Autoantibodies in inﬂammatory arthritis
, M.S. Chimenti
Rheumatology, Allergy and Clinical Immunology, Department of “Medicina dei Sistemi”,UniversityofRome“Tor Vergata”, Rome, Italy
Reumatologia, Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, viale del Policlinico 155, 00161 Rome, Italy
Received 19 February 2016
Accepted 28 February 2016
Available online 9 March 2016
Rheumatoid arthritis (RA) is a systemic chronic inﬂammatory disease characterized by extensive synovitis
resulting in erosions of articular cartilage and marginal bone with joint destruction. The lack of immunological
tolerance in RA represents the ﬁrst step toward the development of autoimmunity. Susceptible individuals,
under the inﬂuence of environmental factors, such as tobacco smoke, and silica exposure, develop
autoimmune phenomena that result in the presence of autoantibodies. HLA and non-HLA haplotypes play a
major rolein determining thedevelopment of speciﬁc autoantibodies differentiating anti-citrullinated antibodies
(ACPA)-positive and negative RA patients. Rheumatoid factor (RF) and ACPA are the serological markers for RA,
and during the preclinical immunological phase, autoantibody titers increase with a progressive spread of ACPA
antigens repertoire. The presence of ACPA represents an independent risk factor for developing RA in patients
with undifferentiated arthritis or arthralgia. Moreover, anti-CarP antibodies have been identiﬁed in patients
with RA as well as in individuals before the onset of clinical symptoms of RA. Several autoantibodies mainly
targeting post-translational modiﬁed proteins have been investigated as possible biomarkers to improve the
early diagnosis, prognosis and response to therapy in RA patients. Psoriatic arthritis (PsA) is distinguished
from RA by infrequent positivity for RF and ACPA, together with other distinctive clinical features. Actually, spe-
ciﬁc autoantibodies havenot been described. Recently, anti-CarP antibodies have been reported in sera from PsA
patients with active disease. Further investigations on autoantibodies showing high speciﬁcity and sensibility as
well as relevantcorrelation with disease severity, progression, and response to therapy are awaited in inﬂamma-
© 2016 Elsevier B.V. All rights reserved.
1. Mechanisms of autoantibody formation in inﬂammatoryarthritis...................................... 674
1.1. Genesimplicatedinautoantibodyformation............................................ 674
1.2. Environmentalfactorsimplicatedinautoantibodyformation .................................... 674
2. Preclinicalimmunologicalphaseinrheumatoidarthritis.......................................... 675
3. Autoantibodiesinundifferentiatedarthritis................................................ 675
4. Autoantibodiesinrheumatoidarthritis.................................................. 675
4.1. Classicalautoantibodies ..................................................... 675
4.2. Additionalautoantibodies .................................................... 676
4.3. Autoantibodiesareassociatedwithdiseaseoutcome ........................................ 677
5. Autoantibodiesinpsoriaticarthritis ................................................... 677
6. Conclusion .............................................................. 679
Take-homemessages ............................................................ 679
Acknowledgments ............................................................. 679
Autoimmunity Reviews 15 (2016) 673–683
⁎Corresponding authorat: Reumatologia,Dipartimentodi Medicina Internae Specialità Mediche,Sapienza Università di Roma, Vialedel Policlinico155, 00161 Rome, Italy.Tel.: +39 06
49974673; fax: +39 06 49974642.
E-mail address: email@example.com (C. Perricone).
These authors contributed equally to this paper.
1568-9972/© 2016 Elsevier B.V. All rights reserved.
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1. Mechanisms of autoantibody formation in inﬂammatory arthritis
Inﬂammatory arthritis is a group of rheumatologic conditions affect-
ing approximately 3% of the adult population . Rheumatoid arthritis
(RA) is the most prevalent inﬂammatory chronic systemic disease char-
acterized by extensive synovitis and an autoimmune response leading
to cartilage and bone erosions with consequent joint destruction .
The loss of the immunological tolerance to self-antigens represents
the ﬁrst step toward the development of autoimmune phenomena.
Susceptible individuals, under the inﬂuence of genetic and environmen-
tal factors, develop an underlying autoimmunity that manifests as the
presence of autoantibodies .(SeeFig. 1.)
1.1. Genes implicated in autoantibody formation
It is well known that several genes contribute to the loss of tolerance.
