British Journal of Rheumatology 1997;36:322–327
COMPOUND HETEROZYGOSITY FOR THE SHARED EPITOPE AND THE RISK AND
SEVERITY OF RHEUMATOID ARTHRITIS IN EXTENDED PEDIGREES
J. E. McDONAGH, A. DUNN,* W. E. R. OLLIER† and D. J. WALKER‡
Bloomsbury Rheumatology Unit, Middlesex Hospital, London, *Regional Blood Transfusion Service, Barrack Road, Newcastle
upon Tyne, †Arthritis and Rheumatism Council Epidemiology Research Unit, University of Manchester, Manchester and
‡Department of Rheumatology, Freeman Hospital, Newcastle upon Tyne
SUMMARY
The objective was to explore the role of HLA-DRB1 genes in determining disease severity in rheumatoid arthritis (RA). The
population comprised extended pedigrees of 17 multicase RA families. Family members were genotyped for both HLA-DRB1
alleles using restriction fragment length polymorphism (RFLP). Identification of HLA-DRB1*04 variants was performed using
the Multiplex ARMS-RFLP technique. Compound heterozygote individuals carrying two different alleles containing the shared
epitope (SE) were at greatest risk of developing RA (odds ratio = 36, 95% CI 9.1–143). A synergistic or additive effect of these
alleles is suggested. Individuals carrying no SE alleles expressed milder disease, as measured by the Spread Severity (SS) index,
compared to compound heterozygotes (P = 0.045). Compound heterozygosity was not invariably associated with severe disease
with six (50%) having clinically mild disease at a median age of 57.5 yr and median disease duration of 16 yr. Inheriting two
different SE-bearing alleles results in an increased risk of RA and, on average, greater disease severity. This is not, however,
invariably associated with severe disease, making it of limited use as a predictor of prognosis.
K : Rheumatoid arthritis, HLA-DR4, Shared epitope, Disease severity, Family studies.
R arthritis (RA) is a heterogeneous disease,
in onset, expression and outcome. The unpredictability
of the course of the disease and the response to therapy
is a major concern for both patient and rheumatologist,
and there remains a need for prognostic indicators in
the management of such patients. A good prognostic
indicator would be useful in justifying aggressive early
intervention.
There is now good evidence that HLA-DR4 is
associated with disease severity rather than disease
susceptibility [1] with increased representation in
hospital RA, erosive disease, as well as extra-articular
manifestations. The association with HLA-DR4 was,
however, not sufficiently strong to be useful clinically,
in that many patients with RA and DR4 express mild
disease.
The further definition of DR4 subtypes and the
observation that not all DR4 subtypes are associated
with RA has led to the ‘shared epitope hypothesis’ [2].
Again, the association was not sufficiently robust to be
clinically useful.
There is now evidence that both parental HLA
haplotypes are important in RA [3], suggesting a
recessive mode of inheritance. A multiple additive risk
of shared epitopes (SE) was therefore possible. Several
authors have reported a hierarchy of disease susceptibility with a more pronounced association with
*0401(Dw4) and *0404(Dw14) in RA patients with
severe disease [4]. Individuals inheriting two SE-bearing alleles were at greater risk of RA, but the greatest
risk was conferred by two different types, known as the
compound heterozygote.
It is now generally accepted that the association of
HLA-DRB1*04 is more with disease severity than
disease susceptibility. Familial RA also tends to
represent more severe disease, especially when
probands are ascertained in hospital, as in this study.
We therefore studied the DR4 subtypes and the
influence of the SE on disease severity in a population
of 17 multicase RA families as part of a 10 yr follow-up
study. The extended pedigree nature of the multicase
RA families attempted to address a wider spectrum of
disease severity in contrast to nuclear families.
Furthermore, the prospective nature of the study
allowed more definitive assessment of disease severity.
POPULATION
The study formed part of a 10 yr follow-up of 17
multicase RA families as previously described [5].
Additional family members who were now available
and eligible for study were also included to extend the
pedigrees further.
METHODS
HLA-DR specificities were assigned to family
members using both serology [6] and a restriction
fragment length polymorphism (RFLP) technique [7].
The variants of HLA-DR4 were determined using
the Multiplex ARMS-RFLP (amplification refractory
mutation system-restriction fragment length polymorphism) [8]. HLA DR frequencies in the normal
population were determined from an analysis of 363
healthy Caucasoid blood donors [9]. The frequencies of
DR4 subtypes were compared with data from a control
population [10].
