ArticlePDF AvailableLiterature Review

The influence of ACPA status and characteristics on the course of RA

Authors:

Abstract

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, and affects 0.5-1% of the population. Although it poses a considerable health problem, relatively little remains known about the disease pathogenesis and etiology. In the past decade, anti-citrullinated protein antibodies (ACPA) have emerged as suspects in the development and/or progression of RA. Citrullinated proteins--containing the amino acid citrulline, generated post-translationally from arginine--are found in the joints of patients with RA, but are not specific for the disease. This situation contrasts with the presence of ACPA, which are mostly found in individuals with RA. Intriguingly, ACPA can also be found in individuals before symptom onset. In these instances the ACPA response seems to be in its infancy, recognizing only a few citrullinated antigens and not using the full isotype repertoire. These characteristics of the ACPA response mature before clinical disease precipitates. Evidence is emerging that ACPA status can further characterize the heterogeneous RA phenotype, not only with respect to outcome, but perhaps also with respect to intervention. This Review summarizes the evolution of the ACPA response and its putative role in disease pathogenesis, as well as its relationship with clinical phenotype and diagnostic potential.
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Department of
Rheumatology, Leiden
University Medical
Center, PO Box9600,
2300RC Leiden,
TheNetherlands.
(A.Willemze, L.A.Trouw,
R.E.M.Toes,
T.W.J.Huizinga).
Correspondence to:
T.W.J. Huizinga
t.w.j.huizinga@lumc.nl
The influence of ACPA status and
characteristics on the course of RA
Annemiek Willemze, LeendertA. Trouw, RenéE.M. Toes and TomW.J. Huizinga
Abstract | Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, and affects 0.5–1%
of the population. Although it poses a considerable health problem, relatively little remains known about
the disease pathogenesis and etiology. In the past decade, anti-citrullinated protein antibodies (ACPA) have
emerged as suspects in the development and/or progression of RA. Citrullinated proteins—containing the
amino acid citrulline, generated post-translationally from arginine—are found in the joints of patients with
RA, but are not specific for the disease. This situation contrasts with the presence of ACPA, which are mostly
found in individuals with RA. Intriguingly, ACPA can also be found in individuals before symptom onset. In these
instances the ACPA response seems to be in its infancy, recognizing only a few citrullinated antigens and not
using the full isotype repertoire. These characteristics of the ACPA response mature before clinical disease
precipitates. Evidence is emerging that ACPA status can further characterize the heterogeneous RA phenotype,
not only with respect to outcome, but perhaps also with respect to intervention. This Review summarizes the
evolution of the ACPA response and its putative role in disease pathogenesis, as well as its relationship with
clinical phenotype and diagnostic potential.
Willemze, A. etal. Nat. Rev. Rheumatol. 8, 144–152 (2012); published online 31 January 2012; doi:10.1038/nrrheum.2011.204
Introduction
Autoantibodies in RA
Rheumatoid arthritis (RA), one of the most common
autoimmune diseases, affects 0.5–1% of the popula-
tion and is characterized by persistent synovitis, sys-
temic inflammation and expression of autoantibodies.1
Various autoantibodies have been described in RA,
including antibodies against ribosomal proteins (anti-
RA33 antibodies)2,3 and against carbamylated proteins
(anti-CarP antibodies).4 The first RA-associated anti-
body, rheumatoid factor (RF), was known by 1940,5 and
was later found to be directed to the Fc region of IgG.
More than 20years later, Nienhuis etal.6 described anti-
bodies labeling perinuclear granules in the superficial
cells of the human buccal mucosa epithelium, which
were named anti-perinuclear factor anti bodies (APF).
