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LETTERS
1033
alleles are primarily a risk factor for anti–cyclic citrullinated peptide
antibodies and are not an independent risk factor to develop
rheumatoid arthritis. Arthritis Rheum 2006;54:1117–21.
5. Huizinga TW, Amos CI, van der Helm-van Mil AH, Chen W, van
Gaalen FA, Jawaheer D, et al. Refining the complex rheumatoid
arthritis phenotype based on specificity of the HLA–DRB1 shared
epitope for antibodies to citrullinated proteins. Arthritis Rheum
2005;52:3433–8.
DOI 10.1002/art.22555
Reply
Figure 1. Sharp/van der Heijde scores (mean ⫾ SEM) in rheumatoid
arthritis patients with TNFA ⫺308 genotype AA ⫹ AG and those with
genotype GG, during 4 years of followup. P ⫽ 0.8, 0.7, 0.8, and 0.7,
respectively, at baseline and at 1 year, 2 years, and 4 years of followup,
by Mann-Whitney test.
In our opinion, because the TNFA ⫺308 A allele is in
linkage disequilibrium with HLA–DR3, which is reported to be
associated with only anti-CCP–negative RA, and RA patients
without anti-CCP antibodies generally experience a less severe
disease course compared with RA patients who have anti-CCP
antibodies, the analysis of the association between the TNFA
⫺308 A allele and the rate of joint destruction should be
corrected for the presence or absence of anti-CCP antibodies.
Therefore, we analyzed white RA patients who were included
in the Leiden Early Arthritis Clinic, and we did not observe an
association between the TNFA ⫺308 A allele and radiographic
joint destruction in RA patients, neither in the presence nor in
the absence of anti-CCP antibodies.
A. H. van der Helm-van Mil
F. A. Kurreeman
R. E. Toes
T. W. Huizinga
Leiden University Medical Center
Leiden, The Netherlands
1. Khanna D, Wu H, Park G, Gersuk V, Gold RH, Nepom GT, et al.
Association of tumor necrosis factor ␣ polymorphism, but not the
shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort. Arthritis Rheum
2006;54:1105–16.
2. Irigoyen P, Lee AT, Wener MH, Li W, Kern M, Batliwalla F, et al.
Regulation of anti–cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA–DR3 and the shared
epitope alleles. Arthritis Rheum 2005;52:3813–8.
3. Verpoort KN, van Gaalen FA, van der Helm-van Mil AH, Schreuder GM, Breedveld FC, Huizinga TW, et al. Association of
HLA–DR3 with anti–cyclic citrullinated peptide antibody–negative
rheumatoid arthritis. Arthritis Rheum 2005;52:3058–62.
4. Van der Helm-van Mil AH, Verpoort KN, Breedveld FC, Huizinga
TW, Toes ER, de Vries RR. The HLA–DRB1 shared epitope
To the Editor:
Dr. van der Helm-van Mil et al suggest that our
analyses of the relationships of the rate of joint destruction
with the TNFA ⫺308 A allele and with the SE should be
corrected for the presence or absence of anti-CCP antibodies
in our RF-positive early RA cohort. They base this on their
finding that the TNFA ⫺308 A allele was not associated with
the Sharp/van der Heijde scores at baseline, 1, 2, and 4 years in
their Leiden Early Arthritis cohort of 327 patients, 56% of
whom were anti-CCP positive and ⬃55% of whom were RF
positive (1). They assume, based on their data (1), that our
finding of HLA–DRB1*0301 in 55% of our patients with the
TNFA ⫺308 AA ⫹ AG genotype (versus 3% of those with the
GG genotype) indicates that these patients would be anti-CCP
negative and therefore should have less radiographic progression, because anti-CCP–negative RA is associated with less
severe joint damage (2).
Similarly, they reason that both the SE and RF are
associated with anti-CCP antibodies, and anti-CCP antibodies
are significantly associated with more rapid joint destruction;
therefore, we should have found that the presence of the SE is
associated with more rapid radiographic progression rather
than less rapid progression, as we reported.
