1013
study, of 36 klebsiella isolates, only another 2 capable of absorbing out the lymphocytotoxic acti-
further were
vity of the initial antiserum. Antisera raised to these isolates produced similar lymphocytotoxic activity, whereas no lysis occurred with antisera of other klebsiella isolates.9 These results strongly suggest cross-reactivity between a klebsiella serotype and a gene product closely associated with HLA B 27 in ankylosing spondylitis patients. B 27 must be an essential part of this complex since the anti-klebsiella antiserum did not lyse the lymphocytes of B 27 negative patients with ankylosing spondylitis. The failure to lyse B 27 lymphocytes from healthy individuals also suggests that this gene complex must be altered in some way in the diseased group. Factor B polymorphism may also be involved in this inherited predisposition to ankylosing spondylitis. Arneson et a1.1O found that, of B 27 individuals, those with ankylos-
ing spondylitis carried BfS, whereas the disease-free controls were equally divided among BfS and BfF. The gene-controlling factor B is very close to the HLA-B locus, so that the ankylosing spondylitis predisposition may be due to a closely associated gene on the factor B side of the HLA-B 27 locus.
findings of klebsiella and B 27 cross-reactivity in ankylosing spondylitis provide substantial support for the molecular-mimicry hypothesis for HLA and disease association. The weakness of the hypothesis is in its failure to explain how persistent infection in the absence of These
immune response results in this disease with its uninvolvement. It also does not account for the rarer B 27 negative patients; nor does it explain the strong HLA-B 27 association with the reactive arthritis which occurs after salmonella or Yersinia enterocolitica infections, when no such cross-reactivity can be demonstrated between that tissue type and the microorganisms. It would also be unwise at this stage to extrapolate from the data in ankylosing spondylitis to other strong HLA and disease associations. The explanations for these are probably many and diverse. an
ique joint
CIMETIDINE AND GASTRIC CANCER THE preliminary communication by Mr Elder and his colleagues on p. 1005 raises questions that are being increasingly discussed by gastroenterologists, biochemists, drug regulatory authorities, and others, though little of the debate has hitherto been held in public. In the first place the issues arise from the observation that certain
be transformed in acidic aqueous media at temperatures to N-nitroso compounds, .::any of which are known to have mutagenic and carcinogenic properties. The wide distribution of amines in the environment has long been discussed as a possible source of carcinogens produced by nitrosation; and, for une thing, it has been suggested that the increased incidence of gastric cancer in some areas where the nitrate amines can
physiological
9 Geczy, A F., Yap, J. Lancet, March 31, 1979, p. 719. 10 Arnason, A., Thorsteinsson, J., Sigurbergsson, K. Lancet, 1978, i, 339.
content of drinking water and vegetables is high could be the result of in-vivo formation of N-nitroso compounds. Examining the potential carcinogenicity of nitrosatable drugs, a W.H.O. studv group’,’ concluded last year that, if material quantities of N-nitroso compounds are formed in vivo, drugs contribute only marginally to the pool of nitrosatable precursors. Nevertheless the unanimous view of the W.H.O. group was that "any orally-administered readily-nitrosatable drug that generates a demonstrably carcinogenic derivative should be withdrawn provided a suitable replacement is available."
Nothing like enough is known about the extent of the formation of N-nitroso compounds under different conditions in man to enable any pathological significance to be assessed, whether the origin of these compounds is a drug or another environmental source. It is against this background of uncertainty that the report on p. 1005 must be judged. Indeed it is the uncertainty which has prompted this journal to publish it, so that the subject may be freely discussed. Mr Elder and his colleagues are wondering whether the anxieties about nitrosatable drugs are in any way applicable to the widely used H2 blocking drug, cimetidine. Their three case-reports describe patients who had been treated with cimetidine for varying lengths of time and who were then found to have carcinoma of the stomach. These cases do nothing, of course, to establish cause and effect. In case 2 cimetidine was given for only 10 weeks and it is very unlikely to have induced permanent mucosal change in so short a time. Case 1, however, may prompt inquiry about a possible similarity between the effects on gastric mucosa of cimetidine and of partial gastric resection, which has been shown experimentally to sensitise the mucosa to carcinogens.3 Moreover, is cimetidine nitrosatable? Some unpublished evidence indicates that it is-in vitro, under conditions similar to those in the stomach. But the biological properties of the compound so formed are not known. In a letter on p. 1039, Dr Francis Roe, commenting behalf of the manufacturers of cimetidine, remarks that there is no evidence that "any nitroso-compound which could conceivably be formed from cimetidine in the stomach would behave biologically like N-methyl-N’nitro-N-nitrosoguanidine", a carcinogen which Mr Elder and his colleagues believe may be analogous to nitrosocimetidine. Large long-term experiments in rats fed very high doses of cimetidine have produced no evidence of increased risk of malignancy.
