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"TO* flUT- VinVi. rtii-pgjjVjT Systemic Sclerosis Secondary to Occupational Exposure GREGORY R. Owens, M.O., Thomas A. MEDSGER, M.o. Pittsburgh, Pennsylvania rECETWED Systemic sclerosis is a multisystem disease charac autoantibodies were absent (anti-<^QtQfl&JL,NE2/ti*iSKY terized by widespread flbrotic and degenerative SC1-70, and anti-PM-SCl). The results of other sero changes in the skin, vasculature, and internal organslogic studies, including anti-SM, anti-RNP, and rheu [1], Pulmonary involvement, including either pulmo matoid factor, were negative.; A chest radiograph nary fibrosis [2] or pulmonary arterial hypertension revealed interstitial changes in all lung fields consis due to vascular obliteration (3], is commonly seen in tent with pulmonary fibrosis. Pulmonary function patients with this disorder. The etiology of systemic tests showed a forced vital capacity of 3.09 liters (61 sclerosis is unknown. A number of occupational and percent of predicted), a total lung capacity of 4.36 other exposures have been implicated as potential liters (64 percent of predicted), and a single-breath causes of systemic sclerosis or closely related condi diffusing capacity for carbon monoxide of 4.0 ml/min tions, including silica dust [4], epoxy resins [5], rape- ute/mm Hg (14 percent of predicted). Arterial desatu seed oil [6], carbidopa [7], bleomycin [8], and benzene ration from 92 to 78 percent occurred with minimal [9]. We report herein the case histories of two chemical exercise. An open lung biopsy procedure revealed pul workers exposed to meta-phenylenediamine in the monary fibrosis with minimal inflammation. No ab same building in whom systemic sclerosis subsequent normality of the pulmonary vasculature was noted. ly developed. Therapy with prednisone 60 mg/day, D-penicilla- mine 250 mg/day, and nasal oxygen at 2 litem/minute CASE REPORTS was started. The patient noted an improvement in Patient 1 respiratory symptoms, but two months later as the This 39-year-old man worked in a restaurant and in corticosteroid dose was decreased to 35 mg/day, short the shipping department of a rayon manufacturing ness of breath worsened and the partial pressure of company. Since 1981, he had been employed as a oxygen at this time was 48 mm Hg. High-dose predni chemical operator in Building 156 in a large chemical sone therapy was re-instituted with symptomatic im company in the Charleston, West Virginia, area where provement he unloaded and transferred chemicals. During Au gust 1981, he had worked primarily with meta-phenyl- Patient 2 enediamine and had been involved in three accidental This 58-year-old man had worked his entire adult spills with this chemical. In October 1983, Raynaud's life for the same large chemical corporation in the phenomenon, swelling of the hands, and hyperpig Charleston, West Virginia, area as did Patient 1. From mentation of his hands and forearms developed. Fol 1944 to 1948, he worked as a laborer, primarily clean lowing another chemical accident in January 1984, in ing pipes containing vinyl chloride. From 1948 to 1977, which he was exposed to fumes of meta-phenylenedi he worked as a chemical operator. During this time, he amine, he experienced the sudden onset of a produc was exposed to a variety of chemical compounds, pri tive cough, fatigue, and shortness of breath. He was marily of the amine class, and specifically meta-phe unsuccessfully treated with bronchodilators and anti nylenediamine. He worked as a supervisor in Building biotics and was referred to our institution. Physical 156 from 1977 to 1981, where he was exposed to the examination revealed normal vital signs, with the ex same amines and, in addition, silicon tetrachloride. He ception of a respiratory rate of 22/minute. Results of retired in 1981 because of health problems. examination of the ears, nose, and throat were normal. In January 1980, reflux esophagitis with heartburn Evaluation of the lungs showed a few bibasilar rales. developed, followed one month later by diffuse swell Results of cardiac ana abdominal examinations were ing and redness of both hands. In August 1980, he normal. Periungual erythema and puffy fingers bila noted the onset of Raynaud's phenomenon, shortness terally were present, as were mild skin thickening and of breath, and pedal edema and was treated with furo- hyperpigmentation of the fingers and dorsum of the semide. Bradycardia was detected, and an electrocar forearms. diogram revealed complete heart block. A pacemaker Laboratory evaluation revealed a normal blood cell was inserted. count, and the erythrocyte sedimentation rate was 7 His condition remained clinically stable until 1983, mm/hour. Levels of electrolytes and creatinine were when shortness of breath worsened such that he could normal, as were the results of liver function tests. An walk only one block without stopping. In addition, he antinuclear antibody was positive at 1:100 with a ho reported the development of a chronic cough produc mogeneous pattern, but all scleroderma-selective tive ofscanty amounts of white sputum. He was hospi talized twice in 1983 for pneumonia. In 1984, he was treated with prednisone and a theophylline com From the Divuioos at Pulmonary Medicine and Rheumatology and Oimcal pound. He denied chest pain or paroxysmal nocturnal Immunology, Department of Medicine. University of Pittsburgh. Pittsburgh. Pennsylvania. Requests for reprints should be addressed to Dr. Gregory R. Owens. University of Pittsburgh, School of Medicine. Division of Pulmonary Medicine. 