Monozygotic twins discordant for rheumatoid arthritisa genetic clinical and psychological study of 8 sets.код для вставкиСкачать
Arthritis and Rheumatism oficia~~uumal of the dmerican Rheumatism association JANUARY, 1968 VOL. XI,NO. 1 Monozygotic Twins Discordant for Rheumatoid Arthritis : A Grenetic,Clinical and Psychological Study of 8 Sets By SANFORDMEYERO-, RALPH F. JACOX, AND D. WILSONHESS T deals with an investigation of monozygotic twins should provide inforof 8 sets of monozygotic twins, all mation as to whether rheumatoid arthritis women, and all discordant for rheumatoid may be an inheritable disease. Reports to arthritis. We have attempted to examine date of some 50 twin pairs indicate that developmental and environmental vari- rheumatoid arthritis is discordant in 64 per ables which might explain why rheumatoid cent of the sets studied. There is adequate disease developed in one twin, or why it reason, however, to disqualify many of these cases because of uncertainty of clinfailed to occur in the co-twin. Reported observations of instances of ical diagnosis and of zygosity. familial aggregation of rheumatoid arOur investigation of the occurrence of thritis have contributed to the notion that rheumatoid arthritis in monozygotic twins this disease may be caused by some in- began several years ago with the chance heritable characteristic predisposing the appearance of 2 women, each with an patient to develop arthritis.1,7,s~13,14~17,18identical twin, who came to the University Recently, the study by Bunim, O’Brien of Rochester Arthritis Clinical Study Cenand Burch of possible familial incidence of ter for treatment of rheumatoid arthritis. rheumatoid arthritis in American Indian It was found that their twin sisters were populations has suggested that while clus- unaffected. From this point, largely by tering of rheumatoid arthritis may occur in chance, 7 more arthritic women were certain families, a careful statistical evalu- found who had identical twin sisters who ation provides no pattern which can be were free of joint disease. No systematic effort has been made to survey the cominterpreted as genetically significant? The nearly identical genetic constitution munity, although publicity brought to our HIS REPORT From the University of Rochester School of Medicine and Dentistry. This study was supported by Research Grant MH05339 and Career Program Award K3-MH22,260 from the N.I.M.H., U.S.P.H.S.; by Nat i d Foundation Grant # CRMC 24; and by the Arthritis Foundation. SANFORD MEYEROWITZ,M.D.: Assistant Profesof Psychiutry and Medicine. RALPHF. JACOX, M.D.: Professor of Medicine. D. WUON HESS, PHD.: Formerly Assistant Professor of Psychiatry (Psychology) and Pediatrics (Psychology). Presently Professor of Psychology, Gallaudet College, Washington, D.C. SOT ARTHRITISAND RHEUMATISM,VOL. 11, No. 1 (February 1968) 1 2 MEmOWITZ, JACOX, HESS ++ ++ ++ ++ ++ ++ ++ ++ 00 00 o= 00 + 00 0 0 3c 0 0 00 00 0 00 c o 00 c o 00 00 ++ ++ ++ + cc c = ++ 0 == ++ ++ cc cc 00 O D oa 00 ++ +t 0 0 ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ o c ++ Sf ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 ++ ++ +It1 00 ++ ++ ++ ++ ++ 00 00 00 00 00 00 00 00 00 ++ ++ ++ ++ ++ ++ ++ ++ ++ MONOZYGOTIC TWISS DISCORDANT FOR RA attention 3 twin sets who reside outside the state. In one of the 9 sets a definite diagnosis of rheumatoid arthritis in the affected twin was not established (Set 9, Table 2). The remaining 8 sets are reported here. An extensive history, physical examination, serologic testing and other laboratory studies were carried out in all subjects of the 8 sets. Monozygosity was established by detailed blood typing ( Table 1) and by identification of like appearance. In 3 of the twin sets, skin was successfully grafted from the normal to the affected individual. Skin grafts were not carried out in the other sets. In each of the 8 sets, one twin fulfilled the diagnostic criteria of the American Rheumatism Associationla for classical or definite rheumatoid arthritis, while none of the co-twins showed any evidence of rheumatoid disease (Table 2). In 6 of these 8 sets, there was serological discordance: rheumatoid factor was present in the twin with the disease but not in the co-twin. The remaining 2 sets of twins are children in whom there were no serological changes. Early in the study we became impressed by the frequent occurrence of some type of psychological stress in the ultimately affected twin. In 7 of the 8 twin sets, both the normal and rheumatoid sisters had extensive unstructured interviews which focused on their life events. Developmental and psychological data were obtained through interviews of the mothers of the 3 youngest sets of twins. A battery of psychological tests to identify variables of personality and intelligence was administered in all cases. In 4 adult twin sets, a history of psychological stress prior to disease onset was elicited in the ultimately affected twin, with no comparable experience for the normal sister. Adequate psychosocial .data could not be obtained in the case of the fifth pair of adult twins. In 2 of the 3 pairs of younger twins, a similar finding of discordant psychologic stress antedating disease onset was suggested. We also noted 3 a personality trend of heightened activity in both twin sisters of all sets. CASEMATERIAL" Set 1 Mary H.i (SMH Unit No. 50-71-77)was examined at Strong Memorial Hospital on January 19, 1961, and on May 15, 1963. When this unmarried woman was initially seen in our clinic in 1961, she was 49 years old. She reported that her first joint symptoms began at age 28, in November, 1940, after a bout of bronchopneumonia. At this time her wrist became acutely swollen, tender, warm, and red. This promptly subsided with salicylate therapy, but in February of 1941, she developed painful fingers, back pain, and pain in both elbows. These symptoms again subsided with salicylate therapy, but the patient continued to have residual stiffness of the right wrist. In May of 1943, pain began in her fingers, neck, knees, ankles, and hips. These symptoms were severe enough that the patient had to stop work, and she has not been employable since that time. During the next 2 years, the patient had continuous joint pain and stiffness. In 1946, she began to be more physically active and helped with home chores. In 1952, the patient had a recurrence of joint symptoms that were of still greater severity. During the next 9 years she developed progressive disability which was not appreciably relieved by steroid therapy. Severe crippling of the hands and elbows was apparent by 1959. The patient had had a laparotomy for an ovarian tumor a t age 15.This was followed by recurrent phlebitis of the left leg. In 1959, she developed an ulceration of the right leg which was probably related to steroid therapy. The patient was admitted to another hospital in 1960 for an acute abdominal emergency which was considered to be caused by a perforation of a diverticulum of the colon. She was known to have a systolic hypertension of 180 mm. of mercury in 1952. She was given cortisone and developed edema and a rapid gain in weight. She had had 'In this presentation of case material, psychosocial data are presented in some detail for Sets 1 and 2 to illustrate the scope of our inquiry. Brevity, however, permits only summaries of psychosocial factors in the remaining twin sets. tThe names used are fictitious. To assist the reader in distinguishing the siblings, the one with rheumatoid arthritis in each twin pair is designated by the choice of a first name which contains the letter 7. 51 24 26 60 60 66 66 65 65 16 16 1962 1963 1962 1962 1964 1964 1961 1961 1964 1964 Normal Set 4 Rheum Normal Set 5 Rheum Normal Set 6 Rheum Normal 14 14 8 8 41 41 1963 1963 1962 1962 1964 1964 Rheum Normal Set 8 Rheum Normal Set 9 Rheum Nnrmal set 7 Normal Set 3 Rheum Normal Set 2 Rheum 1963 Age 49 Initial Exam. 1961 Set 1 Rheum Sets Twin 2 yrs. 1 yr. 3 yrs. 2 yrs. 5 yrs. 4 yrs. 2 yrs. 6 mos. 6 mos. 21 yrs. Duration of R.A. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. Neg. N eg. Neg. Neg. Neg. ANF-Neg. Neg. ANF-Neg. 1 :1280 Neg. Strongly Positive Neg. Neg. Neg. Neg. 1 :5120 Neg. 1 :2560 Neg. Neg. 1:640 1 L.E. Strongly Positive Neg. L.E. Test Done Not Not Done Not Done Not Done Not Done Not Done “Take” “Take” “Take” Skin Graft Classificatitn of Disease 1%- Possible R.A., Class I, Stage 1 Definite R.A., Class IT, Stage 1 Definite R.A., Class 11, Stage 1 Classical R.A., Class 11, Stage 2 Classical RA., Class 11, Stage, Undet. Class 11, Stage 2 Classical R.A., Classical R.A., Class 11, Stage 2 Definite R.A., Class I, Stage I Classical R.A., Class IV, Stage 3 Clinical and Serologic Data Neg. of Neg. 1:320 N eg. 1 5120 Latex Test Table $.