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Occurrence of ankylosing spondylitis in a nationwide series of twins.

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ARTHRITIS & RHEUMATISM Volume 38
Number 3, March 1995, pp 381-383
0 1995, American College of Rheumatology
38 1
OCCURRENCE OF ANKYLOSING SPONDYLITIS IN A
NATIONWIDE SERIES OF TWINS
PENTTI JARVINEN
Objective. To obtain information on the rate of
concordance for ankylosing spondylitis (AS) in a
population-based series of twins.
Methods. AS cases were identified by record
linkage of the population-based Finnish Twin Cohort
and the nationwide registry for fully reimbursed medications. A clinical examination was performed to establish concordance for AS.
Results. There were 6 monozygotic (MZ) pairs
and 20 dizygotic (DZ) pairs with at least 1 member
affected by AS. Three MZ pairs and 3 DZ pairs were
concordant for the disease. All affected subjects were
HLA-B27 positive. The pairwise concordance rate was
50% in MZ twins and 20% in HLA-B27 positive DZ
twins (95% confidence intervals 11.8-88.2% and 4.3%48.1 %, respectively).
Conclusion. These results indicate that AS disease expression is largely, but not entirely, genetically
based, with a gene or genes other than B27 probably
playing a role.
Both genetic and environmental influences play
a role in the etiopathogenesis of ankvlosing spondylitis
(AS) (1). This disease shows a striking association with
a genetic marker, HLA-B27. Family studies have
shown that -20% of the first-degree relatives f AS
probands also have this disease. Among ranuomly
selected B27 positive individuals, the risk is substantially smaller. These observations suggest either the
influence of additional genes or the role of a shared
environment. Indeed, the presence of HLA-Bw60 has
been reported to increase susceptibility to AS in B27
positive patients (2).
Supported by the Rheumatism Research Foundation,
Finland.
Pentti Jarvinen, MD: Rheumatism Foundation Hospital,
Heinola, Finland.
Address reprint requests to Pentti Jarvinen, MD, Kiljava
Hospital, FIN45250 Kiljava, Finland.
Submitted for publication March 21, 1994; accepted in
revised form September 10, 1994.
There have been 110 previously reported
population-based studies of AS in twins. The published data, consisting of case reports and small case
series, are too sparse to allow estimation of concordance rates for AS in monozygotic (MZ) and dizygotic
(DZ) twins (3). The only definitive conclusion to be
drawn from these reports is that there are MZ twins
who are discordant for AS (4).The present study was
undertaken to estimate rates of twin concordance for
AS, using data from the Finnish Twin Cohort.
PATIENTS AND METHODS
Twenty-seven individual twins who had been diagnosed by their attending physicians as having AS, representing 26 twin pairs (6 MZ pairs anti 20 DZ pairs; both members
of 1 DZ pair were identified independently of each other),
were identified by record linkage of the population-based
Finnish Twin Cohort (consisting of 4,137 MZ twins and 9,162
same-sexed DZ twins) and the nationwide registry for fully
reimbursed medications (5). Twin zygosity was determined
by examining the response of both members of the twin pair
to questions on the similarity of appearance and confusions
by strangers during childhood (6) and was verified in apparently MZ pairs by determining the genetic markers included
in paternity examinations routinely performed in Finland (7).
After approval of the study by the institutional ethics
committee, clinical examinations were performed. AS was
diagnosed according to the New York criteria for definite AS
(8). In some instances twins were visited at home. Chest
expansion was measured at the level of the fourth intercostal
space and was recorded as abnormal if <2.5 cm. Anterior
spinal flexion was measured by Schober’s test. Lateral
spinal flexion and extension werle evaluated subjectively and
recorded as abnormal if judged to be <75% of normal.
Ophthalmologic sequelae of anterior uveitis were recorded.
Functional outcome was graded 1-4 according to the Steinbrocker criteria (9). In the MZ pair with both AS and
rheumatoid arthritis (RA) (see below), the complete HLA
type was documented by antibtody-dependent cytotoxicity
testing (lo), initiated for the present study. In others, only
HLA-B27 was tested in the present study. The prevalence of
HLA-B27 in the Finnish population is 14%. After informed
consent was obtained, radiographs of the sacroiliac joints
were taken if current ones were not available. However,
JARVINEN
382
Table 1. Demographic and dislease characteristics of the probands
with ankylosing spondylitis
No. maleslno. females
Mean (range)
onset, years
Mean (range) current
age, years
Mean radiologic grade of
sacroiliitis, 0-4 scale
Extraarticular
manifestations, %I
Monozygotic
twins (n = 6)
Dizygotic
twins (n = 21)*
511
24.7
(15-38)
45.8
(37-57) t
3.3
I912
21.3
(1 1-33)
49.5
(36-68)$
3.4
50
52
* Both members of I dizygotic pair were identified by record linkage
independently of each other.
t One index twin from a monozygotic pair had died at the age of 42.
$ One index twin from a dizygcitic pair had died at the age of 68.
8 Anterior uveitis and aortitis.
asymptomatic B27 negative twin sibs of B27 positive DZ
probands were not requeste:d to undergo radiography. The
radiographs were read by a radiologist who was unaware of
the clinical data and were sclored according to the New York
radiographic criteria (grader;0-4) (8). Existing spinal radiographs were reviewed, or new ones were obtained when
clinically indicated.