440 Scaife Hall, 3550 Terrace Street. Pittsburgh. Pennsylvania 15261. Manuscript submitted January IS. 1988. and accepted m revised form April 1.1988. dyspnea. Physical examination in 1984 revealed normal vital signs. Examination of the head, eyes, ears, nose, and throat was significant only for telangiectasia of the left cheek and bridge of the nose. The lungs revealed biba- 114 July 1988 The American Journal of Medicine Volume 85 ucc 060791 SYSTEMIC SCLEROSIS / OWENS MID MEDSGER silar dry rales. Results of examination of the heart and abdomen were normal. The extremities showed sclerodactyly, telangiectasia over the fingers, and diffuse hyperpigmentation. Laboratory evaluation revealed a normal complete blood cell count, and the erythrocyte sedimentation rate was 6 mm/hour. Electrolyte and serum creatinine levels were normal. Serologic studies, including anti nuclear antibody, extractable nuclear antigen, rheu matoid factor, anti-centromere, anti-SCl-70, anti-SM, and anti-RNP, were all negative. The chest radiograph showed bibasilar interstitial markings consistent with pulmonary fibrosis, and an esophagTam revealed a mild dilation of the esophagus with gastroesophageal reflux. The electrocardiogram showed complete heart block with a paced rhythm of 70 beats/minute. Pulmo nary function tests revealed a forced vital capacity of 4.37 liters (86 percent of predicted) and a single breath carbon monoxide diffusing capacity of 10.7 ml/ minute/mm Hg (40 percent of predicted). Arterial blood gases showed a pH of 7.46, a partial carbon diox ide pressure of 37 mm Hg, and a partial pressure of oxygen of 75 mm Hg. He was treated with D-penicillamine 500 mg and prednisone 10 mg daily. The patient was seen in follow-up two years later, at which time there was no change in his symptoms, pulmonary function, or arterial blood gases. COMMENTS Systemic sclerosis is a disease of multiple organ sys tems that occurs primarily in women and that has an incidence of up to 12 cases per million population per year [10]. Although there is no clear reason for the development of the disease in the majority of patients, exposure to certain chemical agents may be associated with its occurrence. Workers who are exposed to siliceous dusts are pre disposed to the development of systemic sclerosis. A variety of reports have documented an unusually high prevalence of systemic sclerosis in underground gold miners [11], sand blasters [12], and workers in potter ies and foundries [13]. The risk of the development of systemic sclerosis was estimated to be increased 17fold in gold miners from South Africa [11] and in creased 110-fold among German underground coal miners [14]. Systemic sclerosis most commonly devel oped in motormen in the mines who were exposed to the highest concentrations of respirable silica [4]. Another circumstance followed by the development of scleroderma after a delay of five to more than 20 years is the injection of foreign substances, usually silicone or paraffin, almost exclusively for breast aug mentation [15]. This association has been noted al most exclusively from Japan. Other evidence for an association between chemical agents and scleroderma comes from the epidemic of "toxic oil syndrome" in Spain in 1981 [6]. This epi demic occurred after the ingestion of adulterated cooking oil, rape seed oil. After an acute illness, the victims experienced the development of skin changes reminiscent of scleroderma and sometimes more typi cal of eosinophilic fasciitis, as well as neuropathies, the sicca syndrome, and pulmonary and esophageal dys function. Exposure to vinyl chloride by inhalation or transcutaneously has also been documented to produce a scle roderma-like disease. In one study, skin changes indis tinguishable from scleroderma developed in 10 of 200 workers who produced vinyl chloride [16]. However, a number of clinical features suggested that the result ing condition was not typical systemic sclerosis. The skin lesions that were noted tended to be nodular. Clubbing and radiographic evidence of lysis of the dis tal phalanx and erosive sacroiliitis occurred, and he patic fibrosis was evident. A genetic susceptibility to this condition has been suspected [18]. Yamakage tt al [5] described a scleroderma-like dis order occurring in men engaged in the polymerization of epoxy resins. This disease occurred after only short term exposure and with a relatively high incidence (six of 233 workers). The authors suggested that a biogenic amine, bis(4 amino-3-methyl-cyclohexyl) methane, was the causative agent. Neither of the two workers whose case histories were provided had evidence of pulmonary involvement The same authors also de scribed an association between the development of generalized morphea and exposure to organic solvents [19]. Although these subjects were not studied pro spectively for internal organ involvement the major ity of the patients had either esophageal dysfunction or pulmonary fibrosis, suggesting a systemic rather than an isolated cutaneous process. The development of other pseudo-sclerodermatous states has been described in persons with elevated lev els of the amine serotonin (L-5-hydroxytryptophan). Both endogenous increases, as seen in the carcinoid syndrome [20], and treatment with exogenous seroto nin for intention myoclonus [7] have been associated with the development of a scleroderma-like syndrome. The most pertinent case reports in the literature relate to the development of scleroderma in persons exposed to aliphatic and aromatic hydrocarbon sol vents [19,21-26], Numerous instances of systemic scle rosis following occupational exposure to trichlorethylene [21--23] or perchlorethylene [24] have been described. Exposure to benzene, an aromatic hydro carbon, may be followed by disease that tends to be limited to the hands and feet