Rheumatoid Arthritis Pathogenesis

Immunity
Review
Immunopathogenesis of Rheumatoid Arthritis

Gary S. Firestein1,* and Iain B. McInnes2,*
1University of California San Diego, La Jolla, CA 92093, USA
2Instituteof Infection Immunity and Inflammation, University of Glasgow, Glasgow G128QQ, UK
*Correspondence: [email protected] (G.S.F.), [email protected] (I.B.M.)
http://dx.doi.org/10.1016/j.immuni.2017.02.006
Rheumatoid arthritis (RA) is the most common inflammatory arthropathy. The majority of evidence, derived
from genetics, tissue analyses, models, and clinical studies, points to an immune-mediated etiology associ-
ated with stromal tissue dysregulation that together propogate chronic inflammation and articular destruc-
tion. A pre-RA phase lasting months to years may be characterized by the presence of circulating autoanti-
bodies, increasing concentration and range of inflammatory cytokines and chemokines, and altered
metabolism. Clinical disease onset comprises synovitis and systemic comorbidities affecting the vascula-
ture, metabolism, and bone. Targeted immune therapeutics and aggressive treatment strategies have sub-
stantially improved clinical outcomes and informed pathogenetic understanding, but no cure as yet exists.
Herein we review recent data that support intriguing models of disease pathogenesis. They allude to the
possibility of restoration of immunologic homeostasis and thus a state of tolerance associated with drug-
free remission. This target represents a bold vision for the future of RA therapeutics.
Immune dysregulation was first implicated in the pathogenesis Genetics of Rheumatoid Arthritis
of rheumatoid arthritis (RA) by the discovery of anti-immuno- Genetic factors clearly play a role in RA risk, severity, and pro-
globulin G (IgG) antibodies known as rheumatoid factors, gression. Monozygotic twins share RA on about 12%–15% of
initially by Erik Waaler and then more fully described by H.M. occasions compared to 1% for the general population and
Rose in the 1940s. However, concepts of how immune re- around 2%–5% for fraternal twins or other first-degree relatives.
sponses contribute to disease have evolved dramatically over This relatively low concordance implicates many other factors,
the last 50 years. Autoreactivity as a pivotal step dominates including those in the environment and the microbiome in
the conceptual landscape, although other mechanisms, both pathogenesis. Note also that gene sequences are not the
immunologic and tissue-derived, clearly contribute to disease sole determinant of heritability, and epigenetic marks probably
pathogenesis. Thus, RA is characterized by evidence of disor- also contribute, especially for monozygotic twins (Kaminsky
dered innate immunity, including immune complex-mediated et al., 2009).
complement activation, adaptive immune responses against The most important genetic risk allele for RA resides in the
‘‘self’’-antigens comprising predominantly post-translationally class II major histocompatibility (MHC) locus, accounting for
modified proteins, dysregulated cytokine networks, osteoclast about 40% of the genetic influence. The odds ratio of developing
and chondrocyte activation, and imprinting of resident stromal RA in individuals with MHC class II HLA-DR4 alleles is about 5:1.
cells that in turn develop semi-autonomous features that sup- This link between HLA-DR and RA was initially described in the
port disease progression (Arend and Firestein, 2012; Firestein, 1970s with the observation that HLA-DR4 is present in 70% of
2003). RA patients, compared with about 30% of controls. A so-called
Based on substantial new data identifying the immunologic shared ‘‘susceptibility epitope’’ (SE) was identified in amino
and metabolic events that precede onset of clinical disease, acids 70 through 74 in the third hypervariable region of the
even by years (i.e., ‘‘pre-RA’’), and the increasing impact of the DRb chain. The sequence associated with disease is generally
application of the advanced molecular ‘‘omics’’ revolution to dis- glutamine-leucine-arginine-alanine-alanine (QKRAA), which is
ease investigation, an integrated hypothesis for disease pathol- present in some DR4 and DR14, in addition to DR1b chains.
ogy is emerging (Catrina et al., 2016; Tan and Smolen, 2016). In The SE with the closest links to RA include DRB*0401,
this review, we will posit that RA starts with a high-risk genetic DRB*0404, DRB*0101, and DRB*1402. More than 90% of pa-
background that, in combination with epigenomic marks that tients with RA express at least one of these variants (Weyand
contribute to heritability and disease chronicity and stochastic et al., 1992). The SE is also associated with increased disease
environmental exposures that create neo-epitopes, launches a severity, such as extra-articular manifestations and progression
cascade of events inducing synovitis and ultimately chronic of erosions.
