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The role of hla antigens as indicators of disease progression in psoriatic arthritis.

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ARTHRITIS & RHEUMATISM Volume 38
Number 6, June 1995, pp 845-850
0 1995, American College of Rheumatology
845
THE ROLE OF HLA ANTIGENS AS INDICATORS OF DISEASE
PROGRESSION IN PSORIATIC ARTHRITIS
Multivariate Relative Risk Model
DAFNA D. GLADMAN and VERNON T. FAREWELL
Objective. To identify HLA markers for the development of severe disease in psoriatic arthritis (PsA).
Methods. Patients with PsA who were followed
up prospectively over a 14-year period were included.
Clinical and laboratory assessments of both active inflammation and clinical damage were performed at
6-month intervals according to a standard protocol,
which also included serologic HLA typing for class I and
I1 antigens. Progression of damage was defined as
transition into higher damage states, defined by the
number of damaged joints. Both univariate and multivariate models were developed to identify predictors for
progression of damage.
Results. Univariate analysis revealed that the
HLA antigens B27, B39, and DQw3 were associated
with disease progression, while HLA-DR7 was “protective.” The best multivariate model identified the HLA
antigens B27, when DR7 was present, and DQw3, when
DR7 was not present, as predicting disease progression
across all transitions, while HLA-B39 was associated
with progression in early disease. The addition of these
HLA indicators to a model containing clinical variables
resulted in a significant improvement in fit.
Conclusion. The HLA antigens associated with
PsA, B27 and B39, are risk factors for disease progression, as is the HLA class I1 antigen DQw3. In combinaSupported by grants from the Medical Research Council of
Canada, the Ontario Ministry of Health, and The Canadian Arthritis
Society.
Dafna D. Gladman, MD, FRCPC: University of Toronto,
Toronto, Ontario, Canada; Vernon T. Farewell, PhD: University of
Waterloo, Waterloo, Ontario, Canada.
Address reprint requests to Dafna D. Gladman, MD,
FRCPC, The Wellesley Hospital, 160 Wellesley Street, E. Jones
Building, #102, Toronto, Ontario, Canada, M4Y 153.
Submitted for publication August 15, 1994; accepted in
revised form December 27, 1994.
tion with clinical measures of disease, these HLA variables are the dominant predictors of progression.
Psoriatic arthritis (PsA) has been defined as an
inflammatory arthritis, usually rheumatoid factor negative, associated with psoriasis. It has been reported
to occur in 1042% of patients with psoriasis (1,2), PsA
has been thought to be a benign arthropathy, and
physicians have been relluctant to use aggressive
disease-suppressive therapy, because of the prevalence of significant adverse effects of this treatment.
Consequently, there is a paucity of reports of psoriatic
arthritis drug trials in the literature, as compared with
trials of treatment for rheumatoid arthritis. However,
it has been shown that joint deformity and destruction,
as well as disability, are quite frequent among patients
with PsA, thus challenging the concept that it is a
benign arthropathy (3). It has been suggested that, in
order for damage and disability to be avoided, treatment should be started earlier than is generally done.
It would be very useful for clinicians caring for
patients with PsA to identify those who are destined to
develop severe disease, in order to design a rational
approach to treatment. Since some patients with PsA
do have a more benign course, we hypothesized that
there may be prognostic indicators for disease severity
in PsA, which may be identified. We have recently
identified certain clinical predictors for disease progression in PsA (4). However, these clinical features
are variables that change over time. It would be
advantageous to identify markers for disease progression that are stable, such as HLA antigens.
The association between HLA antigens and
PsA has been used to identify patients who are destined to develop psoriasis or PsA (5-14). The associations found have generally been with class I HLA
antigens, encoded by the HLA-A, B, and C loci of the
GLADMAN AND FAREWELL
846
major histocompatibility complex (MHC). HLA antigens B13, B16 and its spllits B38 and B39, as well as
B17 and Cw6, have been associated with psoriasis,
with or without arthritis. HLA-B27 has been associated with psoriatic arthritis. HLA antigens may identify patients with a particular pattern of PsA (5-13).
