Relapsing Polychondritis

All information taken from and online source : Medscape.com 

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 central nervous system.

The array of possible presenting symptoms and the episodic nature of relapsing polychondritis may result in a significant delay in diagnosis. In addition, no laboratory findings are specific for relapsing polychondritis. A laboratory evaluation commensurate with the spectrum of reported symptoms is indicated to ascertain the presence of complicating conditions. The mainstay of treatment is systemic corticosteroid therapy.

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.[4]

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.[5]

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.[5] However, anticollagen type II antibodies are not specific to relapsing polychondritis; they have been identified in other arthritides such asrheumatoid 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 granulomatosissystemic lupus erythematosus, or RA and in healthy controls.[6]

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.[7] 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 diseaseBehçet 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.[8]

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.[9]

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.[10]

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.[11]

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.[12]

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.[13]

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.[13]

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.[14]

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.[15]

Table. Autoimmune Conditions Reported in Patients With Relapsing Polychondritis(Open Table in a new window)

Disease Patients With Condition/Total Patients References
Systemic vasculitis 3 (5%) of 62 Zeuner et al[16]
11 (10%) of 112 Michet et al[17]
8 (12%) of 66 Trentham and Le[18]
28 (18%) of 159 McAdam et al[15]
50 (13%) of 399 Total
Cutaneous leukocytoclastic vasculitis 2 (33%) of 6 Priori et al[19]
6 (5%) of 112 Michet et al[17]
8 (7%) of 118 Total
Thyroid disease 8 (5%) of 159 McAdam et al[15]
10 (15%) of 66 Trentham and Le[18]
2 (33%) of 6 Priori et al[19]
4 (4%) of 112 Michet et al[17]
2 (3%) of 62 Zeuner et al[16]
26 (6%) of 405 Total
Rheumatoid arthritis* 8 (5%) of 159 McAdam et al[15]
3 (2%) of 180 Piette et al[20]
8 (7%) of 112 Michet et al[17]
7 (11%) of 62 Zeuner et al[16]
26 (5%) of 513 Total
Systemic lupus erythematosus† 2 (1%) of 159 McAdam et al[15]
9 (5%) of 180 Piette et al[20]
1 (17%) of 6 Priori et al[19]
6 (5%) of 112 Michet et al[17]
3 (5%) of 62 Zeuner et al[16]
21 (4%) of 519 Total
Sjögren syndrome (possible) 5 (3%) of 159 McAdam et al[15]
5 (5%) of 111 Piette et al[20]
10 (4%) of 270 Total
Ulcerative colitis 3 (2%) of 159 McAdam et al[15]
2 (3%) of 62 Zeuner et al[16]
5 (2%) of 221 Total
Crohn disease 2 (1%) of 180 Piette et al[20]
1 (2%) 62 Zeuner et al[16]
1 (100%) of 1 Haigh et al[21]
4 (2%) of 243 Total
Mixed connective-tissue disease 5 (3%) of 180 Piette et al[20]
2 (2%) of 112 Michet et al[17]
7 (2%) of 292 Total
Takayasu arteritis 3 (2%) of 180 Piette et al[20]
Mesenteric panniculitis 3 (2%) of 180 Piette et al[20]
Spondyloarthropathy 2 (1%) of 180 Piette et al[20]
3 (3%) of 112 Michet et al[17]
2 (3%) of 62 Zeuner et al[16]
7 (2%) of 354 Total
Diabetes mellitus 1 (2%) of 62 Zeuner et al[16]
3 (2%) of 159 McAdam et al[15]
4 (2%) of 221 Total
Reactive arthritis/psoriatic arthritis 2 (1%) of 159 McAdam et al[15]
1 (< 1%) of 112 Michet et al[17]
3 (1%) of 271 Total
Systemic sclerosis 2 (1%) of 159 McAdam et al[15]
Raynaud syndrome 2 (1%) of 159 McAdam et al[15]
Glomerulonephritis 2 (1%) of 159 McAdam et al[15]
Dysgammaglobulinemia 2 (1%)of 159 McAdam et al[15]
Pernicious anemia 1 (1%) of 159 McAdam et al[15]
Behçet disease* 1 (< 1%) of 112 Michet et al[17]
Psoriasis 2 (1%) of 180 Piette et al[20]
Lichen planus 2 (1%) of 180 Piette et al[20]
Primary biliary cirrhosis 1 (< 1%) of 112 Michet et al[17]
*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.[22]