Individual indices of disease severity, including the
Submitted 23 May 1996; revised version accepted 13 September
1996.
Correspondence to: Janet E. McDonagh, Bloomsbury Rheumatology Unit, Arthur Stanley House, Middlesex Hospital, 40–50
Tottenham Street, London W1P 9PG.
= 1997 British Society for Rheumatology
322
323
McDONAGH ET AL.: SHARED EPITOPE AND DISEASE SEVERITY IN RA
Spread Severity (SS) index (maximum score = 44) [11],
the modified Larsen X-ray score (maximum
score = 50), the Health Assessment Questionnaire
(HAQ) scores, presence of nodules, disease-modifying
anti-rheumatic drug (DMARD) usage and major joint
replacement surgery were compared between subgroups of patients defined by the presence and
combination of alleles carrying the SE, i.e. (SE−/−,
SE+/−, SE+/+ identical, SE+/+ compound).
In view of the small numbers involved, the median
values of each individual severity marker were then
empirically used to define a summative disease severity
score, i.e. a patient had severe RA if the following
criteria were satisfied: SS index q 16 and HAQ q 1.87
and Larsen score q 11. Otherwise, their disease was
described as mild.
Analysis
The association between RA and (i) specific
HLA-DRB1 alleles and (ii) combinations of HLADRB1 alleles carrying the SE are expressed as odds
ratios (OR) with 95% confidence intervals (CI). For the
purpose of comparison, all OR were calculated relative
to the RA risk in individuals who were SE negative on
both HLA haplotypes. Comparisons between subgroups of individuals were performed using x2, Fisher’s
exact and Mann–Whitney U-analyses when appropriate.
RESULTS
Population
Two hundred and 45 family members were seen at
follow-up. One declined venepuncture and four
samples were unsuitable for analysis.
HLA-DRB1 allele and phenotype distributions in
multicase RA families
One hundred and 48 (61.7%) family members were
DR4 positive (Table I).
The main DR4 subtypes found in this population
were DRB1*0401 (50%) and DRB1*0408 (10%)
TABLE I
Frequencies of HLA-DRB1 alleles (including the subtype of
HLA-DRB1*04) in the family members
RA cases
(%)
(n = 40)
Unaffected
blood
relatives
(%)
(n = 165)
Unaffected
non-blood
relatives
(%)
(n = 35)
Controls [9]
(%)
(n = 363)
*01
10 (25)
40 (24)
10 (29)
96 (26)
*04
*0401
*0402
*0403
*0404
*0405
*0407
*0408
*0413
30
28
0
0
2
0
1
5
1
11 (31)
10 (35)
0
0
0
0
0
1 (3)
0
134 (37)
–
–
–
–
–
–
–
–
1 (3)
5 (1)
HLA-DR
phenotype
*10
(75)*
(70)
(5)
(2.5)
(12.5)
(2.5)
2 (5)
107
86
2
4
3
1
3
19
0
(65)*
(52)
(1)
(2)
(2)
(0.6)
(2)
(11)
1 (0.6)
*P Q 0.001 when compared to controls.
TABLE II
The shared epitope (SE) in RA cases, unaffected family members and
controls
RA
patients
(n = 40)
SE−/−
5
SE+/−
18
SE+/+ (identical)
*01/*01
0
*0401/*0401
5
SE+/+ (compound)
*01/*0401
5
*01/*0404
0
*01/*0408
0
*01/*0405
0
*01/*0413
1
*01/*10
0
*0401/*0404
2
*0401/*0408
4
Unaffected Unaffected
blood
non-blood Controls
relatives
relatives
[10]
(n = 165)
(n = 35) (n = 139)
(12.5)*
(45)
43 (26)*
75 (45.5)‡
(12.5)
6 (4)
11 (7)
1 (3)
0
5 (4)
6 (4)
17
2
1
1
0
0
0
9
0
0
0
0
0
1 (3)
0
0
4 (3)
–
–
–
–
–
1 (1)
–
(12.5)‡
(2.5)
(2.5)
(10)†
(10)†
(1)
(1)
(1)
(5.5)†
14 (40)
19 (54)‡
75 (54)
48 (34.5)
*P Q 0.001 when compared to controls.
†P Q 0.01 when compared to controls.
‡P Q 0.05 when compared to controls.
