Anti-type II collagen antibodies are associated with early radiographic destruction in rheumatoid arthritis.

Abstract

We have previously reported that high levels of antibodies specific for native human type II collagen (anti-CII) at the time of RA diagnosis were associated with concurrent but not later signs of inflammation. This was associated with CII/anti-CII immune complex (IC)-induced production of pro-inflammatory cytokines in vitro. In contrast, anti-cyclic citrullinated peptide antibodies (anti-CCP) were associated both with late inflammation and late radiological destruction in the same RA cohort. We therefore hypothesized that anti-CII are also associated with early erosions.
Two-hundred-and-fifty-six patients from an early RA cohort were included. Baseline levels of anti-CII, anti-CCP and anti-mutated citrullinated vimentin were analyzed with ELISA, and rheumatoid factor levels were determined by nephelometry. Radiographs of hands and feet at baseline, after one and after two years were quantified using the 32-joints Larsen erosion score.
Levels of anti-CII were bimodally distributed in the RA cohort, with a small (3.1%, 8/256) group of very high outliers with a median level 87 times higher than the median for the healthy control group. Using a cut-off discriminating the outlier group that was associated with anti-CII IC-induced production of proinflammatory cytokines in vitro, baseline anti-CII antibodies were significantly (p = 0.0486) associated with increased radiographic damage at the time of diagnosis. Anti-CII-positive patient had also significantly increased HAQ score (p = 0.0303), CRP (p = 0.0026) and ESR (p = 0.0396) at the time of diagnosis but not during follow-up. The median age among anti-CII-positive subjects was 12 years higher than among the anti-CII-negative patients.
In contrary to anti-CCP, anti-CII-positive patients with RA have increased joint destruction and HAQ score at baseline. Anti-CII thus characterizes an early inflammatory/destructive phenotype, in contrast to the late appearance of an inflammatory/destructive phenotype in anti-CCP positive RA patients. The anti-CII phenotype might account for part of the elderly acute onset RA phenotype with rather good prognosis.

Full text

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RESEARCH ARTICLEOpen Access
Anti-type II collagen antibodies are associated
with early radiographic destruction in rheumatoid
arthritis
Mohammed Mullazehi1, Marius C Wick3, Lars Klareskog2, Ronald van Vollenhoven2and Johan Rönnelid1,2*
Abstract
Introduction: We have previously reported that high levels of antibodies specific for native human type II collagen
(anti-CII) at the time of RA diagnosis were associated with concurrent but not later signs of inflammation. This was
associated with CII/anti-CII immune complex (IC)-induced production of pro-inflammatory cytokines in vitro. In
contrast, anti-cyclic citrullinated peptide antibodies (anti-CCP) were associated both with late inflammation and late
radiological destruction in the same RA cohort. We therefore hypothesized that anti-CII are also associated with
early erosions.
Methods: Two-hundred-and-fifty-six patients from an early RA cohort were included. Baseline levels of anti-CII, anti-
CCP and anti-mutated citrullinated vimentin were analyzed with ELISA, and rheumatoid factor levels were
determined by nephelometry. Radiographs of hands and feet at baseline, after one and after two years were
quantified using the 32-joints Larsen erosion score.
Results: Levels of anti-CII were bimodally distributed in the RA cohort, with a small (3.1%, 8/256) group of very
high outliers with a median level 87 times higher than the median for the healthy control group. Using a cut-off
discriminating the outlier group that was associated with anti-CII IC-induced production of proinflammatory
cytokines in vitro, baseline anti-CII antibodies were significantly (p = 0.0486) associated with increased radiographic
damage at the time of diagnosis. Anti-CII-positive patient had also significantly increased HAQ score (p = 0.0303),
CRP (p = 0.0026) and ESR (p = 0.0396) at the time of diagnosis but not during follow-up. The median age among
anti-CII-positive subjects was 12 years higher than among the anti-CII-negative patients.
Conclusion: In contrary to anti-CCP, anti-CII-positive patients with RA have increased joint destruction and HAQ
score at baseline. Anti-CII thus characterizes an early inflammatory/destructive phenotype, in contrast to the late
appearance of an inflammatory/destructive phenotype in anti-CCP positive RA patients. The anti-CII phenotype
might account for part of the elderly acute onset RA phenotype with rather good prognosis.