We have previously studied HLA antigen distribution
in 158 patients with PsA and 101 patients with uncomplicated psoriasis (12). We confirmed previously reported associations of HLA-B13, B17, B38, B39,
Cw6, and DR7 with psoriasis, and showed that HLAB27 and B7 occur more commonly in patients with
PsA. When HLA antigen distribution was examined
according to clinical pattern of PsA, HLA-B27 was
associated with back involvement among patients with
PsA, while HLA-B38 and B39 occurred more frequently among patients with peripheral polyarthritis.
Similar results were observed by Salvarani et a1 (13) in
Italian patients. Class I1 HLA antigens, encoded by
the HLA-D loci of the MHE, have also been studied in
psoriasis and PsA. Associations of HLA-DR7 and
psoriasis (7), and HLA-DR4 and PsA (6-8) have been
reported, although several other investigators have
found no such association (9-12).
The aim of the present investigation was to
identify HLA markers for disease progression in PsA.
PATIENTS AND METHODS
Patient population. The University of Toronto psoriatic arthritis clinic at The Wdlesley Hospital has the largest
population of PsA patients ever studied as a group (3). This
clinic serves as a primary, secondary, and tertiary referral
center, with patients being ireferred by family physicians,
dermatologists, internists, rheumatologists, and the Psoriasis Education and Research Centre (3). It thus includes a
population of several patients with mild and several with
severe disease, providing a full spectrum of the disease,
including its early forms.
At the initial visit, information was obtained regarding the age at onset of both skin and joint disease, pattern of
joint disease at onset, and family history of both skin and
joint disease. At each visit, a complete history and physical
examination were obtained and the findings recorded on a
data retrieval form. Inquiry was made into the presence of
joint inflammation, use of medications, Steinbrocker functional level (15), and general medical history including the
relationship between skin andl joint manifestations, presence
of nail involvement, and other extraarticular features. Physical examination consisted of a general medical examination
with particular attention to skin, nails, ocular and cardiac
features, as well as both peripheral and axial joints. The
numbers of actively inflamed joints (stress pain, tenderness,
effusion) and deformed joints (ankylosis, subluxation, or
decreased range of motion attributable to joint damage
rather than inflammation) were recorded (16); these measurements have been shown to be reliable in PsA (16). Spinal
disease was evaluated by testing for sacroiliac stress pain,
using at least 3 techniques, and by measurements of back
and neck movements in all planes (3,1620).
The assessments were performed by the rheumatology fellows who were assigned to the psoriatic arthritis clinic
for at least 6 months during the period of the study. Before
beginning work at the clinic, each fellow was trained in the
completion of the protocol and, specifically, how to examine
joints for inflammation and damage. Patients were followed
up at the clinic at approximately 6-month intervals.
Laboratory evaluation included complete blood cell
and differential counts, and erythrocyte sedimentation rate
(ESR) by the Westergren method. Biochemical tests of
kidney and liver function were performed, and serum uric
acid, serum lipid, and serum proteins were measured. Serologic tests included latex fixation test for rheumatoid factor,
fluorescent antibody test for antinuclear antibody (using
HEp-2 cells as substrate; titer > I :40 considered positive),
and measurement of serum complement levels.
HLA typing. HLA typing for both class I and class I1
antigens was performed by serologic techniques, using the
microcytotoxicity assay (12).
Outcome measures. Individual joint damage was assessed clinically on the basis of a decrease in range of motion
of >20% of the normal range, which could not be attributed
to active inflammation, the presence of contractures, subluxation, loosening or ankylosis, or previous surgery (16).
The number of deformed joints and their location were
recorded. The outcome variable for this analysis was the
number of damaged joints, divided into 4 categories: 0
damaged joints (state l), 1 4 damaged joints (state 2), 5-9
damaged joints (state 3), and 210 damaged joints (state 4).
At each clinic visit, the patient was classified as being in 1 of
the 4 states.
Statistical analysis. The data for all patients were
entered on a PC into a SAS database. The quality of the data
was examined continuously, by ensuring that protocols were
completed at each visit and through checking programs to
assure correct data entry, as well as review of computer
printouts against the protocols. Procedures to link data from
the database with appropriate software packages to perform
the needed analyses have been established.
