American Journal of Hematology 40:47-50 (1992)
Relapsing Polychondritis: A Paraneoplastic Syndrome Associated With Myelodysplastic Syndromes Koen Van Besien, Guido Tricot, and Ronald Hoffman Division of Hernatology/Oncology, Indiana University School of Medicine, Indianapolis
We report an unusual case of a patient with a myelodysplasticsyndromeassociated with life threatening relapsing polychondritis. The improvement in symptoms attributable to the relapsing polychondritis during treatment of the hematologic disorder suggests that relapsing polychondritis is a paraneoplastic syndrome associated with myelodysplastic syndromes. IC' 1992 Wiley-Liss, Inc. Key words: hematologicdisorder, peripheral cytopenias, dysplastic bone marrow
INTRODUCTION The myelodysplastic syndromes (MDS) are clonal disorders of hematopoiesis characterized by peripheral cytopenias and a dysplastic bone marrow that is usually hypercellular [ I ] . The prognosis in general is poor and results of treatment are disappointing 121. Morbidity and mortality are usually due to infections or hemorrhagic episodes [3,4]. Relapsing polychondritis (RP) is a relatively rare, often episodic form of inflammatory disease characterized by potentially destructive lesions involving organs of special sense, laryngotracheobronchial structures, the cardiovascular system, and joints [S-81. It is generally assumed to be an auto-immune disorder [ M I . The diagnosis is based on the clinical features but can be confirmed by biopsy of affected cartilage. We report here a young patient with a MDS subtype, refractory anemia with excess blasts in transformation (RAEB-t), that was associated with severe RP. The RP was extremely disabling and ultimately resulted in respiratory failure. Treatment of the underlying hematologic disorder led to a temporary improvement in the symptoms of RP, strongly suggesting a paraneoplastic nature of the syndrome. CASE REPORT
A 19 year old college student presented to his local physician due to a football related injury. A routine blood count revealed a moderate anemia with a hemoglobin of 10.7 g/dl. The white blood cell count was 7.6 X IO'/L with 7% blasts, 4% myelocytes. 2% metamyelocytes, 63% granulocytes, 12% lymphocytes, 7% monocytes, 0 1992 Wiley-Liss, Inc.
1% eosinophils, and 6% basophils. The platelet count was 107 X IOy/L. The patient had lost 20 pounds in the 3 months prior to this visit and had suffered several nose bleeds. Physical examination was unremarkable. A bone marrow biopsy was 100% cellular. Megakaryocytes were increased; atypical megakaryocytes and micromegakaryocytes were seen. The erythroid series was megaloblastic. Nuclear atypia and intercellular bridging were present. The niyeloid series showed hypogranulation and dysniyelopoiesis. Approximately 1S% blasts were present. Cytogenetic analysis of the bone marrow revealed an abnormal clone with a monosomy 7 and the addition of a small ring chromosome. In addition, some cells also showed a deletion of chromosome 6. A diagnosis of MDS (refractory anemia with excess blasts in transformation) was made. Approximately 3 weeks after initial diagnosis, the patient was admitted because of intermittent fever up to 38°C and pain in the right ankle. On physical examination slight swelling and tenderness of the right ankle was found. An extensive work-up was unrevealing. Repeat bone marrow aspirate revealed only 4% blasts. While in the hospital, the patient developed an effusion of the left knee and tenderness and erythema of the right pinna. The synovial fluid of the right knee revealed 54 X IOy/L
Received for publication April 5, 1991: accepted November 18. 1991. Address reprint requests to Ronald Hoffman M.D., Indiana University Medical Center, 975 W Walnut Street IB 442, Indianspolis I N , 462025121.