Although it became clear that APF were highly specific
for RA, testing for these antibodies was rather cumber-
some; therefore, RF was assessed in daily practice. In
1979, anti-keratin antibodies (AKA) were described, and
found to be present in approximately 50% of patients
with RA.7 Again, although these antibodies were more
specific than RF for RA, the presence of RF was much
more convenient to visualize. It was not until 1995 that
the protein filaggrin was shown to be the common
antigen targeted by both APF and AKA.8 Since then,
research into this unique autoantibody system has taken
off with unprecedented speed, reaching a climax early
in 2011 with the inclusion of anti-citrullinated protein
antibodies (ACPA) in the new classification criteria
forRA.9,10
Testing for ACPA
After the discovery of filaggrin as the target of APF and
AKA, it took only a year to reveal the molecular identity
of the antigens that these autoantibodies recognize: the
nonclassical amino acid citrulline, embedded in a protein
backbone.11,12 Citrulline is a non-encoded amino acid,
generated by a post-translational modification of arginine
mediated by protein-arginine deiminase enzymes.13 This
modification takes place during a variety of bio logical pro-
cesses, including inflammation. In 1998, the first ELISA
using citrullinated peptides (derived from several filaggrin
epitopes) was developed,12 and was followed, in 2000, by
the first ELISA based on artificial cyclic citrullinated pep-
tides (CCP).14 The first commercial version of this test,
the CCP2 assay, became available in 2002 and enabled
routine testing for antibodies directed against citrullinated
epitopes as a biomarker for RA.14–18 As well as the CCP2
assay, a few other assays for ACPA, such as CCP3 and
MCV (Mutated Citrullinated Vimentin), have made their
way into the clinic. These assays differ slightly in terms of
specificity and sensitivity.19
Implications of the ACPA response
As anti-CCP2 antibodies recognize a variety of citrul-
linated peptides and proteins, these antibodies are now
called ACPA.20 In this Review, we discuss potential roles of
ACPA in RA pathogenesis, the mechanisms that underlie
Competing interests
The authors declare no competing interests.
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the occurrence and evolution of the ACPA response,
as well as the relationship of these autoantibodies
with clinical phenotypes and disease outcomes.
ACPA: cause or consequence?
The association with RA
ACPA are strongly associated with RA, which suggests
they have a prominent role in disease patho genesis.
Indeed, it has been suggested that ACPA are the ‘spark that
lights the RA fire’, and are directly involved in a vicious
circle that explains the chronicity of RA.21–23 The efficacy
of selective B-cell depletion in the treatment of RA pro-
vides evidence for the involvement of Bcells and possi-
bly autoantibodies in its patho genesis.24,25 Furthermore,
most ACPA-positive patients with RA seem to be ACPA-
positive years before the onset of disease,26 although the
extent of the ACPA armament seems to be limited at this
preclinical stage. Intriguingly, both the epitope recognition
profile and isotype usage of the ACPA-response increase
substantially before the appearance of clinical symptoms,
indicating the involvement of ACPA in disease precipita-
tion.27,28 Moreover, ACPA levels show an increase around
2years before the onset of symptoms, after which they
seem to stabilize at fairly high levels—it has been estimated
that the amount of IgG ACPA can reach up to 30 μg/ml in
the sera of patients with high ACPA titers.20 This amount
would be approximately equivalent to >1 ACPA IgG for
every 1,000 IgG molecules present.20
Histological differences in inflamed joints have been
found between ACPA-positive and ACPA-negative
patients with RA. For example, synovial tissue immune
cell infiltrates differ with respect to lymphocyte numbers
as well as markers of fibrosis; altered synovial inflam-
matory architecture might indicate a role for ACPA in
synovial inflammation.29
Interaction of the ACPA and RF responses
Although the appearance of ACPA in the preclini-
cal phase tends to precede that of RF, RF can also be
detected years before clinical disease onset.26,30 RF seems
to preferen tially interact with hypoglycosylated IgG.31
ACPA are hypoglycosylated as compared with total IgG;32
thus, one might infer that RF can enhance the patho-
logical effects of ACPA through preferential binding
to ACPA and potentiation of the subsequent immune
response. Indeed, in a study in ACPA-positive Native
Americans, RF was mostly detected in patients with RA
and not in healthy individuals.33
Immunological consequences of ACPA deposition
To be effective, antibodies must, in general, recruit
immune effector mechanisms mediated by activation
of the complement system34 or Fc receptor-positive
cells.35 The complement system can be activated via three
pathways: the classical pathway, the lectin pathway and
the alternative pathway.36 Each pathway is initiated by
a specific recognition molecule. The classical pathway
is initiated by C1q, the lectin pathway by mannose-
binding lectin or ficolins, and the alternative pathway
through the spontaneous low-level activation of C3.
