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COMBINED PLASMA EXCHANGE AND IMMUNOSUPPRESSION IN MYASTHENIA GRAVIS
688
Letters
to
the Editor
COMBINED PLASMA EXCHANGE AND
IMMUNOSUPPRESSION IN MYASTHENIA GRAVIS
SiR,—Dr Behan and his colleagues (Sept. 1, p. 438) report plasma exchange coupled with immunosuppressive treat-
that
bring about a striking clinical improvement in myasgravis, confirming the results of other studies. 1-4 They imply that plasma exchange was essential for this response and suggest that their treatment regimen may have altered the natural history of the disease. A tendency to attribute exceptional benefit to a new technique such as plasma exchange is understandable. Following our original report of its ability to produce a short remission in MG,’ we naturally hoped that a synergistic action with immunosuppressive treatment might be demonstrable, leading to additional long-term benefit. To our knowledge, no such
ment can
thenia
effect has yet been shown. Behan et al. present no control data on the effects of immunosuppressive treatment alone. When we compared plasma exchange with and without immunosuppression4 we found no significant difference in the long-term improvement between the groups, judged not only on clinical grounds (as in Behan’s study) but also on the decline in antiAChR antibody. In other words, no cumulative long-term benefit attributable to repeated plasma exchange per se could be demonstrated with the immunosuppressive regimen used. Their suggestion that plasma exchange with azathioprine 150 mg daily for 3 months and prednisone 100 mg daily (reducing to zero by 4 months in most cases) may have altered the natural history of the disease may be premature. At a mean follow-up period of nine months, 28% of their patients had had recurrences and the recurrent disease was usually more severe. Furthermore one patient died from marrow suppression and septicxmia, attributable to the treatment. Short courses of less intense immunosuppression with high-dose steroids can lead to a limited period of remission,5 but because of the subsequent tendency to relapse this form of treatment has generally been superseded by maintenance steroid treatment. This can lead to sustained remission or marked improvement in over 85% of cases,6,7 and no deaths were reported in those studies of 38
patients. Plasma exchange can produce short-term improvement, and in 30 patients receiving monthly courses of plasma exchange (9-12 litres) for periods of up to two years8 we have shown its clinical value in the severely ill, symptoms being controlled while other forms of maintenance immunotherapy (e.g., prednisone up to 100 mg on alternate days and azathioprine 2-5mg/kg daily) become effective. It would seem inappropriate to use plasma exchange and intense immunotherapy for pure ocular disease, as Behan and colleagues appear to have done, in view of the mortality they encountered with their regimen Pinching AJ, Peters DK, Newsom-Davis J. Remission of myasthenia gravis following plasma exchange. Lancet 1976; ii: 1373-76. 2. Dau PC, Lindstrom JM, Cassel JK, Denys EH, Shev EE, Spitter LE. Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis. N Engl J Med 1977, 1134-40. 3. Newsom-Davis J, Pinching AJ, Vincent A, Wilson SG. Function of circulating antibody to acetylcholine receptor in myasthenia gravis investigated by plasma exchange. Neurology (Minneap) 1978; 28: 266-72. 4. Newsom-Davis J, Vincent A, Wilson SG, Ward CD. Long-term effects of repeated plasma exchange in myasthenia gravis. Lancet 1979; i: 464-68. 5. Namba T, Brunner NG, Shapiro MS, Grob D. Corticotropin therapy in myasthenia gravis: Effects, indications, and limitations. Neurology (Minneap) 1971; 21: 1008-18. 6. Mann JD, Johns TR, Campa JF. Long-term administration of corticosteroids in myasthenia gravis. Neurology(Minneap) 1976; 26: 729-40. 7. Jenkins RB. Treatment of myasthenia gravis with prednisone. Lancet 1972; 1
i: 765-67. 8 Newsom-Davis press
J. Plasma exchange
in
myasthenia gravis. Plasmatherapy (in
and the fact that almost all ocular cases respond well to alternate-day prednisone alone, often at low dosage.6.9 We would also advise against the short (3 month) period of azathioprine treatment. Although the drug is effective in MG, clinical effects are often slow in appearing’° and the induced decline in anti-AChR antibody has a relatively long half-time.’ Moreover, coincident azathioprine treatment does not influence the recovery-rate of anti-AChR antibody following a course of plasma exchange." Behan et al. suggest that our patient with congenital MG might have responded to plasma exchange if treatment had been prolonged. We think this is unlikely. This patient, who was the son of a cousin marriage, had no detectable anti-AChR antibody in serum3 and no other features of autoimmune disease. He had already failed to respond to high-dose steroids and thymectomy. He thus falls within that group of patients with congenital MG, in which familial cases are common, no immunological abnormalities are evident, and anti-AChR anttbody is not detectable.12 We have argued that these cases have a different (non-immunological) causation from acquired MG, and thus are not likely to benefit from immunotherapy. Department of Neurological Science, Royal Free Hospital, London NW3 2QG
JOHN NEWSOM-DAVIS ANGELA VINCENT
PROLONGED SURVIVAL OF CORNEAL ALLOGRAFTS IN RABBITS TREATED WITH CYCLOSPORIN A
SIR,-Corneal grafting is the most commonly practised alloand the results are usually excellent as long as the coris maintained in its pristine avascular state. Unfortunately, many of the conditions producing corneal opacification, also produce vascularisation, and here corneal grafting is less satisfactory.’Such diseases account for much of the world’s blindness. Allograft rejection has emerged as the major obstacle to successful grafting today. Tissue matching has not proved to be a practicable solution to this problem, and conventional immunosuppression, with its attendant hazards, may not be justifiable for a non-essential organ graft. It seems, however, that less immunosuppression is required to check corneal graft rejection than is needed to prevent or reverse the process in other grafted organs-e.g., corneal allograft rejection can at times be reversed with topical corticosteroids. Cyclosporin A, effective in preserving allografts in a wide range of animals, and with low myelotoxicity, offers a prospect of circumventing the dilemma of systemic immunosuppression for tissue grafts in a non-essential organ. With this in mmd we have investigated the effect of cyclosporin A on the outcome of corneal grafts in rabbits.