--Summary None None None Osteoporosis, Goiter, Hypertension, Arteriosclerosis, Absent Reflexes None Enlarged Thyroid Hypertension Concordant Diseases b “8 q A MONOZYGOTIC TWINS DISCORDANT FOR R A measles, chicken pox, pertussis and mumps in early childhood. Ph&cal Examituztfon. Blood pressure, 80/ 100. The patient was a thin, chronically ill woman of 49 with severe, deforming, and destructive arthritis of the hands, wrists, elbows and knees. Rheumatoid nodules were present over the extensor surfaces of both elbows. The skin was thin with numerous ecchymotic lesions over the forearms. The fundi showed early arteriosclerotic changes. The heart and lungs were normal. There were no other pertinent physical abnormalities. Laboratory Data. Latex fixation test, 1:5120. LE preparation was positive with one cell seen in every 2-3 high power fields. Paper electrophoresis showed 2.6 g. of albumin and 1.5 g. of gamma globulin with the other components normal. Roentgenogrums. The hands showed multiple destructive changes of the carpal joints with intercarpal fusions on the right. There were metacarpal erosions with narrowing of the joint spaces in the fingers of the right hand with an associated ulnar drift. In the left hand there were marked subluxation deformities of the metacarpal-phalangeal joints. There were erosions of the bases of the proximal phalanges of both first toes, and there was narrowing and erosion of the talonavicular joint in the right ankle. The patient was admitted to the hospital on October 22, 1962, with findings of a right-sided weakness and dysarthria considered to be due to a cerebral thrombosis. The blood pressure at this time was 170/105. She continued to have active rheumatoid arthritis with progressive deterioration of joint function. At this time, the LE test was negative, but the test for antinuclear factor was positive. When she was last seen in January, 1966, she continued to have severe active rheumatoid arthritis with progressive deterioration of joint function and residual effects of the cerebral thrombosis. May H., unmarried twin sister of Mary H., age 51, was seen at the Strong Memorial Hospital on May 17, 1963. This woman has had no joint symptoms and considered herself to be in good health. She had a repair of an inguinal hernia at age 21. A fibroid tumor was excised from the right breast at age 31. At age 47, she developed right leg pain of sciatic distribution which was relieved b y bed rest, and she has had no severe recurrence of this symptom. Physical Examination. This subject was three inches shorter than her affected sister. (The difference in height appeared at age 14-18.) The blood pressure was 158/92. She was a welldeveloped, well-nourished woman who had no 5 stigmata of joint disease. A complete physical examination revealed no abnormalities. Laboratory Data. Latex fixation, LE, and ANF tests were negative. Psychosocial History These twins were born prematurely, May first, weighing 3 lb., Mary five minutes later, weighing 3% lb. This was the only pregnancy of their mother, who was then 24. Their parents moved 3 times to different cities before the twins were 6, at which time their father, an engineer, died of a cerebral vascular accident at age 32. He had had severe hypertension. The twins and their mother returned to the mother’s native city, and through their childhood, they lived with their maternal grandparents. Their mother worked and had her own apartment. One of the twins would live with her alternately for a period of several months, the other staying with the grandparents. Both twins describe considerable interest and attraction to sports from a young age-basketball, baseball, bicycling, horseback riding, swimming and gym. They were close, dressed alike until their teens, and were in the same class until high school. At age 13 they had their menarche, May a few months before Mary. They became less alike in appearance at this point. Throughout childhood Mary was considered by the mother and her sister to be less healthy and especially vulnerable to frequent colds. Because of the laparotomy and subsequent thrombophlebitis at age 15, Mary fell behind a year in school and had to give up sports, thereafter “staying home and reading” while her sister remained active. Mary graduated from high school at 18 and immediately went to work as a secretary in an insurance company. She enjoyed the work although she and others considered it an extremely hard job. Some personality differences between the twins are apparent. Both sisters characterize one another in terms which largely agree with our ohservations. Mary has been the more assertive, less acquiescent and the more contained of the two. Most characteristically, she “takes over and manages” in times of crisis, according to her sister. She is “bothered by many things” but “stores up feelings until they reach the saturation point.” In 1933, when the twins were 21, their mother remarried, this time to a man who proved to be epileptic and, from description, probably chronically psychotic. He required ”managing,” and everyone agrees that only Mary had the motivation, tact and patience to deal with him. The ensuing years are described as “upsetting, with tension all the time.” Mary describes working hard at her job during the day. Then at night she had to deal with the stepfather, who was suspi- 6 cious of visitors and especially of any young men with whom the girls went out. Onset of her disease took place in this setting in 1940. Further demand was made upon Mary when her mother became sick and required care during the following years. (The mother fractured a hip in 1943 and again in 1945. She developed “heart trouble” in 1948 and diabetes in 1952.)As her sister pointed out, “Mary would have liked to be active also, but she got stuck.” May, the healthy co-twin, has remained steadily employed through the years. Although unmarried, she has led a fairly active social life. She has had to devote some time in the evenings to the care of her sister, who has become progressively incapacitated since 1952. Their mother, in spite of her own illnesses, resumed a fairly active life and took care of Mary during the day. For the past few years Mary has required total care. Wheelchair-bound, she must be bathed, dressed and assisted at meals. The demand on May increased markedly in June, 1964, when her mother died of carcinoma of the bowel at age 75. The mother had had symptoms of rectal bleeding for over a year which she had minimized. She died shortly after an exploratory laparotomy. Since the death of the mother, May has engaged a succession of people to take care of her sister while she is away at work. These arrangements have been unsatisfactory. May spends her evenings looking after her sister except for rare occasions when she can get a “sitter” for Mary so that she can be relieved of responsibility for a few hours. When seen in July, 1965, May did not complain about this situation, but there were manifestations of distress. She indicated that it was difficult for her, that she felt confined, but that she’d “make the best of it.” She was experiencing frequent headaches and felt “nervous” and “tied up in a knot.” She could relax only when she was able to get someone to stay with her sister so that she could get out even for a short time. Summation. These identical twin sisters have been discordant for rheumatoid arthritis for 26 years. The affected twin has classical rheumatoid arthritis, Class IV, Stage 3, with positive latex fixation and LE tests. She has had, however, no clinical evidence of systemic lupus erythematosus. These twins are concordant for hypertension. The twin with rheumatoid arthritis has cerebrovascular disease, whereas her co-twin, who is hypertensive, has no detectable central nervous system MEYEROWITZ, JACOX, HESS abnormality. We have no explanation for the growth spurt in the affected twin which occurred before the clinical onset of rheumatoid arthritis. These twins were active young girls whose early lives were characterized by frequent moves, the death of their father when they were 6, and then a period of disruption of the family. A notable difference between the sisters became apparent at age 15 when the subsequently affected twin, in association with an illness at that time, became less active physically than her sister. Rheumatoid arthritis appeared at age 28, in a setting of several years of demanding and frustrating devotion to the care of the psychotic stepfather. The unaffected twin has remained more active and, until recently, was less confined by responsibility to other family members. Currently, she is beginning to manifest distress as she attempts to cope with the care of her sister. This situation resembles that in which the affected twin was involved prior to the onset of her illness. Thus far, however, the unaffected twin has not demonstrated any major deviations from health. These twin sisters remain under study at periodic intervals. Set 2 Ruth P. (SMH Unit No. 51-64-61),then a 24year-old, married, mother of one, was first seen in Strong Memorial Hospital on March 5, 1962. In September, 1961, this patient first observed pain in the first right interphalangeal joint. Shortly thereafter, she had pain and swelling in all proximal interphalangeal joints and in the distal interphalangeal joints. In January, 1962, she had onset of pain in both feet and knees associated with stiffness, especially in the ankles. At this time, she had easy fatigue. In April of 1960 she had “bursitis” of the left shoulder and a similar pain in the right shoulder in December of 1961. The past history was notable for pneumonia at age 13, a tonsillectomy at age 7#, and an appendectomy in 1960. She had a pregnancy in 1961. She was found to have a positive skin test and suspicious x-rays for healed histoplasmosis while a student nurse in the South. 