48
Case Report: Van Besien et al.
white blood cells, but was sterile. Crystals were absent. Serum rheumatoid factor was negative. He also developed a nonproductive cough and a small left pleural effusion. Thoracentesis was attempted but unsuccessful. Bronchoscopy with bronchoalveolar lavage was unrevealing. Total body gallium scan failed to reveal an inflammatory focus. Because of the arthritic symptoms, the patient was treated with sodium salicylate and discharged. During ensuing weeks he developed inflammation of both pinnae and bilateral sclerokeratitis. A diagnosis of RP was made and treatment with corticosteroids (prednisone 1 mg/kg) initiated. Initially, his symptoms improved and the corticosteroids were tapered rapidly. Three weeks later he was readmitted because of a left Bell’s palsy and recurrent fevers. Head CT scan and MRI were normal; lumbar puncture revealed a nornial cerebrospinal fluid. Four days after the lumbar puncture he developed paraparesis. CT scan revealed an epidural hematoma extending from the midbody of L2 down to the margin of L3. This was evacuated, but there was little recuperation of neurologic function. During the admission, he also developed a left otitis media which required placement of ear tubes. Cultures of the middle ear fluid were sterile. The steroid therapy was continued and broad-spectrum antibiotics were added. Over the next days, the patient developed bilateral interstitial pulmonary infiltrates and continued to have fever. A repeat bronchoscopy with bronchoalveolar lavage was negative. An open lung biopsy showed acute inflammation and intra-alveolar hemorrhage; cultures were negative. Ultrasound of the heart did not show signs of endocarditis but severely decreased left ventricular systolic function was found. An abdominal CT scan revealed a 2 X 3 cm hypodense lesion in the left kidney that had not been present on a previous CT. CT guided fine needle aspiration revealed only sterile fluid. The patient also developed hematuria and proteinuria of 2 g/24 hours and severe hypertension that could be controlled only with a combination of calcium channel blockers, beta blockers, and ACE inhibitors. The patient deteriorated rapidly. The RP in combination with immobilization and corticosteroid therapy led to rapid muscle wasting, and intravenous hyperalimentation was initiated. When the pulmonary infiltrates acutely worsened, the patient had to be intubated. A third bronchoalveolar lavage failed to reveal an infectious cause for the pulmonary infiltrates. Empirical treatment with amphotericin B was started, but did not result in any apparent benefit. It was then assumed that most of the patient’s symptoms, including the fever, cardiomyopathy, proteinuria, hematuria, hypertension, pul inonary infiltrates, eye symptoms, and joint and cartilage symptoms were due to RP and that the RP was paraneoplastic in nature. It was decided to treat the underlying myelodysplastic syn-
drome with intensive Chemotherapy. The patient was treated with high dose cytosine arabinoside (2 g/m2 IV every 12 hours for a total of 10 doses). Within 48 hours he defervesced. Pulmonary symptoms improved and he was extubated. Eye symptoms improved rapidly and surprisingly the paraplegia also improved; the patient gained some strength and mobility in the lower extremities and intensive rehabilitation was started. Corticosteroid therapy was slowly tapered and amphotericin B was stopped. Due to the chemotherapy the patient became profoundly granulocytopenic and thrombocytopenic, but remained afebrile. Approximately 14 days after the completion of chemotherapy the granulocyte count recovered, but the platelet count remained low. A bone marrow aspirate was hypercellular, with 10% blasts and dysplastic features in the three hematopoietic lineages. The cytogenetic abnormalities persisted. Fever recurred and within 72 hours of the first signs of recovery of granulocytes, bilateral scleritis recurred followed by a fulminant retinal and optic nerve vasculitis leading to almost complete blindness of both eyes despite treatment with high doses of methylprednisolone ( 1 g IV q 6 hours for I week) and cyclophosphamide (100 mg po q day). Muscle strength in the lower extremities decreased rapidly and arthritic symptoms recurred. The patient also developed orchitis for which no infectious cause could be determined. Over the next several weeks, with continued immunosuppressive therapy (cyclophosphamide 100 mg/d and a tapering dose of steroids), the patient’s conditions stabilized. The possibility of success with further chemotherapy was felt to be low, and the risks high. A second course of induction chemotherapy was therefore not attempted. With supportive care and immunosuppressive therapy the patient has remained in a stable clinical and hematologic condition for 10 months later (Fig. I illustrates the clinical course of the patient).