destructive arthritis (Figure 1). Based on the diversity of clinical The SE region predominantly faces away from the antigen-
responses to highly targeted therapeutic agents, we propose binding groove that binds processed peptides for presentation
that RA probably does not comprise a single entity. Rather, it to T cells, which has raised some questions about their precise
is perhaps more appropriately considered a syndrome with a contributory role (Firestein and Zvaifler, 2002). RA-specific pep-
common clinical phenotype arising from diverse pathways oper- tides that bind to QKRAA-containing molecules have been diffi-
ating variably, albeit often with overlap, in individual patients cult to identify (Kirschmann et al., 1995). This observation led to
(Firestein, 2014). the notion that SE might also partially contribute by shaping the
Immunity 46, February 21, 2017 ª 2017 Elsevier Inc. 183

Immunity
Review
Figure 1. Sequence of Events Leading to
the Development of Clinically Detectable
Rheumatoid Arthritis: Two Potential
Models
In model A (left), a pre-RA phase comprises early
generation of autoantibodies (ACPAs) that can
bind post-translationally modified self-proteins,
particularly via citrullination. This is followed by
amplification of the range of specificities of ACPA
and by the elaboration of cytokines and chemo-
kines, complement, and metabolic disturbance in
the months prior to clinical development of dis-
ease. A transition event that requires a ‘‘second
hit’’ (as yet poorly understood) permits the
development of synovitis. The latter is character-
ized by frank inflammation, stromal compartment
changes, and tissue modification leading to
articular damage. In model B (right), which is not
mutually exclusive, there is an early interaction
between innate immune activation and stromal
factors that lead to stromal cell alteration,
including epigenetic modifications that initiate a
cycle of inflammatory stromal-mediated damage.
Autoimmunity can arise as a result of these in-
teractions that in turn can contribute directly or in
an amplification loop to disease perpetuation.
citrullinated peptides are also character-

ized by the presence of ‘‘anti-citrullinated
peptide antibodies’’ (ACPAs), observed
in 80%–90% of RA patients.
Together these data support the notion
that HLA-DR risk for RA is based at least
in part on the increased efficiency of an-
tigen presentation for altered peptides
rather than native proteins (van der
Helm-van Mil et al., 2006). Citrullination
of peptides in the presence of environ-
mental stress is ubiquitous in mammalian
cells and is not a unique feature of
RA. Instead, production of antibodies
recognizing citrullinated peptides differ-
entiates individuals at risk. The emer-
gence of numerous other post-transla-
T cell repertoire in the thymus, altering intracellular HLA-DR traf- tionally modified protein targets, e.g., via carbamylation or
ficking and antigen loading, or serving as an autoantigen. acetylation, recognized by autoantibodies in RA is consistent
More recently, linkage disequilibrium and informatics-based with the notion of altered presentation of post-translationally
studies to understand the role of the SE identified additional modified peptides; other families of altered peptides could be
amino acids located in the base of the antigen binding groove implicated in discrete subsets of patients.
as a likely explanation for antigen selection, especially leucine Overall, genome-wide association studies (GWASs) and
or valine variants at amino acid 11 (Raychaudhuri et al., 2012). meta-genomic analyses have identified more than 100 single-
Serine at amino acid 11 confers decreased risk for RA. The risk nucleotide polymorphisms (SNPs) and genes associated with
alleles, especially deep within the cleft, could directly increase ACPA+ RA beyond the HLA. RA-associated SNPs tend to cluster
risk via presentation of arthritogenic antigens, such as citrulli- around immune genes (Okada et al., 2014). The genetic archi-
nated proteins. For example, citrullinated vimentin peptides tecture of RA has recently been extensively reviewed (Kim
bind much more avidly to the RA HLA-DR than does native et al., 2017). In brief, individual SNPs usually provide modest
protein; in contrast, other MHCs do not exhibit this differential contribution to risk with odds ratios typically in the 1.05- to
binding (Hill et al., 2003; Law et al., 2012). Subsequent crystal 1.2-fold range, though this need not infer low functional impact.
studies have characterized in detail the nature of the citrullinated Combinations of these genes can potentially interact to increase
peptide binding to HLADRB1 (Scally et al., 2013). RA-associated risk. For example, a relatively rare combination of HLA-DR,
alleles present citrullinated peptides efficiently to T cells, PTPN22, and TRAF1-C5 SNPs increases risk more than
which, in turn, produce higher amounts of cytokines IL-17 and 40-fold. While there are undoubtedly additional combinations
IFN-g than to native peptide. Adaptive immune responses to or rare variants with high penetrance, the contribution of newly
184 Immunity 46, February 21, 2017

Immunity
Review
identified genes to overall risk is growing increasingly small. mechanisms that enhance risk are not fully understood for each,
Notably, meta-analyses of patients with ACPA RA show it is likely that local tissue stress leads to post-translational modi-
some differences from ACPA+ disease, consistent with the fication of peptides with subsequent antibody formation serving
idea that ‘‘seronegative RA’’ should be considered a distinct as a common mechanism.