Our analysis was based on a model for rates of
transition between damage states, developed by Kalbfleisch
and Lawless (21,22). Three such rates were studied: the rate
of transition from state 1 to state 2, the rate of transition from
state 2 to state 3, and the rate of transition from state 3 to
state 4. Let Hi(tIX,, . . . , Xk) denote the rate of transition
from state i to state i + 1 for an individual with prognostic
characteristics XI, . . . , xk. These rates are related to
prognostic factors through the equation
log(Hi(tlXl, . . . , X,))
= log(Ai) t-
Bi1.x~
+ . . . B,k.Xk.
The regression coefficients, the B,’s, were estimated from
the data, and a non-zero coefficient indicated that the associated X variable was influencing the transition rate from
state i - 1 to state i. The relative risk, or ratio of transition
rates, for the transition from state i to state i + 1, comparing
847
HLA AND PsA DISEASE PROGRESSION
an individual with the variable Xj coded 1 to an individual
with the variable coded 0, is exp(Bij). The simplest form of
this type of model assumes that a variable Xj has the same
effect on all transitions and that therefore B, = B, = B,.
The data used for the maximum likelihood estimation
are technically described as panel data. Individuals are
observed at separated points in time and, at each of these
times, the current disease state is recorded. There is no
requirement, for example, that clinic visits be equally
spaced. The information that is entered into the likelihood
function is that, between any two visits, the damage state
has either remained the same or has changed to a more
advanced state. One or more between-state transitions will
have been required to reach a more advanced state, and
likelihood function will reflect the necessary number of
transitions. Likelihood ratio chi-square tests are used to test
for non-zero regression coefficients and to test if simplifying
assumptions of common covariate effects across the different transitions are reasonable. Estimates of the mean time
spent in various states are derived from the maximum
likelihood estimates of the various parameters. Individuals
are classified in different damage states when they first
present to the clinic. This was modeled by stratification of
the model on initial state. This effectively allows the Ai
values to depend on the initial damage state.
There are a variety of ways to consider alternative
models. The initial, or baseline, model was taken to be the
stratified model with no prognostic factors. The focus of the
analysis was to identify variables coding the presence and
absence of HLA antigens which contributed further improvement in model fit. The approach taken was to first fit
single-factor models which assumed constant effects across
transitions. The explanatory variables were coded with
binary (0 or 1) variables where a 1 would code the presence
of the HLA antigen associated with the variable. The assumption of common effects was then tested for each variable individually. These analyses were used to suggest a
reduced model which included variables found to have
significant common effects andlor evidence for differential
effects across transitions. Nonsignificant variables in the
multivariate model were then eliminated, and the potential
improvement from the addition of other variables was examined to check the exclusions based on the univariate
analyses. Summary multivariate models, which include only
those variables that retained significance, are presented.
Likelihood ratio chi-square statistics are presented for each
variable, but they should of course be interpreted with some
caution since the models presented are the end result of a
model-building procedure. Likelihood ratio chi-square statistics are also used to evaluate the significance of adding
groups of variables to previously identified models.
RESULTS
At the time of this analysis there were 305
patients registered at the PsA clinic who had fewer
than 10 damaged joints upon presentation to the clinic.
Of these patients, 276 have been HLA typed. Their
demographic characteristics are shown in Table 1. The
Table 1. Demographics of the: study population
~~~~~
~
~
No. of patients
No. femaleho. male
Age at presentation, mean (ran,ge)
Duration of psoriatic arthritis at
presentation, mean (range)
Arthritis pattern at presentation,
% of patients
Distal
Oligoarthritis
Polyarthritis
Back alone
Back with distal
Back with oligoarthritis
Back with polyarthritis
276
1281148
42.1 (15.2-79.2)
6.9 (0.1-47.3)
19.2
27.2
32.2
4.3
3.3
4.3
8.7
characteristics of their arthritis at presentation to the
psoriatic arthritis clinic are shown in Table 2.
As outlined in Patients and Methods, the outcome measure used was transition between damage
states. The various transitions that were observed are
summarized in Table 3. Note that not all patients
experienced a change in state and that transitions
through more than 1 state could occur between clinic
visits. An analysis of our data, not incorporating
prognostic factors, provided estimates of 10.96, 6.16,
and 3.86 years for the mean amount of time in the first
3 states, respectively. The respective approximate
95% confidence intervals were 9.16-13.14, 5.35-7.61,
and 3.21-4.65.