graft, nea
Outbred strains of Dutch rabbits weighing about 2 kg were used. Penetrating corneal grafts 6 mm in diameter were exchanged between animals paired to ensure that grafts were exchanged between animals bred in different colonies. Suture material was left exposed to encourage vasculansation. 14 days later skin grafts were exchanged to ensure rejection of the cornea. Only animals with uncomplicated corneal grafts were skin grafted and included in the study. Animals were examined on alternate days by slit-lamp examination Cjratt rejection was diagnosed when an anterior chamber inflammator% KC, Schwartzman RJ. Oral corticosteroids in the treatment of ocular myasthenia gravis. Ann NY Acad Sci 1976; 274: 652-58. Matell G, Bergström L, Franksson C, Hammarström L, Lefvert AK, Möller E, von Reis G, Smith E. Effects of some immuno-suppressive procedures on myasthenia gravis. Ann NY Acad Sci 1976; 274: 659-76. Newsom-Davis J, Ward CD, Wilson SG, Pinching AJ, Vincent A. Plasma exchange in myasthenia gravis short and long term benefits? In: Clark EC, Dau PC, eds. Plasmapheresis and the immunology of myasthenia gravis. Boston: Houghton Mifflin, 1979. Vincent A, Newsom-Davis J. Absence of anti-acetylcholine receptor antibodies in congenital myasthenia gravis. Lancet 1979; i: 441-42. Batchelor JR, Casey TA, Gibbs DC, Lloyd DF, Werb A, Prasaad SS, James A. HLA matching and corneal grafting. Lancet 1976; i. 551-54
9. Fischer
10
11
12. 1.
Letters
to
the Editor
COMBINED PLASMA EXCHANGE AND
IMMUNOSUPPRESSION IN MYASTHENIA GRAVIS
SiR,—Dr Behan and his colleagues (Sept. 1, p. 438) report plasma exchange coupled with immunosuppressive treat-
that
bring about a striking clinical improvement in myasgravis, confirming the results of other studies. 1-4 They imply that plasma exchange was essential for this response and suggest that their treatment regimen may have altered the natural history of the disease. A tendency to attribute exceptional benefit to a new technique such as plasma exchange is understandable. Following our original report of its ability to produce a short remission in MG,’ we naturally hoped that a synergistic action with immunosuppressive treatment might be demonstrable, leading to additional long-term benefit. To our knowledge, no such
ment can
thenia
effect has yet been shown. Behan et al. present no control data on the effects of immunosuppressive treatment alone. When we compared plasma exchange with and without immunosuppression4 we found no significant difference in the long-term improvement between the groups, judged not only on clinical grounds (as in Behan’s study) but also on the decline in antiAChR antibody. In other words, no cumulative long-term benefit attributable to repeated plasma exchange per se could be demonstrated with the immunosuppressive regimen used. Their suggestion that plasma exchange with azathioprine 150 mg daily for 3 months and prednisone 100 mg daily (reducing to zero by 4 months in most cases) may have altered the natural history of the disease may be premature. At a mean follow-up period of nine months, 28% of their patients had had recurrences and the recurrent disease was usually more severe. Furthermore one patient died from marrow suppression and septicxmia, attributable to the treatment. Short courses of less intense immunosuppression with high-dose steroids can lead to a limited period of remission,5 but because of the subsequent tendency to relapse this form of treatment has generally been superseded by maintenance steroid treatment. This can lead to sustained remission or marked improvement in over 85% of cases,6,7 and no deaths were reported in those studies of 38
patients. Plasma exchange can produce short-term improvement, and in 30 patients receiving monthly courses of plasma exchange (9-12 litres) for periods of up to two years8 we have shown its clinical value in the severely ill, symptoms being controlled while other forms of maintenance immunotherapy (e.g., prednisone up to 100 mg on alternate days and azathioprine 2-5mg/kg daily) become effective. It would seem inappropriate to use plasma exchange and intense immunotherapy for pure ocular disease, as Behan and colleagues appear to have done, in view of the mortality they encountered with their regimen Pinching AJ, Peters DK, Newsom-Davis J. Remission of myasthenia gravis following plasma exchange. Lancet 1976; ii: 1373-76. 2. Dau PC, Lindstrom JM, Cassel JK, Denys EH, Shev EE, Spitter LE. Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis. N Engl J Med 1977, 1134-40. 3. Newsom-Davis J, Pinching AJ, Vincent A, Wilson SG. Function of circulating antibody to acetylcholine receptor in myasthenia gravis investigated by plasma exchange. Neurology (Minneap) 1978; 28: 266-72. 4. Newsom-Davis J, Vincent A, Wilson SG, Ward CD. Long-term effects of repeated plasma exchange in myasthenia gravis. Lancet 1979; i: 464-68. 5. Namba T, Brunner NG, Shapiro MS, Grob D. Corticotropin therapy in myasthenia gravis: Effects, indications, and limitations. Neurology (Minneap) 1971; 21: 1008-18. 6. Mann JD, Johns TR, Campa JF. Long-term administration of corticosteroids in myasthenia gravis. Neurology(Minneap) 1976; 26: 729-40. 7. Jenkins RB. Treatment of myasthenia gravis with prednisone. Lancet 1972; 1