Introduction
A vast majority of patients with rheumatoid arthritis (RA)
experience pain, functional deterioration, rigidity and work
disability due to atrophy and irreversible joint destruction
if not treated efficiently and early. Several different autoan-
tibodies such as rheumatoid factor (RF) [1] and antibodies
against citrullinated proteins/peptides (ACPAs), like anti-
cyclic citrullinated peptide antibodies (anti-CCP) [2,3] and
antibodies against modified citrullinated vimentin (anti-
MCV) [4] that have been identified in the serum of patients
with RA have a negative prognostic impact on future joint
destruction. In earlier studies of a Swedish RA cohort
investigated before the systematic introduction of biological
agents, we have demonstrated that RF, anti-CCP and anti-
MCV detected in serum from patients with RA were asso-
ciated with late inflammation and late increased rate of
radiographic damage [5,6]. In a recently published study
we discovered that high levels of anti-native human col-
lagen type II (anti-CII) antibodies in the same group of
patients with RA were, in contrast, associated with labora-
tory measures of inflammation at disease onset [7], which
can be explained by pro-inflammatory cytokine induction
* Correspondence: johan.ronnelid@igp.uu.se
1Clinical Immunology, Department of Immunology, Genetics and Pathology,
Rudbeck Laboratory C5, Uppsala University, Uppsala, SE-75185, Sweden
Full list of author information is available at the end of the article
Mullazehi et al. Arthritis Research & Therapy 2012, 14:R100
http://arthritis-research.com/content/14/3/R100
© 2012 Rönnelid et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

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driven by surface-bound immune complexes (IC) contain-
ing anti-CII [8]. We therefore hypothesized that anti-CII
antibodies were also associated with early joint destruction
in this group of patients with RA.
To address this question, we performed the present
study in which we focused on joint destruction in a pro-
spective early RA cohort (n = 256), utilizing radiological
data from multiple occasions, with parallel investigations
of RF, anti-CCP, anti-MCV and anti-CII antibody serum
levels.
Materials and methods
Patients
In total, 256 patients from a cohort with early RA (< 12
months of disease duration at the time of diagnosis) were
included between January 1995 and October 2000. All
patients fulfilled the 1987 American College of Rheuma-
tology classification criteria for RA [9]. Sera were obtained
at the time of diagnosis and thereafter stored at -70°C and
used for the various autoantibody analyses on different
occasions. All patients had been given informed consent
and the study was approved by the ethics committees at
Uppsala University and Karolinska Institutet, respectively.
Materials and methods
Results about the prognostic impact of anti-CCP [6],
anti-MCV [5] and anti-CII on acute inflammation [7],
based on a somewhat different patient selection, have
been published previously. The 256 patients included in
this present analysis represent individuals for whom
complete data for RF, anti-CCP, anti-CII and consecutive
radiographs were available. Anti-MCV levels were ana-
lyzed at a later time point than the other analyses, when
2 out of 256 baseline serum samples were no longer
available.
For the anti-CII ELISA that was performed as previously
described [7], Maxisorb ELISA plates (Nunc, Roskilde,
Denmark) were coated with human native CII (ELISA
grade, Chondrex, Redmond, Washington DC, USA,
diluted to 2.5 μg/ml in ice-cold PBS immediately prior to
coating. Blocking was done with PBS with 1% ELISA
grade bovine serum albumin. Serum samples were diluted
at 1:100, and antibodies were detected with a F(ab’)2 frag-
mented antibody against human gamma chain that had
been pre-adsorbed against bovine proteins (Jackson, Cam-
bridgeshire, UK). Internal controls were investigated
together with patient samples on each occasion. The intra-
assay coefficient of variation for the internal control close
to the cutoff value was 15%.
Radiographs were scored blinded to treatment, in pairs
(hands and feet), and in chronological sequence, by an
experienced investigator (MCW) using the Larsen
method [10]. In each case, 32 joints were scored. The ori-
ginal Larsen score [10] was modified slightly by excluding
grade 1 [11], so that the scale became 0 to 4, as described
previously [6]. Thus, the maximum possible score was
160. Larsen scores were obtained at baseline, and after
one and two years. The change in Larsen score (Δ Larsen
score) was calculated by subtracting the baseline score
values from the respective annual scores.