The HLA alleles considered in our analysis
included the HLA antigens that had previously been
shown to be associated with PsA, including HLA-A2,
B13, B16, B17, B27, B37, B38, B39, Cw6, DR4, DR7,
and DQw3. Table 4 shows the results of the univariate
analyses for these antigens and an indication of the
percentage of the study population with each antigen.
Information on antigens B37, C6, and DQw3 was not
available for 19, 38, and 20 individuals, respectively.
Any models involving these antigens excluded individuals for whom typing data were not available. HLAB16, B27, B39, and DQw3 demonstrated a positive
Features of active disease and damage at presentation in
patients with psoriatic arthritis
Table 2.
No. (%) with no actively inflamed joints
No. (%) with 1-5 actively inflame:djoints
No. (%) with PS actively inflame'djoints
No- (%) with no d&med joints
No. (%) with 1-5 deformed joints
No. (%) with 25 deformed joints
Mean 2 SEM no. of active joints at presentation
Mean SEM no. of effusions at Presentation
Mean 2 SEM no. of deformed joiints at presentation
*
14 (5.1)
80 (29.0)
182 (65.9)
190 (68.8)
69 (25.0)
17 (6.2)
9.2 2 0.5
2.3 t 0.2
1.0 2 0.1
GLADMAN AND FAREWELL
848
Table 3. Observed changes in damage states between clinic visits*
Entry state
Transition
2
1
Table 5. Best multivariate model including HLA indicators for
subsequent damage in psoriatic arthritis*
Relative risk
3
1-2
1-3
HLA allele
State
1-2
State
2-3
State
34
2 (degree
of freedom)
1 4
827
B27 X DR7
B39
DR7
DQw3
DQw3 x DR7
1.25
2.30
7.45*
1.05
1.90
0.42
1.25
2.30
1.30
1.05
1.90
0.42
1.25
2.30
1.76
1.05
1.90
0.42
1.14 ( I )
5.19 (I)
17.66 (1)
0.05 ( I )
12.20 (1)
7.01 (1)
2-3
2-4
3 4
* Values are the number of patients. At entry, there were 190
patients in state I , 69 in state 2, and 17 in state 3.
* Only low transition
association with disease progression. HLA-DR7 appeared to be “protective” against progression. Only
B39 provided evidence for different effects on different
transitions.
Based on the variabl’esused in Table 4, the best
multivariate model includes B27, B39, and DQw3,
with B39 influencing the rate of development of the
first damaged joint but having less of a role subsequently. However, investigation of interactions indicated that the influence of both B27 and of DQw3
depended on the presence or absence of DR7. Thus,
the best multivariate model, which is summarized in
Table 5 , includes 6 variables, i.e., the presence of B27,
B39, DR7, and DQw3, and the interaction terms B27 X
DR7 and DQw3 x DR7. It should be noted that, of
individuals without DR7, 41 (23.7%) had B27 and 78
(47.5%) had DQw3, while of individuals with DR7, 15
(14.6%) had B27 and 35 (313%) had DQw3. Because of
Table 4. Univariate analysis of HLA indicators for subsequent
damage in patients with psoriatic arthritis*
HLA
allele
Frequencyt
RR
1 df
A2
B13
B16
B17
B27
B37
B38
B39
Cw6
DR4
DR7
DQw3
157 (56.9)
31 (11.2)
43 (15.6)
48 (17.4)
56 (20.3)
4 (1.6)
25 (9.1)
18 (6.5)
58 (24.4)
79 (28.6)
103 (37.3)
113 (44.1)
1.2:9
0.79
1.44
3.43
1.43
4.30$
0.39
7.14§
0.40
0.31
10.768
0.03
3.07
5.23$
6son
2
0.91
1.53
1.42
0.87
2.15
1.01
1.31
0.63
1.44
7
2 (differential
effect), 2 df
1.32
0.03
3.12
0.57
5.21
0.00
0.87
10.m
0.38
2.51
1.30
1.34
* Relative risk (RR) >1 is associated with disease progression when
antigen is present. df = degree($;)of freedom.
t Values are the number (%) of patients.
