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Relapsing polychondritis
Original Contributions
RELAPSING POLYCHONDRITIS Immunomicroscopic Findings in Cartilage of Ear Biopsy Specimens Rafael Valenzuela, M.D., * Peter A. Cooperrider, M.D., t Prema Gogate, M.D.,:t. Sharad D. Deodhar, M.D., Ph.D., § and Wilma F. Bergfeld, M.D.II
Abstract Two cases of relapsing polychondritis are reported. Direct immunofluorescence examination of ear biopsy specimens in both patients showed the presence of granular deposits of immunoglobulins and the C3 component of complement at the chondrofibrous junction. These findings suggest that immunomicroscopic examination of ear cartilage could be diagnostically useful in this disease.
Relapsing polychondritis is a disorder characterized by recurrent prominent inflammation of the cartilaginous tissue of different organs, primarily ear and nasal septum. Its etiology is unknown, but certain laboratory observations point toward an immune pathogenesis. In addition, 25 per cent of the patients have a preceding or coexistent rheumatic or autoimmune disease. The diagnosis is based primarily on the clinical features and histologic confirmation of chondritis. We report new immunopathologic findings that could have specific diagnostic value.
CASE REPORTS
Casel
A 62 year old white woman had a four year history of recurrent inflammation of the cartilaginous portions of the external ear, which lasted only a few days and then resolved with no treatmen t other than Valisone ointment. In addition, she had recurrent bouts of episcleritis and uveitis with secondary glaucoma, fluctuating hearing loss bilaterally, and episodic sinusitis with a rheumatoid arthritis-like syndrome (latex negative) and
*Head, General Immunopathology Section, Department of Immunopathology, The Cleveland Clinic Foundation, Cleveland, Ohio, tFormerly, Fellow, Department of Dermatology, The Cleveland Clinic Foundation, Cleveland, Ohio. tSpecial Fellow, Department of Immunopathology, The Cleveland Clinic Foundation, Cleveland, Ohio. §Head, Department of Immunopathology, The Cleveland Clinic Foundation, Cleveland, Ohio. IIHead, Dermatopathology Section, Department of Pathology, The Cleveland Clinic Foundation, Cleveland, Ohio.
19
HUMAN PATHOLOGY - VOLUME I I, :"I:U!vIBER I
jl1JIlUlIY
fever. She had been admitted to the hospital in the past for acute febrile vasculitis involving the joints, periarticular tissue, and eye that resolved with nitrogen mustard and methotrexate, She had a 19 year history of asthma and hypertension, The family history revealed that her daughter had a isolated episode of diffuse vasculitis and episcleritis that went into remission with immunosuppressive therapy, Recent laboratory studies revealed increased acute phase reactants and a normal complete blood count and SMA profile, At present, the chondritis is still episodic. She is receiving long term therapy with a low dosage of prednisone, which is increased to 15 mg. daily during her flares with only moderate treatment success.
19811
nous structures were clinically involved. The complete blood count and SMA profile were within normal limits, An antinuclear factor determination was positive (l :20). The patient was initially treated with 150 mg. of dapsone for one week; the dosage was increased to 250 mg, the following week. The drug was discontinued after clinical resolution of the inflammatory reaction of the left ear. Since her initial visit the patient has experienced two exacerbations, which have been controlled by a two week period of prednisone treatment, 30 mg. per day, with subsequent tapering, Dapsone was discontinued because of malaise, headache, and nausea. MATERIALS AND METHODS
Case 2 A 48 year old white woman had a one year history of recurrent episodes of "tender red ears," which spontaneously resolved without treatment over a period of four to six weeks. The history revealed one episode of alopecia areata and allergic contact dermatitis. On her first visit the patient had had a four day history of a red tender left ear. No other cartilagi-
Figure 1. Swollen red ear with absent auricular deformity, Early stage of relapsing' polychondl'itis.