Two male probands, representing 1 MZ and 1 DZ
pair, had died. Analysis of their hospital records and spinal
radiographs showed that the MZ twin proband had definite
AS, and the DZ twin probanid had classic AS with a bamboo
spine. One asymptomatic and clinically unaffected B27 positive DZ twin refused to cooperate with respect to the
sacroiliac radiography.
RESULTS
Pertinent data on the probands are shown in
Table 1. All probands had AS according to the New
York criteria. The were no significant differences
between the MZ twin and DZ twin probands with
regard to age at onset of AS, disease duration, severity
of sacroiliitis, or frequency of extraarticular manifestations. The mean functional score was 2.3. In contrast, a normal functional score and a somewhat
shorter duration of AS were noted in the AS cases
identified as a result of the present followup study. For
probands, the mean disease duration was 27 years.
Twin concordance rates are shown in Table 2.
In summary, both members of 3 MZ pairs and 3 DZ
pairs had AS. Two MZ pairs were discordant for all
features of AS. In addition, in 1 MZ pair and 4 DZ
pairs, the less severely alffected member, who was not
classified as having AS, did have grade 2 radiologic
sacroiliitis. All affected subjects were HLA-B27 positive. In contrast, all 5 individual twins who were B27
negative were unaffected members of DZ pairs. Two
MZ twin probands and 1 DZ twin proband had aortic
insufficiency. Three DZ twin probands had had total
hip replacements. Four individuals, representing 3
twin pairs (1 MZ), were diagnosed as having both AS
and RA.
DISCUSSION
There are a number of issues that should be
considered with regard to the study design of the
current investigation. Because the clinical expression
of AS varies widely and there is great variation in the
need for treatment, most cases remain undiagnosed. A
clinic-based twin series would obviously favor inclusion of severe cases as probands. In contrast, if the
probands are recruited by advertising, MZ twins and
twins concordant for the disease are preferentially
recruited. (MZ twins are known to be more interested
in participating in studies than are DZ twins.) To
minimize these biases, AS cases in the present study
were sought by record linkage from two sources of
data: the population-based Finnish Twin Cohort and
the nationwide registry for fully reimbursed medications. Those identified were used as probands. Both
members of the available twin pairs were then examined, and concordance rates were determined
based on fulfillment of the New York criteria for definite AS (8).
In this study, all features of AS segregated with
HLA-B27. The 20% pairwise concordance rate in B27
positive DZ twins is well in accordance with earlier
observations made in family studies (11). The MZ
concordance rate indicates the maximum level of
Table 2. Pairwise concordance rates for 6 monozygotic (MZ) and
20 dizygotic (DZ) twin pairs with at least 1 member affected by
ankylosing spondylitis*
MZ pairs
Ankylosing
spondylitis
Radiologic
sacroiliitis (grade 2)
Anterior uveitis
DZ pairs
(1 1.8-88.2)
20t
(4.3-48.1)
66.7
(22.3-95.7)
33.3
(4.3-77.7)
(23-77)
13.3t
(1.7-40.5)
50
SO$
* Values for pairwise concordance rates are percentages. Values in
parentheses are 95% confidence intervals; exact values were used
(ref. 15).
t Concordance was based on 15 B27 positive DZ twin pairs. The
pairwise concordance rate for all 20 DZ twin pairs was 15% (95%
confidence interval 3.2-37.9).
$ Concordance was based on 14 B27 positive DZ twin pairs.
AS
CONCORDANCE IN TWINS
383
possible genetic contribution for AS. Since the pairwise concordance rate was greater in MZ twins than in
B27 positive DZ twins, a role for additional genetic
factors, such as HLA-Bw60, is possible, although the
influence of a more similar environment in the MZ
pairs cannot be excluded. The pairwise concordance
rate for radiologic sacroiliitis was greater than that for
definite AS.
In this series, 3 MZ twin pairs were discordant
for definite AS. All 3 of these pairs were well over 50
years old and will therefore probably remain discordant. Although not shown in the case of idiopathic AS,
it is postulated that differences in environmental exposure between members of MZ pairs explain the
discordance, despite the presence of known genetic
markers of the disease (12). Interestingly, both
probands of the totally discordant MZ sets had had
infections that had not occurred in their unaffected
twins.
The findings of the present series are compatible with those of the Arthritis and Rheumatism Council (UK) Twin Survey, which was designed to avoid
selection. In that study, only 1 of the 2 MZ and none of
the DZ twin pairs was concordant for clinical and
radiologic spondylitis (3). In a case series providing
evidence for the importance of environmental factors,
Eastmond and Woodrow (4) described 3 MZ pairs in
which at least I member had AS and found discordance in 2 of them, and a difference in disease severity
in the third.
AS and RA can occur concomitantly in the
same individual (13). In the present series, secondary
seropositive RA occurred in as many as 4 subjects
with AS. The MZ pair was completely discordant for
both diseases despite the presence of HLA-B27, B40
(typing for the Bw60,61 split of B40 was not performed), and DR4.
The results of this first systematic population-
based study of twins with AS are compatible with the
conclusion that genetic factcirs play a dominant role in
the disease expression. The occurrence of clearly
discordant MZ pairs indicates that environmental or
stochastic events are also relevant. Close observation
of MZ twin pairs who are discordant for AS may
provide valuable clues on .the environmental conditions that favor disease expression (14).
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Semin Arthritis Rheum 22:319-334, 1993
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Erratum
In the list of reviewers for 1994 published in the December 1994 issue of Arthritis and Rheumatism, the name
of Dr. Kaisa Granfors was inadvertently omitted. We regret the error.
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