Document 2R8j9GDmYKYOgxQKE96DeYn0L

THELANCET,JANUARY 1 /8,1983 53 complications after elective termination before 16 weeks' gestation. One was performed by suction evacuation, the other by hysterotomy. If the pregnant EDS IV patient is first seen late in pregnancy, she must be cared for as a high-risk patient. Vaginal delivery and delivery by elective caesarean section have both been advocated for such patients. However, on the basis ofthe experience ofpatients in our group there does not appear to be a mode which has fewer complications. We suggest that all patients should be carefully monitored during labour and for several days post partum so that prompt intervention can be initiated in the event ofvessel or uterine rupture. We cannot emphasise too strongly that EDS IV is a distinct type ofEDS which differs in clinical and biochemical features from all other forms. Those complications which affect women with EDS IV are not to be expected in patients with other forms of EDS.24 We thank Dr John Butt, ChiefMedical Examiner, Province ofAlberta, for hi) cooperation in li&sue collection for diagnostic studies; Mary Hoff and Karen David for excellent technical assistance; and Marion Brown and Diane Dawson for prepanng the manuscript. This study was supported in part by funds from the Alberta Children's Foundation and grants from the U.S. Public Health Service (AM 21557, GM 07266), the March of Dimes Birth Defects Foundation (6-298), and the Poncin Scholarship Fund. P. H. B. is an Established Investigator of the American Heart Association. Correspondence should be addressed to P, H. B., Department ofPathology SM*30, University of Washington, Seattle WA 98195, U.S.A. REFERENCES 1. Brighton p. The Ehlert-Duiios syndrome. London; Hrinemgno, 1970. 2. McKusiekVA,Hrntibiedj>ordersofconneaivetmuc,4thed. Si Louis; Mosby, 1972. 3. Hollister DW. Heritable disorders of connective tissue; Ehlers-Danlos syndrome. Ptdwtr Ct\n N Am )97B;23; 575-91. 4. Pinnell SR-Disorders ofcnllaeen In' Sttnbun'JB, Wvngaarden JB, Frtdeockson DJI. cds. The rr.etahs!:c 1366*94. of i&bcnied disease. ?Jew York; McCraw-H.il, 1978: 3. Bornstein f\ Byers PH. Disorders ofcollagen metabolism. In; Bondy PK, Rosenberg LE, eds. Mctsboltc control end disease, 6th ed. Philadelphia: W8 Saunders, 1980: 1089-1133. 6. Hollister DW, Byers PH, Holbrook KA. Genetic disorders of collagen metabolism. AdpHum Genti 1982; 12: 1-87. 7. Bytrs PH. Inherited dliordcn of colleges biosynthesis: Ehlen-Danlot syndrome, the Marian syndrome and osteogenesis imperfects. In: Spate) JA, ed. Qtnical medicine. Philadelphia. JB Lippmcott (in press). 8. Byers PH, Barth GS, Holbrook KA, Molecular mechanisms of connective tissue abnormalities in the Ehlers-Danlos syndrome. Collaftn Rtl Res 1981; It 475-89 9. Van Meefceren JA. De dilatabilitate extrsordmina cutis. In: Observations mediconchirugicte. Chap, 32, Amsterdam, 1682. Cited in McKusicfcVA. Heritable disorders of connective tissue, 4th ed St Louis; Moaby, 1972. 10- Barabss AP. Vascular complications in Ehlen-Danlos syndrome. J C&rdmatc Surf 1972; 13: 160. 11. Byers PH, Holbrook KA, McGillivray B, MacLeod PM, Lowry RB- Qtnical and ultrastructural heterogeneity oftype IV Ehlen-Dtnlw syndrome. Hum Gtmtl 1979; 47j 141-50, 12. Pope FM. Martin GR, Lichtenstein JR, et al. Patients with Ehlers-Danloa syndrome type IV tack type III collagen Proc Nqi( Acad Set U$A 1975;7?i 1314-16. 13. Pope FM, Martin GR, McKusick VA. Inheritance ofEhlers-Danlos type IV syndrome JMtdGtntt 1977, 14; 200-04, 14 Aumailley M, KnegT, Dessau W,M&ller PK.Timp) R, Brtcsud H. Biochemical and immunological studies of fibroblasts derived from a patient with Ehlers-Danlos Syndrome type IV Arch Dermatol Rtt I960; 2*9; 169-77 15 Byers PH, Holbrook KA, Barsh GS, Smith LT, Bornstein P. Altered secretion oftype III procolUgcn in a form ofrype IV Ehlers-Danlos syndrome: biochemical studies in Cultivated fibroblasts Lab Inrun 1981;44: 336-41 16. Holbrook KA, Byers PH. Ultrsstructural eharactemticsofihe skin in a form ofEhlers- Danlos syndrome type IV1 storage in the rough endoplasmic reticulum. Lab Inveu 1981,44: 342-50 17 Bornstein P, Sage H Structurally distinct collagen\ypp%, Annu Rfv Biothem 1980,49: 957-1014 18. Laemmh UK. Cleavage of structural ptottms during the assembly of the head of bacteriophage T4 Nature 1970, 227: 680-85, 19 Pope FM. Jones PM. IX'ells RS, Ijwrence D EDS IV (acrogena): new autosomal dominant and recessive types J Roy Sot Med 1980,73: 180-85 20 Pearl \X\ Spicer M F.hler-Danlos svndrome South Med J 1981,74: 80-82, 21 Bcighion P Obstetric aspects of the Ehlers-Danlos syndrome Hr J Obtirt Gvnattoi 1909,14: 97 -104 22 Stoddard FJ, Myrf i RE Connective tissue disorders m obstetrics and gynecology Am JObttfi GvHftc/ 1968. 