For instance, gene factors may affect antigen processing and presenta-
tion, lymphocyte proliferation and differentiation, and may encode for
receptors of T and B cells . HLAhaplotypes still playa major role in de-
termining the development of speciﬁc autoantibodies. In particular, in
RA, the amino acid sequence QKRAA, QRRAA, or RRRAA at positions
70–74 of the DRβ1 chain, called “shared epitope”(SE), is associated
with the production of anti-citrullinated antibodies (ACPA) and with
the disease susceptibility [5–7]. Multiple alleles in the DRB1 gene
share the SE such as HLA-DRB1*0401, *0404, *0405, *0408, *0101,
*0102, *1001, and *1402 . Indeed, the conversion of arginine to citrul-
line at multiple pockets dramatically increases peptide afﬁnity for
DRB1*0401 and other SE alleles . The increased peptide–MHC afﬁnity
leads to the activation of CD4+ T cells and can initiate an autoimmune
response to citrullinated self-antigens in RA patients [10,11]. The pecu-
liarity of the HLA-DRB1-SE is the association with a more severe disease
characterized by early onset, rapid radiographic progression, and the
presence of ACPA . It has also been demonstrated that SE acts as a
signal transduction ligand that binds to cell surface calreticulin and ac-
tivates theNO-mediated oxidative signal in turn inﬂuencing the regula-
tion of immunity [13,14]. The SE is also important in dendritic cells in
which promotes the production of IL-6 and IL-23, activating and
expanding Th17 cells . The SE can also directly enhance the
differentiation of Th17 cells expressing the receptor activator for NF-
κB ligand . Very recently, a protective role for the development of
ACPA in RA has been identiﬁed for the HLA-DRB1*13 alleles; indeed, pa-
tients with the HLA-DRB1*13 have lower ACPA levels and decreased
citrullinated epitope recognition . Seronegative and seropositive
RA can also be distinguished by non-HLA genes . For instance, the
second most important genetic association in Caucasian population is
in the gene protein tyrosine phosphatase non-receptor type 22
(PTPN22) encoding a tyrosine phosphatase, Lyp, a powerful inhibitor
of T cell activation. It has been hypothesized that the disease-
associated allele would produce a protein affecting the threshold for B
and T cell receptor signaling . The single nucleotide polymorphism
in PTPN22 increases the risk of RA by 40–80% (OR 1.4–1.8) [20–22].In
contrast, in the Asian population, the most important genetic associa-
tion is with the peptidylarginine deiminases citrullinatin isoenzyme 4
(PADI4) gene [23,24]. PADI4 is one of several isoenzymes carrying the
post-translational conversion of arginine residues to citrulline, and
this may be related to the production of ACPA . ACPA-positive and
ACPA-negative patients have partial genetic overlap, but evidences
supporting a different genetic risk proﬁle are increasing, suggesting
that not only from a genetic perspective but also from pathogenic and
clinical perspective, ACPA-positive and ACPA-negative represent two
forms of RA [26–28]. For ACPA-negative disease, HLA-DRB1*03 and
the gene interferon regulatory factor 5 seem to predispose to ACPA-
negative RA [29–35]. Recently, Viatte et al. have conﬁrmed the results
from the Rheumatoid Arthritis Consortium International evidencing
known markers, including ANKRD55 (a gene of unknown function),
and identifying new and speciﬁc markers of anti-CCP negative RA,
such as prolactin and NFIA .
1.2. Environmental factors implicated in autoantibody formation
Data gathered from the literature point at an interaction with envi-
ronmental factors, which seems necessary for the development of in-
ﬂammatory arthritides. The risk factors suggested so far include diet,
coffee intake, alcohol, and body mass index . Cigarette smoking is
the only risk factor clearly associated with disease susceptibility.
Smoke has several detrimental arrows including complementactivation
PTM generates neoepitopes
on self proteins, responsible
of the pathogenesis
of autoimmune diseases
C HN C OH
Fig. 1. Carbamylation occurs on differentamino acids via different mechanisms.Homocitrulline is one methylene group longer and is generated from a lysine residue following a reaction of
cyanate, which is present in the body in equilibrium with urea. Most carbamylation is believed to take place during inﬂammation when myeloperoxidase (MPO) is released from
neutrophils. MPO converts thiocyanate to cyanate, now allowing more carbamylation to occur. PTM: post-translational modiﬁcation; PC: plasmacells.
674 P. Conigliaro et al. / Autoimmunity Reviews 15 (2016) 673–683
in vitro, induction of pro-inﬂammatory IL-1α,IL-1β, IL-6, and IL-8 and
changes in gene expressions with a signiﬁcant up-regulation of the
heat-shock proteins in synovial ﬁbroblasts [38–41]. Of interest, the
association is true for ACPA-positive RA rather than ACPA-negative RA
patients . The number of the SE copies further modiﬁes the risk.
Smokers who do not carry the SE have a 1.5-fold elevated risk of devel-
oping ACPA and RA compared with non-smokers who do not carry the
SE. This risk increases to 21-fold in smokers carrying two copies of the
SE. Moreover, smoking increases the proportion of citrulline-positive
cells in the lungs . These ﬁndings suggested that smoking triggers
citrullination in lungs through activation of PAD providing a substrate
for the immune activation . Carbamylation is a process similar
to citrullination but the main difference concerns the modiﬁcation of
lysine instead of arginine . Effects of carbamylation on proteins
include changing of their polymerization ability, sensitivity to protein-
ases, and antibody antigen binding avidity [45,46].Mostofthe
carbamylation process is believed to take place during inﬂammation
when myeloperoxidase (MPO) is released from neutrophils indicat-
ing that MPO released from neutrophils can further increase the
level of carbamylation during inﬂammation [47,44].Consequences
of carbamylation have been reported to occur at the protein, cellular,
and systemic level .Anti-CarP antibodies have been identiﬁed in
patients with RA and in individuals before the onset of clinical symp-
toms of RA [44,49]. The presence of anti-CarP antibodies in RA patients
did not show signiﬁcant associations with genetic risk factors (HLA-
DRB1 alleles and PTPN22) and smoking suggesting that different bio-
logical mechanisms may be involved in the formation of anti-CarP and
anti-CCP antibodies . Another environmental risk factor identiﬁed
in RA is the notorious Porphyromonas (P.)Gingivalis, the only bacterium
known so far ofcontaining the enzyme PADinvolved in citrullination of
both bacterial and human proteins such as arginine in ﬁbrin in
periodontal tissue [51,52]. RA is prevalent in individuals with chronic
periodontitis . Therefore, P. gingivalis can potentially contribute to
the generation of de novo epitopes that may trigger the formation of au-
toantibodies. Contradictory data have been published regarding the
correlation between the levels of antibodies against P. gingivalis and
ACPA in RA patients [51,54,55]. ACPA might be produced outside the
joint in the mucosal sites such as lung and gingiva. As a consequence,
ACPA might cross-react through molecular mimicry with citrullinated
epitopes in the joint initiating an inﬂammatory response in genetically
susceptible individuals. Other substances may be associated with a
higher risk of developing ACPA-positive RA, such as silica ,
especially in tobacco smokers. Silica exposure has been linked with
the development of autoimmunity in several contests,probably associ-
ated with an alteration of Fas-mediated apoptosis in T lymphocytes
2. Preclinical immunological phase in rheumatoid arthritis
The identiﬁcation of patients in a preclinical phase may lead to an
early diagnosis and a prompt treatment with better disease outcomes.