rather than becoming a multisystem disorder [9,25]. Methylene chloride, pre sent in many paint removers, may cause acute pneu monitis [26], a circumstance similar to the disease pre sent in our patients. There are several reasons to believe that the devel opment of systemic sclerosis in the two workers re ported in this study is more than coincidental. First, only 20 other men were employed during the time spent in Building 156 by the two workers. Likewise, the onset and explosive progression of disease shortly after several documented chemical accidents in Pa tient 1 reinforces the likelihood of a relationship of disease to the workplace. An epidemiologic survey of the facility would provide a definitive answer to the association of the workplace and the onset of disease. However, it has not been possible to carry out such an evaluation. Elucidating a specific causative exposure in these two patients is more difficult One patient had been exposed to vinyl chloride, a known cause of a sclero derma-like syndrome, in the past Because of the pro longed delay between the vinyl chloride exposure and the onset of scleroderma, we believe this agent was not a causative one. Likewise, both patients were intermit tently exposed to silicon tetrachloride, which yields hydrochloric acid and free silica upon chemical break- July 1988 The American Journal o( Medrane Volume 85 119 UCC - SV8TCHIC SCLEROSIS / OWEHS AND MEDSGER down. It is possible that the disease described herein was precipitated by an unusual type of exposure to silica, but this seems unlikely. The most attractive potential causative agent is meta-phenylenediamine. In the company facilities, this agent was used most commonly in Building 156. Second, Patient I was sub jected to heavy exposure several times shortly before the development of an explosive syndrome, which in cluded lung involvement. Finally, as detailed earlier, other biogenic amines have been implicated in the development of scleroderma-like illnesses. Although chemically induced systemic sclerosis may account for only a small fraction of scleroderma cases, the recognition of specific causative agents may ulti mately lead to an improved understanding of the mechanism of disease induction, including vascular, immunologic, and fibroproliferative events, and possi bly to the development of rational therapy. REFERENCES 1. Medsger T: Systemic sclerosis (scleroderma), eosinophilic taseitis and catanous In: McCarty QJ Jr. d. Arthritis and abed conditions, 9th ed. Philadelphia: Laa and Febiger. 1985: 996-1034. 2. Owens 6, Fino G, Herbert 0, ef af. Pulmonary function in progressive systemic sclerosis: comparison of CREST syndrom* variant with diffuM scleroderma. Chast 1983: 84: $46-550. 3.5tupi A Steen V, Owens G. BamesL Rodnan G, Medager T. Pumonary hyper tension in the CREST syndrome variant of systemic sclerosis. Arthritis Rlsium 1986: 39 515-524. 4. Rodnan G, Benedek T. Medager T. Cammarata R: The association of progressive systemic sclerous (scleroderma) with coal meters' pneumoconiosis and other forma of silicosis. Ann Intern Med 1967; 66: 323-334. 5. Yamak^e A, Ishikawa H. Sarto Y. Hatton A Occupational sderodermakka disorder occurring n men engaged in the polymenzatian of epoxy resets. Dermato- logica 1980: 161: 33-40. S.Alonzo-Ruz A Zea-Mendoza A. Satazar-VaHnas J. Rocamore-Ripol A Tone od syndrome: a syndrome with features overlapping those of various forma of sclero derma. Semin Arthntis Rheum 1986; 15: 200-212. 7. Sternberg E. Van Woent M. Young S. at af: Development of a sderodorma-Ske illness during therapy with L-5-hydroxytryptophan and carbidopa. N Engl J Med 1980: 303: 782-787. 8. Fetch W, Rodnan G, Buckingham R. Prince R. Yknketsteei A Beomycet induced scleroderma. J Rhtunatd I960: 7- 651-659. ICanak L Szegedi G: Benzene exposure and systems sderosis (letter). Ann Intern Med 1987: 107: 118. 10. Medsger T: Epidemiology of prowassive systemic sclerosis. Can Rheum Os 1979; 5: 15-25. 1L Erasmus L Scleroderma in gold mere ei the tMtwatervand with particular reference to pulmonary manifestations- S Afr J Lab Oei Med 1957; 3: 209-231. 12. Ztskmd M, Wed H. Anderson A Sameti 8, Netison A Waggenpack C: SKieous m shipyard sandbiastars. Environ Res 1976: 2: 237-243. 13. ParV.es WR: Oeciatianal kxtg disorders. 2nd ed. London: Butterworths. 1982; 157. 1A Haustem U. Ziegler V, Zschunke E. Munzberger H. hopping H: Progressive systemic sderosis with silicosis m the German Democratic Republic. In: Black C. Myers A eds. Systemic sdermis (scleroderma). New York: Gower Medical Pub lishing. 198$; 138-141. 15. Kumagai Y. Shiokawa Y. Medsger T. Rodnan G: Clocal spectrum of connective tissue disease after cosmetic surgery Observations on 18 patients and a review of the Japanese iterative. Arthntis Rheivn 1984: 27: 1-12. IS. Langauer-Lewewicka H. Kurabauer H, Byczkowska Z. Wocka-Martk T: Vinyl chioridt dbeasa: neivok)0cal daturhances. kit Arch Occup Environ Haatthl983: 52: 151-157. . 17. veltman G. Lange C. Juhe S. Stein G, Bachner V: Clinical mandestahons and corn# of vinyl chloride disease. Am NY Acad So 1975: 246: 6-17. 18. Stock C, Perak* S, McMMrtar A. VMNh K, Laurant lb Genetic susceptibility to sderodannaatt syndrome in symptomatic and asymptomatic workers exposed to vinyl Chloride. J Rheumatol 1966:13:1059-1082. IB. Yamakate A Ishikawa H: Ganaraized morpheakke Sderoderma occurring m people exposed to organic solvents. DermatologKl 1982; 165: 186-193. 20. Fries J. Undpan J. Bui J: Scleroderma-ike lesions and the carcinoid syn drome. Arch Intern Med 1973:131: 550-553. 