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In vitro rheumatoid factor synthesis in patients taking second-line drugs for rheumatoid arthritis.

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1090
IN VITRO RHEUMATOID FACTOR SYNTHESIS IN
PATIENTS TAKING SECOND-LINE DRUGS FOR
RHEUMATOID ARTHRITIS
Independent Associations with Disease Activity
NANCY J. OLSEN, LEIGH F. CALLAHAN, and THEODORE PINCUS
Rheumatoid arthritis (RA) patients whose unstimulated peripheral blood mononuclear cells produce
high levels of IgM rheumatoid factor (IgM-RF) in vitro
have more severe disease activity. RA patients being
treated with second-line agents, including gold salts,
penicillamine, or methotrexate, tend to be low producers or nonproducers of IgM-RF in vitro. The possibility
that low production or nonproduction of IgM-RF in
vitro may be explained by treatment with second-line
agents alone, irrespective of disease activity, was analyzed in 133 RA patients whose disease status was
assessed by multiple laboratory and clinical measures.
The results indicate that treatment with second-line
agents and in vitro IgM-RF synthesis are independently
associated with disease activity.
In vitro synthesis of IgM rheumatoid factor
(IgM-RF) by unstimulated peripheral blood mononuclear cells (PBMC) is seen in approximately 50% of
patients with rheumatoid arthritis (RA) (1-3). IgM-RF
synthesis in vitro is less likely to be seen in patients
with less severe disease activity (1-3) and in patients
From the Division of Rheumatology and Immunology,
Department of Medicine, Vanderbilt University School of Medicine,
Nashville, Tennessee.
Supported in part by NIH Biomedical Research Support
grant RR-05424, NIH General Clinical Research Centers grant
5M01RR-00095, Pfizer Laboratories, NIH grant AM-21393 to the
American Rheumatism Association Medical Information System,
and by Smith Kline and French Laboratories, the Arthritis Foundation, the Jack C. Massey Foundation, and the Maury County Lupus
Fund.
Nancy J. Olsen, MD; Leigh F. Callahan, BS; Theodore
Pincus, MD.
Address reprint requests to Nancy J. Olsen, MD, B-3219
Medical Center North, Vanderbilt University, Nashville, T N 37232.
Submitted for publication December 7, 1987; accepted in
revised form April 8, 1988.
Arthritis and Rheumatism, Vol. 31, No. 9 (September 1988)
treated with second-line agents such as gold, penicillamine, methotrexate, or azathioprine (4-6). One possible interpretation of these findings is that lower
levels of in vitro R F synthesis result primarily from an
effect of the drug, rather than as a correlate of lower
disease activity. This suggests that treatment of RA
patients with a second-line agent may ablate in vitro
IgM-RF synthesis regardless of clinical response (7).
We measured in vitro synthesis of IgM-RF by
PBMC from 133 RA patients in whom an extensive
clinical and laboratory evaluation was conducted. The
results confirm earlier findings that patients with more
severe disease status tend to be high producers of
IgM-RF in vitro, whereas patients taking second-line
agents tend to be nonproducers or low producers of
IgM-RF. Lower levels of JgM-RF synthesis in patients
taking second-line drugs cannot be explained by the
use of these drugs alone, since levels of IgM-RF
synthesis in these patients are independently associated with disease severity.
PATIENTS AND METHODS
Patients. The study group consisted of 133 patients
with definite or classic RA, as defined by the American
Rheumatism Association revised criteria (8). The patients
studied were seen in the following clinical settings: 83 from
the Vanderbilt University Hospital and clinic, 27 from the
Nashville Veterans Administration Medical Center, 11 from
the private practice of Dr. Joseph Huston in Nashville, and
12 from other private physicians. Demographic characteristics of the study population are shown in Table 1.
