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Treatment of childhood mixed connective tissue disease with plasmapheresis
proposed rules that have been issued thus far, the FederalRegister, vol. 45, no. 79, April 22, 1980, contains those for microbiology and immunology devices, including culture media, serologic reagents, and test systems. Most of these are listed as Class I; about half of the immunologic test systems are recommended for Class II; none is proposed for Class III.
The Role of the Scientist Although the government usually conducts its role responsibly, its performance is sometimes flawed by mistakes, misadventure, or the lack of timely and effective contributions by the academic community. The input of knowledgeable individuals in the private sector, therefore, becomes especially important when legal or
regulatory changes are in the offing. Scientists should play their part in the decision-making process more frequently and more forcibly by keeping abreast of federal regulatory activities and by actively participating in legislative and rule-making processes.
photosensitivity, alopecia, insect bites, or trauma. She had not taken any medications. On examination she appeared well developed, had normal vital signs, and was in no distress. Her hands were diffusely swollen, moderately stiff, and her fingers were sausageshaped. Upon exposure to cold, her hands and feet became dusky without a blanching phase. A few 1 cm nonulcerated nodules were present in the subcutaneous tissue anteriorly below both knees. The thyroid was slightly enlarged. She had no synovial thickening, warmth, effusion, or tophus formation. The right upper quadrant of her abdomen was tender but there was no hepatospleno-
megaly. Aside from mild proximal muscle weakness, a neurologic exam was normal. She had no lymphadenopathy. Laboratory tests showed a hemoglobin of 12.1 gm/dl and a total white blood cell count of 4800/mi with a normal leukocyte differential. The erythrocyte sedimentation rate was 45 ram/hr. Both serum glutamic oxalacetic transaminase (SGOT) and lactic dehydrogenase (LDH) were markedly elevated. A diffuse elevation of gamma globulins was present on protein electrophoresis. The fluorescent antinuclear antibody test was positive in a speckled pattern with a titer of 6400. Antibodies to ENA exceeded 10,240 and were
Case R e p o r t Treatment of Childhood Mixed Connective Tissue Disease with Plasmapheresis Alex Hertzman, M.D. Charles L. Cooke, M.D. Gilberto E. Rodriquez, M.D. David Sharp, M.D. Atedical College of Virginia Richmond, Virginia23298 Mixed connective tissue disease (MCTD) is a clinical and immunologic entity with features of rheumatoid arthritis, scleroderma, polymyositis, and systemic lupus erythematosus (SLE). In addition, affected individuals have antibodies to extractable nuclear antigen (ENA), which confer on the patient a better prognosis than that for patients with so-called overlap syndromes (2). A relative absence of renal involvement also contributes to this favorable prognosis, at least in adults. According to Singsen et al. (5), however, the prognosis for childhood MCTD is not as good. Our recent successful treatment of a child with MCTD by plasmapheresis without recourse to the use of steroids is therefore of special significance.
Case History A 12-year-old female was evaluated in May 1979 for the recent onset of nodules on her legs. Five months earlier, she had noted diffuse swelling of her fingers (not limited to specific joints) and had experienced classic Raynaud's phenomenon. She had lost six pounds and also complained of malaise, fatigue, and anorexia. There was no history of morning stiffness,
142
Editors: Herman Friedman, Mario R. Escobar, and Noel R. Rose Editorial Committee: Charles D. Graber, Ph.D., Medical University of South Carolina; John R. Kateley, Ph.D., Edward W. Sparrow Hospital Association; Bruce S. Rabin, M.D., Ph.D., University of Pittsburgh School of Medicine; Robert F. Ritchie, M.D., Foundation for Blood Research, Maine; John L. Sever, M.D., Ph.D., National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health; Steven Specter, Ph.D., University of South Florida College of Medicine; Roy W. Stevens, Ph.D., New York State Health Department Laboratories; Norman Talal, M.D., VA Hospital and University of California Medical Center at San Francisco; Eng M. Tan, M.D., University of Colorado Medical Center; Gabriel Virella, M.D., Ph.D., Medical University of South Carolina. Subscription Rates in U.S. and Canada: one year $54.00; two years $103.00; three years $146.00. All other countries: one year $62.00; two years $118.50; three years $168.00. Single copies are $2.50 in U.S. and Canada; $2.90 in all other countries. Single issues are available in quantity (prices available upon request). Volume 1 (1980), 24 issues $46.50. All subscriptions are payable in advance. Foreign subscriptions are sent guaranteed air mail. First class postage paid in U.S. and Canada. Address correspondence regatding subscription to: Clinical Immunology Newsletter, G. K. Hall & Co., 70 Lincoln St., Boston, Massachusetts 02111. Please include zip code in subscription address. The Clinical Immunology Newsletter is published twice monthly. All rights, including that of translation into other languages, reserved. Photomechanical reproduction (photocopy, microcopy) of this newsletter or parts thereof without special permission of the publisher is prohibited.