DISCUSSION This young patient presented with a classic MDS [ I ] . By virtue of the number of blasts in the bone marrow and the cytogenetic abnormalities his prognosis was felt to be poor [ 3 ] . When the patient presented with fever and arthralgias an extensive investigation failed to reveal an infectious cause. The fever resolved only after treatment with salicylates. Some weeks later the patient developed also manifestations of chondritis and sclerokeratitis. At that time a diagnosis of RP was made. Treatment of RP is aimed at suppressing the inflammatory process [5-71. Corticosteroids are the treatment of choice but occasionally other immunosuppressive agents such as azathioprine have been used. This patient’s symptoms at first responded to treatment with steroids.
Case Report: MDS and Relapsing Polychondritis
wsc (xloe/L) 4
2 3
7/11
5112
211
3011
5
2712
6
a
7
2613
2314
DATE
Fig. 1. White blood cell count and clinical events. 1 = Fever, arthritis, chondritis. 2 = Bells palsy, fever, skleroteratitis. 3 = Epidural hematoma and paraparesis. 4 = Development of interstitial pulmonary infiltrates and cardiomyopathy. 5 = Respiratory failure and intubation. 6 = Administration of high dose ARA-C. 7 = Extubation, defervescence. 8 = Orchitis, optic nerve and retinal vasculitis. For detailed discussion of clinical events and their treatment, see text.
However, after tapering of the steroid dose he developed a Bell’s palsy and recurrent ocular inflammation followed by a serous otitis, cardioniyopathy, pulmonary infiltrates, proteinuria, hematuria, hypertension, and fever. All these symptoms can be attributed to RP (9-141. The second episode of polychondritis could not be controlled by treatment with corticosteroids. Aggressive chemotherapy and the resulting pancytopenia led to short term improvement of the RP. Neurologic function also markedly improved. This was followed by an extremely fulminant recurrence of RP, associated temporally with the recurrence of MDS. Interestingly, the recurrence of RP also led to a rapid deterioration in neurologic function and was accompanied by an episode of orchitis. To the best of our knowledge, orchitis has not been previously reported to be associated with relapsing polychondritis. However, the onset of orchitis simultaneously with a flare-up of keratouveitis suggests that each was due to a common etiology, RP. The onset of RP within weeks of the diagnosis of MDS, as well as the short term improvement during chemotherapy-induced marrow aplasia, suggest that the relationship between the two disorders is not coincidental. Paraneoplastic disorders (i.e., disorders caused by neoplasms in parts of the body not physically affected by the tumor) [ 151 are uncommon in hematologic malignancies except for coagulation abnormalities in acute promyelocytic leukemia and hypercalcemia in myeloma. How-
49
ever Sweet’s syndrome has been associated with acute leukemia [ 161, acquired ichthyosis with lymphoma and Hodgkin’s disease [ 171, pruritus with lymphoma and leukemia [ 181, and pemphigus with lymphoma and leukemia 1191. A few cases of RP have previously been reported in association with Hodgkin’s disease [20], lymphoma 1211, solid tumors [25], and acute leukemia [6]. The association between MDS and RP has only rarely been mentioned in the literature. Michet et al. [8] mention that six of their patients with RP had evolving myeloproliferative or dysmyelopoeietic disorders. Arlet et al. present a series of 12 cases of RP, two of which had an MDS at the time of diagnosis (one case of refractory anemia with ringsideroblasts and one case of refractory anemia with excess blasts) [21 1. It could be argued that antileukemic therapy is merely aggressive immunosuppression and therefore caused an improvement in symptoms of RP. However, the recurrence of symptoms of RP at the time of granulocyte recovery is suggestive of a cause and effect relationship. In addition more aggressive immunosuppressive therapy with steroids and cyclophosphamide could not prevent the progression of symptoms. The pathophysiology of RP is unclear. Formation of autoantibodies to type I1 collagen and cartilage has been demonstrated by several groups [23,24] and an animal model of type I1 collagen induced auricular chondritis has been developed 124,251. However, the exact role of these antibodies in the pathogenesis of the syndrome remains unclear. In conclusion, RP can rarely accompany MDS and can cause severe morbidity. The disease appears to be paraneoplastic in nature and may respond to treatment of the underlying hematological disorder. REFERENCES 1 . Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classifi-
2. 3.
