal RP involvement included infection, vasculitis, and uremia.
  • Pathological findings from biopsy include segmental necrotizing glomerulonephritis with or without crescents, interstitial lymphocytic infiltrates, interstitial fibrosis, active tubulitis, and glomerulosclerosis.
  • Most patients were treated with prednisone with results varying from stabilization of renal function to renal failure.
  • Chang-Miller et al proposed that the pathogenesis of renal involvement in RP derives from the deposition of immune complexes leading to glomerular damage.
• Other conditions
• • Myelodysplasia is associated with RP.
  • Acute mastitis may be found in RP.

Causes

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

Three intriguing case reports suggest that hormonal influences may be of importance in RP. Two men have developed RP 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.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Rheumatoid arthritis
Polyarteritis nodosa
Cogan syndrome
Infectious perichondritis
MAGIC syndrome (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 from Pseudomonas aeruginosa); also, fungi, 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)
Reiter syndrome
Acute gonococcal arthropathy
Rheumatic fever
Wegener granulomatosis
Polyarteritis nodosa
Systemic lupus erythematosus and other collagen-vascular disorders

Nasal chondritis

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

Ocular inflammation (large differential)

Reiter syndrome (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 RP, 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

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• No specific diagnostic laboratory findings exist in patients with RP.
• Anemia, if present, usually is 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) often are present.
• Mild leukocytosis may be detected.
• Because RP 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) for evaluation of other autoimmune connective tissue diseases.
• For a vasculitis workup, perform a CBC count with differential; metabolic panel; creatinine, liver transaminase, and serum alkaline phosphatase levels; urinalysis dipstick and microscopic evaluation of sediment; cryoglobulins; viral hepatitis panel; and antineutrophil cytoplasmic antibody (ANCA) tests (eg, cytoplasmic ANCA, perinuclear ANCA, antimyeloperoxidase and antiproteinase 3 antibody titers).
• Use the purified protein derivative test for exposure to tuberculosis (tuberculosis often is 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 for patients with respiratory complaints.
  • 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 radiograph (posteroanterior [PA] and lateral views)
• • Tracheal stenosis may be observed on plain radiographs.
  • Calcification of cartilaginous structures supports the diagnosis of RP.
  • Coexisting systemic vasculitis may be suggested by the presence of pulmonary parenchymal infiltrates.
• Spiral CT (without contrast) scanned from the superior trachea to the lower lobe bronchi is advised in patients with RP and respiratory complaints.
• • Spiral CT scan is a noninvasive test that readily identifies tracheal and bronchial thickening, stenosis, and calcification.
  • High-resolution CT scans can identify airtrapping and diffuse or focal thickening of the airways.
  • CT scan results correlate well with pulmonary function tests, identifying obstructive patterns. CT scan is not only safer but also is more sensitive and specific than endoscopy; therefore, endoscopy is not recommended.
• MRI has been a useful adjunct for the clinical diagnosis of RP.
• • MRI is better able to distinguish between edema, fibrosis, and inflammation than is CT imaging.
  • T1-weighted images, T2-weighted images, and T1-weighted images with gadolinium contrast provide characterization of RP-related changes in cartilaginous tissues.
  • MRI also detects thickening of the thoracic aorta before dilatation occurs.
  • MRI may be useful for following the effects of treatment.
• PA 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.
• Bone scintigraphy
• • 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 also has been found to show increased uptake in affected areas.
  • Bone 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).

Other Tests

• Pulmonary function testing with flow-volume loop studies
• • Pulmonary function testing (PFT) is strongly recommended in patients presenting with respiratory complaints, since PFT may assist in the differential diagnosis and provide information about severity of the disease.
  • PFT in persons RP with 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.
• Electrocardiogram
• • Perform ECG to assess patients with RP who demonstrate signs of vasculitis.
  • Also, perform ECG to monitor these patients, since they may incur silent ischemia if vasculitis has developed.
• Echocardiogram: Echocardiogram may be needed to assess aortic root dilatation and degree of aortic regurgitation.

Procedures

• Intubation may be dangerous and futile.
• Tracheostomy usually is the best route for providing an airway for patients with RP 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 histopathologic data are required to meet the diagnostic criteria for RP.
• Biopsy of skin lesions (nonadjacent to cartilage) may provide useful adjunctive information.

Histologic Findings

Biopsy specimens from the cartilage of patients with RP demonstrate 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 RP 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 eventually is destroyed and is 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

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Medical Care

No controlled trials of therapy for 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 corticosteroids. 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, rare patients can be treated successfully by only intermittent administration of high doses during flares of the condition. McAdam et al found that continuous prednisone decreased the severity, frequency, and duration of relapses.
• 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 patients' corticosteroid requirements while controlling symptoms. Case reports have described successful treatment with infliximab and etanercept, antitumor necrosis factor-alpha antibodies, and anakinra, an interleukin 1 receptor antagonist.
• Oral administration of nonsteroidal anti-inflammatory drugs (NSAIDs) has not been effective.
• Medical care must include assessment and treatment for other confounding or concurrent autoimmune disorders.