We did not report the anti-CCP status of our cohort,
because it was not available when we planned and began our
observational study in 1992 and 1993. In response to the letter
from van der Helm-van Mil and colleagues, Specialty Laboratories (Valencia, CA), which has kindly performed serologic
studies and maintained a frozen specimen bank for our study,
was able to locate frozen specimens from 122 of the 189
patients analyzed in the TNFA ⫺308 polymorphism study (3);
specimens from the remaining 67 patients were not readily
accessible. There were no statistically significant differences in
radiographic progression rates (total Sharp score), joint space
narrowing scores, or erosion scores between the 122 anti-CCP–
positive patients analyzed and the 67 excluded patients (P ⫽
0.47–0.88), nor in the presence of the TNFA ⫺308 A allele, the
presence of the SE, age at onset, and sex between these 2
subsets (P ⫽ 0.36–0.81).
Specialty Laboratories performed anti-CCP antibody
assays in the 122 specimens (test no. 3133: cyclic citrullinated
peptide IgG antibody. Online at http://www.specialtylabs.com/
tests/details.asp?id⫽3133). One hundred eight specimens
(88.5%) are anti-CCP positive, which is consistent with the estimate of van der Helm-van Mil et al that 82–87% of RFpositive patients with RA are also anti-CCP antibody positive.
Among the 122-patient subset, 90 (74%) have the SE, and 14
of the 122 specimens are DRB1*0301 positive. The presence
1034
of DRB1*0301 is associated with anti-CCP antibody positivity
(10 of 14; P ⫽ 0.056 for the association), contrasting with the
reported association of anti-CCP antibody negativity with
DRB1*0301-positive patients in the Leiden cohort (54 of 93)
(1). The presence of the SE is associated with the presence of
anti-CCP antibody; 85 of 90 patients with the SE are also
anti-CCP positive (P ⫽ 0.002). The TNFA ⫺308 AA ⫹ AG
genotype (29 of the 122-patient subset) is associated with the
presence of anti-CCP antibodies (22 of 29; P ⫽ 0.022) and also
with DRB1*0301 (13 of 29; P ⬍ 0.0001), as we originally
reported (3) with the 189-patient cohort (27 of 49 patients with
the TNFA ⫺308 AA ⫹ AG haplotype had DRB1*0301; P ⬍
0.0001).
Linear regression modeling of the unweighted total
Sharp scores as a function of age at symptom onset, female sex,
TNFA ⫺308 A or not, and anti-CCP antibody status showed a
significant positive relationship with TNFA ⫺308 AA ⫹ AG
(coefficient 2.63, standard error 0.69, P ⬍ 0.0001) and a
marginal relationship with female sex (P ⫽ 0.095) but not with
the presence of anti-CCP antibodies (P ⫽ 0.23; model R2 ⫽
0.13). A similar analysis weighted by the number of radiographic observations for each patient increased the significance of the relationship with female sex (P ⬍ 0.0001) and
TNFA ⫺308 AA ⫹ AG presence (coefficient 2.74, standard
error 0.34, P ⬍ 0.0001), and a positive relationship with
anti-CCP antibody was now evident (coefficient 1.29, standard
error 0.47, P ⫽ 0.006; model R2 ⫽ 0.13). Age at onset was not
significant in either analysis.
Thus, the analysis of anti-CCP antibody status in a
122-patient subset of 189 RF-positive patients with early RA in
our original report supports some of the findings in the Leiden
early RA cohort (88.5% of our RF-positive patients are also
anti-CCP antibody positive; 94% of SE-positive patients are
also anti-CCP antibody positive), but does not support others
(only 29% of HLA–DRB1*0301–positive patients are antiCCP antibody negative). Both weighted and unweighted linear
regression analyses support the significant association of
TNFA ⫺308 AA ⫹ AG with the rate of radiographic damage,
with the contribution of anti-CCP antibodies reaching significance only in the weighted analysis.
