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Rheumatoid Arthritis
Autoantibodies and Diagnosis of Rheumatoid Arthritis
a report by
J Erik Oswald and Tom WJ Huizinga
Department of Rheumatology, Leiden University Medical Centre
Antibodies to citrullinated proteins (anti-CCP) are highly specific for RA, 228 patients were anti-CCP-positive and 226 were anti-CCP-negative.
rheumatoid arthritis (RA) and precede the onset of disease symptoms: The early symptoms, such as tender and swollen joint count and C-reactive
years before the manifestation of clinical signs of RA, patients already protein level at inclusion, as well as swollen joint count and radiological
have an antibody response against autoantigens. In a Dutch and destruction during four years of follow-up, were compared for the two
Swedish retrospective case-controlled study in patients who were groups. There were no differences in morning stiffness, type, location and
blood donors and whose serum samples could be retrieved from blood distribution of early symptoms, patient-rated disease activity, C-reactive
bank archives, autoantibodies were found in blood samples taken protein and ‘mean tender and swollen joint count’ at inclusion between
years before the manifestation of disease signs. These antibodies were RA patients with and without anti-CCP antibodies. At follow-up, patients
immunoglobulin M (IgM) rheumafactors and anti-CCP antibodies.
1–3
with anti-CCP antibodies had more swollen joints and more severe
These antibodies could be detected 14 years before the onset of radiological destruction. Nevertheless, the distribution of affected joints,
disease signs and symptoms, but intriguingly the proportion those that were swollen or those that had bone erosions and joint-space
of patients who had autoantibodies, as well as the titre of the narrowing, was similar. The phenotype of RA patients with or without
autoantibodies, rose during the years before disease onset. At anti-CCP antibodies is similar with respect to clinical presentation, but
the onset of disease, approximately 50% of the patients had differs in terms of the disease course.
7
Previous findings suggest that
autoantibodies. Of the antibodies present, the most specific antibodies development to RA follows a different course with the presence of
were antibodies against citrulline. anti-CCP antibodies, with a disease-modifying effect towards a more
persistent and destructive disease course (see Figure 3).
1,8
Citrullination is the post-translational modification of the amino acid
arginine to citrulline (see Figure 1). It is unknown which antigens are Risk Factors for Developing Antibodies to
citrinullated in vivo in patients; however, several tests have been Citrullinated Proteins
described, and the most specific test to date is the so-called anti-CCP2 The most important genetic risk factor for RA is the human leukocyte
test, in which an artificial peptide is used.
4
Although risk factors have antigen (HLA) class II alleles. In particular, the major histocompatibility
been described (see below), it is not yet clear why tolerance to complex class II DR beta 1 (HLA-DRB1) alleles encoding for the shared
citrullinated antigens leads to an immune response to citrullinated epitope (SE) confer a higher risk of developing RA.
9
The SE hypothesis
antigens. The specificity of a positive anti-CCP test as a screening postulates that the SE motif is directly involved in the pathogenesis of
method among the general population is not high. Furthermore, the RA by allowing the presentation of an arthritogenic peptide to T cells.
10
chances of a false-positive test increase with advancing age.
4
However, Recently, it was observed that the SE alleles are a risk factor only for
the clinical value of a positive anti-CCP test in patients with signs of
arthritis is clear. A positive anti-CCP test result implies a significant
J Erik Oswald works in the Department of Internal Medicine
change to the development of RA in patients with undifferentiated
at the Leiden University Medical Centre, where he is
arthritis (UA).
5
In many areas, ‘early arthritis clinics’ (EACs) exist. These
finishing his rheumatology training. He received his MD
clinics provide the opportunity to build better patient care, to describe
from the Free University of Amsterdam in1989.
the onset and follow-up of inflammatory arthritis and to study the
pathogenesis of arthritis. In the EAC of Leiden, The Netherlands, all
patients with recent-onset inflammatory arthritis are included. Figure 2
shows the dynamics of disease in this EAC, where the anti-CCP test
Tom WJ Huizinga is Chairman of the Department of
results of patients with recent-onset UA were studied.
5,6
Rheumatology, Leiden University Medical Centre. He has
received several grants, including a fellowship of the Royal
Netherlands Academy of Arts and Sciences (KNAW) to study
While 30–50% of all UA patients develop RA – as per the American
the regulation of tumour necrosis factor-alpha production in
College of Rheumatology (ACR) criteria – UA is seen as a precursor to RA. rheumatoid arthritis. Professor Huizinga has also received a
The presence of anti-CCP antibodies in UA means a patient is 38 times
number of prizes for his work, including the Boerhaave prize
for outstanding contributions to immunology. Professor
more likely to develop RA compared with patients without this antibody
Huizinga serves on eight Editorial Boards and has authored
response. This raises the issue of whether anti-CCP-positive and -negative
or co-authored over 240 peer-reviewed articles. He received his MD from the University of
RA are clinically different disease entities. Therefore, an investigation took
Amsterdam in 1986, after which he joined the army as a blood tranfusion specialist. He then
received his PhD on the characterisation of fc-gamma receptors before post-doctoral studies
place to determine whether RA patients with anti-CCP antibodies have a at Dartmouth Medical School, New Hampshire.
different clinical presentation and disease course compared with patients
E: t.w.j.huizinga@lumc.nl
without these autoantibodies. In a cohort of 454 incident patients with
© TOUCH BRIEFINGS 2008 27
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