- Email: [email protected]
Plasmapheresis: A pediatric perspective
EDITOR'S C O L U M N
Plasmapheresis: A pediatric perspective THE INTRODUCTION of new and expensive "interme-
diate" technologies into clinical research and practise, particularly if the disease is dangerous and the technique is appealing, almost invariably creates advocates and adversaries. The plasma exchange (pheresis) narrative portends to be little different. In 1914, Abel, Rowntree, and Turner I described plasmapheresis while attempting to develop an artificial kidney, and suggested that through its use in the harvest of antitoxic serum "great economy might be effected in the use of horses. ''~ The first therapeutic application of pheresis caused, in 1960, a striking reduction in the hyperviscosity manifestations of Waldenstrom macroglobulinemia. 3 During the past five years interest in the technique has been remarkable. Dramatic responses to therapy, in very small groups of patients, are recorded for such diverse conditions as cancer, pemphigus, severe rhesus isoimmunization, schizophrenia, myasthenia gravis, hepatitis, and a wide variety of rheumatic diseases-all because of their presumed immunologic basis, and generally because they were not responsive to more conventional treatment. Large scale plasmapheresis became possible with the commercial availability, since 1970, of sophisticated continuous- or discontinuous-flow cell separators which allow selective removal of red cells, white cells, and platelets, or their combined return to the patient at the expense of plasma. In this latter fashion, as much as 6 to 8 L of plasma can be removed over two to four hours (depending on patient size), and exchange effected with frozen plasma or with substitutes such as purified protein fractions, reconstituted dried plasma, or albumin? Potential immediate risks of the procedure include transfer of hepatitis, depletion of clotting factors and immunoglobulins, hypotension, bacterial infections, and embolization. '-~ Thus, appropriate laboratory studies must be carefully monitored whenever large amounts of plasma are removed. Theoretically, any abnormal plasma constituent, or one present in excess concentration, can be removed by pheresis; hence its recent popularity. In addition to Waldenstrom macroglobulinemia, 3 the hyperviscosity symptoms caused by the paraprotein aggregates o f multiple myeloma may be improved by pheresis, '~ and other investigators have reversed the severe failure of "my-
232
The Journal o f P E D I A T R I C S Vol. 98, No. 2, pp. 232-235
eloma kidney," presumably caused by the tubular deposition of light chains, via plasmapheresis5 Successful treatment of homozygous familial hypercholesterolemia has also been reported? Additionally, pheresis has been utilized to reduce levels of circulating anticoagulants (Factor VIII antibodies and others) in hemophilia, and in some patients with systemic lupus erythematosus and associated conditions. See related articles, pp. 194, 237, and 240.
Abbreviations used: SLE: systemic lupus erythematosus IC: immune complex RA: rheumatoid arthritis The greatest interest in plasmapheresis has centered around treatment of a variety of illnesses which can be described as "antibody," "autoimmune," or "immune complex" mediated? The rationale for such treatment falls into several broad theoretical categories: (1) Removal of specific (auto)antibodies believed to mediate a specific disease; (2) removal of nonspecific inflammatory mediators such as complement, C-reactive protein, or fibrinogen; (3) removal of immune complexes; (4) replacement of a not previously recognized "missing" factor; (5) fnally, there are many disorders in which evidence of altered humoral or cell-mediated immunity exists, but is not clearly linked to disease pathogenesis. In this latter situation, plasmapheresis can become a powerful investigational tool to demonstrate the existence of a pathologic circulating substance which can then be further sought and elucidated. Removal of a "specific" antibody. One example of this situation is myasthenia gravis, particularly during crisis, or when unresponsive to toxic levels of medication. '~ Long-term follow-up of response to pheresis is not available, but sustained improvement of myasthenia usually requires other, additional treatment modes. Some investigators recommend the concomitant addition of an immunosuppressive drug with initiation of plasmapheresis; this makes evaluation of separate effects very difficult. Another important example is Goodpasture syndrome, in which
0022-3476/81/020232 +04500.40/0 9 1981 The C. V. Mosby Co.