7 MONOZYGOTIC TWINS DISCORDANT FOR FL4 Physical Examination. The blood pressure was 115/75. She presented as a well-developed, well-nourished young woman who was in no acute distress. The third and fourth proximal interphalangeal joints of both hands were swollen, warm and tender. The interphalangeal joints of both thumbs and the metacarpal joints of both fifth fingers were swollen, tender and painful on motion. The right wrist was slightly swollen and tender. The knees were not swollen, but there was tenderness on pressure over the medial aspect of each knee joint. The metatarsal joints of both feet were tender. The remaining physical examination revealed a diffusely enlarged thyroid gland, but was otherwise negative. When the patient was seen again in May, 1962, she showed a small effusion in the right knee and complained of stiffness and aching in both knees. Cold therapy was begun, and during the next 2 weeks she developed more symptoms of pain in each knee and bilateral knee effusions. She received 550 mg. of gold, during which time she continued to have knee, finger, and toe symptoms with continuing evidence of inflammation in these joints. She returned to her home in the South in August, 1962 to continue therapy there. She was seen again in May, 1963.After returning home, her symptoms continued for several months, but then all evidence of joint pain and stiffness disappeared. On physical examination in 1963, the only joint abnormality was a mild ligamentous relaxation of the right knee joint. There was no active synovitis and the patient was considered to be in remission. Laboratory Data. Serum latex fixation titer, 1 :320. LE test showed moderate leukoagglutination and 1 LE cell seen in March of 1962. On May 1, 1963, the latex was 1:40 and the LE and ANF tests were both negative. Roentgenograms. In April, 1962, there was soft tissue swelling of the second, third, fourth, and fifth proximal interphalangeal joints of the left hand and the second, third, and fourth proximal interphalangeal joints of the right hand. There was slight narrowing of the joint spaces. There was mild osteoporosis of the metatarsal bones. A chest x-ray showed multiple bilateral small pulmonaqy calcific densities. Phyllis D. (SMH Unit No. 55-73-07),unmarried twin sister of Ruth P., was 26 when seen at Strong Memorial Hospital on May 2, 1963. She had no complaints and had no history of any joint or muscle symptoms. In early life, she had had frequent throat and urinary tract infections. She, like her sister, was found to have a positive histoplasmin skin test in nursing school, but she did not develop any calcific densities in the lung. She had an appendectomy in March, 1963. Her menarche started 3 months later than that of her sister. Physical Examination. The blood pressure was 110/70. She was 25 lb. heavier than her sister and ?h inch taller. She had a strikingly similar appearance to that of her sister. No abnormal physical findings were observed except for a diffusely enlarged thyroid gland. Laboratory Data. Latex fixation, ANF and LE tests were all negative. Roentgenogram. A film of the chest was negative with no calcific densities seen; films of the hands and feet were negative. Psychosocial History These twins were born and raised in a small rural community in the deep South, the middle siblings of a family of 6. Ruth, the first-born, weighed X pound less than her sister. I n their words, they were “tomboys” as young girls, spending their time outdoors, playing, gardening, and working with their father, a commercial fisherman, on his boat. Ruth was the first to contract the usual childhood diseases and was more incapacitated by them. This contributed to their jointly held notion that she is the less healthy of the two. They were together through high school and nursing school, closely sharing interests and dressing alike until they were 20. Shortly after becoming nurses, they joined the Army and were stationed together. Interviews reveal that Ruth is quieter, more reserved and less dependent on her sister. Ruth seeks active solutions and, as her sister says, “She’s quiet, doesn’t get in anybody’s way, just goes ahead and does what she has to.” Phyllis, her sister, is prone to “fuss and fight” openly but “gets along with most people.” She recognizes a greater need to be close to others. The twins had seldom dated, but while in the Army, Ruth married a young man she had known a short time and of whom her sister disapproved. Because of her Army assignment, she was then separated from her husband for six months, during which time she discovered she was pregnant. I n September, 1960, she left the Army to join him i n the North, moving in with his immigrant family. Her mother-in-law, who speaks little English, was suspicious and accusatory to an extent suggesting paranoid psychosis. Her brother, 2 years older, drowned on the fishing boat in December and she was unable to return for the funeral. The baby was born in March. 1961, and 4 months later her mother-in-law, having lost another job because of her suspicious behavior, urged that Ruth go to work while she looked after 8 the baby. Ruth described feeling “pretty bad” and pressured during this “rough period”, but also felt that she’d rather work “hard and steady to make the time go faster.” Still experiencing sadness and “feeling like crying,” she started work as a nurse on a busy medical ward. She describes “keeping everything in-mother-in-law wouldn’t understand me anyway.” Ruth reported that she “exploded once” to her mother-in-law, “but regretted it-you just have to accept her”. In this setting, the first joint symptoms began in September, 1961. Ruth persuaded her husband to leave his parents, and in the summer of 1962, they moved to the area in the South where she grew up. When seen in follownp in May, 1963, all clinical evidence of her disease had disappeared. The healthy twin, Phyllis, during the corresponding time period, remained unmarried and continued to work as a nurse. Phyllis can describe her affective experience when her sister left her to move North. She reports missing her, and feeling lonesome and bored for a while. She noticed that she tended to eat more at this time and gained some weight. However, she recalls “getting used to it” after a short time. She began visiting home frequently and, when her brother died, assumed a great deal of responsibility to help the family through this period. Six months after the separation from her sister, she left the Army and moved to a large city about 40 miles from her home, obtaining a job at the same hospital in which her next younger sister was a student nurse. Phyllis describes becoming close to this sister. She looked after her and went home frequently, where she continued to assume an active and helpful role. When her twin sister returned to the South in the summer of 1962, Phyllis helped her and her husband buy a trailer and moved in with them. She does not get along with her brother-in-law and plans to move again to live with her younger sister. Phyllis continues to be in good health, having had only appendicitis in March, 1963. She dates some, but has no plans for marriage. She has enjoyed her work and her apparent mothering role with the younger sister. In reviewing parallel events for Phyllis, particularly regarding affective experiences and activities, it appears clear that for her the separation from her sister was a qualitatively different experience than Ruth‘s “entrapment”, and that the associated affect was less in intensity and duration. During the same period, in contrast to her sister, Phyllis was notably active, free to make frequent trips home and to assume the preferred role of responsibility and care for others. MEYEROWJTZ, JACOX, HFSS Of the sets we have studied, only in this set did such a separation of twins take place in close relationship to the affected twin’s illness. In the others, there has either been no separation, or else, as in one case, it took place years before. Summation. These twin sisters, age 26 years, were clinically and serologically discordant for rheumatoid srthritis. The affected twin had a definite rheumatoid arthritis, Class I, Stage 1. These twins were concordant for a diffusely enlarged thyroid gland. They had relatively similar life experiences until age 23, when the ultimately affected twin married. Six months later, the sisters separated for the €rst time. During the following year, the one who married became involved in a series of demanding and frustrating life events, in which setting rheumatoid arthritis developed. Her sister did not have a comparable experience. It is of interest that the affected twin’s disease showed sharp remission when she was able to leave the stressful situation with her in-laws and move back to the South with her husband and child. Set 3 Rita M. (SMH Unit No. 53-14-00),then a 60year-old, married, childless woman, was admitted to Strong Memorial Hospital on March 5, 1962. A little over 2 years before this admission, she first developed pain in the metacarpal and proximal interphalangeal joints. This was associated with swollen fingers and stiffness. A latex fixation test done at this time was said to be positive and the patient was treated with corticosteroids. Six months later, on reducing the steroids, she developed pain in the knees and ankles. This was sufficient to cause her discomfort on weightbearing, and at this time she was unable to use her hands for fine motion. Past History. The patient had chicken pox, measles, and mumps in childhood. Both she and her sister had smallpox in 1910. In 1933, at age 31, the patient had a right oophorectomy and appendectomy. In 1940, she had a left oophorectomy. Her general health has been excellent otherwise. Physical Examination. The blood pressure was 136/78. The patient appeared to be her stated age of 60 and was somewhat obese. The skeletal examination revealed that both elbows were re- 9 MONOZYGOTIC TWINS DISCORDANT FOR RA stricted by 20” of full extension. Both were somewhat tender but there was no active synovitis or swelling. Subcutaneous nodules were palpable over the extensor surfaces of the right forearm. The right wrist was swollen, tender, and limited in motion. The left wrist was normal. There was some fusiform swelling over the proximal interphalangeal joints of each hand with no deformities. Grip was poor bilaterally. The knees were tender, but had a full range of motion. No fluid was demonstrable within these joints. There was pain and mild limitation of motion in the right subastragular joint. The left had similar but less severe discomfort and there was considerable soft tissue swelling around this joint. All metatarsal joints were tender and slightly swollen. An aortic, grade 11, systolic murmur was heard. No diastolic murmurs were present. The heart was not enlarged. The remainder of the physical examination was normal. Laboratory Data. Latex fixation test, 1:320. LE test was negative. ANF test was not done. Roentgenograms. The hands showed demineralization of the carpal bones of the right wrist; the small joints of the hands were negative; the elbows were negative; soft tissue swelling of the left ankle was seen; the chest film showed a normal heart with fibrotic changes in both lung apices compatible with healed tuberculosis. Josephine K., identical twin sister of Rita M., married mother of 2 children, was seen at Strong Memorial Hospital, March 5, 1962. She had never