(Table II). DRB1*0404 was less prevalent than the
latter (2%). Of the RA patients, 87.5% (35/40) carried
at least one SE allele, 45% (18/40) carrying a single SE
allele and 42.5% (17/40) two SE alleles compared to
73.9, 45.5 and 28.5%, respectively, in unaffected blood
relatives and 46, 34.5 and 11.5%, respectively, in
controls (Table II).
The HLA-DRB1 phenotype and risk of RA
The frequencies of the various phenotype combinations were compared between the family members and
a control population. There were significantly less RA
cases (12.5% vs 54%, respectively; x2 = 21.6;
P Q 0.001) and unaffected blood relatives (26% vs
54%, respectively; x 2 = 24.7; P Q 0.001) negative for
the SE than in the control population due to the
increase of the SE in the families generally. As
expected, there were significantly more compound
heterozygotes for the SE in the RA cases (x2 = 25.2;
P Q 0.001) and the unaffected blood relatives
(x 2 = 15.7; P Q 0.001) (Table II). There was only one
non-blood relative who was a compound heterozygote
for the SE: HLA-DRB1*01/*10.
The greatest risk for RA was with the compound
heterozygotes (OR = 36, 95% CI 9.1–143) with the
following hierarchy of risk: DRB1*0401/*0404
(OR = 30, 95% CI 2.3–390) followed by DRB1*01/
*0401 (OR = 18.8, 95% CI 3.8–92.5), *0401/*0401
(OR = 12.5, 95% CI 2.8–55.6) and SE+/−
(OR = 5.6, 95% CI 2–16.2) (Table III). The greatest
risk for RA was in the compound heterozygotes
*0401/*0404 or *0401/*0408 (OR = 90, 95% CI
9–900), although the numbers of cases and controls
were small, resulting in wide CIs. No unaffected family
members were positive for both HLA-DRB1*0401/
*0404 genotypes. There was only one compound
heterozygote in the non-blood relatives without RA:
HLA-DRB1*01/*10.
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BRITISH JOURNAL OF RHEUMATOLOGY VOL. 36 NO. 3
In order to limit the potential bias to greater
numbers of DR4 homozogotes in familial RA,
comparisons of HLA frequencies were re-analysed
within the families (Table III). The highest OR, though
not as dramatic, was still observed in association with
the DR4-positive compound heterozygotes compared
to the other combinations (OR = 5.76, 95% CI
1.43–23).
There was an increased frequency of RA observed in
the compound heterozygotes (DRB1*0401/*0404,
DRB*01/*0401) compared to the heterozygotes carrying a single SE allele (e.g. *01/SE−, *0401/SE−,
*0404/SE−), suggesting a synergistic effect of these
alleles, although this was not statistically significant
(P q 0.05).
The HLA-DRB1 phenotype and disease expression
in RA
None of the SE-negative RA patients had nodular
disease and none had received DMARD therapy or
undergone major joint replacement surgery, unlike the
other SE-positive RA patients. When the SE-positive
subgroups were compared with the SE-negative
patients, the SE+/+ (all) patients had significantly
more severe disease as measured by the SS score (mean
scores 20.3 vs 9, respectively, P = 0.04) and the X-ray
score (mean scores 19.9 vs 4.7, respectively, P = 0.05).
This became more obvious when only DR4-positive
SE+/+ patients were considered: mean SS scores 21.5
vs 9, respectively, P = 0.01; mean X-ray scores 21.3 vs
4.7, respectively, P = 0.009. When the DR4-positive
SE+/+ group was subdivided into the *0401/*0401
homozygotes and the *0401/*0404 or *0401/*0408
compound heterozygotes and then compared with the
SE−/− subgroup, the *0401/*0401 homozygous RA
patients had a higher X-ray score which just achieved
statistical significance (mean scores 14.6 vs 4.75,
respectively, P = 0.05). The *0401/*0404 or *0401/
*0408 compound heterozygous patients, however, had
more severe disease as measured both by the SS score
(mean scores 27 vs 9, respectively, P = 0.006) as well as
a significantly higher X-ray score (mean scores 26.8 vs
TABLE III
Association between HLA-DRB1 phenotype and disease in RA
patients
Specific
phenotype
SE−/−
SE+/−
SE+/+
Identical alleles
*0401/*0401
Compound
heterozygotes
All
*01/*0401
*0401/*0404
*0401/*0404 or
*0401/*0408
Odds ratio (95% CI)
(compared to
controls)
Odds ratio (95% CI)
(compared to
family members)
1
5.6 (2.0–16.2)
15.9 (5.1–49.5)
1
2.06 (0.72–5.95)
2.53 (0.65–9.86)
12.5 (2.8–55.6)
3.91 (0.96–15.9)
36 (9.1–143)
3.44 (1.1–10.8)
18.8 (3.8–92.5)
30 (2.3–390)
2.53 (0.65–9.9)
–
90 (9.0–900)
5.73 (1.43–23)
TABLE IV
Demographic details of patients with respect to the presence of the
shared epitope
Mean age
of disease
Mean age
onset
2.. (yr) 2.. (yr)
Mean
disease
duration
2.. (yr)
5 53.8 2 13.3 26.6 2 10.6
18 57.7 2 12.1 36.9 2 11
17 54.7 2 15.2 32.2 2 12.4
21.2 2 16.8
20.8 2 12.2
22.6 2 12.4
n
SE−/−
SE+/−
SE+/+ all
SE+/+ identical
*0401/*0401
SE+/+ compound
*0401/*0404 or
*0401/*0408
52 2 16.1 29.6 2 13.3
5
6
48.8 2 11.6
34 2 11.5
22.4 2 8.8
15.3 2 4.4
4.7, respectively, P = 0.01) than the SE-negative
patients.