Recent studies have demonstrated the presence of both rheumatoid fac-
tor (RF) and ACPA up to 10 years before the onset of RA in the so-called
“pre-articular or lymphoid phase”of the disease [58–61]. The autoanti-
body titers increase as the onset of disease approach together with a
progressive increase of ACPA antigens repertoire, known as epitope
spreading . Indeed, ACPA reactivity against characteristic speciﬁc-
ities, in particular α-enolase, ﬁbrinogen β36–52 and β74, and ﬁlaggrin
seem to increase before disease onset in asymptomatic individuals
. This immunologic phenomenon has also been associated with a
higher risk of progression to RA [64,65]. All together, these data sug-
gested that the adaptive immune response against autoantigens is initi-
ated years before the clinical signs of the disease. Likewise, in certain
murine models of arthritis, it has been observed an increase in antibody
levels before the onset of clinical symptoms or before the relapse of ar-
thritis [66,67]. Recently, anti-CarP antibodies were detected in mice
with collagen-induced arthritis (CIA) and appeared after immunization,
which caused local inﬂammation, combined with the notion that
inﬂammation can induce carbamylation and lead to a break of B cell
tolerance to carbamylated proteins . Furthermore, in a model of
chronic antigen-mediated polyarthritis the production of ACPA, RF,
and anti-type II collagen (CII) antibodies was observed in the absence
of clinical signs of arthritis and increased before the relapse of arthritis
3. Autoantibodies in undifferentiated arthritis
The term “undifferentiated arthritis”is used to describe those
patients with early inﬂammatory arthritis during the ﬁrst weeks to
months following symptom onset, where it is not possible to establish
a speciﬁc diagnosis. Many of these patients reach spontaneous remis-
sion without need to take a chance to adverse effect of treatment
while others will eventually be diagnosed with RA after further evolu-
tion of the symptoms and ﬁndings . In this contest, it is essential
to recognize those patients with undifferentiated arthritis and positive
predictive factors of RA development. ACPA-positive patients with un-
differentiated arthritis have a chance of 90% to progress to full-blown
RA within 3 years . Indeed, ACPA represents an independent risk
factor for developing RA in patients with undifferentiated arthritis or
arthralgia [64,70,71]. Moreover, also the titer of ACPA in patients with
arthralgia seems to predict future arthritis [72,73]. The ACPA isotype
switchingto IgG, IgA, IgM, or IgE occurs before disease onset in undiffer-
entiated arthritis, without further changes after diagnosis .Ina
recent large cohort study of subjects with general musculoskeletal
symptoms (n = 2028), anti-CCP positivity was associated with a risk
rate (RR) of 36.8 for a diagnosis of inﬂammatory arthritis and an RR of
50.4 for a diagnosis of RA. The sensitivity and speciﬁcity of anti-CCP
for the diagnosis of inﬂammatory arthritis were 57.4% and 98.1%, re-
spectively, while they increased to 64.9% and 97.9% for the diagnosis
of RA . Recently, also anti-CarP antibodies have been associated
with the risk of developing RA (hazard ratio 1.56) in 340 patients
with arthralgia during a median follow-up period of 3 years indepen-
dently to anti-CCP antibody positivity . Furthermore, the levels of
anti-CarP antibodies were higher in individuals who subsequently de-
veloped RA compared with controls, and their concentration and fre-
quency increased gradually after the disease onset. The sensitivity of
anti-CarP antibodies was 13.9% in pre-symptomatic individuals and
increased to 42.2% after the development of RA . Indeed, current hy-
pothesis suggests that these antibodies could be involved in the patho-
genesis of RA since they appear several years before RF appearance and
before thediagnosis of RA, similarly to whatoccurs for ACPA [49,72,77].
However, anti-CarP antibodies have been alsodetected in other formsof
non-RA early arthritis such as in juvenile idiopathic arthritis (16.7%), re-
active arthritis (16%), spondyloarthritis (15%) or psoriatic arthritis (9%)
[78,79]. Further investigations are needed to shed more light on the
presence of anti-CarP antibodies in other autoimmune/inﬂammatory
arthritis different from RA.