Key points
The identification of anti-citrullinated protein antibodies (ACPA) has
resulted in the identification of a subset of patients with RA with a more
homogeneousoutcome
ACPA are highly specific for RA and can be present years before the first clinical
sign of the disease
Maturation of the ACPA response is associated with the emergence of clinical
symptoms and the transition to RA
The presence of ACPA in RA is associated with greater radiological joint damage
and with different response to therapy
Initiation of complement activation via each of these
pathways involves the formation of C3 convertase com-
plexes (composed of different subunits in each pathway),
which cleave complement C3 to produce biologically
active complement fragments. These fragments attract
and activate immune cells through their complement
receptors. Intriguingly, ACPA can activate human
complement not only via the classical pathway, which is
known to be activated by antibodies present in immune
complexes, but also via the alternative pathway.37 These
observations are reminiscent of findings from animal
models of arthritis, which show that the alternative
pathway of complement activation is crucially involved
in autoantibody-mediatedarthritis.38
Besides activating complement, ACPA are also readily
capable of triggering immune cell responses via Fc recep-
tors (FcR). For example, immune complexes containing
ACPA and citrullinated fibrinogen have been shown to
trigger TNF secretion through engagement of FcγR on
macrophages.39 Such findings should be interpreted in
the context that many immune complexed model anti-
gens, such as ovalbumin, elicit similar effects. Thus, these
data do not necessarily indicate the involvement of ACPA
in disease pathogenesis. Nevertheless, they are of rele-
vance to understanding the pathogenic role of ACPA, as
they show that these autoantibodies do have the potency
to recruit powerful immune effector mechanisms.
Similarly, it was shown in 2010 that ACPA can also acti-
vate FcεR-expressing cells,40 which are normally involved
in the control of parasitic infections. Intriguingly, as in
many parasite-infected hosts, antigens recognized by the
immune system in patients with autoimmune disease
persist systemically for prolonged periods in the face of a
strong antigen-specific immune response. Such responses
are often characterized by the presence of IgE, the anti-
body isotype bound by high affinity immunoglobulin
εreceptor subunit β (FcεRI). Owing to the high affinity
of this receptor for IgE, the surfaces of FcεRI-expressing
cells, such as basophils, are coated with IgE. We reported
the direct, highly specific exvivo activation of basophils
by IgE-ACPA induced by citrullinated proteins.40 These
data are important as they show that immune cells from
ACPA-positive patients with RA, but not from ACPA-
negative patients, mediate a specific biological response
to citrullinated protein antigens. Intriguingly, we also
observed increased levels of histamine within the synovial
fluid of IgE ACPA-positive patients with RA (we discuss
ACPA isotypes in the next section), as well as increased
numbers of mast cells with a degranulated pheno type in
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the synovia of these patients, as compared with ACPA-
negative patients.40 These data suggest that mast cells
contribute to synovial inflammation through triggering
of FcεRI-receptors by crosslinked IgE ACPA, indicating
that ACPA contribute to disease pathogenesis, rather
than being a consequence of synovial inflammation.
This notion is further supported by observations made
in animal models showing that dif ferent ACPA, reactive
with several citrullinated antigens, are able to initiate and
enhance arthritis.41–44 Findings made in these models also
indicate that ACPA recognize citrullinated proteins in a
hapten-like manner (that is, ACPA binds to citrulline as
if it were a small molecule. This molecule can be recog-
nized in the context of different protein backbones).44
Thus, ACPA and anti-CCP2 antibodies crossreact with a
variety of citrullinated proteins that bear little sequence
homology; this cross reactivity, however, is not absolute, as
indicated by studies using specific citrullinated peptides,
some of which did not bind ACPA. The implications of
the fine specificity of the ACPA response are discussed
in the next section.20,45
Altogether, these data provide fertile soil to fuel the
hypothesis that ACPA play an important part in disease
pathogenesis, although further evidence is required to
substantiate this putative role in RA. In the following sec-
tions, we discuss characteristics of the ACPA response, and
summarize emerging evidence for how these antibodies
are related to clinical course and treatment outcomes
inRA.
ACPA characteristics
The B-cell lineage generates antibody-secreting plasma
cells and memory Bcells, which have enhanced capability
to respond to a specific initiating antigen by producing
antibodies. The most important function of antibodies
is protection of the host against invading pathogens, pri-
marily through neutralization of molecules essential to
the lifecycle of the pathogen and/or the recruitment of
powerful immune effector mechanisms capable of killing
pathogens or pathogen-infected cells.
To be properly effective, an antibody response needs to
develop through avidity maturation and isotype switch-
ing stages. Tcells are intimately involved in these pro-
cesses as they provide the helper activity essential for the
maturation of most B-cell responses (Figure1). Similarly,
diversification of the antibody response, through rec-
ognition of more epitopes, is thought to contribute to
itsefficacy.