Surgical Care

Surgeries encountered in the care of patients with RP may include tracheostomy, permanent tracheotomy placement, aortic aneurysm repair, and cardiac valve replacement. 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.

Consultations

RP is a complex condition requiring a team approach to care for the patient.

• Dermatologists or specialists in infectious diseases often are involved early in the course 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 also should 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 RP.

Diet

No special recommendations have been noted.

Activity

No special recommendations have been noted.

MEDICATION

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Prednisone is the drug of choice for 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 eventually may be maintained on MTX alone. Dapsone has been beneficial in some patients with mild RP, although more current clinical experience has not found dapsone to be as useful.

Drug Category: Corticosteroids

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

Drug Category: Disease-modifying antirheumatic agents

Inhibit cell growth and proliferation.

Drug Category: Anti-inflammatory agents

Possibly inhibit lysosomal enzyme activity, which in turn may reduce inflammation.

Drug Category: Antitumor necrosis factor-alpha inhibitors

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

Drug Category: Immune stimulants/Interleukin 1 inhibitors

FOLLOW-UP

Section 8 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Complications

• Complications of 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 for RP was reported to be 66-74% (45% if RP 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. This data may represent patients with less severe disease than those presented in earlier reports.
• The most frequent causes of death include infection secondary to corticosteroid treatment or respiratory compromise (10-50% of deaths result from airway complications), systemic vasculitis, and malignancy unrelated to RP.
• The presence of complications of RP, including saddle-nose deformity, systemic vasculitis, laryngotracheobronchial stricture, arthritis, and anemia, in patients younger than 51 years portends a poorer prognosis than in age-matched patients with RP 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 RP 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

Section 9 of 11  

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• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Delay in diagnosis is common. Intubation can be difficult in patients with RP, 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 RP or patients who develop RP during pregnancy fare well overall. Of RP 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 RP, and only 30% of the patients require changes in medication. Of 24 pregnancies observed in patients with RP, 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 other systemic diseases in pregnancy and in RP often is disconcerting to practitioners and to patients. One study reported a concurrent prevalence of other inflammatory disorders to occur in 45% of patients with RP, including RA, systemic lupus erythematosus with antiphospholipid syndrome, Takayasu arteritis, and ankylosing spondylitis. Patients who are severely affected by RP are advised against pregnancy; however, analysis of 25 pregnancies did not find a difference in pregnancy outcome in patients with concurrent systemic disease and RP.
  • Systemic administration of prednisone is the treatment of choice for pregnant patients with RP. NSAIDs have been used, but are not effective, and must be withdrawn 8 weeks prior to delivery because of the risk of problems for 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" (Bermas, 1995; Papo, 1997).
  • 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 a well-known toxin in the first trimester, and MTX is also toxic in early pregnancy.

MULTIMEDIA

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• Multimedia
• References

Media file 1:  Auricular edema and erythema sparing the lobule. Courtesy of Gregory J. Raugi, MD, PhD.
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Media file 2:  Severe auricular edema and inflammation. Courtesy of the University of Washington, Division of Dermatology.
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Media file 3:  Forward listing ear. Courtesy of the University of Washington, Division of Dermatology.
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Media file 4:  Floppy ear. Courtesy of the University of Washington, Division of Dermatology.
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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.
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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.
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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.
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Media file 8:  Unilateral episcleritis. Courtesy of Gregory J. Raugi, MD, PhD.
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Media file 9:  Saddle-nose deformity. Courtesy of the University of Washington, Division of Dermatology.
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Media file 10:  Tracheal stenosis on chest x-ray film. Courtesy of Julie E. Takasugi, MD.
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Media type:  X-RAY

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Alsalameh S, Mollenhauer J, Scheuplein F, et al. Preferential cellular and humoral immune reactivities to native and denatured collagen types IX and XI in a patient with fatal relapsing polychondritis. J Rheumatol. Aug 1993;20(8):1419-24. [Medline].
• Anderson NG, Garcia-Valenzuela E, Martin DF, et al. Hypopyon uveitis and relapsing polychondritis: a report of 2 patients and review of autoimmune hypopyon uveitis. Ophthalmology. Jun 2004;111(6):1251-4.
• Arundell FW, Haserick JR. Familial chronic atrophic polychondritis. Arch Dermatol. 1960;82:439-40.
• Astudillo L, Launay F, Lamant L, et al. Sweet''s syndrome revealing relapsing polychondritis. Int J Dermatol. Oct 2004;43(10):720-2.
• Berg AM, Kasznica J, Hopkins P, Simms RW. Relapsing polychondritis and aseptic meningitis. J Rheumatol. Mar 1996;23(3):567-9. [Medline].