4. Autoantibodies in rheumatoid arthritis
4.1. Classical autoantibodies
RF and ACPA are well-known serological markers for RA diagnosis
according to the 2010 American College of Rheumatology (ACR)/
European League Against Rheumatism (EULAR) classiﬁcation criteria
. RF is present in about 50–80% of patients affected by RA. It has a
moderate speciﬁcity, around 66%, as it is detected in other autoimmune
diseases, systemic infections, and in up to 10% of healthy subjects .
Nevertheless, manydifferences exist between RF in health and disease.
The former is an IgM produced by B1 cells as “natural”antibody that
shows low afﬁnity and polyreactivity, the last undergoes isotype
switching and somatic hypermutation as consequence of B cells
675P. Conigliaro et al. / Autoimmunity Reviews 15 (2016) 673–683
receiving help from T cells . The lack of high speciﬁcity of RF has
stimulated the research of other autoantibodies more speciﬁc for the
diagnosis of RA. The identiﬁcation of ACPA led to relevant and novel
insights into RA diagnosis and etiopathology. Indeed, RA constitutes
at least two clinical syndromes, ACPA-positive and ACPA-negative
RA, that share many clinical features, but differ with respect to
genetic background, predisposing environmental factors and clinical
progression/remission [30,69,83,84]. ACPA recognize a variety of post-
translational modiﬁed proteins generated from the enzymatic reaction
catalyzed by PAD, such as ﬁlaggrin, ﬁbrinogen, vimentin, type II and
type I collagen, alpha enolase, heat-shock protein-90, and many others
(Table 1). Citrullination is the critical step for the recognition of the dif-
ferent proteins, highly expressed in the synovial membrane during in-
ﬂammation, by ACPA . Interestingly, PAD enzymes were found in
monocytes (PADI4) and macrophages (PADI2 and PADI4) in synovial
ﬂuid suggesting that citrullination may take place locally in the joint
and B cells secreting ACPA have been detected in synovial ﬂuid from
RA patients [2,86–88]. Another observation that strongly supports the
role of ACPA in RA pathogenesis comes from genetic studies such as
the associations, abovementioned, with the gene encoding PADI4 or
with HLA-DRB1 genes [25,69]. These autoantibodies show high speciﬁc-
ity (98%),sensitivity comparable with RF (68%) . There are different
assays for measuring ACPA, the widely used are based on cyclic
citrullinated peptides (CCP), both second-generation (CCP2) (patients
peptide libraries) or third-generation CCP (CCP3) (combinatorial pep-
tide libraries) [70,90,91]. There is no evidence so far that testing ACPA
ﬁne speciﬁcities may improve speciﬁcity and sensitivity of anti-CCP
assays, although they could be important for understanding disease
4.2. Additional autoantibodies
Other autoantibodies have been studied in RA and suggested as pos-
sible biomarkers, when considered alone or in combination, to improve
diagnosis, prognosis, and response to therapy .Mostofthemcanbe
recognized by ACPA being part of this subgroup of autoantibodies (refer
to Table 1). Anti-Ra33 antibodies(directed against an antigen of 33 kDa)
recognize both unmodiﬁed and citrullinated heterogeneous nuclear
protein (hnRNP) A2/B1, proteins present in spliceosome. They have
been described in approximately 36% of patients affected by RA and
they showed a high speciﬁcity (90–96%) and a low sensitivity (32%)
[94,95]. Anti-Ra33 antibodies have been associated with early arthritis
and also with a mild disease leaving a possible space as a prognostic
marker . In a recent study, Konig et al. identiﬁed three subgroups
of RA patients; the ﬁrst one who presented antibodies against
citrullinated Ra33 with long-lasting disease and erosive pattern, those
anti-native Ra33-positive, entirely in early phases and with minimal
erosions, and lastly, patients positive for both native and citrullinated
Ra33 that showed rapidly progressive disease . Anti-mutated
citrullinated vimentin (MCV) antibodies bind a mutated and
citrullinated vimentin expressed in synovial tissues. The mutations oc-
curring in vimentin (glycine to arginine) increase antigenicity and diag-
nostic value compared with anti-citrullinated vimentin antibodies, also
known as anti-Sa antibodies . In early RA, anti-MCV sensitivity and
speciﬁcity (64% and 97%) are higher than those of RF .Arecent
meta-analysis, which included a total of 12 studies and 2003 RA pa-
tients, demonstrated a higher sensitivity of anti-MCV (68.6%) than
anti-CCP (61.7%) in the diagnosis of RA, although anti-MCV speciﬁcity
(94.2%) remained lower than that of anti-CCP (97.1%) . High levels
of anti-MCV antibodies seem to predict a rapid erosive disease in early
RA and have been associated with active disease and worst outcomes
[101,102]. Anti-malondialdehyde (MDA) andanti-malondialdehyde ac-
etaldehyde (MAA) antibodies are the result of post-translational modi-
ﬁcations such as the lipid peroxidation . Antibodies against MDA
adducts, especially MDA-LDL, have been identiﬁed in RA patients and
associated with cardiovascular disease as myocardial infarction .