Fine specificity and epitope spreading
ACPA can recognize a variety of citrullinated antigens,
including citrullinated fibrinogen,46,47 citrullinated vimen-
tin (which is also known as the Sa antigen),48 citrullinated
typeII collagen,49 citrullinated α-enolase50 and many more
citrullinated proteins. An increase or shift in the antigen
recognition profile (a phe nomenon known as epitope
spreading) can have important pathophysiological con-
sequences, as has been described in, for example, systemic
lupus erythematosus51 and pemphigus.52 Autoantibodies
such as anti-desmoglein antibodies present in patients
with pemphigus vulgaris have been convincingly shown
to mediate a pathogenic effect, through transfer into
experimental animals.52 Furthermore, in pemphigus
(of which there are two major types: pemphigus folia-
ceus and pemphigus vulgaris,) reactivity against dif-
ferent desmoglein epitopes is associated with different
outcomes. In patients with pemphigus foliaceus, auto-
antibodies to desmoglein-1 occur. These autoantibodies
mediate blistering of the skin through loss of adhesion
in the superficial epidermis, where desmoglein-1, but
not desmoglein-3, is expressed. By contrast, in mucosal
pemphigus vulgaris, the presence of anti-desmoglein-3
IgG antibodies causes blistering of the mucosae, where
desmoglein-3 is expressed.53 Importantly, the example of
pemphigus elegantly demon strates that intra molecular
epitope spreading might modulate remissions and
relapses, as auto antibodies that recognize the EC5 domain
of desmoglein-1 seem to be nonpathogenic, whereas those
directed against the EC1 and EC2 domain of the molecule
are associated with disease onset (appearing at this stage)
and active disease. Passive transfer experiments have
demonstrated that anti-EC1 and anti-EC2 auto antibodies
are pathogenic, whereas anti-EC5 autoantibodies are
incap able of inducing blisters in mice.54 Pemphigus is,
therefore, a prototype disease that indicates the relevance
of epitope spreading in the transition from the preclinical
to the clinical stage of autoimmune disease.
The ACPA immune response in RA starts several years
before diagnosis of the disease, even before the onset of
symptoms, but in a restricted manner with low antibody
titers and limited peptide reactivity.27 ACPA titers and
peptide-recognition profiles increase as the individual
approaches disease onset.26 Likewise, in patients with
arthralgia, the development of arthritis is predicted not
HLA HLA
ACPA
Citrulline
B cell
Naive
T cell
Dendritic
cell
TH cell
Figure 1 | ACPA production by Bcells can be stimulated by autoreactive Tcells.
Dendritic cells present peptides to naive Tcells in complex with HLA class II
molecules, activating the Tcells and leading to TH cell-mediated stimulation
of Bcells. In the context of APCA production, we hypothesize that Bcells can
recognize citrullinated peptide complexes, for example on apoptotic cells. Bcells
can internalize these complexes, process them and present peptides from them
in complex with HLA molecules encoded by SE alleles (these peptides may or may
not be citrullinated), to Tcells. When Tcells recognize those peptides they can
provide help to the Bcells, resulting in the production of ACPA. Antibodies to
different epitopes (including citrullinated epitopes) of the internalized peptide
complex can be produced, leading to the production of ACPA. Therefore, T-cell
help stimulates the production and maturation of ACPA. Abbreviations:
ACPA, anti-citrullinated protein antibodies, SE, shared epitope; TH cell, T helper cell.
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only by the presence of ACPA, but also by their levels.55,56
High titers of ACPA are associated with the recognition of
more citrullinated epitopes (Figure2a). Indeed, patients
with arthralgia who have an extended ACPA repertoire
are at higher risk of develop ing arthritis.56 Sim ilar ly,
ACPA-positive patients with early arthritis who do not
fulfill the American College of Rheumatology (ACR) clas-
sification criteria for RA are more likely to develop RA if
their ACPA response is reactive to more citrullinated epi-
topes.28 These findings are consistent with the notion that
a ‘broader’ ACPA recog nition profile is associated with
the transition towards (persistent) disease, and resemble
the observations made in pemphigus with the exception
that, thus far, no speci fic anti-citrullinated epitope or
protein reactivity has been identified that would predict
disease course in RA. Given the hapten-like recognition of
citrullinated antigens and the high crossreactivity towards
multiple citrullinated proteins of the ACPA response, this
lack of fine specificity is perhaps not surprising.
Isotype profiles
Isotype switching is another event involved in enhancing
the efficacy of (auto)antibodies, and leads to an increase
in the diversity of antibody structure that enables the acti-
vation of more immune effector mechanisms. ACPA can
be present in different forms, including IgG, IgA, IgM
and IgE (Figure2b). In ACPA-positive patients with RA,
IgG1 and IgG4 ACPA are usually present (in 99% and
98% of patients, respectively); IgM and IgA are present
in around 60% of patients, and IgG2 and IG3 are foundin
80% and 60% of patients, respectively.33,40,57,58 Healthy
family members of patients with RA display fewer ACPA
isotypes than their kin with the disease.33 Nonetheless,
multiple ACPA isotypes are present before the onset of
RA.58 Likewise, the ACPA isotype distribution does not
seem to significantly expand anymore during disease
progression from undifferen tiated arthritis (UA) to RA,
indicating that most of the expansionof isotype usage by
ACPA takes place before the onset ofarthritis.