clinical pathologic entity. Epidemiologic/genetic studies, particularly those arising from
Intriguing individual non-MHC linkages are associated with impressive Swedish registries, have highlighted the role of ciga-
peptidyl arginase deiminase (PADI) and PTPN22. PADI gene rette smoking as a prominent environmental risk factor for RA,
products are enzymes that convert arginine to citrulline, creating pointing to a role for pulmonary mucosal biology in disease etiol-
new potential antigens that bind to RA-associated MHC pro- ogy. The amount and duration of smoking are important, with the
teins. An extended PADI4 haplotype prolongs its mRNA stability highest risk observed with greater than 20 pack-years of expo-
and could, therefore, increase peptide citrullination (Suzuki et al., sure. Risk declines slowly back to normal within 10 years of
2003). Up to a 2-fold increase in risk of RA was observed with smoking cessation (Ka €llberg et al., 2011), suggesting that effects
PADI4 SNPs in Asian and North American cohorts. The are not solely toxin dependent but may also arise by altering
PTPN22 allele with an amino acid substitution (R620W) doubles immunologic function. Notably, other pulmonary exposures
the risk of developing ACPA+ but not ACPA RA. This SNP is can replace smoking in increasing risk, e.g., silica or textile
also associated with many other immune-mediated diseases, dust. Nevertheless, mechanisms underlying the relationship
including systemic lupus erythematosus (SLE) and type 1 dia- with smoking are uncertain (Catrina et al., 2014). Exposure to
betes (Rawlings et al., 2015). The R620W allele is a gain-of-func- inhaled toxic chemicals in cigarette smoke can potentially in-
tion change mutation in the PTPN22 protein, a phosphatase that crease PADI expression in the airway and increase protein citrul-
regulates (among other signal proteins) Lck and ZAP70. Thus, lination (Vassallo et al., 2014). Smoking-related risk interacts in a
modified T cell receptor signaling could alter either the T cell synergistic manner with MHC risk alleles. The QKRAA-contain-
repertoire in the thymus or immune responses, or tolerance in ing HLA chains alone modestly increase the likelihood of devel-
the periphery. The R620W allele, however, also positively regu- oping RA 4- to 6-fold, but this risk increases up to 20- to 40-fold
lates TLR-induced type 1 IFN expression in myeloid cells via when combined with smoking (Lundström et al., 2009).
reduced efficiency of PTPN22W-mediated TRAF3 ubiquitination Thus in individuals carrying risk HLA alleles, such peptides
and thus could amplify innate cytokine expression to promote could be more efficiently presented and ACPAs generated via
disease (Wang et al., 2013). subsequent T-B cell help. Alternatively, ‘‘innate’’ B cell subsets
A number of genes involved with adaptive immunity have could initiate responses to modified self-peptides, and thereafter
RA-associated SNPs in a various populations (Yamamoto present peptide to T cells. In this model, production of ‘‘autoan-
et al., 2015). In addition to PTPN22, the co-stimulation receptors tibodies’’ could result from ‘‘auto-reactive’’ T cell clones that are
CTLA and CD28 have emerged from GWASs. Other genes asso- available to respond to modified peptides because they were not
ciated with B cell function and/or antigen presentation such as deleted during development since the altered proteins/peptides
BTLA (B and T lymphocyte attenuator), Fc receptors, and were not present in the thymus (Linn-Rasker et al., 2006). A cor-
CD40 have been identified. Signal transduction genes and path- ollary to this would be that a major immunologic regulatory deficit
ways that regulate immune function such as TRAF1-C5 and in RA patients is a failure to regulate T cell recognition of post-
STAT4, cell migration (ELMO1), and fetal development (LBH) translationally modified self-proteins across a range of specific-
are also identified. Finally, multiple gene polymorphisms have ities—as observed above, this is compatible with the expression
been identified in cytokine or cytokine receptor coding loci, of a relatively broad autoantibody spectrum in clinical disease.
including TNF. This is especially relevant in light of the pivotal Broncho-alveolar immunohistology shows high levels of citrul-
role of cytokines in synovitis described below and the conse- linated proteins in pulmonary macrophages and smoking in-
quent efficacy of targeted anti-cytokine, and cytokine receptor creases such citrullinated proteins in broncho-alveolar lavage
signal pathway therapeutics. In some cases, the causative muta- fluid (Makrygiannakis et al., 2008). However, citrullinated pro-
tions can alter expression or function. For instance, RA-associ- teins can also be present in the context of other diseases or
ated TNF promoter polymorphisms at positions 238 and even in clinically normal lungs (Catrina et al., 2014). Thus, risk
308 can potentially modulate TNF gene expression (Fonseca from smoking might be more complex than via PADI induction
et al., 2007). An IL-6 receptor polymorphism that is functionally and may include promotion of epigenetic alterations, notably
implicated in the intensity of IL-6 signaling is also associated DNA methylation with inflammatory potential (Tsaprouni et al.,
with RA (Ferreira et al., 2013). Thus, the genetic clues to RA path- 2014). Perhaps the location of citrullination and the stochastic
ogenesis implicate inflammation and adaptive and innate immu- combination of altered peptides, innate leukocyte subsets, and
nity at the core of pathogenesis. mucosal inflammation conspire a permissive microenvironment
for the creation of ACPAs. High-resolution CT studies demon-
Interactions between Genes and Environment: RA as a strate associations between ACPA formation and bronchial
‘‘Mucosal Disease’’? thickening in the pre-RA stages and support the idea that inflam-
RA is properly considered an immune-mediated disease with a matory responses are required (Reynisdottir et al., 2014). More
strong genetic influence. However, its origins may involve the recent studies have shown signs of local inflammation in bron-
interface between external influences and the immune system, chial tissues of untreated RA patients (Reynisdottir et al.,
manifest especially at mucosal surfaces. Three sites have been 2016). Using B cell barcoding techniques, the frequency of circu-
associated particularly with RA, namely (1) the lungs, (2) the lating IgA plasmablasts was found to be elevated in at-risk sub-
oral mucosa, and (3) the gastrointestinal tract. Whereas precise jects without RA who are ACPA positive, providing further
Immunity 46, February 21, 2017 185

Immunity
Review
evidence for a mucosal origin for at least a proportion of the auto- marks have been identified in RA that alter cell function and
immunity detected in RA (Kinslow et al., 2016). permanently imprint some lineages, most notably synovial fibro-
The relationship between the microbiome and RA has been blast-like synoviocytes (FLS).