Volume 98 Number 2
the therapeutic use of plasmapheresis has produced a dramatic reduction in mortality, presumably because of a rapid decrease in antiglomerular basement membrane antibody levels. 11 Similar success has been reported with other categories of rapidly progressive crescentic glomerulonephritis, at least some of which also may have transient high levels of circulating IC. 12 Removal of nonspecific inflammatory mediators. Serum levels of globulins, fibrinogen, complement, and other substances, whose importance in mediating tissue injury is increasingly well established, are affected by plasmapheresis? 3 " In some cases rapid re-equilibration from the extravascular pool occurs; in others, increased production of such mediators may result from negative feedback, although even brief reductions can be postulated to alter the proliferation of immunologically competent cells? ..... The degree to which such mediators of inflammation are removed by pheresis, and the direct and indirect effects thereof, remain largely speculative. Removal of immune complexes. Systemic lupus erythematosus is the IC disease in which there is the most experience with plasmapheresis. Jones 2. . . . 6 has studied over 20 patients and notes the value of pheresis as an adjunctive therapy in severe SLE unresponsive to conventional therapy, wherein high levels of immune complexes are present. The rate of fall of IC levels is often more rapid than can be explained by the volume of plasma removed. One possible mechanism to explain this result is reversal of transient overload of the phagocytic reticuloendothelial system by IC, with subsequent regeneration of specific membrane IC receptors on macrophages, monocytes, and polymorphs? ~ Other possibly immune complex-mediated illnesses reported to respond to pheresis include polyarteritis nodosa and Wegner granulomatosis. TM
Replacement of a "missing" factor. In this regard, a patient with thrombotic thrombocytopenic purpura was reported to improve following exchange with plasma, but not when exchanged with red cells and albumin~; it was hypothesized that the missing factor which was replaced might be an inhibitor of platelet aggregation. Research uses of plasmapheresis. Other diseases in which small numbers of patients are reported to have benefited from plasmapheresis include: childhood dermatomyositis,~~ Raynaud syndrome, ~ Crohn disease, ~ pemphigus vulgaris, ~ and many others. The etiology of these diseases remains largely unknown, but much evidence suggests that immunologic mechanisms contribute to tissue injury. The reported, frequency and levels of circulating IC varies widely in these illnesses, and their pathogenetic role, if any, is unclear. Rheumatoid arthritis has received particular attention
Editor's column
233
as possibly benefiting from plasma exchange. Wallace and co-workers 24 demonstrated sustained benefit (two weeks to eight months) after an uncontrolled study of pheresis, but no significant changes in levels of circulating IC could be demonstrated, and they thus postulated that plasma factor(s) which modify lymphocyte or neutrophil function were removed. Rothwell and associates, ~ in a controlled but not prospective investigation, showed that circulating IC levels in RA were reduced by pheresis, but the clinical benefits were no greater than those effected by hospitalization alone. In this issue are three related reports regarding plasmapheresis for the relatively uncommon rheumatic diseases of childhood. 2~-~ Dau and Bennington '-''~report response to plasmapheresis in a child with dermatomyositis, but two issues remain unresolved. Did the child have an adequate course of conventional therapy, including immunosuppressives, prior to instituting plasma exchange and was the diagnosis entirely correct? With regard to the latter, the development of hypocomplementemia, high titers of antinuclear antibodies and rheumatoid factor, and hypertension might suggest evolution toward another illness. These issues are particularly relevant as we move to develop criteria for controlled, multicenter pheresis studies, which must include precise definitions of disease characteristics, and norms of "conventional" treatment required prior to instituting an "experimental" therapy. Finally, the suggestion by Dau and Bennington that the histopathologic clearing of microvessel IgG and IgM deposits implicates autoantibody or IC as the cause of vasculopathy, and the suggestion that absence of inflammatory infiltration at one prepheresis muscle biopsy connotes absence of a lymphocytotoxic action are perhaps premature. Anderson and Ziter ~7 correctly note the anecdotal nature of their observation regarding plasmapheresis for childhood dermatomyositis, the need for controlled studies, and concern for costs and potential complications. Their heroic endeavors clearly benefited a very ill child; however, the severe musculoskeletal structural changes in this patient suggest that earlier intervention with methotrexate or pheresis could have been considered. The reports of Dau, Anderson and their colleagues should cause awareness of plasma exchange as one way to treat severe, unresponsive childhood dermatomyositis, but the reports also serve to stress the need for a thorough search for therapeutic alternatives, particularly for use in continuous or polycyclic childhood dermatomyositis,~ prior to plasmapheresis. Brewer and associates2" selected four children with specific, long-standing, and difficult to eradicate complications of juvenile rheumatoid arthritis to test the ability