i: 765-67. 8 Newsom-Davis press
J. Plasma exchange
in
myasthenia gravis. Plasmatherapy (in
and the fact that almost all ocular cases respond well to alternate-day prednisone alone, often at low dosage.6.9 We would also advise against the short (3 month) period of azathioprine treatment. Although the drug is effective in MG, clinical effects are often slow in appearing’° and the induced decline in anti-AChR antibody has a relatively long half-time.’ Moreover, coincident azathioprine treatment does not influence the recovery-rate of anti-AChR antibody following a course of plasma exchange." Behan et al. suggest that our patient with congenital MG might have responded to plasma exchange if treatment had been prolonged. We think this is unlikely. This patient, who was the son of a cousin marriage, had no detectable anti-AChR antibody in serum3 and no other features of autoimmune disease. He had already failed to respond to high-dose steroids and thymectomy. He thus falls within that group of patients with congenital MG, in which familial cases are common, no immunological abnormalities are evident, and anti-AChR anttbody is not detectable.12 We have argued that these cases have a different (non-immunological) causation from acquired MG, and thus are not likely to benefit from immunotherapy. Department of Neurological Science, Royal Free Hospital, London NW3 2QG
JOHN NEWSOM-DAVIS ANGELA VINCENT
PROLONGED SURVIVAL OF CORNEAL ALLOGRAFTS IN RABBITS TREATED WITH CYCLOSPORIN A
SIR,-Corneal grafting is the most commonly practised alloand the results are usually excellent as long as the coris maintained in its pristine avascular state. Unfortunately, many of the conditions producing corneal opacification, also produce vascularisation, and here corneal grafting is less satisfactory.’Such diseases account for much of the world’s blindness. Allograft rejection has emerged as the major obstacle to successful grafting today. Tissue matching has not proved to be a practicable solution to this problem, and conventional immunosuppression, with its attendant hazards, may not be justifiable for a non-essential organ graft. It seems, however, that less immunosuppression is required to check corneal graft rejection than is needed to prevent or reverse the process in other grafted organs-e.g., corneal allograft rejection can at times be reversed with topical corticosteroids. Cyclosporin A, effective in preserving allografts in a wide range of animals, and with low myelotoxicity, offers a prospect of circumventing the dilemma of systemic immunosuppression for tissue grafts in a non-essential organ. With this in mmd we have investigated the effect of cyclosporin A on the outcome of corneal grafts in rabbits.
graft, nea
Outbred strains of Dutch rabbits weighing about 2 kg were used. Penetrating corneal grafts 6 mm in diameter were exchanged between animals paired to ensure that grafts were exchanged between animals bred in different colonies. Suture material was left exposed to encourage vasculansation. 14 days later skin grafts were exchanged to ensure rejection of the cornea. Only animals with uncomplicated corneal grafts were skin grafted and included in the study. Animals were examined on alternate days by slit-lamp examination Cjratt rejection was diagnosed when an anterior chamber inflammator% KC, Schwartzman RJ. Oral corticosteroids in the treatment of ocular myasthenia gravis. Ann NY Acad Sci 1976; 274: 652-58. Matell G, Bergström L, Franksson C, Hammarström L, Lefvert AK, Möller E, von Reis G, Smith E. Effects of some immuno-suppressive procedures on myasthenia gravis. Ann NY Acad Sci 1976; 274: 659-76. Newsom-Davis J, Ward CD, Wilson SG, Pinching AJ, Vincent A. Plasma exchange in myasthenia gravis short and long term benefits? In: Clark EC, Dau PC, eds. Plasmapheresis and the immunology of myasthenia gravis. Boston: Houghton Mifflin, 1979. Vincent A, Newsom-Davis J. Absence of anti-acetylcholine receptor antibodies in congenital myasthenia gravis. Lancet 1979; i: 441-42. Batchelor JR, Casey TA, Gibbs DC, Lloyd DF, Werb A, Prasaad SS, James A. HLA matching and corneal grafting. Lancet 1976; i. 551-54
9. Fischer
10
11
12. 1.