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Monozygotic twins discordant for rheumatoid arthritisa genetic clinical and psychological study of 8 sets.

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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
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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. Tamen, in 4 de 5
adulte geminos afficite, un period0 de stress psychologic precedeva le declaration del
morbo, sin comparabile experientia pro le non-afficite fraternos. Le signification de iste
constatationes es discutite.
REFERENCES
1. Barter, R. W.: Familial incidence of rheumatoid arthritis and acute rheumatism in 100
rheumatoid arthritics. Ann. Rheum. Dis.
11:39, 1952.
2. Brandt, G., and Weihe, F. A.: Polyarthritis
rheumatica bei zwillingen. Z. Menschl.
Vererb. Konstitutionsl. 23: 169, 1939.
3. Bunim, J. J., Burch, T. A., and O’Brien,
W. M.: Iduence of genetic and environmental factors on the occurrence of rheu-
matoid arthritis and rheumatoid factor in
American Indians. Bull. Rheum. Dis. 15:
349, 1964.
4. Claussen, F., and Steiner, F.: Verh Deutsch.
Ges. Inn. Med. 50 Kongr:299, 1938.
5. Cleveland, S. E., Reitman, E. E., Brewer,
E. J., Jr.: Psychological factors in juvenile
rheumatoid arthritis. Arthritis Rheum. 8:
1152, 1965.
6. Cormier, B. M., Wittkower, E. D., Marcotte,
MONOZYGOTIC TWINS DISCORDANT FOR RA
Y., and Forget, F.: Psychological aspects
of rheumatoid arthritis. Canad. Med. Ass.
J. 77:533, 1957.
7. de BlBcourt, J. J., Polman, A., and de Blkcourt-Meindersma, T.: Hereditary factors
in rheumatoid arthritis and ankylosing
spondylitis. Ann. Rheum. Dis. 20:215,1981.
8. Edstrom, G.: Klinische studien iiber den
chronischen gelenkrheumatismus: I. Das
erbbild. Acta. Med. Scand. 108:398,1941.
9. Gowans, J. D. C., Evangelista, I., and OSullivan, M. A.: Familial factors in rheumatoid
arthritis. Arch. Int. Med. 113:744, 1964.
10. Grossman, A. J., Leifer, P., and Batterman,
R. C.: The occurrence of rheumatoid arthritis in twins. Acta Rheum. Scand. 2:161,
1956.
11. Johnson, A., Shapiro, L. B., and Alexander,
F.: Preliminary report on a psychosomatic
study of rheumatoid arthritis. Psychosom.
Med. 9:295,1947.
12. Leonhardt, T.: Family studies in systemic
lupus erythematosus. Acta Med. Scand.
176:1984 (Suppl. #416).
13. Lewis-Faning, E.: Report on enquiry into
aetiological factors associated with rheumatoid arthritis. AM. Rheum. Dis. Lond.
9:94, 1950 (Suppl.)
21
14. Miall, W. E.: Rheumatoid arthritis in males.
An epidemiological study of a Welsh
mining community. Ann. Rheum. Dis. 14:
150, 1955.
15. Moesmann, G.: Factors precipitating and
predisposing to rheumatoid arthritis as illustrated by studies in monozygotic twins.
Acta Rheum. Scand. 5:291, 1959.
16. Ropes, M. W., Bennett, G. A., Cobb, S.,
Jacox, R., and Jessar, R. A.: 1958 revision
of diagnostic criteria for orheumatoid arthritis. Arthritis Rheum. 2:16, 1959.
17. Short, C. L., Abrams, N. R., and Sartwell,
P. E.: Factors associated with onset of
rheumatoid arthritis: A statistical study of
293 patients and controls. Am. Rheum.
Assoc.: Rheum. Dis. W. B. Saunders, Co.,
Philadelphia, 1952.
18. Stecher, R. M., Hersh, A. H., Solomon, W. M.,
and Wolpaw, R.: Genetics of rheumatoid
arthritis: Analysis of 224 families. Am. J.
Hum. Genet. 5:118, 1953.
19. Steinbrocker, O.,Traeger, C. H., and Batterman, R. C.: Therapeutic criteria in rheumatoid arthritis. J.A.M.A. 140359, 1949.
20. Thymann, G.: Polyarthritis in twins. Acta
Genet. 7:148, 1957.
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