The addition of anti-CCP antibody does not explain
our finding that radiographic damage did not progress more
rapidly in SE-positive patients. We agree with the Leiden
findings that SE-positive anti-CCP–positive patients (n ⫽ 85;
progression rates of median total Sharp score [TSS] 1.06; joint
space narrowing [JSN] score 0.19; erosion score 0.66) tend to
progress more rapidly than SE-negative anti-CCP–positive
patients (n ⫽ 23; median TSS 0.40; JSN 0.07; erosion 0.42), but
these differences are not significant by the Kruskal-Wallis test
(P ⫽ 0.89, P ⫽ 0.62, and P ⫽ 0.77, respectively). The findings
with respect to association of radiographic progression with SE
status in our cohort remain perplexing (3).
The differences between the findings in the 2 early RA
cohorts probably are due to differences in the patient populations. We limited our study to RA patients with positive RF
and active disease as judged by joint counts. The lack of
RF-negative patients in our cohort probably influences our
findings. Only 11% of our subjects were anti-CCP negative, but
44% of the Leiden cohort were anti-CCP negative, and about
45% were rheumatoid factor negative (1). The finding that
only 29% of our HLA–DRB1*0301 patients were negative for
LETTERS
anti-CCP antibodies, versus negative anti-CCP antibodies in
58% of the Leiden HLA–DRB1*0301 patients may help
explain the differences in the effect of the presence of the
TNFA ⫺308 A allele in radiographic progression.
Van der Helm-van Mil et al did not present a separate
analysis of their approximately 180 RF-positive patients, although they report that analysis of their 182 anti-CCP
antibody–positive patients showed no significant differences in
Sharp/van der Heijde scores between those with and without
the TNFA ⫺308 A allele. The relative distribution of the TNFA
⫺308 A/G alleles among their RF-positive and RF-negative
and anti-CCP antibody–positive and anti-CCP antibody–negative
subsets is not known. Perhaps our findings apply only to
RF-positive patients. Alternatively, the sample sizes of our
cohort and of the RF-positive subset of the Leiden cohort are
probably marginal for determining the relationship of the
TNFA ⫺308 A allele with radiographic progression in seropositive RA patients. Careful additional studies with larger cohorts of seropositive RA patients will be needed to explain the
differences between our findings and those of the Leiden
group, and to confirm or refute the proposed association of
radiographic progression with this presumably important gene
that encodes TNF␣.
We thank Punchong Hanvivadhanakul and Michelle Kim from the
University of California at Los Angeles for their assistance in identifying and
preparing the specimens for assaying.
Dinesh Khanna, MD, MSc
University of Cincinnati
Cincinnati, OH
Hui Wu, MD
Grace S. Park, MPH
Richard H. Gold, MD
Betty P. Tsao, PhD
Harold E. Paulus, MD
David Geffen School of Medicine at UCLA
Los Angeles, CA
Lony C. Lim, PhD
Navanit Lal, MD
Cabrini Delaney, BS
Specialty Laboratories
Valencia, CA
John T. Sharp, MD
University of Washington
Seattle, WA
1. Verpoort KN, van Gaalen FA, van der Helm-van Mil AH, Schreuder GM, Breedveld FC, Huizinga TW, et al. Association of HLA–
DR3 with anti–cyclic citrullinated peptide antibody–negative rheumatoid arthritis. Arthritis Rheum 2005;52:3058–62.
2. Huizinga TW, Amos CI, van der Helm-van Mil AH, Chen W, van
Gaalen FA, Jawaheer D, et al. Refining the complex rheumatoid
arthritis phenotype based on specificity of the HLA–DRB1 shared
epitope for antibodies to citrullinated proteins. Arthritis Rheum
2005;52:3433–8.
3. Khanna D, Wu H, Park G, Gersuk V, Gold RH, Nepom JT, et al.
Association of tumor necrosis factor ␣ polymorphism, but not the
shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort. Arthritis Rheum
2006;54:1105–16.
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