21.SaihanE. Burton J. Keaton It A new syndrome with pipnentahon. scleroder ma. gynaacomasba, Raynaud's phenomenon, and pviftaral neuropathy. Br J Dermatol 1978: 437-440, 22. Findt-Hansan H. Hager H: Sderoderma after octupatxxial exposure to tnehlorethytene and trichlorethane. Acta Oerm Venarool (Stockh) 1987; 67.263-264. 23. LocVay J, Kaly C, Cannon G. Cofcy T. Aldrich V. Lwrtgston G: Progressive systemic sderosis associated with exposiae to tricMoroethytene. J Occup Med 1987: 29 493-496. 2A Sparrow G: A connective tissue dsorder sknlar to vinyl chloride disease in a patient exposed to porcNorethylene. On Derm 1977: 2: 17-22. 25. Welder B: Do solvents cause scleroderma? kit J Dermatol 1983:22:157-158. 26. Buie S, Pratt D, May J: Diffuse pulmonary injury Mowing pant remover expo sure. Am J Med 1986: 81: 702-704. 116 July 1988 The American Journal of Medicine Volume 85 ucc 060793 Mffteaotk 3qnm DntCM July 7, 19S5 John L. McClaugherty, Attorney at Law Jackson, Kelly, Holt & O'Farrell 1600 Laidley Tower ?. 0. 3ox 553 Charleston, Vest Virginia 25322 Re: Sherman L. Handley Claim No. 84-49760 Dear Mr. McClaugherty: I saw this patient on 3-6-84 at the request :: hij pulmonary disease specialist. Dr. Patel. He gave a his rv that in October of 1983 he had developed swelling ri hi nar.es quite suddenly and he also noticed that his fingers bee e purple in the cold. He said he had been working at low temperatures of minus 5 degrees Farenheit and caught a cold and cough. On January 23rd he became dyspneic on exertion and could not climb a flight of stairs. He was seen by physicians and given antibiotics, then he was admitted to the hospital and was seen by Dr. Patel who found a pulmonary infiltrate and suspected scleroderma with pulmonary involvement. ' At this time he was very breathless even on walking into the living room; the skin of his hands had become tight; weight had decreased 7 pounds in the hospital; and he had developed indigestion on medications and severe heartburn. While he denied dysphagia, he said he was now unable to drink quickly. He said he was told he had a hiatus hernia. His fingertips were numb. He said he was a chemical operator at Carbide emptying out tanks and that he believed that silicon tetra chloride releasing hydrochloric acid fumes was the cause of all his problems. ucc 060794 J 4 wC .1 ey at Lav r When I examined him I found his blood pressure to be 130/90. He weighed 176 pounds and was 5'10". There were telangiectases over his chest and he said they had been present 10 years. The lung sounds were normal. The only other finding was of scleroderma of the forearms and hands and left cheek of his face. On 5-3-35 I found harsh breath sounds and fine crackling rales ever the right mid zone bilaterally but less on the left. The patient was already taking prednisone, 40 mg daily at breakfast. Other lab tests performed by Dr. Patel had shown a strongly positive antinuclear antibody test at a titer of : .1 540 1 did net repeat this. A blood count showed an elevated white count of 13,300 with 767. polymorphs which I interpreted as being du i to the high dose prednisone. His sarun cholesterol Wc S -So a --3 high, again which I interpreted as being caused cr aggravated y prednisone. At this point it was clear that the patient was suffering from the disease scleroderma with pulmonary involvement and his pulmonary involvement was his main problem. I told Mr. Handley that there was no treatment known to be safe and effective for this disease but some physicians use a drug called D-penicillamine. I told him that I do not use this drug for that purpose but that the physicians at the University of Pittsburgh see a lot of cases of scleroderma and do use th drug. If he wished I would refer him there. As it turned out, the patient went to Pittsburgh with one disease scleroderma and returned with four diseases, three of them iatrogenic. When he came back he had not only scleroderma but also cushing syndrome secondary to high dose prednisone: recurrent pneumothorax requiring emergency admission to the Charleston Area Medical Center and resulting from open lung biopsy; and the nephrotic syndrome resulting from D-penicillamine medication. I attempted to reduce the prednisone dosage but it was increased again by the Pittsburgh physicians. I also stopped the Penicillamine and the nephrotic syndrome cleared only to return again on restarting a very small dose. (It is also possible that while I was prescribing a very small dose, the patient may have been taking a larger dose since he believed it would save his life). ucc 060795 _cnn V-.' ,aur.ar;y, ar.Ci s' nev 3*.* Beeson and McDermott Textbook of Medicine, I4th edition, states that there is a 3 to 1 ratio of females to males in this disease* In a 1985 article entitled Pulmonary Involvement in Systemic Sclerosis, Dr. Owens and his colleagues in Pittsburgh fail to mention the percentage of patients who are female. However, in an article entitled Pulmonary Function in Progressive Systemic Sclerosis published iri Chest 84-5 1983, they had 83 women and 5 men with CREST syndrome and 67 women and 10 men with diffuse scleroderma. In their article "Interstitial Lung Diseas ,in Scleroderma" Silver and Associates, Arthritis and Rheumatism, 271 254, 1984 studied 20 patients with interstitial lung disease ;o scleroderma. Of these, 9 were females and were males , ;50% males). In another paper by the Pittsburgh group, American Journal of Medicine 77, 489 1984 they reported 69" of 26 patients with diffusa scleroderma were females and 86% of 22 patients with the CREST svndrome were females. However, they so on to sav that in their 'methods ' that the 22 patients with the CREST syndrome had been selected from 51 patients in their research unit over an 18 month interval from June of 1981 through December of 1982. While scleroderma is more often seen in