234
Editor's column
of pheresis to ameliorate these problems. The objective improvement in two children, as measured by partial remission, corticosteroid sparing, and partial growth catchup should suggest the need for prospective, controlled multicenter studies, with particular attention to patients' serologic status, and duration of pheresis and replacement fluids employed in those who do and do not respond. Properly, the Baylor group stresses that plasmapheresis is an intermediate technology, with removal of a specific pathologic entity the ultimate future goal. It should be treated as a research procedure, performed in an intensive care setting, and reserved for severe illness unresponsive to maximal conventional therapy. The problems inherent in plasmapheresis for the immediate future are easy to recognize: (1) the cost is prohibitive, with a series of phereses easily reaching $20,000 even before time and manpower requirements are calculated. (2) The majority of reports describing efficacy are anecdotal, are not prospective, lack controls, and do not include extended follow-up. (3) The side-effects remain relatively unknown, and occasionally obscured by enthusiasm for the procedure. (4) Collaborative studies to gather sufficient numbers of comparable patients for statistical comparison of outcome are almost nonexistent. (5) Criteria to determine which, and how much, "conventional" treatment should be applied prior to therapeutic pheresis have not been developed. (6) Immunosuppressive agents are frequently advocated, on either theoretical or aphoristic grounds, along with the initiation of pheresis. This practice makes evaluation of the therapeutic merits of each even more complex. (7) Our tools to measure circulating immune complexes and other immunoreactants are still relatively primitive. Thus, when a patient does improve following plasma exchange, we are commonly at a loss to explain why. (8) There is little agreement as to how many phereses should be employed, with what volume of plasma exchange, and over what period of time; this issue is critical when asking whether "more" would have worked when "less" did not. Most investigators of plasmapheresis are acutely aware of the above concerns, but too few clearly delineate these issues in the otherwise optimistic reports which imply that the practitioner should soon, if not now, embrance the new technology. Because plasma exchange capability is now commonly available, an informal survey of pediatric rheumatologists, who might be expected to treat the largest concentrations of children severely afflicted with rheumatic diseases, appeared in order. Of 23 respondents, all in academic settings, 16 had not employed pheresis. Seven individuals reported modest improvement in ten children with diverse diseases, but no change in an additional ten
The Journal of Pediatrics February 1981 patients. Each specialist embraced the research utility of plasma exchange, and all agreed about its adjunctive treatment potential in life-threatening situations, although the majority have yet to apply it clinically. Unfortunately, only today (10/9/80) I received in the mail an unsolicited commercial brochure which discussed pheresis, and "suggested" that I contact a local sales representative. Already, some rheumatologists are performing plasmapheresis in their offices. Perhaps, however, cooler heads may yet prevail. The World Health Organization is sponsoring conferences to evaluate the merits of plasmapheresis, and the National Institutes of Health have been requested to advise third party carriers regarding its therapeutic value. Additionally, the Arthritis Foundation is developing a position statement regarding appropriate clinical applications of plasma exchange. These efforts should be applauded and fostered. In summary, plasmapheresis is an exciting research tool whose potential treatment applications can prematurely tempt the clinician. It clearly has a therapeutic place in life-threatening illness, but probably only following application of appropriate conventional treatment alternatives. Undoubtedly, there is an atavistic relationship between pheresis and the phlebotomy by which our medical ancestors removed the ill humors which resided in "red bile." Perhaps we have come full circle and the "anciens" will once again be proven correct, as they so often were when we identified the active ingredient in so many "folk" remedies. For plasmapheresis, however, the challenge of the 80s will be to provide proof of its efficacy via controlled, prospective investigations, and follow-up to demonstrate differences in outcome from conventional therapies. Such a perspective will allow us to view the pheresis anecdote appropriately as a germinal seed which leads to growth of rigorous scientific evaluation. Bernhard H. Singsen, M.D. Department of Child Health University of Missouri Columbia, MO 65212
REFERENCES
1. Abel JJ, Rowntree LG, and Turner BB: Plasma removal with return of corpuscles (plasmapheresis), J Pharmacol Exp Ther 5:625, 1914. 2. Jones JV: Plasmapheresis: Great economy in the use of horses, N Engl J Med 297:1173, 1977. 3. Soloman A, and Fahey JL: Plasmapheresis therapy in macroglobulinemia, Ann Intern Med 58:789, 1963. 4. Keesey J: Discussion, in Dau PC, editor: Plasmapheresis and the immunobiology of myasthenia gravis, Boston, 1979, Houghton Mifflin Company, p 269. 5. Jones JV: Plasmapheresis in the management of immunecomplex disease, in Dau PC, editor: Plasmapheresis and the
Volume 98 Number 2
6.
