Document emNar3o5046GndxXvQopVRY0g

R&s 117000 Bessemer Road Welwyn Garden City Hertfordshire AL7 1 HO Telephone Welwyn Garden 23400 (STD Code 07073) Telex 264251 Fax Welwyn Garden 35556 (STD Code 07073) Dr T R Torkelson Health & Environmental Science 1803 Building Dow Chemical Midland Michigan 48640 USA Chemical Industries PLC Petrochemicals and Plastics Division Your ref pur ref ,, JS/SEN/DSO-16 Tel ext 16 Marcfite1983 Dear Ted GENETIC SUSCEPTIBILITY TO SCLERODEKMA-LIKE SYNDROME INDUCED BY VC You may have come across the paper in Lancet by Dr Ann Walker etc. This relates to Vinatex workers at the Staveley Factory now taken over by Norsk Hydro. I enclose a copy of the paper, January 1 1983, pages 53-55. Ann Walker likes to keep the pot boiling but I don't think she really manages to prove anything. However, Dr Brian Bennett who noticed the paper first, got our experts Dr Ted Davies in our Immunology Section and Geoff Paddle to comment. I know you like to have critiques on your file. You are welcome to have a copy of our critiques for what they are worth. With best wishes. Yours sincerely J Stafford Health & Environment Protection THE LANCET,JANUARY 1/8.1983 55 R&S 117001 pabeers typed in the proem study also showed an increased auditionbetween BS and DR3 and a significantly increased frequency of DR5. The VC group A and the scleroderma Child Health 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 markers in VC disease and scleroderma. Autoantibody responses, however, are totally different: in none of the VCdisease patients could we detect any evidence ofcither andcentromere or anti-Sd-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 and-centromere antibody is unlikely to be AN APPEAL AND A PROGRAMME FROM UNICEF THE obviously starving child is the extreme tip of the mountain ofmalnutrition. Most ofthe 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 by UNICEFs executive director, James P. Grant, profTers four strategies by which to break the cycle ofmalnutrition and disease, to his estimate, the lives of 20 000 children a day could be saved by these relatively inexpensive measures. 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, arid documented medical histories are available for study. We know that approximately 150 people in the work population Oral rehydratiatt therapy (ORT) permits the mother to make up her own oral rehydration solution (one teaspoonful of salt to eight teaspoonfuls of sugar per litre of boiled, cooled water) or to buy cheap packets of ready-made salts and administer the mixture in her hum which the patients came were exposed to VC and that symptoms later attributed to severe VC disease developed ih 28 of these. A further 27 were classified as having mild symptoms ofVC disease. Ofthis total of55,44 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 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 Narsngwal, India, the death-rate among young children has been halved by community workers using oral rchydration salts and penicillin. Grant writes: "The need for ORT is clear, the technology is known, the means ofdissemination are available. The receptiveness ofparents has been demonstrated. The levels remains to be answered. That 11 ofthe21 patients classified as having severe disease were t)R3 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 Do-one in the latter group was cither 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 .cost is small. And only an inexcusable lack of nativ ..al and international will can nowfrevent the bringing ofits benefits to the vast majority ofchildren in need''. The development of more subie and effective vaccines and the reduction in their cost has made (he second plan ofmast initialand boater 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 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 BS-DR3-linked. In contrast DR5, which has a raised frequency in the whole patient group, might be associated with a susceptibility easier. The influence ofgenetic factors on the susceptibility to industrial or related chemicals has not been widely 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: "I 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 tobottle feeding was removed not only from the nurseries but from everywhere else in the hospital. 