20
At the time of active chondritis, ear biopsy specimens obtained from both patients were composed of skin and fibrocartilaginous tissue. The tissues were divided into two specimens. One was fixed in Zenker's solution, embeddecl in paraffin, and stained with hematoxylin and eosin, periodic acid-Schiff, alcian blue, and trichrome for histopathologic examination. The other specimen was immediately frozen in liquid nitrogen. The frozen tissue was sectioned at 3 microns in a Lipshaw crytostat at -200 C. and incubated with fluorescein labeled antihuman IgG, IgA, IgM, C3 component of complement, albumin, and fibrinogen at room temperature in a humidity chamber for 30 minutes. The slides were then washed in three changes of phosphate buffereel saline solution (pH 7.4), caverslipped with buffered glycerin (l: 10) as a mounting medium, and examined under a Zeiss fluorescence microscope. Blocking studies were performed with unlabeled antisera.* All the antisera used showed a single precipitation arc in the expected migration areas· when tested by immunoelectrophoresis against normal human serum or plasma. As a negative control, we processed a portion of normal auricular fibrocartilaginous tissue for immunornicroscopic examination as already described.
"'Ilvlaml, Costa Mesa, Caliloruia ll:!li~li. The lluOI'esc'ein labeled antiseru were obtained from Behring Diagnostic, American Hocchst Corporation. Somerville, New Jersey 0887(\.
RELAPSING POLYCHONDRITIS- VALENZUELA
ET AL.
RESULTS The skin biopsy specimens showed mild focal nonspecific lymphohistiocytic inflammation, with negative immunofluorescence results. The fibrocartilaginous tissues from both patients showed a remarkable perichondritis, which was characterized by degeneration of the marginal chondrocytes, decreased basophilia, and poor alcian blue and Masson staining of the cartilaginous tissue (Fig. 2). The perichondrial inflammatory infiltration was composed of neutrophils, lymphocytes, plasma cells, and histiocytes. Numerous granular aggregates at the chondrofibrous junction stained PAS positive. In both cases immunornicroscopic examination revealed granular fluorescent deposits along the chondrofibrous junction, which extended focally into the marginal cartilaginous areas, with IgG, IgA, IgM, and C3 antisera in the first case and IgG, IgA, and C3 in the second case (Fig. 3). Granular fluorescent deposits (with IgM and C3 antisera) were observed in occasional perichondrial vessel walls in the first case. This specific fluorescence was inhibited by previous incubation with unlabeled antisera. Antihuman and antifibrinogen antisera yielded negative results in both cases. The negative control
Figure 3. Photomicrograph showing coarsely granular deposits of IgG at the chondrofibrous junction extending focally into the marginal cartilaginous tissue. The perichondrial tissue is present in the lower part of the photograph. (Specimen stained with fluorescent goat antihuman IgG. x400.)
showed only fluorescence.
nonspecific
background
DISCUSSION
.. '
...
':'
..
Figure 2. Degenerating changes in the marginal cartilage. A marked mixed inflammatory reaction is observed in the adjacent perichondrial fibrous tissue. (Hematoxylin and eosin stain. x400.)
