Relapsing Polychondritis: Review of Current Status and Case Report By Charles R. Arkin and Alfonse T. Masi

R

ELAPSING POLYCHONDRITIS is a rare disorder characterized by relapsing episodes of inflammation and degeneration of cartilage and connective tissue, resulting in pain and deformity of the nose and the pinna of the ears, hoarseness, arthropathy, loss of hearing, fever, and malaise. Also sometimes associated with this condition is involvement of the tracheobronchial tree, heart valves, eyes, and aorta.ld3 HISTORICAL

ASPECTS

This syndrome was first described in 1923 by Jaksch-Wartenhorst,4 and this first case was reviewed in English by Pearson in 1960.’ Jaksch-Wartenhorst reported a 32-yr-old brewery worker in Prague who initially had joint swelling and pain associated with fever. Later he developed burning pains in both external ears, which slowly became swollen and in 3 mo receded and shrank, leaving deformity of both pinna. He then developed a painless collapse of the middle segment of his nose, leaving a saddle nose deformity. By that time, there was nearly complete stenosis of both external auditory canals and decreased hearing was observed, even with the canals held open. A constant mild dizziness and tinnitus were present. Biopsy of the nasal septum showed “no cartilaginous matrix and hyperplastic mucosal membranes. ” Jaksch-Wartenhorst called this disorder polychondropathia. In 1936, Alther? and Von Meyenberge separately reported the autopsy of a lCyr-old boy who had degeneration and destruction of the cartilage of his ears, nose, ribs, joints, larynx, and tracheobronchial tree. They named this disorder chondromalacia. Bean et al.’ in 1958 published a summary of eight previous cases, added an additional one, and suggested the name chronic atrophic polychondritis. By that time, significant eye involvement was appreciated, and corticosteroids were employed in the treatment. Pearson, Kline, and Newcomer’ in 1960 reviewed ten previously reported cases and added four additional ones, two of which had other associated diseases. One had an acute vasculitis; the other had spondylitis, most likely ankylosing spondylitis, and psoriasis. Because of the episodic nature of this syndrome, they From ihe Section of Rheumaiology. Division of Connective Tissue Diseases, Department of Medicine, University of Tennessee College of Medicine and Baptist Memorial Hospital. Memphis, Tenn. Supported in part by Grants AM-12049 and AM-05055 of the National Institutes of Arthritis, Metabolism, and Digestive Diseases, Bethesda, Md. Charles R. Arkin, M.D.: Clinical Assistant Professor of Medicine, Department of Medicine, University of Tennessee College of Medicine and Department of Medicine, Baptist Memorial Hospital, Memphis, Tenn. Alfonse T. Masi, M.D., Dr. P.H.: Professor of Medicine and Director, Division of Connective Tissue Diseases, University of Tennessee College of Medicine and Baptist Memorial Hospital. Memphis, Tenn. Requests for reprints should be addressed to: Dr. A. T. Masi, 858 Madison Ave., Memphis, Term. 38163. 0 1975 by Grune & Stratton, Inc. Seminars in Arthritis and Rheumatism, Vol. 5. No. 1 (August). 1975

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suggested it be called relapsing polychondritis, which is now the generally accepted name. Recently, a new name has been suggested, diffuse chondrolysis,8 but this term has not received wide acceptance. BASIC ANATOMY

AND

PHYSIOLOGY

Relapsing polychondritis is primarily a disease affecting cartilage and connective tissue. In order to understand what is known about its pathogenesis and pathology, a brief review of the anatomy, physiology, and biochemistry of normal cartilage and connective tissue seems appropriate. The two basic components of connective tissue are the cellular and the intercellular matrix. The cellular components derived from mesenchymal cells include chondrocytes of cartilage, osteocytes of bone, and fibroblasts of other connective tissues. The intercellular matrix is composed of fibrillar elements and ground substance. The fibrillar elements include collagen, reticulum, and elastic fibers9 loosely linked with components of the ground substance,‘O which is an amophorus material between the cellular and fibrillar components. The ground substance is composed of macromolecules called mucopolysaccharides and mucoproteins. The mucopolysaccharides are also referred to as glycosaminoglycans. Chondroitin sulfate A and B are the major mucopolysaccharides of cartilage. A mixture of chondroitin sulfate and hyaluronic acid are found primarily in tendons, heart valves, and the aorta. Keratosulfate has been identified in the cornea, nucleous pulposus, and in aging cartilage. Also present in the ground substance are varying amounts of electrolytes, proteins, and hpids 11.12 The structure of cartilage consists of four zones. The most superificial zone is the tangential zone, consisting of flattened cells. The next zone is the transitional or intermediate zone, with plump ovoid cells in random orientation. The third zone is the radial zone, in which the cells tend to be more round and arranged in short irregular columns. The innermost zone is the calcified zone, adjacent to the bone.‘O The cartilage chondrocytes lie imbedded in the intercellular matrix. The matrix stains basophilic with hematoxylin and eosin, and metachromatic with certain other stains; the latter is characteristic of mucopolysaccharides present in the cartilage.13 A constant process of maintenance and catabolism exists in cartilage, as well as other connective tissue. The cells degrade the fibrillar elements and ground substance by lysomal enzymes, mainly proteases and collagenases.‘4-17 The cells at the same time rebuild new intercellular substance. It has been suggested that antibodies and the complement system, acting together, may initiate the catabolic process. Antibody-complement complexes may alter the chondrocyte cell membrane, releasing the lysomal enzymes.” ETIOLOGY AND

PATHOGENESIS

In relapsing polychondritis, the primary abnormality appears to be in the mucopolysaccharide component of the ground substance, resulting in a structural weakness.18 This accounts for the symptoms and physical findings of the disease except for episcleritis, iritis, and anemia.lg

RELAPSING

POLYCHONDRITIS

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Biosynthetic Defect

One possible pathogenetic mechanism could be a defect in biosynthesis. Against this being the only mechanism is the demonstration of mucopolysaccharides in regenerative perichondral tissue in patients with relapsing polychondritisls and the demonstration in some of these patients of islands of normal cartilage.2*‘g Enzymatic Proteolysis

Another possible mechanism is an abnormal loss of mucopolysaccharides. Supporting this theory are the changes in several animal models which closely resemble those seen in relapsing polychondritis.20-22 Crude papain injected intravenously into young rabbits will collapse the normally rigid ears within 4 hr, and biopsy of the collapsed ear cartilage shows loss of metachromasia and of basophilia. Reconstitution of cartilagenous matrix occurs spontaneously, resulting in restoration of the ears to their usual appearance within 7 days.*O Papain protease is the active factor in the crude papain, and after injection of the papain, chondroitin sulfate has been reported in the blood and urine of the rabbits.” A marked depletion of mucopolysaccharides in cartilage has also been demonstrated by radioactive labeling techniques. 22 These experiments would suggest a direct enzymatic action on the mucopolysaccharides which results in the release of chondroitin sulfate. Injection of papain will also alter the structure of the aorta in rabbits.23 Thomas et a1.24demonstrated that high doses of vitamin A will induce changes in cartilage similar to those seen after papain injection, with serum rises in chondroitin sulfate. It was suggested that these changes resulted from activation of proteolytic enzymes with properties similar to papain protease. In relapsing polychondritis, a depletion of the mucopolysaccharides has been demonstrated in cartilage and other connective tissues2 This observation might suggest excessive proteolytic enzyme activity in the connective tissue, but the cause for this is not known. Miscellaneous Factors

In the original case described by Jaksch-Wartenhorst, he suggested that his patient’s excessive use of alcohol was in some way a possible etiologic fact0r.l Also, infectious agents have been incriminated in the etiology of relapsing polychondritis.3.7*25 Syphilis, tuberculosis, diptheria, scarlet fever, varicella, rubella, typhus, erysipelas, blastomycosis, and actinomyocosis have been associated with a perichondritis of the larynx and thyroid cartilage, but no severe generalized cartilaginous destruction has been observed.’ In many reports of relapsing polychondritis, attempts to culture an infectious agent have failed, and the use of antibiotics have been of no help in treating this disorder.3*7,25,26 Trauma has been suggested as a possible etiological factor. Kahn and Kilburg”’ reported one patient with the onset of polychondritis after receiving sunburn the preceding summer and frostbite on the ears the winter of the onset of the disease. Hainer and Hamiltonz8 reported a case of a gardener who, just before the onset of polychondritis, had received a scratch to his ear while working on a holly tree.

