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Heterogeneity of hla associations in systemic onset juvenile rheumatoid arthritis.

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796
HETEROGENEITY OF HLA ASSOCIATIONS IN
SYSTEMIC ONSET
JUVENILE RHEUMATOID ARTHRITIS
DAVID N. GLASS and DAVID A. LITVIN
Two genetic markers, HLA-Bw35 and HLA-B8,
are found to be associated with “febrile” or “systemic”
onset juvenile rheumatoid arthritis (JRA). Evidence is
presented that JRA patients are probably heterogeneous with respect to these antigens.
Juvenile rheumatoid arthritis (JRA) is a clinically heterogeneous disease in terms of its onset (1). The
three types of onset are described as 1) polyarticular
(>4 joints involved), 2) pauciarticular (<4 joints), and 3)
a febrile or “systemic” onset group. This third type of
onset with fever and characteristic skin changes may be
associated with pauciarticular or polyarticular arthritis
or with neither. Further divisions may be made by sex
and age of onset: girls with pauciarticular disease with
an early age of onset and serum antinuclear antibodies
are particularly at risk for iritis (2). Boys, again with
pauciarticular onset, but in an age group approximately
8-9 years or older, are at risk of developing sacroiliitis,
spondylitis, or both (3).
HLA associations have been sought and both reinforce and add to these clinically evident divisions. The
polyarticular group is associated with HLA-Dw3 (4).
The pauciarticular group is associated with HLAFrom the Tissue Typing Laboratory, the Department of
Medicine, Robert B. Brigham Hospital, and Harvard Medical School,
Boston, Massachusetts.
Supported by grants from the USPHS, AM1 1414, AM05577,
AM0049, the Gebbie Foundation, The New England Peabody Home
Foundation, and the Arthritis Foundation.
David N. Glass, MD: Assistant Professor of Medicine and
Assistant Physician, Robert B. Brigham Hospital and Harvard Medical School; David A. Litvin, MS: Research Assistant, Robert B. Brigham Hospital.
Address reprint requests to David N. Glass, Robert B. Brigham Hospital, 125 Parker Hill Avenue, Boston, Massachusetts 02120.
Submitted for publication October 29, 1979; accepted in revised form February 19, 1980.
Arthritis and Rheumatism, Vol. 23, No. 7 (July 1980)
DRw8 and to an antigen “Tmo,” related to HLA-Dw7
and HLA-Dwl 1; pauciarticular patients (with an older
age of onset) show increased frequency of HLA-B27
(5-8).
Using a combination of clinical parameters including sex, age, and mode of disease onset, we report
an association between HLA-Bw35 and HLA-B8 in
children with systemic onset JRA.
MATERIALS AND METHODS
Two hundred forty-eight white patients attending the
JRA Clinic of the Robert B. Brigham Hospital over a 4-year
period and who had given consent to venipuncture were studied. The diagnosis of JRA and the mode of onset were established according to ARA criteria (9,lO). In the systemic onset
group the associated arthritis was also established as poly- or
pauciarticular. HLA-A and B typing was carried out on peripheral blood lymphocytes. Typing for 39 antigens was done
by complement dependent microdroplet cytotoxicity; the antisera were kindly provided by the NIAID (National Institutes
of Allergy and Infectious Diseases) serum bank (11). Data
were tabulated by mode and age of onset; those with early onset, 8 years or younger, were compared with those of later onset, 9 years or older ( 5 ) . Statistical analyses included the 2
test and relative risk (RR) (12). The controls for HLA typing
were 283 unrelated adults, with additional control data on
North American white populations taken from the Seventh
International Histocompatibility Workshop, a study of 290 individuals (13).
RESULTS
Three HLA antigens Bw35, B8, B27 were found
to occur more commonly than expected in the JRA
population or in some clinically evident subdivision (see
Table 1).
HLA-Bw35. The HLA-Bw35 genetic marker occurs with a frequency of 0.09 in the control population
GENETIC MARKERS IN JRA
.-e
797
GLASS AND LITVIN
798
and was found to a similar and normal extent in the
JRA population as a whole (0.10). However, this antigen was increased in the following subdivisions:patients
with onset at less than 8 years of age (frequency 0.15, 2
6.62, P < 0.02), the systemic onset group (frequency
0.17,y 4.21, P < 0.05), and those patients with the combination of a systemic onset and pauciarticular arthritis
(frequency 0.20, 2 13.09, P < 0.001). In contrast the
systemic onset patients with polyarticular disease in association did not have an increase in HLA-Bw35; the $
value for the difference in frequency of this antigen between the two systemic onset groups (see lines 14 and
15, Table 1) was 4.27 (P < 0.05).