A recent study demonstrated the presence of both MAA adducts and
anti-MAA adducts in RA patients suggesting that these are more stable
than MDA adducts and more likely to be present in vivo .Further-
more, a positive correlation was observed between anti-MAA antibod-
ies and the presence of ACPA revealed by multiplex antigen array
. However, anti-MAA antibodies are not very speciﬁcandnotsuit-
able for diagnostic purpose since they have been detected also in pa-
tients affected by alcohol-induced hepatitis or cirrhosis and type 2
diabetes [105,106]. Antibodies anti-PAD4 have been identiﬁed in
22–45% of RA patients and they show a speciﬁcity that is lower than
50% [107–109]. A speciﬁc group of anti-PAD4 antibodies cross-reacts
with PAD3 and anti-PAD3 antibodies were detected in 12–18%of RA pa-
tients . Patients with the cross-reactive PAD3/PAD4 antibodies
seem to display an aggressive RA in terms of radiographic joint damage
and progression of the disease . BRAF, a serine–threonine kinase
involved in the MAPK pathway, has been identiﬁed in RA by a
proteomic approach aimed at the identiﬁcation of autoantigens .
Anti-BRAF antibodies have been detected in 21–32% of RA patients
[109,111]. However, anti-BRAF antibodies display a low speciﬁcity
since they were detected also in systemic lupus erythematosus (SLE)
and Sjogren's syndrome in almost similar percentages .
Anti-CII antibodies have been detected in about 30% of RA patients
and they show a low speciﬁcity since they were detected also in other
autoimmune diseases such as SLE, systemic sclerosis, and recurrent
polychondritis. Anti-CII antibodies recognize different epitopes in
human RA and murine models of arthritis, some of them shared
between the different species including citrullinated-CII, C1, and U1
epitope . High titers of anti-CII antibodies in RA synovial ﬂuid
and B cells producing anti-CII antibodies in RA synovia were reported
[114,115]. Moreover, it has been demonstrated that serum and synovial
titers of anti-CII IgG correlate with levels of acute phase proteins
and pro-inﬂammatory cytokines, as TNF-αand IL-6 . Immune-
Anti-citrullinated protein antibodies in sera of patients with rheumatoid arthritis.
Antigen Sensitivity (%) Speciﬁcity (%) Assay Correlation References
Keratine 36–59 88–99 ELISA Early disease 
Filaggrin 76 96 ELISA CCP-1 Unknown [2,3]
CCP-patients peptide libraries 75.4 94.4–99 ELISA CCP-2 Severity and erosive disease 
CCP-combinatorial peptide libraries 75–81.6 92–96.8 ELISA CCP-3 Early disease [5,6]
Fibrinogen/ﬁbrin 60.9–83 95–98.7 Immuno blotting Unknown [7,8]
Vimentin 47 98 Immuno blotting Severity and erosive disease [9–11]
MCV 64–82 97–98 ELISA Severity and rapid erosive disease [11–14]
Collagen type II 41 94 ELISA Early acute inﬂammation and early radiographic damage [15–17]
Collagen type I 32 99 ELISA Unknown 
alpha-enolase 37–62 98 ELISA Unknown 
BiP 95 Not known Immuno blotting Unknown 
HSP-90 29 96 ELISA Interstitial lung disease 
CCP: cyclic citrullinated peptides; MCV: mutated citrullinated vimentin; BiP: stress protein immunoglobulin heavy-chain binding protein; ELISA: enzyme-linked immunosorbent assay;
HSP-90: heat-shock protein-90.
676 P. Conigliaro et al. / Autoimmunity Reviews 15 (2016) 673–683
complexes containing anti-CII were detected in human RA sera and
could induce cytokine production such as TNF-α,IL-1β, CXCL8 via Fcγ
receptor IIa expressed on macrophages . Antibodies against the
stress protein immunoglobulin heavy-chain binding protein (BiP), in
the native and citrullinated forms, are found in 64–72% of RA patients
and display a speciﬁcity of 71% and a sensitivity of 73% [118,119].
They have been implicated in the pathogenesis of RA since BiP was
found to stimulate synovial T-cell and polymorphonuclearcell prolifer-
ation [120,121].Anti-CarP antibodies have been extensively described
in RA patients. These antibodies are a family different from ACPA that
were identiﬁed for the ﬁrst time in 35–45% of RA patients, mostly in
ACPA-positive patients (49–74%), but also in ACPA-negative patients
(16–30%) [122,123]. Inhibition studies conﬁrmed that these antibodies
overlapped only partially with the occurrence of ACPA . In a recent
study anti-CarP antibodies demonstrated in early arthritis a sensitivity
of 44% and a speciﬁcity of 89%, both lower than those of anti-CCP and
RF . Therefore, anti-CarP antibodies could be useful for early diagno-
sis especially in ACPA-negative patients and for identifyingpatients that
require an aggressive treatment [76,124]. How anti-CarP antibodies
would contribute to arthritis is unknown but may involve immune
complex formation between anti-CarP antibodies and carbamylated
proteins in the joint.
4.3. Autoantibodies are associated with disease outcome
Autoantibodies have been largely investigated in order to establish
serological markers able to early conﬁrm clinical diagnosis of RA and
to predict disease evolution .
High RF serum levels have been associated with an aggressive
articular disease, extra-articular manifestations, and a worse outcome
[125,126]. Likewise, ACPA have been associated with disease severity,
radiological progression of the disease, disability, and increased mortal-
ity in RA [83,127–131]. The combination of ACPA and RF positivity cor-
relates with a more severe and erosive disease and they associate with a
worse disease outcome when compared with seronegative RA .