7.
8.
9. 10.
II.
12.
13.
14.
15.
16.
17.
immunobiology of myasthenia gravis, Boston, 1979, Houghton Mifflin Company. Powles R, Smith C, Kohn J, and Fairley GH: Method of removing abnormal protein rapidly from patients with malignant paraproteinaemias, Br Med J 3:664, 1971. Misiani R, Remuzzi G, Bertani T, et al: Plasmapheresis in the treatment of acute renal failure in multiple myeloma, Am J Med 66:684, 1979. Witztum JL, Williams JC, Ostlund R, Sherman L, Siccard G, and Schonfeld G: Successful plasmapheresis in a 4year-old child with homozygous familial hypercholesterolemia, J PEDIATR97:615, 1980. Raich PC, and Traver MI: Therapeutic plasmapheresis, Wis Med J 78:37, 1979. Dau PC, editor: Plasmapheresis and the immunobiology of myasthenia gravis, Boston, 1979, Houghton Mifflin Company. Rosenblatt SG, Knight W, Bannayan GA, et al: Treatment of Goodpasture's syndrome with plasmapheresis. A case report and review of the literature, Am J Med 66:689, 1979. Kincaid-Smith P, and d'Apice AJF: Plasmapheresis in rapidly progressive glomerulonephritis, Am J Med 65:564, 1978. Lockwood CM, Pearson RA, Rees AJ, et al: Immunosuppression and plasma-exchange in the treatment of Goodpasture's syndrome, Lancet 1:711, 1976. Birdsall HH, Brewer EJ, Rossen RD, et al: Clinical improvement associated with hypocomplementemia following plasmapheresis, in Dau PC, editor: Plasmapheresis and the immunobiology of myasthenia gravis, Boston, 1979, Houghton Mifflin Company. Dau PC, Lindstrom JM, Cassel CK, et al: Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis, N Engl J Med 297:1134, 1977. Jones JV, Bucknall RC, Cumming RH, and Asplin CM: Plasmapheresis in the management of acute systemic lupus erythematous? Lancet 1:709, 1976. Haakenstad AO, and Mannik M: Saturation of the reticu-
Editor's column
18.
19.
20.
21.
22.
23.
24.
25.
26. 27.
28.
29.