$ P < 0.05.
§ P < 0.02.
ll P < 0.01.
P
0.29
<0.02
<0.001
0.82
<0.001
<0.001
states were associated with 839.
the linkage disequilibrium between DR4 and DQw3,
there may be particular interest in DR4. However,
neither the variable coding DR4 (2 = 0.226, 1 degree
of freedom [dfl, P = 0.63) nor the interaction DR4 X
DQw3 (2= 0.372, 1 df, P = 0.542) added significantly
to the best-fitting multivariate model.
The term involving DR7 alone was included to
ensure a valid test of the interaction terms and was not
significant in itself. The presence of B27 was estimated
to have minimal impact if DR7 is not present but to be
associated with an increased risk (relative risk [RR] =
2.30 x 1.25 = 2.88) in the presence of DR7. DQw3
was, however, associated with an increased risk (RR
= 1.90) in the absence of DR7 but was estimated to
have little impact when DR7 is present (RR = 1.90 X
0.42 = 0.80). The presence of B39 was estimated to
have a dramatic effect (RR = 7.45) on the transition
from state 1 to state 2 but, with our data, could not be
demonstrated to have an effect on the rate of subsequent damage (2 = 1.52, 2 df, P > 0.10).
While it is difficult to summarize adequately the
information contributing to the estimated relative
risks, Table 6 gives some indication of the effects
present in the model shown in Table 5. Table 6
presents the percentage of patients experiencing progression during followup, subdivided with respect to
the presence or absence of certain HLA antigens.
Although this does not reflect the times spent in each
state or the amount of progression, the table does
reflect the relative risks estimated in Table 5 .
In an earlier study (4), we identified the presence of >4 joints with effusions and an ESR <15
mm/hour as clinical variables related to progression in
PsA. The addition of these variables to the HLA-based
model presented in Table 5 did not significantly improve the fit of the model (2 = 5.01, 2 df, P = 0.082).
In contrast, the addition of the HLA variables, includ-
849
HLA AND PsA DISEASE PROGRESSION
Table 6. Relationship between HLA antigens and psoriatic arthritis disease progression, expressed
as the number (%) of patients with progression in the presence or absence of HLA antigens
~~~~~~~~~
DQw3
B27
HLA
antigen
B39*
DR7 -
DR7 +
DR7 -
DR7 +
Negative?
Positivet
65/177 (36.7)
10/13 (76.9)
35/86 (40.7)
41/78 (52.6)
26/57 (45.6)
12/35 (34.3)
61/132 (46.2)
20/41 (48.8)
34/88 (38.6)
11/15 (73.3)
* Restricted to transitions from state I
t B39, DQw3, and B27.
ing separate transition effects for B39, to a model with
effusions and ESR did result in a significant improvement in fit (?= 25.58, 5 df, P < 0,001).
Also identified as being related to subsequent
disease progression in our earlier study (4)were the
use of medication beyond the nonsteroidal antiinflammatory drug level (including gold, chloroquine, methotrexate, or azathioprine, and retinoids or psoralen
ultraviolet A) and the use of oral corticosteroids.
These medication variables did add significantly to the
HLA model shown in Table 5 (2= 17.57, 2 df, P <
0.001). Table 7 presents the results of fitting a model
with HLA, clinical, and medication variables. As
expected from the results presented above, only the
HLA and medication variables were significantly related to progression in this multivariate model.
DISCUSSION
Previous studies of HLA antigens in psoriatic
arthritis have suggested that there may be a relationship between HLA antigens and disease expression.