Cell cultures. Mononuclear cells were obtained from
heparinized peripheral blood by centrifugation on FicollHypaque cushions. Cells were extensively washed, then
resuspended at 106/ml in RPMI tissue culture medium
(Gibco, Grand Island, NY) supplemented with 10% fetal calf
RF SYNTHESIS IN RA PATIENTS
1091
Table 1. Demographic features of rheumatoid arthritis (RA) patients classified according to levels of IgM rheumatoid factor (ISM-RF)or
treatment with second-line drugs
~~
~
Treatment with
second-line
drugt
IgM-RF producer status*
All RA
patients
No. of patients
Mean age (years)
Mean age at onset (years)
Mean disease duration (years)
Mean years formal education
96 female
3
'6 white
96 HLA-DR4+
133
56
45
11
11
53
87
61
High
Low
producers
producers
Nonproducers
Yes
No
34
26
54
44
73
57
46
10
II
56
86
58
48
57
47
85
56
44
I1
57
44
14
I1
50
85
66
10
10
50
92
63
10
II
55
95
65
10
55
89
60
~
* Levels of IgM-RF synthesis: high producers > 1.8 ng anti-IgM; low producers X . 6 and 5 I .8 ng anti-IgM; nonproducers 50.6 ng anti-IgM.
None of the differences between the 3 IgM producer groups or the 2 treatment groups are statistically significant.
t Second-line drugs include gold salts, penicillamine, hydroxychloroquine, azathioprine, and methotrexate.
serum (Flow Laboratories, McLean, VA), glutamine (Flow),
penicillin, and gentamicin. Cultures were done with and
without pokeweed mitogen (PWM; Sigma, St. Loiris, MO) at
10 pg/ml. Cells were dispensed in 0.20-ml volumes into
round-bottom microwells (Costar, Cambridge, MA), and
incubated for 14 days. Replicate supernatants were pooled
and stored at -70°C until assayed.
Radioimmunoassays. Total IgM secreted in the culture
supernatants was measured by solid-phase radioimmunoassay as previously described (6). Briefly, polyvinyl chloride
microwells were coated with anti-human IgM (Tago, Burlingame, CA), for at least 4 hours, then washed and blocked
with 10% newborn calf serum (Gibco). Aliquots of culture
supernatants, diluted plasma samples, or medium alone were
added to the prepared wells for at least 4 hours. After
washing, the final layer of '2sI-labeled F(ab'), anti-human IgM
(Tago) was added. Individual wells were then cut apart and
counted in a gamma counter (Beckman, Fullerton, CA).
Results were standardized with a pool of normal human
serum and expressed as ngiml.
The assay for IgM-RF was done in parallel with that
for IgM; the only difference was in the use of heataggregated human IgG (Pel-Freez, Rogers, AR) as the first
layer. Results were normalized to selected standard seropositive samples and expressed as ng of anti-IgM bound per
microwell. Sixty of the 133 patients (45%) produced >0.6 ng
anti-IgM of IgM-RF in unstimulated cultures, a level that
exceeded 2 standard deviations from the mean for normal
individuals. This finding is similar to that obtained in previous studies ( 2 ) , and suggests that the study populations are
comparable. Seventy-three patients who produced 50.6 ng
anti-IgM of IgM-RF were classified as nonproducers. The 34
patients with the highest IgM-RF production (> 1.8 ng antiIgM of IgM-RF) were classified as high producers, and the 26
patients whose cells secreted between 0.6 and 1.8 ng antiIgM were classified as low producers.
Clinical assessment. Clinical assessment included 4
types of measures: (a) Joint counts were performed according to a modified Ritchie Index (9) to assess tenderness,
swelling, pain on motion, limited motion, and deformity in 42
joints. (b) Radiographs of the hands were analyzed for
erosion, joint space narrowing, and malalignment, quantitatively, using a modification of the methods of Sharp et a1
(10,l I). (c) Twenty-five-foot walking time was measured
using a standard method (l2,13). (d) Self-report questionnaires to determine difficulty in performing standardized
activities of daily living (ADL) were quantitatively scored
( 13-1 5).
