- Email: [email protected]
Possible causes of acute pseudogout in older patients with osteoarthritis
Letters to the Editor matosis. Medicine (Baltimore). 1995;74: 152–161. 6. Stone JH, Millward CL, Criswell LA. Two genitourinary manifestations of Wegener’s granulomatosis. J Rheumatol. 1997;24: 1846 –1848. 7. Kurman RJ, ed. Blaustein’s Pathology of the Female Genital Tract. 4th ed. New York: Springer-Verlag; 1994.
POSSIBLE CAUSES OF ACUTE PSEUDOGOUT IN OLDER PATIENTS WITH OSTEOARTHRITIS
Figure 2. Necrotic and bleeding cervix, magnified with a green filter.
an extensive necrotizing granulomatous inflammation compatible with Wegener’s granulomatosis (7). The patient was treated with prednisone (40 mg per day orally) and cyclophosphamide (2 mg/kg per day orally). Three months later, colposcopic and cytologic examinations were normal, and the dose of prednisone was tapered. One year later, the patient was doing well and taking prednisone (10 mg per day) and cyclophosphamide (2 mg/kg per day orally). We initially suspected cervical carcinoma because the patient had been immunosuppressed from long-term cyclophosphamide therapy, although alkylating agents usually cause a neoplastic disorder in proliferating cells of hemopoietic and lymphoid tissue. Despite the colposcopic examination that appeared consistent with cervical carcinoma, cytologic and histologic examinations did not show malignant cells. We were able to differentiate Wegener’s granulomatosis from tuberculosis affecting the uterine cervix owing to the absence of caseating granulomas, the negative skin test, and the normal chest radiograph. In addition, the increased titer of c-ANCA and the presence of proteinuria favored the diagnosis of a flare of Wegener’s granulomatosis. The absence of hilar lymphadenopathy and the presence of necrotizing gran-
ulomas made the diagnosis of sarcoidosis unlikely. We conclude that Wegener’s granulomatosis can affect the uterine cervix. The Pap smear test proved to be a useful tool for its diagnosis, which was subsequently confirmed by histopathologic examination. Vassiliki D. Malamou-Mitsi, MD Niki J. Agnantis, MD Lina S. Pappa, MD Department of Cytopathology Evangelos Paraskevaidis, MD Minas Paschopoulos, MD Department of Obstetrics and Gynecology Alexandros A. Drosos, MD Department of Internal Medicine Medical School University of Ioannina Ioannina, Greece 1. Sneller MC. Wegener’s granulomatosis (clinical conference). JAMA. 1995;273: 1288 –1291. 2. Boki KA, Dafni U, Karpouzas A, et al. Necrotizing vasculitis in Greece: clinical, immunological and immunogenetic aspects. A study of 66 patients. Br J Rheumatol. 1997; 36:1059 –1066. 3. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener’s granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med. 1983; 98:76 – 85. 4. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488 – 498. 5. Huong DLT, Papo T, Piette J-C, et al. Urogenital manifestations of Wegener granuloJuly 2000
To the Editor: I read with great interest the report of a patient who developed acute pseudogout after intra-articular injection of high-molecular-weight hyaluronic acid (1). However, the authors did not mention other possible causes of acute pseudogout in older patients with osteoarthritis. Hypothyroidism, a common disorder in elderly patients, frequently causes pseudogout (2). Although the prevalence of hypothyroidism increases with age (3), thyroid function is not routinely tested in older patients, and hypothyroidism can go undiscovered. Further, thyroid hormones are potent stimulants of hypertrophy of growth plate chondrocytes and differentiation of articuloarchondrocytes (4). the latter may lead to increased elaboration of inorganic pyrophosphate. Pseudogout can also be caused by the increased production of proinflammatory cytokines in the joint. Glycosaminoglycan hyaluronate, which is part of the extracellular environment in bone marrow, induces macrophagelike cells to secrete interleukin-1 beta and interleukin-6 by different transduction pathways (5). In addition, the binding of CD 44, a ubiquitous molecule known as hyaluronic acid receptor, to hyaluronan can augment interleukin-6 production in synovial cells in patients with rheumatoid arthritis (6). Thus intraarticular injection of high-molecular-
THE AMERICAN JOURNAL OF MEDICINE威
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Letters to the Editor
weight hyaluronic acid may activate transcription factors, resulting in the increased production of proinflammatory cytokines. We reported a patient with an attack of pseudogout after treatment with granulocyte colony-stimulating factor, whose synovial interleukin-8 and interleukin-6 concentrations were markedly increased (7). Interleukin-8 is the major neutrophil chemotaxin in synovial fluid in patients with pseudogout (8). Synovial concentrations of interleukin-6 and other proinflammatory cytokines may be increased in patients with osteoarthritis and rheumatoid arthritis (9). Production of interleukin-8 by synovial cells and monocytes is enhanced in the presence of inorganic pyrophosphate (10). These data suggest that pseudogout could be exacerbated by the increased production of cytokines in knee joints. Although a causal relation between proinflammatory cytokines and pseudogout has not been conclusively demonstrated, intra-articular injection of high-molecular-weight hyaluronic acid may alter the cytokine balance. Measurement of synovial cytokines may provide valuable information about the pathogenesis of pseudogout in patients with osteoarthritis. Shinji Teramoto, MD Department of Internal Medicine San-no Hospital, Tokyo, Japan Medical Research Center International University of Health and Welfare Tochigi, Japan 1. Ali Y, Weinstein M, Jokl P. Acute pseudogout following intraarticular injection of high molecular weight hyaluronic acid. Am J Med. 1999;107:641– 642. 2. Dorwart BB, Schumacher HR. Joint effusions, chondrocalcinosis and other rheumatic manifestations in hypothyroidism. A clinicopathological study. Am J Med. 1975;59:780 –790. 3. Lindeman RD, Schade DS, LaRue A, et al. Subclinical hypothyroidism in a biethnic, urban community. J Am Geriatr Soc. 1999; 47:703–709. 4. Rosenthal AK, Henry LA. Thyroid hor76
July 2000
5.