Maturation of the response
During a B-cell response against recall antigens, isotype
switching and affinity maturation typically occur in
germi nal centers. Following somatic hypermutation,
different B-cell clones will compete for antigens pre-
sented on follicu lar dendritic cells. Bcells that express
immuno globulins of sufficiently high avidity will acquire
the signals necessary for survival and proliferation. As a
result, the total avidity of the immune response—defined
as the overall binding strength of polyclonal antibodies
to a multi valent antigen—increases, because low avidity
Bcells will not be stimulated and will eventually dis-
appear from the population. The avidity maturation of
antibody responses against recall antigens, mostly fol-
lowing vacci nation, has been studied extensively, but
autoantibody responses seem to behave differently.59–61
For example, the avidity of ACPA is significantly lower
than the avidity of anti bodies to the recall antigens tetanus
toxoid and diphtheria toxoid, pointing to a different regu-
lation of autoantibody responses as compared with recall
antigens. In individual patients with RA, ACPA do not
show avidity maturation during longi tudinal follow up
and even in patients who displayed extensive isotype
switching, ACPA avidity was relatively low,62 indicating
that these two m aturation process es are uncoupled in the
ACPA response.
ACPA
B cell
ACPA
IgA ACPA
IgG ACPA IgM ACPA
B cell
a
b
Fine specicity
Isotypes
HLA
HLA
Citrulline
IgE ACPA
Mast
cell
Figure 2 | Fine specificity and isotype profiles are important characteristics of an
ACPA response. a | ACPA can recognize different citrullinated antigens, including for
example citrullinated vimentin, citrullinated fibrinogen and citrullinated α-enolase.
Although it is the citrulline moiety that binds to the autoantibody, the context of the
amino acids surrounding the citrulline are important for recognition by ACPA with
differing fine specificities. The ACPA recognition profile seems to be established in
undifferentiated arthritis, with a broader profile being associated with subsequent
progression to persistent disease. The peptides presented by the Bcells may or
may not be citrullinated. b | Different antibody isotypes can activate the immune
system via different pathways. For example, IgM, IgA and the different IgG
subclasses activate the complement system to different extents. Although IgG is
the most common isotype of ACPA in RA, the other isotypes also occur in some
patients. Different isotypes recruit different effector functions, for example, IgE-ACPA
can activate FcεR1-positive cells, such as mast cells, adding participation of these
cells to a subsequent inflammatory process. Furthermore, the presence of IgM
ACPA indicates an ongoing immune response, with recruitment of new Bcells into
the ACPA response. Abbreviations: ACPA, anti-citrullinated protein antibodies; RA,
rheumatoid arthritis.
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The data described above indicate that ACPA-
producing Bcells behave differently from ‘conventional
Bcells. In 2010, rituximab was shown in mice to specifi-
cally deplete Bcells that produce autoantibodies, while
sparing the ‘conventional’ plasma cells that produce pro-
tective antibodies.63 Treatments that target the crucial
biological mechanisms underlying ‘conventional’ B-cell
responses might, therefore, prove not to be as effective
as anticipated, because the mechanisms that regulate
ACPA-producing Bcells might be different.64
Together, the collection of data described above pro-
vides credible support for the notion that the ACPA
response shifts from ‘infancy’ to ‘adulthood’ before transi-
tion to clinical disease (Figure3). Whether the matura-
tion of the ACPA response is a consequence or a cause of
disease initiation is not known, but identifying the master
switches responsible for the expansion of the ACPA
response might be instrumental for further elucidation
of the disease pathogenesis.
ACPA and clinical features
ACPA status and categorization of patients
The first description of RA was made in 1800 in Paris.
Sixty years later, the disease was named ‘rheumatoid
arthritis’ for the first time by an English rheumato logist,
Alfred Baring Garrod.65 As RA seems to be a highly
hetero geneous disease, several classification criteria
have been developed over the years, such as the 1956
ARA criteria,66 1961 Rome criteria67 and 1966 New York
criteria,68 with the aim of identifying more homogenous
patient groups to facilitate comparison of international
studies. Since 1987 the disease has been classified based
on the ACR 1987 criteria,69 which were developed using
an analytical approach in which RA was defined by a
regression analysis of disease characteristics of ‘classic
cases’. As different disease manifestations are included in
these criteria, a heterogeneous set of patients with con-
ceivably different ‘pathogenic’ backgrounds are identified
by them.
