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.[1]
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.
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.[2]
In 1960, Pearson, Kline, and Newcomer reviewed 12 cases and expanded the clinical spectrum of relapsing polychondritis to include nonconcurring inflammation of the auricles, nasal septum, peripheral joints, and larynx, with occasional involvement of the middle and inner ears, the eyes, costal cartilages, spine, trachea, bronchi, and epiglottis. They noted that, after a few episodes of inflammation, the cartilage was replaced by fibrous connective tissue. The term relapsing polychondritis was introduced in that review.[3, 4]
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.[5]
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.[6]
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.[6] However, anticollagen type II antibodies are not specific to relapsing polychondritis; they have been identified in other arthritides such as rheumatoid arthritis (RA). The epitope specificity of the antibodies in relapsing polychondritis differs from those in RA, suggesting different mechanisms for formation and pathophysiologic roles.
Autoantibodies to minor cartilage-specific collagens (ie, types IX and XI) have been described. They are more likely to be found in association with antibodies to type II collagen in patients with relapsing polychondritis. Furthermore, levels of antibodies to matrilin 1, an extracellular matrix protein predominantly expressed in tracheal cartilage, were significantly higher in patients with relapsing polychondritis, especially in those with respiratory symptoms, than in patients with Wegener granulomatosis, systemic lupus erythematosus, or RA and in healthy controls.[7]
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.[8] A report of relapsing polychondritis in the newborn of a mother with relapsing polychondritis suggests that antibodies crossing the placenta are necessary and sufficient to elicit the entire clinical syndrome.
Using proteomic surveillance to identify ubiquitous cellular proteins in patients with relapsing polychondritis, researchers identified 5 proteins that may be autoantigens. These include (1) tubulin-alpha ubiquitous/6, which, as a family, are main components in microtubules; (2) vimentin, an intermediate filament protein; (3) alpha-enolase; (4) calreticulin, a Ca2+ –binding chaperon indispensable for cardiac development; and (5) colligin-1/2. All but tubulin-alpha have been described as autoantigens in other autoimmune diseases (eg, RA, mixed connective-tissue disease, Behçet disease). Although autoantibodies to tubulin-alpha have been reported in other autoimmune conditions, immunoglobulin G (IgG) antibodies to tubulin-alpha chains are rarely reported and may have diagnostic value in persons with relapsing polychondritis.[9]
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.[10]
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.[11]
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.[12]
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.[13]
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.[14]
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.[14]
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.[15]
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.[16]
Table. Autoimmune Conditions Reported in Patients With Relapsing Polychondritis
View Table | See Table |
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.[23]
Shimizu et al propose that the pathogenesis of relapsing polychondritis may involve alteration of gut microbiota. Their study found that the gut microbiome in patients with relapsing polychondritis contains higher numbers of microbes that produce propionate, which is a short-chain fatty acid that may affect interleukin-10 (IL-10)–producing regulatory T (Treg) cell differentiation in gut-associated lymphoid tissues.[24]
These authors suggest that in relapsing polychondritis, continuous stimulation of intestinal T cells by excessive propionate leads to the spontaneous production of IL-10 and a subsequent refractory period of T cells. In turn, hyporesponsiveness of Treg cells upon activation may associate with production by PBMC and subsequent chondritis.[24]
our findings suggested that propionate-producing gut microbes became predominant, leading to defective Treg cell function upon activation in patients with RP. Decreased production of IL10 by Treg cells and increased production of the inflammatory cytokine tumor necrosis factor–α TNFα by PBMC may lead to chondritis in patients with relapsing polychondritis.[24]
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.[25]
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%. Another study reported a survival rate of 94% at 8 years.ref18} However, those 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. In those with renal disease, uremia is the third most frequent cause of death.
Complications of relapsing polychondritis such as saddle-nose deformity (see the image below), 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. In patients older than 51 years, only anemia is associated with a poorer prognosis. Renal involvement is a poor prognostic factor at all ages.
View Image | Saddle-nose deformity. Courtesy of the University of Washington, Division of Dermatology. |
Complications of relapsing polychondritis include the following:
Relapsing polychondritis is most common in whites. Although the disorder has been found in persons of all races, few data are available for nonwhite persons.
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.[26, 19] Saddle-nose deformity and subglottic stricture are more common in females.
Relapsing polychondritis may occur at any age, but onset is usually in the fourth or fifth decade of life. No relationship exists between age of onset and sex.[1]
The wide 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.[19] In fact, one third of patients with diagnosed relapsing polychondritis see five 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:
On the basis of a retrospective study of 142 patients with RP, Dion et al proposed that the following three distinct clinical phenotypes of the disease exist[28] :
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.
Three of the six following clinical features are necessary for diagnosis:
One of the following three sets are necessary for diagnosis:
One of the following two conditions is necessary for diagnosis:
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.[29] See the image below.
View Image | 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 one or more episodes. See the images below.