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Rogers and Lansburyzg reported a case in which a patient received several injections of gonadotrophin. After each injection, the patient had a flareup of her polychondritis symptoms. It was felt that the injections of the foreign material might be acting as a precipitating factor.2 Immunologic Studies Many authors have suggested autoimmunity as an etiologic or pathogenetic factor. Harwood2s injected guinea pigs with extracts from their own cartilage either alone or in Freud’s adjuvant, but no reaction in the guinea pigs’ cartilage was observed. Glynn and Holborow30 injected small quantities of chondroitin sulfate, together with Group A beta hemolytic streptococci, into rabbits. Precipitins were produced against chondroitin sulfate, and an acute synovitis resulted. They believed that chondroitin sulfate in the injection acted as a haptene which, together with the streptococci, resulted in an antibody with immunologic specificity against the chondroitin sulfate of the rabbits cartilage. Di Ferrante31 produced precipitins in rabbits by injecting protein polysaccharides from bovine nasal cartilage in Freund’s adjuvant. It was postulated that the antibodies were directed toward determinants consisting of carbohydrate and amino acid residues linked in three dimensional arrangements specific for different protein polysaccharides. Dolan and associates3 reacted the serum from two relapsing polychondritis patients and one normal subject with normal cartilage, using an immunofluorescent technique. All preparations exhibited fluorescence, but the normal serum to a lesser degree. Hughes et a1.2demonstrated by a fluorescent antibody technique anticartilage antibodies in two of their three cases of relapsing polychondritis. Normal serum gave a nonspecific fluorescence which was distinguished from the anticartilage pattern. However, they found an anticartilage pattern in 2 of 12 patients tested with rheumatoid arthritis, but in none of 11 other patients with vasculitis or SLE. They suggested that the anticartilage antibodies could either play an etiologic role, or could more likely be the result of cartilage destruction. Rogers et a1.32reported one patient with relapsing polychondritis, and by indirect immunofluorescence demonstrated anticartilage antibody activity which they could not demonstrate in control subjects and several RA and SLE patients. Herman and Dennis33 in 1973 reported serial studies performed on three patients with relapsing polychondritis in an attempt to define a potential immunopathologic factor. They were unable to identify a circulating antibody to cartilaginous matrix or chondrocytes. Delayed hypersensitivity to cartilaginous constituents was studied by peripheral blood lymphocyte transformation and the release of a macrophage-aggregation factor. Positive results were obtained which correlated with periods of overt disease activity. This observation suggests that antigenic cartilaginous components may facilitate the perpetuation of cartilaginous inflammation by cellular immune mechanisms. Rajapakse and Bywaters studied two cases of relapsing polychondritis and found no evidence of humoral immunity by double diffusion or immunofluorescent staining methods. By the macrophage migration inhibition method and lymphocyte transformation, they also demonstrated cell-mediated immunity to cartilage in the two patients. This cellular immunity was absent in nine control subjects, including three with RA,

RELAPSING

45

POLYCHONDRITIS

two with Still’s disease, and one each with sarcoid, polyarthritis, ankylosing spondyhtis, and rheumatic fever. It is obvious from the above discussion that immune mechanisms are involved in relapsing polychondritis, but it is not known whether they are, on the one hand, etiologic or pathogenic, or, on the other hand, secondary to the antigenic stimulation of cartilage or its degradation products released during active disease. PATHOLOGY

General Features

The normal cartilage, when stained with hematoxylin and eosin, appears basophilic because the acid mucopolysaccharides are stained by the hematoxylin.‘“*25 Periodic acid-Shiff stain has also been used to study cartilage, and strong staining by this technique suggests a high concentration of glycogen and neutral polysaccharides. I8 Stains such as toluidine blue demonstrate the characteristic metachromasia of normal cartilage. 35Another staining technique used to demonstrate mucopolysaccharides is Alcian Blue;2*‘s by varying the molarity of the magnesium chloride in this dye, one can stain the different classes of mucopolysaccharides. The pathologic findings in relapsing polychondritis in all the cartilage, whether it be from the nose, ear, trachea, or ribs, is believed to be similar.1*2~3~1x In the acute phase, basophilia is lost with emergence of acidophilia, lacunar breakdown, infiltration of neutrophils into the cartilaginous matrix, and loss of metachromasia. As inflammation continues, the delicate fibrillation condenses into irregular whorls of collagen with plasma cell and lymphocyte infiltration. Chondrocytes dedifferentiate, forming fibroblasts with the development of collagen fibers.36 At this stage, periodic acid-Shiff and Alcian Blue staining shows significant loss of all classes of mucopolysaccharides from the cartilage. After destruction of the cartilage, granulation tissue replaces cartilage, with occasional small sites of cartilage regeneration. An overabundance of granulation tissue leads to thickened nodularities in some areas, resulting in knots on the ears or narrowing of the trachea. Cystic spaces which contain a gelatinous fluid are also seen as the inflammation subsides. Focal areas of calcification and bone formation may be seen as the lesions age further.1*3*18 Articular

Of considerable interest is a report on the pathologic changes in the synovium and cartilage by Mitchell and Sheppard. 37They described findings from an open biopsy of a swollen metacarpophalangeal joint in a patient with classical relapsing polychondritis and compared their findings to normal and RA synovium.38 The polychondritis patient showed a synovitis characterized by chronic inflammation with a predominance of plasma cells. The lining of the synovium had an increase of type A cells. Hughes and associates2 also described similar synovial biopsy findings of a patient with relapsing polychondritis. Cartilage of Mitchell and Sheppard’s patient also showed definite changes. In the superficial zone, the surface appeared irregular, with a moderate loss of staining. Many of the cells were absent from lacunae, being replaced with round