suspected for many years and supported by pre-clinical studies. Most information on epigenetics in RA comes from studies of
For example, arthritis susceptibility and severity in a variety of RA joint samples, including synovial tissue and FLS. Candidate
rodent strains is decreased when maintained germ-free or in gene approaches showed that the IL6, CXCL12, and EFNB1 pro-
environments with a restricted bacterial flora (Liu et al., 2016). moters are hypomethylated in rheumatoid FLS while others, like
These data suggest that bacteria provide complex adjuvant DR3, EBF2, and IRX1, are hypermethylated (Karouzakis et al.,
functions that enhance autoimmunity, either directly (e.g., bacte- 2011). Genome-wide approaches have identified a large number
rial cell walls or lipopolysaccharides) or by critically altering the of differentially methylated loci in RA FLS compared with normal
immunoregulatory mucosal environment. The latter could sup- or osteoarthritis (OA) FLS (Nakano et al., 2013a). The methylation
port particularly the generation of type 17 responses implicated pattern in RA FLS is stable over many cell passages in tissue
in several animal models of RA (Miossec and Kolls, 2012). culture and involves genes and pathways related to cell adhe-
In humans, inflammation of the oral mucosa, particularly sion, matrix regulation, immune function, and cytokine signaling.
periodontitis, is associated with increased susceptibility to RA. While synovial cytokines can transiently alter the methylome
The most common bacteria implicated in periodontitis is by regulating DNA methyl transferase (DNMT) expression, the
P. gingivalis, since it can express PADI. P. gingivalis could poten- changes are reversible in culture and suggest that cytokines
tially citrullinate peptides in the oral mucosa that, in the context alone are not solely responsible for the ex vivo profile observed
of inflammation, could promote ACPA generation (Wegner (Nakano et al., 2013b). The cells, therefore, appear to be ‘‘im-
et al., 2010). While this concept is attractive, a clear association printed,’’ which could contribute particularly to the persistent
between P. gingivalis compared other bacteria is not consis- aggressive phenotype of RA FLS.
tently observed in unbiased microbiome studies. More recent The functional relevance of differential methylation was
data suggest that P. gingivalis or other bacteria could act, confirmed for several candidate genes identified via integrative
instead, by ligating Toll-like receptor 2 (TLR2) (de Aquino et al., analysis of various ‘‘omics’’ platforms. For example, the develop-
2014). This process could increase IL-1 production and stimulate ment gene LBH was identified because it has several RA-asso-
local Th17 cell differentiation. An intriguing recent study identi- ciated SNPs and differentially methylated loci (DMLs) (Ham-
fied that A. actinomycetemcomitans initiates hypercitrullination maker et al., 2016). LBH regulates the cell cycle—a functional
through the effect of a toxin, leukotoxin A (LtxA), mediated on SNP in an LBH enhancer was identified adjacent to a DML in
neutrophils and was detected in RA patients’ oral microbiome FLS, and modification of the enhancer methylation status
wherein it could act as a bacterial trigger to disease (Konig altered LBH transcription (Ekwall et al., 2015). In addition, a
et al., 2016a). DML in PTPN11, the gene encoding the oncogene SHP2, led
In the colon, Prevotella copri species were enriched in an un- to discovery of a novel intron enhancer that regulates PTPN11
biased analysis of the gastrointestinal microbiome in early RA expression and contributes to high levels of SHP2 in RA FLS
patients. Bacteroides species were decreased in the same pa- (Zhang et al., 2015). In future, incorporating epigenetic marks
tients (Scher et al., 2013). While not fully understood, the over- into the systematic analysis of cell function should help identify
representation of Prevotella was not observed in chronic RA or key pathogenic genes and provides a rich source of potential
in other forms of arthritis. Subsequent studies in the Chinese therapeutic targets.
population have extended these observations to include novel We still do not know when in the evolution of RA the epigenetic
microbial species and demonstrated common expression in imprinting occurs. Recent data in FLS from patients with early RA
oral and GI mucosal sites in individuals that, remarkably, was (<1 year of symptoms) show that they also have an abnormal
correlated with ACPA levels and CRP. Moreover, further alter- methylation pattern. However, the early RA methylome can be
ations in the microbiome occurred upon therapeutic immune distinguished from late RA, especially for pathways related to
modification (Zhang et al., 2015). cell growth and differentiation (Ai et al., 2015). DNA methylation
signatures in RA FLS probably occur very early or even antedate
Epigenetics: Integrating Environmental Stress and the clinical disease. However, it is not static and can evolve over time
Genome due to synovial inflammatory environment.