6.
7.
8.
9.
10.
mones induce features of the hypertrophic phenotype and stimulate correlates of CDDP crystal formation in articular chondrocytes. J Rheumatol. 1999;26:395– 401. Khaldoyanidi S, Moll J, Karakhanova S, et al. Hyaluronate-enhanced hematopoiesis: two different receptors trigger the release of interleukin-1 beta and interleukin-6 from bone marrow macrophages. Blood. 1999;94:940 –949. Fujii K, Tanaka Y, Hubscher S, et al. Crosslinking of CD44 on rheumatoid synovial cells augment interleukin 6 production. Lab Invest. 1999;79:1439 –1446. Teramoto S, Yamamoto H, Ouchi Y. Increased synovial interleukin-8 and interleukin-6 levels in pseudogout associated with granulocyte colony-stimulating factor. Ann Intern Med. 1998;129:424 – 425. Letter. Miller EL, Brelsford WG. Interleukin-8: the major neutrophil chemotoxin in a case of pseudogout. J Rheumatol. 1994;20: 1250 –1252. van Leeuwen MA, Westra J, Limburg PC, et al. Interleukin-6 in relation to other proinflammatory cytokines, chemotactic activity and neutrophil activation in rheumatoid synovial fluid. Ann Rheum Dis. 1995;54:33–38. Hachicha M, Naccache PH, McColl SR. Inflammatory microcrystals differentially regulate the secretion of macrophage inflammatory protein 1 and interleukin 8 by human neutrophils: a possible mechanism of neutrophil recruitment to sites of inflammation in synovitis. J Exp Med. 1995; 182:2019 –2025.
WHO WAS OSLER? To the Editor: William Osler, born a little more than 150 years ago, was the most influential physician and medical educator of his day. Renowned for his warmth, literacy, and character, he remains a central figure in the pantheon of internal medicine, yet it has been suggested that many medical students cannot identify him (1). Is this true? Have our students lost sight of a man who is certainly “among the most esteemed and distinguished physicians in the history of medicine” (2)? To find out, I gave an unannounced quiz to a convenience sample of housestaff at a large universityaffiliated teaching hospital. Fifteen
THE AMERICAN JOURNAL OF MEDICINE威
Volume 109
residents who attended a regularly scheduled noon lecture were asked to answer 10 multiple-choice questions about Osler’s career and contributions. A modest honorarium was promised for the best score. As might have been expected in a hospital that had recently established an Osler Teaching Award, 12 residents knew that Osler was known for his bedside teaching. Eight correctly indicated on these multiple-choice questions that he had written a textbook, and 8 that he was identified with internal medicine. Six correctly identified his year of birth, while 6 also knew that he had worked in Philadelphia and Baltimore and that his Pulitzer Prize-winning biography was written by Harvey Cushing. Only 4, however, could pick him out of a rogues’ gallery (a term he would have loved), which also included likenesses of James Paget, Sigmund Freud, William Withering, and Samuel Gross. Three knew that Osler “retired” to Oxford, and only 2 that he was born in Canada, although many recognized, with admirable ingenuity, that his knighthood argued for some sort of British origin. And, finally, only 2 recognized Aequanimitas as one of Osler’s most enduring writings. All years of our residency were represented among those who took the quiz. Ten residents were US born and trained, and they had a mean score of 3.5, with none answering more than 5 questions correctly. One international graduate, who had read a monograph about Osler distributed by a pharmaceutical company, answered all 10 questions correctly. The mean score for the remaining 4 international graduates was 3; none of them answered more than 5 questions correctly. Does this matter? Is the history of medicine relevant? Yes, and yes. McClure (3) has observed that in order to build the future, it is essential to know the past. And what a past Osler represents. He is for us the mythic hero of internal medicine, the “compleat” consultant, and the father of
POSSIBLE CAUSES OF ACUTE PSEUDOGOUT IN OLDER PATIENTS WITH OSTEOARTHRITIS
Figure 2. Necrotic and bleeding cervix, magnified with a green filter.