Laboratory assessment. The laboratory assessment
included 4 types of measures: (a) Westergren erythrocyte
sedimentation rate (ESR) was measured by standard methods (16). (b) Serum RF was assayed using latex agglutination
(16). (c) The ratio of helper (CD4) to suppressor (CD8) T
cells was measured by automated flow cytometry at Diaclin
Laboratories (Nashville, TN) (The normal CD4:CD8 ratio
found in our laboratory is 2.06 0.70, mean 2 SD.) (17). (d)
Complete HLA typing for A, B, C and DR loci was performed for most of the patients by Dr. Peter Stastny at the
University of Texas Health Science Center in Dallas and, for
some of the VAMC patients, by Dr. Gary Niblack at the
Nashville VAMC, using a microcytotoxicity assay (18).
Statistical analyses. The data were entered into a VAX
11/780 microcomputer using the Statistical Package for the
Social Sciences (19). Correlations between continuous variables were computed according to Pearson's r. Mean levels of
various disease status measures were determined in patient
groups classified according to production of spontaneous
IgM-RF or treatment status. Statistical significance was
tested using one-way analysis of variance. Analysis of covariance was used to control for possible confounding effects of
unstimulated total IgM synthesis, which is correlated with
unstimulated IgM-RF synthesis (r = 0.28). Dichotomous
variables were studied using cross-tabulations, and statistical
significance was tested using 2-tailed chi-square tests. Adjustment for multiple comparisons was calculated according to
the Bonferroni adjustment (20).
Multiple logistic regression analyses were performed
to examine the independence and significance of spontane-
*
OLSEN ET AL
1092
ous in vitro IgM-RF synthesis and treatment with long-acting
drugs in explaining severity of disease status, using the
maximum likelihood ratio method (21). Regressions were
modeled with 5 different measures of clinical status as
dependent variables. The dependent variables were dichotomized using median values for each measure. Partial odds
ratios are reported for the independent variables as the odds
of having higher disease activity, controlling for the other
variables in the regression model. The significance and
independence of IgM-RF and second-line drug therapy in
explaining each clinical status measure were analyzed controlling for age, sex, duration of disease, total IgM synthesis,
and HLA-DR4 status.
RESULTS
Patient population. The 133 study patients had
demographic features that were typical for a series of RA
patients, except that there was a greater proportion of
males due to the inclusion of 27 patients from the
VAMC. Patients in the 3 IgM-RF producer categories
did not differ significantly in mean levels of any demographic variable (Table 1).
At the time of assessment, 48 of the 133 patients
were taking a second-line drug, including 22 receiving
methotrexate, 18 receiving gold salts, 6 receiving hydroxychloroquine, and 1 each receiving penicillamine
and azathioprine. There were 85 patients who were not
taking any second-line agents, many of whom were
studied on their initial visit, prior to beginning therapy
with second-line drugs. No significant differences were
seen in mean levels of any demographic variable be-
tween patients under treatment with a second-line drug
and those not under such treatment (Table 1).
In vitro IgM-RF synthesis and disease status.
Comparisons among high-producer, low-producer,
and nonproducer patients for in vitro IgM-RF suggested marked differences between the high-producer
group and the remaining patients in most disease
status measures (Table 2). In addition, the mean ratio
of unstimulated IgM-RF to total IgM was 8.93 x lop3
for the high producers, and only 1.70 X lop3 in the
remaining patients ( P < 0.001). This suggested that the
observed differences in disease status according to
IgM-RF production cannot be explained by differences
in total IgM synthesis.
Spontaneous IgM-RF synthesis was correlated
with PWM-induced IgM-RF synthesis (r = 0.62, P <
O.OOOl), but no significant correlations between disease
status variables and PWM-induced IgM-RF were seen
(data not shown). In addition, ratios of PWM-induced
IgM-RF to total IgM were not significantly higher in the
IgM-RF high-producer group (4.32 X
than in the
remaining patients (2.22 x
( P = 0.2). These
findings suggest that IgM-RF that is produced by unstimulated cells in vitro is most closely related to
disease activity.