reactive only to the ribonucleoprotein (RNP) fraction. Anti-doublestranded DNA was negative. The CI q-binding assay for circulating immune complexes was within normal limits; however, the Raji cell test was elevated to 50 mg/ml, the normal value being less than 15 mg/ml. Roentgenograms of the chest and cervical spine were normal. A skin biopsy of one leg nodule was interpreted as being compatible with erythema nodosum (Figures 1 and 2). IgM deposition at the dermalepidermal junction was demonstrated by immunofluorescence. An electromyogram revealed changes indicative of an inflammatory myopathy. The urinalysis was normal. After informed consent had been obtained, plasmapheresis treatment was instituted in July 1979. Over the subsequent five and one-half weeks, the patient had a total of 10 plasma exchanges, nine of which exchanged slightly over one liter of plasma for one-half liter of plasminate plus normal saline to compensate for volume deficit. Technical difficulties interrupted one exchange before the intended volume was attained. Just before her tenth exchange, the Raji cell assay returned to normal. Her nodular lesions were"much improved, and her hand swelling had completely disappeared. Her plasmapheresis treatments were reduced to one every third week, and she has remained stable on that regimen. On one occasion when she missed an exchange because she was out of town, she experienced some joint swelling and a recurrence of leg nodules. She is currently asymptomatic, continues to do well in school, and plays on a field hockey team. At no time during her disease was she treated with corticosteroids. Discussion Sharp et al. (4) first described a number of patients with features of SLE, scleroderma, rheumatoid arthritis, and polymyositis. All these patients had circulating antibodies to calf thymus ENA, a finding that signifies a favorable prognosis and helps to differentiate these disorders
la Ib Fig. I: Biopsy o f leg lesion showing changes typical o f erythema nodosum, a) The epidermis is normal. The dermis shows slight edema with minimal lymphohistiocytic perivascular infiltrates, b) The panniculus has normal Iobules, but the septa sho w fibrinoid exudation, edema, and a mild inflammatory infiltrate loosely arranged around dilated vessels.
from the so-called overlap syndromes. A better prognosis in the case of affected adults is also related to the absence of significant renal involvement. Singsen et al. (5) have reported, however, that the prognosis in children is guarded. MCTD in children appears to be more severe than in adults and often requires corticosteroid treatment for extended periods of time, as with other childhood connective tissue disorders such as SLE. Side effects resulting from the use of high doses of corticosteroids are particularly bothersome in the adolescent female because of the dermatologic and cushingoid changes that can be psychologically devastating. Other more serious complications, such as growth retardation, osteoporosis, reduced resistance to infection, glaucoma, cataracts, and hypoglycemia, are also possible. For these reasons, alternate forms of therapy in MCTD are desirable and necessary. On this account, our patient was offered and accepted the option of treatment by plasmapheresis. It is widely theorized that plasmapheresis operates by removal of circulating immune complexes (1,3, 6) that are considered to
play an important pathogenetic role in MCTD. It is worth noting that our patient's serum was negative by the Clq-binding assay but repeatedly positive by the Raji test, with the highest titer ever recorded by our laboratory. The reason for this discrepancy is not known, but it might be explained by such factors as the size of the immune complexes or the presence of non-complementfixing antibody in the complexes. The patient responded promptly to treatment with plasmapheresis, and her MCTD has remained in remission for almost two years with treatments administered every three weeks. On the one occasion when she missed a plasmapheresis, her symptoms promptly recurred. Treatment with repeated plasmapheresis is clearly successful in our case and has obviated the need for corticosteroids. She has developed no renal disease in more than 18 months of therapy, and her laboratory indices of inflammation have remained negative. She has encountered no side effects from plasmapheresis. Therefore, we recommend application of this novel treatment as a first course for children and adolescents with MCTD, before treatment with corti-
143
costeroids is implemented. Moreover, it should be used as an alternative to corticosteroids whenever side effects f r o m the latter present a problem.
