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HLA and Recurrent Episodic Arthropathy Associated with Rubella Vaccination.

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1192
HLA AND RECURRENT EPISODIC
ARTHROPATHY ASSOCIATED WITH
RUBELLA VACCINATION
MARIE M. GRIFFITHS, SPOTSWOOD L. SPRUANCE, PEARAY L. OGRA,
GEORGE R. THOMPSON, and CHARLES W. DeWITT
The frequencies of 21 HLA antigens in 33 patients
who developed recurrent, episodic arthropathy after receiving the HPV-77 DK-12 rubella vaccine have been
determined and compared with those of a control population. Trends toward increased frequencies of HLA antigens B12 (P = 0.02) and B14 ( P = 0.04) and of the
haplotype A2, B12 (P = 0.01) did not reach significance
when corrections for the number of antigen determinations
were included in the statistical analysis. These data show
that the syndrome of recurrent arthropathy following rubella vaccination is genetically distinct from the connective tissue diseases associated with HLA-B27.
The frequent occurrence of acute short-lived
polyarthritis and polyarthralgia as sequelae to natural
From the University of Utah School of Medicine, Salt Lake
City, Utah; The State University of New York at Buffalo and the
Childrens Hospital, Buffalo, New York; and The University of Michigan and Wayne County General Hospital, Eloise, Michigan.
Supported by NIH Grants 5 R01 AM 13463-07, AM 1705002, and HD 10088.
Marie M. Griffiths, Ph.D.: Research Instructor, Department
of Medicine, University of Utah; Spotswood L. Spruance, M.D.:
Assistant Professor, Department of Medicine, University of Utah;
Pearay L. Ogra, M.D.: Professor, Departments of Pediatrics and
Microbiology, School of Medicine, SUNY at Buffalo, and Divisions
of Clinical Infectious Diseases and Virology, Childrens Hospital;
George R. Thompson, M.D.: Professor, Department of Medicine and
Director, Rheumatology Section, Wayne County General Hospital,
The University of Michigan; Charles W. Dewitt, Ph.D.: Professor,
Department of Pathology, University of Utah.
Address reprint requests to Marie M. Griffiths, Ph.D., Division of Infectious Diseases, School of Medicine, 50 North Medical
Drive, Salt Lake City, Utah 84132.
Submitted for publication February 1 1 , 1977; accepted April
4. 1977.
Arthritis and Rheumatism, Vol. 20, No. 6 (July-August 1977)
rubella infection and to immunization with rubella vaccine has been well documented (1-10). Chronic joint
problems have not been associated with natural rubella.
However, in a few rare instances, an arthropathy develops in children 2-8 weeks after parenteral administration of rubella vaccine and reoccurs intermittently for
several months or years after vaccination (10-15).
In 1970 a national immunization program was
carried out with a live attenuated rubella vaccine prepared in dog kidney cells (HPV-77 DK-12). Three of the
authors (SLS, GRT, PLO)were independently involved
in the clinical trials of this vaccine at that time in Utah,
Michigan, and New York. Short- and long-term followup studies of the clinical and immunologic parameters
of postvaccination complications in these three patient
populations have subsequently been reported (9-14,16).
Joint symptoms characterized by pain in the knee(s)
upon attempts to extend the joint completely were manifested episodically for extended periods of time in a very
Small percentage of the children in all three study
groups. It is possible that those children who experienced recurrent attacks of postvaccination arthropathy
have an underlying genetic susceptibility to connective
tissue disease, or that they are uniquely susceptible to
some mutation of rubella virus that occurred during its
attentuation in tissue culture.
Studies with highly inbred strains of mice and
guinea pigs have shown that susceptibility to tumor
induction by oncogenic viruses and the level of antibody
response to synthetic polypeptides are related t o immune response (Ir) genes. Some Ir genes are closely
HLA AND RECURRENT ARTHROPATHY
linked to the major histocompatibility complex (17-20).