women, it certainly occurs in men too. The true prevalence of any disease in a comnunity is hard to estimate. There have been many attempts to estimate the prevalence of rheumatoid arthritis in various countries and the figures suggest that somewhere between .5% and 2% of the adult population suffers from the comnon disease rheumatoid arthritis. During the period when I saw 77 patients with scleroderma, I saw 1860 patients with rheumatoid arthritis. Thus, scleroderma is 1/20 as comnon as the common disease rheumatoid arthritis. It is unconxnon but it is not rare. When Dr. Owens learned that Sherman Handley had worked for Carbide, he formed a belief that breathing chemicals must have caused scleroderma in this particular case. When he heard of another patient who had attended the Cleveland Clinic, this solidified his belief. UCC 060796 John l. McC la higher bVy, Attorney at La*-? * = : SnerTtar. L. Handley ra a I like to distinguish in my own mind between my beliefs ana knowledge. Many people used to believe that the world was flat, today very few believe that. We now have knowledge that it is round. Thus, people's beliefs can sometimes be confirmed as knowledge accumulates but other times beliefs can be demonstrated to be false by acquiring new knowledge. Therefore, we have to question Dr. Owens beliefs and .look at his stated reasons for coming to the belief. Dr. Owens states that it is unusual for men to get scleroderma in the first place. He also says that it is very unusual for the disease to have a very rapid onset of symptoms. So unusual was this cct-binsticn that Dr. Owens thought that a lung biopsy was needed. The question then is: How common is scleroderma lung ir. r.er. ar.d car. it have a sudden onset and progression?' Silver and Associates, Arthritis and Rheumatism, 271, 254, 1934 state that lung disease has a slow gradual deterioration or a rapid downhill course and this is unpredictable by any testing method used at the present time. 3arnett and Coventry, The Medical Journal of Australia, 1040, 1969, report on treatment of 61 personally observed patients with systemic scleroderma seen in Melbourne. They state "these cases presented a very diverse picture, varying from patients with ischemia and sclerotic changes of the fingers only, who lived in good health to old age, to patients rapidly developing skin changes over the whole body who died within a few months or years." Most of us who treat numbers of patients with scleroderma are aware of this peculiar variation in the clinical course of the disease. The first patient I saw in Morgantown in 1974 was an 18 year old girl who died of her disease in less than 12 months. I diagnosed a 75 year old man as suffering from scleroderma of recent onset in November of 1985 and after assuring him that his disease was mild and it was safe for him to take a vacation in Buffalo, New York, I was called by a physician from New York to say that he had been admitted in a crisis and was in pulmonary failure. That patient has returned UCC 060797 McClau rby} Attorney at Law 3 ; a 2TTu Ar.blsy -2CTJ3 to the Charleston Area Medical Center where he is now on permanent kidney dialysis and who will clearly die in the near future. Last month I saw a middle aged man, a dispatcher working for a food company, whose onset of disease was explosively sudden in 1383 and in May 1986 he was in the Charleston Area Medical Center having lest 80 pounds weight, unable to swallow food or to digest it or to stand up by himself. These things happen. Scleroderma frequently has an explosive onset in men and in A majority of patients with scleroderma are housewives. In Table I, I list the occupations of men with scleroderma; 100 men with rheumatoid arohritis; and 89 men with osteoarthritis. There were 2 men who worked for Carbide, one was Mr. Kancleyand the otr.er was a man sent over by the Medical Department because of a positive antinuclear antibody test and Raynaud's phenomenon, tthile this cces not conform to the ARA criteria for scleroderma, I include this as a possible case. Since so many patients with osteoarthritis have retired, I have examined those employed and expressed in parenthesis the percentage of the total employed under occupation. Thus, we find that of 100 men with rheumatoid arthritis seen in my office between 1984 and 1986 57, worked for Union Carbide. Of 89 men with osteoarthritis seen in the same time period, 49 were still employed and 4% worked for Carbide. The question may now be asked: Is the presence of two Carbide employees among 24 men with scleroderma an unusual event in my practice? The answer is no. In my practice only the presence of four or more patients with scleroderma who were employed by Union Carbide would have been an unusual or unexpected event. The disease remains a condition seen mostly in housewives and those that occur in males are distributed among the many occupations of the workers of the Kanawha Valley according to the laws of chance. Based upon my examination of Mr. Handley, my review of the literature, and my review of the occupations of men with scleroderma, rheumatoid arthritis or UCC 06tn98 John L. McCLaugharty, Attorney at Law 31 e: Sherman L. -iandlev July 7, 1335 Page 6 osteoarthritis seen by me in my office around the time that Mr. Handley was seen, I conclude that there is no causal relationship between Mr. Handley's scleroderma and his occupation. PDS/l-w Enclosure Paul D. Saville, M.D., F.A.C.P. ucc 060799 ucc 060800 RHEUMATOID ARTHRITIS OCCUPATION MALE UHW Office Carpentry Driver Bub, Truck Erjulp. Carbide* DuPont* Allied Chemical* Columbia Gan Mechanic Dept. Nat. Res. 45 25 9 6 5 2 1 1 3 1 100 Random Male Patients Total Rheumatoid Arthritis 1975 - 1986 Is i860 TABLE I PROGRESSIVE SYSTEMIC SCLEROSIS OCCUPATION # MALE UMW Office Carbide* Libbey Owens (Engineering, Boat) Construction Retired Dept. Voc. Rehab. Child 8 5 2 I 4 2 l I Total Scleroderma Patients from 1975 - March 1, 1986 is 77 - 24 Male 53 Female OSTEOARTHRITIS OCCUPATION # HALE UMW Office Postal Plunbing Carpentry Mechanic , Sales Janitor Bus Driver Barber Dentist Unemployed Carbide* Monsanto* Alloy* Elk Metals 13 (27X) 12 (25%) 3 (6%) 3 (6%) 2 (4%) 3 (6%) 2 (4%) 2 (4%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 2 (4%) 1 (2%) 1 (2%) 1 (2%) Total Male Osteoarthritis in Current Files 1983, 1984, 1985, 1986 - 89 finployed Over 65 49 40 % Represents Deployed Only '* * Chemical Plants > 6-6-86 *'r JILUJ IIJPB1LJII II _ J _ . System.:: Sc'erosii Secondary :: Oc:apariona! E:\~os:::; "z?IZZ-'/ B. ; "-'.MAS - Systemic sc.irosis ; a multisystem disease characmzT'zsq z" "viCrfy^._ici ribror:: and df?C6iiEraEiv? autoantibodies vers absent 'anti-oer.trtrr.ere ant;SCl-"'}. and anti-PM-SC. Tbs results ,:her sero cnanges in :n- skin, vjscuiature. mu internal organslogic studies. including anti-SM. anti-RNP. and rheu [li- Pulmonary involvement. inducing either pulmo matoid factor, were negative. A chest radiograph nary fibrosis 2l or pulmonary arterial hypertension revealed interstitial changes in all lung fields consis due to vascuiar obliteration !"]. is commonly seen in tent with pulmonary fibrosis. Pulmonary function patients with this disorder. The etiology of systemic tests showed a forced vital capacity of '.09 iiier- >61 sclerosis is un.-tnown. A number of occupational and percenc of predictedi. a total lung capacity o: 4.03 other exposures have been implicated as potential liters '.84 percent of predicted), and a singie-iireath causes of systemic sclerosis or closely reiated condi diffusing capacity for carbon monoxide of 4.0 mi min tions. inducing siiica dust [4], epoxy resins [5], rape- ute/mm Hg 114 percent of predicted). Arterial d-.-satu- seed oil [6], carbiaopa bleomycin [3), and benzene ration from 92 to 73 percent occurred with minimal [9]. We report herein the case histories of two chemical exercise. An open lung biopsy procedure reveaied pul workers exposed to meta-phenyienediamine in the monary fibrosis with minimal inflammation. X>; ab same building m whom systemic sclerosis subsequent normality of the pulmonary vasculature was r. -ted. ly developed. Therapy with prednisone 30 mg dav, D-peni.iila- >1ct tttrc-: rr.ir.s 250 mg, day. ir.d nasai oxygen at 2 Titer? :r. route vis started. The r '..nee an imp: / err..-.:: in Patient 1 r;?pirctory symptemi. cut two montr.sTate: 'he rr.ir. -vcrxea :n a :?siaurant ana :r* ccrv.costeroid dose was aecr=asea to rtrg cay, -.-..-rt- of a raven manufaciunr.e ness of breath worsened one the partial p:.-.;e : -"onr he had been employed as i oxygen at this time was 43 mm Hg. Higr.-iose tr-dm- chemicai operator in Budding led in a large chemicai sor.e therapy was re-instituted with symptomatic im company in the Charleston. West Virginia, area where provement. he unloaded and transferred chemicals. During Au gust 1931, he had worxed primarily with meta-phenyl- Patient 2 enediamir.e and had been involved in three accidental This 58-year-old man had worked his entire adult spills with this chemical. In October 1983, Raynaud's life for the same large chemical corporation in the phenomenon, swelling of the hands, and hyperpig Charleston, West Virginia, area as did Patient 1. From mentation of his hands and forearms developed. Fol 1944 to 1948, he worked as a laborer, primarily clean lowing another chemical accident in -January 1984, in ing pipes containing vinyl chloride. From 1948 to 1977, which he was exposed to fumes of meta-phenylenedi- he worked as a chemical operator. During this time, he amine, he experienced the sudden onset of a produc was exposed to a variety of chemical compounds, pri tive cough, fatigue, and shortness of breath. He was marily of the amine class, and specifically meta-phe unsuccessfully treated with bronchodilaton and anti nyienediamine. He worked as a supervisor in Building biotics and was referred to our institution. Physical 156 from 1977 to 1981, where he was exposed to the examination revealed normal vital signs, with the ex same amines and, in addition, silicon tetrachloride. He ception of a respiratory rate of 22/minute. Results of retired in 1981 because of health problems. examination of the ears, nose, and throat were normal. In January 1980, reflux esophagitis with heartburn Evaluation of tha lungs showed a few bibasilar rales. developed, followed one month later by diffuse swell Results of cardiac and abdominal examinations were ing and redness of both hands. In August 1980. he aormal Periungual erythema and puffy fingers bila noted the onset of Raynaud's phenomenon, shortness terally were present, as were mild skin thickening and of breath, and pedal edema and was treated with furo- hyperpigmentation of the fingers and dorsum of the semide. Bradycardia was detected, and an electrocar forearms. diogram revealed complete heart block. A pacemaker Laboratory evaluation revealed a normal blood cell was inserted. count, and the erythrocyte sedimentation rate was T His condition remained clinically stable until 1933, mm/hour. Levels of electrolytes and creatinine were when shortness of breath worsened such that he could normal, as were the results of liver function tests. An walk only one block without stopping. In addition, he antinuclear antibody was positive at 1:100 with a ho reported the development of a chronic cough produc mogeneous pattern, but all scleroderma-selective tive of scanty amounts of white sputum. He was hospi