IgM-RF synthesis in vitro according to treatment
with second-line agents. The highest values for IgM-RF
synthesis were seen in patients who were not receiving
second-line agents (Figure 1). and the mean level of
IgM-RF synthesis in patients n o t being treated with
Table 2. Clinical and laboratory measures of disease status in rheumatoid arthritis patients
classified according to levels of IgM rheumatoid factor (IgM-RF) synthesis*
All RA
patients
No. of patients
Clinical measures
Joint count score
Radiographic score
25-ft walking time (seconds)
ADL difficulty score
Laboratory measures
ESR (mm/hour)
RF latex fixation titer
Plasma RF (ng anti-IgM)
CD4:CD8 ratio
IgM-RF
high
producers
IgM-RF
nonproducers
and low
producers
Pt
133
34
99
-
13.7
1.34
10. I
2.0
16.0
1.59
11.4
2.2
12.8
1.23
9.7
2.0
0.009
0.009
0.05
0.09
35
1:1,802
7,168
2.22
51
I :2,634
9,851
2.06
30
0.001
0.020
0.001
0.30
1: 1,518
6,284
2.26
* Values are the means. ADL = activities of daily living; ESR = erythrocyte sedimentation rate. See
Table 1 for definitions of producer status.
t High producers versus nonproducers and low producers, by one-way analysis of variance,
controlling for unstirnulated total IgM synthesis.
RF SYNTHESIS IN RA PATIENTS
1093
Table 3. Clinical and laboratory measures of disease status in
rheumatoid arthritis (RA) patients classified according to treatment with second-line drugs*
All RA
patients
No. of patients
a
a
Clinical measures
Joint count score
Radiographic score
25-ft walking time (seconds)
ADL difficulty score
Laboratory measures
ESR (mm/hour)
R F latex fixation titer
Plasma IgM-RF (ng
anti-lgM)
CD4:CD8 ratio
IgM-RF synthesis
Treatment with
second-line drug
Yes
No
133
48
85
13.7
I .34
10. I
2.0
11.7
1.37
9.1
I .8
14.7
1.32
10.7
2.2
35
1 : 1,802
27
1 : 1,965
7,168
2.22
1.3
8,106
2.15
0.9
Pt
0.05
0.44
0.13
0.02
40
0.01
1: 1,708 0.31
5,553
2.26
1.5
0.04
0.56
0.16
* Values are the means. ADL = activities of daily living; ESR =
erythrocyte sedimentation rate; RF = rheumatoid factor. See Table
1 for definition of second-line drugs.
t Comparison of the 2 treatment groups by one-way analysis of
variance, controlling for total IgM synthesis by analysis of covariance.
a
Y
a
a
--
ma
a
NO
YES
Treatment With Second-Line Drug
Figure 1. Synthesis of unstimulated IgM rheumatoid factor (IgMRF) by blood mononuclear cells from 133 rheumatoid arthritis
patients. Eighty-five patients did not receive a second-line drug
(gold salts, penicillamine, hydroxychloroquine, azathioprine, or
methotrexate) and 48 patients did.
second-line drugs was 1.5 ng, compared with 0.9 ng in
those taking second-line drugs (Table 3). Patients
treated with methotrexate had a lower mean level of
IgM-RF synthesis (0.7 ng) than patients treated with
hydroxychloroquine (0.9 ng) or gold (1 .O ng), but these
differences were not statistically significant, and re-
sults for all second-line agents were pooled. Consistent with previous studies, the observed differences
suggest that low-producer or nonproducer status is
more likely to be present in patients being treated with
second-line agents.
Disease status tended to be better in patients
taking second-line drugs, although this was not true for
all measures (Table 3). The absence of statistical significance in most analyses may suggest that differences in
disease status in patients who are high producers of in
vitro IgM-RF are likely to be more important than
differences in the use of second-line agents.
IgM-RF synthesis in vitro according to disease
status and treatment. Disease status variables and in
vitro IgM-RF synthesis were analyzed separately in
patients who were receiving second-line drugs and
those who were not receiving these drugs. Nine of the
48 patients who were receiving a second-line agent
were high producers of IgM-RF, and these 9 patients
showed poorer disease status than the remaining 39
patients (Table 4). In the 85 patients who were not
taking a second-line drug, more severe disease status
was seen in the 25 high producers of IgM-RF than in
the 60 low producers or nonproducers of IgM-RF
(Table 4). These results again suggest that production
of IgM-RF is more closely related to disease activity
than to treatment with second-line drugs.