This knowledge has led to a widespread search for association between human diseases and human histocompatibility antigens (HLA).
Certain connective tissue diseases show a strong
correlation with HLA-B27 (21-25). The immune response to rubella virus in humans is also related to HLA
(26-29). In view of these associations, we were interested
in seeing if those patients who had experienced recurrent
episodes of post-rubella-vaccination arthropathy were
genetica.lly predisposed to this complication. Accordingly¶ HLA types were determined in 33 patients who
developed this syndrome after receiving HPV-77 DK- 12
rubella vaccine in 1970- 1971.
MATERIALS AND METHODS
Patients. Twenty-nine unrelated Caucasian patients
(and 4 similarly affected siblings in three families) were selected for our study. Six were from Detroit, Michigan, 8 were
from Salt Lake County, Utah, and 19 were from Buffalo, New
York. All patients received the HPV-77 DK-12 rubella vaccine
and subsequently experienced recurrent attacks of pain and
stiffness of the knee(s), the so-called catcher’s crouch syn-
drome (30). Documentation of this syndrome as a complication of rubella vaccination has previously been reported from
multiple independent sources (1&15,30). The mean duration
of recurrent arthritic attacks for patients from the three geo!graphicareas was 2.7 years in Detroit (range 1.5 to 5.5 years),
2.8 years in Salt Lake County (range 7 months to 5.5 years),
and 2.3 years in Buffalo (range 4 months to 6.5 years). Patients
were between 2 and 26 years of age (mean 10 years) at the time
of immunization.
Tissue Typing. All HLA determinations were performed by the same technician in the Clinical Pathology Laboratories at the University of Utah in Salt Lake City. Heparinized blood samples were collected in VacutaineP tubes from
patients in Buffalo and Detroit and were received in Salt Lake
City and typed within 48 hours. HLA typing was performed by
a standard microlymphocytotoxicitytest (31) with a numbered
series of typing trays (582000 series) from the Research Resources Branch of the National Institute of Allergy and Infectious Diseases (NIAID). Typing trays contained 72 wells
and determined 21 different specificities. Control frequencies
in a mixed racial population of 646 North Americans were
determined from an NIAID computerized data analysis of the
well frequencies reported by 21 laboratories using 646 typing
trays of the 682000 series. The tissue types of one or both
parents of 26 of the 33 patients were also determined to confirm the patient’s phenotype or to allow haplotype determinations.
Statistical Analysis. Statistical analyses were performed in the Division of Biostatistics, Department of Family
and Community Medicine, University of Utah Medical Center. By x* tests with Yate’s correction, antigen frequencies
among patients were compared with frequencies among control populations for significance of difference. Values of signif-
1193
icance were corrected (32) by multiplying by the number of
antigens determined.
RESULTS
The frequencies (percentages) of 2 1 different
HLA antigens in 33 patients (18 male and 15 female)
with clinical evidence of prolonged episodic postrubella
vaccine arthropathy were compared with the HLA antigen frequencies in a North American control population (Table 1). N o individual HLA antigen was significantly increased or decreased in the patient population.
The frequency of HLA-B27 was particularly interesting in this study because microbial infections have
been implicated as initiating events in several of the B27associated diseases (24,25,33). The incidence of HLAB27 in our patient group was not elevated above that of
a normal population. Further, of the 6 children with
apparently chronic disease for 5 years or longer, 2 were
B27-positive and 4 were B27-negative. Therefore postrubella vaccine arthropathy could not be grouped on the
basis of HLA typing with the B27-associated connective
tissue diseases that are considered to have a genetic risk
factor.
The potential for developing chronic rubella infection should be, in part, a function of the individual
host’s immune response system, and there is some evidence for a correlation between postvaccination arthropathy and the immune response to rubella virus
(34). HLA-A28, A l , B8, and B14 are thought to be
related to the immune response to rubella virus (26-29).