Therefore, the great variation in disease course and
treatment response among patients with RA can be
explained by the classification criteria describing a hetero-
geneous syndrome. ACPA have an exquisite specificity for
RA,70 and for this reason ACPA status was included in the
new 2010 ACR–European League Against Rheumatism
(EULAR) classification criteria for RA,9,10 alongside RF
levels (already included in the 1987 criteria).69
ACPA-positive and ACPA-negative disease have
been shown to be associated with different genetic and
environ mental risk factors, fuelling the hypothesis that
different pathophysiological mechanisms underlie these
two separate disease subsets.71–73
For example, ACPA-negative RA associates with HLA-
DR3,74,75 whereas the HLA shared epitope (SE) alleles
predispose to ACPA-positive disease.71 Likewise, the
contri bution of smoking to disease risk is mainly con-
fined to the ACPA-positive HLA-SE-positive patient
group.73 It has even been suggested that a specific interac-
tion between environment (that is, smoking) and genetic
background (HLA expression profile)76 might explain
the reactivity against a specific citrullinated antigen.
Although this hypothesis turned out to be incorrect,77,78
it is clear that the HLA constitution of an individual does
influence the ability of the ACPA response to recognize
particular citrullinated antigens.78,79
Thus, although studies investigating ACPA charac-
teristics in relation to clinical phenotypes have not yet
resulted in further refinement of the ACPA-positive sub-
group,80 it is clear that stratifying patients with RA on the
basis of ACPA status has resulted in the identification of
more homogenous patient groups, with respect to both
disease course and response to treatment.
ACPA and treatment outcomes
So what are the therapeutic implications of subgrouping
patients with RA according to ACPA status? Logically,
diseases with distinct pathogenesis might benefit from
different treatment strategies. Methotrexate is the most
Figure 3 | The maturation of the anti-citrullinated antibody response in the development of RA. The maturation of the
dragon is depicted as a metaphor for the development of the ACPA response. Breaking of tolerance against citrullinated
antigens can occur in healthy individuals, represented by the hatching of a dragon egg. Although immature in terms of
isotype profile and breadth of antigen recognition, this early ACPA response might still be harmful, and potentially
contributes to the progression of preclinical arthritis to early RA. We hypothesize that maturation of the ACPA response
takes place during the preclinical phases, such that by the time early arthritis emerges clinically, the isotype and antigen-
recognition profiles of the ACPA response are established. Greater breadth of ACPA isotype usage and/or recognition
profiles predispose an individual to develop the full disease, but the ACPA response does not mature any further as the
disease becomes more severe. Abbreviations: ACPA, anti-citrullinated protein antibodies; RA, rheumatoid arthritis.
Slowly
progressive
Rapidly
progressive
Pre-RA
Healthy Undifferentiated
arthritis Early RA
Induction of
autoimmunity
Maturation of the
antibody response
No additional changes
RA
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prominent DMARD. A few years ago, we performed a
double-blind placebo controlled randomized trial com-
paring two treatment strategies in patients with UA.
Interestingly, the outcome of this study indicated that
ACPA-positive patients with UA treated with metho-
trexate are less likely to progress to RA, and do so at
a later time point as compared with a placebo control
group. Unexpectedly, no effect of methotrexate therapy
on progression to RA in the ACPA-negative group was
observed.81 Interestingly, among patients with UA, those
with low or intermediate ACPA levels respond better to
methotrexate than patients with high ACPA levels.82
The randomized trial data not only indicate that the two
ACPA subgroups respond differently to metho trexate
treatment, but also that in patients with high APCA
levels, methotrexate monotherapy might be insufficient.
Indeed, the presence of ACPA and IgM RF together
with elevated levels of C-reactive protein is predictive
of more rapid radiographic progression in patients with
RA. Patients with ACPA and IgM RF are also more likely
to respond insufficiently to methotrexate monotherapy
for recent-onset RA.83
Not only in regard to response to DMARDs does
ACPA status seem to matter. In a trial published in
2011,84 208 patients with RA refractory to therapy with
TNF blockers were treated with rituximab. Rituximab is a
monoclonal antibody directed towards the B-cell marker
CD20, and has been shown to be an effective treatment
in RA. In these patients, the presence of ACPA predicted
a better EULAR response to rituximab at 24weeks. Thus,
rituximab might have a greater role in ACPA-positive
patients with RA than in ACPA-negative individuals.84
The mechanisms of rituximab efficacy, and of B-cell
involvement in RA, are incompletely known; the basis
for these differing outcomes remains to be elucidated.