1 myselfrejected samples and donations from the milk companies". Over the next two years, investigated. There arc very close associations between the incidence of infection, diarrhoea, and death among the susceptibility to some drug complications and HLA markers,*-*10415a1n* d7 8a* weak association has been reported between HLA markers and susceptibility to Kaplan's C. M. BLACK AST) OTHERS. REFERENCES--continued syndrome." 4. Kallcnters CGM, Via 4a Voon-Backa JM. D'Aman J, Tbt TH. Scleredema, HKHiMlfN^acyorBt/DRjiAKttnxknMiDdiMooniQflArilMhiploiypr *nb Xt thank the naff cf the tiaait tvpw* laboratory at Guy'a Hcspiul for impaired evlhihr muntioc respooac. Chm E*f Immurni 1981,43; *7<~85 i uiatiDCe and Dr P. J. Maddooa and Prof. M. I. V. Jitiod for radtac the acript. Carrcapoodencc should be addicted nx C M. B.( West MMdlocx Umnuy Hospital, Hlrwonb, Middlne* TW7 OAF. 5. GUdmao DD, Krywooc EC. Baron Murray, Lee P, Cane 0, Mcrvci H Increased frequency ^DR5 ia urkroderma. Anknni 1981; 84: 8S4-+56. 8. BUcfc CM, Veto Kl. Batchelor JR, ct aL HLA annftaa in ackrodrnna Ankn/n (in preoj 7. Wtrtf MA, Sefamon U, Watkins J, V'alkr AE, Dirt* CS- Immuiwlorial ib the paihofcpcu* otviajl chhnde diKJK OrMtdJ 1978, i: 9 J4- 78 REFERENCES 8. Wcfeb Kl, Batchelor JR, In* Tf DM, ed. Handbook de*pefimenial immunology Oxford: Blackwell Scientific Publication*, 1978 chapter 1). > G--wan S Vfl Aknk fmt Xay-W AW l9T8j*i 275-T7. 1 Cw4ct JM. Firm Mj. Stu A Aot)oryiiiittdttpaoiiutoimy1chhrufa.Gdl f Wooley PH. Gn/Hs AJ, Panayi G$ Batchelor JR, ftbJi Kl. Gibton TG, HLA-DR uufeu and imty to odium aurmluoiMllrir and D-pcatctlUmiftc in ibnnuiMi AW Tiwmd 1986, ii 14-19. anbrim. H AW 1910. MS; )00. X Lio R. Aadcnoa H, KicMou Do* S. F*chheio AS, SeliWT Q. The 10. Rotclttlor JR, Wekh Kl. Tisoco RM, ft 1. HydriJliitnc*tnduccd ayttefluc lupi* |i mlnrr nfiliiinrw nug; A^Sa 197% 248* ZJ-4I. ----- J*r~tj~i~jTrMnrii1i mint .> iffl* tfythabaiaAo. ififtnnwT of HLA-DR amd m oo pacrpubihly. Lmmut 191^ c 1107-09. I 11, Ryder Jp flilriom E, Snipard A, HLAaad di*ra*c rt^utry. Tn***A*ngm 1979, Rifrrnvcs &mmmd Jf /f mf nat cobntm auppL JO- t 54 THE LANCETJANUARY I /8,198 3 Of the data obtained on the VC-disease patients the HLA types and the anticentromere and anri-Scl-70 results are directly comparable to our previous findings in a study on patients with classical scleroderma.* Patients PATIENTS AND METHODS 44 of the 53 patients with symptoms of VC disease originally described and classified by Ward et al.7 were available for ih.'t 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-tike skin lesions; 3 of these had radiological evidence of acro-ostcohsis. 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-function tests was the reduction of diffusion capacity to below 70% ofcotmaL HLA Typing All patients were typed for HLA A, B, and DR locus antigens with sera standardised against 8th histocompatibility workshop seta. Lymphocytes were prepared from 10 ml blood taken into an equal volume of0-5% EDTA. Separation ofB and T cells and the HLA typing methods used have been described previously.* The statistical significance of the HLA associations with VC disease were determined with the y1 test with Yates' correction. Multiplication ofthe p value by the number ofDR antigens tested for was used to allow for the possibility that the difference in DR3 frequency between groups could have occurred by chance because oj" the number of observations made. This correction may not be necessary, however, because the DR3 difference is paralleled by the B8 difference, and these two antigens are in close 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 ate similar enough to meet this criterion. Anti-centromere Antibodies These were detected with an indirect immunofluorescence technique. The antibodies were observed ss discrete granular immunofluorescence on the interpbase nuclei, with characteristic localisation on mitotic figures.