had any joint symptoms and considered herself to be in good health. The only significant finding in her past history was that at age 28, a left nephrectomy was carried out for reasons that were not clear. This occurred shortly after the delivery of her first child. She had a tonsillectomy and appendectomy at age 21 and 22, shortly after her marriage. She had the same childhood diseases at approximately the same time as her sister. Physical Examination. The blood pressure was 128/70. She was a well-developed, well-nourished woman who had no stigmata of joint disease. The general physical examination was negative except for the nephrectomy scar in the left flank area and a laparotomy scar. Laboratory Data. The latex fixation test and the LE test were negative. Psychosocial Factors These twins remained very much identified with one another until quite late in life. Clear role differentiation (reflecting the actual birth order) developed early and has persisted: Rita, the affected twin, has always been the “baby” of the family who was more indulged and protected by her twin sister and others. They both experienced what they view as a pleasant childhood. They describe active participation in sports through college. Later they both became extremely committed to numerous church, club, and other organized social activities. Also, both place great emphasis on travel. Differences in life experience ensued after marriage. The ultimately affected twin has had an unsuccessful marriage with numerous disappointments, particularly that of childlessness. She has had continuing frustration because of her husband’s general lack of success. The onset of her illness followed a period of unusual involvement in various activities which entailed a high degree of responsibility and which, for the first time, the patient felt were beyond her usual energetic capacities. Summation. These 60-year-old, identical twin sisters were discordant for rheumatoid arthritis for 2 years at the time studied. ( A communication 3 years later, in 1965, revealed continued symptoms in the affected twin and no arthritic symptoms in the normal twin.) The affected twin has classical rheumatoid arthritis, Class 11, Stage 2, with a positive test for rheumatoid factor. Both twins have otherwise enjoyed good heaIth except for a number of surgical procedures, the reasons for which are unclear. Set 4 Marjorie D., a 66-year-old, married, mother of 2 was seen at University Hospital, Seattle, Wash- ington, on August 11, 1964. This patient stated that 4 years previously she first noted mild discomfort in the fifth left finger without other symptoms. One year later she developed a hot, swollen, painful ankle. Two years ago she had the sudden onset of a polyarthritis involving the feet, knees and hands. These complaints have been sufficiently severe that at times the patient has had to remain in bed and has frequently had to use crutches. Her predominant involvement has been pain, discomfort and disability in the hands and wrists. She has had morning stiffness and recurrent left temporomandibular pain. At the time of study her incapacity consisted of weakness of grip and easy fatigue. The past history revealed that the patient has had definite symptoms and signs of angina pectons and congestive heart failure which began 10 8 years before at age 58. She has taken diuretics and digitalis therapy since that time. At age 15 she developed a goiter which gradually increased in size. In 1949, at age 51, she developed a mild exophthalmus and shortly afterwards had a thyroidectomy for compressive symptoms. She had measles and chicken pox as a child, but not mumps. At age 26 she had an attack of pleurisy without any residual disease. A t age 27, she had a uterine suspension and appendectomy. In 1950, at age 52, she had her menopause, to which she attributed the typical depressive symptoms she then developed, but this also coincided with her mother’s death. PhysicaZ Examination. Blood pressure, 160/80. This patient had a striking physical resemblance to her sister, Hazel C., but in contrast was thinner and appeared chronically ill. There were several large, rubbery nodules palpable over the extensor surfaces of the left elbow. The olecranon bursa was thickened and contained fluiid. A small palpable nodule was present in the right olecranon bursa. There was swelling of the proximal interphalangeal joints. The metacarpal-phalangeal joints were negative. Both wrists were thickened and showed tenderness on extremes of motion. There was increased mobility of the radial-ulnar articulation in both wrists. The grip was bilaterally weak. The hips and knees were normal. There was increased heat and swelling over the left lateral malleolus with a normal range of motion in the ankle joint. There was bilateral slight thickening and tenderness of the metatarsal joints. Examination of the lungs showed a few crepitant rales at the left lower lobe. There was an absent right carotid pulse. There was a prominent pulsation in the abdomen associated with a small mass. Over this area a definite systolic bruit could be heard. Pelvic examination revealed senile vaginitis. There was absence of the lower tendon and biceps reflexes. (The patient stated that in the past no physician had ever been able to elicit tendon reflexes in herself or her twin sister.) Laboratory Data. Latex fixation test, 1:2560. LE test negative. ANF negative. Roentgenograms. The chest showed calcified hilar nodes with calcification in the aortic arch, but no cardiomegaly. There was diffuse, skeletal demineralization. There was diffuse demineralization and marginal erosions in the hands. Obliteration of the joint spaces was seen in the distal interphalangeal and proximal interphalangeal joints of the third and fourth right fingers and the third left finger. There were minor erosions seen in the joints of the second, fourth left and the fifth right fingers. There were pseudocysts and MEYEROWITZ, JACOX, HESS articular erosions of the metacarpal phalangeal joints of the second and fourth fingers of the right hand and the second and fifth fingers of the left hand. Erosive changes were present in the intercarpal joints, in the heads of the fifth metatarsal joints bilaterally, in the fourth and fifth metatarsal joints of the left foot, and the second and third metatarsal joints of the right foot. Bilateral 0s tibiale externu was present, with a similar lesion noted in the patient’s twin sister. Mrs. Hazel C., the twin of Marjorie D., a widow, was seen at University Hospital, Seattle, Washington on August 12, 1964. She stated that at age 29 she developed acute pain and swelling of the right knee and left wrist. At this time her husband simultaneously developed pain and swelling of the right wrist and the left knee. Mrs. C. was disabled to the extent that she was confined to bed and used crutches for 3 months. There was subsequent clearing of all joint symptoms until age 62, when she had the onset of an acutely red and sore left ankle which persisted for 2 days. It is significant that the husband at the time of the first joint symptoms was kept in the Veteran’s Administration Hospital for 3 months. He was treated with physical therapy for contracture deformity of the left knee. Mrs. C. and her husband were told that they had “inflammatory rheumatism”. She denied any symptoms of gonorrhea in herself or her husband. Apart from the above, she has had no morning stiffness and has had no joint symptoms for the past 2 years. At the time seen, Mrs. C.’s complaints related to hypertension which was first diagnosed at age 54 in 1952. Her first symptom was recurrent epistaxis. In 1960, because of a reported blood pressure of 260/190, she was treated with reserpine and a diuretic medication. Recently she has noted dizziness, infrequent substernal pain radiating into the jaw and transient visual disturbance described as “gray outs” which last for 30 minutes and usually occur with overexertion and overfatigue. In the past history, Mrs. C. had a thyroidectomy in 1942, at age 44, because of compressive symptoms from a goiter that began at age 15. Her menopause occurred at age 42 with no complications. She had measles, chicken pox, and mumps in childhood and had frequent colds in her early life. Other than this she has had good health. Physical Examination. Blood pressure, 170/90. Hazel C. was a well-developed, well-nourished woman who weighed 15 pounds more than her sister, Marjorie. She did not appear chronically ill. There was a large bony nodule at the distal interphalangeal joint of the fifth finger of the right hand. Smaller nodules at the distal inter- 11 MONOZYGOTIC TWINS DISCORDANT FOR RA phalangeal joints were present in the left hand. The left knee had a slight increase in the lateral and anterior-posterior motion compared to the right, but both knees had a normal range of motion with no effusion present. There was a prominent fat pad on the lateral malleolus of the right ankle with no evidence of inflammation. All joints had a normal range of motion without evidence of a synovitis. The fundoscopic examination showed mild arteriolar constriction. There was no cardiac enlargement, and no significant murmurs were heard. A systolic bruit was present in the upper abdomen, where a prominent pulsation was present. No mass could be palpated. The vaginal examination revealed senile changes. There was an absence of the lower tendon and biceps reflexes similar to that found in her sister. Laboratory Data. Latex fixation, ANF and LE tests were negative. Roentgenogram. Normal cardiac silhouette with arteriosclerotic densities seen in the aortic knob. There was diffuse skeletal demineralization. There was prominent spurring of the distal interphalangeal joints, which was most conspicuous in the fifth finger. Degenerative changes were present in the first metatarsal joints bilaterally. An 0s tibiak e r t m was seen bilaterally. There was no radiographic evidence of rheumatoid arthritis. These changes were consistent with osteoarthritis. P