talized twice in 1983 for pneumonia. In 1984, he was treated with prednisone and a theophylline com from tte Omsnni of Pulmonary Median* and Rheumatolocy and Clinical pound. He denied chest pain or paroxysmal nocturnal Immunology. Department of Median*. University of PittsburMi. Pittsburgh. Penrnyfvina. Requests for reprints should be addressed to Or. Gregory R. Owens. Unrversity of Pittsburgh, School of Methane. Owaan ol Ptdmonary Median*. MO Scad* Had. 3550 Terrace Street. Pittsburgh. Penmytvama 15261. Manuscript submitted January 15.19SS. and accepted at revised form April I, IMS. dyspnea. Physical examination in 1984 revealed normal vital signs. Examination of the head, eyes, ears, nose, and throat was significant only for telangiectasia of the left cheek and bridge of the nose. The lungs revealed biba- 114 July 1988 The American Journal of Medicine Volume 85 ucc 060801 3Y57IMIC 3CU3QSIS C'.VE'IS A,'ID MEDSGE3 ur dr-' rales. Results .>t examinuficn of :r.e .'.eurt and min were normal. Ths ixirirn:::?; -hi'''''id sciero* ,av:yiv. -cmniie'jtjsia over the fingers. anti ait'fuse v * .i1. *`P. i v'r'Tiiii ^`>moL0r -- ; .t:*-he .sj .5 -nir* '-.our mi me. :enni ';r?acinine 5 were normal. beroionc scuGirs. including antiiur antibody. _-:<::acraoie nuciear ir.figen. rheu- facior. ar.ri-'iencromere. inti-fiC.-TO. aiui-SM, nd anti-ENP. were all negative. The chest radiograph ,`.','.ved bibasiiar interstitial markings consistent with 'olmonarv fibrosis. and an esopnagram revealed a mid dilation oi tne esophagus with rastroesopnageai reflux. The iiectrocardiqgram showed complete heart dock with a paced rhythm of 70 beats/minuie. Pulmo- '.ary function tests revealed a forced vital capacity of 1.77 liters `56 percent of predicted) and a singleireach carbon monoxide diffusing capacity of 10.7 mV minute/mm Hg '40 percent of predicted). Arterial blood gases showed a pH of 7.46. a partial carbon dioxcie pressure of 37 mm Hg, and a partial pressure of ixygen of 75 mm Hg. He was treated with D-peniciila- mine 500 mg and prednisone 10 mg daiiv. The patient was seen in roilow-up two years later, at which time `here was no charge in his symptoms, pulmonary function, or arterial blood gases. 7;. sremic sclerosis is a disease or multiple rgan sys- irr.s '.hat occurs primarily in women ana :hat has an midence of up to 12 rases per million copulation per pear flu']. Althoug.i there is no clear reason for the ieveiopment of the disease in the majority of patients, exposure to certain chemical agents may be associated with its occurrence. Workers who are exposed to siliceous dusts are pre disposed to the development of systemic sclerosis. A variety of reports have documented an unusually high prevalence of systemic sclerosis in underground gold miners [llj, sand blasters (12), and workers in potter ies and foundries [13]. The risk of the development of systemic sclerosis was estimated to be increased 17fold in gold miners from South Africa [11] and in creased 110-fold among German underground coal miners [14]. Systemic sclerosis most commonly devel oped in motormen in the mines who were exposed to the highest concentrations of respirable silica [4], Another circumstance followed by the development of scleroderma after a delay of five to more than 20 years is the injection of foreign suhatancsa, usually silicone or paraffin, almoatexclusively for breast aug mentation [15]. This association has bean noted al most exclusively from Japan. Other evidence for an association between chemical agents and scleroderma comes from the epidemic of "toxic oil syndrome" in Spain in 1981 [6|. This epi demic occurred after the ingestion of adulterated cooking oil. rape seed oil. After an acute illness, the victims experienced the development of skin changes reminiscent of scleroderma and sometimes more typi cal of eosinophilic fasciitis, as well as neuropathies, the sicca syndrome, and pulmonary and esophageal dys function. Exposure to vinyl chloride by inhalation or transcu- taneously has also been documented to produce a scle roderma-like disease. In one study, skin changes indis- -.iruMiina^e .rom ^lerouernu .yv.-kers 'vho ;r- v;:!v: .1, nu.TsOtr -i;` Jsuturea : '.:V v.12 not 'v^'ca. `''fTTlic '.ill! T.!i' ^ '* - i it r".i M'**''*" 2 `3SLii:* Tl'. 'e auidr. 4 . 'ric ;.i- 1'dllC llirrsia jVICdnr. ! lldliicy VanuAatfe Jt y5l aescr:::re 2 -'^rouerr^u-uke dis order iccumns ;n T.en er/iiw*rd m '-he ri-iymerization of epoxy resins. This disease ccurred ar er oniy short term exposure and with a re.ui.veiy high mcidence six li'j'.Z writers). The authors '.ages'ed :h: a biogenic amine. bis4 amino-o-mec.iyi-.-ycifjhexyi. metnane. was the causative agent. Neither of the two workers whose case histories were orovided had evidence of pulmonary involvement. The same authors also de scribed an association between 'he development of generalized morphea and exposure to organic solvents ;L9l. Although tnese subjects were not studied pro- spectiveiy tor internal organ involvement, the major ity of the patients had eitner ssopr.ageai dysfunction or pulmonary fibrosis, suggesting a systemic rather than an isolated cutaneous process. The development of other pseudo-sclerodermatous states has been described in z ersons witr. elevated lev els ,i the amine serotonin L-:-hydroxyrryprophan). 3o:n .-ndogenous ir.rra,s -sen ir. r.e mrcmoid -r..:: me ,27 ana 'reatme.'.; v :n rX :g or -is sera to- " Ta'-''/C .. 1"' c ^ with 'he isveiopment o; a - t.r ...-rma-hits syndrome. 7he most pertinent ;ase :tz< r.s ir. -.