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yellow droplets. Electron microscopic studies of the superficial zone showed that many chrondrocytes contained large amounts of lipid and lysosomes, and many cells appeared dead, with large collections of fat remaining in the lacunae. In the intermediate and deep zones, many chrondrocytes were also thought to be dead. The normal appearing chrondrocytes present contained only an occasional lysosome. Most of the cells were located in clear pericellular spaces, and some had processes which contained at their ends round, electron-dense, multivesicular bodies which had not previously been described in cartilage, either from normals or rheumatoid arthritis. It was suggested that these multivesicular bodies might play some role in matrix destruction. Heart Valves Verity et al.18 in 1963 presented a classic description of the pathology of relapsing polychondritis where no evidence of aortic or cardiac involvement could be found, and they concluded that this was not part of the disease. However, in 1966, Yamazaki et al.3g reported a patient with relapsing polychondritis who had peripheral symptoms for 17 yr before suddenly developing aortic insufficiency, and they believed that this was a complication of the disease. Self et al-l9 in 1967 described autopsy findings of a patient with relapsing polychondritis that demonstrated disrupted aortic elastic fibers typical of cystic medial necrosis. They performed periodic acid-Shiff and Alcian Blue stains on the aorta and described them as normal. Pearson et al.40 in the same year emphasized the importance of aortic insufficiency in relapsing polychondritis, as well as aneurysma1 dilatation of the aorta. Two of their patients required surgery because of aortic regurgitation; at surgery, the aortic ring was dilated with normal valvular cusps. Histologically, the ascending aorta showed medial vascularization with inflammatory cellular response, some perivascular flbroplasia, decreased collagen, and profound fragmentation of the elastic tissue fibers. They described depletion of the acid mucopolysaccharides by the Alcian Blue technique, but normal periodic acid-Shiff staining. Later, Hainer and Hamiltonz8 described a patient with aortic insufficiency and a dissecting aneurysm extending from the valvular ring to the descending aorta. Hughes et al2 reported a case that required a Starr-Edwards valve replacement for aortic regurgitation; interestingly, 22 mo later, the patient died of a ruptured aneurysm of the abdominal aorta. They found depletion of all classes of mucopolysaccharides in the aortic wall, not just acid mucopolysaccharides, as proposed previously. I9 The involved aorta with usual staining techniques can appear almost normal* or can show areas of patchy destruction of the elastic and muscular fibers of the media with secondary fibrosis of the intima and adventitia.41 Alexander et a1.42 reported a patient requiring aortic and mitral valve replacement by Starr-Edwards valves. Both excised valves were markedly atrophic. The leaflets were retracted and their free margins were thickened and rolled, but not calcified. Amino acid analysis of the excised valves revealed a 50% decrease in hydroxyproline and a 24% decrease in glycine content as compared to normal, and significant increase in proline, alanine, valine, leucine, isoiuecine, and tyrosine. Since hydroxyproline and glycine are the major amino acids in collagen, the decrease in these values in the valves of this patient would suggest a significant

RELAPSING

POLYCHONDRITIS

loss in the valvular collagen in relapsing polychondritis. revealed an increase in the valvular content of fatty triglycerides with a normal cholesterol. The significance relapsing polychondritis heart valves is not known.

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Further clinical analysis acids and a decrease in of these lipid changes in

Ocular Eyes involved in patients with relapsing polychondritis have been infrequently studied histologically. In the first case report of Verity et al.,” a study of the eyes, which were clinically normal prior to death, revealed a minimal decrease in basophilia and fragmentation of the elastic tissue in the scleroconjunctival angle. Scattered mast cells, plasma cells, and lymphocytes were present about the episcleral vessels. Barth and Berson43 presented a patient with relapsing polychondritis who developed extensive marginal keratitis with hypopyon which progressed to ulceration and perforation of the cornea, with resulting blindness; the eye was enucleated because of severe pain. Microscopic examination revealed a moderate inflammatory reaction in the peripheral cornea1 stroma predominately composed of plasma cells and polymorphonuclear leukocytes. The cornea1 stroma was necrotic and edematous. The iris was infiltrated with lymphocytes, plasma cells, and granulation tissue. These changes are fairly nonspecific and are seen in a number of diseases, especially in formsof vasculitis, such as polyarteritis nodosa and Wegener’s granulomatosis.44 A gradual thinning of the sclera following repeated episodes of episcleritis in a case of relapsing polychondritis has been observed. 45 It was suggested that the scleral absorption was analogous to that observed with cartilage because, phylogenetically, sclera is closely related to cartilage. Other Organ Lesions Muscles are not usually involved in relapsing polychondritis. Muscle biopsies taken in the course of this disease are generally norma1.‘z3 One instance is reported where the muscle biospy showed focal areas of degeneration,46 but this finding remains unexplained. Renal involvement is rare in relapsing polychondritis; if present, it is usually found with an associated vasculitis syndrome. Middleton4’ reported a patient with scleroderma and relapsing polychondritis who, at autopsy, had occlusive hyaline thickening and laminated fibrosis of the walls of the intrarenal arteries and arterioles. This is similar to the renal changes seen in scleroderma. In one of the cases reported by Dolan et a1.,3 renal biopsy revealed only moderate arteriolar sclerosis and focal round cell infiltration of a nonspecific variety. The postmortem examination of another patient reported by Herman and Dennis”” showed microscopic changes in the kidney compatible with polyarteritis. In case 3 of Hughes et al.,* a renal biopsy showed severe glomerulonephritis, with fibrinoid necrosis of the tufts of 14 of 16 glomeruli and extensive crescent formations. It might be mentioned that a few cases of slightly abnormal liver function tests have been reported in relapsing polychondritis patients. At postmortem examination, the most striking findings involving the liver were nonspecific changes of passive congestion and fatty metamorphosis.3

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CASE REPORT The patient, Mrs. T.T., is a 56-yr-old white female farmer’s wife who was seen in May 1974 because of painful swelling and redness of the pinna of her right ear. The patient stated that about 4 yr previously, an episode of painful swelling over the bridge of her nose lasted for several weeks and then cleared. In 1972, she had the first swelling of the right external ear; this became extremely painful and red and lasted about 2 wk, then cleared without treatment. She denied any preceding trauma. Since that time, the patient has had at least four or five episodes of swelling of her ear, and recalls at least one episode involving the left ear. She also had one additional episode of swelling over the bridge of the nose. Each of the episodes lasted from 2 to 3 wk and then cleared spontaneously. The patient denies any joint swelling, although she noted some stiffness in her knees, ankles, hands, and hips. She has been unaware of any pain in the costocartilage area or any problems with her neck. She has felt as though there has been some decrease in her hearing, but she denies any dizziness. Of special interest is the family history-her mother, who died at age 73 of a stroke, had numerous attacks of swelling of the external ears, which became red and painful. Each episode would last for several weeks, and then clear. The patient also has one sister who has had two episodes of marked swelling of the left pinna lasting for several weeks and then clearing; the last such spell was 2 yr ago. Examination in May 1974 revealed a well-developed, somewhat obese white female with blood pressure of 160/100, pulse 96 and regular, temperature 98”F, height 64 in, and weight 178 lb. The general examination was normal, except for redness and swelling of the pinna of the right ear, with complete sparing of the noncartilaginous lobule. There was no deformity of the nose or any joint involvement. Laboratory studies included hematocrit, 45; hemoglobin, 15.2; WBC count 9200 with 65% segmented neutrophils, 33% lymphocytes, 1% esinophils, and 1% monocytes. Westergren sedimentation rate was 18 mm fall in 1 hr. Urinalysis revealed a trace of albumin, but was otherwise normal. SMA18 was normal except for slight increase in alkaline phosphatase to 130 (normal 30 to 70). Serum complement by the C3 method was normal, rheumatoid factor negative, fluorescent antinuclear antibody negative, DNA binding, 12.3% (normal O-20); VDRL negative. PA and lateral chest x-ray were normal. Electrocardiogram normal. X-ray of the trachea with tomograms and xerography normal. Testing of the hearing revealed some high-tone deafness noted, especially in the right ear. Evaluation of vestibular function was normal. Biopsy of both the inflamed right ear cartilage and the quiescent left ear cartilage were obtained. Both cartilages showed pathologic findings, with loss of normal basophilia and metachromasia. There was a considerable perivascular infiltration of polymorphonuclear leukocytes, monocytes, and some endothelial proliferation of capillaries in the right ear (Fig. lA,B).

CLINICAL

FEATURES

Demographic Relapsing polychondritis may occur at any age; one report of the disease was found at birth,46 another at age 2 yr,4s and one case has been reported of a patient in the ninth decade.2 The sex prevalence is almost equal, with reported cases occurring in 69 males and 63 females.* This disorder occurs mainly in whites, but has been reported in three Arundell and Haserick46 in 1960 reported Blacks25*32*57and in three Asians. 28*3g.57 a patient who had the typical findings of relapsing polychondritis during her second pregnancy, and at birth the infant had tender, red swollen knees and lower calves. The acute symptoms subsided after 6 wk, but the infant then developed a saddle nose deformity. The mother received no treatment for the relapsing polychondritis during her pregnancy. There have been two additional cases of *Statistics in this paper are derived from the 114 cases reviewed by Hughes et al.Y and the 17 additional cases which the authors have found in the literature,X.J’.““.‘l~,‘y..~“~~l~plus the case report in this paper.