HLA-B27. This gene, present in 0.04 of the controls was increased in the total JRA population (frequency 0.09, $ 11.07, P < 0.001) and especially those
with onset of 9 years or older (frequency 0.12, 2 17.36,
P < 0.001), in those with pauciarticular disease (frequency 0.12, $ 18.01, P < 0.001), and to a greater extent in those with pauciarticular disease with onset at
age 9 years or older (frequency 0.20, 2 39.05, P <
0.001).
HLA-B8. This gene, with a frequency of 0.1 1 in
a normal population, was increased in the JRA populations as a whole (frequency 0.17, 2 7.98, P < 0.01)
and especially for those with onset at age 9 years or
greater (frequency 0.19, 2 9.20, P < 0.01). An increase
was also found in those with polyarticular onset disease
(frequency 0.17, 2 4.40, P < 0.05), in those with polyarticular onset at an older age (frequency 0.19, 2 5.22,
P < 0.05), and in those with the systemic presentation
(frequency 0.22,y 7.56, P < O.Ol), particularly if aged 9
or older at the time of onset (frequency 0.33, $ 11.03, P
< 0.001).
Examination of the control HLA-A,B data
showed only one significant difference from the Seventh
International Workshop data for North American
whites, namely HLA-A2, with a gene frequency of 0.20
of the controls as opposed to 0.28 in the Workshop data
(210.44, P < 0.01).
DISCUSSION
An increase in frequency of HLA-Bw35 and
HLA-B8 in systemic onset patients with JRA is demonstrated in this series. The antigen HLA-Dw3, reported
by Gershwin et a1 to be increased in polyarticular JRA,
is in linkage dysequilibrium with HLA-B8. Therefore
the increased frequency of HLA-B8 as described here
in polyarticular JRA is in part predictable (4). The increase in HLA-Bw35 found in several subdivisions of
this JRA population when evaluated separately makes
it likely that the HLA-Bw35 observations are not simply a consequence of statistical manipulation, a type I
error (14). The HLA-B27 observation in pauciarticular
JRA patients confirms previous reports, so that correction factors have not been applied to these probability
tests (6).
Preceding studies by other investigators have
not shown an increase in HLA-Bw35, although one
series contained 5 systemic onset patients, two of whom
were reported to have HLA-Bw35 (4). In a series of 8
patients Barnes et a1 reported an association between
systemic onset JRA and HLA-B12, a finding not evident in this study (15). An increase in HLA-B15, an antigen that may cross-react with HLA-Bw35, has been
reported in two studies of JRA patients involving pauciand polyarticular subgroups in one study (16) and polyarticular in the other (8). The only D locus antigen
reported to be associated with systemic onset JRA,
HLA-Dw7, is not in linkage disequilibrium with either
Bw35 or B8, the antigens of most relevance in this study
(5,13). Accordingly, the relationship between the HLAB and HLA-D series associations cannot be fully evaluated at this time except to imply an even greater heterogeneity than the data presented here would suggest.
HLA-Bw35 has been associated with two disease
populations in which an immunopathology is manifest-patients with glomerular nephritis with IgA mesengial deposits and those with a small vessel (venular)
vasculitis (17,18). It may be of additional interest that
IgA deficiency has been reported in JRA (19). In the
vasculitis study HLA-Bw35 was present in association
with, and is presumed to be linked to, HLA-A1 1. Increase in this A series antigen was not found in the present JRA study.
When the systemic onset group is divided in two
on the basis of the associated arthritis, whether paucior polyarticular, those with the more limited form of arthritis were found to have the highest frequency of
HLA-Bw35 (see Table 1).
It may be concluded from this study that systemic onset JRA has a genetically determined predisposition. The HLA antigens involved in this predisposition, Bw35 and B8, appear to be associated with
separate components of the systemic group; the age of
onset and form of arthritis are both relevant features in
this division. Some form of susceptibility common to
the polyarticular and systemic onset groups, as shown
by the increase in HLA-B8 in both, is also evident. Bywaters has suggested that the characteristic features of
Still's disease, with its sudden febrile onset, are not in
GENETIC MARKERS IN JRA
themselves specific (20). This view is reinforced by these
findings: two HLA associations within the systemic
group and an HLA association common to patients with
a systemic onset and a polyarticular presentation.