Epigenetic modifications decorate genomic DNA and contribute Perhaps even more intriguing, DNA methylation patterns, as
to regulation of gene expression. The role of these marks had well as transcriptomes, can vary between joints (Ai et al.,
been widely viewed as key determinants of orderly gene expres- 2016). Early studies using histology and immunohistochemistry
sion during development as well as lineage-dependent RNA suggested that the various joints involved with RA are similar.
transcription throughout life. Their contribution to pathogenesis However, recent studies show that the DNA methylation
is now more clearly understood in many diseases, especially patterns and transcriptomes differ between RA hip and
cancer. A variety of epigenetic mechanisms have been impli- knee FLS (Ai et al., 2016). Of interest, the pathways involved
cated in RA, including DNA methylation, histone modification, are related to therapeutic targets, including IL-6-JAK-STAT
and microRNA expression. Because the science of epigenetics signaling. It is not clear whether cells are imprinted elsewhere
in autoimmunity is still relatively young, it is uncertain whether and then migrate to the joint or whether they attain a local pheno-
some or all of these disease-specific alterations are inherited, type after arriving. These data provide a possible explanation of
develop during life due to stochastic exposures, cause disease, why some joints improve in RA while others do not when patients
or are actually caused by disease. Regardless, stable epigenetic are treated with a given targeted agent.

Immunity
Review
Sequencing studies suggest that the pattern of microRNA (mir) The specificity of antibodies varies widely but include citrulli-
in RA compared with OA leukocytes and FLS exhibit global nated epitopes on fibrinogen, vimentin, fibronectin, collagen,
differences in expression. A growing number of mirs have been enolase, histones, and many others (Anzilotti et al., 2006). There
evaluated using a candidate gene approach. One example is does not appear to be a single dominant specificity of ACPA, nor
mir124a, which is dysregulated in RA and can suppress cell a particular pattern that predicts disease onset, phenotype, or
cycle and chemokine gene expression. Increasing mir124a severity (van Beers et al., 2013). Notably, in patients with early
levels in RA FLS suppresses MCP-1 production (Nakamachi undifferentiated inflammatory arthritis, ACPAs can predict indi-
et al., 2009). On the other hand, mir203 overexpression in- viduals who will progress to RA.
creases MMP and IL-6 expression (Stanczyk et al., 2011), while In established disease, ACPAs are present in the serum of
mir155 knockdown decreases the same gene expression in 80% to 90% of RA patients and are independently associated
RA FLS. mir155 is also implicated in monocyte activation and with greater disease activity, extra-articular manifestations,
cytokine production in part via regulation of TLR signaling. and joint damage. The antibodies alone are not especially path-
mir16, mir124a, mir202, mir134a, mir23, mir346, and mir15a ogenic and do not cause arthritis when injected into normal mice.
(and perhaps several others) are differentially expressed in RA- However, they can exacerbate disease in mice with arthritis,
derived cells, although their pathogenic role still needs to be perhaps because of the presence of citrullinated substrates
defined (Bottini and Firestein, 2013a). that can ultimately lead to local complement fixation. They likely
There is considerably less genome-wide information on his- act together with rheumatoid factors (RFs), which are autoanti-
tone marks in RA. There are a variety of ways that histones can bodies that bind to the Fc portion of IgG. ACPAs are more sen-
be modified, including methylation, acetylation, and citrullina- sitive and specific for RA than RFs, with specificity approaching
tion. Histone deacetylases, which remove acetyl groups and 90%. ACPAs are also present in nearly 20% of unaffected first-
remodel chromatin, are expressed in RA FLS and can regulate degree relatives and more than 10% of more distant relatives
their function (Huber et al., 2007). For example, induced in Native American RA patients (El-Gabalawy et al., 2009).
HDAC1 or 2 deficiency increases p53 tumor suppressor gene ACPAs and RFs are also produced by synovial tissue B cells
and matrix metalloproteinase 1 (MMP1) expression in RA syno- and can be detected in synovial fluid, suggesting that they could
vial cells (Horiuchi et al., 2009). Pro-inflammatory cytokines play a role in local innate immunity activation and complement
can increase HDAC1 expression in FLS and contribute to chro- fixation. Evaluation of the phylogenetic tree of RF-producing
matin remodeling. HDAC inhibitors suppress adjuvant arthritis cells from the synovium suggests that affinity maturation occurs
in rats and collagen-induced arthritis in mice, supporting the in the joint (Randen et al., 1992).