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Fig. 1. (A) Biopsy from involved right ear cartilage of Mrs. T.T. shows patchy loss of normal basophilia and inflammation of perichondrium. (B) Biopsy from a clinically uninvolved area of ear cartilage of a patient who had a basal cell carcinoma of ear excised. Hematoxylin and eosin. x 100.

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Table 1. Precentage

Frequency

of Major Clinical

Features Positive at Presentation

and During the Course of Relapsing Polvchondritis

Features inflammation

of pinna

Arthropathy Nasal cartilage Laryngotracheal

involvement involvement

Presenting Features of 113 Cases (%)

Positive Features During course of 132 cases (%)

32

86

22

70

17

72

12

44

Fever

4

45

Episcleritis

10

39

Hearing impairment

-

Conjunctivitis lritis Aortic

insufficiencv

-

30 4

23

3

19 9

women with active relapsing polychondritis during their pregnancy. Both children were horn normal and remained so. One of the women was on corticosteroids,’ the other on salicylates33 during the pregnancy. Familial Occurrence In the case which we reported, there was family history of the patient’s mother and sister having episodes of inflammation of the external ear, but this was not confirmed by biopsy as being relapsing polychondritis. In one of Pearson’s patient’s, there was a history of a sibling with episodes of external ear inflammation. However, no documented familial occurrence has been reported. The per cent frequency of the presenting manifestations and main clinical features found in the course of relapsing polychondritis is shown in Table 1. External Ear The external ears are involved in 86% of reported cases, and was the initial symptom in 32%. Helix and antihelix become swollen and tender in the acute phase, with a violaceous hue and obliteration of the normal contours. An acute episode of inflammation may last only a few days or up to several weeks and then subside spontaneously. After a single long attack or repeated shorter attacks, loss of cartilage in the ear results in the pinna becoming flabby and droopy; it may even flop up and down as the patient walks. These external ear changes are frequently referred to as “cauliflower ears.“2p50 The lobulus of the ear which contains no cartilage is conspicously spared. 48At times, a clear, serous-like discharge exudes from the external ear.3 Auditory Hearing impairment was noted in 30% of reported cases; the suggested mechanisms include: (1) eustachian tube obstruction and serous otitis media, (2) closure of the external auditory meatus during the acute inflammatory phase, (3) inflammation of the middle ear, and (4) neurosensory hearing 10~s.~~ Dalyeo described a patient with bilateral hearing loss due to serous otitis which he attributed to chondritis of the nasopharyngeal two-thirds of the eustachian tube. Cody and Sone.9’ reported three additional cases of conductive hearing impairment, presumably due to dysfunction of the eustachian tube as a result of

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inflammation of the cartilaginous portion of the eustachian tube. Ten patients have been reported with neurosensory hearing 10ss,~‘-~~ and it has been shown that the hearing impairment is of the cochlear type, presumably due to inflammation of the internal auditory artery or its branch, the cochlear artery. Four of the eight patients with neurosensory hearing loss reported by Cody and Sones”’ had sudden onset of hearing impairment reaching a maximum loss in 24 hr. The others had a slower onset which gradually reached maximum hearing loss over a period from 3 wk to 24 mo. One of their patients had hearing loss as the very first manifestation of relapsing polychondritis. Reversal of the neurosensory hearing loss has been observed on several occasions with corticosteroid treatment.1,62 Ves tibular Vestibular dysfunction is common and manifests as vertigo, ataxia, nausea, or vomiting. Cody and Sones 61 found vestibular dysfunction in eight of their 40 patients, as indicated by an abnormal caloric test, but none had spontaneous nystagmus. They suggested that the abnormality was due to an arteritis of either the internal auditory artery or its vestibular branch. Nasal Nasal cartilage involvement was present in 72% of reported cases and was the initial symptom in 17%. The nose may be acutely inflamed, tender and red. After repeated bouts of inflammation, the nasal cartilage can collapse, forming the “saddle nose” deformity (Fig. 2) but the nasal cartilage can change without overt inflammation.3 Swain and StroudSo reported a case with the development of a classical “saddle nose” deformity while the patient was asleep and which spontaneously improved within 3 days. This is the only reported instance of spontaneous improvement of this deformity. Associated with the cartilaginous inflam-

Fig. 2. Classical ear and saddle nose deformity shown in patient with relapsing polychondritis reported in reference 40 and reproduced by permission of Dr. Carl M. Pearson and Association of American Physicians.

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mation is severe crusting inside the nose, rhinorrhea, and epistaxis.2*45 Anosmia has not been reported to date. Laryngotracheal

Laryngotracheal involvement including the epiglottis, bronchial, and thyroid cartilages was the initial symptom in 12% of reported cases, and occurred sometime in 44%. The patient may complain of tenderness over the trachea or larynx, as the cartilage of these structures becomes inflamed, and hoarseness is a common complaint. Due to respiratory passage swelling, dyspnea and wheezing may occur. Also, secondary infections such as tracheitis, bronchitis, or pneumonia may occur. As the disease progresses, airway collapse may lead to death.2 Articular

Arthropathy

has been reported in 70% of cases and was the initial symptom in presentation may be either transient arthralgia or arthritis. Occasionally, more persistent arthritis with marked swelling and increase in local heat may occur. Commonly, joints of both the upper and lower extremities are involved, including hands and feet. Arthropathy may be monoartitular or polyariticular, but not particularly symmetrical, and not usually deforming. However, Rogers and Lansbury2g reported a patient who had a dislocation of the right sternoclavicular joint and the manubriogladiolar junction, as well as marked deformity of the wrists and the hands. Also, Hilding65 reported a patient with relapsing polychondritis with multiple joint dislocations without demonstrable destruction of the bone or joint surface. Involvement of the costocartilage occurred in 29% of reported cases. Initially, there may be only pain in the chest, but this involvement may result in chest wall deformity and a flail chest due to costocartilage destruction. Transient tenosynovitis, although not common in relapsing polychondritis, has been reported in at least two cases.33’4g Back pain may also be part of the clinical picture of relapsing polychondritis. One of the cases reported by Pearson et al. had ankylosing spondylitis.’ Other cases with the radiologic changes of spondylitis have been reported, and back pain has been the initial symptom in a few patients.43v66Dorsal kyphosis may be noted, and aching in the cervical, dorsal, or lumbar areas has been described.2g~4g~50~51~53~67 One case has been reported of actual destruction of an intervertebral disc in the cervical area.88 22%. The most common

Ocular

Ocular involvement occurs in at least 60% of patients and was the initial manifestation in 14%. The most common eye involvement is episcleritis, then conjunctivitis, i&is, and keratitis,* with other less common involvements reported. Rucker and Fergusonsg reported a patient with paresis of the left lateral rectus muscles and severe pain in that eye, with photophobia and exophthalmos; the latter disappeared in 12 days. Then the patient developed exophthalmos in the right eye, with mild paresis of the right lateral rectus muscle. On corticosteroid treatment, the abducent paresis improved, as did the exophthalmos. Another patient was reported by Hughes et al.2 to have transient lateral rectus muscle