Statistical analysis
Non-parametric tests were employed due to the bimodal
appearance of anti-CII antibodies. The Mann-Whitney U
test was used for the comparison of Larsen score between
different groups. P values less than 0.05 were considered
significant. The cutoff value was placed between anti-CII
levels supporting or not supporting IC-induced cytokine
production in vitro (200 AU/ml) as described previously
[7,8]. As can be seen from Figure 1, this cutoff also
delimited a patient group with high discrete outlier
values.
Results
Anti-CII-positive patients with RA had higher levels of C-
reactive protein (CRP) (P = 0.0026) and erythrocyte sedi-
mentation rate (ESR) (P = 0.0396) and displayed a higher
health assessment questionnaire (HAQ) score (P = 0.0303)
at the time of diagnosis, compared to anti-CII-negative
patients. There was also a trend for higher 28-joint disease
activity score (DAS28) among anti-CII-positive patients
(P = 0.08). The median age at diagnosis was 12 years
higher among anti-CII-positive patients (68 vs. 56 years,
P < 0.05). Baseline characteristics are summarized in Table
1. The increased measures for CRP, ESR and HAQ scores
among anti-CII-positive patients were evident only at the
time of diagnosis, and not at any other time point between
3 months to 5 years after diagnosis (data not shown).
Comparisons for median Larsen score and changes in
median Larsen scores during the first 2 years after diag-
nosis are presented for the 256 patients with early RA
(Table 2). Radiographic scores did not differ between RF-
positive and RF-negative patients at any time point. How-
ever, analysis of the change in Larsen score revealed
increased rates of radiographic damage in RF-positive
compared to RF-negative patients between baseline and 2
years (P = 0.0354), and especially between 1 year and 2
years (P = 0.0009) (Table 2). Similar data, but with stron-
ger statistical significance, were also recorded for anti-
CCP and anti-MCV antibodies [5,6].
Whereas anti-CII levels among 100 healthy controls
(the same group as used to define the reference range in
[7]) showed a normal distribution (Figure 1A), anti-CII
levels were bimodally distributed among the patients
with RA (Figure 1B). The outlier group was clearly sepa-
rated from the remaining patients showing a distribution
quite similar to the control group, as there were no
patients showing anti-CII levels between 57 AU/mL on
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one hand and the outlier groups with anti-CII levels
between 471 and 3520 AU/mL on the other (Figure 1B).
The cutoff point used (> 200 AU/mL) was based on this
bimodal distribution and our earlier findings that higher
anti-CII levels are associated with the functional effects
of anti-CII-containing IC formed in vitro [7,8]. High
anti-CII levels were significantly (P = 0.0486) associated
with increased Larsen score at baseline (Table 2). A
sizeable but non-significant difference between the med-
ian anti-CII levels was sustained at all investigated time
points (Table 2, Figure 2). There were no differences in
changes in Larsen scores between patients with and
without anti-CII antibodies (Δ Larsen score; Table 2).
Discussion
As has been shown earlier, autoantibodies traditionally
associated with RA, such as RF [5], anti-CCP [6] and
anti-MCV [5], were associated with late increased rates
of radiographic destruction in the early RA cohort
reported here. In this paper, we have demonstrated that
patients with increased levels of anti-CII autoantibodies
at the time of diagnosis have more radiographic destruc-
tions measured by median Larsen scores at baseline.
This is accompanied by a significantly higher HAQ
score among anti-CII-positive patients at the time of
diagnosis, but not at any later time point.
We can thus distinguish two different phenotypes of
patient with RA, viz. a group of patients with antibodies
traditionally characterized by late inflammation and late
increased radiographic destruction, and another group
of patients who are positive for anti-CII antibodies,
which is characterized by early inflammation [7] and
early radiographic destruction.
The Larsen and the Sharp-van der Heide scoring sys-
tems are highly correlated [12,13], especially when omit-
ting Larsen grade 1 (soft tissue swelling and
periarticular osteoporosis), as was advocated by Arvi
Larsen in the modified Larsen scoring system [11]. It is
therefore plausible that raised anti-CII levels are asso-
ciated with breakdown of CII. Such an association might
occur either due to a direct effect of anti-CII on carti-
lage as has been claimed by others [14], or indirectly via
induction of pro-inflammatory cytokines by macro-
phages in the pannus tissue [7,8].