Epidemiology

Frequency

United States

In clinical reports and reviews, relapsing polychondritis is reported to be a rare disease. The annual incidence in Rochester, Minnesota, was noted to be 3.5 cases per million population.[23]

Mortality/Morbidity

The 5-year survival rate associated with relapsing polychondritis has been reported to be 66-74% (45% if relapsing polychondritis occurs with systemic vasculitis), with a 10-year survival rate of 55%. In another report, a survival rate of 94% at 8 years has been reported.[18] 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 regurgitationmitral 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.[24, 18] 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.

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.[18] 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 (See the image below.)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

Diagnostic criteria for relapsing polychondritis 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 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. See the image below.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. See the images below.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.[25]
    • 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 epistaxismay be present.
    • A saddle-nose deformity may develop in longstanding disease. See the image below.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%). See the image below.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 keratitisis 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, andmyocardial 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. See the image below.Severe auricular edema and inflammation. Courtesy of the University of Washington, Division of Dermatology.
      • Various nonspecific skin lesions have been reported.
        • Aphthous ulcersare 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 syndromeurticarial vasculitis, andKaposi 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.[26, 27]
      • 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.[28]
      • 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.[29] The two types of MAGIC syndrome are as follows:[30]
        • 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.[31] 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.[32, 33]
        • Aseptic meningitishas been reported infrequently in relapsing polychondritis.[34]
        • 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.[35]
        • 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.[35]
        • 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 underlyingmyelodysplastic syndromeand, less often, lymphoma. These cases may be paraneoplastic in nature.
        • Acute mastitis may be found in relapsing polychondritis.[21]
        • 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.[36]

Differential Diagnoses

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, as follows:

  • 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 Results

Chest radiography (posteroanterior [PA] and lateral views)

Tracheal stenosis may be observed on plain radiographs. See the image below.

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.[37] 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.

FDG-PET/CT

Yamashita et al reported on the use of of fluorodeoxyglucose (FDG)-PET/CT for the diagnosis of relapsing polychondritis and evaluation of disease activity. According to the authors, FDG-PET/CT is a potentially powerful tool for the early diagnosis of RPC, especially in patients without easily biopsied organ involvement, and facilitates evaluation of disease extent and disease activity during treatment. Typical FDG accumulation was noted in the following sites in the 13 patients studied[38] :

  • Tracheobronchial tree (nine patients)
  • Costal cartilage (five)
  • Joints (five)
  • Larynx (four)
  • Nasal cavity/paranasal sinuses (three)
  • Auricles (three)
  • Lymph nodes (three)
  • Aorta (one)

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 PA and lateral 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-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-67 citrate scintigraphy has also been found to show increased uptake in affected areas.

Other Tests

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.

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.

An 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.

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.[15] See the images below.

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.

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.[39, 40, 41, 42, 43]

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.

Medication Summary

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, methotrexate (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

Class Summary

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.

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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.

Disease-modifying antirheumatic agents

Class Summary

These agents inhibit cell growth and proliferation.

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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.

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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.

Monoclonal antibodies – Antitumor necrosis factor-alpha inhibitors

Class Summary

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.

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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.

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Etanercept (Enbrel)

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

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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.

Anti-CD20 antigen on B lymphocytes

Class Summary

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

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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.

Interleukin-1 receptor antagonists

Class Summary

These agents have anti-inflammatory characteristics.

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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.

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.[18] 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.

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