References I. Lockwood, C. M. 1979. Plasmaexchange: An overview. Plasma Ther. 1(1):1-12.
2. Oetgen, W. J., J. A. Boice, and O. J. llowless. 1981. Mixed connective tissue disease in children and adolescents. Pediatrics 67:333-337. 3. Plasmapheresis. 1978. Br. Med. J. 1011-12. 4. Sharp, G. C., et al. 1972. Mixed connective tissue disease--An apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear
antigen (ENA). Am. J. Med. 52:148159. 5. Singsen, B. H., el al. 1977. Mixed connective tissue disease in childhood. A clinical and serological survey. J. Pediatr. 90:893-900. 6. Wallace, D. J., et al. 1979. Plasmapheresis and lymphoplasmapheresis in the management of rheumatoid arthritis. Arthritis Rheum. 22(7): 703-710.
Invitation to Contributors
Case Reports Reports documenting interesting case presentations are invited for possible publication in the Clinical hnmunology
Newsletter. Submitted case reports should be written concisely and should contain: 1. a brief clinical history summarizing the s y m p t o m s and course o f the illness; 2. a description o f immunological and other laboratory tests performed; and 3. results of these laboratory tests as related to the clinical Observations of the patients and the outcome of the disease process and therapy, if appropriate. References should be listed in alphabetical order and should contain complete identification of authors, date, article or chapter title, journal or book title, volume number and inclusive page numbers for journals, and publisher and place of publication for books.
Letters Letters expressing opinion(s) or helpful technical ideas and procedures are encouraged. Each contribution should be written concisely and should present one m a j o r point. The Newsletter will attempt to publish as m a n y letters as possible, especially fhose of interest to a wide range of biomedical scientists. Questions and Answers Questions about immunological techniques, laboratory procedures for immunology, and general problems in clinical immunology are invited and will be answered by the editorial board or by selected individuals in the field. Submission of Material Four copies of material submitted for publication in the Newsletter should be sent to: Dr. H. M. Frobar
Clinical hnnttmology Newsletter G. K. Hall & Co. 70 Lincoln Street Boston, Massachusetts 02111
144
The Role of the Scientist Although the government usually conducts its role responsibly, its performance is sometimes flawed by mistakes, misadventure, or the lack of timely and effective contributions by the academic community. The input of knowledgeable individuals in the private sector, therefore, becomes especially important when legal or
regulatory changes are in the offing. Scientists should play their part in the decision-making process more frequently and more forcibly by keeping abreast of federal regulatory activities and by actively participating in legislative and rule-making processes.
photosensitivity, alopecia, insect bites, or trauma. She had not taken any medications. On examination she appeared well developed, had normal vital signs, and was in no distress. Her hands were diffusely swollen, moderately stiff, and her fingers were sausageshaped. Upon exposure to cold, her hands and feet became dusky without a blanching phase. A few 1 cm nonulcerated nodules were present in the subcutaneous tissue anteriorly below both knees. The thyroid was slightly enlarged. She had no synovial thickening, warmth, effusion, or tophus formation. The right upper quadrant of her abdomen was tender but there was no hepatospleno-
megaly. Aside from mild proximal muscle weakness, a neurologic exam was normal. She had no lymphadenopathy. Laboratory tests showed a hemoglobin of 12.1 gm/dl and a total white blood cell count of 4800/mi with a normal leukocyte differential. The erythrocyte sedimentation rate was 45 ram/hr. Both serum glutamic oxalacetic transaminase (SGOT) and lactic dehydrogenase (LDH) were markedly elevated. A diffuse elevation of gamma globulins was present on protein electrophoresis. The fluorescent antinuclear antibody test was positive in a speckled pattern with a titer of 6400. Antibodies to ENA exceeded 10,240 and were
Case R e p o r t Treatment of Childhood Mixed Connective Tissue Disease with Plasmapheresis Alex Hertzman, M.D. Charles L. Cooke, M.D. Gilberto E. Rodriquez, M.D. David Sharp, M.D. Atedical College of Virginia Richmond, Virginia23298 Mixed connective tissue disease (MCTD) is a clinical and immunologic entity with features of rheumatoid arthritis, scleroderma, polymyositis, and systemic lupus erythematosus (SLE). In addition, affected individuals have antibodies to extractable nuclear antigen (ENA), which confer on the patient a better prognosis than that for patients with so-called overlap syndromes (2). A relative absence of renal involvement also contributes to this favorable prognosis, at least in adults. According to Singsen et al. (5), however, the prognosis for childhood MCTD is not as good. Our recent successful treatment of a child with MCTD by plasmapheresis without recourse to the use of steroids is therefore of special significance.
