754
Antinuclear antibody by fluorescence was positive at a titre of 320 in a speckled pattern. On day 1, we increased the prednisolone to 0-8 mg/kg and started bredinin 75 mg every other day. Continuous apheresis was done on days 2, 9, 16, and 22 (fig 1). Apheresis had little effect on anti-dsDNA titres in plasma in every case so the amount of anti-dsDNA removed, calculated from the difference (U/ml) multiplied by the plasma volume (ml), was small (fig 2). Much more antibody was detected in the rinsed solution of the columns (fig 2). On the day after each treatment, the anti-dsDNA titre was moderately raised above the immediate post-apheresis
clinical manifestations. Precipitating factors, including smoking, infections,4and endocrine influences,5,6 might modify the risk dictated by the immunogenetic complement of the host. It is unlikely that smoking has a unique effect on the immune system; and there is no evidence that smoking is genetically determined.
titre. These data support the existence of an extravascular pool of anti-dsDNA (eg, a pool of deposited antibodies in the walls of renal glomeruli). With continuous anti-dsDnA apheresis, antibodies in the extravascular pool are drawn back into circulating blood. By thorough depletion of the extravascular pool, tissue damage due to the antibodies (or their immune complexes) should be reducedindeed in four patients proteinuria was much reduced after a course of continuous anti-dsDNA apheresis. In all patients, the high titres of anti-dsDNA were rapidly diminished after only two, three, or four treatments with this potent apheresis. A rebound effect from B-cell activation triggered by the depletion of anti-dsDNA was barely observed, even one week after each treatment, when the peak effect might be expected.’ The dose of prednisolone and bredinin we administered should have been enough to suppress such rebound effects. Few adverse effects of the aphereses were observed in any patient.
Thyroid
K. SUZUKI Internal Medicine I, National Defence Medical College, Saitama 359, Japan
M. HARA
T. ISHIZUKA T. HIROSE M. HARIGAI K. KITANI M. KAWAGOE H. NAKAMURA
1. Kinoshita M, Aotsuka S, Funahashi T, et al. Selective removal of anti-doublestranded DNA antibodies by immunoadsorption with dextran sulphate in a patient with systemic lupus erythematosus. Ann Rheum Dis 1989; 48: 856-60. 2. Hashimoto H, Tsuda H, Kanai Y, et al. The effect of adsorbent plasmapheresis using dextran sulphate column in SLE patients. Second International Confefence on Systemic Erythematosus, 1989; p 24 (abstr). 3. Aotsuka S, Funahashi T, Tani N, et al. Adsorption of anti-dsDNA antibodies by immobilized polyanionic compounds. Clin Exp Immunol 1990; 79: 215-20. 4. Mabuchi H, Michishita I, Takeda M, et al. A new low density lipoprotein apheresis system using two dextran sulphate cellulose columns in an automated colomn regenerating unit (LDL continuous apheresis). Atherosclerosis 1987; 68: 19-25. 5. Clough JD, Calabrese LH Theoretical aspects of immune complex removal by plasmapheresis. Plasma Ther 1981, 2: 73-81. 6. Kamata K, Okubo M, Ishigamori E, et al Immunosuppressive effect of bredinin on cell-mediated and humoral immune reactions in experimental animals. Transplantation 1983; 35: 144-49 7. Brystryn, JC. Plasmapheresis therapy of pemphigus. Arch Dermatol 1988, 124: 1702-04.
Association between Graves’ ophthalmopathy and smoking SIR,-Dr Shine and colleagues (May 26, p 1261) report the association between smoking and Graves’ ophthalmopathy. We have analysed data from 83 Hungarian patients with Graves’ disease with respect to smoking habits and HLA markers and confirm the findings of Shine et al (table). There was a significant association between ophthalmopathy and smoking in our patient population (p < 0-0001). We disagree, however, that genetic factors are not important in Graves’ eye disease; the presence of HLA-DR3 and/or B8 was significantly associated with eye disease (p < 0-01). Genetic factors mapping within the major histocompatibility complex are important determinants of both susceptibility to Graves’ hyperthyroidisml-3 and Graves’ eye disease and their SMOKING HABITS AND HLA MARKERS IN PATIENTS WITH GRAVES’ DISEASE
Ill Department of Medicine, Teaching Hospital of Debrecen, Hungary
CSABA BALAZS
Megyer Verellato, Debrecen
VALERIA STENSZKY
Research Laboratory, Health Sciences Centre, St John’s, Newfoundland AIB 3V6, Canada
NADIR R. FARID
1.