102: 240-52 23 PyenizRF MaicrnalandletalcomplicationofpregnancyiniheMarfansyndrome Am J Mtd 1981,47: 785-90 24, Taylor D|. \X tlcux I, Russell JK Fhlers Danlos svndrome during pregnancy a case report and revif* of the literature Obutt GvntcoiSun-1961,2*: 277 Industrial Medicine GENETIC SUSCEPTIBILITY TO SCLERODERMA-LEKE SYNDROME INDUCED BY VINYL CHLORIDE C. M. Black K. I. Welsh A. E. Walker R. M . Bernstein L. J. Catoggio A. R. McGregor J. K. Lloyd Jones Wat Middlesex University Hospital, Isleworth, Middlesex; Royal National Hospitalfor Rheumatic Diseases, Bath; Tissue Typing Laboratory, Guy's Hospital, London; Department of Dermatology, Chesterfield Royal Hospital, Chesterfield; Hammersmith Hospital, Du Cane Road, London; and Department of Rheumatology, Harlow Wood Orthopaedic Hospital, Nr Mansfield, Nottinghamshire Summary Vinyl chloride (VC) monomer can induce a scleroderma-like syndrome in a proportion of workers exposed to it during production of golwinvl chloride. As part of a 5-year tollow-up study HLA A, B, and DR antigens and anti-centromere and anti-scleroderma-70 antibodies were determined in 44 such workers. 21 of these had severe and 23 mild forms of vinyl-chloride disease. 50 patients with "classical'' scleroderma and 148 healthy hospital workers acted as controls. 11 of the 21 patients classified as having severe VC disease were DR3 positive, and 8 of these had both B8 and DR3 antigens. None of the 23 patients with mild disease carried either antigen. The HLAfmrigen frequencies in VC disease mirrored those found in scleroderma (raised DR5 frequency and increased linkage disequilibrium between B8 and DR3). There were, however, significant differences in the frequency of autoantibodies in the two conditions. INTRODUCTION Vinyl chloride (VC) was first polymerised to polyvinyl chloride (PVC) in Germany in the 1930s, but it was many years before reports of liver changes1 and acro-osteolysis2 in workers involved in PVC production began to appear. These and many subsequent reports3 indicate that exposure to vinyl chloride can lead to a syndrome characterised by sclerotic changes in the skin, skin nodules, clubbing of the fingers, osteolysis, Raynaud's phenomenon, thrombocytopenia, portal fibrosis and impaired hepatic function, and pulmonary fibrosis. Excessive fatigue, muscle and joint pains, central nervous system symptoms, and impotence have also been described. Although only some workers who had been in contact with vinyl chloride developed symptoms, no studies on genetic markers in those affected have been reported. Vinyl-chloride disease is, however, clinically very similar to scleroderma, and the observations by ourselves and others that susceptibility to scleroderma is linked, albeit weakly, to HLA markers4'6 led us to study 44 of the 53 patients with symptoms of vinyl-chloride disease originally described by Ward et al.7 These patients are men who had developed either mild or severe forms of the disease after exposure to vinyl chloride. They were studied, as part ofa 5-year follow-up, for HLA-region allotypes, Gm allotypes, complement allotypes, and autoantibodies to centromere, Scl-70, and collagen subtypes. In addition we were able to determine the number of workers from the same factories who had been exposed to vinyl chloride but had no symptoms ofvinyl-chloride disease. ucc 060991 54 THE LANCET. |ANL'ARY 1/8. 