235
loendothelial system with soluble immune complexes, J Immunol 112:1939, 1974. d'Apice AJF, Kincaid-Smith P: Treatment of glomerulonephritis by plasma exchange, in Kincaid-Smith P, d'Apice AJF, and Atkins RC, editors: Progress in glomerulonephritis, New York, 1979, John Wiley & Sons, Inc. Byrnes J J, and Khurana M: Treatment of thrombotic thrombocytopenic purpura with plasma, N Engl J Med 297:1386, 1977. Brewer EJ, Gianniani EH, Rossen RD, et al: Plasma exchange therapy of a childhood onset dermatomyositis patient, Arthritis Rheum 23:509, 1980. O'Reilly MJG, Talpos G, Roberts VC, et al: Controlled trial of plasma exchange in treatment of Raynaud's syndrome, Br Med J 1:1113, t979. Holdstock GE, Fisher JA, Hamblin TJ, and Loehry C: Plasmapheresis in Crohn's disease, Digestion 19:197, 1979. Auerbach R, and Bystryn JC: Plasmapheresis and immunosuppressive therapy: Effect on levels of intercellular antibodies in pemphigus vulgaris, Arch Dermatol 115:728, 1979. Wallace D J, Goldfinger D, Cratti R, et al: Plasmapheresis and lymphoplasmapheresis in the management of rheumatoid arthritis, Arthritis Rheum 22:703, 1979. Rothwell RS, Davis P, Gordan PA, et al: A controlled study of plasma exchange in the treatment of severe rheumatoid arthritis, Arthritis Rheum 23:785, 1980. Dau PC, and Bennington JL: Plasmapheresis in childhood dermatomyositis. J PEDIATR 98:237, 1981. Anderson L, and Ziter FA: Plasmapheresis via central catheter in dermatomyositis: A new method for selected pediatric patients, J PEmATR 98:240, 1981. Brewer EJ, Nickeson RW Jr, Rossen RD. Person DA. Giannini EH, and Milam JD: Plasma exchange in selected patients with juvenile rheumatoid arthritis. J PEI)IATR 98:194, 1981. Spencer C, Kornreich H, Bernstein B, et al: Thrce courses of juvenile dermatomyositis, Arthritis Rheum 22:661, 1979.
Plasmapheresis: A pediatric perspective THE INTRODUCTION of new and expensive "interme-
diate" technologies into clinical research and practise, particularly if the disease is dangerous and the technique is appealing, almost invariably creates advocates and adversaries. The plasma exchange (pheresis) narrative portends to be little different. In 1914, Abel, Rowntree, and Turner I described plasmapheresis while attempting to develop an artificial kidney, and suggested that through its use in the harvest of antitoxic serum "great economy might be effected in the use of horses. ''~ The first therapeutic application of pheresis caused, in 1960, a striking reduction in the hyperviscosity manifestations of Waldenstrom macroglobulinemia. 3 During the past five years interest in the technique has been remarkable. Dramatic responses to therapy, in very small groups of patients, are recorded for such diverse conditions as cancer, pemphigus, severe rhesus isoimmunization, schizophrenia, myasthenia gravis, hepatitis, and a wide variety of rheumatic diseases-all because of their presumed immunologic basis, and generally because they were not responsive to more conventional treatment. Large scale plasmapheresis became possible with the commercial availability, since 1970, of sophisticated continuous- or discontinuous-flow cell separators which allow selective removal of red cells, white cells, and platelets, or their combined return to the patient at the expense of plasma. In this latter fashion, as much as 6 to 8 L of plasma can be removed over two to four hours (depending on patient size), and exchange effected with frozen plasma or with substitutes such as purified protein fractions, reconstituted dried plasma, or albumin? Potential immediate risks of the procedure include transfer of hepatitis, depletion of clotting factors and immunoglobulins, hypotension, bacterial infections, and embolization. '-~ Thus, appropriate laboratory studies must be carefully monitored whenever large amounts of plasma are removed. Theoretically, any abnormal plasma constituent, or one present in excess concentration, can be removed by pheresis; hence its recent popularity. In addition to Waldenstrom macroglobulinemia, 3 the hyperviscosity symptoms caused by the paraprotein aggregates o f multiple myeloma may be improved by pheresis, '~ and other investigators have reversed the severe failure of "my-
232
The Journal o f P E D I A T R I C S Vol. 98, No. 2, pp. 232-235
eloma kidney," presumably caused by the tubular deposition of light chains, via plasmapheresis5 Successful treatment of homozygous familial hypercholesterolemia has also been reported? Additionally, pheresis has been utilized to reduce levels of circulating anticoagulants (Factor VIII antibodies and others) in hemophilia, and in some patients with systemic lupus erythematosus and associated conditions. See related articles, pp. 194, 237, and 240.