s y c h m d Factors These twins have had physically active lives. The affected twin, who earlier tended to be more dominant and assertive, has placed greater emphasis on recreational physical activity, and this still represents an important kind of gratification. The unaffected twin, who is currently depressed, has lost her husband and only son, and suffered a prolonged period of stress in caring for her demented mother through a deteriorating illness. Until her husband’s death she had enjoyed a positive and sustaining relationship with him. By contrast, the ultimately affected twin has been involved in a frustrating, conflict-ridden marriage for 48 years. This situation has become more intense for the last 12 years because of a chronic conflict between her husband and son. Her remaining opportunity for pleasurable activities with her son was threatened by this disagreement. The onset of generalized polyarthritis occurred within one week after a violent argument in which her husband forbade the son to visit and spend time with her. Summation.This set of identical %-yearold female twins are serologically, radio- graphically and clinically discordant for rheumatoid arthritis. The affected twin has classical rheumatoid arthritis, Class 11, Stage 2. The unaffected twin had an illness at age 29 which may have been an infectious arthritis which cleared without residual joint disease. These twins are concordant for mild generalized osteoporosis, goiter, hypertension and abdominal aortic arteriosclerotic disease. They have a concordant skeletal anomaly of bilateral 0s tibiale externa. They both have had an unexplained absence of the lower tendon and biceps reflexes. presumably for years. Set 5 Shirley T. (SMH Unit No. 50-38-85),a 65year-old, unmarried woman, was seen in Strong Memorial Hospital, July 14, 1961. This patient was moderately deaf, and, because of her birth in Poland and subsequent lack of education, she understood English imperfectly. She also showed evidence of a chronic paranoid psychosis which most likely is schizophrenia. Thus the history was obtained with difficulty. At age 60, the patient had the onset of pain and stiffness in both knees which gradually increased to involve the hands, back and elbows. She attributed the onset of these symptoms to a “hex” put on her by her priest while she was attending Mass. During the next 3 years, she developed progressive deformity of her joints associated with pain and stiffness. Two years ago, she noted the appearance of nodules on the extensor surfaces of both elbows. When she was first seen, she was obviously disabled by disease of the knees, hands, wrists and elbows. Evaluation of the past history was difficult. The patient never married. She lived with her married twin sister. She worked as a seamstress for 40 years. For the past 3 years, she had had a progressive hearing loss. At age 3, she fractured her right tibia which was improperly treated and which subsequently healed by malunion. Physical Examination. Blood pressure, 130/80. This patient was suspicious and frequently expressed paranoid delusions during the physical examination. Memory and orientation were intact. There was a severe angulated deformity of the right lower leg as a result of the childhood fracture. The right wrist was swollen, tender, hot and restricted in motion. The left wrist was sim. ilarly involved but had a greater range of mo. tion. All metacarpal-phalangeal joints were ten- 12 MEYEROWFIZ, JACOX, HESS she was admitted to the hospital for study and treatment of severe cervical pain. A positive test for the rheumatoid factor was found at this time. The patient was placed on steroid medication which has been continued to the present. She has been treated intermittently with intra-articular injections of steroids into both knees and wrist joints. During the past 2 years, the patient has had persistent bilateral knee effusions, stiffness and aching in the shoulders and hips. There has been intermittent pain in the sternoclavicular joints. She has had no pain in the low back, ankles or elbows. When seen, the patient had a Mrs. Elizabeth V., the twin sister of Shirley T., significant amount of morning stiffness and easy was seen at Strong Memorial Hospital on July 14. fatigue. 1961. She gave no history of any joint symptoms At age 6, the patient had a tonsillectomy. At at any time. The history was incomplete because age 8, she had acute appendicitis with subsequent of her unwillingness to cooperate in this study, intestinal obstruction which required 2 laparotobut on physical examination, there were no stig- mies. She has had frequent injuries, with an epimata of any joint disease and she had no nodules. sode at age 12 when she fell from a trapeze and Laboratory Data. Negative serum latex fixation hurt her wrists. At age 12, she again injured her test. Negative LE test. hand in a diving board accident, and at age 14 Summation. These are 65-year-old, iden- she injured her neck in a tumbling class. The tical twin sisters who are discordant for patient has had measles, mumps, and chicken pox as a child. She had no unusual susceptibility to rheumatoid arthritis by clinical and sero- respiratory illness. logical evidence, with the affected twin Physical Examillation. Blood pressure, 108/64. having had signs and symptoms of the dis- The patient was a very attractive young woman ease for 5 years, indicating classical rheu- who weighed 14 lb. less than her twin and was matoid arthritis, Class 11, Stage unde- a half inch taller. The second right proximal interphalangeal joint was cyanotic, swollen and paintermined. (In spite of a strongly positive ful on motion. The left wrist had increased heat LE test, the affected twin had no clinical and diffuse swelling. There was increased mobilevidence of systemic lupus erythematosus. ) ity of the left radial ulnar articulation. There was It was not possible to obtain detailed psy- swelling and tenderness of the right sternoclavicuchosocial data because of the lack of CO- lar articulation. The neck had marked limitation of motion with pain on attempted lateral motion, operation of both sisters. The affected flexion and extension. The hip joints showed a twin has remained unmarried, in contrast free range of motion. The knees had no effusion to her sister, upon whom she appears quite and had a normal range of motion without instadependent. The difficulty in communicat- bility. Both ankles were normal. The second left ing with the affected twin was heightened metatarsal joint was swollen and tender. There was increased vascularity of the sclera of the left by a manifest psychosis with paranoid de- eye, but the remainder of the physical examinzilusions (probably chronic paranoid schizo- tion was negative. Laborutmy Data. Latex fixation test, 1:1280. phrenia), by her deafness, and also by her ANF and LE tests, negative. poor command of English. Roentgenograms.The hands showed diffuse osteoporosis. There were cyst-like erosions of the Set 6 head of the proximal phalanx of the second right Henrietta D., age 16, was studied August 1 0 1964, at the University Hospital, Seattle, Wash- finger. The feet showed demineralization without any destructive lesions. ington. Helen D., twin sister of Henrietta, was also Two years before, at age 14, this patient first noted acute joint symptoms. These were charac- seen at the University Hospital, Seattle, Washterized by stiffness of the hands, feet and neck. ington, on August 11, 1964. This young woman considered herself to be in Within a few weeks, pain and swelling of the secexcellent health. She had noted mild intermittent ond right finger developed, and 4 months later der and swollen. There was an ulnar drift of the fingers with fusiform swelling of the proximal interphalangeal joints. There was a 15" flexion contracture of both knees with no effusion or active synovitis. The left ankle was limited in motion, Each elbow was limited by 30" of full extension. Laboratory Data. Latex fixation test, 1:5120. The LE test showed leukoagglutination with 8-10 LE cells seen in the entire smear. Roentgenograms. The patient refused to have any radiographs made. MONOZYGOTIC TWINS DISCORDANT FOR RA aching in the right knee after “cheerleading” and other types of unaccustomed exercise. She denied any morning stiffness or other joint aching. Her previous health had been excellent. She has not had any accidental injuries as were noted for her twin sister. She also had a tonsillectomy at age 6. She had the same childhood diseases as her twin sister except for appendicitis. Physical Examination. Blood pressure, 96/62. The patient was a very attractive healthy-appearing young woman who showed a striking resemblance to her twin sister. The physical examination was completely negative. All joints were normal. Laboratory Data. Latex fixation test, negative. ANF and LE tests negative. Roentgenograms. Hands and feet were normal with a normal bone age of 16 years. Psychosocial Factors. These twins have had until now rather similar life experiences. Until the onset of illness, both twins were actively engaged and skillful at a large number of physical activities some of which had a public exhibitionistic quality ( e.g., competitive diving, skiing, modeling, dancing). These were strongly stimulated and at times initiated by their mother. Some distinguishing personality characteristics include the ultimately affected twin’s greater competitiveness in these activities, and also her relatively greater discomfort and inability to cope with everyday stressful situations around school and family tensions. A number of injuries of the affected twin may or may not have been caused by her increased competitiveness and attendant risk-taking. Nevertheless, these led to a restriction of her physical activities so that she was no longer able to join her sister in numerous tandem activities which had been gratifying. This restriction was quite clear during months prior to disease onset, although there is no evidence of any other particularly