4.
5. 6.
7. 8.
cation of the myelodyspkastic syndromes. Br J Haematol 5 I: 189-199, 1982. Tricot GJ, Lauer RC. Appelbaum FR, et al.: Management of the myelodysplastic syndromes. Semin Oncol 14:444453, 1987. Tricot G. Vlietinck R, Boogaerts MA, Hendrickx B, De Wolf-Peeters C. Van den Berghe H. Verwilghen RL: Prognostic factors in the myelodysplastic syndromes: importance of initial data on peripheral blood counts, bone marrow cytology. trephine biopsy and chromosomal analysis. Br J Haeniatol 60: 19-32, 1985. Foucar K. Langdon RM. Armitage JL, et al.: Myelodysplastic syndromes: A clinical and pathologic analysib of 109 cases. Cancer 56553-561, 1985. Herman J (ed): Polychondritis. In “Primer o n Rheumatic Diseases.” Arthritis Foundation 1988, pp 14 1-142. Mc Adam LP, O’Hanlan MA. Bluestone R . Pearson CM: Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine (Baltimore) 55:193-215. 1976. Arkin CR. Masi AT: Relapsing ptrlychondritis: Review of current status and case report. Semin Arthritis Rheum 5:41-62, 1975. Michet JR, McKenna CH. Luthra HS. O’Fallon WM: Relapsing pofy-
50
9. 10.
11,
12. 13,
14.
IS.
16.
Case Report: Van Besien et al. chondritis: survival and predictive role of early disease manifestations. Ann Intern Med 104:74-78. 1986. Sundarani MB. Rajput AH: Nervous system complications of relapsing polychondntis. Neurology 33513-515, 1983. Stewart SS. Ashizowa T, Dudley AW, Goldberg JW, Lidsky MU: Central vasculitis in relapsing polychondritis. Neurology 38: 1 5 6 15 2 , 1988. Netter JM, Guillauseau PJ, Fafet D, Tinsit J. Chanson Ph, Haguenau M. Lubetzki J: Manifestations neurologiques de la polychondrite atrophiante. Presse Med 31:1525-1526. 1989. Isaac BL. Liesegang TJ. Michet CJ: Ocular and systemic findings in relapsing polychondritis. Ophthalmology 93:68 1-689. 1986. DoIan DL. Lenimon BG. Teitelbaum LS: Relapsing polychondritis: Analytical literature review and studies on pathogenesis. Am J Med 44:28S-299, 1966. Giroux L, Paquin F. Guirard-Desjardins MJ, Lefaivre V: Relapsing polychondritis an auto-immune disease. Semin Arthritis Rheum 13:182-1 86, 1087. B u m PA. Ridgway EC: Paraneoplastic Syndromes. I n Devita VT. Hellman S, Rosenberg SA (eds): "Cancsr, Principles and Practice of Oncology." JB Lippincott. 1989. pp 189&1941. Cohen PR. Kurrock R: Sweet syndrome and malignancy. Am J Med 83:1220-1226. 1978,
17. Flint G L , Flam M. Soter NA: Acquired ichthyoqis. Arch Dermatol 1 1 1 : 1 4 4 ~ l 4 4 7 1975. . 18. Cornia FE: Pruritus, an uncommon but important symptom of systemic cancer. Arch Dermatol 9 2 : 3 6 3 9 . 1965. 19. Anhalt GJ. Kim S, Stanley JR. et al.: Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med 323:1729-1735. 1990. 20. Millei- SB, Donlan JC, Roth SB: Hodgkin's disease presenting as relapsing polychondritis. Arthritis Rheum 17598-602, 1974. 21. Arlet PH. Pris J . Vilain C . Laroche M. Le Tallec Y: Polychondrite chronique atrophiante: particularitis cliniques. Presse Med 18: 1.57160. 1989. 22. Foidart JM, Shigeto A, Martin GR, Zizic T M , Barnett EV, Lowley TJ, Katz SI: Antibodies to type I t collagen in relapsing polychondritis. N Engl J Med299:1703-1207. 1978. 23. Ebringer R. Rook G. Swanor GT, Bottazzo GF. Doniack D: Autoantibodies to cartilage and type I1 collagen in relapsing polychondritis and other rheumatic diseases. Ann Rheum Dis 4 0 : 4 7 3 4 7 9 . 198 I . 24. Cremer MA, Pitcock JA. Stuart JM, Kang AH. Taunea AS: Auricular chondritis in rats. J Exp Med 154:535-540. 19x1. 25. McCune WJ. Schiller AL. Dynesius-Trentham RA. Trentham DE: Type II collagen induced auricular chondritis. Arthritis Rheum 25:266273, 1981.