an extensive necrotizing granulomatous inflammation compatible with Wegener’s granulomatosis (7). The patient was treated with prednisone (40 mg per day orally) and cyclophosphamide (2 mg/kg per day orally). Three months later, colposcopic and cytologic examinations were normal, and the dose of prednisone was tapered. One year later, the patient was doing well and taking prednisone (10 mg per day) and cyclophosphamide (2 mg/kg per day orally). We initially suspected cervical carcinoma because the patient had been immunosuppressed from long-term cyclophosphamide therapy, although alkylating agents usually cause a neoplastic disorder in proliferating cells of hemopoietic and lymphoid tissue. Despite the colposcopic examination that appeared consistent with cervical carcinoma, cytologic and histologic examinations did not show malignant cells. We were able to differentiate Wegener’s granulomatosis from tuberculosis affecting the uterine cervix owing to the absence of caseating granulomas, the negative skin test, and the normal chest radiograph. In addition, the increased titer of c-ANCA and the presence of proteinuria favored the diagnosis of a flare of Wegener’s granulomatosis. The absence of hilar lymphadenopathy and the presence of necrotizing gran-
ulomas made the diagnosis of sarcoidosis unlikely. We conclude that Wegener’s granulomatosis can affect the uterine cervix. The Pap smear test proved to be a useful tool for its diagnosis, which was subsequently confirmed by histopathologic examination. Vassiliki D. Malamou-Mitsi, MD Niki J. Agnantis, MD Lina S. Pappa, MD Department of Cytopathology Evangelos Paraskevaidis, MD Minas Paschopoulos, MD Department of Obstetrics and Gynecology Alexandros A. Drosos, MD Department of Internal Medicine Medical School University of Ioannina Ioannina, Greece 1. Sneller MC. Wegener’s granulomatosis (clinical conference). JAMA. 1995;273: 1288 –1291. 2. Boki KA, Dafni U, Karpouzas A, et al. Necrotizing vasculitis in Greece: clinical, immunological and immunogenetic aspects. A study of 66 patients. Br J Rheumatol. 1997; 36:1059 –1066. 3. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener’s granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med. 1983; 98:76 – 85. 4. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488 – 498. 5. Huong DLT, Papo T, Piette J-C, et al. Urogenital manifestations of Wegener granuloJuly 2000
To the Editor: I read with great interest the report of a patient who developed acute pseudogout after intra-articular injection of high-molecular-weight hyaluronic acid (1). However, the authors did not mention other possible causes of acute pseudogout in older patients with osteoarthritis. Hypothyroidism, a common disorder in elderly patients, frequently causes pseudogout (2). Although the prevalence of hypothyroidism increases with age (3), thyroid function is not routinely tested in older patients, and hypothyroidism can go undiscovered. Further, thyroid hormones are potent stimulants of hypertrophy of growth plate chondrocytes and differentiation of articuloarchondrocytes (4). the latter may lead to increased elaboration of inorganic pyrophosphate. Pseudogout can also be caused by the increased production of proinflammatory cytokines in the joint. Glycosaminoglycan hyaluronate, which is part of the extracellular environment in bone marrow, induces macrophagelike cells to secrete interleukin-1 beta and interleukin-6 by different transduction pathways (5). In addition, the binding of CD 44, a ubiquitous molecule known as hyaluronic acid receptor, to hyaluronan can augment interleukin-6 production in synovial cells in patients with rheumatoid arthritis (6). Thus intraarticular injection of high-molecular-
THE AMERICAN JOURNAL OF MEDICINE威
Volume 109 75
Letters to the Editor
weight hyaluronic acid may activate transcription factors, resulting in the increased production of proinflammatory cytokines. We reported a patient with an attack of pseudogout after treatment with granulocyte colony-stimulating factor, whose synovial interleukin-8 and interleukin-6 concentrations were markedly increased (7). Interleukin-8 is the major neutrophil chemotaxin in synovial fluid in patients with pseudogout (8). Synovial concentrations of interleukin-6 and other proinflammatory cytokines may be increased in patients with osteoarthritis and rheumatoid arthritis (9). Production of interleukin-8 by synovial cells and monocytes is enhanced in the presence of inorganic pyrophosphate (10). These data suggest that pseudogout could be exacerbated by the increased production of cytokines in knee joints. Although a causal relation between proinflammatory cytokines and pseudogout has not been conclusively demonstrated, intra-articular injection of high-molecular-weight hyaluronic acid may alter the cytokine balance. Measurement of synovial cytokines may provide valuable information about the pathogenesis of pseudogout in patients with osteoarthritis. Shinji Teramoto, MD Department of Internal Medicine San-no Hospital, Tokyo, Japan Medical Research Center International University of Health and Welfare Tochigi, Japan 1. Ali Y, Weinstein M, Jokl P. Acute pseudogout following intraarticular injection of high molecular weight hyaluronic acid. Am J Med. 1999;107:641– 642. 2. Dorwart BB, Schumacher HR. Joint effusions, chondrocalcinosis and other rheumatic manifestations in hypothyroidism. A clinicopathological study. Am J Med. 1975;59:780 –790. 3. Lindeman RD, Schade DS, LaRue A, et al. Subclinical hypothyroidism in a biethnic, urban community. J Am Geriatr Soc. 1999; 47:703–709. 4. Rosenthal AK, Henry LA. Thyroid hor76
July 2000
5.
