194
believe that plasma exchange would do any more than temporarily lower the serum concentration of any IgG antibodies by about 20%, a useless contribution when the antibody is probably being synthesised within the CNS compartment. I am not in the least surprised that the participants in this debate found no value in these procedures-I am a bit surprised that they even thought they were worth studying. I know of only two treatments that can deal with established secondary immune responses (T-cells and B-cells). One is total body irradiation followed by a bone-marrow transplant. To justify that, one would have to be certain that the patients’ disease was going to cripple them, and then make that decision before it was too late-and this is one of the biggest difficulties in multiple sclerosis. The alternative is the "Gorski manoeuvre" (after the immunologist in the Polish team who conceived it and established it in mice with severe autoimmune disease’). This procedure reduces a mean serum antibody level of around 130 units down to about 6. My own team have lowered IgM anti-B or anti-A titres from 256 to 2-4 in three separate patients by this manoeuvre. The concept involves a series of plasma exchanges (eg, for IgM one will do; for IgG three in 3 days) to achieve a 70-90% reduction of antibodies, which will remove negative feedback and encourage the memory clones of committed lymphocytes to go into division. Even then, if cyclophosphamide alone is used, it is still not possible to achieve a large enough elimination. The Polish team followed the last of the exchanges with a dose of immunomodulator; they chose a thymic to
factor extract and we have used this too because these extracts make CD4 helper T-cells release activators for B-cells. This requires that such T-cells should be uninhibited, so no corticosteroids, cyclosporin, or other immunosuppressives should be active for 4-72 hours while the T-cytokines are being released and acting. In future we might be able to use a combination of interleukins 4 and 6. The effect is to increase recruitment in the number of specific memory cells that would go into division, and exactly 24 hours after the thymic extract quite acceptable doses of cyclophosphamide can be given such as 20 mg/kg, and again at 48 hours. These doses will catch the lined-up lymphocytes at a crucial moment during their preparation for division and synthesis and result in a sharp reduction in antibody concentrations. In some patients remissions of up to one year without any need for other treatments have been achieved in myasthenia gravis and similar diseases. Nevertheless, even with such clever manoeuvres, it still remains almost impossible to delete all reactive clones and almost always their products will return. The beauty of the Gorski manoeuvre is that it is repeatable, provided skin testing is done for whichever immunomodulator is used a second time. Department of Immunology, Charing Cross and Westminster Medical School, London SW1 P 2AP, UK
J. R. HOBBS
A, Podobinski R, Nowaczyk M, Korczak-Kowalska G. Immunomodulatory effects of thymic factor (TFX) on the interactions between T- and B-cells and their sensitivity to immunosuppressive agents. In: Byrom NA, Hobbs JR, eds. Thymic factor therapy. New York: Raven, 1984: 103-12.
1. Gorski
Megadose methylprednisolone or IVIG for idiopathic thrombocytopenic purpura SiR,—Ozsoylu et all reported the successful use of megadose for chronic (MDMP) idiopathic (ITP) in a 7-year-old boy after the failure of the usual dose of prednisone and intravenous gammaglobulin (IVIG). We disagree with some aspects of this
methylprednisolone
thrombocytopenic
purpura
report.