Relapsing Polychondritis: A Paraneoplastic Syndrome Associated With Myelodysplastic Syndromes Koen Van Besien, Guido Tricot, and Ronald Hoffman Division of Hernatology/Oncology, Indiana University School of Medicine, Indianapolis
We report an unusual case of a patient with a myelodysplasticsyndromeassociated with life threatening relapsing polychondritis. The improvement in symptoms attributable to the relapsing polychondritis during treatment of the hematologic disorder suggests that relapsing polychondritis is a paraneoplastic syndrome associated with myelodysplastic syndromes. IC' 1992 Wiley-Liss, Inc. Key words: hematologicdisorder, peripheral cytopenias, dysplastic bone marrow
INTRODUCTION The myelodysplastic syndromes (MDS) are clonal disorders of hematopoiesis characterized by peripheral cytopenias and a dysplastic bone marrow that is usually hypercellular [ I ] . The prognosis in general is poor and results of treatment are disappointing 121. Morbidity and mortality are usually due to infections or hemorrhagic episodes [3,4]. Relapsing polychondritis (RP) is a relatively rare, often episodic form of inflammatory disease characterized by potentially destructive lesions involving organs of special sense, laryngotracheobronchial structures, the cardiovascular system, and joints [S-81. It is generally assumed to be an auto-immune disorder [ M I . The diagnosis is based on the clinical features but can be confirmed by biopsy of affected cartilage. We report here a young patient with a MDS subtype, refractory anemia with excess blasts in transformation (RAEB-t), that was associated with severe RP. The RP was extremely disabling and ultimately resulted in respiratory failure. Treatment of the underlying hematologic disorder led to a temporary improvement in the symptoms of RP, strongly suggesting a paraneoplastic nature of the syndrome. CASE REPORT
A 19 year old college student presented to his local physician due to a football related injury. A routine blood count revealed a moderate anemia with a hemoglobin of 10.7 g/dl. The white blood cell count was 7.6 X IO'/L with 7% blasts, 4% myelocytes. 2% metamyelocytes, 63% granulocytes, 12% lymphocytes, 7% monocytes, 0 1992 Wiley-Liss, Inc.
1% eosinophils, and 6% basophils. The platelet count was 107 X IOy/L. The patient had lost 20 pounds in the 3 months prior to this visit and had suffered several nose bleeds. Physical examination was unremarkable. A bone marrow biopsy was 100% cellular. Megakaryocytes were increased; atypical megakaryocytes and micromegakaryocytes were seen. The erythroid series was megaloblastic. Nuclear atypia and intercellular bridging were present. The niyeloid series showed hypogranulation and dysniyelopoiesis. Approximately 1S% blasts were present. Cytogenetic analysis of the bone marrow revealed an abnormal clone with a monosomy 7 and the addition of a small ring chromosome. In addition, some cells also showed a deletion of chromosome 6. A diagnosis of MDS (refractory anemia with excess blasts in transformation) was made. Approximately 3 weeks after initial diagnosis, the patient was admitted because of intermittent fever up to 38°C and pain in the right ankle. On physical examination slight swelling and tenderness of the right ankle was found. An extensive work-up was unrevealing. Repeat bone marrow aspirate revealed only 4% blasts. While in the hospital, the patient developed an effusion of the left knee and tenderness and erythema of the right pinna. The synovial fluid of the right knee revealed 54 X IOy/L
Received for publication April 5, 1991: accepted November 18. 1991. Address reprint requests to Ronald Hoffman M.D., Indiana University Medical Center, 975 W Walnut Street IB 442, Indianspolis I N , 462025121.