Relapsing polychondritis, originally described as polychondropathy, I has now become a well established entity. Although a wealth of clinical information about this disorder has been published.r" its etiology remains unknown. The coexistence of different rheumatic or autoimmune diseases (25 per cent of the cases) suggests immunologic mechanisms underlying the pathogenesis of this disease." Attempts to demonstrate cartilage autoantibodies in the patient's sera have yielded variable but mostly negative resuIts.2-4,7-12 Some investigators have documented lymphocyte sensitization to various cartilage components using both lymphocyte blastic transformation and macrophage migration inhibition techniques."?" The diagnosis of relapsing polychondritis relies on the clinical findings and the histopathologic confirmation of chondritis. The laboratory is helpful only in excluding other diagnostic possibilities. Our immunornicroscopic findings
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HUMAN PATHOLOGY-VOLUME 11, NUMBER 1 January 1980
suggest that immunoglobulins and complement could play an active role in the pathogenesis of relapsing polychondritis. It is unlikely that the immunofluorescent deposits are due to the presence of exudated plasma proteins in the inflammatory areas, since they did not react with antialbumin or antifibrinogen antisera. The immunomicroscopic appearance of the deposits (granular) points toward the presence of immune complexes rather than autoantibodies at the chondrofibrous junction; in the latter situation one would expect to see a diffuse fluorescent staining of the marginal cartilaginous tissue. McAdam et al." detected decreased serum complement level in only one of 21 patients with relapsing polychondritis. However, McKenna et aJ.13 reported a decreased level of total hemolytic complement in the inflammatory effusion of the affected ear when simultaneous quantitation of total serum hemolytic complement was normal, suggesting that local activation of the complement system was taking place. Shaul and Schumacher" described, by electron microscopic examination of the ear cartilage, the presence of electron dense deposits at the superficial cartilage. They hypothesized that the material might be of immunoglobulin origin, an assumption that is in agreement with our immunomicroscopic findings. The presence of IgM and C3 in the vessel walls in our first case is also interesting, as there is a high incidence of vascular involvement in this disease, a fact that led McAdam et a1. 3 to suggest that at least a proportion of the cases of relapsing polychondritis may fall into the spectrum of systemic vasculitis. Although further immunopathologic studies will be needed to evaluate the exact clinical significance of our findings, immunomicroscopic examination of auricular biopsy specimens could be a specific laboratory
test for the diagnosis of relapsing polychondritis, since to our knowledge the findings described have not been detected in any other disease.
REFERENCES I. Jaksch-Wartenhorst., R.: Polychondropathia. Wien. Arch. Inn, Med., 6:933-100, 1923. 2. Dolan, D. 1., Lemmon, G. B., and Teitelbaum, S. 1.: Relapsing polychondritis. Analytical literature review and studies on pathogenesis. Am. J. Med., 41 :285-299, 1966. 3. McAdam, 1. P., O'Hanlan, M. A., Bluestone, R., et al.: Relapsing polychondritis: prospective study of 23 patients and review of the literature. Medicine, 55: 193-213, 1976. 4. Hughes, R. A. C., Berry, C. 1., Seifert, M., et al.: Relapsing polychondritis, Three cases with a clinicopathological study and literature review. Quart. J. Med., 41 :363-380, 1972. 5. Kay, R. 1., and Sones, D. A.: Relapsing polychondritis. Clinical and pathological features in fourteen cases. Ann. Intern. Med., 60:653664, 1964. 6. Pearson, C. M., Kline, H. M., and Newcomber, V. D.: Relapsing polychondritis. New Eng. J. Med., 263:51-58, 1960. 7. Rogers, P. H., Boden, G., and Tourtellotte, C. D.: Relapsing polychonclritis with insulin resistance and antibodies to cartilage. Am. J. Meel.,55:243-248, 1973. 8. Herman, J. H., and Hess, E. V.: Immunopathologic studies in relapsing polychondritis. Arthr. Rheum., 14:166, 1971. 9. Rajapakse, D. A., and Bywaters, E. G. 1.: Cellmediated immunity to cartilage proteoglycan in relapsing polychondritis. CHn. Exp. .Immunol.,16:497-502, 1974. 10. Herman, J. H., and Dennis, M. V.: Immunopathologic studies in relapsing polychondritis. J. Clin. Invest., 52 :549~558, 1973.. 11. Menkes, C. J" Delriet, S. F., Chouraki, L.,.et al.: Polychondrite ehronique atrophiante: deux cas dont l'un avec cataracte et arterite des members inferieurs, Ann. Med. Intern., 121 :895-904, 1970. 12. Shaul, S. R., and Schumacher, H. R.: Relapsing polychondritis. Electron microscopy study of ear cartilage. Arthr, Rheum., 18:617-625, 1975. 13. McKenna, C. H., Luthra, H. 5., and Jordon, R. E.: Hypocomplementemic ear effusion in relapsing polychondritis, Mayo Clin. Proc., 51 :495-497, 1976.