notion that histone modifications can participate in inflammatory A subset of patients with RA develops antibodies against other
joint disease (Joosten et al., 2011). classes of modified proteins. For example, lysine and cyanate
are converted to homocitrulline and can form neo-epitopes
Pre-RA: An Evolving Immunologic Response? through non-enzymatic processes analogous to conversion of
As noted before, protein modification through citrullination is arginine to citrulline, giving rise to anti-carbamylated protein an-
actually common, especially in the context of inflammation or tibodies (ACarPs) present in a minority of patients with RA,
stress. What is strikingly different in RA is the generation of anti- including about 30% of ACPA patients (Shi et al., 2011). A vari-
bodies against these epitopes, likely arising due to the unique ety of substrates are cambamylated and can lead to antibody
properties of the binding pocket of RA-associated HLA-DR formation with multiple specificities, such as fibronectin. As
alleles and presumably other regulatory deficits (e.g., in T cells with ACPAs, they are observed about 40% of RA patients prior
themselves) that permit emergence of autoreactivity over time. to the onset of clinical synovitis (Shi et al., 2014). Like ACPAs,
The teleologic explanation for induction of PADIs in normal im- the ACarPs do not cause arthritis, but immunizing mice with car-
mune responses is not known. PADIs have other potential func- bamylated peptides is arthritogenic, and transferring lympho-
tions that regulate cell migration and gene expression through cytes from immunized animals can transfer disease to naive
citrullination of chemokines and histones (Christophorou et al., mice (Mydel et al., 2010). Autoantibodies that identify acetylated
2014). PADI2, for example, migrates to the nucleus and probably proteins have also been described (Juarez et al., 2016). Finally,
modifies many proteins involved in gene expression. Thus, pro- there are data that challenge the notion of loss of tolerance to cit-
tein citrullination could have a variety of functions that regulate rullination as a definitive early event—e.g., anti-native RA33 and
homeostasis and cell responses to stress. citrullinated RA33 were detected as a continuum in a recent anal-
The presence of citrullinated peptides in the lungs or other ysis with native reactivity dominant in earlier disease (Konig et al.,
mucosal sites could thus represent the ‘‘original sin’’ in a 2016b). Further sequential studies of detailed antibody profiles
pathway that ultimately leads to inflammatory joint disease. against the spectrum of the ‘‘citrullome’’ in RA would be helpful
ACPAs, along with other antibody systems, are detected years in resolving these issues.
or perhaps even decades before clinical disease is apparent.
Over time, the serum levels of ACPAs gradually increase and Evolution from a High-Risk State to Clinical Synovitis
reach a peak at the time of disease onset through the first year The foregoing demonstrates that in high-risk individuals with a
of symptoms. A concomitant rise in blood chemokines and cyto- characteristic genetic (and possibly epigenetic) background,
kines and other altered metabolic parameters suggest an stochastic events especially at mucosal surfaces can lead to
ongoing and gradually accelerating subclinical systemic inflam- protein modification and ultimately antibody formation recog-
matory pathology (Deane et al., 2010). APCA specificities at all nizing altered peptides. The site of antibody production could
stages are quite broad and increase during the ‘‘pre-RA phase.’’ be either at the site of stress or in lymphoid organs defined by

Immunity
Review
Figure 2. Myeloid Cells, Particularly
Macrophages, Are Central to the
Perpetuation of Disease Pathogenesis
Pathways that can activate macrophages in RA
synovitis are shown that promote cytokine
release—IL-6 and TNF in particular, and probably
GM-CSF, are of central importance as defined by
the clear therapeutic benefits achieved upon their
inhibition.
providing an enticing route to subse-

quent leukocyte recruitment and the
imitation of a vicious cycle of articular
inflammation (Krishnamurthy et al.,
2016). In addition, ACPAs most likely to
progress disease exhibit an altered
glycosylation state (Rombouts et al.,
2015), though the functional conse-
quences of these observations remains
less well understood.
Once in the joint in established dis-
ease, autoantibodies may bind to
antigen, fix complement, release
dendritic cells that process arthritogenic peptide at mucosal sur- chemotactic fragments, and initiate a cascade of events that
faces and migrate centrally to relevant draining lymph nodes. activates other resident cells, recruits new innate and adaptive
Lymph nodes in pre- and early RA are not normal (Rodrı́guez- immune cells, and promotes stromal cell activation (Tan and
Carrio et al., 2016). By definition, however, disease emerges in Smolen, 2016). These, in turn, can produce additional cyto-
the joints. That ACPAs, rheumatoid RFs, ACarPs, and perhaps kines and chemokines to create a positive feedback loop
other antibody systems do not typically lead to inflammatory and ultimately a self-perpetuating process with inadequate
joint disease per se suggests that a ‘‘second hit’’ is required, at negative regulators required for termination (Figures 2 and
least in model systems for tissue localization. 3). The joint is uniquely susceptible to promote such a series
The nature of this second signal is not well defined but could of events. For example, the vasculature is already porous
comprise some combination of vascular, neuro-regulatory, mi- and facilitates ingress of proteins and cells. The synovial
crotrauma, or transient infection-dependent pathways. In addi- intimal lining, which forms the surface of the synovium and
tion, there have long been suggestions that articular infections, contains macrophage-like and fibroblast-like synoviocytes
e.g., Epstein-Barr virus, could further contribute (Tan and Smo- (FLS), is not an effective barrier because there are no tight
len, 2016). In animal models, the formation of immune com- junctions or an organized basement membrane. Once in the
plexes can trigger synovitis. The inciting complexes do not joint, antibodies can be displayed on cartilage to promote
have to be specific for altered peptides but can actually be irrel- complement fixation. Murine models involving antibodies
evant; even immunocomplexes with antibody and horseradish to type II collagen or glucose-6-phosphate isomerase are
peroxidase is sufficient in some mouse models. Thus, a variety particularly effective at inducing synovitis because of their
of random tissue insults (e.g., microtrauma, viral infection) could propensity to bind to these articular surfaces. The former is
lead to synovial vascular activation in the presence of the requi- pathogenic because it is a critical component of hyaline carti-
site size and charge of complexes that permits Fc receptor lage and the latter most likely adheres to negatively charged
engagement in the synovium. Triggered synovial innate cells cartilage surfaces (Matsumoto et al., 2002).