differentiating stressful situation for one twin and not the other during the period preceding disease onset. Summation. The affected 16-year-old female twin, Henrietta, has classical rheumatoid arthritis, Class 11, Stage 2, with a positive test for rheumatoid factor. Her identical twin sister, Helen, has neither serologic, radiographic, or clinical evidence of any rheumatoid disease. Set 7 Sarah E. (SMH Unit No. 56-82-82)was seen at Strong Memorial Hospital on October 8, 1963, when she was 14 years old. 13 This patient first noted the appearance of pain on motion, warmth and swelling in the left knee nearly 3 years before. Six months later, she developed pain, swelling and increased warmth in the right knee, She was admitted to a hospital for one week, where fluid was aspirated from the left knee on 3 different occasions and intraarticular injections of steroids were made. At the time the patient was first seen in 1963, she complained of morning stiffness and had bilateral knee pain and had intermittent discomfort of the left wrist and shoulder, without pain on motion or limitation of motion. She had recently noted some discomfort in both temporomandibular joints. There was no history of any preceding streptococcal illness nor of any migratory polyarthritis. The patient has had measles, chicken pox and mumps. She had pneumonia at age 5, and at an early age had a mild skin disease diagnosed as eczema. Her general health had otherwise been excellent. The menarche began at age 11. A maternal first cousin, a 13-year-old girl, has rheumatoid arthritis. Physical Examination. Blood pressure 120/80. The patient was a pleasant, cooperative, intelligent young woman who did not appear ill. The physical examination was completely negative except for the following joint abnormalities. The left knee was swollen and warm with a large synovial effusion demonstrable. The right knee was swollen, warm, with a small effusion present. Both knees had a normal range of motion and neither showed any instability. The remaining joints appeared normal. An open synovial biopsy and two weeks later a synovectomy was done on the left knee. Numerous “rice bodies” were seen on both occasions. The synovium was markedly inflamed and the articular cartilage of the lateral femoral condyle was softened. Pathologic changes were present which were consistent with an active rheumatoid arthritis. The patient’s left leg was placed in a long leg brace. She wore this for 6 months. When last seen in May of 1965, neither knee showed any effusion and both had a normal range of motion. The patient was attending high school and was carrying out her usual physical activities. She occasionally complained of some discomfort in the right fifth proximal phalangeal joint and some aching and stiffness in both knees. Laboratory Data. Latex fixation, ANF and LE tests were negative. AS0 titer was 250. Susan E., the twin sister of Sarah E., was studied in October, 1963. She denied any symptoms of stiffness or any swollen joints and stated that she had no complaints. In the past history, she had infantile eczema until age 3 months, 14 when tliis cleared. Her sister's eczema persisted until she was 12 months old. Susan had measles a t age 3, followed by pneumonia similar to the disease experienced by her sister. At age 10 she had a severe finger laceration which healed without any residuum. Her menarche began at age 11, shortly after that of her sister. On complete physical examination, no abnormalities were noted. The blood pressure was 118/78. She showed a striking resemblance to her twin, Sarah. Laboratory Data. Latex, ANF and LE tests were all negative. Psychosocial Factors These twin girls are greatly involved in physical activity, such as swimming, gymnastics and baseball, in which they excel. They also work on the family farm. In spite of some lack of clarity in eliciting psychological data, there appeared to be consistent accounts of personality differences in terms of the ultimately affected twin assuming a more dominant, outgoing role in which she was given and accepted, although resentfully, more responsibility. Both girls, especially the affected twin, were called upon to do much more work around the house and farm during the year and a half preceding disease onset in the affected twin, because of illnesses and hospitalizations of both parents. The affected twin can recall her resentment about being given the larger share to do, but it is not possible to delineate clearly to what extent this was a psychologically stressful situation. Summation. These identical twin girls studied shortly before their 15th birthday are discordant for definite Class 11, Stage 1, sero-negative rheumatoid arthritis. Both are extremely active girls who were in good health except for some minor discordant illnesses up until the gradual onset of monoarticular arthritis nearly 3 years before in one of them. Set 8 Carol B. (SMH Unit No. 56-68-55), then age 8, was first seen at Strong Memorial Hospital on June 6, 1962. In August, 1961, when she was 7, this patient's parents first noted swelling of her right knee. The knee was aspirated, but the fluid reaccumulated rapidly and continued to be swollen and yet free of pain, Repeat joint aspiration was made in September, 1961, which wa.c negative on culture. A biopsy was done on October 27, 1961, which revealed a moderately chronic MEYEROWITZ, JACOX, HESS inflammation of the synovium considered to be compatible with the diagnosis of rheumatoid arthritis. The patient continued to have swelling of the knee and slowly developed a flexion contracture during the next few months. She denied any symptoms of morning stiffness or other joint coinplaints. She had had measles, mumps, and chicken pox as a child with no other medical illness or surgical procedure. Physical Examination. Blood pressure, 98/66. The patient was a well-developed, well-nourished young girl in no distress. The complete physical examination was unremarkable except for the right knee which had an increase in warmth. A small effusion was present with associated evidence of synovial thickening. The right knee was limited by 25" of full extension. Forced motion was somewhat painful. The left knee was normal and all other joints were normal. The patient was treated by a serial application of casts and after 3 weeks the right knee was fully extended. A double caliper walking brace was fitted to the patient's right leg which she wore for nearly a year. She had intensive physical therapy and used night splints during this time. Despite good therapy, the patient continued to have a chronic effusion in the right knee. The range of motion remained normal. In July, 1964, a t age 10, she first complained of stiffness and swelling of the left knee. This joint showed an increase in warmth and a small effusion. When the patient was last seen on December 16, 1964, a continued synovitis of both knees was observed. Laboratory Data. Latex fixation, LE and ANF tests were all negative. Roentgenograms of the knees were negative. Connie B., twin sister of Carol B., was first seen at Strong Memorial Hospital in 1962. When examined in August of 1963, at age 9, she gave a history of having no joint symptoms whatsoever and of being unusually active. She had measles at age 4 and mumps at age 5, within one day of the time that her sister got the same diseases. At age 7 she fractured her forearm which healed without complications; this accident occurred several weeks after the onset of her sister's arthritis. Physical examination. The blood pressure was 92/68. A complete physical examination revealed a normal, healthy, young girl with no stigmata of any joint disease. Laboratory Data. Latex fixation tests, LE and ANF all negative. Psychosocial Factors These twins have been extremely active physically since they could walk. Some consistent personality differentiation has detected, with the 15 MONOZYGOTIC TWIh-S DISCORDANT FOR RA affected twin more overtly aggressive. However, no differentiating life experience was detected. During the year preceding disease onset, the family had to adjust to a move to a new community. The mother was depressed during this period. However, the response of the twins to the move and to mother’s distress was apparently minimal; there is no evidence that these events affected one more than the other. Summation. These are 12-year-old identical twins, one of whom has had definite rheumatoid arthritis, Class 11, Stage 1, for 5 years (by last followup). This was initially a monoarticular arthritis, but now consists of bilateral knee disease. Both twins are serologically negative. Both twins have otherwise had unremarkable health. TESTDATA PSYCHOLOGICAL A rather extensive battery of psychological tests was administered to 7 of the 8 sets of twins. The twins of Set 5 were not tested. Measures of IQ and cognitive functioning showed the high degree of relationship expected between identical twins. Except for the dull-normal level in Set 8, the twins’ capacities fell within the range of average to bright-normal intelligence. Tests purportedly sensithe to certain kinds of organic defects did not distinguish the arthritic twins as a group. Greatly condensing the results from various projective techniques, the arthritic twins revealed lowered productivity, somewhat less adequate defenses, possibly with feelings of psychological vulnerability, and response patterns which resembled, at least partially, those of psychosomatic groups. Indices of the level of anxiety, of body-image boundaries, and of the amount and directio3 of expression of aggression, i.e., internalizing vs. actingout, were non-differentiating and tended not to confirm expected relationships with rheumatoid arthritis. Interpretations based on more detailed analyses will be included in a forthcoming publication dealing more extensively with psychological aspects of this study. DISCUSSION Genetic Aspects Any phenotypical differences between monozygotic partners must be due to environmental influence, whereas dizygotic