OLSEN ET AL
1094
Table 4. Clinical and hboratory measures of disease status in rheumatoid arthritis (RA) patients
classified according to treatment with second-line drugs and levels of IgM rheumatoid factor synthesis*
Patients receiving drugs
No. of patients
Joint count score
Radiographic score
25-ft walking time (seconds)
ADL difficulty score
ESK (mmihour)
Patients not receiving drugs
No. of patients
Joint count score
Radiographic score
25-ft walking time (seconds)
ADL difficulty score
ESR (mmihour)
All RA
patients
IgM-RF
high
producers
IgM-RF
nonproducers
and low
producers
Pt
48
11.7
1.4
9.1
1.8
27
9
14.8
I .5
13.4
1.7
47
39
11.3
I .3
8.0
2.2
22
0.225
0.61
0.005
0.035
0.001
85
14.7
I .33
10.7
2.2
40
25
16.8
I .68
10.8
2.2
54
60
13.4
1.18
10.7
2.1
34
0.04
0.005
0.63
0.61
0.01 I
-
* Values are the means. ADL = activities of daily living; ESR == erythrocyte sedimentation rate. See
Table 1 for definition of second-line drugs.
+ High producers versus nonproducers and low producers, by one-way analysis of variance,
controlling for total IgM synthesis by analysis of covariance.
Regression analyses were performed to determine whether low production of IgM-RF in vitro and
treatment with second-line drugs were independently
associated with less severe disease status, and to
further analyze the statistical significance of associations between production of IgM-RF in vitro, disease
status, and treatment with second-line drugs, since
many differences (shown in Tables 2 , 3, and 4) would
not be significant according to stringent criteria for
multiple comparisons (20).
Univariate analyses indicated that both a high
level of unstimulated in vitro IgM-RF synthesis and
absence of treatment with a second-line agent were
associated with significantly increased odds ratio values for higher disease activity according to 5 measures
(Table 5), although all disease measures were not
uniformly affected. In multivariate analyses, the relative risks associated with high in vitro IgM-RF synthesis and absence of second-line therapy to explain
elevated levels for the 5 disease measures were not
significantly changed (Table 5). This indicated that in
vitro IgM-RF production and treatment status with
second-line drugs are independently associated with
values for the disease status measures. Other variables
were not significantly associated with disease measures except for HLA-DR4 positivity and duration of
disease, which, as we have reported elsewhere, are
associated with more severe changes (1 1,22).
DISCUSSION
LJnstimulated or spontaneous in vitro IgM-RF
synthesis by PBMC was measured in 133 patients with
RA. Sixty of these patients (45%) had levels of spontaneous in vitro IgM-RF synthesis which exceeded the
normal range (>0.6 ng anti-IgM). The patients with the
Table 5. Relative frequencies (odds ratios) for disease measures,
according to IgM rheumatoid factor (IgM-RF) synthesis, treatment
with second-line drugs, and other variables*
Radio- ADL
25-ft
Joint graphic difficulty walking
ESR count score
score
time
~____
Univariate analyses
IgM-RF > 1.8
Not taking secondline drug
Multivariate analyses
IgM-RF > 1.8
Not taking secondline drug
HLA-DR4+
Disease duration (years)
________
~~
6.4t
1.6
2.7:
2.0
2.9
2.9t
2.5$
1.0
2.8t
2.5:
6.45
1.1
2.7:
1.7
2.6$
0.9
2.5
1.1 5
2.9;
1.3
I .O
2.4:
1 .0
1.0
3.01 3.2t
1.7 3.3s
I . IS
1 .0
* Cut points for the dependent variables are: erythrocyte sedimentation rate (ESR) 31 mmihour; joint count 13.5; radiographic score
1.3; activities of daily living (ADL) score 2.0; 25-ft walking time 8.5
seconds.
t P < 0.01.