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53

weakness. Anderson45 described a patient with thinning of the anterior sclera resulting in a bluish discoloration. Detachment of the retina, episcleritis, and cecocentral scotoma were also noted in this patient. Bergaust and Abrahamson7” recorded a case of relapsing polychondritis with recurrent eye complications, including scleroiritis, sclerokeratitis, and bilateral panuveitis with exudative chorioretinitis. Cases with retinal exudate,3 retinal artery thrombosis,4Q and complete blindness43s65have been reported in association with relapsing polychondritis. Cardiovascular

Heart valve abnormalities have been described in 12 cases of polychondritis.2*4QJ3Ten of the twelve patients were males, and aortic insufficiency was the most common abnormality, being present in 11 patients. Heart failure occurs which, at times, has been controlled by digitalization and diuretics,3Q,53 but at other times has required either a valvuloplasty or Starr-Edwards valve replacement.2*40 Alexander, Derr, and Sako42 described a patient who developed severe aortic, mitral and tricuspid insufficiency associated with intractable heart failure. The patient had aortic and mitral valve replacement with Starr-Edwards valves, resulting in a dramatic improvement. Hemry et a1.4Qin 1972 reported a patient with relapsing polychondritis who also had mitral regurgitation due to a “floppy” valve, the so-called “Barlow syndrome.” This resulted in a loud apical midsystolic click, followed by a systolic murmur which lengthened with Valsalva maneuver. It was postulated that the lesion was due to involvement of the connective tissue of the chordae tendineae, allowing its lengthening and the valve leaflet to bellow up into the left atrium. The temporal development of valvular involvement in relationship to other manifestations of the disease varies considerably. in the case described above by Hemry et al., a mitral murmur was noted within 6 mo of the onset of symptoms. Owen, Irby, and Toone recorded a patient in whom aortic insufficiency was noted 20 mo after the onset of disease. The longest interval between the onset of relapsing polychondritis and the development of a valvular lesion was 17 yr, as reported by Y amazaki.3Q Aneurysm of the ascending aorta has been noted in six of ten patients with aortic regurgitation.* Other aneurysms include three involving the descending aorta; one the thoracic aorta45 which was successfully repaired surgically; and two the abdominal aorta,2*45 but both of these patients died from rupture of their aneurysms. Dermal

Skin lesions have not been found typical of relapsing polychondritis. One patient with alopecia 65has been described, but this developed prior to the clinical onset of the disease. Retardation of finger and toenail growth for 5 mo was reported by Bean et a1.7 An erythematous maculopapular eruption on the extremities was reported in one patient by Herman and Dennis.33 Erytbematous and vesicular skin nodules on the limbs and trunk were observed on one patient recorded by Pearson.’ Skin biopsy of these lesions revealed nonspecific vasculitis and necrosis of the subcutaneous fat. The same author reported another patient who had pustular psoriasis preceding the onset of polychondritis by about 8 yr.

54

ARKIN AND

LABORATORY

MASI

FINDINGS

No specific diagnostic laboratory abnormalities are found in relapsing polychondritis, but a number of different laboratory studies may be abnormal, as shown in Table 2. Anemia is present in about 62% of reported cases, and the anemia is mainly normocytic normochromic. 2*28Serum iron and iron-binding capacity have both been reported to be low. This suggests a hypoproliferative anemia, as seen in collagen and other chronic diseases. Dolan et a1.3reported one case in which hemolytic anemia was believed present. Bone marrow examination is usually normal in appearance, with stainable iron present.3*28 In one case of Herman and Dennis,33 the bone marrow revealed 8%10% plasma cells, and the patient had a polyclonal gammopathy seen on protein electrophoresis. It was believed that this did not represent multiple myeloma, but rather a chronic disease-induced plasmocytosis, as has been described in rheumatoid arthritis and other chronic diseases.71 An elevated sedimentation rate is the most consistent laboratory abnormality, and frequently has been found above 100 mm in 1 hr by the Westergren method.2,3.48*55When combining all reported cases, the sedimentation rate is elevated about 88% of the time. Leukocytosis and eosinophilia are also frequently noted.2*3 The serum has been reported positive for rheumatoid factor in 10 of 56 determinations on patients with relapsing polychondritis. Some of the patients had other findings of rheumatoid arthritis, thus allowing the dual diagnosis of rheumatoid arthritis and relapsing polychondritis to be made.4s There are at least three instances of a positive LE cell preparation reported in patients with relapsing polychondritis.3*32*66In one case, the patient had definite findings of SLE,3 and in the other two cases the LE prep which was initially found positive was later negative after 466and 10 yr.32 Nonspecific serum protein abnormalities have been noted, consisting of diminished serum albumin, as well as alpha-2 and gamma globulins.3 However, elevations of beta and gamma globulins have also been noted.1g~4g~54 Only in the cases have the immune globulins been most recent reported measured.32~33~4g~54*67~7z Several cases had completely normal immune globu1ins.33J4*70Elevation of IgG was noted in two patients,32*4gelevation of IgA in one patient,67 elevation of IgG and IgM in one patient,32 of IgG, IgA and IgM in one patient.33 Table 2.

Laboratory

Abnormalities

and Their

Frequency

in Relapsing Polychondritis Percentage

Laboratory

Test

NO. Tested

No.

Positive

Positive

ESR elevation

95

84

Anemia

84

52

62

Leukocytosis

84

37

44

Eosinophilia

88

62

11

18

Rheumatoid

factor

56

IO

18

Treponemal

serology

57

5

9

L.E. prep

61

3

5

Significant A.S.O. titer Antinuclear factor

23 7

5 1

22 14

RELAPSING

POLYCHONDRITIS

55

Serum complement determination has only been reported in six patients. One patient had a normal total hemolytic complement,4g four had normal C3 determinations, and one had an elevation of C3.32*33 Antinuclear factor was reported normal in six of the seven cases in whom it was done.32*33*37.4g.72 In two cases, haptoglobin levels were determined and found to be elevated.33 In two cases, cryoglobulins and thyroid antibodies were searched for, but not found.33.73 A few patients had positive serology for syphilis, and elevated antistreptolysin 0 titers have been reported.2 Kaye and Sones48 reported the use of urinary acid mucopolysaccharide determinations by the method of Di Ferrante and Rich.74 This test detects the amount of glucuronic acid in the urinary mucopolysaccharides, and the amount was compared to the creatinine content of the same specimen. The ratio between the two was calculated, and a ratio of 4.21 or greater was considered abnormal. They performed this test on four patients with relapsing polychondritis, and three had flares during the period of observation with a significant increase found in the ratio during the time of the flare, reaching as high as 17.6. In each patient, the ratio returned to normal after moderation of the symptoms. This would appear to be a useful test for detecting the presence of, as well as a gross quantitation of, cartilaginous destruction. The test, however, is infrequently used because of difficulty in performance, and when performed, it may be normal during flares of relapsing polychondritis.4g*50 The ECG, when performed on patients with relapsing polychondritis, has usually been normal. First degree heart block has been reported on a few occasions.2g*33 Also, evidence of left ventricular hypertrophy and nonspecific ST-T wave changes have been noted.3g Radiologic findings are of interest in relapsing polychondritis. Evidence of cartilaginous destruction and its effect on other structures is a major finding. X-ray of the ear can show calcification of the pinna. 5o Dolan found this present in 40% of his patients.3 Also, x-ray of the trachea and the nose may reveal clacification of the cartilage. Tomograms of the trachea can demonstrate narrowing of the trachea. This has been observed in up to 30% of patients so x-rayed.3 The use of xerography of the neck can also be used to evaluate tracheal size. Also, calcification of the larynx has been observed.54 Cinebronchography has been used to demonstrate narrowing of the bronchial tree.37 Chest x-ray in the acutely ill patient may demonstrate pneumonia or atelectasis due to partially or completely collapsed airways.lg There may also be evidence of cardiomegaly, pulmonary congestion, widening of the aortic arch, prominence of the ascending, and possibly descending aorta when cardiovascular involvement is present.53 X-ray of the skeletal system usually shows good bony mineralization, and the changes primarily involve the joints. Soft tissue swelling may frequently be noted.“2 Eburnation of the bone has been described, and periarticular osteoporosis and bony erosion have been described, but significant deformity is rare.3*8.37 Rogers and Lansbury, however, described a patient with relapsing polychondritis with multiple deformed joints in 1955.2g X-rays of the spine are usually normal, but a few cases have demonstrated definite abnormalities. Severe kyphosis, joint space narrowing, and erosion of the