6.
7.
8.
9.
10.
mones induce features of the hypertrophic phenotype and stimulate correlates of CDDP crystal formation in articular chondrocytes. J Rheumatol. 1999;26:395– 401. Khaldoyanidi S, Moll J, Karakhanova S, et al. Hyaluronate-enhanced hematopoiesis: two different receptors trigger the release of interleukin-1 beta and interleukin-6 from bone marrow macrophages. Blood. 1999;94:940 –949. Fujii K, Tanaka Y, Hubscher S, et al. Crosslinking of CD44 on rheumatoid synovial cells augment interleukin 6 production. Lab Invest. 1999;79:1439 –1446. Teramoto S, Yamamoto H, Ouchi Y. Increased synovial interleukin-8 and interleukin-6 levels in pseudogout associated with granulocyte colony-stimulating factor. Ann Intern Med. 1998;129:424 – 425. Letter. Miller EL, Brelsford WG. Interleukin-8: the major neutrophil chemotoxin in a case of pseudogout. J Rheumatol. 1994;20: 1250 –1252. van Leeuwen MA, Westra J, Limburg PC, et al. Interleukin-6 in relation to other proinflammatory cytokines, chemotactic activity and neutrophil activation in rheumatoid synovial fluid. Ann Rheum Dis. 1995;54:33–38. Hachicha M, Naccache PH, McColl SR. Inflammatory microcrystals differentially regulate the secretion of macrophage inflammatory protein 1 and interleukin 8 by human neutrophils: a possible mechanism of neutrophil recruitment to sites of inflammation in synovitis. J Exp Med. 1995; 182:2019 –2025.
WHO WAS OSLER? To the Editor: William Osler, born a little more than 150 years ago, was the most influential physician and medical educator of his day. Renowned for his warmth, literacy, and character, he remains a central figure in the pantheon of internal medicine, yet it has been suggested that many medical students cannot identify him (1). Is this true? Have our students lost sight of a man who is certainly “among the most esteemed and distinguished physicians in the history of medicine” (2)? To find out, I gave an unannounced quiz to a convenience sample of housestaff at a large universityaffiliated teaching hospital. Fifteen
THE AMERICAN JOURNAL OF MEDICINE威
Volume 109
residents who attended a regularly scheduled noon lecture were asked to answer 10 multiple-choice questions about Osler’s career and contributions. A modest honorarium was promised for the best score. As might have been expected in a hospital that had recently established an Osler Teaching Award, 12 residents knew that Osler was known for his bedside teaching. Eight correctly indicated on these multiple-choice questions that he had written a textbook, and 8 that he was identified with internal medicine. Six correctly identified his year of birth, while 6 also knew that he had worked in Philadelphia and Baltimore and that his Pulitzer Prize-winning biography was written by Harvey Cushing. Only 4, however, could pick him out of a rogues’ gallery (a term he would have loved), which also included likenesses of James Paget, Sigmund Freud, William Withering, and Samuel Gross. Three knew that Osler “retired” to Oxford, and only 2 that he was born in Canada, although many recognized, with admirable ingenuity, that his knighthood argued for some sort of British origin. And, finally, only 2 recognized Aequanimitas as one of Osler’s most enduring writings. All years of our residency were represented among those who took the quiz. Ten residents were US born and trained, and they had a mean score of 3.5, with none answering more than 5 questions correctly. One international graduate, who had read a monograph about Osler distributed by a pharmaceutical company, answered all 10 questions correctly. The mean score for the remaining 4 international graduates was 3; none of them answered more than 5 questions correctly. Does this matter? Is the history of medicine relevant? Yes, and yes. McClure (3) has observed that in order to build the future, it is essential to know the past. And what a past Osler represents. He is for us the mythic hero of internal medicine, the “compleat” consultant, and the father of