* Scleroderma-70 Antibodies Antibody to nuclear antigen Sel-70 waa detected by means of double imnaucdifluiion in 0-4% agarose gel with a freshly prepartd tirract of rabbit thymus powder (Pel-frtvm BioiogicaJa Inc., Rogers A & K) as the source of antigen.* A prototype scrum was provided by Prof. E. M. Tin. TABLE I-CUN1CAL FEATURES (W) IN VC DISEASE AND SCLEROO-WA . VCdacHc Symptom Tout Croup A Group 6 Skbrakfou (rt-44) (n-2I) (n - 2 J) <o-W) Di/Tusc ftcttfoder^B 4-7 9-J 0 J2 0 Rjyiuud'i phenomenon 74-4 8J-7 60-9 960 Sricrotfaetyfy 9-J 19 0 0 *4-0 OlCUlOBl* 0 0 0 so 0 Acrmclcrm 7-0 14-J 0 72 0 Tcbnficcuii* 9-J 190 0 40-0 Digital pittas euv 0 0 0 80-0 Antmtpa 81-4 9J-I 6J-2 720 Arthritis 16*6 28-8 8-7 JO-O Myalgia JJ-8 66-7 4J-J 260 Abnormal luof frocuon 55-8 9J-2 19-1 46-3 RESULTS 16 (36 *4%) ofthc 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 n). The frequency ofDR3 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 II 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 DR3 (table 11), 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 B8 and DR3, are in linkage disequilibrium. The frequencies ofHLA Bw35 and DR1, which arc 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 autoantibody production, and such antibodies were not observed in VC disease. No anti-centromere or anti-ScI-70 antibodies were found in any of the VC patients (tabic til). Although these were not looked for in the original study, only 3 ofthe 44 patients had changed groups in the 5 years before follow-up. These antibodies persist for many years in scleroderma patients. TABLE It--HLA ANTIGEN FREQUENCIES <Wl IN VC DISEASE. SCLERODERMA. ANO CONTROLS VC<tiK**e Aoiifcn Control* Sclcrodenru Tout (n-146) (n-W) (0*44) Group A Group 3 (o-il) At B7 B8 DRl DR2 DRl DR4 DRS DR* DR7 gStcJDRl 21-6 20*1 22-1 14-9 21-6 28-4 111 14-4 24-8 HH M-0 -0 10*0 JO-O no M-0 19*4 MO* M-0 14 0 ua# 27-1 no 16-2 t*2 22-7 21-0 ** M-9* i* 2* 8 MJ hi M-* *! 14*1 (4-1 0-4 IS a* IS 8 |O-0 M *8 17 4 11 1 44* hi SO 4 n mt 44 % * Wi pCOOS. fyCO-OOI. *iK0 01. IW <* *N A. ffrmlwt 11 **--*" iwvmmJ - *" with mr* VC ttu. * ik>fon>>W fT'l**,l TABLE m-ACTOAXTlROOlO IN VC OtSCAaf ANtl *tt *-.** *** Daw* VCrfisMt Scferodcnzu CREST No. ef potnv* 44 w 18 No. m uHKnrMMfr OfltodHt 0 16 IT S* W ***)*! 0 17 7 DISCUSSION This is the first report on the frequency ofgenetic markers in patients with VC disease, but an increased association berween antigens B8 and DR3 and an increased frequency of DR5 in scleroderma have already been described.4'* The R&S 117002 /V- ` R&S 117003 thelancet.jastaRY 1/8,1983 t. 53 complications sfio 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 experiatet ofpatients in our group there does not appear to be a mode which has fewer complications. We suggest that all pancuts should be carefully monitored during labour and for several days post pamun 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 npt to be expected in patients with other forms of EDS.14 Wc think Dr John Bet, ChiefMedical Examiner, Province ofAlbert*, for hit cooperation in tone eeUccxion for dtagnottic trodiet; Miry Hoff and Karen David for exeelirt technical i&imance; and Marion Brown and Diane Dawson for preparing manuaciipt. This study was supported in part by fundi from the Albert* Children'* Foundation and gtantifrothe UJ>. Public Health Service (AM 21577, GM 07266), the March of Dunn 3uth Defect* Foundation (6-296), cd the Foncia Scholarship Fund. P, H. B. is an Established Invcsiigzer a the American Heart Association* Correspondence ibonld be addressed to P, H. B., Department ofPathology SM-301 University of ^Tniujgtoo, Seattle WA 98197. VSA. references I. ttipiM F. The EUrvDcm lyndrwm. I amkw. Hninwi, 1970 2 MeKu*ickVA-Hcriubfccr4avofaBtiaccifvtiitoi*,4ifc4.SL0uii'MaabylIf72. 1. Hottutw DW. (farttaftfc aordwt of reaacaire liaue: EWtnDiAlsi tv*dfoia/ r*d+t* ChmtfAm 1971. ; 575-91. I. 4 Piontli $R. DiMtem aCifn la: StutiuiyJl, 1 ppmia |St Fr(4itkiM DS. d. Th* sMUbnltf ima of inherited diksst Kr* Vurk. McGrvw-HiU, |970: t >66-94. 