A trend toward increased frequency of HLA-B14 in our
patient group was noted but did not reach statistical
significance when corrected for the number of HLA
antigen determinations.
Table 2 lists tissue typing data, ABO types, and
the duration of disease for individual patients. When
children with symptoms for 2 years or longer were compared with those children whose attacks ceased within 2
years, no apparent association could be noted between
the length of time during which episodes reoccurred and
any HLA antigen or haplotype. Three sets of siblings
were included in the study and are designated as such in
Table 2. No haplotype or individual HLA antigen was
common to all three families.
Association of disease with particular haplotypes
can often be demonstrated when only weak associations
with single HLA antigens are obvious (35). Accordingly,
haplotypes were determined on 19 patients (Table 2),
and haplotypes of 5 additional patients were assumed on
the basis that homozygosity for the one expressed an-
GRIFFITHS ET AL
tigen is common (patients FB, LK, DM, JR, and MG).
The A l , B8 haplotype was of interest in this study
because of its association with the congenital rubella
syndrome (29). Three of 24 haplotypes were A l , B8
(12.5%), and this frequency was not significantly higher
than the A l , B8 haplotype frequency reported by Terasaki (35) for control North American populations
(8.9%: x' = 0.062, P > 0.5). The frequency of the
haplotype A2, B12 (20%) was somewhat higher than
normal (5.9%),but again the increase was not significant
when corrections were made for the number of possible
B12 haplotypes (x' = 6.55, P = 0.011; P corrected >
0.5).
sible mechanisms can be considered: a) the triggering of
nonviral joint disease by rubella vaccine in a patient
population that is genetically predisposed to the development of connective tissue disease; and b) the development of chronic infection of joint tissue as a result of
ineffective immune clearance of the virus from the joint
space.
In this report an attempt was made to differentiate between these alternatives on the basis of HLA
antigens. With the typing sera available, the syndrome
of recurrent postrubella vaccine arthropathy did not
appear to represent the triggering of an underlying susceptibility to those connective tissue diseases that have
been associated with HLA-B27. Neither could we demonstrate an increased incidence of those HLA antigens
that are related to the immune response to rubella virus.
Four major loci (HLA-A, B, C, and D) in the
DISCUSSION
The means by which rubella vaccine initiates recurrent episodic arthropathy is not known. Two pos-
Table 1. H L A Antigen Frequencies (%) in Patients with Recurrent Postrubella Vaccine Arihropathy
Patients
Male
(n = 18)
Female
(n = 15)
Control
Population*
( n = 646)
Total
(n = 33)
No.
%I
No.
%
No.
YO
%
Chi
Square?
Al
A2
A28
A3
A9 (W23,W24)
A10 (W25, W26)
All
A19 (W29,W30
W31, W32)
7
9
1
4
2
1
4
4
39
50
6
22
3
9
0
3
I
3
2
3
20
60
0
20
7
20
13
20
10
I8
1
7
3
4
6
7
30
55
3
21
9
12
18
21
22
42
6
25
20
16
10
21
0.818
1.555
0.113
0.0867
I .729
0.118
1.429
0.0389
B5
BW35
B18
B7
BW22
B27
B8
BIZ
B13
BW40
B14
BW15
BW16
0
3
2
2
2
13
13
13
33
7
13
7
40
13
0
13
13
20
2
6
5
15
9
30
9
9
12
39
15
12
18
6
12
8
13
6
19
6
8
14
21
6
18
7
12
8
0.00674
0.00852
0.116
I .864
0.116
0.0128
0.00125
5.142$
2.931
0.388
4.1855
0.59
0.255
Antigen
1
5
2
1
3
7
3
4
4
0
1
11
6
22
22
0
17
6
28
11
6
17
39
17
22
22
0
6
5
1
2
1
6
2
0
2
2
3
3
10
3
3
4
13
5
4
6
2
4
~~
* Frequencies
(7%) for a mixed racial population of North Americans were determined by testing 646
trays of these antisera (No.82000, Research Resources Branch, NIAID) in 21 laboratories.
t Chi square test with Yate's correction was used to find the significance of difference between the control
population and the total patient group.