There were no significant differences between
severity indices when the SE+/+ and SE+/− patients
were compared, although there was a significantly
greater proportion of nodular disease in the former
(71% vs 28%, P = 0.01). When the SE+/+ patients
were subdivided, the SE+/+ identical patients tended
to have more nodular disease than the SE+/− patients
(80% vs 28%, P = 0.06). Significantly more SE+/+
compound patients also had nodular disease (67% vs
28%, P = 0.04) as well as having received DMARD
therapy at some time (83% vs 44%, P = 0.04) than
their true heterozygous SE+/− counterparts. When
only the DR4-positive compound heterozygous
patients (DRB1*0401/*0404 or *0401/*0408) were
considered, they had a significantly higher SS score
than their SE+/− counterparts (P = 0.02). When the
*0401/*0401 homozygous patients were compared with
the *0401/*0404 or *0401/*0408 compound heterozygous patients, the latter had significantly more
severe disease as measured by the SS score (mean scores
25.5 vs 14, respectively, P = 0.04) when compared to
the DR4 homozygotes. These differences appeared not
to be explained by disease duration and age as these
showed no significant difference between the subgroups
(Table IV). The DR4-positive compound heterozygotes
tended to be younger and had had their disease for a
shorter period, but these differences did not reach
TABLE V
Disease severity and the shared epitope (SE)
Mild RA* (%)
(n = 27)
SE−/−
SE−/+
SE+/+ identical
SE+/+ compound
including:
*0401/*0408
*0401/*0404
*0401/*01
*0413/*01
Severe RA† (%)
(n = 13)
5
12
4
6
(19)
(44)
(15)
(22)
0
6 (46)
1 (8)
6 (46)
1
1
3
1
(4)
(4)
(11)
(4)
3 (23)
1 (8)
2 (15)
0
*Mild RA if SS index E16 and HAQ E1.87 and Larsen score
E11.
†Severe RA if SS index q16 and HAQ q1.87 and Larsen score
q11 (see Methods).
McDONAGH ET AL.: SHARED EPITOPE AND DISEASE SEVERITY IN RA
TABLE VI
Disease characteristics of two sisters who share the same compound
heterozygous phenotype (HLA-DRB1*0401/*0408)
Age (yr)
Disease duration (yr)
SS index
X-ray score
HAQ
Nodules (ever)
Rheumatoid factor titre
DMARD current
Major joint replacement surgery
Sister A
Sister B
39
14
21
10
1.37
no
1/320
yes
no
33
15
39
50
2.75
yes
1/40
yes
yes
statistical significance (P q 0.05). Other comparisons
were not significant.
The presence or absence of the SE was compared
between severe disease, defined as SS index q 16 and
HAQ q 1.87 and Larsen score q 11, and mild disease
if these criteria were not met (Table V).
Compound heterozygosity for the SE does, therefore, associate with more severe disease, but this is not
without exception. To illustrate this, Table VI describes
disease characteristics of two sisters with RA, both
carriers of the DRB1*0401/*0408 genotype combination, one with mild disease and the other with severe
disease.
DISCUSSION
This study in multicase extended RA pedigrees has
confirmed previous data of a hierarchy of risk for RA
with various HLA-DRB1 genotype combinations in
reference to the SE [4, 10, 12–14].