5 Bomnctn P, Bjtn PH DnrdtnTalh|a mctibolum. la. Booty PK, RoKntag LE, c^. MtuboiawiiiMtiHiiK, 0th cd. Philadclpho: 9TB Saunders, 1900: 10*9-1155. 6 Hollmo DV, Bym PlL flolbraek RA Genetic diw4n oi aUipa tneutalum, A* Hum Gn* 19*2.12: l-*7. 7. Bters PH. lnhcmed dsrtci ofcella*eft bAptboir FMm TVinlni gyBdrome, the Marfan yntfiotnc nd wceafcnroa upperfetta. la Spinel JA. cd. QiajcaJ mediciiK. . Philadelphia: JB Uyattn (in proa). S B^oi PH, Banh GS. Hah uni KA. Mukntu inertuftMiff d mninniiT un * iboormalima in the DuereDaaloa ejnidioae. Co/fa/m At/JUi 19*1, |: 475-19, 9.Vbd Mcekeren JA. Dt i*ubi)itte cetnordinvu cmn. In: Ofcvcrvtfioai tftedkiiochiAigioe,Qap J2,AmatcrdaiB,l6*2.CtedinMcRwa<kVA Heritable diwiden ofeeinarruu in. 4th cd. St Loan: Motby, 1772. 10. Bacvbts AP. VumW ft ia amiii ia Ehkre-Daaloa lyndmc. ] fifrfum Sxtj 1972; 12: 1*0. 11. Byers PH, Holbrook KA, McGiHimf B, MacLeod PM, Uvr| KB. QokiI and elitumctvnl bae^oo^ ft]fpt IV blrrDuIa ijsdnae,1/m <7; 141-50. 1979; 12. Pope FM, Mnv OL LehaMaa )K, ci aL Pitieim with EUnvDiahi tyodrooe type IV lack type Ql ahea. NotlAmASti USA 1775; 72:1314--)*. I). Pape FM, Martin GR, MJn4 VA InhcmaftceofEikrvDralo* fjjx fV syndrome. J Mad Gam 1977; 14; 2UM34. 14. Aumailley M, KricfT. Dotro W, MOJtei PK*Tnpl R, Bncaud H iicchcBucal and' UBiBundopal amin kbrofelaui derived 6om potseat with EhkrvDaiiia* syndrome type IV. A*t* DmnaiWJtei 1900; 211: J*P-77. HBytn PH, Holbrook KA Bed GS, Smith LT, Bomucui P, Altered Mcretwo of ryf* 111 prerolbf*n a fors sf*yp* IV EhtavDintoa tyndrooc. hwjitmnil nudm ia euhivmedftbrohiMa Luhom 19B);44:5M-41. I* HoAnokKAtByoiTH. r^rnnuyunlcbinacnaiaaftbtiLBOihmdTlilttv Dialoi syndrom* type JV norqp ia the roufft radapliamjr ra^Jea. Lsk /m 1M1; 4*: 542-50. 17 Benroem F, S**e H. Senmf^ty dmma<olU*q typm.^w *re 19*0,41: 957-1014. I* Uaab UR. Hrmp U merer*) proenae dunnf the mratty d the of bocieroptuft T*. ifTO; 227: *00-43. 19. Pope FM, JtOo PM, Beh RS, Livnott D. EDS IV (soogrnal ar* air----mil dominant and irn -- n yjn J Moy Sot MU 1900; 75: 100-03 20 Pearl W, Spkcr M. Cfafe-Dftataa lyndmaM. Somt* MU] 19*1,74.- *0- 42. 21. Bci*hign P. Obnonc fin U the Ehkra-Danlm syndraoK 4r ] 06*m GymmuM 19*9,7*: 97-104 22. SiodtedF7*Mycs*R Ctntn iwe umie dawden ui ohnemes oU *ypm>ka*j Am ] Ottm Gyved 1944. U& 240-52. 23. ** 1 n--plniiinnTifiTTHfii^niiks Mtrfm syinlrmaf In J MM 1941; 47: 743-90 24. Ttyte DJ, Rikm L Kmd 0L bkn Dankn lysdw dnrmf |WT[majr a case repwt and review U** Mmn. 0*a*o GymmU Son 19*1,54 277, Industrial Medicine GENETIC SUSCEPTIBIUTV TO SCLERODERMA-LIKE 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 West Middlesex University Hospital, Islewarih, Middlesex; Royal National HospitalJar Rheumatic Diseases, Bath; Tissue Typing Laboratory, Guy's Hospital, London; Department oj Dermatology, ChesterfieldRoydl Hospital, Chesterfield; Hammersmith Hospital, Du Cane Road, London; and Department of Rheumatology, Harlot? 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 polyvinyl chloride. As pan ofa 5-year follow-up study HLA A, B, and DR antigens and anti-centromere and anti-scleroderma-70 antibodies were determined in 44 such workers. 21 of theje 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 HLA- antigen 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 (PVQ in Germany in the 1930s, but it was many years before reports of liver changes' and acro-osteolysis2 in workers involved in PVC production began to appear. These and many subsequent reports' 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 unpaired 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 afTected 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 markers4-4 led us to study 44 of the 53 patients w ith symptoms of vinyl-chloride disease originally described by Ward ct al.7 These patients are men who had developed either mild or severe forms of the disease after exposure to vinyl chloride. They were snidied, as pan ofa 5-ycar 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 ofworkers from the same factories who had been exposed to vinyl chloride but had no symptoms ofvinyl-chloride disease. ; UL 1"