Abbreviations used: SLE: systemic lupus erythematosus IC: immune complex RA: rheumatoid arthritis The greatest interest in plasmapheresis has centered around treatment of a variety of illnesses which can be described as "antibody," "autoimmune," or "immune complex" mediated? The rationale for such treatment falls into several broad theoretical categories: (1) Removal of specific (auto)antibodies believed to mediate a specific disease; (2) removal of nonspecific inflammatory mediators such as complement, C-reactive protein, or fibrinogen; (3) removal of immune complexes; (4) replacement of a not previously recognized "missing" factor; (5) fnally, there are many disorders in which evidence of altered humoral or cell-mediated immunity exists, but is not clearly linked to disease pathogenesis. In this latter situation, plasmapheresis can become a powerful investigational tool to demonstrate the existence of a pathologic circulating substance which can then be further sought and elucidated. Removal of a "specific" antibody. One example of this situation is myasthenia gravis, particularly during crisis, or when unresponsive to toxic levels of medication. '~ Long-term follow-up of response to pheresis is not available, but sustained improvement of myasthenia usually requires other, additional treatment modes. Some investigators recommend the concomitant addition of an immunosuppressive drug with initiation of plasmapheresis; this makes evaluation of separate effects very difficult. Another important example is Goodpasture syndrome, in which
0022-3476/81/020232 +04500.40/0 9 1981 The C. V. Mosby Co.
Volume 98 Number 2
the therapeutic use of plasmapheresis has produced a dramatic reduction in mortality, presumably because of a rapid decrease in antiglomerular basement membrane antibody levels. 11 Similar success has been reported with other categories of rapidly progressive crescentic glomerulonephritis, at least some of which also may have transient high levels of circulating IC. 12 Removal of nonspecific inflammatory mediators. Serum levels of globulins, fibrinogen, complement, and other substances, whose importance in mediating tissue injury is increasingly well established, are affected by plasmapheresis? 3 " In some cases rapid re-equilibration from the extravascular pool occurs; in others, increased production of such mediators may result from negative feedback, although even brief reductions can be postulated to alter the proliferation of immunologically competent cells? ..... The degree to which such mediators of inflammation are removed by pheresis, and the direct and indirect effects thereof, remain largely speculative. Removal of immune complexes. Systemic lupus erythematosus is the IC disease in which there is the most experience with plasmapheresis. Jones 2. . . . 6 has studied over 20 patients and notes the value of pheresis as an adjunctive therapy in severe SLE unresponsive to conventional therapy, wherein high levels of immune complexes are present. The rate of fall of IC levels is often more rapid than can be explained by the volume of plasma removed. One possible mechanism to explain this result is reversal of transient overload of the phagocytic reticuloendothelial system by IC, with subsequent regeneration of specific membrane IC receptors on macrophages, monocytes, and polymorphs? ~ Other possibly immune complex-mediated illnesses reported to respond to pheresis include polyarteritis nodosa and Wegner granulomatosis. TM
Replacement of a "missing" factor. In this regard, a patient with thrombotic thrombocytopenic purpura was reported to improve following exchange with plasma, but not when exchanged with red cells and albumin~; it was hypothesized that the missing factor which was replaced might be an inhibitor of platelet aggregation. Research uses of plasmapheresis. Other diseases in which small numbers of patients are reported to have benefited from plasmapheresis include: childhood dermatomyositis,~~ Raynaud syndrome, ~ Crohn disease, ~ pemphigus vulgaris, ~ and many others. The etiology of these diseases remains largely unknown, but much evidence suggests that immunologic mechanisms contribute to tissue injury. The reported, frequency and levels of circulating IC varies widely in these illnesses, and their pathogenetic role, if any, is unclear. Rheumatoid arthritis has received particular attention
Editor's column
233