like mast cells could release vasoactive mediators and increase One of the important lessons of this prolonged and stepwise
antibody access to the joint. Complement activation across this pre-RA process is that the sequence of events does not
range of effector pathways could act to accelerate this require autoimmunity against native proteins in the earliest
response. Other mechanisms like Toll-like receptor engage- stages. The immune response could be more properly consid-
ment or triggering via various danger-sensing molecules could ered a normal appropriate adaptive immune response to
theoretically cause a similar cascade. Recent data suggest a altered antigens that are viewed as ‘‘foreign’’ because they
potential role for ACPAs beyond immune complexes depending were not generated during thymic development and patho-
upon their chemical properties and cellular specificity. genic T cells could not be deleted. The high-risk individuals
Intriguing studies suggest that ACPA recognition of osteoclast with ‘‘unfortunate’’ HLA-DR alleles happen to bind to these
(OC) membrane epitopes, e.g., citrullinated vimentin, can pro- modified proteins more avidly than the native molecule. Later,
mote osteoclastogenesis—thus an early route to articular perhaps through epitope spreading, more traditional auto-
involvement via systemic ACPA expression may be via local immunity develops and leads to production of antibodies
OC activation (Harre et al., 2012). Moreover, one consequence commonly detected in chronic RA that bind to collagens and
of ACPA OC binding is the induction of pain and release of IL-8, many other native proteins.

Immunity
Review
Figure 3. Mechanisms that Drive the Chronicity of RA

Distinct pathways combine to mediate failed resolution of disease—these include adaptive, innate, and stromal components with additional impact of the
systemic features of disease. The latter may be both consequence of the chronic inflammation and could promote the chronicity, e.g., via creation of pro-in-
flammatory lipid profiles, promotion of bone remodeling, and secondary osteoarthritis.
Early Role for Stromal Cells as Important Pathogenic alternate models of contribution of stromal cells and autoim-
Factors munity in a notional hierarchy—note that these are not mutu-
Compelling data implicate adaptive immune responses in the ally exclusive).
pathogenesis of RA, but alternative hypotheses propose that
stromal elements can also play a critical role. Early pioneering Pathologic Characteristics of Clinical Synovitis
studies by Gay and colleagues showed that FLS assume an The histologic appearances of RA synovitis have been exten-
autonomous aggressive phenotype that is maintained for sively characterized. Normal synovial membrane is relatively
months after removal from the patient (Mu € ller-Ladner et al., acellular, comprising scattered macrophages within a stromal
1996). These data and the destructive potential of fibroblasts tissue curated by FLS and sparse blood vessels. Its primary
led to the notion that FLS are imprinted or permanently function is to lubricate and nourish the articular surface, which
altered in RA and could either initiate or exacerbate disease lacks a blood supply. During the pre-RA phase, the synovial
(Firestein, 1996; Bottini and Firestein, 2013b). Numerous appearance is not markedly altered; biopsy studies or ACPA+
mechanisms for ‘‘partial transformation’’ have been impli- arthralgia are remarkably benign, with no obvious leukocyte
cated, including abnormal DNA methylation (see below), infiltrates nor transcriptional changes (de Hair et al., 2014).
somatic mutations in various genes (e.g., p53, mitochondria, However, with the onset of clinically evident articular swelling
vimentin), defective PTEN expression, and high levels of sen- (including that detected by MRI or power-Doppler ultrasound
trin (Pap et al., 2000; Franz et al., 2000; Firestein et al., 1997; imaging), the synovium assumes a rather different appearance
and reviewed in Bottini and Firestein, 2013b). In addition, acti- (reviewed by McInnes and Schett, 2011). The lining layer,
vated FLS can play an active role in antigen presentation and normally 2–3 cells thickness, expands up to 10–12 cells
contribute to local adaptive immune responses (Tran et al., depth, comprising macrophages and FLS. Underlying this is
2007). Finally, the synovial fibroblasts are not a uniform a dense interstitial cellular infiltrate containing cells character-
population but segregate into different phenotypes based, in istic of innate (e.g., macrophages, dendritic cells, mast cells,
part, on their cytokine profiles (Croft et al., 2016). The role of natural killer [NK] cells, innate lymphoid cells) and adaptive
mesenchymal cells in disease initiation and progression (e.g., B and T lymphocytes, plasma cells) responses. This
represents an interesting therapeutic opportunity because no is associated with significant neovascularization, with some
approved agents currently target these cells (see Figure 1 for lymphangiogenesis.