Balazs C, Stenszky V, Szerze P, Kozma L, Leovey A. Connection between HLA, B8 antigen and suppressor T cell activity in Graves’ disease. Transplant Proc 1979, 11:
1314-15 2 Fand NR, Stenszky V, Balazs C, Bear JC. The major histocompatability complex and autoimmune thyroid disease. M Sinai J Med 1986; 53: 6-10 3 Stenszky V, Kozma L, Balazs C, et al. The genetics of Graves’ disease HLA and disease susceptibility. J Clin Endocrinol Metab 1985; 61: 735-44. 4. Asari S, Amino N, Horikawa M, Miyai K. Incidence of autibodies to Yersima enterocolitica: high incidence of serotype 05 in thyroid disease in Japan. Endocrinol Jpn 1989; 36: 381-86. 5. Smith EM Hormonal activities of lymphokines, monokines and other cytokines. Prog Allergy 1988; 43: 121-39 6. Eisenstein Z, Engelsman E, Weiss M, Laechman Y, Sredni B. Production of and response to interleukin-2 in Graves’ disease. J Clin Immunol 1988; 8: 349-55 7. Anon. Smoking and immunity Lancet 1990; 335: 1561-63.
autoimmune
** This letter has been shown to Dr Shine and Dr Weetman, whose reply follows.-ED. L. SIR,-We are delighted that Dr Balazs and colleagues have confirmed our finding of an association between ophthalmopathy and smoking. However, we1 and others2 have been unable to show an association between HLA B8 or DR3 and ophthalmopathy in over 200 patients. These contrasting findings may mean that, although ophthalmopathy has different genetic associations in geographically distinct populations, smoking exerts a strong environmental influence which is comparable in dissimilar groups. Institute of Ophthalmology, London EC1V 9AT, UK
Addenbrookes
BRIAN SHINE
Hospital,
TONY WEETMAN
Cambridge
1 Weetman AP, So AK, Warner CA, Foroni L, Fells P, Shine B. Immunogenetics of Graves’ ophthalmopathy. Clin Endocrinol 1988; 28: 619-28. 2. Kendall-Taylor P, Stephenson A, Stratton A, Papiha SS, Perros P, Roberts DF Differentiation of autoimmune ophthalmopathy from Graves’ hyperthyroidism by analysis of genetic markers. Clin Endocrinol 1988; 28: 601-10.
Inhibitory potencies of UK-69 578 and thiorphan SIR,-Kahn and colleagues have reported that the atriopeptidase inhibitor sinorphan, the pro-drug of (S)-thiorphan, increases circulating levels of atrial natriuretic factor (ANF), decreases plasma renin activity, and lowers pulmonary capillary pressure in patients with grade 3 or 4 congestive heart failure, observations that are similar to our earlier findings with the selective atriopeptidase inhibitor UK-69 578.zKahn et al indicate that (S)-thiorphan is some 20-fold more potent than UK-69 578 in vitro. Details of experimental conditions and substrates are omitted from their comparison. We have evaluated the inhibitory potency of UK-69 578 and thiorphan (both of which are racemates) under the same experimental conditions with both endogenous and synthetic substrates. Solutions of thiorphan were prepared in 01 mol/l sodium bicarbonate under nitrogen atmosphere, to prevent oxidation to the disulphide, and all experiments were done with degassed buffers. Thin-layer chromatography confirmed minimum disulphide formation. Measurement of atriopeptidase inhibition was done with
[glycine-1-14C]hippuryl phenylalanylarginine3 constants
determined
and inhibiton by Lineweaver-Burke analysis; potency
Antinuclear antibody by fluorescence was positive at a titre of 320 in a speckled pattern. On day 1, we increased the prednisolone to 0-8 mg/kg and started bredinin 75 mg every other day. Continuous apheresis was done on days 2, 9, 16, and 22 (fig 1). Apheresis had little effect on anti-dsDNA titres in plasma in every case so the amount of anti-dsDNA removed, calculated from the difference (U/ml) multiplied by the plasma volume (ml), was small (fig 2). Much more antibody was detected in the rinsed solution of the columns (fig 2). On the day after each treatment, the anti-dsDNA titre was moderately raised above the immediate post-apheresis
clinical manifestations. Precipitating factors, including smoking, infections,4and endocrine influences,5,6 might modify the risk dictated by the immunogenetic complement of the host. It is unlikely that smoking has a unique effect on the immune system; and there is no evidence that smoking is genetically determined.