First, no clear difference was shown between acute and chronic ITP. According to Ozsoylu et al, both have a favourable outlook. We think this is not so. Acute ITP in children has an 80-85% spontaneous remission rate, whereas chronic ITP in children, as in adults, rarely remits without treatment.2 Second, they say that with IVIG almost all patients have side-effects, mentioning haemolysis3.4 This notion differs from the general experience that IVIG is safe with a very low frequency of major side-effects.5 Haemolysis associated with the use of IVIG is
very rare. Furthermore, IVIG has been proposed as a therapeutic option in autoimmune haemolytic anaemia.6 We do not think that a high frequency of side-effects is good reason to choose MDMP
instead of IVIG. Third, the therapeutic approaches in acute and chronic ITP are also different. In acute disease, treatment, when necessary, tends to rapidly raise the platelet count to avoid haemorrhage. In this sense IVIG and MDMP have shown their usefulness. In chronic disease,
(eg, prednisone, splenectomy, immunosuppressives) produce sustained recovery of platelets. In children over 6 years old with chronic ITP, splenectomy is an alternative that should be considered after the failure of normal-dose prednisone. treatment
tends
to
Haematology Department, Hospital Britanico DE BS. AS, Perdriel 74 (1280), Capital Federal, Argentina
G. R. STEMMELIN C. M. SHANLEY J. M. CERESETTO E. O. BULLORSKY
Özsoylu S,
Hicsonmez G, Duru F. Megadose methylprednisolone for chronic idiopathic thrombocytopenic purpura. Lancet 1990; 336: 1078-79. 2. Williams W, Beutlher E, Erslev A, Lichtman MA. Thombocytopenia due to enhanced platelet destruction by immunologic mechanisms. In. Hematology, 4th ed Toronto: McGraw-Hill, 1991: 137-98. 3. Nakamura S, Yoshido T, Ohtake S, Matsuda T. Hemolysis due to high dose intravenous gammaglobulin treatment for patients with idiopathic thrombocytopenic purpura. Acta Haematol 1986; 76: 115-18. 4. Kim HC, Park CL, Cowan JH III, et al. Massive intravascular hemolysis with intravenous immunoglobulin in bone marrow transplant recipients. AmJ Pediatr Hematol Oncol 1988; 10: 69-74. 5. Berkman SA, Lee ML, Gale RP. Clinical uses of intravenous immunoglobulins. Ann 1.
Intern Med 1990; 112: 278-92. 6. Bussel JB, Cunningham-Runaldes C, Abraham C. Intravenous treatment of autoimmune hemolytic anemia with very high-dose gammaglobulin. Vox Sang 1986; 41: 264
Long-term safety and tolerability of intravenous immunoglobulin SIR,-Intravenous immunoglobulins (IVIG) have been used treat to patients with primary and more recently for autoimmune diseases.1 Several commercial preparations have been licensed by the regulatory authorities in the UK, most having passed formal clinical trials to show that they are well tolerated and do not transmit hepatitis viruses. However, a brief look at the history of IVIG therapy over the last decade suggests that we should not be complacent. There were two major and two minor outbreaks of non-A, non-B hepatitis associated with four different IVIG preparations during the 1980s, and during the last year there has been a small cluster of cases in Italy associated with a licensed preparation.2-4 Most experts agree that the manufacturing methods used for these "second generation" preparations are on the edge of safety, and much depends on the standard of management of the factory and on the degree of viral contamination in the plasma pools that provide the starting material. This concern has led to the recent introduction of specific antiviral steps in the process, providing "third generation" IVIGs. We summarise our experience with a second-generation IVIG in patients with primary hypogammaglobulinaemia, providing a useful yardstick with which to compare new preparations. 42 patients (6 X-linked, 36 common variable) had liver function tested at routine clinic visits; all patients had exclusively received ’Sandoglobulin’, at doses of 200-400 mg/kg every two weeks for up to 8 years (mean 3 years). In 10 patients, transient minor increases (< 100 IU/1) in serum aspartate transaminase and/or alanine transferase developed, but there was no evidence of chronic liver disease on formal assessment in 1989. 1 patient had chronic liver disease with splenomegaly and persistently raised serum transaminases associated with chronic inflammatory bowel disease. Tolerability was generally satisfactory, although minor reactions were common. The following data relate to records kept prospectively by 28 patients (5 X-linked, 23 common variable) receiving 1385 infusions of IVIG. There were fifty-five reactions (none in 15 patients, one [all mild] in 6, two to five in 3, and over five in 4). The main symptoms during reactions were shivering and/or headache 44, nausea/vomiting 6, tightness in chest 3, faintness 1, and aching of joints 1.