1983 Of the data obtained on the VC-disease patients the HLA types and the anticentromere and anti-Scl-70 results are directly comparable to our previous findings in a study on patients with classical scleroderma.6 PATIENTS AND METHODS Patients 44 of the 53 patients with symptoms of VC disease originally described and classified by Ward et al.7 were available for this 5-year follow-up. The patients were divided into two groups. Group A consisted of 21 patients moderately or severely disabled with arthralgias, Raynaud's phenomenon (symptomatic or clinically observed), dyspnoea, and scleroderma-like skin lesions; 3 of these had radiological evidence of acro-osteolysis. Group B consisted of 23 mildly disabled patients who presented with miscellaneous symptoms that were not confirmed by visible abnormalities or overt clinical signs. These clinical findings are compared with the results obtained in 50 scleroderma patients (see table t). The most notable abnormality on serial lung-fimction tests was the reduction of diffusion capacity to below 70% ofnormaL HLA Typing All patients were typed for HLA A, B, and DR locus antigens with sera standardised against 8th histocompatibility workshop sera. Lymphocytes were prepared from 10 ml blood taken into an equal volume ofO'5% EDTA. Separation ofB and T cells and the HLA typing methods used have been described previously.9 The statistical significance of the HLA associations with VC disease were determined with the x2 test with Yates' correction. Multiplication of the p value by the number of DR antigens tested for was used to allow for the possibility that the difference in DR3 frequency between groups could have occurred by chance because of the number of observations made. This correction may not be necessary, however, because the DR3 difference is paralleled by the BS diflereuce, and these rwo antigens are in dose linkage disequilibrium. Such corrections need not be applied when previous studies have shown a similar association. It is a matter of debate whether or not VC disease and idiopathic scleroderma are similar enough to meet this criterion. A nti-centromere A ntibodies These were detected with an indirect immunofluorescence technique. The antibodies were observed as discrete granular immunofluorescence on the interphase nuclei, with characteristic localisation on mitotic figures.6 Scleroderma-70 Antibodies Antibody to nuclear antigen Sd-70 was detected by means of double immunodifliision in 0-4% agarose gel with a freshly prepared extract of rabbit thymus powder (Pel-freeze Biologicals Inc., Rogers A & K.) as the source of antigen.6 A prototype serum was provided by Prof. E. M. Tan. TABLE I--CLINICAL FEATURES (%) IN VC DISEASE AND SCLERODERMA Svmptom Diffuse scleroderma Raynaud's phenomenon Sclerodactyly Calcinosis Acroselcrosis Telangiectasia Digital pitting scars Arthralgia Arthritis Myalgia Abnormal lung function Total (n-44) 4-7 74-4 9-3 0 7-0 9-3 0 81-4 18-6 55-8 55-8 VC disease Group A Group B Scleroderma (n-2l) (n-23) (n-50) 9*5 85*7 19-0 0 14-3 19*0 0 95-2 28-6 66-7 95-2 0 60-9 0 0 0 0 0 65*2 8-7 43-5 19*1 32*0 96*0 94-0 50-0 72-0 60*0 80-0 72-0 30-0 26-0 46- 3 RESULTS 16(36'4%) ofthe 44 patients were DR5 positive, compared with 22 (14-9%) of the 148 controls. This difference is significant with p<0-05, and the. observation is an exact parallel of the finding that DR5 frequency is raised in scleroderma (table II). The frequency of DR3 in the VC-disease patients was less than that in the controls, but on further analysis we were surprised to find that the 11 VC-disease patients who were DR3 positive were all in group A--i.e., they had the more severe symptoms. Thus 11 of the 21 group-A patients were DR3 positive, compared with none ofthe 23 group-B patients (p=<0'001, corrected p value = 0'004). The group-A patients thus had raised DR 3 (table II), and both the group-A and the scleroderma patients had raised B8, DR3. Indeed the group-A patients were very similar to the scleroderma patients in terms ofHLA antigen frequencies. Apart from the B8, DR3, and DR5 there was also a raised frequency of B7 and a lowered frequency of DR2 in both disorders--a surprising observation, because these antigens, like BS and DR3, are in linkage disequilibrium. The frequencies of HLA Bw35 and DR1, which are raised in scleroderma, especially the CREST form (calcinosis, Raynaud's oesophagus, sclerodactyly, telangiectasia), were marginally lowered in VC disease. In scleroderma these antigens tended to be associated with autoantibodv production, and such antibodies were not observed in VC disease. ' y A No anti-centromere or anti-Scl-70 antibodies were found in any of the VC patients (table hi). Although these were not X looked for in the original study, only 3 of the 44 patients had changed groups in the 5 years before follow-up. These antibodies persist for many years in scleroderma patients. TABLE II--HLA antigen FREQUENCIES <%) IN VC DISEASE, SCLERODERMA, AND