The anti-CII cutoff used in the present study (200 U/
mL) was based on the almost dichotomous distribution
of anti-CII antibodies among patients with RA shown in
Figure 1B, where anti-CII-positive and -negative subjects
were clearly separated. Another argument for the use of
this cutoff is that the dichotomous distribution of anti-
CII among patients with RA clearly distinguished
patients whose anti-CII levels permitted IC-induced
cytokine induction from those with autoantibody levels
too low to induce IL-1b or tumor necrosis factor (TNF)
[8]. All anti-CII-negative patients had levels below 60
AU/mL, whereas the anti-CII-positive patients had levels
between 471 and 3,520 AU/mL, thus clearly within the
range of cytokine induction by the corresponding sur-
face-bound IC [8].
Another major difference between ACPA and anti-CII
concerns the kinetics of appearance. Whereas ACPA
and RF levels slowly increase years before diagnosis
[15,16] and thereafter remain rather stable for years
[3,6], anti-CII levels seem to be highest around the time
Figure 1 Distribution of anti-native human collagen type II
(anti-CII) antibodies. A) the distribution of anti-CII antibodies
among 100 healthy blood donors is shown; B) the distribution of
anti-CII antibodies among 274 patients with RA [7]; radiological data
were available for 256 of these patients. The vertical arrow
represents the cutoff value separating the majority of patients with
rheumatoid arthritis (RA) and the discrete group with very high anti-
CII levels associated with cytokine production in our in vitro
immune complex assay [7,8].
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of the beginning of clinical disease. Elevated anti-CII
levels do not precede clinical onset of RA [17], and after
peaking around the time of diagnosis, levels drop during
the first year, according to our own [7] and other [18]
investigations. This short window of appearance of anti-
CII in early RA, together with our earlier studies linking
anti-CII to cytokine-driven inflammation using both
functional in vitro experiments [8] as well as clinical fol-
low-up studies [7], imply that the long-term effect of
initially raised anti-CII levels might be limited, and that
the major impact is around the time of disease onset.
Initial appearance of anti-CII might in fact be prognosti-
cally advantageous. As initially raised anti-CII levels are
associated both with raised CRP and ESR [7] and with
augmented joint destruction around the time of diagno-
sis, and as these differences are no longer evident after
one year, patients with RA and an early appearance of
anti-CII might erroneously give an impression of a more
severe prognosis than is actually the case. The general
belief among rheumatologists is that a certain subgroup
of patients with acute disease onset eventually have a
rather good prognosis and need only rather limited
treatment. This has been formally proven, as a recent
study showed that both acute onset of RA and short
symptom duration before inclusion in the study are
associated with drug-free remission [19]. We speculate
that at least some of these patients belong to the initially
anti-CII-positive RA subgroup. This hypothesis should
be investigated in other follow-up cohorts.
In this study, early RA was defined as < 12 months of
symtoms before enrolment. Given the fact that anti-CII
levels often drop sharply within the first months [7], we
cannot rule out that some initially anti-CII-positive
patients might have dropped to levels below the cutoff
before diagnosis of RA.
The more active onset of destructive joint disease in
anti-CII-positive RA patients might also initiate an ear-
lier health care contact by patients after the first apear-
ance of joint symtoms. This was also the case in our
earlier larger study, where anti-CII-positive patients had
a significantly shorter duration of joint symtoms before
diagnosis of RA [7]. Acute onset RA is common among
older individuals [20], and the median age among our
anti-CII-positive patients was 12 years higher than
among anti-CII-negative patients (Table 1).