since
the
late
1970s
hypogammaglobulinaemia
believe that plasma exchange would do any more than temporarily lower the serum concentration of any IgG antibodies by about 20%, a useless contribution when the antibody is probably being synthesised within the CNS compartment. I am not in the least surprised that the participants in this debate found no value in these procedures-I am a bit surprised that they even thought they were worth studying. I know of only two treatments that can deal with established secondary immune responses (T-cells and B-cells). One is total body irradiation followed by a bone-marrow transplant. To justify that, one would have to be certain that the patients’ disease was going to cripple them, and then make that decision before it was too late-and this is one of the biggest difficulties in multiple sclerosis. The alternative is the "Gorski manoeuvre" (after the immunologist in the Polish team who conceived it and established it in mice with severe autoimmune disease’). This procedure reduces a mean serum antibody level of around 130 units down to about 6. My own team have lowered IgM anti-B or anti-A titres from 256 to 2-4 in three separate patients by this manoeuvre. The concept involves a series of plasma exchanges (eg, for IgM one will do; for IgG three in 3 days) to achieve a 70-90% reduction of antibodies, which will remove negative feedback and encourage the memory clones of committed lymphocytes to go into division. Even then, if cyclophosphamide alone is used, it is still not possible to achieve a large enough elimination. The Polish team followed the last of the exchanges with a dose of immunomodulator; they chose a thymic to
factor extract and we have used this too because these extracts make CD4 helper T-cells release activators for B-cells. This requires that such T-cells should be uninhibited, so no corticosteroids, cyclosporin, or other immunosuppressives should be active for 4-72 hours while the T-cytokines are being released and acting. In future we might be able to use a combination of interleukins 4 and 6. The effect is to increase recruitment in the number of specific memory cells that would go into division, and exactly 24 hours after the thymic extract quite acceptable doses of cyclophosphamide can be given such as 20 mg/kg, and again at 48 hours. These doses will catch the lined-up lymphocytes at a crucial moment during their preparation for division and synthesis and result in a sharp reduction in antibody concentrations. In some patients remissions of up to one year without any need for other treatments have been achieved in myasthenia gravis and similar diseases. Nevertheless, even with such clever manoeuvres, it still remains almost impossible to delete all reactive clones and almost always their products will return. The beauty of the Gorski manoeuvre is that it is repeatable, provided skin testing is done for whichever immunomodulator is used a second time. Department of Immunology, Charing Cross and Westminster Medical School, London SW1 P 2AP, UK
J. R. HOBBS
A, Podobinski R, Nowaczyk M, Korczak-Kowalska G. Immunomodulatory effects of thymic factor (TFX) on the interactions between T- and B-cells and their sensitivity to immunosuppressive agents. In: Byrom NA, Hobbs JR, eds. Thymic factor therapy. New York: Raven, 1984: 103-12.
1. Gorski
Megadose methylprednisolone or IVIG for idiopathic thrombocytopenic purpura SiR,—Ozsoylu et all reported the successful use of megadose for chronic (MDMP) idiopathic (ITP) in a 7-year-old boy after the failure of the usual dose of prednisone and intravenous gammaglobulin (IVIG). We disagree with some aspects of this
methylprednisolone
thrombocytopenic
purpura
report.