CONTROLS VC disease Antigen Controls Scleroderma Total (n- 148) (**-50) (n-44) Al B7 B8 DRl DR2 DR3 DR4 DR5 DR6 DR7 B8 and DR3 21-6 20*3 22-3 14-9 21-6 28*4 33-8 14*9 20-9 26-8 19*6$ 36-0 30-0 30-0 20-0 12-0 36-0 30-0 30-0* 20-0 14-0 32-0+ 27-3 25-0 18-2 18-2 22-7 25-0 25-0 36-4* 18-2 29*5 18-2 Group A (n* 21) 38-1 28-6 38*1 14-3 14-3 52-4 23-8 28-6 23-8 19*0 38*14: Group B (n-23) 17-4 21-7 0-0* 21-7 30-4 0-0+ 26-1 43-5 13-4 39* I 0*0 *p<0-05; -f*p<Q*Q01; ^p<0*01, for the delta values (i.e., B8 and DR3 are in greater linkage disequilibrium m the scleroderma patients and in the patients with severe VC diseases than in the control population). TABLE UI'-AUTOANTIBODIES IN VC DISEASE AND SCLERODERMA Disease VC disease Stkratcma CREST No. of patients 14 50 18 No. with anti-centromere antibodies D JL. 17 No. with anti-Scl-70 antibodies 17. 7 X \ DISCUSSION This is the first report on the frequency of genetic markers in patients with VC disease, but an increased association between antigens B8 and DR3 and an increased frequency of DR5 in scleroderma have already been described.4-6 The ucc 060992 THE LANCET,JANUARY 1/8,1983 55 patients typed in the present study also showed an increased association between B8 and DR3 and a significantly increased frequency of DR5. The VC group A and the scleroderma 'group are remarkably similar in terms of HLA-antigen | frequencies. There is therefore a striking similarity in both ; the clinical symptoms and in the HLA-region genetic tparkers in VC disease and scleroderma. Autoantibody responses, however, are totally different: itTnon'e of the VC- disease patients could we detect any evidence of either anti centromere or anti-ScI-70 antibodies. The anti-centromere result is significant, because such antibodies are generally found only in the CREST form ofscleroderma, and both the CREST form and VC disease are limited forms of scleroderma. Thus anti-centromere antibody is unlikely to be involved in any disease limitation process. VC disease is unusual in that (i) the causative agent is known; (ii) only some members ofthe population exposed to the agent develop the symptoms; and (iii) the total population exposed to the causative agent are numerically known, and documented medical histories are available for study. We know that approximately 150 people in the work population from which the patients came were exposed to VC and that symptoms later attributed to severe VC disease developed in 28 of these. A further 27 were classified as having mild symptoms ofVC disease. Ofthis total of 55,44 were available for follow-up--21 with severe and 23 with mild disease. Although increased awareness of the problems associated with acute exposure to vinyl chloride and better safety precautions have almost prevented new cases ofVC disease, the question of* what happens after chronic exposure to low levels remains to beAnswered. That U ofthe 21 patients classified as having severe disease were DR3 positive (8 ofthese were also B8 positive) is difficult to explain. Ifthe VC is more likely to affect B8, DR3 positive workers, then the frequency of the antigens in the mildly affected patient group should be also raised. In fact no-one in the latter group was either B8 or DR3, and the disparity in the frequency ofthese antigens is highly significant (p=0 0006, corrected p=0-004). The most likely explanation is that B8 and DR3 are associated not with the susceptibility to the disease but to its progression from mild symptoms to a more severe form. This is an important point, because it might apply to the group of autoimmune diseases which are B8-DR3-linked. In contrast DR5, which has a raised frequency in the whole patient group, might be associated with a susceptibility marker. The influence of genetic factors on the susceptibility to industrial or related chemicals has not been widely investigated. There are very close associations between susceptibility to some drug complications and HLA markers,'10 and a weak association has been reported between HLA markers and susceptibility to Kaplan's syndrome.11 We thank the stall of the tissue typing laboratory at Guy's Hospital for technical assistance and Dr P J. Maddison and Prof. M ]. V. Jayson for reading the script Correspondence should be addressed to: C M B., West Middlesex University Hospital, Isleworth, Middlesex TW`7 6AF REFERENCES 1 GauviinS Vinvl chloride proc Hflvbot MeJ 197ft; 27S-7? 