48
Case Report: Van Besien et al.
white blood cells, but was sterile. Crystals were absent. Serum rheumatoid factor was negative. He also developed a nonproductive cough and a small left pleural effusion. Thoracentesis was attempted but unsuccessful. Bronchoscopy with bronchoalveolar lavage was unrevealing. Total body gallium scan failed to reveal an inflammatory focus. Because of the arthritic symptoms, the patient was treated with sodium salicylate and discharged. During ensuing weeks he developed inflammation of both pinnae and bilateral sclerokeratitis. A diagnosis of RP was made and treatment with corticosteroids (prednisone 1 mg/kg) initiated. Initially, his symptoms improved and the corticosteroids were tapered rapidly. Three weeks later he was readmitted because of a left Bell’s palsy and recurrent fevers. Head CT scan and MRI were normal; lumbar puncture revealed a nornial cerebrospinal fluid. Four days after the lumbar puncture he developed paraparesis. CT scan revealed an epidural hematoma extending from the midbody of L2 down to the margin of L3. This was evacuated, but there was little recuperation of neurologic function. During the admission, he also developed a left otitis media which required placement of ear tubes. Cultures of the middle ear fluid were sterile. The steroid therapy was continued and broad-spectrum antibiotics were added. Over the next days, the patient developed bilateral interstitial pulmonary infiltrates and continued to have fever. A repeat bronchoscopy with bronchoalveolar lavage was negative. An open lung biopsy showed acute inflammation and intra-alveolar hemorrhage; cultures were negative. Ultrasound of the heart did not show signs of endocarditis but severely decreased left ventricular systolic function was found. An abdominal CT scan revealed a 2 X 3 cm hypodense lesion in the left kidney that had not been present on a previous CT. CT guided fine needle aspiration revealed only sterile fluid. The patient also developed hematuria and proteinuria of 2 g/24 hours and severe hypertension that could be controlled only with a combination of calcium channel blockers, beta blockers, and ACE inhibitors. The patient deteriorated rapidly. The RP in combination with immobilization and corticosteroid therapy led to rapid muscle wasting, and intravenous hyperalimentation was initiated. When the pulmonary infiltrates acutely worsened, the patient had to be intubated. A third bronchoalveolar lavage failed to reveal an infectious cause for the pulmonary infiltrates. Empirical treatment with amphotericin B was started, but did not result in any apparent benefit. It was then assumed that most of the patient’s symptoms, including the fever, cardiomyopathy, proteinuria, hematuria, hypertension, pul inonary infiltrates, eye symptoms, and joint and cartilage symptoms were due to RP and that the RP was paraneoplastic in nature. It was decided to treat the underlying myelodysplastic syn-
drome with intensive Chemotherapy. The patient was treated with high dose cytosine arabinoside (2 g/m2 IV every 12 hours for a total of 10 doses). Within 48 hours he defervesced. Pulmonary symptoms improved and he was extubated. Eye symptoms improved rapidly and surprisingly the paraplegia also improved; the patient gained some strength and mobility in the lower extremities and intensive rehabilitation was started. Corticosteroid therapy was slowly tapered and amphotericin B was stopped. Due to the chemotherapy the patient became profoundly granulocytopenic and thrombocytopenic, but remained afebrile. Approximately 14 days after the completion of chemotherapy the granulocyte count recovered, but the platelet count remained low. A bone marrow aspirate was hypercellular, with 10% blasts and dysplastic features in the three hematopoietic lineages. The cytogenetic abnormalities persisted. Fever recurred and within 72 hours of the first signs of recovery of granulocytes, bilateral scleritis recurred followed by a fulminant retinal and optic nerve vasculitis leading to almost complete blindness of both eyes despite treatment with high doses of methylprednisolone ( 1 g IV q 6 hours for I week) and cyclophosphamide (100 mg po q day). Muscle strength in the lower extremities decreased rapidly and arthritic symptoms recurred. The patient also developed orchitis for which no infectious cause could be determined. Over the next several weeks, with continued immunosuppressive therapy (cyclophosphamide 100 mg/d and a tapering dose of steroids), the patient’s conditions stabilized. The possibility of success with further chemotherapy was felt to be low, and the risks high. A second course of induction chemotherapy was therefore not attempted. With supportive care and immunosuppressive therapy the patient has remained in a stable clinical and hematologic condition for 10 months later (Fig. I illustrates the clinical course of the patient).