View Image | Forward listing ear. Courtesy of the University of Washington, Division of Dermatology. |
View Image | Bilateral inflammation and structural collapse of the auricles in a patient found to have aortic dissection. Courtesy of the University of Washington,.... |
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.[30] Effusions may accompany arthritis and may be noninflammatory or mildly inflammatory.
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.
Nasal chondritis
Nasal chondritis occurs in 48%-72% of patients with relapsing polychondritis. The nasal chondritis is acute and painful and accompanied by a feeling of fullness over the nasal bridge. Mild epistaxis may be present. A saddle-nose deformity may develop in longstanding disease.[29] See the image below.
View Image | Saddle-nose deformity. Courtesy of the University of Washington, Division of Dermatology. |
Ocular inflammation
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. 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.
View Image | Unilateral episcleritis. Courtesy of Gregory J. Raugi, MD, PhD. |
Other ocular findings may include the following:
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. Findings may include the folllowing:
Audiovestibular damage
Audiovestibular derangements are experienced by 46%-50% of patients, usually those with concomitant auricular chondritis. Sudden loss of hearing is usually permanent, while tinnitus, nausea, vomiting, nystagmus, and vertigo may subside. In some patients, hearing loss is attributed to vasculitic damage to the eighth cranial nerve.
Cardiovascular disease
Relapsing polychondritis has been reported to affect the cardiovascular system in 24% of patients. Aortic and mitral valve regurgitation, aortic aneurysm, aortitis, aortic thrombosis, pericarditis, first- to third-degree heart block, and myocardial infarction, at times mediated through ostial stenosis of a coronary artery or arteries, have been reported.
Relapsing polychondritis aortitis exhibits inflammation in the media, leading to loss of glycosaminoglycans and elastic tissue.[31] Any region of the aorta and more than one region simultaneously may be affected. In descending order of frequency, they include the following:
The most common clinical presentations include aortic arch syndrome, abdominal aortic aneurysm, and aortic regurgitation. Silent rupture and death may occur.
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.
View Image | Severe auricular edema and inflammation. Courtesy of the University of Washington, Division of Dermatology. |
Various nonspecific skin lesions have been reported, as follows:
Other cutaneous lesions reported in patients with relapsing polychondritis and vasculitis included the following:
Isolated case reports of other cutaneous manifestations of relapsing polychondritis include the following:
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.[37]
Two types of MAGIC syndrome exist.[38] 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.[39] Neurologic symptoms may present before other more frequent manifestations of relapsing polychondritis. Manifestations may include the following:
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.[43] 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.[43]
Pathological biopsy findings include segmental necrotizing glomerulonephritis with or without crescents, interstitial lymphocytic infiltrates, interstitial fibrosis, active tubulitis, and glomerulosclerosis. The response to treatment varies from stabilization of renal function to renal failure.
Other conditions
Relapsing polychondritis has been seen in patients with underlying myelodysplastic syndrome and, less often, lymphoma. These cases may be paraneoplastic in nature.
Acute mastitis may be found in relapsing polychondritis.[22] Thromboembolism has been reported.
The cause of relapsing polychondritis is not known. Familial clustering has not been observed. A genotyping study by Terao et al found that HLA-DRB1*16:02, HLA-DQB1*05:02 and HLA-B*67:01, in linkage disequilibrium with each other, are associated with susceptibility to relapsing polychondritis. In Germans, susceptibility for developing relapsing polychondritis has been found to be increased slightly by the HLA-DR4 haplotype.[44]
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.[45]
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 the following studies:
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:
Tracheal stenosis may be observed on plain radiographs. See the image below.
View Image | 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), 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.[46] 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.
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[47] :
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.
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 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.
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.
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.
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.
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.[16] See the images below.
View Image | 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 .... |
View Image | 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.... |
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 cyclosporine. MTX has been dosed 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 the following:
In a French multicenter retrospective cohort study that included 41 patients with relapsing polychondritis treated with biologics (105 instances; TNF inhibitors, n=60; tocilizumab, n=17; anakinra, n=15; rituximab, n=7; abatacept, n=6), the overall response rate during the first 6 months of treatment was 62.9%; however the complete response rate was 19.0%. Reduction in corticosteroid doses was highly variable.[57]
Differences in clinical response rates varied with organ involvement. There were trends toward a lower response rate in patients with associated myelodysplastic syndrome and a higher response rate for nasal/auricular chondritis, sternal chondritis, and concomitant exposure to non-biologic disease-modifying antirheumatic drugs.[57]
Orally administered nonsteroidal anti-inflammatory drugs (NSAIDs) have not been effective.
Medical care must include assessment for and treatment of other confounding or concurrent autoimmune disorders.
Surgeries encountered in the care of patients with relapsing polychondritis may include the following:
Subglottic stenosis can be treated with submucosal corticosteroid injection followed by serial dilation. Wierzbicka et al reported good airway patency for more than 24 months in eight of 12 patients with relapsing polychondritis or other autoimmune disorders treated with this approach.[58]
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.