$ P = 0.024, P corrected > 0.1.
5 P = 0.043, P corrected > 0.1.
HLA AND RECURRENT ARTHROPATHY
1195
Table 2. Phenotypes or Haplotypes of Patients with Postrubella Vaccine A rthropathy
Parental Typing
Geographic
Area
Detroit
Patient
MG
LM
sc
DiY$
DoY$
sc
Salt Lake City
Buffalo
Blood
Group
0
0
AB
AB
B
B
DH
BF
CB
MS
TB
BJ
LB
TG
KB
BBS
CBS
DK
DM
NW
JLC
RM
JR
DH
JC
GG
MG
MZ
AL
MN$
DNS
FNS
LP
Phenotype* or
Haplotype
4
0
B
0
B
A
0
A
B
B
A
0
AI,A9,B8,BW40
A3,B7/A28,B14
A3,B7/A1 I,BW35
A1 l,BW35/-,913
A3,--,B7,B12
A3,AW31,B12,B27
A2,A3,BW35,BW40
A2,B7/A9,B 12
A2,--,B5,B14
A2,AIO,BW35,BW 16
A2,BW 15/A2,B 13
A3,AW31,B7,BW40
A2,--,B5,B12
A2,B 12/A1 ,BW 16
A2,AIO,B12,B14
A W30,B 13/AW32,B 14
AI,B14/AW30,B13
A 1 ,BW22/A 1 ,B 14
A2,AI I,B27,BW16
Father
Duration7
(years)
3 .O
2.0
5.5
I .5
A2,BW40/A1 ,B8
AW29,B 12/A1 ,B8
A9,BWI5/--,B18
A2,B12/A1 ,B8
A2,B 12/ A2,B7
A2,B 18/AW30,A1 l,B12/A2,B7
A2,BW22/A3,B7
AI,AlO,B12,BW16
A2,AIl,B27,BW35
AI,AI l,BW22,A2,B12/A I ,B13
A2,AW31,B7,B 12
A 10,B7/AIO,B18
0
0
A
A
AB
A
0
Mother
1.5
2.5
+
+
+
-
+
+
+
1 .o
1 .o
4.0
5.5
0.6
1 .o
4.0
5.5
6.5
0.5
5.0
0.6
2.8
1.7
3.9
4.5
0.6
0.6
1.2
0.3
3.6
I .5
0.5
1.8
0.7
1.2
5.8
* Phenotypes
are presented when either a) only I parent was typed who showed both A or both B
antigens of the patient, b) parents were not typed, or c) typing of both parents did not allow determination of the genotype of the patient, i.e., KB, mother (Al,A2,B8,BW40) and KB, father (Al,A9,B8,BW40).
Period of time after receiving HPV-77 DK-12 rubella vaccine during which patient experienced recurrent
episodic attacks of arthropathy.
$ Siblings.
human histocompatibility complex have been recognized. HLA-A, B, and C are detected serologically,
whereas D locus gene products are defined in mixed
lymphocyte cultures (MLC). Adult rheumatoid arthritis
has not been related to an increased incidence of individual HLA-A and B antigens (36), but it has been associated with an MLC-defined locus (37). Likewise, the
association of juvenile chronic polyarticular arthritis
with HLA-B27 is weak (38), and a much stronger association with HLA-DW3 and the Ia allele B5 is found (39).
It is possible that A, B, o r C antigens that are not
detected by our typing sera or that antigens of the D
locus would similarly define a common genetic background in our patient population.
GRIFFITHS ET AL
1196
Further attempts to investigate the relationship
between recurrent postrubella arthropathy a n d the immune response to rubella virus are indicated.
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1197
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