DISCUSSION This young patient presented with a classic MDS [ I ] . By virtue of the number of blasts in the bone marrow and the cytogenetic abnormalities his prognosis was felt to be poor [ 3 ] . When the patient presented with fever and arthralgias an extensive investigation failed to reveal an infectious cause. The fever resolved only after treatment with salicylates. Some weeks later the patient developed also manifestations of chondritis and sclerokeratitis. At that time a diagnosis of RP was made. Treatment of RP is aimed at suppressing the inflammatory process [5-71. Corticosteroids are the treatment of choice but occasionally other immunosuppressive agents such as azathioprine have been used. This patient’s symptoms at first responded to treatment with steroids.
Case Report: MDS and Relapsing Polychondritis
wsc (xloe/L) 4
2 3
7/11
5112
211
3011
5
2712
6
a
7
2613
2314
DATE
Fig. 1. White blood cell count and clinical events. 1 = Fever, arthritis, chondritis. 2 = Bells palsy, fever, skleroteratitis. 3 = Epidural hematoma and paraparesis. 4 = Development of interstitial pulmonary infiltrates and cardiomyopathy. 5 = Respiratory failure and intubation. 6 = Administration of high dose ARA-C. 7 = Extubation, defervescence. 8 = Orchitis, optic nerve and retinal vasculitis. For detailed discussion of clinical events and their treatment, see text.
However, after tapering of the steroid dose he developed a Bell’s palsy and recurrent ocular inflammation followed by a serous otitis, cardioniyopathy, pulmonary infiltrates, proteinuria, hematuria, hypertension, and fever. All these symptoms can be attributed to RP (9-141. The second episode of polychondritis could not be controlled by treatment with corticosteroids. Aggressive chemotherapy and the resulting pancytopenia led to short term improvement of the RP. Neurologic function also markedly improved. This was followed by an extremely fulminant recurrence of RP, associated temporally with the recurrence of MDS. Interestingly, the recurrence of RP also led to a rapid deterioration in neurologic function and was accompanied by an episode of orchitis. To the best of our knowledge, orchitis has not been previously reported to be associated with relapsing polychondritis. However, the onset of orchitis simultaneously with a flare-up of keratouveitis suggests that each was due to a common etiology, RP. The onset of RP within weeks of the diagnosis of MDS, as well as the short term improvement during chemotherapy-induced marrow aplasia, suggest that the relationship between the two disorders is not coincidental. Paraneoplastic disorders (i.e., disorders caused by neoplasms in parts of the body not physically affected by the tumor) [ 151 are uncommon in hematologic malignancies except for coagulation abnormalities in acute promyelocytic leukemia and hypercalcemia in myeloma. How-
49
ever Sweet’s syndrome has been associated with acute leukemia [ 161, acquired ichthyosis with lymphoma and Hodgkin’s disease [ 171, pruritus with lymphoma and leukemia [ 181, and pemphigus with lymphoma and leukemia 1191. A few cases of RP have previously been reported in association with Hodgkin’s disease [20], lymphoma 1211, solid tumors [25], and acute leukemia [6]. The association between MDS and RP has only rarely been mentioned in the literature. Michet et al. [8] mention that six of their patients with RP had evolving myeloproliferative or dysmyelopoeietic disorders. Arlet et al. present a series of 12 cases of RP, two of which had an MDS at the time of diagnosis (one case of refractory anemia with ringsideroblasts and one case of refractory anemia with excess blasts) [21 1. It could be argued that antileukemic therapy is merely aggressive immunosuppression and therefore caused an improvement in symptoms of RP. However, the recurrence of symptoms of RP at the time of granulocyte recovery is suggestive of a cause and effect relationship. In addition more aggressive immunosuppressive therapy with steroids and cyclophosphamide could not prevent the progression of symptoms. The pathophysiology of RP is unclear. Formation of autoantibodies to type I1 collagen and cartilage has been demonstrated by several groups [23,24] and an animal model of type I1 collagen induced auricular chondritis has been developed 124,251. However, the exact role of these antibodies in the pathogenesis of the syndrome remains unclear. In conclusion, RP can rarely accompany MDS and can cause severe morbidity. The disease appears to be paraneoplastic in nature and may respond to treatment of the underlying hematological disorder. REFERENCES 1 . Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classifi-
2. 3.