Department of Immunopathology The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, Ohio 44106 (Dr. Valenzuela)
22
RELAPSING POLYCHONDRITIS Immunomicroscopic Findings in Cartilage of Ear Biopsy Specimens Rafael Valenzuela, M.D., * Peter A. Cooperrider, M.D., t Prema Gogate, M.D.,:t. Sharad D. Deodhar, M.D., Ph.D., § and Wilma F. Bergfeld, M.D.II
Abstract Two cases of relapsing polychondritis are reported. Direct immunofluorescence examination of ear biopsy specimens in both patients showed the presence of granular deposits of immunoglobulins and the C3 component of complement at the chondrofibrous junction. These findings suggest that immunomicroscopic examination of ear cartilage could be diagnostically useful in this disease.
Relapsing polychondritis is a disorder characterized by recurrent prominent inflammation of the cartilaginous tissue of different organs, primarily ear and nasal septum. Its etiology is unknown, but certain laboratory observations point toward an immune pathogenesis. In addition, 25 per cent of the patients have a preceding or coexistent rheumatic or autoimmune disease. The diagnosis is based primarily on the clinical features and histologic confirmation of chondritis. We report new immunopathologic findings that could have specific diagnostic value.
CASE REPORTS
Casel
A 62 year old white woman had a four year history of recurrent inflammation of the cartilaginous portions of the external ear, which lasted only a few days and then resolved with no treatmen t other than Valisone ointment. In addition, she had recurrent bouts of episcleritis and uveitis with secondary glaucoma, fluctuating hearing loss bilaterally, and episodic sinusitis with a rheumatoid arthritis-like syndrome (latex negative) and
*Head, General Immunopathology Section, Department of Immunopathology, The Cleveland Clinic Foundation, Cleveland, Ohio, tFormerly, Fellow, Department of Dermatology, The Cleveland Clinic Foundation, Cleveland, Ohio. tSpecial Fellow, Department of Immunopathology, The Cleveland Clinic Foundation, Cleveland, Ohio. §Head, Department of Immunopathology, The Cleveland Clinic Foundation, Cleveland, Ohio. IIHead, Dermatopathology Section, Department of Pathology, The Cleveland Clinic Foundation, Cleveland, Ohio.
19
HUMAN PATHOLOGY - VOLUME I I, :"I:U!vIBER I
jl1JIlUlIY
fever. She had been admitted to the hospital in the past for acute febrile vasculitis involving the joints, periarticular tissue, and eye that resolved with nitrogen mustard and methotrexate, She had a 19 year history of asthma and hypertension, The family history revealed that her daughter had a isolated episode of diffuse vasculitis and episcleritis that went into remission with immunosuppressive therapy, Recent laboratory studies revealed increased acute phase reactants and a normal complete blood count and SMA profile, At present, the chondritis is still episodic. She is receiving long term therapy with a low dosage of prednisone, which is increased to 15 mg. daily during her flares with only moderate treatment success.
19811
nous structures were clinically involved. The complete blood count and SMA profile were within normal limits, An antinuclear factor determination was positive (l :20). The patient was initially treated with 150 mg. of dapsone for one week; the dosage was increased to 250 mg, the following week. The drug was discontinued after clinical resolution of the inflammatory reaction of the left ear. Since her initial visit the patient has experienced two exacerbations, which have been controlled by a two week period of prednisone treatment, 30 mg. per day, with subsequent tapering, Dapsone was discontinued because of malaise, headache, and nausea. MATERIALS AND METHODS
Case 2 A 48 year old white woman had a one year history of recurrent episodes of "tender red ears," which spontaneously resolved without treatment over a period of four to six weeks. The history revealed one episode of alopecia areata and allergic contact dermatitis. On her first visit the patient had had a four day history of a red tender left ear. No other cartilagi-
Figure 1. Swollen red ear with absent auricular deformity, Early stage of relapsing' polychondl'itis.