partners may also differ because of different genic characteristics. If one assumes a nearly identical environment for monozygotic partners, then interpair differences should be minimal. In practice, however, judgments about concordance or discordance of traits may be fraught with inaccuracies. Thus, diabetes in a co-twin may have an early onset, whereas the partner’s disease may appear after many years. The severity of disease may also vary. An epileptic twin may have chronic epilepsy while the co-twin may have seizures only with stress, such as during fever or after a head injury. One of a monozygotic set of twins may have early environmental stresses not existing for the partner. In some cases, a common placenta may starve out a co-twin by virtue of a different circulation. Despite these variabilities, the twin model affords a unique opportunity to investigate the role of genic versus environmental factors in the induction of a disease process. A review of the world literature of monozygotic twins reported by Moesmann in 195915 reveals that a total of 50 cases have been published in which rheumatoid arthritis occurred in identical twins either concordantly or discordantly. The degree of concordance reported in this series is 36 per cent. A careful evaluation of these reported studies reveals, however, that many of the cases cannot be fitted into modern diagnostic criteria for rheumatoid arthritis. Many of these reports also contain little information concerning the method for identifying zygosity. The most accurate study is that of Moesmann’s own cases. Three sets of twins were observed to be discordant for rheumatoid arthritis. In all of these affected individuals, 16 the diagnosis of rheumatoid arthritis was clearly established. In one twin set, age 36, the discordance had continued for 21 years. Another twin set of 63-year-old women were discordant for 30 years. A third twin set of 71-year-old men was described in which the affected individual had his disease for 5 years. His unaffected brother died at age 69 with no stigmata of rheumatoid arthritis. Moesmann includes a fourth set of 50-year-old women with concordant arthritis who had sero-negative tests for the rheumatoid factor.16 From the history and from an analysis of the published roentgenograms of the hands of these twins, we feel that the disease in this set should be classified as osteoarthritis rather than as a variant of rheumatoid arthritis as suggested by Moesmann. In many other twin reports a diagnosis of rheumatoid arthritis appears to be confused with a diagnosis of recurrent rheumatic fever. An example is found in the study of Brandt and Weihe? in which, in 9 twin sets, it appears that the twins should be diagnosed as having had rheumatic fever. A number of this group developed rheumatic heart disease. One discordant set reported by these authors can be identified as having classical rheumatoid arthritis. Two other twin sets can be identified as having probable rheumatoid arthritis. In Edstrom’s series of monozygotic twins identified as having concordant rheumatoid arthritis? it is noted that one set had a short course of insidious polyarthritis which then underwent complete recovery. Thus, one cannot establish a diagnosis of rheumatoid arthritis with certainty. In 2 sets of discordant twins, there was a similar problem of accurate diagnosis. One set had chorea and acute polyarthritis. In all of these twin sets, there was ultimate recovery of the affected member without any joint disability. Thymann’s report20 of discordant rheumatoid arthritis in 8 twins and of concordant disease in 3 twins is a brief abstract MFXEROWlTZ, JACOX, HEX which gives no details of diagnostic criteria, nor of methods used for establishing zygosity. Claussen and Steiner’s study of 43 monozygotic twins4 consisted of a questionnaire type of investigation. This report provides no details by which one can judge either the method of zygosity determination or the criteria by which a diagnosis was determined. Grossman reported 73year-old Negro twins with late onset type of rheumatoid arthritis in which there is no question about the diagnosis of rheumatoid arthritis.1° There is, however, little description of the method of determining zygosity. This analysis of the reported literature, including our own 8 twin sets, indicates that 28 twin sets can be identified as monozygotic. In 25 instances rheumatoid arthritis was discordant. There is, therefore, an overall incidence of concordance of only 10.7 per cent. A point of interest in our investigation is that in 6 twin sets, rheumatoid arthritis was not only clinically discordant but also serologically discordant. These data provide evidence against the notion that rheumatoid arthritis is inherited. The study of Bunim et al. of American Indian populations3 also shows that the distribution of rheumatoid disease in these groups cannot be interpreted as being genetically significant. We have not been impressed with any family history of rheumatoid arthritis in our subjects. Nor has there been any history of collagen disease in our twin families similar to that described by Leonhardtl? in his study of disseminated lupus erythematosus. Clinical Aspects The clinical findings in our investigation clearly reveal discordant rheumatoid disease in each set. None of the unaffected twins had significant symptoms of joint disease except for the unexplained atypical acute arthritis in Hazel C. of Set 4, occurring 38 years before she was studied. MONOZYGOTIC TWINS DISCORDANT FOR RA Our investigation, furthermore, reveals no patterns of growth, development or other physical illnesses that would appear etiologically related to the subsequent occurrence of rheumatoid arthritis. There is no consistent trend in birth size or birth order nor in adult size. There are no notable differential lags in developmental achievements, such as walking or talking, within twin pairs. Menarche is reported to have occurred in both sisters of each pair within hours to months of one another (except that such information is unavailable for Set 5 and menses have not begun in Set 8). Within all twin pairs the same childhood diseases occurred, except that in Set 4 only the unaffected twin had mumps. On this there is no information in Set 5. Many of the twin sets were concordant for other deviations of health or concordant with respect to certain bone abnormalities. In several instances, concordant thyroid disease, hypertension, and vascular disease was seen. Discordant illnesses such as herpes zoster, pneumonia and cerebral vascular accident, are scattered through the 8 sets. An apparently high incidence of abdominal surgical procedures occurred, more frequently involving the affected twin. In Set 1, the affected twin had an operation for “ovarian tumor” with subsequent complications at age 15. In Set 3, both twins had such procedures in their twenties and thirties for appendectomy, oophorectomy and nephrectomy. In Set 5, there is no history of such procedures. In Set 2, the affected twin had an appendectomy at age 23, a year before the onset of rheumatoid disease; her sister had the same procedure at age 26. The affected twin of Set 4 had a uterine suspension and appendectomy at age 27, and the affected twin of Set 6 had surgery for intestinal obstruction and appendicitis at age 8, while neither of their sisters have had such procedures. In Sets 7 and 8, the 14- and 8-year-olds, there was no history of surgical operations. Any re- 17 lationship of such procedures to the later occurrence of rheumatoid arthritis can be no more than a point of speculation. The most direct consequence of these surgical procedures may be the psychologic effects of the resultant restriction of physical activity in previously active young girls. One is always concerned about the problem of delayed onset of disease in twin studies. Duration of discordant disease ranges from 4 to 26 years in our twin material. The two cases by Moesmann15 who had their disease more than 15 years, and the case in our own series who has had the disease for 26 years, suggest that the risk of later disease in the unaffected twin may not be an important factor. Psychosocial Aspects The data discussed here pertain to only 7 of the 8 sets of twins. In the case of Set 5, adequate psychosocial data could not be obtained for reasons mentioned in the description of the case material. We believe that the most striking finding in the psychosocial data pertains to the involvement of the ultimately affected twin, for months to years prior to disease onset, in a series of life events which are inferred to be demanding and restricting. The quality of these life events has a tendency to be similar in the different individuals studied, and we have chosen the term entrapment to denote the particular nature of this psychological stress experience. It consists of conditions under which the individual feels responsible to meet the demands of a close object or of a situation, initially with the premise that they must do something about the situation. They respond with characteristic heightened activity-managing, doing for or taking care of. (Their preference for this kind of activity will be discussed below.) Such situations, which are perceived as demanding, finally come to impose limitations on their own mobility and comfortable high activity level. It is at this point that the occurrence of psycho- 18 logical stress is inferred from the presence of disruptive or unpleasant affect, either directly expressed or reported by the patient and/or reported by the others interviewed. Such psychological stress with the quality of entrapment was clearly seen to occur prior to disease onset in the affected sibling of each of the 4 sets of adult twins considered here. Comparable involvement was not seen in the unaffected twin in each of these adult sets. Entrapment in these adult twins has been illustrated in the case material: in Set 1, the devotion of the affected twin to the care of the psychotic stepfather; in Set 2, the attempt of the affected twin to carry on and maintain herself in a difficult situation with her in-laws through the medium of going back to work; in Set 3, the affected twin’s involvement in activities that were beyond her capacity in the broader context of the chronically disappointing marriage; and in Set 4, the affected twin’s involvement in a chronically frustrating marital situation, further accentuated by the threat of being cut off from her son who was the only source of pleasurable activity. Of the 3 younger pairs of twins, the discordant occurrence of psychological stress also with the quality of entrapment is only suggested in 2 (Sets 6 and 7), and is not seen at all in the third pair (Set 8). Examining both concordant and discordant personality traits in the clinical material, we are next impressed with the regular appearance of a conspicuous preference for activity in both members of the 7 sets. Other observer^^.