RF seems to enhance the pathological effects of ACPA through preferen-
tial binding to ACPA and potentiation of the subsequent immune re-
sponse. Moreover, the course of ACPA-positive disease seems to be
characterized by more persistent inﬂammation than its ACPA-negative
counterpart . Similar results were obtained in patients with undif-
ferentiated arthritis where the presence of ACPA seems to predict more
joint damage, progression to RA, and severe disease resulting in poor
prognosis compared to ACPA-negative patients [64,83,134–136].
However, despite the fact that almost 40% of RA patients are ACPA neg-
ative, aggressive disease and severe radiologic progression can be pres-
ent. For these reasons, new biomarkers are needed for early diagnosis
and prognosis [58,91]. The presence of anti-CarP antibodies in ACPA-
negative RApatients has been associated with increased disease activity
and severe joint damage . Comparable to ACPA, anti-CarP antibod-
ies are independently associated with increased joint damage at the
baseline of RA diagnosis . Recently, anti-CarP antibodies have been
associated in a large cohort of patients with inﬂammatory arthritides
(n = 1995) with increased disability and higher disease activity .
Therefore, anti-CarP antibodies may be a useful biomarker to identify
ACPA-negative patients who might evolve in RA and newly diagnosed
RA patients who would require prompt and aggressive treatment .
Nonetheless, their signiﬁcance in RA is still under investigation. For in-
stance, Alessandri et al. found that anti-CarP can be detected in up to
9.2% of healthy ﬁrst-degree relatives of patients withRA, a similar prev-
alence than anti-CCP and RF. Besides, it is not known whether thesesub-
jects will develop RA, it should be underlined that these autoantibodies
did not correlate with anti-CCP neither with RF . Anti-MCV anti-
bodies have been demonstrated to perform better than ACPA as predic-
tor of radiographic damage; conversely, its additional diagnostic and
prognostic role in comparison to ACPA in both early and established
RA is controversial . Some authors found that anti-MCV might
identify a subset of RA patients with aggressive early erosive disease
. Recently published ESPOIR cohort study compared the ability of
ACPA, against anti-MCV antibodies and citrullinated ﬁbrinogen to pre-
dict 1-year rapid radiographic progression in early RA, and suggested
that anti-MCV antibodies can be more discriminant to predict radio-
graphic progression risk . Anti-CII antibodies seem to characterize
an early inﬂammatory/destructive phenotype, in contrast to the late ap-
pearance of an inﬂammatory/destructive phenotype in ACPA-positive
RA patients . Anti-CII antibodies have been associated with in-
creased radiographic damage at the time of diagnosis in a prospective
cohort of early RA patients .
Autoantibody presence also seems to correlate with extra-articular
clinicalmanifestations, such as the heart involvement. Itis well reported
that RA is an independent risk factor for cardiovascular events, which
cause up to 40% of deaths in these patients [142,143]. Lopez-Longo
et al. investigated the association between ACPA and ischemic heart dis-
ease in RA patients, and they found that ACPA presence is independent-
ly associated with the development of ischemic heart disease that is
irrespective of the titers of autoantibodies . The presence of auto-
antibodies characterize RA phenotype not only in terms of outcome
but also in terms of clinical intervention . Stratifying patients
with undifferentiated arthritis or RA on ACPA presence led to the iden-
tiﬁcation of more homogenous patient groups in terms of both disease
course and response to treatment. Evidence from the literature
suggested that low/intermediate pretreatment levels of ACPA were
associated with a more favorable response to methotrexate treatment
in recent-onset ACPA-positive arthritis, whereas high levels were asso-
ciated with an insufﬁcient response . Likewise, in another study,
methotrexate postponed RA diagnosis and retarded radiographic joint
damage in ACPA-positive patients compared with undifferentiated
ACPA-negative patients . The BeSt study described that RA ACPA-
positive patients treated only with DMARDS undergo greater joint
destruction, while no difference in radiographic progression in RA
ACPA-positive and RA ACPA-negative patients with combination
therapy occurred . More recently, 2-year results from the AMPLE
trial investigated the impact of baseline ACPA concentration on
efﬁcacy outcomes following treatment with subcutaneous abatacept
or adalimumab. In both treatment groups, ACPA-negative patients
responded worse than antibody-positive patients. Patients with the
highest baseline ACPA concentrations had a better clinical response to
abatacept than patients with lower concentrations had. Such observa-
tion was not found in the adalimumab treated group . Moreover,
Gardette et al. investigated whether serum anti-CCPantibody could pre-
dict a good response to rituximab (RTX) in RA patients . In this
study, 114 RA patients were evaluated fora primary end point(decrease
in DAS28 N1.2 at 6 months) and secondary efﬁcacy criteria including a
good response and remission according to EULAR criteria. In accordance
with this study, high anti-CCP antibody levels were associated with
good response together with trend for remission .