20
At the time of active chondritis, ear biopsy specimens obtained from both patients were composed of skin and fibrocartilaginous tissue. The tissues were divided into two specimens. One was fixed in Zenker's solution, embeddecl in paraffin, and stained with hematoxylin and eosin, periodic acid-Schiff, alcian blue, and trichrome for histopathologic examination. The other specimen was immediately frozen in liquid nitrogen. The frozen tissue was sectioned at 3 microns in a Lipshaw crytostat at -200 C. and incubated with fluorescein labeled antihuman IgG, IgA, IgM, C3 component of complement, albumin, and fibrinogen at room temperature in a humidity chamber for 30 minutes. The slides were then washed in three changes of phosphate buffereel saline solution (pH 7.4), caverslipped with buffered glycerin (l: 10) as a mounting medium, and examined under a Zeiss fluorescence microscope. Blocking studies were performed with unlabeled antisera.* All the antisera used showed a single precipitation arc in the expected migration areas· when tested by immunoelectrophoresis against normal human serum or plasma. As a negative control, we processed a portion of normal auricular fibrocartilaginous tissue for immunornicroscopic examination as already described.
"'Ilvlaml, Costa Mesa, Caliloruia ll:!li~li. The lluOI'esc'ein labeled antiseru were obtained from Behring Diagnostic, American Hocchst Corporation. Somerville, New Jersey 0887(\.
RELAPSING POLYCHONDRITIS- VALENZUELA
ET AL.
RESULTS The skin biopsy specimens showed mild focal nonspecific lymphohistiocytic inflammation, with negative immunofluorescence results. The fibrocartilaginous tissues from both patients showed a remarkable perichondritis, which was characterized by degeneration of the marginal chondrocytes, decreased basophilia, and poor alcian blue and Masson staining of the cartilaginous tissue (Fig. 2). The perichondrial inflammatory infiltration was composed of neutrophils, lymphocytes, plasma cells, and histiocytes. Numerous granular aggregates at the chondrofibrous junction stained PAS positive. In both cases immunornicroscopic examination revealed granular fluorescent deposits along the chondrofibrous junction, which extended focally into the marginal cartilaginous areas, with IgG, IgA, IgM, and C3 antisera in the first case and IgG, IgA, and C3 in the second case (Fig. 3). Granular fluorescent deposits (with IgM and C3 antisera) were observed in occasional perichondrial vessel walls in the first case. This specific fluorescence was inhibited by previous incubation with unlabeled antisera. Antihuman and antifibrinogen antisera yielded negative results in both cases. The negative control
Figure 3. Photomicrograph showing coarsely granular deposits of IgG at the chondrofibrous junction extending focally into the marginal cartilaginous tissue. The perichondrial tissue is present in the lower part of the photograph. (Specimen stained with fluorescent goat antihuman IgG. x400.)
showed only fluorescence.
nonspecific
background
DISCUSSION
.. '
...
':'
..
Figure 2. Degenerating changes in the marginal cartilage. A marked mixed inflammatory reaction is observed in the adjacent perichondrial fibrous tissue. (Hematoxylin and eosin stain. x400.)