56

ARKIN

AND MA.9

vertebral end plates have been reported. 52*e7The sacroiliac joints have been involved with erosive irregularities of the cartilage-bony borders and partial obliteration of the joint space, somewhat similar to ankylosing spondylitis.52 Biopsy of the involved cartilage is frequently useful. Biopsy should be obtained from regions most recently involved, but care should be taken to choose a site which will cause minimal disfigurement. 48The pathologic findings in the cartilage have been previously described in this paper and, if typical, together with the clinical picture presented above, allow the diagnosis of relapsing polychondritis to be made, ASSOCIATED

CONDITIONS

Relapsing polychondritis usually occurs alone, but there have been recorded instances of its association with other diseases. The conjoint diagnoses of relapsing poiychondritis and rheumatoid arthritis have been made in five cases.1*43*48Systemic lupus erythematosus has been diagnosed in three patients,32+48*66ankylosing spondylitis in two,1*53 and Sjogren’s syndrome in three.2g~48~61Histologically proven vasculitis has been observed in several cases,1.2,42and scleroderma in one.44 Chronic ulcerative colitis has been reported in two cases of relapsing polychondritis. Rosen et a1.73described a patient who had the onset of colitis at age 9; polychondritis, however, did not occur until 27. Reefe and Sierra57 reported a patient who had ulcerative colitis for 13 yr prior to the onset of relapsing polychondritis. They presented biopsy proof of these two diagnoses. Diabetes mellitus has been reported in two patients with relapsing polychondritis.32,48 In the patient of Roger’s et a1.,32numerous antibodies including high titers of insulin antibody and associated insulin-resistant diabetes was found. Myxedema has also been reported in two patients with relapsing polychondritis.48*75There have been three cases of malignancy developing soon after the onset of relapsing polychondritis. These included carcinoma of the pancreas and prostate and Hodgkin’s disease.55*56 DIAGNOSIS

AND

DIFFERENTIAL

DIAGNOSIS

The diagnosis of relapsing polychondritis is based on the combination of clinical and pathological features. Criteria should include recurrent inflammation of two or more cartilaginous sites, at least one involving an organ of special sense, and biopsy of an involved cartilage with the pathologic findings consistent with those seen in this disorder.3*48The similarity of some of the clinical features of relapsing polychondritis and other disorders, especially involving those of connective tissues, must be considered. Inflammation of the external ear, which is commonly seen in relapsing polychondritis, must be distinguished from infectious perichondritis of the auricle. The latter usually is associated with chronic external otitis or following mastoid surgery. Occasionally, infectious perichondritis may follow trauma to the external ear, with laceration or hematoma formation. The most frequent etiologic agent causing infectious perichondritis is Pseudomonas aeruginosa, and it is frequently associated with an elevated temperature, leukocytosis, and regional adenopathy. This condition clears with appropriate systemic antibiotic treatment.64

RELAPSING

57

POLYCHONDRITIS

Nodular deformities of the external ear must be distinguished from chondrodermatitis nodularis chronica helics, which is a nodular degenerative lesion of the helix of unknown etiology. 76 It has some of the microscopic features of relapsing polychondritis, but it is unassociated with any systemic manifestations. Calcification of cartilaginous structures, especially the external ear as mentioned above, may be seen in patients with relapsing polychondritis; however, this is not pathognomonic. Calcification of the pinna has also been observed in Addison’s disease, ochronosis, acromegaly, essential hypertension, diabetes mellitus, hyperthyroidism, and familial cold hypersensitivity.77 Wegener’s granulomatosis is a syndrome which has features superfically resembling polychondritis. Wegener’s is frequently associated with a collapse of the nasal septum; thus, the saddle nose deformity develops. Also, respiratory involvement is common, with lesions in the trachea, bronchial tree, and lungs. The lesions in the respiratory tree are characterized by ulcerative granulomas of the mucosa. This is distinctly different from relapsing polychondritis in which mucosal lesions are rare. Fleeting arthritis can also be seen in Wegener’s granulomatosis, but inflammation of the external ear has not been reported.‘*3s78 The articular manifestations of relapsing polychondritis may be similar to rheumatoid arthritis and, as mentioned above, both diseases have been observed in the same patient.1.43*48The arthritis in relapsing polychondritis is not usually associated with rheumatoid nodules or positive rheumatoid factor.’ Reiter’s syndrome resembles polychondritis because of the arthritis and eye lesions, but differs in that the urethral, dermal, and mucosal lesions that are commonly seen in Reiter’s are not part of the usual clinical picture of relapsing polychondritis.25.27 Cogan’s syndrome, which is believed to be a variant of polyarteritis nodosa, has several features in common with relapsing polychondritis. Cogan’s syndrome involvement includes interstitial keratitis and vestibular auditory problems such as severe vertigo, tinnitus, ataxia, and bilateral sensory neural deafness. No artitular, respiratory, or external ear abnormalities are associated with Cogan’s syndrome.7g,s0 TREATMENT

The treatment of relapsing polychondritis, to date, is aimed at suppressing the inflammation in the cartilage and connective tissue and attempts at mechanical repair of vital stuctures damaged by the disease. Numerous types of drug therapy have been tried. Salicylates in doses of 2 to 5 g per day have been used, but only moderate improvement in the condition has been reported. The use of phenylbutazone and antimalarials have been reported,46*48*63,6sbut have been found to be of little, if any, benefit. Indomethacin has also been used, but without significant improvement.53 Corticosteroids

Corticosteroids used systemically are the drugs of choice at the present time. They are frequently effective in laryngotracheobronchial and external ear manifestations.3 The other manifestations generally do not respond as well to corticosteroids. Barth and Berson43 reported two of five cases with significant

58

ARKIN AND MASI

improvement of keratitis with systemic corticosteroid treatment. They emphasized, however, that treatment must be started early in the course of the eye disease. RabuzzioS2 found that one of his patients with mild sensory neural hearing loss due to relapsing polychondritis had restoration of normal hearing with the treatment of 20 mg of prednisone daily. Three cases of relapsing polychondritis reported by Cody and Sones,‘j’ who had the recent onset of deafness, had dramatic improvement of their hearing after being treated with prednisone in a dose range of 20-40 mg/day. Cody and Sones”l also noted in six of their patients a relationship between the development of sensory neural hearing impairment and decrease in the corticosteroid dosage. In three patients, the hearing loss occurred while prednisone was decreased to 10 mg or less per day, in two patients when the dose of the corticosteroids was significantly reduced; in one patient the hearing loss was directly related to discontinuing corticosteroid treatment. Corticosteroids are usually started in the dose range of 30-60 mg of prednisone daily or an equivalent dose of another corticosteroid preparation. The higher dose is used especially in cases of eye, tracheal, or inner ear involvement, and is gradually reduced as clinical response is noted. The usual maintenance dose is between 5-20 mg of prednisone but, interestingly, even lower in some patients3 With corticosteroid treatment the anemia may improve, and the sedimentation rate and the urinary excretion of mucopolysaccharides may decrease to norma1.3*48 Owen et al.53 reported a patient with relapsing polychondritis who was kept under control with 35 mg of prednisone given on alternate days. The patient, however, showed signs of flareup of her symptoms with reduction of the prednisone dose to 30 mg every other day. Giving the prednisone in alternate day therapy is generally not recommended. Cytotoxic Drugs