5. Autoantibodies in psoriatic arthritis
Psoriatic arthritis (PsA) is a chronic inﬂammatory arthropathy sero-
negative for RF, and associated with psoriasis . PsA is classiﬁed
among the SpA group because it shares with SpA several clinical
manifestations as peripheral and axial joints involvement (arthritis,
spondylitis, and sacro-ileitis), skin and nail diseases, dactylitis and
enthesitis . The overall prevalence of PsA has been reported to
range from 0.01% (95% CI 0.00–0.17) in the Middle East to 0.19%
(95% CI 0/16–0.32) in Europe . Peripheral joint involvement is a
potentially debilitating feature of PsA: it is commonly symmetrical
and polyarticular that often affects distal interphalangeal joints
distinguishing PsA from RA . Characteristic extra-articular
manifestations of PsA include psoriasis, nail psoriasis, uveitis, and in-
ﬂammatory bowel disease (IBD), that may be frequently unrecognized
or undertreated . The extra-articular concomitant diseases, also
677P. Conigliaro et al. / Autoimmunity Reviews 15 (2016) 673–683
called comorbidities, such as obesity, dyslipidemia, type II diabetes, liver
disease, and cardiovascular disease, are reported to be increased in pa-
tients with PsA, and their role in the progression and clinical response
to treatment remains under investigations [154–157]. The Group for
Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)
developed and recently updated the treatment recommendations for
the key manifestations of PsA, including related comorbidities .
The development of the Classiﬁcation Criteria for Psoriatic Arthritis
(CASPAR) facilitates clinicians in the classiﬁcation of PsA .Among
the several classiﬁcation criteria that have been published, CASPAR
criteria result to be simple and easy to use and show high sensitivity
by introducing the family history of psoriasis . Medical history,
physical examination, blood tests, and imaging (radiography, ultra-
sound, and magnetic resonance) of the joints are used for diagnostic
purposes . The diagnosis of PsA is thus mainly clinical and diagnos-
tic biomarkers are not yet available. Enthesitis seems to be the primum
movens of the disease, as well as the prominent clinical feature at
presentation in up to 38% of PsA patients . Monocyte-derived
cytokines, as myeloid-related protein (S100A8/A9), seem to play a
role in the propagation and perpetuation of the inﬂammatory process
in patients with psoriasis and PsA, because of an activated monocyte/
macrophage systeminvolved in the “enthesal-complex”. Evidence
from the literature suggests that autoimmune processes may drive
features of PsA . Autoimmunity, in PsA pathogenesis, has been sug-
gested by the presence of lymphoid aggregates in synovial tissues .
Histologically, PsA is characterized by lining layer hyperplasia, B and T
lymphocytes' inﬁltrates, innate immune cells' activation, and joint vas-
cular remodeling and angiogenesis . We previously reported an
abnormal distribution of peripheral blood B cell in both RA and PsA pa-
tients suggestinga role of B cells in PsA pathogenesis . An autoim-
mune model describing potential autoantigens in the skin and joints of
PsA patients has not been identiﬁed so far . PsA is distinguished
from RA by infrequent positivity for RF and ACPA, together with other
distinctive clinical features [167,168]. Few studies looked for ACPA in
PsA patients and found far lower prevalence compared to patients
with RA (Table 2). However, authors described that presence of ACPA
was signiﬁcantly correlated with polyarticularinvolvement (often sym-
metric), presence of erosions, and presence of the shared epitope .
Prevalence and prognostic value of ACPA in PsA remain debated
[170–175]. Detection of antinuclear antibodies (ANA) was recently re-
ported as more frequent in sera from PsA patients than in those from
controls suggesting that ANA could be a diagnosis orientation tool in au-
toimmune arthropathies .TNF-αantagonists commonly used for
treatment of moderate-to-severe psoriasis and PsA have been associat-
ed with induction of autoantibodie s in PsA patients [177–179].Recently,
it has been described that routine autoantibodies monitoring in RA and
PsA patients do not represent useful tool to predict the development of
anti-adalimumab antibodies . Indeed anti-adalimumab antibodies
have been proposed as an early marker associated to a poor clinical re-
sponse to the treatment .Speciﬁc anti-PsA peptide antibodies
were described in PsA patients and only in a small proportion of patients
with psoriasis without PsA, suggesting that they could be speciﬁc
for PsA . Anti-PsA peptide antibodies target peptide epitopes
expressed in skin proteins (ﬁbrillin, desmocollin, and keratin) and in
N-RAP, highly expressed within the entheses .Moreover,theseau-
toantibodies bind the Toll-like receptors (TLR)2that play critical roles in
the activation of innate immunity contributing to autoimmunity .
More recently, authors reported a gene array analysis of paired synovial
membranes and peripheral blood cells in patients with PsA. They iden-
tiﬁed the modulation of cluster of genes encoding for molecules in-
volved in cell migration and tissue invasion, in neoangiogenesis, in the
process of bone formation, and in a T cell immune response with prev-
alent up-regulation of several Th17-related genes . Anti-CarP anti-
bodies were reported in sera from PsA patients with active disease in
the absence of RF and/or ACPA speciﬁcities . In accordance with
such evidence, the measurement of anti-CarP antibodies shows a good
Prevalence of several autoantibodies in the sera of patients with Psoriatic Arthritis.