^^^^ have previously noted the interest and participation of patients with rheumatoid arthritis in sports and other forms of physical activity. Various psychological implications of this activity have been emphasized. In the twins we have studied, this activity includes, first, body movement, as manifested by a lively interest and participation in athletics and physical recreation, at times retrospectively MEYEROWI’IZ, JACOX, HESS described by the older twins, but seen currently in the children who were studied. The mothers of each of the younger twins (Sets 6, 7 and 8) describe in some detail the extraordinary physical activity of these children. In Set 6 the mother reports extremely active behavior since age 2; the twins appeared to her to “wear out their friends” by their activity. The emphasis on physical activity has persisted since, leading to a great involvement in competitive sports, at which they have excelled. For example, at age 13, one twin took first place and her sister second place in an interstate diving meet. In Set 7 there were similar observations; here, in addition to the prominent involvement in athletics, both girls have enjoyed outdoor work on the farm. In Set 8 the mother also reports that her twin daughters were “on the move every minute, never sitting still” since they began to walk. Even after the illness in the affected twin she “was riding horses with her brace . . . and even in the wheelchair was doing things you wouldn’t think possible.” This broad term, actioity, may also include a dimension of preferred mobility in space so that in the adult subjects there is seen a great interest and actual involvement in travel and moving. Another dimension of activity consists of a characteristic style of object-relating with an emphasis on managing, assuming responsibility, doing for and taking care of others. From a theoretical viewpoint, the observed activity is inferred to be a derivative of a specific style of ego functioning which is relatively autonomous, that is, not necessarily a reactive of defensive pattern. Such people appear most “comfortable” when they can maintain a self-representation of being active. Either physical activity or objectrelating is seen to be emphasized in different individuals or in the same individual at different times in life. Also, with the occurrence of psychologic stress, the same 19 MONOZYGOTIC TWINS DISCORDANT FOR RA ego style becomes a preferred form of defense or coping. Any number of personality differences between twins can be detected in the material. One aspect of the developmental psychology of twins consists of the differentiation of each twin’s identity into differing or comp!ementary positions regarding any number of dimensions. Parents and other family members attributing differing characteristics, both real and imagined, to twins contribute further to polarization of identity. Among the prominent dimensions of identity differentiation within the twin pairs we have studied are some of the following: the more dominant versus the more passive twin (variably expressed as the older versus the younger, or the leader versus the follower ) ; lability versus control (the freedom of one twin to express resentment in contrast to the relative inhibition of the other); or the more competitive versus the less competitive twin. A large number of such differences can be detected in any twin set. The above are just a few examples which seem most prominent in the case material. There is no consistent relationship between the presence of any one of these personality characteristics and the occurrence of rheumatoid arthritis. However, such differentiating personality characteristics in one twin are seen to have a relationship to the occurrence of psychologic stress in that twin. As an example, in Set 6, the ultimately affected twin was always the much more competitive one, to whom top performance was more important, so that it may be inferred that the restriction imposed by her injuries was more psychologically stressful for her than it would have been for her sister. Similarily, in Set 1, it was the affected twin who always assumed more responsibility, and hence she was more vulnerable to becoming involved in the psychologically stressful situation of taking care of the psychotic stepfather. In the other cases where psychological stress is an issue, it is also possiblc to identify one or more specific differential personality characteristics of the ultimately affected twin which played a role in determining which life events were psychologically stressful for her. However, there is no implication that any single personality characteristic was directly related to the occurrence of rheumatoid arthritis. The main similarity in personality characteristics, as already mentioned, pertains to the dimension of activity, and we find that this pattern, which exists in both twins of each set, tends to be seen in other rheumatoid arthritis patients we have studied. This suggests that rheumatoid arthritis may tend to develop in a particular kind of individual who may be identifiable through a cluster of personality traits seen with relative frequency. Furthermore, such an individual who is vulnerable to the illness may first develop the disease in a setting of psychologic stress. One must assume that there are multiple and as yet unknown factors in the pathogenesis of rheumatoid arthritis. We can only state that the onset of manifest rheumatoid arthritis seems to be determined by factors mediated in the course of psychological stress. It is difficult to delineate with certainty the role of psychologic stress because judgments about scch stress do not lend themselves to precise quantitation or reliability. Ordinarily in such a clinical study, the patient serves as her own control, comparing one time segment to another in terms of feeling states, life events and diseases. It should be pointed out, however, that twin studies provide additional control for analysis of psychological factors. Data about judgments and feelings of one twin can be compared with observations of the cotwin. For these reasons a retrospective history can be more accurately interpreted. SUMMARY Detailed clinical, psychosocial and laboratory data have been collected in 8 20 MEYEROWllZ, JACOX, HESS proven monozygotic twin pairs discordant set. A similar finding of psychological stress for rheumatoid arthritis. The diagnosis was experience was less clearly demonstrated established clearly in each of the affected in 2 of the 3 younger sets of twins and not twins, while no evidence of the disease seen in the third set of children. In all cases appears in their sisters. In the 6 sets in there was no comparable experience of which rheumatoid factor was present in the such stress for the unaffected sister. In addition, there was a personality trend affected women, their co-twins had negative latex-fixation tests. In the 2 youngest towards great involvement in physical acsets, with disease onset in childhood, rheu- tivity in both twin sisters of all sets. Howmatoid factor is absent in the affected girls ever, no consistent personality trends were found which would differentiate the twin as well as their healthy co-twins. Critical review of previous reports of with rheumatoid disease from her sister. arthritis in twins in the world literature These findings imply that the onset of leads us to conclude that in 20 monozy- rheumatoid arthritis is related to factors gotic twin sets, in only 3 instances has mediated in the course of psychological there. been concordance of rheumatoid stress. arthritis. Adding the 8 sets in our series, 25 ACKNOWLEDGMENTS out of 28 sets have been discordant. These We are grateful to Dr. John L. Decker and findings provide evidence against hypotheses that heredity is an important factor in Dr. Louis A. Healey for having made it possible for us to study 3 of the twin pairs. Dr. F. H. Allen, rheumatoid disease. at the Community Blood Council of Greater Jr., Our investigation reveals no consistent New York, carried out the detailed blood typing. differential patterns of development or Dr. Lester A. Cramer and Dr. Alton Ochsner, Jr. health deviations preceding the occurrence performed the skin grafting. We appreciate Dr. of disease in one twin of each pair. De- William A. Greene’s valuable assistance and adtailed psychosocial data obtained from 4 vice in the analysis of the psychological data. out of the 5 adult twin sets reveals, how- Helpful criticism and guidance came from Dr. ever, that in all 4 affected twins a period George L. Engel and Dr. Karel Planansky. Mrs. of psychological stress preceded disease on- Ruth Phillips provided technical assistance. SUMMARIOININTERLINGUA Detaliate datos clinic, psychologic, e laboratorial esseva notate pro 8 pares de geminos monozygotic con discordantia relative a arthritis rheumatoide. Ante le declaration del morbo, nulle systematic deviationes disveloppamental o sanitari esseva traciabile in le subjectos afficite, differentiante les ab lor co-geminos. 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