titre. These data support the existence of an extravascular pool of anti-dsDNA (eg, a pool of deposited antibodies in the walls of renal glomeruli). With continuous anti-dsDnA apheresis, antibodies in the extravascular pool are drawn back into circulating blood. By thorough depletion of the extravascular pool, tissue damage due to the antibodies (or their immune complexes) should be reducedindeed in four patients proteinuria was much reduced after a course of continuous anti-dsDNA apheresis. In all patients, the high titres of anti-dsDNA were rapidly diminished after only two, three, or four treatments with this potent apheresis. A rebound effect from B-cell activation triggered by the depletion of anti-dsDNA was barely observed, even one week after each treatment, when the peak effect might be expected.’ The dose of prednisolone and bredinin we administered should have been enough to suppress such rebound effects. Few adverse effects of the aphereses were observed in any patient.
Thyroid
K. SUZUKI Internal Medicine I, National Defence Medical College, Saitama 359, Japan
M. HARA
T. ISHIZUKA T. HIROSE M. HARIGAI K. KITANI M. KAWAGOE H. NAKAMURA
1. Kinoshita M, Aotsuka S, Funahashi T, et al. Selective removal of anti-doublestranded DNA antibodies by immunoadsorption with dextran sulphate in a patient with systemic lupus erythematosus. Ann Rheum Dis 1989; 48: 856-60. 2. Hashimoto H, Tsuda H, Kanai Y, et al. The effect of adsorbent plasmapheresis using dextran sulphate column in SLE patients. Second International Confefence on Systemic Erythematosus, 1989; p 24 (abstr). 3. Aotsuka S, Funahashi T, Tani N, et al. Adsorption of anti-dsDNA antibodies by immobilized polyanionic compounds. Clin Exp Immunol 1990; 79: 215-20. 4. Mabuchi H, Michishita I, Takeda M, et al. A new low density lipoprotein apheresis system using two dextran sulphate cellulose columns in an automated colomn regenerating unit (LDL continuous apheresis). Atherosclerosis 1987; 68: 19-25. 5. Clough JD, Calabrese LH Theoretical aspects of immune complex removal by plasmapheresis. Plasma Ther 1981, 2: 73-81. 6. Kamata K, Okubo M, Ishigamori E, et al Immunosuppressive effect of bredinin on cell-mediated and humoral immune reactions in experimental animals. Transplantation 1983; 35: 144-49 7. Brystryn, JC. Plasmapheresis therapy of pemphigus. Arch Dermatol 1988, 124: 1702-04.
Association between Graves’ ophthalmopathy and smoking SIR,-Dr Shine and colleagues (May 26, p 1261) report the association between smoking and Graves’ ophthalmopathy. We have analysed data from 83 Hungarian patients with Graves’ disease with respect to smoking habits and HLA markers and confirm the findings of Shine et al (table). There was a significant association between ophthalmopathy and smoking in our patient population (p < 0-0001). We disagree, however, that genetic factors are not important in Graves’ eye disease; the presence of HLA-DR3 and/or B8 was significantly associated with eye disease (p < 0-01). Genetic factors mapping within the major histocompatibility complex are important determinants of both susceptibility to Graves’ hyperthyroidisml-3 and Graves’ eye disease and their SMOKING HABITS AND HLA MARKERS IN PATIENTS WITH GRAVES’ DISEASE
Ill Department of Medicine, Teaching Hospital of Debrecen, Hungary
CSABA BALAZS
Megyer Verellato, Debrecen
VALERIA STENSZKY
Research Laboratory, Health Sciences Centre, St John’s, Newfoundland AIB 3V6, Canada
NADIR R. FARID
1.