One earlier study has also implicated an association
between anti-CII and simultaneously occurring inflam-
mation in RA. In the study by Kim et al [21], patients
Table 1 Baseline characteristics of the 256 patients with rheumatoid arthritis (RA)
All RA
patients
(n = 256)
Anti-CII-negative RA
patients
(n = 248)
Anti-CII positive (> 200 AU/ml) RA
patients
(n = 8)
P Mann Whitney/chi
square
Age at inclusion (years)
Female (%: number/total number)
56
71.5
(183/256)
5.0
63.3
(162/256)
57.8
(148/256)
70.9
(180/254)
14
22.0
2
56
71.4
(177/248)
5.0
62.9 (158/248)
68
75.0 (6/8)
NS (0.17)
NS (0.82)
Disease duration at inclusion (months)
RF-positive, (%; number positive/total
number)
Anti-CCP2- positive, (%;number positive/
total number)
Anti-MCV- positive (2 patients missing)
4.5
50.0 (4/8)
NS (0.32)
NS (0.43)
58.5
(145/248)
71.1
(175/246)
14
21.5
2
37.5
(3/8)
62.5 (5/8)
NS (0.24)
NS (0.60)
CRP (mg/l)
ESR (mm/h)
Physician’s assessment of disease activity
(0-4)
Number of swollen joints
Number of tender joints
DAS28
Global VAS
Pain VAS
HAQ
Patients starting DMARD therapy at
baseline (%)
37
40.5
2
0.0026
0.0396
NS (0.28)
9.0
7
5.005
45
45
0.880
83.6
(214/256)
9.0
7
4.990
45
45
0.880
83.5 (207/248)
8.5
8
5.760
40
35
1.500
87.5
(7/8)
NS (0.82)
NS (0.46)
NS (0.08)
NS (0.93)
NS (0.39)
0.0303
NS (0.76)
Results are presented as medians and percentages (ratios). Differences between anti-native human collagen type II (anti-CII)-negative and anti-CII-positive
patients were analyzed using the Mann-Whitney U test; differences between proportions were analyzed using the Chi square test or Fisher’s exact test as
appropriate. Anti-CCP, anti-cyclic citrullinated peptide antibodies; Anti-MCV, antibodies against modified citrullinated vimentin; CRP, C-reactive protein; ESR,
erythrocyte sedimentation rate; DAS28, 28-joint disease activity score; VAS, visual analogue scale; HAQ, health assessment questionnaire; DMARD, disease-
modifying anti-rheumatic drug; NS, not significant.
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Table 2 Association between baseline autoantibody status and radiological destruction
RF+ (n = 162) vs RF- (n = 94) Anti-CCP + (n = 148) vs anti-CCP- (n = 108) Anti-MCV+ (n = 180) vs anti-MCV- (n = 74) Anti-CII + (> 200 AU/mL; n = 8)
versus anti-CII- (n = 248)
Larsen score
baseline
Larsen score 1
year
Larsen score 2
years
ΔLarsen score 1 yr
-baseline
ΔLarsen score 2
yrs -baseline
ΔLarsen score 2
yrs -1 yr
4.000 versus 5.000, P = NS (0.13)4.000 versus 5.000, P = NS (0.16) 4.375 versus 5.000, P = NS (0.21) 13.750 versus 4.375, P = 0.0486*
10,500 versus10.500, P = NS (0.65) 10.500 versus 10,750, P = NS (0.66) 11.000 versus 10.000, P = NS (0.99) 21.500 versus 10.500, P = NS (0.0799)
14.000 versus 13.250, P = NS (0.69) 14.000 versus 13.000, P = NS (0.57) 14.375 versus 10,250, P = NS (0.24) 24.000 versus 13.500, P = NS (0.19)
4.500 versus 4.250, P = NS (0.32) 4.500 versus 4.250, P = NS (0.29)4.500 versus 3.750, P = NS (0.19) 7.375 versus 4.250, P = NS (0.27)
7.250 versus 6.250, P = 0.0354*7.500 versus 6.250
P = 0.0102*
2.750 versus 1.000, p < 0.0001*
7.750 versus 5.250, P = 0.0028* 9.250 versus 6.500, P = NS (0.50)
2.500 versus 1.250, P = 0.0009* 2.750 versus 1.000, p < 0.0001*3.000 versus 2,.250, P = NS (0.48)
Differences in median Larsen score between patients with and without different autoantibodies and changes in median Larsen score are given for 256 patients with early rheumatoid arthritis. Anti-MCV data were
missing for two patients. ΔLarsen score, difference in Larsen score; RF, rheumatoid factor; Anti-CCP, anti-cyclic citrullinated peptide antibodies; Anti-MCV, antibodies against modified citrullinated vimentin; Anti-CII,
anti-native human collagen type II. *P < 0.05.