Relapsing polychondritis, originally described as polychondropathy, I has now become a well established entity. Although a wealth of clinical information about this disorder has been published.r" its etiology remains unknown. The coexistence of different rheumatic or autoimmune diseases (25 per cent of the cases) suggests immunologic mechanisms underlying the pathogenesis of this disease." Attempts to demonstrate cartilage autoantibodies in the patient's sera have yielded variable but mostly negative resuIts.2-4,7-12 Some investigators have documented lymphocyte sensitization to various cartilage components using both lymphocyte blastic transformation and macrophage migration inhibition techniques."?" The diagnosis of relapsing polychondritis relies on the clinical findings and the histopathologic confirmation of chondritis. The laboratory is helpful only in excluding other diagnostic possibilities. Our immunornicroscopic findings
21
HUMAN PATHOLOGY-VOLUME 11, NUMBER 1 January 1980
suggest that immunoglobulins and complement could play an active role in the pathogenesis of relapsing polychondritis. It is unlikely that the immunofluorescent deposits are due to the presence of exudated plasma proteins in the inflammatory areas, since they did not react with antialbumin or antifibrinogen antisera. The immunomicroscopic appearance of the deposits (granular) points toward the presence of immune complexes rather than autoantibodies at the chondrofibrous junction; in the latter situation one would expect to see a diffuse fluorescent staining of the marginal cartilaginous tissue. McAdam et al." detected decreased serum complement level in only one of 21 patients with relapsing polychondritis. However, McKenna et aJ.13 reported a decreased level of total hemolytic complement in the inflammatory effusion of the affected ear when simultaneous quantitation of total serum hemolytic complement was normal, suggesting that local activation of the complement system was taking place. Shaul and Schumacher" described, by electron microscopic examination of the ear cartilage, the presence of electron dense deposits at the superficial cartilage. They hypothesized that the material might be of immunoglobulin origin, an assumption that is in agreement with our immunomicroscopic findings. The presence of IgM and C3 in the vessel walls in our first case is also interesting, as there is a high incidence of vascular involvement in this disease, a fact that led McAdam et a1. 3 to suggest that at least a proportion of the cases of relapsing polychondritis may fall into the spectrum of systemic vasculitis. Although further immunopathologic studies will be needed to evaluate the exact clinical significance of our findings, immunomicroscopic examination of auricular biopsy specimens could be a specific laboratory
test for the diagnosis of relapsing polychondritis, since to our knowledge the findings described have not been detected in any other disease.
REFERENCES I. Jaksch-Wartenhorst., R.: Polychondropathia. Wien. Arch. Inn, Med., 6:933-100, 1923. 2. Dolan, D. 1., Lemmon, G. B., and Teitelbaum, S. 1.: Relapsing polychondritis. Analytical literature review and studies on pathogenesis. Am. J. Med., 41 :285-299, 1966. 3. McAdam, 1. P., O'Hanlan, M. A., Bluestone, R., et al.: Relapsing polychondritis: prospective study of 23 patients and review of the literature. Medicine, 55: 193-213, 1976. 4. Hughes, R. A. C., Berry, C. 1., Seifert, M., et al.: Relapsing polychondritis, Three cases with a clinicopathological study and literature review. Quart. J. Med., 41 :363-380, 1972. 5. Kay, R. 1., and Sones, D. A.: Relapsing polychondritis. Clinical and pathological features in fourteen cases. Ann. Intern. Med., 60:653664, 1964. 6. Pearson, C. M., Kline, H. M., and Newcomber, V. D.: Relapsing polychondritis. New Eng. J. Med., 263:51-58, 1960. 7. Rogers, P. H., Boden, G., and Tourtellotte, C. D.: Relapsing polychonclritis with insulin resistance and antibodies to cartilage. Am. J. Meel.,55:243-248, 1973. 8. Herman, J. H., and Hess, E. V.: Immunopathologic studies in relapsing polychondritis. Arthr. Rheum., 14:166, 1971. 9. Rajapakse, D. A., and Bywaters, E. G. 1.: Cellmediated immunity to cartilage proteoglycan in relapsing polychondritis. CHn. Exp. .Immunol.,16:497-502, 1974. 10. Herman, J. H., and Dennis, M. V.: Immunopathologic studies in relapsing polychondritis. J. Clin. Invest., 52 :549~558, 1973.. 11. Menkes, C. J" Delriet, S. F., Chouraki, L.,.et al.: Polychondrite ehronique atrophiante: deux cas dont l'un avec cataracte et arterite des members inferieurs, Ann. Med. Intern., 121 :895-904, 1970. 12. Shaul, S. R., and Schumacher, H. R.: Relapsing polychondritis. Electron microscopy study of ear cartilage. Arthr, Rheum., 18:617-625, 1975. 13. McKenna, C. H., Luthra, H. 5., and Jordon, R. E.: Hypocomplementemic ear effusion in relapsing polychondritis, Mayo Clin. Proc., 51 :495-497, 1976.
Department of Immunopathology The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, Ohio 44106 (Dr. Valenzuela)
22