Balazs C, Stenszky V, Szerze P, Kozma L, Leovey A. Connection between HLA, B8 antigen and suppressor T cell activity in Graves’ disease. Transplant Proc 1979, 11:
1314-15 2 Fand NR, Stenszky V, Balazs C, Bear JC. The major histocompatability complex and autoimmune thyroid disease. M Sinai J Med 1986; 53: 6-10 3 Stenszky V, Kozma L, Balazs C, et al. The genetics of Graves’ disease HLA and disease susceptibility. J Clin Endocrinol Metab 1985; 61: 735-44. 4. Asari S, Amino N, Horikawa M, Miyai K. Incidence of autibodies to Yersima enterocolitica: high incidence of serotype 05 in thyroid disease in Japan. Endocrinol Jpn 1989; 36: 381-86. 5. Smith EM Hormonal activities of lymphokines, monokines and other cytokines. Prog Allergy 1988; 43: 121-39 6. Eisenstein Z, Engelsman E, Weiss M, Laechman Y, Sredni B. Production of and response to interleukin-2 in Graves’ disease. J Clin Immunol 1988; 8: 349-55 7. Anon. Smoking and immunity Lancet 1990; 335: 1561-63.
autoimmune
** This letter has been shown to Dr Shine and Dr Weetman, whose reply follows.-ED. L. SIR,-We are delighted that Dr Balazs and colleagues have confirmed our finding of an association between ophthalmopathy and smoking. However, we1 and others2 have been unable to show an association between HLA B8 or DR3 and ophthalmopathy in over 200 patients. These contrasting findings may mean that, although ophthalmopathy has different genetic associations in geographically distinct populations, smoking exerts a strong environmental influence which is comparable in dissimilar groups. Institute of Ophthalmology, London EC1V 9AT, UK
Addenbrookes
BRIAN SHINE
Hospital,
TONY WEETMAN
Cambridge
1 Weetman AP, So AK, Warner CA, Foroni L, Fells P, Shine B. Immunogenetics of Graves’ ophthalmopathy. Clin Endocrinol 1988; 28: 619-28. 2. Kendall-Taylor P, Stephenson A, Stratton A, Papiha SS, Perros P, Roberts DF Differentiation of autoimmune ophthalmopathy from Graves’ hyperthyroidism by analysis of genetic markers. Clin Endocrinol 1988; 28: 601-10.
Inhibitory potencies of UK-69 578 and thiorphan SIR,-Kahn and colleagues have reported that the atriopeptidase inhibitor sinorphan, the pro-drug of (S)-thiorphan, increases circulating levels of atrial natriuretic factor (ANF), decreases plasma renin activity, and lowers pulmonary capillary pressure in patients with grade 3 or 4 congestive heart failure, observations that are similar to our earlier findings with the selective atriopeptidase inhibitor UK-69 578.zKahn et al indicate that (S)-thiorphan is some 20-fold more potent than UK-69 578 in vitro. Details of experimental conditions and substrates are omitted from their comparison. We have evaluated the inhibitory potency of UK-69 578 and thiorphan (both of which are racemates) under the same experimental conditions with both endogenous and synthetic substrates. Solutions of thiorphan were prepared in 01 mol/l sodium bicarbonate under nitrogen atmosphere, to prevent oxidation to the disulphide, and all experiments were done with degassed buffers. Thin-layer chromatography confirmed minimum disulphide formation. Measurement of atriopeptidase inhibition was done with
[glycine-1-14C]hippuryl phenylalanylarginine3 constants
determined
and inhibiton by Lineweaver-Burke analysis; potency