Authors PsA patients (N) Controls (N) Autoantibodies tested Autoantibodies positivity in PsA
Silvy et al., 2015 232 HC (91) ANA⁎
Chimenti et al., 2015 30 HC (40) Anti-CarP
ANA 3.4% §
No patients with anti-CCP
Dalmády et al., 2013 46 PsO (42)
Anti-MCV Anti-MCV levels
Signiﬁcantly higher in PsA than those in PsO
Pasquetti et al., 2009 218 None Anti-CCP
No patients with RF
Inanc et al., 2007 56 RA (79)
Ouédraogo et al., 2007 102 None Anti-CCP
Alenius et al., 2006 160 PsO (146)
Vander Cruyssen et al., 2005 192 None Anti-CCP
Korendowych et al., 2005 126 RA (40)
Bogliolo et al., 2005 102 None Anti-CCP
Riente et al., 2004 75 AS (43)
Bovine tTg (IgA)
Human tTg (IgA, IgG)
ASCA (IgA, IgG)
No differences between the groups
Hoffmann et al., 2003 45 RA (56)
ASCA (IgA, IgG) No differences between the groups
PsA: psoriatic arthritis; RA:rheumatoid arthritis; HC:healthy controls;PsO: psoriasis;AS: ankylosingspondylitis; ANA:antinuclearantibodies; RF: rheumatoidfactor; anti-CCP:antibodies
to cyclic citrullinated peptides; MCV: mutated citrullinated vimentin; tTg: anti-tissuetransglutaminase antibodies; ASCA: anti-Saccharomyces cerevisiae antibodies.
⁎Detected by indirect immunoﬂuorescence (IFI) on HEp-2 cells.
⁎⁎ At serum dilution 1:160.
678 P. Conigliaro et al. / Autoimmunity Reviews 15 (2016) 673–683
accuracy as diagnostic test to discriminate PsA patients from healthy
controls . In PsA patients with the highest anti-CarP levels, correla-
tions between anti-CarP autoantibodies and the disease activity were
also described . Carbamylation may thus be relevant in inducing
autoimmunity in PsA, and given its systemic effects, it may represent a
trigger for metabolic pathways such as anaerobic cysteine metabolism
and oxidative stress in PsA . Authors investigated the prevalence
of anti-MCV in PsA patients and reported that anti-MCV levels were sig-
niﬁcantly higher in PsA patients than those in patients with psoriasis
. Moreover, the presence of tender knee jointsand nail psoriasisre-
sulted signiﬁcantly associated with anti-MCV positivity in the PsA group
. As above speciﬁed, PsA is classiﬁed among the SpA group and,
given that seronegative SpA, especially ankylosing spondylitis (AS), is
shown to be associated with IBD, severalstudies were performed to in-
vestigate whether anti-Saccharomyces cerevisiae antibodies (ASCA), a
marker for Crohn's disease (CD), were present in SpA and in the sub-
groups PsA, AS, undifferentiated SpA (uSpA) [185–187]. Recent evi-
dence described an elevated serum antibody proﬁle with respect to
anti-ﬂagellin antibodies (anti-CBir1) in AS patients without bowel
symptoms suggesting that anti-CBir1 may be an indicator of subclinical
bowel inﬂammation or predictor of future IBD in AS patients .An
earlier study reported ASCA IgA levels to be signiﬁcantly higher in
SpA, and more speciﬁcally in AS, than in healthy controls and patients
with RA representing one of the ﬁrst serum marker associated with
SpA and also a potential marker of radiological damage and a more se-
vere AS . Other authors analyzed ASCA and IgA antibodies to bo-
vine tissue tranglutaminase (tTg) and failed to show an increased
prevalence of these antibodies in patients with AS and PsA .More-
over, authors described a signiﬁcantly elevated prevalence of IgA anti-
bodies to human tTg in AS patients with low 25-vitamin D3 levels
suggesting that a positive human tTg status entails the risk of a bad vi-
tamin D supply . More recently, anti-Helicobacter pylori antibodies
were detected in patients with axial SpA more frequently than in pa-
tients with CD while ASCA resulted to be more abundant in CD than in
SpA . Nowadays no speciﬁc markers detectable in the sera of PsA
patients have been described that can improve the diagnosis and the
clinical and therapeutic management of these patients. Moreover, bio-
markers able to distinguish between PsA and other inﬂammatory ar-
thropathies and/or psoriasis and that could be used as prognostic
markers are still lacking.
Increasing evidence suggests that autoantibodies are associated with
inﬂammatory arthritides including RA and “seronegative”SpA. The
well-characterized autoantibodies in RA are RF and ACPA, while other
novel antibodies targeting mutated proteins, such as anti-CarP, are ex-
tensively under investigation. Autoantibodies appear to improve the
early diagnosis in both symptomatic and preclinical patients and may
represent a tool to evaluate/predict the response to the therapy. While
correlations between autoantibodies and disease course are supported
by studies in humans and animal models, their pathogenicity in inﬂam-
matory arthritides needs further studies.
•In susceptible individuals, under the inﬂuence of environmental
factors, autoantibodies may be produced in the joints or outside in
the mucosal sites such as lung and gingiva.
•The most relevant autoantibodies in rheumatoid arthritis (RA) appear
to be anti-citrullinated peptide antibodies (ACPA) that recognize a
variety of post-translational modiﬁed proteins, such as ﬁlaggrin,
ﬁbrinogen, vimentin, type II collagen, alpha enolase, and others.
•Several autoantibodies have been investigated and proposed as
potential biomarkers to improve diagnosis and outcome in RA
•Carbamylation seems to take place during inﬂammation when neu-
trophils release myeloperoxidase. The presence of anti-CarP antibod-
ies in ACPA-negative RA patients was associated with increased
disease activity and with more severe joint damage.
•Anti-CarP antibodies have been described in sera of psoriatic arthritis
(PsA) patients representing the ﬁrst evidence of autoantibodies in
PsA. Correlations between anti-CarP levels and disease activity were
also reported in PsA.
The authors declare they have no competing interests.
This paper is dedicated to the memory of our dear Professor Sergio
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