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with anti-CII had, like our patients [7], higher levels of
CRP and ESR than antibody-negative patients with RA,
and also had higher levels of TNF and IL-6. We pre-
sume that both these cytokines have been produced by
macrophages stimulated with anti-CII-containing IC. In
our studies we have shown that anti-CII containing IC
induces the production of TNF, IL-1b and IL8 from
monocytes/macrophages [7,8]. In these experiments we
chose not to study IL-6, due obscuring of the in vitro
signal by high basal IL-6 production. In other systems
we have, however, found patient-derived IC to induce
IL-6 in our in vitro models [22-24]. In contrast to our
present investigation, the study by Kim et al could not
show increased radiologic progression among anti-CII-
positive patients with RA, a finding that can be
explained by the fact that the patients had long-standing
disease with a mean duration of 75.8 months [21]. In
our study the significant difference in Larsen score
between anti-CII-positive and -negative patients was
only evident at the time of diagnosis, and was no longer
visible after one year. Even if our patients were all
included within 12 months of first symtoms, the mean
interval between the first symtoms and diagnosis of RA
was 5.8 months [7]. It is therefore possible that we
would have found bigger differences between the groups
if patients with shorter duration of joint symtoms had
been included.
In conclusion, anti-CII antibodies are associated with
early radiological destruction at the time of diagnosis,
while autoantibodies traditionally associated with RA, such
as RF, anti-CCP and anti-MCV are later associated with
increased rates of radiographic destruction. This finding is
in agreement with our earlier discovery that the same
groups of antibodies are inversely associated with early [7]
and late [5,6] signs of inflammation in the same patient
cohort. It is intriguing to note that the phenotypically
opposite ACPA and anti-CII phenotypes, at least in this
patient cohort, are also statistically inversely related (P =
0.04) as previously described [7]. We speculate that CII
antibodies might stimulate macrophages and fibroblasts
within the synovium to produce the metalloproteinases
that are responsible for being the first enzymes to cleave
the interstitial collagens, resulting in bone and cartilage
destruction. We are currently performing studies to
address this issue.
Conclusions
The occurrence of high levels of anti-CII antibodies
characterizes a small group of patients with RA who
have an elevated degree of joint destruction and elevated
HAQ score at the time of diagnosis. Anti-CII charac-
terizes an early inflammatory/destructive RA phenotype,
in contrast to the late inflammatory/destructive pheno-
type that is associated with ACPA.
Abbreviations
ACPA: antibodies against citrullinated proteins/peptides; anti-CII: anti-native
human collagen type II antibodies; anti-CCP: anti-cyclic citrullinated peptide
antibodies; anti-MCV: antibodies against modified citrullinated vimentin; CRP:
C-reactive protein; DAS28: 28-joint disease activity score; DMARD: disease-
modifying anti-rheumatic drug; ESR: erythrocyte sedimentation rate; HAQ:
health assessment questionnaire: IC: immune complex; PBS: phosphate
buffer saline: RA: rheumatoid arthritis; RF: rheumatoid factor; TNF: tumor
necrosis factor.
Acknowledgements
Financial support was obtained from the Swedish Research Council, the
Swedish Rheumatism Associaton and King Gustav Vth 80-year foundation.
Author details
1Clinical Immunology, Department of Immunology, Genetics and Pathology,
Rudbeck Laboratory C5, Uppsala University, Uppsala, SE-75185, Sweden.
2Department of Medicine, Rheumatology Unit, Building D2:01, Karolinska
Institutet, SE-17176, Stockholm, Sweden.3Department of Radiology,
Innsbruck Medical University, Anichstrasse 35, Innsbruck, A-6020, Austria.
Authors’ contributions
MM planned the study, carried out collagen antibody analyses, performed
statistical analyses, and drafted the manuscript. MCW performed Larsen
scoring and drafted the manuscript. LK took part in the planning discussions
and drafted the manuscript. RvV supervised Larsen scoring and drafted the
manuscript. JR conceived the study, performed statistical analyses, and
drafted the manuscript. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Figure 2 Radiological destruction in 256 patients with
rheumatoid arthritis (RA) at the time of diagnosis, and after
one and two years. Patients are divided into those with high levels
of anti-native human collagen type II (anti-CII) antibodies (n = 8,
arrow in Figure 1B) and those with lower levels (n = 248).
Horizontal bars indicate median levels. One patient in the anti-CII
group was not investigated at two years.
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Received: 21 November 2011 Revised: 1 April 2012
Accepted: 1 May 2012 Published: 1 May 2012
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doi:10.1186/ar3825
Cite this article as: Mullazehi et al.: Anti-type II collagen antibodies are
associated with early radiographic destruction in rheumatoid arthritis.
Arthritis Research & Therapy 2012 14:R100.
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