HLA-DRB1 genotype combinations, the shared epitope
and RA
Several authors have reported the importance of the
gene dosage of the shared epitope in RA. Jawaheer
et al. [13] reported that within a HLA-DR4-positive
group of monozygotic twin pairs, there was no major
difference in concordance rates between those pairs
who were homozygous for HLA-DR4 and those who
had only one HLA-DR4 allele. In contrast, when the
monozygotic pairs who were positive for the SE were
considered, the possession of two alleles, both of which
carried the epitope, showed the greatest association
with RA concordance. Indirect evidence is suggested
by the evidence that compound heterozygotes
(DRB1*0401/*0404 or DRB1*0401/*01) represent
3.6% of a control population [10] compared to 17.5%
of a RA hospital-based population with homozygosity
for *0401 being an infrequent event in the control
population (4.3%). Unselected groups of RA patients
demonstrate a less striking excess of compound
heterozygotes, suggesting that the genotype may be
particularly associated with more severe disease [4].
All alleles encoding the SE, however, are not similar
in their strength of association with RA, despite having
a conserved sequence at amino acid positions 70–74 and
carrying the QRRAA/QKRAA motif, e.g. *0101 and
*0404. In our population, there was a greater risk in the
325
*0401/*01 individuals than in the *0401/*0401
individuals (OR 18.8 vs 12.5, respectively), although still
less than the highest risk seen (OR 90) with the
*0401/*0404 and *0401/*0408 individuals. Several
authors have suggested that such discrepancies may
indicate a role of glycine substitution at position 86 in
RA susceptibility, i.e. DRB1*0404 differs from *0101
and *0408 with the former having a valine residue
instead of glycine at position 86 [14]. Is is interesting,
therefore, to note that there were twice as many
*0401/*0408 compound heterozygotes (n = 4) as
*0401/*0404 (n = 2) with RA. When these patients were
combined, the calculated OR for *0401/*0404 and
*0401/*0408 compound heterozygotes was 90. Owing to
the small numbers involved, however, the 95% CIs are
wide: 9–900. HLA-DRB1*0404 and *0408 alleles were
not represented in heterozygous SE−/+ patients, and
therefore cannot be considered as an independent risk
factor for RA in this population. Neither was there any
DRB1*0404/*0404 homozygosity observed in the RA
group. This makes it unlikely that the amount of class II
antigen on the cell surface is the simple explanation and
supports the hypothesis of synergy between two closely
related DR4 subtypes at the DRB1 locus. In contrast to
these findings, Nepom et al. [15] reported an independent though additive effect of Dw14(DRB1*0404 and
*0408) rather than a synergistic effect. Similarly, other
authors have reported that DRB1*0404 is an RA risk
factor independent of DRB1*0401 [10].
HLA-DRB1*0405 is identical to DRB1*0408 both
in the third hypervariable region 67–74 and position 86
where it also has a glycine. In addition, DRB1*0413
differs from DRB1*0401 only at codon 86 where valine
is present instead of glycine. There was a higher
prevalence of DRB1*0408 (16.7%) compared to
DRB1*0404 (6.7%) in the RA patients although this
difference did not reach statistical significance
(P = 0.21). This is in contrast to the study of
non-familial RA by MacGregor et al. (*0408, 3.5%;
*0404, 17.9%) [10]. This raises the possibility that the
*0408 allele may have a more important role in familial
RA and hence perhaps a role of glycine at position 86,
as in both studies, when in combination with another
SE, it was associated with more severe disease.
HLA-DRB1*0405 was present in only one family
member who did not have RA and DRB1*0413 was
present in only one member who did have RA.
HLA-DRB1 alleles and disease expression
This study was part of a 10 yr follow-up study and
the prospective nature allowed for greater certainty of
disease classification, stability of diagnosis as well as
assessment of disease course and severity. Several
authors have looked specifically at radiological
progression as a measure of disease severity, some
reporting an association of DR4 with erosive change
on X-ray [16] and some not [17]. A prospective study
failed to find a relationship between the severity of rate
of X-ray progression and DR4 [18]. Conflicting results
may be due, at least in part, to patient selection as in
cross-sectional hospital-based studies it may be more
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BRITISH JOURNAL OF RHEUMATOLOGY VOL. 36 NO. 3
difficult to demonstrate a valid association between
DR4 and disease severity as hospital RA tends to be
at the more severe end of the spectrum. Indeed, the
association is not seen in population-based studies
where the milder disease is more prevalent [19].