Case History A 12-year-old female was evaluated in May 1979 for the recent onset of nodules on her legs. Five months earlier, she had noted diffuse swelling of her fingers (not limited to specific joints) and had experienced classic Raynaud's phenomenon. She had lost six pounds and also complained of malaise, fatigue, and anorexia. There was no history of morning stiffness,
142
Editors: Herman Friedman, Mario R. Escobar, and Noel R. Rose Editorial Committee: Charles D. Graber, Ph.D., Medical University of South Carolina; John R. Kateley, Ph.D., Edward W. Sparrow Hospital Association; Bruce S. Rabin, M.D., Ph.D., University of Pittsburgh School of Medicine; Robert F. Ritchie, M.D., Foundation for Blood Research, Maine; John L. Sever, M.D., Ph.D., National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health; Steven Specter, Ph.D., University of South Florida College of Medicine; Roy W. Stevens, Ph.D., New York State Health Department Laboratories; Norman Talal, M.D., VA Hospital and University of California Medical Center at San Francisco; Eng M. Tan, M.D., University of Colorado Medical Center; Gabriel Virella, M.D., Ph.D., Medical University of South Carolina. Subscription Rates in U.S. and Canada: one year $54.00; two years $103.00; three years $146.00. All other countries: one year $62.00; two years $118.50; three years $168.00. Single copies are $2.50 in U.S. and Canada; $2.90 in all other countries. Single issues are available in quantity (prices available upon request). Volume 1 (1980), 24 issues $46.50. All subscriptions are payable in advance. Foreign subscriptions are sent guaranteed air mail. First class postage paid in U.S. and Canada. Address correspondence regatding subscription to: Clinical Immunology Newsletter, G. K. Hall & Co., 70 Lincoln St., Boston, Massachusetts 02111. Please include zip code in subscription address. The Clinical Immunology Newsletter is published twice monthly. All rights, including that of translation into other languages, reserved. Photomechanical reproduction (photocopy, microcopy) of this newsletter or parts thereof without special permission of the publisher is prohibited.
reactive only to the ribonucleoprotein (RNP) fraction. Anti-doublestranded DNA was negative. The CI q-binding assay for circulating immune complexes was within normal limits; however, the Raji cell test was elevated to 50 mg/ml, the normal value being less than 15 mg/ml. Roentgenograms of the chest and cervical spine were normal. A skin biopsy of one leg nodule was interpreted as being compatible with erythema nodosum (Figures 1 and 2). IgM deposition at the dermalepidermal junction was demonstrated by immunofluorescence. An electromyogram revealed changes indicative of an inflammatory myopathy. The urinalysis was normal. After informed consent had been obtained, plasmapheresis treatment was instituted in July 1979. Over the subsequent five and one-half weeks, the patient had a total of 10 plasma exchanges, nine of which exchanged slightly over one liter of plasma for one-half liter of plasminate plus normal saline to compensate for volume deficit. Technical difficulties interrupted one exchange before the intended volume was attained. Just before her tenth exchange, the Raji cell assay returned to normal. Her nodular lesions were"much improved, and her hand swelling had completely disappeared. Her plasmapheresis treatments were reduced to one every third week, and she has remained stable on that regimen. On one occasion when she missed an exchange because she was out of town, she experienced some joint swelling and a recurrence of leg nodules. She is currently asymptomatic, continues to do well in school, and plays on a field hockey team. At no time during her disease was she treated with corticosteroids. Discussion Sharp et al. (4) first described a number of patients with features of SLE, scleroderma, rheumatoid arthritis, and polymyositis. All these patients had circulating antibodies to calf thymus ENA, a finding that signifies a favorable prognosis and helps to differentiate these disorders
la Ib Fig. I: Biopsy o f leg lesion showing changes typical o f erythema nodosum, a) The epidermis is normal. The dermis shows slight edema with minimal lymphohistiocytic perivascular infiltrates, b) The panniculus has normal Iobules, but the septa sho w fibrinoid exudation, edema, and a mild inflammatory infiltrate loosely arranged around dilated vessels.