ACPA and the ‘window of opportunity’
The observation that ACPA status is, to some extent,
related to therapeutic outcome in early disease is intrigu-
ing. For a number of diseases, such as diabetes mel litus,
it has been suggested that a critical period exists in
which interventions might reverse the disease process.
For RA, such a ‘window of opportunity’ might also
exist,85 because symptom duration >12weeks at treat-
ment initiation is a strong and independent risk factor
for a persistent disease course with more joint destruc-
tion.86–89 Although this observation could be explained
by the assumption that acute-versus- insidious symptom
onset characterizes the manifestation of different
disease subsets, it could also be indicative of a window
of opportunity. The difference in outcome in relation
to symptom duration raised the question of whether a
difference in ACPA characteristics could be involved.
However, ACPA-positive patients with symptoms
of RA for <12weeks display no difference in the speci-
ficity and isotype repertoire of their ACPA response
compared with patients with longer symptom duration.
These findings indicate that the ACPA-characteristics
analyzed do not have an impact on the putative window
of opportunity and emphasize further that maturation
of the autoantibody response occurs at an early stage,
before the first signs and symptoms of disease appear.90
ACPA, remission and long-term monitoring
The absence of ACPA and IgM RF are independent pre-
dictors of drug-free remission.91 As we have outlined,
the course of ACPA-positive disease seems to be charac-
terized by more persistent inflammation than its ACPA-
negative counterpart. Together, these data indicate that
treatment decisions in RA can be guided by ACPA status.
Seroconversion is uncommon among ACPA-positive and
ACPA negative patients; therefore, it does not seem to
be useful to repeat ACPA measurements in daily prac-
tice.92,93 Thus, these data support the hypothesis that RA
can be classified into two different disease subsets, and
suggest that developing different classification criteria
for ACPA-positive and ACPA-negative RA might help
to optimize treatment strategies.
ACPA and disease outcome
The emerging relevance of ACPA status to treatment deci-
sions is not only based on differential treatment efficacies,
but is also supported by differences in disease outcome.
Typically, 50–70% of the patients with RA are ACPA
positive.94 Although ACPA-positive and ACPA-negative
patients with RA show a very similar clinical presenta-
tion in the early phase of the disease,95,96 their subsequent
disease course is different—extra-articular manifestations
are clearly influenced by ACPA status. For example, ACPA
positivity is associated with an increased risk of develop-
ing ischemic heart disease97 or lung pathology.98 Likewise,
ACPA-positive patients have more destructive disease
than ACPA negative patients;96,99–101 ACPA-positive
patients develop erosions earlier and more abundantly
than patients without ACPA.102 Owing to their more
severe disease-course, APCA-positive patients require a
more aggressive treatment regimen than ACPA-negative
patients.103 Indeed, in the BeSt study ACPA-positive
patients initially treated with DMARD monotherapy
displayed greater radiographic joint destruction after
2years than ACPA-negative patients.103 In patients ini-
tially treated with combination therapy, by contrast, no
difference with respect to joint destruction was observed
between ACPA-positive and ACPA-negative patients.
These observations suggest that effective treatment with
combination therapy, together with steering treatment
according to disease activity, can prevent radiographic
progression, even in patients with risk factors for severe
damage, such as ACPA-positivepatients.
Some ACPA characteristics, such as the fine-specificity
profile, are no longer associated with the rate of joint
destruction once RA is established.104,105 The ACPA
isotype profile seems, however, to be an exception—in
two cohorts ACPA isotype diversity has been associated
with a higher risk of radiographic progression, equat-
ing to a 1.4-fold increase in risk per isotype used in the
ACPA response, illustrating that an extended isotype
usage is associated with a worse outcome.106
Altogether, therefore, evidence is emerging that ACPA-
positive and ACPA-negative RA represent two different
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disease entities with different outcomes, and, possibly,
different responses to medication. The latter notion is
especially important as it indicates that treatment regi-
mens can be optimized by developing them according
to ACPA status.