$ P < 0.05.
$ P < 0.001.
RF SYNTHESIS IN RA PATIENTS
highest quartile of IgM-RF production levels manifested more severe disease activity, as measured by
joint count scores, radiographic scores, ESR, ADL
difficulty scores, and walking time. Many of these
differences were statistically significant in single variable and regression analyses, and all trends indicated
more severe disease status in RA patients who were
high producers of spontaneous IgM-RF.
Similar results were seen in patients treated
with second-line drugs, including gold, penicillamine,
hydroxychloroquine, azathioprine, or methotrexate,
suggesting that a poor clinical response to therapy with
these second-line agents is associated with continued
production of IgM-RF. These findings confirm our
previous studies that indicate that in vitro production
of IgM-RF b y unstimulated PBMC is associated with
greater disease activity, and is not directly associated
with second-line drug therapy (2,4).
Mean levels of IgM-RF production were lower
in patients taking second-line drugs. Therefore, it is
possible that some reduction of IgM-RF may occur in
all treated patients. This would be consistent with the
observation by Alarcon and associates that treatment
of RA patients with a 1-gm loading dose of parenteral
gold salts resulted in decreased spontaneous IgM-RF
synthesis regardless of the clinical outcome (7). Nevertheless, the results of the present investigation indicate that if significant disease activity continues during
treatment with a second-line drug, spontaneous synthesis of IgM-RF is likely to be high.
Our present findings also suggest that high
levels of unstimulated in vitro IgM-RF synthesis in RA
patients are not simply a result of generalized polyclonal stimulation of IgM production as has been
suggested (23), since correlations with clinical and
immunologic indicators of disease activity were considerably higher for unstimulated in vitro IgM-RF
production than for total in vitro IgM production. This
result indicates that IgM-RF synthesis is a relatively
specific in vitro correlate of disease activity, which
may reflect underlying mechanisms responsible for the
clinical manifestations of rheumatoid arthritis (24).
ACKNOWLEDGMENTS
We thank Lisa Murray and Monteia Moore for
skilled technical support, Raye Brooks for careful evaluation
of the patients, Drs. Jeremy Kaye and E. Paul Nance for
interpreting the radiographs, Dr. Wayne Green and Keith
Shults for flow cytometry analyses, and Drs. Peter Stastny
and Gary Niblack for HLA typing. Drs. Howard Fuchs,
John Sergent, and Joseph Huston were most helpful in
1095
referring patients for study. Marilyn Welch-Fava patiently
prepared the manuscript.
REFERENCES
1. Vaughan J, Chihara T, Moore TL, Robbins DL, Tanimoto K, Johnson JS, McMillan K: Rheumatoid factorproducing cells detected by direct hemolytic plaque
assay. J Clin Invest 58:933-941, 1976
2. Olsen N , Ziff M, Jasin HE: In vitro synthesis of immunoglobulins and IgM-rheumatoid factor by blood mononuclear cells of patients with rheumatoid arthritis. Rheumatol Int 259-66, 1982
3. Koopman WJ, Schrohenloher RE: Enhanced in vitro
synthesis of IgM rheumatoid factor in rheumatoid arthritis. Arthritis Rheum 23:98.5-992, 1980
4. Olsen N, Zi€f' M, Jasin HE: Spontaneous synthesis of IgM
rheumatoid factor by blood mononuclear cells from patients with rheumatoid arthritis: effect of treatment with
gold salts or D-penicillamine. J Rheumatol 11:17-21, 1984
5 . Patel V , Panayi GS, Unger A: Spontaneous and pokeweed mitogen-induced in vitro immunoglobulin and IgM
rheumatoid factor production by peripheral blood and
synovial fluid mononuclear cells in rheumatoid arthritis.