as possibly benefiting from plasma exchange. Wallace and co-workers 24 demonstrated sustained benefit (two weeks to eight months) after an uncontrolled study of pheresis, but no significant changes in levels of circulating IC could be demonstrated, and they thus postulated that plasma factor(s) which modify lymphocyte or neutrophil function were removed. Rothwell and associates, ~ in a controlled but not prospective investigation, showed that circulating IC levels in RA were reduced by pheresis, but the clinical benefits were no greater than those effected by hospitalization alone. In this issue are three related reports regarding plasmapheresis for the relatively uncommon rheumatic diseases of childhood. 2~-~ Dau and Bennington '-''~report response to plasmapheresis in a child with dermatomyositis, but two issues remain unresolved. Did the child have an adequate course of conventional therapy, including immunosuppressives, prior to instituting plasma exchange and was the diagnosis entirely correct? With regard to the latter, the development of hypocomplementemia, high titers of antinuclear antibodies and rheumatoid factor, and hypertension might suggest evolution toward another illness. These issues are particularly relevant as we move to develop criteria for controlled, multicenter pheresis studies, which must include precise definitions of disease characteristics, and norms of "conventional" treatment required prior to instituting an "experimental" therapy. Finally, the suggestion by Dau and Bennington that the histopathologic clearing of microvessel IgG and IgM deposits implicates autoantibody or IC as the cause of vasculopathy, and the suggestion that absence of inflammatory infiltration at one prepheresis muscle biopsy connotes absence of a lymphocytotoxic action are perhaps premature. Anderson and Ziter ~7 correctly note the anecdotal nature of their observation regarding plasmapheresis for childhood dermatomyositis, the need for controlled studies, and concern for costs and potential complications. Their heroic endeavors clearly benefited a very ill child; however, the severe musculoskeletal structural changes in this patient suggest that earlier intervention with methotrexate or pheresis could have been considered. The reports of Dau, Anderson and their colleagues should cause awareness of plasma exchange as one way to treat severe, unresponsive childhood dermatomyositis, but the reports also serve to stress the need for a thorough search for therapeutic alternatives, particularly for use in continuous or polycyclic childhood dermatomyositis,~ prior to plasmapheresis. Brewer and associates2" selected four children with specific, long-standing, and difficult to eradicate complications of juvenile rheumatoid arthritis to test the ability
234
Editor's column
of pheresis to ameliorate these problems. The objective improvement in two children, as measured by partial remission, corticosteroid sparing, and partial growth catchup should suggest the need for prospective, controlled multicenter studies, with particular attention to patients' serologic status, and duration of pheresis and replacement fluids employed in those who do and do not respond. Properly, the Baylor group stresses that plasmapheresis is an intermediate technology, with removal of a specific pathologic entity the ultimate future goal. It should be treated as a research procedure, performed in an intensive care setting, and reserved for severe illness unresponsive to maximal conventional therapy. The problems inherent in plasmapheresis for the immediate future are easy to recognize: (1) the cost is prohibitive, with a series of phereses easily reaching $20,000 even before time and manpower requirements are calculated. (2) The majority of reports describing efficacy are anecdotal, are not prospective, lack controls, and do not include extended follow-up. (3) The side-effects remain relatively unknown, and occasionally obscured by enthusiasm for the procedure. (4) Collaborative studies to gather sufficient numbers of comparable patients for statistical comparison of outcome are almost nonexistent. (5) Criteria to determine which, and how much, "conventional" treatment should be applied prior to therapeutic pheresis have not been developed. (6) Immunosuppressive agents are frequently advocated, on either theoretical or aphoristic grounds, along with the initiation of pheresis. This practice makes evaluation of the therapeutic merits of each even more complex. (7) Our tools to measure circulating immune complexes and other immunoreactants are still relatively primitive. Thus, when a patient does improve following plasma exchange, we are commonly at a loss to explain why. (8) There is little agreement as to how many phereses should be employed, with what volume of plasma exchange, and over what period of time; this issue is critical when asking whether "more" would have worked when "less" did not. Most investigators of plasmapheresis are acutely aware of the above concerns, but too few clearly delineate these issues in the otherwise optimistic reports which imply that the practitioner should soon, if not now, embrance the new technology. Because plasma exchange capability is now commonly available, an informal survey of pediatric rheumatologists, who might be expected to treat the largest concentrations of children severely afflicted with rheumatic diseases, appeared in order. Of 23 respondents, all in academic settings, 16 had not employed pheresis. Seven individuals reported modest improvement in ten children with diverse diseases, but no change in an additional ten