-.e 'iterature relate to tne development -f jc-erucerma .r. persons exposed to aliphatic and ircmattc uyarocarnon sol vents ,19.21-25;. Numerous instances of systemic scle rosis following occupational exposure to trichiorerhy- lene [21-23] or perehiorethytene [24] have been described. Exposure to benzene, an aromatic hydro carbon, may be followed by disease that tends to be limited to the hands and feet rather than becoming a multisystem disorder [9,25], Methylene chloride, pre sent in many paint removers, may cause acute pneu monitis [26], a circumstance similar to the disease pre sent in our patients. There are several reasons to believe that the devel opment of systemic sclerosis in the two workers re ported in this study is more than coincidental. First, only 20 other men were employed during the time spent in Building 156 by the two workers. Likewise, the onset and explosive progression of disease shortly after several documented chemical accidents in Pa tient 1 reinforces the likelihood of a relationship of disease to the workplace. An epidemiologic survey of the facility would provide a definitive answer to the association of the workplace and the onset of disease. However, it has not been possible to carry out such an evaluation. Elucidating a specific causative exposure in these two patients is more difficult One patient had been exposed to vinyl chloride, a known cause of a sclero derma-like syndrome, in the past Because of the pro longed delay between the vinyl chloride exposure and the onset of scleroderma, we believe this agent was not a causative one. Likewise, both patients were intermit tently exposed to silicon tetrachloride, which yields hydrochloric acid and free silica upon chemical break- My 1988 Th American Journal of Medicine Volume $2 113 ucc 060802 -i -? I ,"!Sv^S | 4 v-df f .M a / a i eMIC 3CUROSJ5 / OWENS AND MEDSGcH down. It is ""ssibls that ths disease described herein was precipitated by an unusual ".-pe ot exposure ;,) silica. tut -.-.is seems uniikeiv. The most attractive potential :v:sativ ugsr.t is tneca-ph.-nyisnediamine. in ..is jrmttany facilities. t.us igsr.t .vas used most ruy hi 3uilcing `.do. .fecund. Patierr '. vas sun-:4rt?s ;h' rziw` `r.9 'i an ^cpir.-1*.2?3'*`*n*cr'me. vhich in- ,ur.j .r.v*,.v*:r.tfnt, F\r.z.lm\ as trailed earner, )C/.cr oiczsrv: immes nave 'i^r. .mpiieatcd in :r.e ,:i icieroaema-dlia .Unesses. Aithousn. c.iemicaily induced systemic sclerosis may account r'or only a small fraction or scleroderma cases, the recognition of specific causative agents may ulti mately lead to an improved understanding of the mechanism a: disease induction, including vascular, immunologic, and fibroproliferative events, and possi bly to the development of rational therapy. 3?SagCS3 1. Mecsger " scepsis (scefocermai ecs.hoc.-viG *3SC;iti$ jna catono* j.s. \t '.IcCar-/ Cj .* sd. Arr.'itis *o<3 Ameo c-ncit.ons. 3th ed. Philadelphia- uja 3M "eo$*r 1ZS5. 795-1014 2. Cwe-s G. f:no G Hercert 0 #*PuifhChary runchon m orofl-esswe systemic sclerosis: iS'T'tarsonJ C"I3T byrc.-cme var.ant with diffuse settrooerma. Cnest 1383: 34- =46-5*0 0.3tuo A. Steen V Owens G. 3ames L Rodnan G. Medsger T- Pulmonary hyper- ersion n the C5T syndrome variant of systemic saerosis. Arthritis Rheum i5B6: 29 515-524 4, Rodnan G, senece* T, MecsaerT Zammarata R: The association of progressive wsiemic rcerosis scie'cce*---vtr> ccai mine's' pneumoconioss anti other ':rm$ r :\cps,$. 'nr*'* l}-?7 ii 2Z2-ZG-i. 5. 'amahia* s."*awa - >*V5 v, Hotter* 4 Occupational sotreaerma-xe c.sc'ce' izzs-ri - -?*> `'^cc.'-re'-`^2t'onc`aco*7''asrs Zermaro- 3. -cnic*i Za- ZsiSGti'-zV-"?! - 'iCArr-ore-A ZC-' 4 "cxic .zrer':"** v>-* ^2;_'=s r.-raop *5 '*;5S c'`^pjys *crms of seers* :er**3. I-?'*-- -*5 .955 .; ;2C-11Z i.j'*Cir5 i, -a,* >c*p: m c-*|5 r c/. I^vetoamanr ct * tc`er`rae,"h3-|ike :-'*u vf-'-c-ti/'ryCtccnjn sr.o caroicspa. N Sr.gt J Med .43c i02 '3C-?Sr 3. '"'t" ' 2-C'*nT"-*'" - `.330 ' 551-::} 9. ,, -** ',5*3 . >57 I s^^'ane ;: 10, Mecsfe' * Scice"- :*-//:: c*ogr*sv*- . .5*9 5 'S!5 -* ; i.. -,. - * 4 a- - :.vf: .ard;.25'?': 'tt- ;:5 12. -ir'is <*r Cacuca' :r; -.r*-3cr-^ ; ';a. i*":-."1 ! 14, -*austeo J. Zccrunve Z. Murcce-?-' - 'cc;*-! - s/sTe^'C srer^sis ,v*r :, ;cs.s .n m* German Ze^'crv : 9^.: . * 5 M/ers 4, *cs. i/S'e^c ;c,ercsi5{sc.eroatfm3- Ne. ";rv >va*f `.fee:; .smng, ;585. 15, /,*:rraga. V Shipa/*a ' Meosge* ", 2 Z zz*':-**-- * -*-**:* `ssj* :'5355 3H*r ccsmit'c s^^erz lose^is?.:-: :*': Cj1 *-: .*: a'*\ - the Japanese iteratyre Arthritis rheum 1?S4 ZT >iZ- 16. Langauer-'.jwewic^ - ^urzeauer , Syczv-wsya 2. acoc Mjf*x * . criorce disease, fteurcoaical tiistureances.-nt Arc.-. -- f;r- . 355 52 151-157 17. Veitman G. Ljnge C. -ye 5, Sten 0 aacme- Z ..i.cs* -- a: :~c -.*. course ot vmvi cnonoe :$aas Ann NY 4ccc ic .57* 1^6 5-'.' 16.SlackC. *eretra 3 Me.**-.* a, Veisr, A ' Geret: :-5:sc': *. sc-'eroaermanke syncrc-* * sy`,`5:cma:cah3csvr'voma:;c to vmyi chionoe. j Rhe'-tatoi 1986 13 1C59-iC62 19. Yamakage A. isrukane - Generaiicec mprrnea-iKe oce'cci'--; -i - oeoote exooseo'3 organ c diverts. Grr,3tc*ogica 1932 15: ;5c-152 20. Pries J. L'fldgren 5-> - 3ce#03em-a-ite -esidns ano ;j'orc'C ir creme Arch Mem Mec 1973, 131. 550-552, 21.Saman . 3unoi. <astch < Anewsynprcmewf c.g^enrorc- :;ir:;e' ma, jyhaecomasva. Ra-^j'-c 3 cneremanoh ore ce'crv^ De^rratO! -973 59 43?-^: : . 22.'nct-wansen H sa?*- - 5- *Frc'mj :cc*oa: era. -* 'crethyie^sanotnchiore'-sr* -ttoCer--'zerv*: i$tr"'--,r5" I:Z-Z:- 21 Looney; <e-fv 3 T---: Z.-.,m a>-:- ;T .`fi'*' - tcefosis issoc H :*'".*'*>?*, . 1':.: 19B7 Z? 493--9a, 24, icof'Cw G. a tprrict .e jt^e t'i'.'t?' ; r ;* `t , - cn ** t i . . j It * y03sen 'j .'e^e 77*'^ .5*' Z 17-1Z 25. 'faice-2:Gosciveits ;a-5*tre'-coe'--a','*v Ze'--itc 1?*.Z 1Z :'. 25. -.* 5. ^ran 2 Ma/. Zm-sesuiminarv r:,,r#" c* sure. Am J Mec 1936 51 m22^2~ 'Xk 1 US July 1988 Th American Journal o( Mcdicint Volume 85 ucc 060803