The Use of Anti-cyclic Citrullinated Peptide (anti-CCP) Antibodies in RA
antibodies are potentially important surrogate markers for diagnosis
and prognosis in rheumatoid arthritis (RA), because they:
as sensitive as, and more specific than, IgM rheumatoid factors (RF)
in early and fully established disease
predict the eventual development into RA when found in undifferentiated
a marker of erosive disease in RA
be detected in healthy individuals years before onset of clinical
described as a marker for RA in 1964, anti-perinuclear factor (APF)
was directed to constituents of the keratohyaline granules near senescent
buccal mucosal cell nuclei, later found to contain the “filament
aggregating protein”filaggrin. Despite its specificity for RA,
because of exacting technical requirements, APF never became widely
used. Anti-keratin antibodies (AKA), first described in 1979, bound
filaggrin tightly bound to keratin in senescent esophageal cells.
As was APF, AKA had greater specificity for RA than RF. Antibodies
to the so-called Sa antigen, described first in 1994, bound post-translationally
modified vimentin, a cytoskeletal intermediate filament protein found
in mesenchymal cells. Since 1998 it has become increasingly evident
that all of the above antibodies likely target citrullinated proteins.
is a non-standard amino acid, created by de-imination of arginine residues
in several proteins by the action of peptidylarginine deiminase (PAD).
There are several isotypes of this enzyme; in the inflammatory RA synovium,
PAD 2 and PAD 4 are abundant. These enzymes cause the local citrullination
of synovial proteins, such as fibrin. Interestingly, citrullinated peptides
fit better in the HLA DR4 (DRB1*0401 or *0404) antigen binding grooves
than the corresponding arginine containing peptides, findings that link
this immune response to the shared epitope hypothesis of RA pathophysiology.
Citrullinated extracellular fibrin in the RA synovium may be one of
the major autoantigens driving the local immune response, suggested
by the discovery of local production of anti-CCP and anti-citrullinated
filaggrin antibodies in the joint. Also, functional haplotypes of PADI4
may be associated with RA.
moiety is the true determinant on proteins recognized by APF, AKA, and
possibly anti-Sa. Detailed studies of citrullinated filaggrin peptides
showed that different patients with RA recognized different linear citrullinated
peptides, indicating a polyclonal response. Flanking regions around
the citrulline residue are important for the reactivity, so not all
sera are reactive with every peptide. The first generation of ELISa
for anti-CCP (CCP1), using several filaggrin epitopes, had high specificity
for RA and a sensitivity of 65-70% (1). Various cyclic epitopes that
mimic true conformational epitopes were selected from libraries of citrullinated
peptides for the widely available 2nd generation anti-CCP assay (CCP2).
of autoimmune serology in RA
has been used as a marker of RA for more than half a century. IgM
RF, the isotype most typically detected, is seen not only in RA but
also in various other conditions. IgA RF, more easily detected than
IgG RF, may be a better indicator of T-cell dependent affinity matured
antibodies directed to particular Fc-gamma epitopes relevant to RA
than IgM RF, but it has never gained wide interest. The combined detection
of IgM and IgA RFs in a serum is a strong indicator of RA.
studies published to date comparing the sensitivity and specificity
of RFs and anti-CCP antibodies for the diagnosis of RA have used the
CCP1 assay. In general, the sensitivity of anti-CCP has been comparable
to RF (50-75%) with a higher specificity (90-95%). More recent studies
using the CCP2 assay show higher sensitivity for RA than CCP1, with
equally high specificity. Of note, three companies (Euro-Diagnostica,
Axis-Shield and Inova) have agreed to use the same coated plates for
their CCP2 assays, allowing more direct comparison of results worldwide.
many early cases of RA, clinical symptoms are milder and nonspecific,
and patients will not fulfill ACR classification criteria for RA.
Therefore, the detection of a disease-specific autoantibody like anti-CCP
could be of great diagnostic and therapeutic importance. Anti-CCP
antibodies may be detected in roughly 50-60% of patients with early
RA at ‘baseline’(e.g., at their initial encounter with
a specialist, usually after 3-6 months of symptoms). The specificity
of anti-CCP is around 95-98% as regards undifferentiated forms of
arthritis that do not develop into RA. IgM RF are often found in the
same patients, but with much lower specificity for RA. One study using
a CCP1 assay showed a sensitivity of 55% and a specificity of 97%
specificity for RA, when both anti-CCP and IgM RF were positive in
the early stage of arthritis (2). More recent studies using the CCP2
assay have shown even higher prevalence at the first visit to clinics;
in one study anti-CCP antibodies were found in 70% of such patients.
Interestingly, using stored samples, anti-CCP could be detected 1.5
to 9 years before the onset of arthritis (3). A study using the CCP2
assay found progression from undifferentiated polyarthritis to RA
in 93% of anti-CCP positive patients but only in 25% of anti-CCP negative
patients after 3 years of follow-up (4). In a study of patients with
RA or palindromic rheumatism, anti-CCP (CCP1) were found in 55% of
both conditions, indicating that palindromic rheumatism is closely
related to and often progresses to RA (5).
observations have indicated that anti-CCP positive early RA patients
may develop a more erosive disease than those without anti-CCP (6).
Other investigators have confirmed this, and suggested the superiority
of anti-CCP over IgM RF in predicting an erosive disease course. The
use of anti-CCP results in the decision whether a patient should be
treated aggressively at an early stage or not is an important area for
research. In addition, the relationship of levels of anti-CCP antibodies
and various therapeutic interventions is under investigation.
use of anti-CCP antibodies may allow the clinical rheumatologist to
better predict the diagnosis and prognosis of individual patients with
RA. Whether this or other serologic tests will allow more rational therapeutic
decision-making and hence influence the long-term outcome of the disease
will be determined by further study.
Authors: Allan S. Wiik, MD, Department of Autoimmunology,
Statens Serum Institut, Copenhagen, Denmark; Walther J. van Venrooij,
MD, Department of Biochemistry, University of Nijmegen, The Netherlands.
Disclosure: Dr. Wiik has no conflict of interest. Dr. van Venrooij is a consultant
for Euro-Diagnostica and Axis-Shield.
Editors: Arthur Kavanaugh, MD; Eric
Matteson, MD; Jack Cush, MD
1. Schellekens GA et al. J Clin Invest 1998;101:273-81.
2. Jansen AL et al.
J Rheumatol 2002;29:2074-6.
S et al. Arthritis Rheum 2003 (in press).
4. van Gaalen F et
al. Arthritis Res Ther 2003;5 (suppl 1):28 (abstract).
5. Salvador G et al.
Rheumatology (Oxford) 2003;42:972-5.
6. Kroot EJ et al.
Arthritis Rheum 2000;43:1831-5.
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to members. This Hotline reflects the views of the authors, and does
not represent a position statement of the College.
2003 American College of Rheumatology
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