Furthermore, although HLA-DRB1 genotyping of
patients attending an early synovitis clinic has been
shown to predict erosive disease [20], medium-term
prospective studies have since reported that although
genomic HLA typing is useful to predict the
development of persistent RA, they found no clinically
useful correlation between the HLA-DRB1 type and
disease severity [21].
Wordsworth et al. [4] suggested that compound
heterozygosity—Dw4/Dw14 (HLA-DRB1*0401/*0404
and *0401/*0408)—was particularly associated with
more severe disease. When individual indices of disease
severity were addressed, the SE−/− group showed
significantly lower X-ray and SS scores than the SE+
groups. Furthermore, none of the SE-negative patients
exhibited nodular disease, had received DMARD
therapy or undergone major joint replacement surgery.
This may in part be due to the fact that familial RA
does represent the more severe end of the spectrum.
There was no difference in the age of disease onset
when the SE−/− group was compared with the other
groups. This is in contrast to the results of Eberhardt
et al. [21] who reported that RA patients who did not
express disease-associated alleles developed RA later in
life and postulated that, without certain genetic factors,
more time is needed for clinical disease to develop. The
SE−/− group, however, was small in our study
(n = 5). More severe disease was associated with the
expression of two SE-positive alleles and was
particularly evident when the compound heterozygotes
were considered, in agreement with previous
authors [4].
Fifty-nine per cent (13/22) of RA cases with at least
one SE allele had severe disease and 70% with two SE
alleles. However, 50% of those with two non-identical
SE alleles had mild disease as classified by our criteria.
HLA-DR1 has previously been reported to be more
associated with mild disease [22], although the criteria
for disease severity vary between studies. Two-thirds of
the compound heterozygotes in our study with mild
disease carried the DR1 allele compared to only
one-third of those with severe disease and this raises the
possibility of a diluting effect on severity by the
inclusion of the DR1 allele. Nonetheless, Benazet et al.
[23] observed an association of more severe articular
damage, as measured by the Steinbrocker index, with
a double dose of the shared epitope in a southern
French population with a relatively higher prevalence
of DR1 (46%) but no extra-articular disease.
There are problems in using material from multicase
families in view of the potential bias to greater numbers
of DR4 homozygotes and the consensus view that
familial RA represents the more severe end of the
spectrum of disease severity [1, 17]. In an attempt to
limit the former bias, comparisons of HLA frequencies
were re-analysed within the families rather than with
controls as above. The highest OR, though not as
dramatic, was still observed in association with the
DR4-positive compound heterozygotes compared to
the other combinations (OR = 5.76, 95% CI 1.43–23).
The definition of disease severity in family studies
does vary and is important to consider. In view of the
multidimensional nature of disease severity, we used a
summative score to divide the RA patients into mild
and severe disease. Although this was arbitrary, we
considered it was valid in view of the extended nature
of the majority of the pedigrees which thus potentially
encompassed a broader spectrum of disease severity
than that previously reported in studies of nuclear
families.
Whether the molecular basis of the effect of
compound heterozygosity for the SE in RA is a
structural influence on peptide binding or of molecular
mimicry has yet to be established. Supporting the latter
hypothesis is evidence of sequence homology between
the SE of DRB1*0401 and proteins of Epstein–Barr
virus [24] and Escherichia coli [25]. Further support is
provided by reports such as that from Wang et al. [26]
who reported a differential effect of rheumatoid factor
production in vitro in *0404-positive B cells compared
to *0401 B cells, with more frequent induction in the
former.
In conclusion, the HLA-DRB1 genotype does
influence the severity of the disease, but all alleles
encoding the SE are not similar in their strength of
association with disease. The presence of particular
genotype combinations is associated with more severe
disease, although this is not absolute as the above data
illustrate, raising the possibility that there may be other
non-DRB1 alleles involved. The role of genotyping in
the prognosis of RA for the clinician and patients
warrants further study.
A
This study was supported by the Newcastle
Rheumatic Research and Education Fund. We are
grateful to the families for their kindness and
cooperation during the course of this study, to Dr Paul
Hessian, Department of Radiology, Royal Victoria
Infirmary, Newcastle upon Tyne, for assisting in the
scoring of the hand X-rays, and to Tim Butler,
Department of Medical Statistics, Newcastle Medical
School, for statistical advice.
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