Immunosuppressive drugs would seem to have a place in the treatment of relapsing polychondritis, especially in conjunction with corticosteroids, in an attempt to lower the dose of corticosteroids required to maintain suppression of the disease. Very little has been written about the use of immunosuppressive drugs in relapsing polychondritis. Hughes et a1.3did mention the use of azathioprine in two of their patients. The first patient received azathioprine 150 mg daily added to 16 mg of methylprednisolone to control persistent periodic fever. In the other case, azathioprine was used in conjunction with corticosteroids to treat a patient with polychondritis and severe glomerulitis, with improvement being noted in the renal function after the onset of treatment. Mahindrakar and Libmansl reported a 26-yr-old patient with progressive tracheal involvement who required 100 mg of prednisone per day to control her symptoms. She had considerable side effects from this high dose and, with reduction of her prednisone to 20 mg daily, had a marked flareup in her symptoms. Azathioprine was added in a dose of 150 mg per day, leaving the prednisone at 20 mg daily. This combination of therapy resulted in complete suppression of her symptoms and return of the sedimentation rate to normal. Miller et a1.56used methotrexate with no improvement.

RELAPSING

59

POLYCHONDRITIS

Surgical Procedures

Tracheal collapse has already been mentioned as a potentially lethal OCcurence. Any sign of respiratory distress with tracheal inflammation should be observed closely and treated early with tracheostomy.82 Perichondrial inflammatory masses may narrow the airway; one case with the surgical removal of the masses and reconstruction of the airway has been described by Daly in 1966.60 Collapse of the nasal cartilage with development of saddle nose deformity is of considerable cosmetic distress to the patient. It is generally believed that the deformity worsens after nasal surgery.48 Jones51 reported a patient in which he corrected the nasal deformity with a soft silastic sponge implant. In an editorial note accompanying his report, extreme caution was recommended in the use of this type of surgery. Cardiac vascular involvement, when severe, may lead to congestive heart failure, with all the usual signs and symptoms. This should be treated in the If this therapy does not normal manner-first with diuretics and digitalis. 28*3g*53 control the heart failure, valvular replacement with prosthetic valves should be performed. z40 Aneurysms occurring in the aorta have been successfully resected2s45 and definitely represent a potentially lethal abnormality. PROGNOSIS

Relapsing polychondritis may be a fulminant disease with a rapid downhill course. Of the 132 cases reviewed, 29 patients died, with a mean survival of 5% yr from onset.2 Almost half of the deaths were due to respiratory involvement, mainly airway collapse.‘~‘8~1g~s2 Also pneumonia, with or without airway collapse, has resulted in death.2 Two deaths were due to ruptured abdominal aneurysms,2*45 one of these followed shortly after amputation of the left leg due to gangrene secondary to a vasculitis. 45The second patient died 22 mo after surgery for aortic valvular replacement.* One patient died from progressive heart failure secondary to aortic regurgitation. 4LAnother patient died as a result of a ruptured cranial aneurysm. Other deaths have been due to miscellaneous causes not specifically related to the primary disease process; however, several may have been related to steroid treatment of the polychondritis,* and two from malignancies.55 A more common prognosis for relapsing polychondritis is a low grade and smoldering course over many years. 3 Many patients have had almost complete control of their symptoms with the use of corticosteroid therapy, some on very low dose. Beans3 in 1967 reported complete recovery of one of his patients whom he had originally described in 1958.7 Thurston and Curtiss4 reported a patient with relapsing polychondritis who survived up to 24 yr after the onset of his disease. In the case presented in this paper, her disease has been very mild over 4 yr, with each episode spontaneously clearing without treatment or deformity, and the authors suspect that many patients have this milder form of the disease process. SUMMARY

This communication has attempted to review the present state of published knowledge on the syndrome of relapsing polychondritis. Basic anatomic, physio-

60

ARKIN AND MASI

logic, and biochemical changes in this disorder are summarized and the role of metabolic and immunologic alterations in the pathogenesis discussed. An additional case of relapsing polychondritis is reported, and the clinical features of this case, plus those of 131 previously reported, are reviewed with discussion of present day therapeutic experience and prognosis. ACKNOWLEDGMENT The authors thank George F. Bale, M.D., Pathologist, Baptist Memorial Hospital, for assistance in preparation and interpretation of pathologic materials on case T.T. included in this report; Carl M. Pearson, M.D., for his generous offer of illustrative materials and comments on this review; and Thomas W. Meriwether, M.D., and David E. Trentham, manuscript; and Mrs. Sandra W. Mabry for clerial assistance

M.D., for their critical review of the in preparation of the manuscript.

REFERENCES 1. Pearson CM, Kline HM, Newcomer VD: Relapsing polychondritis. N Engl J Med 263:5158, 1960 2. Hughes RAC, Berry CL, Seifert M, et al: Relapsing polychondritis. Quart J Med New Series XLI, 163:363-380, 1972 3. Dolan DL, Lemmon GB, Teitelbaum SL: Relapsing polychondritis. Am J Med 41:285299, 1966 4. Jaksch-Wartenhorst R: Polychondropathia. Weiner Archive Innere Med 6:93-100, 1923 5. Altherr F: Uber einen Fall von systematisierter Chondromalacie. Arch Path Anat 297:44-479,1936 6. von Meyenberg H: Uber Chondromalacia. Schweiz Med Wchnschr 17:1239-1240,1936 7. Bean WB, Drevets CC, Chapman JS: atrophic polychondritis. Medicine Chronic 37:353-363,195s WB: Relapsing polychondritis 8. Reed (Diffuse chondrolysis). Arch Dermatol 106:412, 1972 9. Castor CW: The study of connective tissue. Hollander JL, McCarty DJ (eds): Arthritis and Allied Conditions: A Textbook of Rheumatology (ed 8). Philadelphia, Lea & Febiger, 1972 pp. 5 I66 10. Mankin HJ: The structure, chemistry and metabolism of articular cartilage. Bull Rheum Dis 171447-452, 1967 Il. Bollet AJ: Connective tissue polysaccharide metabolsim and the pathogenesis of osteoarthritis. Advan Intern Med 13:33-60, 1967 12. Silbert JE: Biochemistry and metabolism of mucopolysaccharides. Bull Rheum Dis 22:680-684, 1971-72 13. Kantor TG, Schubert M: The differences in permeability of cartilage to cationic and anionic dyes. J Histochem Cytochem 5:28-32, 1957

14. Fell HB, Coombs RRA, Dingle JT: The breakdown of embryonic (chick) cartilage and bone cultivated in the presence of complementsufficient antiserum. I. Morphological changes. Int Arch Allergy 30:146-176,1966 15. Dingle JT, Fell HB, Coombs, RRA: The breakdown of embryonic cartilage and bone cultivated in the presence of complement-sufficient antiserum. II. Biochemical changes and the role of lysosomal system. Int Arch Allergy 31:283303, 1967 16. Ziff M, Gribetz HJ, LoSpalluto J: Effect of leukocyte and synovial membrane extracts on cartilage mucoprotein. J Clin Invest 39:405-412, 1960 17. Lachmann PJ, Coombs RRA, Fell HB, et al: The breakdown of embryonic (chick) cartilage and bone cultivated in the presence of comIII. Immuplement-sufficient antiserum. nological analysis. Int Arch Allergy 36:4699485, 1969 18. Verity MA, Larson WM, Madden SC: Relapsing polychondritis. Am J Path 42:251269, 1963 19. Self J, Hammarsten lapsing polychondritis. 120:109112, 1967