Relapsing polychondritis is a complex condition that requires a team approach for patient care, as follows:
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.
Clinical Context: 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.
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.
Clinical Context: 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.
Clinical Context: Recombinant interleukin 1 receptor antagonist expressed from Escherichia coli. Natural interleukin 1 receptor antagonist produced by macrophages/activated monocytes blocking effects of interleukin 1.
Clinical Context: Bactericidal and bacteriostatic against mycobacteria; mechanism of action is similar to that of sulfonamides in which competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. Used in some patients in whom prednisone did not control symptoms. Successes and failures have been reported; therefore, prednisone remains the DOC.
These agents possibly inhibit lysosomal enzyme activity, which in turn may reduce inflammation.
Clinical Context: 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.
Clinical Context: Soluble, dimeric recombinant TNF receptor fused to the Fc fragment of human IgG1. This binds to TNF and inhibits its activities.
Clinical Context: Recombinant fully-human IgG1 anti-tumor necrosis factor monoclonal antibody. It binds to TNF-alpha and reduces it ability to effect its biological activities.
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.
Clinical Context: 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.
CD20 is a B-lymphocyte antigen that regulates cell cycle initiation. Use described in one case report.
Clinical Context: 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.
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.[19] However, those 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.
Dion et al identified three factors associated with death in patients with relapsing polychondritis, as follows[28] :
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.
Disease Patients With Condition/Total Patients References Systemic vasculitis 3 (5%) of 62 Zeuner et al[17] 11 (10%) of 112 Michet et al[18] 8 (12%) of 66 Trentham and Le[19] 28 (18%) of 159 McAdam et al[16] 50 (13%) of 399 Total Cutaneous leukocytoclastic vasculitis 2 (33%) of 6 Priori et al[20] 6 (5%) of 112 Michet et al[18] 8 (7%) of 118 Total Thyroid disease 8 (5%) of 159 McAdam et al[16] 10 (15%) of 66 Trentham and Le[19] 2 (33%) of 6 Priori et al[20] 4 (4%) of 112 Michet et al[18] 2 (3%) of 62 Zeuner et al[17] 26 (6%) of 405 Total Rheumatoid arthritis* 8 (5%) of 159 McAdam et al[16] 3 (2%) of 180 Piette et al[21] 8 (7%) of 112 Michet et al[18] 7 (11%) of 62 Zeuner et al[17] 26 (5%) of 513 Total Systemic lupus erythematosus† 2 (1%) of 159 McAdam et al[16] 9 (5%) of 180 Piette et al[21] 1 (17%) of 6 Priori et al[20] 6 (5%) of 112 Michet et al[18] 3 (5%) of 62 Zeuner et al[17] 21 (4%) of 519 Total Sjögren syndrome (possible) 5 (3%) of 159 McAdam et al[16] 5 (5%) of 111 Piette et al[21] 10 (4%) of 270 Total Ulcerative colitis 3 (2%) of 159 McAdam et al[16] 2 (3%) of 62 Zeuner et al[17] 5 (2%) of 221 Total Crohn disease 2 (1%) of 180 Piette et al[21] 1 (2%) 62 Zeuner et al[17] 1 (100%) of 1 Haigh et al[22] 4 (2%) of 243 Total Mixed connective-tissue disease 5 (3%) of 180 Piette et al[21] 2 (2%) of 112 Michet et al[18] 7 (2%) of 292 Total Takayasu arteritis 3 (2%) of 180 Piette et al[21] Mesenteric panniculitis 3 (2%) of 180 Piette et al[21] Spondyloarthropathy 2 (1%) of 180 Piette et al[21] 3 (3%) of 112 Michet et al[18] 2 (3%) of 62 Zeuner et al[17] 7 (2%) of 354 Total Diabetes mellitus 1 (2%) of 62 Zeuner et al[17] 3 (2%) of 159 McAdam et al[16] 4 (2%) of 221 Total Reactive arthritis/psoriatic arthritis 2 (1%) of 159 McAdam et al[16] 1 (< 1%) of 112 Michet et al[18] 3 (1%) of 271 Total Systemic sclerosis 2 (1%) of 159 McAdam et al[16] Raynaud syndrome 2 (1%) of 159 McAdam et al[16] Glomerulonephritis 2 (1%) of 159 McAdam et al[16] Dysgammaglobulinemia 2 (1%)of 159 McAdam et al[16] Pernicious anemia 1 (1%) of 159 McAdam et al[16] Behçet disease* 1 (< 1%) of 112 Michet et al[18] Psoriasis 2 (1%) of 180 Piette et al[21] Lichen planus 2 (1%) of 180 Piette et al[21] Primary biliary cirrhosis 1 (< 1%) of 112 Michet et al[18] *Individual patients may carry more than one autoimmune diagnosis.
†Reported as 13 (20%) of 66 prevalence by Trentham and Le without division by disease