4.
5. 6.
7. 8.
cation of the myelodyspkastic syndromes. Br J Haematol 5 I: 189-199, 1982. Tricot GJ, Lauer RC. Appelbaum FR, et al.: Management of the myelodysplastic syndromes. Semin Oncol 14:444453, 1987. Tricot G. Vlietinck R, Boogaerts MA, Hendrickx B, De Wolf-Peeters C. Van den Berghe H. Verwilghen RL: Prognostic factors in the myelodysplastic syndromes: importance of initial data on peripheral blood counts, bone marrow cytology. trephine biopsy and chromosomal analysis. Br J Haeniatol 60: 19-32, 1985. Foucar K. Langdon RM. Armitage JL, et al.: Myelodysplastic syndromes: A clinical and pathologic analysib of 109 cases. Cancer 56553-561, 1985. Herman J (ed): Polychondritis. In “Primer o n Rheumatic Diseases.” Arthritis Foundation 1988, pp 14 1-142. Mc Adam LP, O’Hanlan MA. Bluestone R . Pearson CM: Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine (Baltimore) 55:193-215. 1976. Arkin CR. Masi AT: Relapsing ptrlychondritis: Review of current status and case report. Semin Arthritis Rheum 5:41-62, 1975. Michet JR, McKenna CH. Luthra HS. O’Fallon WM: Relapsing pofy-
50
9. 10.
11,
12. 13,
14.
IS.
16.
Case Report: Van Besien et al. chondritis: survival and predictive role of early disease manifestations. Ann Intern Med 104:74-78. 1986. Sundarani MB. Rajput AH: Nervous system complications of relapsing polychondntis. Neurology 33513-515, 1983. Stewart SS. Ashizowa T, Dudley AW, Goldberg JW, Lidsky MU: Central vasculitis in relapsing polychondritis. Neurology 38: 1 5 6 15 2 , 1988. Netter JM, Guillauseau PJ, Fafet D, Tinsit J. Chanson Ph, Haguenau M. Lubetzki J: Manifestations neurologiques de la polychondrite atrophiante. Presse Med 31:1525-1526. 1989. Isaac BL. Liesegang TJ. Michet CJ: Ocular and systemic findings in relapsing polychondritis. Ophthalmology 93:68 1-689. 1986. DoIan DL. Lenimon BG. Teitelbaum LS: Relapsing polychondritis: Analytical literature review and studies on pathogenesis. Am J Med 44:28S-299, 1966. Giroux L, Paquin F. Guirard-Desjardins MJ, Lefaivre V: Relapsing polychondritis an auto-immune disease. Semin Arthritis Rheum 13:182-1 86, 1087. B u m PA. Ridgway EC: Paraneoplastic Syndromes. I n Devita VT. Hellman S, Rosenberg SA (eds): "Cancsr, Principles and Practice of Oncology." JB Lippincott. 1989. pp 189&1941. Cohen PR. Kurrock R: Sweet syndrome and malignancy. Am J Med 83:1220-1226. 1978,
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