First, no clear difference was shown between acute and chronic ITP. According to Ozsoylu et al, both have a favourable outlook. We think this is not so. Acute ITP in children has an 80-85% spontaneous remission rate, whereas chronic ITP in children, as in adults, rarely remits without treatment.2 Second, they say that with IVIG almost all patients have side-effects, mentioning haemolysis3.4 This notion differs from the general experience that IVIG is safe with a very low frequency of major side-effects.5 Haemolysis associated with the use of IVIG is
very rare. Furthermore, IVIG has been proposed as a therapeutic option in autoimmune haemolytic anaemia.6 We do not think that a high frequency of side-effects is good reason to choose MDMP
instead of IVIG. Third, the therapeutic approaches in acute and chronic ITP are also different. In acute disease, treatment, when necessary, tends to rapidly raise the platelet count to avoid haemorrhage. In this sense IVIG and MDMP have shown their usefulness. In chronic disease,
(eg, prednisone, splenectomy, immunosuppressives) produce sustained recovery of platelets. In children over 6 years old with chronic ITP, splenectomy is an alternative that should be considered after the failure of normal-dose prednisone. treatment
tends
to
Haematology Department, Hospital Britanico DE BS. AS, Perdriel 74 (1280), Capital Federal, Argentina
G. R. STEMMELIN C. M. SHANLEY J. M. CERESETTO E. O. BULLORSKY
Özsoylu S,
Hicsonmez G, Duru F. Megadose methylprednisolone for chronic idiopathic thrombocytopenic purpura. Lancet 1990; 336: 1078-79. 2. Williams W, Beutlher E, Erslev A, Lichtman MA. Thombocytopenia due to enhanced platelet destruction by immunologic mechanisms. In. Hematology, 4th ed Toronto: McGraw-Hill, 1991: 137-98. 3. Nakamura S, Yoshido T, Ohtake S, Matsuda T. Hemolysis due to high dose intravenous gammaglobulin treatment for patients with idiopathic thrombocytopenic purpura. Acta Haematol 1986; 76: 115-18. 4. Kim HC, Park CL, Cowan JH III, et al. Massive intravascular hemolysis with intravenous immunoglobulin in bone marrow transplant recipients. AmJ Pediatr Hematol Oncol 1988; 10: 69-74. 5. Berkman SA, Lee ML, Gale RP. Clinical uses of intravenous immunoglobulins. Ann 1.
Intern Med 1990; 112: 278-92. 6. Bussel JB, Cunningham-Runaldes C, Abraham C. Intravenous treatment of autoimmune hemolytic anemia with very high-dose gammaglobulin. Vox Sang 1986; 41: 264
Long-term safety and tolerability of intravenous immunoglobulin SIR,-Intravenous immunoglobulins (IVIG) have been used treat to patients with primary and more recently for autoimmune diseases.1 Several commercial preparations have been licensed by the regulatory authorities in the UK, most having passed formal clinical trials to show that they are well tolerated and do not transmit hepatitis viruses. However, a brief look at the history of IVIG therapy over the last decade suggests that we should not be complacent. There were two major and two minor outbreaks of non-A, non-B hepatitis associated with four different IVIG preparations during the 1980s, and during the last year there has been a small cluster of cases in Italy associated with a licensed preparation.2-4 Most experts agree that the manufacturing methods used for these "second generation" preparations are on the edge of safety, and much depends on the standard of management of the factory and on the degree of viral contamination in the plasma pools that provide the starting material. This concern has led to the recent introduction of specific antiviral steps in the process, providing "third generation" IVIGs. We summarise our experience with a second-generation IVIG in patients with primary hypogammaglobulinaemia, providing a useful yardstick with which to compare new preparations. 42 patients (6 X-linked, 36 common variable) had liver function tested at routine clinic visits; all patients had exclusively received ’Sandoglobulin’, at doses of 200-400 mg/kg every two weeks for up to 8 years (mean 3 years). In 10 patients, transient minor increases (< 100 IU/1) in serum aspartate transaminase and/or alanine transferase developed, but there was no evidence of chronic liver disease on formal assessment in 1989. 1 patient had chronic liver disease with splenomegaly and persistently raised serum transaminases associated with chronic inflammatory bowel disease. Tolerability was generally satisfactory, although minor reactions were common. The following data relate to records kept prospectively by 28 patients (5 X-linked, 23 common variable) receiving 1385 infusions of IVIG. There were fifty-five reactions (none in 15 patients, one [all mild] in 6, two to five in 3, and over five in 4). The main symptoms during reactions were shivering and/or headache 44, nausea/vomiting 6, tightness in chest 3, faintness 1, and aching of joints 1.
since
the
late
1970s
hypogammaglobulinaemia