J Rheumatol 10:364-372, 1983
6. Olsen NJ, Callahan LF, Pincus T: Immunologic studies
of rheumatoid arthritis patients treated with methotrexate. Arthritis Rheum 30:481-488, 1987
7. Alarcon GS, Koopman WJ, Schrohenloher RE: In vitro
IgM and IgM rheumatoid factor production and response to remittive agents in rheumatoid arthritis (letter). Arthritis Rheum 28:356-357, 1985
8. Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA:
1958 revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 9:175-176, 1958
9. Ritchie DM, Boyle JA, McInnes JM, Jasani MK, Calakas TG, Grieveson P, Buchanan WW: Clinical studies
with an articular index for the assessment of joint
tenderness in patients with rheumatoid arthritis. Q J
Med 37:393-406, 1968
10. Sharp JT, Bluhm GB, Brook A, Brower AC, Corbett M,
Decker JL, Genant HK, Gofton JP, Goodman N , Larsen
A, Lidsky MD, Pussila P, Weinstein AS, Weissman BN,
Young DY: Reproducibility of multiple-observer scoring
of radiologic abnormalities in the hands and wrists of
patients with rheumatoid arthritis. Arthritis Rheum 28:
1 6 2 4 , 198.5
11. Kaye JJ, Callahan LF, Nance EP, Brooks R, Pincus T:
Bony ankylosis in rheumatoid arthritis: associations
with longer duration and greater severity of disease.
Invest Radio1 22:303-309, 1987
12. DeCeulaer K, Dick WC: The clinical evaluation of
anti-rheumatic drugs, Textbook of Rheumatology. Edited by WN Kelley, ED Harris Jr, S Ruddy, CB Sledge.
Phiiadelphia, WB Saunders, 1981
1096
13. Pincus T, Callahan LF, Brooks RH: Quantitative nonlaboratory measures to monitor and predict the course
of rheumatoid arthritis, Rehabilitation Management of
Rheumatic Conditions. Second edition. Edited by GE
Ehrlich. Baltimore, Williams & Wilkins, 1986
14. Fries JF, Spitz P, Kraines RG, Holman HR: Measurement of patient outcome in arthritis. Arthritis Rheum 23:
137-145, 1980
15. Pincus T, Summey JA, Soraci SA Jr, Wallston KA,
Hummon NP: Assessment of patient satisfaction in activities of daily living using a modified Stanford Health
Assessment Questionnaire. Arthritis Rheum 26: 1 3 4 6
1353, 1983
16. Baum J, Z B M: Laboratory findings in rheumatoid arthritis, Arthritis and Allied Conditions. Tenth edition. Edited
by DJ McCarty. Philadelphia, Lea & Febiger, 1985
17. Hoffman RA, Kung PC, Hansen WD, Goldstein G:
Simple and rapid measurement of human T lymphocytes
and their subclasses in peripheral blood. Proc Natl Acad
Sci USA 77:4914-4917, 1980
18. Nunez G, Moore SE, Ball GV, Hurd ER, Stastny P:
OLSEN ET AL
Study of HLA antigens in ten multiple-case rheumatoid
arthritis families. J Rheumatol 11: 129-135, 1984
19. SPSS" Users Guide. Second edition. New York, McCraw-Hill, 1986
20. Cupples LA, Heeren T, Schatzkin A, Colton T: Multiple
testing of hypotheses in comparing two groups. Ann
Intern Med 100:122-129, 1984
21. Kleinbaum DC,Kupper LL, Morgenstern H (editors): Epidemiologic Research, Principles and Quantitative Methods. Belmont, CA, Lifetime Learning Publications, 1982
22. Olsen NJ, Callahan LF, Brooks RH, Nance EP, Kaye
JJ, Stastny P, Pincus T: Associations of HLA-DR4 with
rheumatoid factor and radiographic severity in rheumatoid arthritis. Am J Med 84:257-264, 1988
23. Moller E, Strom H, Al-Balaghi S: Role of polyclonal
activation in specific immune responses. Scand J Immuno1 12:177-182, 1980
'24. Olsen N, Jasin HE: Synthesis of rheumatoid factor in
vitro: implications for the pathogenesis of rheumatoid
arthritis. Semin Arthritis Rheum 15:146-156, 1985
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