The Journal of Pediatrics February 1981 patients. Each specialist embraced the research utility of plasma exchange, and all agreed about its adjunctive treatment potential in life-threatening situations, although the majority have yet to apply it clinically. Unfortunately, only today (10/9/80) I received in the mail an unsolicited commercial brochure which discussed pheresis, and "suggested" that I contact a local sales representative. Already, some rheumatologists are performing plasmapheresis in their offices. Perhaps, however, cooler heads may yet prevail. The World Health Organization is sponsoring conferences to evaluate the merits of plasmapheresis, and the National Institutes of Health have been requested to advise third party carriers regarding its therapeutic value. Additionally, the Arthritis Foundation is developing a position statement regarding appropriate clinical applications of plasma exchange. These efforts should be applauded and fostered. In summary, plasmapheresis is an exciting research tool whose potential treatment applications can prematurely tempt the clinician. It clearly has a therapeutic place in life-threatening illness, but probably only following application of appropriate conventional treatment alternatives. Undoubtedly, there is an atavistic relationship between pheresis and the phlebotomy by which our medical ancestors removed the ill humors which resided in "red bile." Perhaps we have come full circle and the "anciens" will once again be proven correct, as they so often were when we identified the active ingredient in so many "folk" remedies. For plasmapheresis, however, the challenge of the 80s will be to provide proof of its efficacy via controlled, prospective investigations, and follow-up to demonstrate differences in outcome from conventional therapies. Such a perspective will allow us to view the pheresis anecdote appropriately as a germinal seed which leads to growth of rigorous scientific evaluation. Bernhard H. Singsen, M.D. Department of Child Health University of Missouri Columbia, MO 65212
REFERENCES
1. Abel JJ, Rowntree LG, and Turner BB: Plasma removal with return of corpuscles (plasmapheresis), J Pharmacol Exp Ther 5:625, 1914. 2. Jones JV: Plasmapheresis: Great economy in the use of horses, N Engl J Med 297:1173, 1977. 3. Soloman A, and Fahey JL: Plasmapheresis therapy in macroglobulinemia, Ann Intern Med 58:789, 1963. 4. Keesey J: Discussion, in Dau PC, editor: Plasmapheresis and the immunobiology of myasthenia gravis, Boston, 1979, Houghton Mifflin Company, p 269. 5. Jones JV: Plasmapheresis in the management of immunecomplex disease, in Dau PC, editor: Plasmapheresis and the
Volume 98 Number 2
6.
7.
8.
9. 10.
II.
12.
13.
14.
15.
16.
17.
immunobiology of myasthenia gravis, Boston, 1979, Houghton Mifflin Company. Powles R, Smith C, Kohn J, and Fairley GH: Method of removing abnormal protein rapidly from patients with malignant paraproteinaemias, Br Med J 3:664, 1971. Misiani R, Remuzzi G, Bertani T, et al: Plasmapheresis in the treatment of acute renal failure in multiple myeloma, Am J Med 66:684, 1979. Witztum JL, Williams JC, Ostlund R, Sherman L, Siccard G, and Schonfeld G: Successful plasmapheresis in a 4year-old child with homozygous familial hypercholesterolemia, J PEDIATR97:615, 1980. Raich PC, and Traver MI: Therapeutic plasmapheresis, Wis Med J 78:37, 1979. Dau PC, editor: Plasmapheresis and the immunobiology of myasthenia gravis, Boston, 1979, Houghton Mifflin Company. Rosenblatt SG, Knight W, Bannayan GA, et al: Treatment of Goodpasture's syndrome with plasmapheresis. A case report and review of the literature, Am J Med 66:689, 1979. Kincaid-Smith P, and d'Apice AJF: Plasmapheresis in rapidly progressive glomerulonephritis, Am J Med 65:564, 1978. Lockwood CM, Pearson RA, Rees AJ, et al: Immunosuppression and plasma-exchange in the treatment of Goodpasture's syndrome, Lancet 1:711, 1976. Birdsall HH, Brewer EJ, Rossen RD, et al: Clinical improvement associated with hypocomplementemia following plasmapheresis, in Dau PC, editor: Plasmapheresis and the immunobiology of myasthenia gravis, Boston, 1979, Houghton Mifflin Company. Dau PC, Lindstrom JM, Cassel CK, et al: Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis, N Engl J Med 297:1134, 1977. Jones JV, Bucknall RC, Cumming RH, and Asplin CM: Plasmapheresis in the management of acute systemic lupus erythematous? Lancet 1:709, 1976. Haakenstad AO, and Mannik M: Saturation of the reticu-
Editor's column
18.
19.
20.
21.
22.
23.
24.
25.
26. 27.
28.
29.
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