on
The danger that treatment with cimetidine could mask an undiagnosed gastric carcinoma was quickly recognised, but its warning has not always been heeded. Mr Elder’s case 2 may again illustrate that endoscopy is much to be preferred to barium meal in these circumstances ; and case 3 looks to be at least another argument for insisting on diagnosis before treatment. 1 BB H O Drug
the groups
Intormation, April—June, 1978, rewsis not vet
PDT DI
78,2 A full report of
available
2 See Lancet, Feb 3, 1979, p. 283. 3 Dahm, K. Hehen, R. Mitschke, H. Langoenbeck Arch. clm. Surg 1977, 344,71 4 Dahm, K., Schreiber, H W. Werner, B. Knrpper, A., Mitschke, H. Innere Med 1977, 4, 297
study, of 36 klebsiella isolates, only another 2 capable of absorbing out the lymphocytotoxic acti-
further were
vity of the initial antiserum. Antisera raised to these isolates produced similar lymphocytotoxic activity, whereas no lysis occurred with antisera of other klebsiella isolates.9 These results strongly suggest cross-reactivity between a klebsiella serotype and a gene product closely associated with HLA B 27 in ankylosing spondylitis patients. B 27 must be an essential part of this complex since the anti-klebsiella antiserum did not lyse the lymphocytes of B 27 negative patients with ankylosing spondylitis. The failure to lyse B 27 lymphocytes from healthy individuals also suggests that this gene complex must be altered in some way in the diseased group. Factor B polymorphism may also be involved in this inherited predisposition to ankylosing spondylitis. Arneson et a1.1O found that, of B 27 individuals, those with ankylos-
ing spondylitis carried BfS, whereas the disease-free controls were equally divided among BfS and BfF. The gene-controlling factor B is very close to the HLA-B locus, so that the ankylosing spondylitis predisposition may be due to a closely associated gene on the factor B side of the HLA-B 27 locus.
findings of klebsiella and B 27 cross-reactivity in ankylosing spondylitis provide substantial support for the molecular-mimicry hypothesis for HLA and disease association. The weakness of the hypothesis is in its failure to explain how persistent infection in the absence of These
immune response results in this disease with its uninvolvement. It also does not account for the rarer B 27 negative patients; nor does it explain the strong HLA-B 27 association with the reactive arthritis which occurs after salmonella or Yersinia enterocolitica infections, when no such cross-reactivity can be demonstrated between that tissue type and the microorganisms. It would also be unwise at this stage to extrapolate from the data in ankylosing spondylitis to other strong HLA and disease associations. The explanations for these are probably many and diverse. an
ique joint
CIMETIDINE AND GASTRIC CANCER THE preliminary communication by Mr Elder and his colleagues on p. 1005 raises questions that are being increasingly discussed by gastroenterologists, biochemists, drug regulatory authorities, and others, though little of the debate has hitherto been held in public. In the first place the issues arise from the observation that certain
be transformed in acidic aqueous media at temperatures to N-nitroso compounds, .::any of which are known to have mutagenic and carcinogenic properties. The wide distribution of amines in the environment has long been discussed as a possible source of carcinogens produced by nitrosation; and, for une thing, it has been suggested that the increased incidence of gastric cancer in some areas where the nitrate amines can
physiological
9 Geczy, A F., Yap, J. Lancet, March 31, 1979, p. 719. 10 Arnason, A., Thorsteinsson, J., Sigurbergsson, K. Lancet, 1978, i, 339.
content of drinking water and vegetables is high could be the result of in-vivo formation of N-nitroso compounds. Examining the potential carcinogenicity of nitrosatable drugs, a W.H.O. studv group’,’ concluded last year that, if material quantities of N-nitroso compounds are formed in vivo, drugs contribute only marginally to the pool of nitrosatable precursors. Nevertheless the unanimous view of the W.H.O. group was that "any orally-administered readily-nitrosatable drug that generates a demonstrably carcinogenic derivative should be withdrawn provided a suitable replacement is available."
Nothing like enough is known about the extent of the formation of N-nitroso compounds under different conditions in man to enable any pathological significance to be assessed, whether the origin of these compounds is a drug or another environmental source. It is against this background of uncertainty that the report on p. 1005 must be judged. Indeed it is the uncertainty which has prompted this journal to publish it, so that the subject may be freely discussed. Mr Elder and his colleagues are wondering whether the anxieties about nitrosatable drugs are in any way applicable to the widely used H2 blocking drug, cimetidine. Their three case-reports describe patients who had been treated with cimetidine for varying lengths of time and who were then found to have carcinoma of the stomach. These cases do nothing, of course, to establish cause and effect. In case 2 cimetidine was given for only 10 weeks and it is very unlikely to have induced permanent mucosal change in so short a time. Case 1, however, may prompt inquiry about a possible similarity between the effects on gastric mucosa of cimetidine and of partial gastric resection, which has been shown experimentally to sensitise the mucosa to carcinogens.3 Moreover, is cimetidine nitrosatable? Some unpublished evidence indicates that it is-in vitro, under conditions similar to those in the stomach. But the biological properties of the compound so formed are not known. In a letter on p. 1039, Dr Francis Roe, commenting behalf of the manufacturers of cimetidine, remarks that there is no evidence that "any nitroso-compound which could conceivably be formed from cimetidine in the stomach would behave biologically like N-methyl-N’nitro-N-nitrosoguanidine", a carcinogen which Mr Elder and his colleagues believe may be analogous to nitrosocimetidine. Large long-term experiments in rats fed very high doses of cimetidine have produced no evidence of increased risk of malignancy.
on
The danger that treatment with cimetidine could mask an undiagnosed gastric carcinoma was quickly recognised, but its warning has not always been heeded. Mr Elder’s case 2 may again illustrate that endoscopy is much to be preferred to barium meal in these circumstances ; and case 3 looks to be at least another argument for insisting on diagnosis before treatment. 1 BB H O Drug
the groups
Intormation, April—June, 1978, rewsis not vet
PDT DI
78,2 A full report of
available
2 See Lancet, Feb 3, 1979, p. 283. 3 Dahm, K. Hehen, R. Mitschke, H. Langoenbeck Arch. clm. Surg 1977, 344,71 4 Dahm, K., Schreiber, H W. Werner, B. Knrpper, A., Mitschke, H. Innere Med 1977, 4, 297