2 C'ordlcrJM Finr? Ml, Sevrin A Acrp-ostcolvsts and exposure 10 vmvl chloride L'jh MeJ 7'rjrd/.' I 46fi, 4. 1-1-14 5 Lilis R, Anderson H Nicholson Wj, Daum S, Fist-hbcm AS, SchkofT Ij The prevalence ol disease among vmvl chloride and polwmvl chloride workers Ann NY Ae+fS;t 147V 241. 22-41 R(f(rt >ur< lOniinuiJat laot v) next cohoun Child Health AN APPEAL AND A PROGRAMME FROM UNICEF The obviously starving child is the extreme tip of the mountain of malnutrition. Most of the 40 000 children who die daily throughout the world succumb to infections superimposed on the seldom visible undernourishment caused by repeated bouts ofdiarrhoea. The 1982-83 report1 * * * 5 6 7 8 9 by UNICEF's executive director, James P. Gram, proffers four strategies by which to break the cycle ofmalnutrition and disease. In his estimate, the lives of 20 000 children a day could be saved by these relatively inexpensive measures. Oral rehydraiion therapy (ORT) permits the mother to make up her own oral rehydration solution (one teaspoonful of salt to eight tea spoonfuls of sugar per litre of boiled, cooled water) or to buy cheap packets of ready-made salts and administer the mixture in her own home to the child dehydrated by diarrhoea. The discovery that adding glucose to a salt solution increases the body's rate of absorption of fluid by 2500% has meant that dehydrated children seldom have to be treated intravenously by trained personnel--if such facilities even exist. In Narangwal, India, the dcatb-rate among young children has been halved by community workers using oral rehydration salts and penicillin. Grant writes: "The need for ORT is clear, the technology is known, the means of dissemination are available. The receptiveness ofparents has been demonstrated. The cost is small. And only an inexcusable lack of national and international will can now prevent the bringing ofits benefits to the vast majority of childien in need". The development of more stable and effective vaccines and the reduction in their cost has made the second plan ofmass initial and booster immunisation feasible. Measles, diphtheria, tetanus, whooping-cough, poliomyelitis, and tuberculosis account for about a third ofall child deaths. The malnourished child is susceptible to disease and disease provokes malnutrition. The third proposal is the promotion of breastfeeding. UNICEF sponsored a four-year study of over 10 000 newborn infants in a hospital in the Philippines. After two years, its director of paediatrics declared: "1 closed the door of the nursery to the milk companies. We stopped giving our babies the standard dose of infant formula. Down came the colourful posters and calendars. In their place, we hung the `baby-killer' posters which show an emaciated baby inside a dirty feeding bottle. Everything that was conducive to bottle feeding was removed not only from the nurseries but from everywhere else in the hospital. I myself rejected samples and donations from the milk companies". Over the next two years, the incidence of infection, diarrhoea, and death among the C. M BLACK AND OTHERS, REFERENCES--continued 4. Killenberj! CGM, Van der Voon-Beelen JM> D'Amaro J, The TH Scleroderma, increased frequency of B8/DR 3 in scleroderma and association ofthe haplotvpe with impaired eellular immune response, C/in Exp Immunol I 98 l, 43: 478-85 5 Gladman DD. Kcvsionc EC, Baron Murrav, Lee P, Cant D, Mervci H Increased frequency of DR5 in scleroderma Arthritis Upturn 1981; 24: 854-5ft 6 Black CM. Welsh KI Batchelor ]R. ct at HLA antigens in scleroderma Anhntis Rheum (in press) 7 Ward MA. Sopsamoru l'. W'atkins J, Walker Ai-.. Darke CS Immunological mechanisms m the pathogenesis of vtnvl chloride disease Br MeJ 7 1976; i 9 36- 38 8 Welsh KI Batchelor |R In WnrDM.ed Handbook of experimental iftimumtlop Ox lord Blackwell St-iennf,i. Publications 1478 chapter 35 9 W'onlcs PH Grittm A), Panaii t,S, Batchelor |R, Welsh KI, Gibson K, HI A UR antigens ami ioxicmv to sodium autnihinmallau jnd 1) peiiK it lam me m rheumatoid arthritis ShntlJ J 148U, 303. 100 JO Batchelor JK, Welsh KI, Tirtiwn RM, el jl H\drjlij7me-iriduu'd systemic lupus erythematosus influence ol Hl.A-DR and sex on suscepuhilny l.ancei 1980, t 1107-09 11. Rvder JP, Anderson h, Svcigaard A HLA and disease repisirv Tmur Antifeni J979, iuppl 20 UCC 060993