JF, Lyne B, et al: ReArch Intern Med

20. Thomas L: Reversible coliapse of rabbit ears after intravenous papain, and prevention of recovery by cortisone. J Exp Med 104:2455252, 1956 21. McCluskey RT, Thomas L: The removal of cartilage matrix, in viva, by papain. J Exp Med 108:371I383, 1958 22. Tsaltas TT: Papain-induced changes in rabbit cartilage: Alterations in chemical structure of cartilage matrix. J Exp Med 108:5077513, 1958 23. Tsaltas TT: Metaplasia of aortic connective tissue to cartilage and bone induced by

RELAPSING

61

POLYCHONDRITIS

the intravenous injection of papain. Nature (Lond) 196:1006-1007, 1962 24. Thomas L, McCluskey RT, Potter JL, et al: Comparison of the effects of papain and vitamin A on cartilage. I. The effects in rabbits. J Exp Med I1 I:705718, 1960 25. Gordon EJ, Perlman AW, Shechter N: Diffuse inflammation of cartilage. J Bone Jt Surg 3OA:944956, 1948 26. Harwood TR: Diffuse perichondritis, chondritis, and iritis. Arch Pathol65:81-87, 1958 27. Kahn A, Kilbury MJ: Generalized chondritis of both ears. Ann Otolaryngol65:615~619, 1956 28. Hainer JW, Hamilton GW: Aortic abnormalities in relapsing polychondritis. N Engl J Med280:1166-1168, 1969 29. Rogers FB, Lansbury J: Atrophy of auricular and nasal cartilages following administration of chorionic gonadotropins in a case of arthritis mutilans with the sicca syndrome. Am J Med Sci 229:55-62, 1955 30. Glynn LE. Holborow EJ: Conversion of tissue polysaccharides to auto-antigens by Group-A Beta-hemolytic streptococci. Lancet 2:449- 5 1, 1952 31. Di Ferrante N: Precipitins in the rabbit produced by protein polysaccharide from bovine nasal cartilage. Science 143:250-252, 1964 32. Rogers PH, Boden G, Tourtellotte CD: Relapsing polychondritis with insulin resistance and antibodies to cartilage. Am J Med 55:243248, 1973 33. Herman JH, Dennis MV: Immunopathologic studies in relapsing polychondritis. J Clin Invest 52:5499558, 1973 34. Rajapakse DA, Bywaters EGL: Cellmediated immunity to cartilage proteoglycan in relapsing polychondritis. Clin Exp. Immunol 16:497-502, 1974 35. Wislocki histochemical

GB, Ladman AJ: Selective and staining of the otolithic

membranes, cupulae and tectorial membrane the inner ear. J Anat (Lond) 89:3- 12, 1955

of

36. Grimaud R, Bodelet B: Polychondrite chronique atrophiante. Acta Otolaryngol 75:104 I1 I, 1973 37. Mitchell N, Shepard N: Relapsing polychondritis; An electron microscopic study of synovium and articular cartilage. J Bone Jt Surg 54A:123551245, 1972 38. Mitchell N, Shepard N: The ultrastructure of articular cartilage in rheumatoid arthritis. J Bone Jt Surg 52A:140551423, 1970 39. Yamazaki N, Yawata K, Hannya H, et al: A case of relapsing polychondritis associated

with aortic

insufficiency.

Jap Heart

J 7:188-195,

1966 40. Pearson CM, Kroening R, Verity MA, et al: Aortic insufficiency and aortic aneurysm in relapsing polychondritis. Trans Assoc Am Physicians SO:7 I-89, 1967 41. Marquis Y, Richardson JB, Ritchie AC, et al: Idiopathic medial aortopathy and arteriopathy. Am J Med 44:939-954, 1968 42. Alexander CS, Derr RF, et al: Abnormal amino acid and lipid composition of aortic valve in relapsing polychondritis. Am J Cardiol 28:337-341, 1971 43. Barth WF, Berson EL: Relapsing arthritis, polychondritis, rheumatoid and blindness. Am J Ophthal66:890-896, 1968 44. Cogan DG: Corneoscleral lesions in periarteritis nodosa and Wegener’s granulomatosis. Trans Am Ophthalmol Sot 53:321-344, 1955 45. Anderson BS: Ocular lesions in relapsing polychondritis and other rheumatoid syndromes. Arch Dermatol82:439~440, 1960 46. Arundell FW, Haserick JR: Familial chronic atrophic polychondritis. Arch Dermatol 82:439-440, 1960 47. Middleton WS: Diffuse systemic sclerosis. Ann Intern Med57:183-197, 1962 48. Kaye RL, Sones DA: Relapsing polychondritis. Ann Intern Med 60:653-664, 1964 49. Hemry DA, Moss AJ, Jacox RF: Relapsing polychondritis, a “floppy” mitral valve, and migratory polytendinitis. Ann Intern Med 77:576-580, 1972 50. Swain RE, Stroud MH: Relapsing polychondritis. Laryngoscope 82:891~898, 1972 5 1. Jones FR: Relapsing polychondritis. Plastic Reconstruct Surg 51:331-333, 1973 52. Johnson TH, Mital N, Rodnan GP, et al: Relapsing polychondritis. Radiology 106:313 315, 1973 53. Owen DS, lrby R, Toone E: Relapsing polychondritis with aortic involvement. Arthritis Rheum 13:877~881, 1970 54. Abrahamsen AM, Bergaust B: Relapsing polychondritis. Acta Med Stand 185:175 178, 1969 55. Odkvist L: Relapsing polychondritis. Acta Otolaryngol70:448-454, 1970 56. Miller SB, Donlan CJ, Roth SB: Hodgkin’s disease presenting as relapsing polychondritis. Arthritis Rheum 17:5988602, 1974 57. Reefe WE, Sierra R: Relapsing polychondritis associated with ulcerative colitis. Med Ann DC 39:27-30, 1970 58. Pearson CM: Personal communication

62

59. Johnson HM: Relapsing polychondritis. Arch Dermatol88:65 l-659, 1963 60. Daly JF: Relapsing polychondritis of the larynx and trachea. Arch Otolaryngol 84:570513, 1966 61. Cody DTR, Sones DA: Relapsing polychondritis: Audiovestibular manifestations. Laryngoscope 81:1208-1222, 1971 62. Rabuzzi, DD: Relapsing polychondritis. Arch Otolaryngol91:188-194, 1970 63. Coste F, Laurent F, Basset F, et al: Polychondritis, polyarthritis, and gougerotSjSgren’s syndrome. Rev Rheum 28:498-503, 1961 64. Ballenger JJ (Editor): Diseases of the Nose, Throat and Ear. (ed 11). Philadelphia, Lea & Febiger, 1969 65. Hilding AC: Syndrome of joint and cartilaginous pathologic changes with destructive iridocyclitis. Arch Intern Med 89445453, 1952 66. Marshall J, LeRoux DG: Chronic atrophic polychondritis: A South African case. S Afr Med J 38:527-529, 1964 67. Spritzer HW, Weaver AL, Diamond HS, et al: Relapsing polychondritis. Report of a case with vertebral column involvement. JAMA 208:355-357, 1969 68. Thould AK, Stansfeld AG, Balme HW: Chronic atrophic perichondritis. Ann Rheum Dis 24:563-568, 1965 69. Rucker CW, Ferguson RJ: Ocular manifestations of relapsing polychondritis. Arch Opthalmol73:46-48, 1965 70. Bergaust B, Abrahamsen AM: Relapsing polychondritis. Acta Ophthalmol 47: 174181, 1969 71. Hayhoe FGJ, Smith DR: Plasmacytosis in

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AND MASI

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