HLA-B27 has been associated with the presence of
spondylarthropathy (5,7,12,13), while HLA-B38, B39,
and DR4 have been associated with a peripheral
Table 7. Multivariate model incorporating clinical, HLA, and
medication indicators for subsequent damage in psoriatic arthritis
Relative risk
Variable
B27
827 X DR7
B39
DR7
DQw3
DQw3 x DK7
>4 effusions
ESR <15 mrnlhour
Past medication
High level
Corticosteroid
State
1-2
State
2-3
State
3-4
2 (degree
offreedom)
1.06
2.47
7.05
0.83
1.63
0.54
1.27
0.83
1.06
2.47
1.06
2.47
0.83
1.63
0.54
1.27
0.83
0.83
1.63
0.54
1.27
0.83
0.06 ( I )
5.39(1)
16.40 ( I )
0.63 (1)
6.86 (1)
3.09 (1)
1.18 (1)
1.91 (1)
2.25
1.58
2.25
1.58
2.25
1.58
8.10(1)
6.73 ( I )
P
0.81
0.02
<0.001
0.43
<0.001
0.08
0.28
0.17
0.004
0.00
arthritis (5-8,12). We previously reported that HLAB17 was associated with an earlier age at onset of PsA,
while B27 was associated with a later age at onset (12).
Patients with HLA-B13 and DR7 had milder disease
than patients who lacked these antigens (12). These
studies have been cross-sectional, and it has not been
possible to consider the role of HLA antigens as
prognostic indicators.
The severity of Ps,A may be judged by the
presence and extent of deformities and damage both
clinically (by the presence of restriction of range of
motion, angulation, ankylosis, or loosening of a joint)
and radiologically (by the presence of erosions, joint
space narrowing, ankylosis, or total disorganization of
the joint), in a manner similar to that described for RA
(15). In addition, one might consider not only the
presence of these changes, but the rate of progression
of the disease. While this is difficult to assess when
patients are seen only once, it is possible to do during
a long-term prospective study. One may thus assess
the pattern of the disease not only in terms of the
classes of PsA already described, but also in terms of
disease progression.
The psoriatic arthritis clinic provided us with a
unique opportunity to perform such an assessment.
The clinic began in 1978, with patients seen at 6-month
intervals, thus providing an ample followup period.
We have previously tested the reliability of the outcome measures used in this study and have shown
them to be valid (16). W e have investigated the effect
of incomplete followup in the clinic on important PsA
characteristics that were documented at the clinic. The
results of these analyses confirmed that incomplete
followup was not associated with disease characteristics (23). We have also HLA typed this population of
patients in the course of their followup (12). Among
the group of 305 patients included in this analysis, 16%
demonstrated more tban 5 deformed joints, a frequency similar to that previously noted in our initial
study of 220 patients attending the clinic (16). The
GLADMAN AND FAREWELL
majority of the patients did not demonstrate deformities on their first assessment.
We have been able to develop a model to
examine prognostic factors. SO far, thkse factors include a high number of effusions, a high medication
level, and a low ESR (4), confirming the clinical
suspicion that joint inflamimation indeed leads to joint
damage. The current investigation is the first attempt
at identifying the role of HLA antigens as prognostic
factors in psoriatic arthritis, with a specific predefined
outcome, namely, progression of damage. The results
identified the HLA antigens B27, when DR7 was
present, and DQw3, when DR7 was not present, as
predicting disease progression across all transitions,
while HLA-B39 was associated with progression in
early disease. These antigens have previously been
associated with PsA. We have now demonstrated that
these same antigens play a role in disease expression.
Moreover, these HLA antigens are the dominant predictors of progression of damage.
This is a very important observation, since it
suggests that individuals who are destined to develop
more severe disease may be identified at the time of
diagnosis. Since HLA antigens are molecules present
in an individual before the dlevelopment of the disease,
they are clearly risk factors for disease expression.
Patients may thus be classified at the time of diagnosis,
or at the time of first presentation, as either being at
risk for disease progression or as being “protected.”
In that way, it may be possible to develop and apply
therapeutic approaches that are more appropriate for
the individual patient.
ACKNOWLElDGMENTS
The authors wish to thank the patients who attend
the psoriatic arthritis clinic, as well as the following rheumatology fellows who have participated in the clinic: Drs. S.
Fox, JC Thorne, R. Shuckett, A. Karasik, M. Sugai, W.
Silecky, J. Hanly, M. Ramsden, M. Stollar, D. Buskila, P.
Langevitz, L. Hamilton, R. Goodman, and G. Hawker. The
contributions of Karen Anhorn, RT and Greg Michener,
MSc, who performed the HLA typing, J. Long, BSc, research assistant, who administers the clinic, and H. Dykstra,
who prepared the manuscript, are acknowledged.
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