from the so-called overlap syndromes. A better prognosis in the case of affected adults is also related to the absence of significant renal involvement. Singsen et al. (5) have reported, however, that the prognosis in children is guarded. MCTD in children appears to be more severe than in adults and often requires corticosteroid treatment for extended periods of time, as with other childhood connective tissue disorders such as SLE. Side effects resulting from the use of high doses of corticosteroids are particularly bothersome in the adolescent female because of the dermatologic and cushingoid changes that can be psychologically devastating. Other more serious complications, such as growth retardation, osteoporosis, reduced resistance to infection, glaucoma, cataracts, and hypoglycemia, are also possible. For these reasons, alternate forms of therapy in MCTD are desirable and necessary. On this account, our patient was offered and accepted the option of treatment by plasmapheresis. It is widely theorized that plasmapheresis operates by removal of circulating immune complexes (1,3, 6) that are considered to
play an important pathogenetic role in MCTD. It is worth noting that our patient's serum was negative by the Clq-binding assay but repeatedly positive by the Raji test, with the highest titer ever recorded by our laboratory. The reason for this discrepancy is not known, but it might be explained by such factors as the size of the immune complexes or the presence of non-complementfixing antibody in the complexes. The patient responded promptly to treatment with plasmapheresis, and her MCTD has remained in remission for almost two years with treatments administered every three weeks. On the one occasion when she missed a plasmapheresis, her symptoms promptly recurred. Treatment with repeated plasmapheresis is clearly successful in our case and has obviated the need for corticosteroids. She has developed no renal disease in more than 18 months of therapy, and her laboratory indices of inflammation have remained negative. She has encountered no side effects from plasmapheresis. Therefore, we recommend application of this novel treatment as a first course for children and adolescents with MCTD, before treatment with corti-
143
costeroids is implemented. Moreover, it should be used as an alternative to corticosteroids whenever side effects f r o m the latter present a problem.
References I. Lockwood, C. M. 1979. Plasmaexchange: An overview. Plasma Ther. 1(1):1-12.
2. Oetgen, W. J., J. A. Boice, and O. J. llowless. 1981. Mixed connective tissue disease in children and adolescents. Pediatrics 67:333-337. 3. Plasmapheresis. 1978. Br. Med. J. 1011-12. 4. Sharp, G. C., et al. 1972. Mixed connective tissue disease--An apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear
antigen (ENA). Am. J. Med. 52:148159. 5. Singsen, B. H., el al. 1977. Mixed connective tissue disease in childhood. A clinical and serological survey. J. Pediatr. 90:893-900. 6. Wallace, D. J., et al. 1979. Plasmapheresis and lymphoplasmapheresis in the management of rheumatoid arthritis. Arthritis Rheum. 22(7): 703-710.
Invitation to Contributors
Case Reports Reports documenting interesting case presentations are invited for possible publication in the Clinical hnmunology
Newsletter. Submitted case reports should be written concisely and should contain: 1. a brief clinical history summarizing the s y m p t o m s and course o f the illness; 2. a description o f immunological and other laboratory tests performed; and 3. results of these laboratory tests as related to the clinical Observations of the patients and the outcome of the disease process and therapy, if appropriate. References should be listed in alphabetical order and should contain complete identification of authors, date, article or chapter title, journal or book title, volume number and inclusive page numbers for journals, and publisher and place of publication for books.
Letters Letters expressing opinion(s) or helpful technical ideas and procedures are encouraged. Each contribution should be written concisely and should present one m a j o r point. The Newsletter will attempt to publish as m a n y letters as possible, especially fhose of interest to a wide range of biomedical scientists. Questions and Answers Questions about immunological techniques, laboratory procedures for immunology, and general problems in clinical immunology are invited and will be answered by the editorial board or by selected individuals in the field. Submission of Material Four copies of material submitted for publication in the Newsletter should be sent to: Dr. H. M. Frobar
Clinical hnnttmology Newsletter G. K. Hall & Co. 70 Lincoln Street Boston, Massachusetts 02111
144