Conclusion
The identification of ACPA has been a major break-
through in the understanding of pathogenesis in RA. It
has become clear that this unique autoantibody response
identifies more homogenous subsets of patients with RA
than those characterized by levels of other auto antibodies,
and that differing disease courses possibly reflect the
involvement of ACPA in disease patho genesis. The eluci-
dation of the characteristics of the ACPA response have
shown that ACPA are not pathogenic perse, as illus-
trated by the fact that most patients are ACPA-positive
a while before they develop disease. Possibly, a more
mature ACPA response—as illustrated by more extensive
isotype switching, enhanced antigen-recognition profile
and higher titers—might be required for these autoanti-
bodies to contribute to disease pathogenesis. Once RA is
established, the ACPA response does not seem to mature
(Figure3). Nonetheless, ACPA status is important for
clinical decision making, as it is the factor that is most
predictive of disease outcome and associates with the
effectiveness of various interventions.
Review criteria
We searched for original articles and abstracts in
PubMed with no restrictions on publication date. The
search terms used in various combinations were
“citrulline”, “rheumatoid”, “arthritis”, “ACPA”, “CCP2” and
“rheumatoid factor”, and the papers cited were chosen
according to the authors’ opinion of their relevance to the
discussion. All papers identified were English-language
full-text papers and abstracts. We also searched the
reference lists of identified articles and several review
papers for further papers of relevance. The search was
completed in October 2011.
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Author contributions
All authors contributed equally to researching data for
the article, writing the article, discussions of the
content, and review and/or editing of the manuscript
before submission.
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... These two disease subsets have a similar clinical presentation 43 but differ in the disease course and response to treatment. [43][44][45][46] ACPA-negative RA is mild, and patients with this disease are more likely to achieve drugfree remission. 47 Unlike ACPA-negative RA, ACPA-positive RA associated with a worse prognosis characterized by the higher rates of erosive damage 43 has different risk factors with most genetic associations [48][49][50] and environmental risks, such as smoking 51,52 and alcohol abstinence. ...
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Rheumatoid arthritis is a chronic inflammatory autoimmune disease of unknown cause. The immune response against citrullinated Ags has recently become the prime suspect for disease pathogenesis. Immunity against citrul-linated Ags is thought to play a pivotal role in the disease for several reasons: 1) citrullinated Ags are expressed in the target organ, the inflamed joint; 2) anti-citrullinated protein Abs are present before the disease becomes manifest and 3) these Abs are highly specific for rheumatoid arthritis. In this review, data from clinical, genetic, biochemical, and animal studies is combined to create a profile of this remarkable autoantibody response. Moreover, a model is proposed of how the anti-citrullinated proteins response is generated and how it could eventually lead to chronic inflammation.
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Objective The 1987 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. Methods A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease—this being the appropriate current paradigm underlying the disease construct “rheumatoid arthritis.” Results In the new criteria set, classification as “definite RA” is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score range 0–5), serologic abnormality (score range 0–3), elevated acute-phase response (score range 0–1), and symptom duration (2 levels; range 0–1). Conclusion This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimize the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct “rheumatoid arthritis.”
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The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a “classification tree” schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91–94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.
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Background Anticitrullinated protein antibodies (ACPA) probably play a pathogenic role in rheumatoid arthritis (RA). The ACPA response is already expanded before the first symptoms of RA and hardly changes thereafter.Objectives To explore the degree of ACPA epitope spreading prior to onset of clinical RA and the pattern of auto-antigen reactivity at the beginning of the immune response.Methods Multiple serial serum samples of 79 RA patients who had donated blood before disease onset were available for analysis. 47 patients tested ACPA (anti-CCP2) positive prior to the onset of clinical RA. Of these patients a median of 6 (IQR 4–9) sequential pre-RA sera spaced 1–2 years apart were tested for reactivity to five distinct citrullinated peptides in an ELISA. Two fibrinogen peptides, 1 vimentin, 1 α-enolase and 1 cyclic citrullinated peptide (CCP1) were tested.ResultsFour out of 47 ACPA positive patients (9%) did not show reactivity to any peptide. In 23 ACPA positive patients seroconversion from ACPA absence to ACPA presence was observed. In 16 (70%) of these patients, the immune response started with reactivity towards one peptide, without preference for a particular peptide. In two patients (9%) it started with two peptides, in three (13%) it started with three peptides and in two (9%) it started with four peptides. The number of recognised peptides increased over time, without a dominant epitope spreading pattern. Median titres of all measured ACPA increased over time in a biphasic manner.ConclusionACPA epitope spreading occurs over several years prior to onset of clinical RA. None of the tested auto-antigens is solely responsible for the initial auto-immune response. ACPA epitope spreading is a random process. ACPA titers increase in a biphasic way, suggesting a ‘second event’ a few years before diagnosis of RA.