The use of sixth chromosome genetic markers in
addition to clinical characteristics in understanding
JRA populations is supported by the observations reported herein.
ACKNOWLEDGMENTS
The support of Dr. Peter Barry, Dr. Carolyn Bell, Dr.
Patricia Fraser, Dr. Jean Jackson, Dr. Robert Lewis, Dr. Peter
H. Schur, and Dr. Sydney Stillman is gratefully acknowledged.
REFERENCES
1. Brewer EJ, Bass J, Baum J, et al: Current proposed revision of JRA criteria. JRA Criteria Subcommittee of the
Diagnostic and Therapeutic Criteria Committee of the
American Rheumatism Association Section of the Arthritis Foundation. Arthritis Rheum 20 (suppl): 195-199, 1977
2. Schaller JG, Johnson GD, Holborow EJ, et a 1 The association of antinuclear antibodies with the chronic iridocyclitis of juvenile rheumatoid arthritis (Still’s disease). Arthritis Rheum 17:409-416, 1974
3. Ansell BM, Bywaters EGL: Diagnosis of “probable”
Still’s disease and its outcome. Ann Rheum Dis 21:253261, 1962
4. Gershwin ME, Opelz G, Terasaki PI, et al: Frequency of
HLA-Dw3 in juvenile rheumatoid arthritis. Tissue Antigens 10:330-336, 1977
5. Stastny P, Fink C: Different HLA-D associations in adult
and juvenile rheumatoid arthritis. J Clin Invest 63: 124130, 1979
6. Rachelefsky GS, Teraski PI, Katz R, et al: Increased
prevalence of W27 in juvenile rheumatoid arthritis. N
Engl J Med 290:892-893, 1974
7. Arnett FC, Bias WB, Stevens MB: Juvenile chronic arthritis: description of a new HLA-B27 subset persisting into
adulthood (abstract). Arthritis Rheum 22:589, 1979
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8. Schaller JG, Ochs HD, Donnall Thomas E, et al: Histocompatibility antigens in childhood-onset arthritis. J Pediatr 88:926-930, 1976
9. S t i h a n JS, Barry PE: Juvenile rheumatoid arthritis: Series 2. Arthritis Rheum (suppl) 20171-175, 1977
10. Gibson DJ, Carpenter CB, Stillman JS, Schur PH: Reexamination of histocompatibility antigens found in patients with juvenile rheumatoid arthritis. N Engl J Med
293~636-638,1975
11. Mittal KK, Mickey MR, Singal ER, et al: Serotyping for
monotransplantation. VIII. Refinement of microdroplet
lymphocyte cytotoxicity test. Transplantation 6:9 13, 1968
12. Woolf B: On estimating the relation between blood
groups and disease. Ann Hum Genet 19:251-253, 1955
13. Histocompatibility Testing 1977. Edited by WF Bodmer,
JR Batchelor, J G Bodmer et al. Report of the VII International Histocompatibility Workshop and Conference,
Copenhagen, Munksgaard, 1978
14. Svejgaard A, Jersild C, Nielsen LS, et al: HL-A antigens
and disease: statistical and genetical considerations. Tissue Antigens 495-105, 1974
15. Barnes CR, Schroeder ML, Petty RE, et a1 The association of HLA antigens and juvenile rheumatoid arthritis
(JRA) subtypes. Abstracts, Annual Meeting of the American Association of Clinical Histocompatibility Typing,
1978
16. Nissila M, Elomaa L, Tilikainen A: HL-A antigens in juvenile rheumatoid arthritis (letter). N Engl J Med
292:430, 1975
17. Noel LH, Descamps B, Jungers P, et al: HLA antigen in
three types of glomerulonephritis. Clin Immunol Immunopathol 10:19-23, 1978
18. Glass D, Soter NA, Gibson D, et a 1 Association between
HLA and cutaneous necrotizing venulitis. Arthritis
Rheum 19:945-949, 1976
19. Petty RE, Cassidy JT, Sullivan DB: Serologic studies in
juvenile rheumatoid arthritis: a review. Arthritis Rheum
20 (suppl):260-267, 1977
20. Bywaters EGL: Heberden oration, 1966: Categorization in
medicine: a survey of Still’s disease. Ann Rheum Dis
26:185-193, 1967
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associations, hla, heterogeneity, systemic, arthritis, juvenile, onset, rheumatoid
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