Immunity
Review
The immunologic properties of RA synovium are now well achieved in psoriasis (Langley et al., 2014) and to some extent
characterized. Synovitis studies relied originally on arthro- spondyloarthropathies (McInnes et al., 2015).
plasty-derived tissues, which were usually by definition end- Future studies using single-cell-based sequencing methodol-
stage disease, but have been expanded by the use of synovial ogies and the availability of detailed transcriptional definitions of
biopsies obtained via arthroscopy or ultrasound methodologies T cells are underway to facilitate characterization of T cell subset
facilitating investigation of all stages of disease (Kelly et al., differentiation in the phases of RA development. Understanding
2015). Macrophages, mainly of M1 phenotype, are potent con- those factors that define T cell differentiation in RA or perhaps
tributors to effector pathology by virtue of release of cytokines other cell lineages that could contribute to the evolution of this
(e.g., TNF, IL-1, IL-6), chemokines, MMPs, vasoactive peptides, unique disease might be critically important because the detec-
and oxygen and nitrogen intermediates. Numerous activation tion of Treg cells in synovium has also been extensively docu-
pathways of macrophages have been described including TLR mented—clearly their functional impact is insufficient, or they
ligands, soluble proteases (via PAR2), cholesterol derivatives, may have a functional deficit. Some evidence suggests that
and immune complexes (Figure 2). The latter, containing RF inadequate Treg cell function is characteristic of RA and is cor-
and ACPA, act via FcgR1 and FcgR3 that are highly expressed rected by TNF blocker therapy (Byng-Maddick and Ehrenstein,
on synovial macrophages. Coincident binding of ACPAs to 2015). However, it is not clear whether this defect is primary or
soluble citrullinated TLR ligands, e.g., cit-fibronectin, may secondary. Re-establishing local T cell homeostatic balance
enhance these effects—by this model ACPAs can bind both via expansion or recovery of Treg cell function is an attractive
TLR and FcR on the same cell to optimize activation (Sokolove approach to future therapeutics, particularly as we seek res-
et al., 2011), leading to high levels of cytokine release. The toration of tolerance as the clinical target (Rossetti et al., 2017;
glycosylation status, particularly sialylation, of ACPAs also Benham et al., 2015).
alters their capacity to promote inflammation (Rombouts et al., Clearly autoantibody production is a hallmark of RA. B cell lin-
2015). Cognate interaction with memory T cells is a further eages at each stage of development are detected in synovium,
intriguing activation pathway—acting via a non-antigen-depen- including the presence of mature plasma cells. The synovium
dent manner, the cytokine-rich synovial milieu, particularly provides a cytokine-rich milieu for B cell survival, e.g., via
IL-15, IL-7, and IL-6, can induce integrin and Ig-superfamily- BAFF, APRIL, IL-6 expression. A particular role for FLS (which
dependent interactions between CD45RO+ memory T cells and are the primary source of IL-6 in the RA synovium) in maintaining
macrophages to drive subsequent macrophage cytokine and this milieu has recently emerged, exemplifying the tissue depen-
chemokine release (McInnes and Schett, 2007). dency of the articular immune response (Bombardieri et al.,
Most interest in the contribution of T cells has however 2011). In a proportion of tissues there are ectopic lymphoid
focused on their antigen-driven role in initiation and perpetuation structures (ELSs) that have been associated with more rapid
of disease. CD45RO T cells are abundant in synovial membrane erosive progression. Prior studies demonstrated that ELSs in
and exhibit an activated phenotype. Fascinating studies have RA tissue contain the enzymatic machinery necessary for anti-
established that RA peripheral blood CD45RO naive T cells gen-driven selection, differentiation, somatic hypermutation,
exhibit unique anabolic metabolic features characterized by and class switching (Pitzalis et al., 2014). Recently, single-cell
low glucose metabolism and lower icATP levels associated sequencing of synovial B cells suggests extensive self-reactivity
with PFKFB3 deficiency that may play a role in their relative particularly to citrullinated histones H2A and H2B and other cit-
senescence and likely therefore their chronic activation state rullinated self-proteins—neutrophil could form a focal event
(Yang et al., 2016). Synovial biopsies from very early RA contain permitting expansion of such clones (Corsiero et al., 2016).
expanded T cell clones that probably represent enrichment for Thus, in addition to antigen presentation and autoantibody for-
self-reactive (or least altered-peptide reactive) clones—this mation and release, B cells should be considered important
feature disappears with disease progression, presumably re- sources of local antigen presentation and of cytokine release
flecting dilution of these clones by secondarily recruited into the milieu.
polyclonal memory T cells (Klarenbeek et al., 2012). The differen- Finally, it is vital to consider the role of the local stromal tissues
tiation state of the synovial T cell is also uncertain. Murine in synovium. FLS have been long recognized to contribute to the
arthritis models strongly suggest a pivotal role for T helper 17 matrix deposition and tissue remodeling that characterizes RA
(Th17) cells (Miossec and Kolls, 2012; Lubberts, 2015). Human (Zvaifler et al., 1994). They exhibit anchorage independence,
data have rather challenged this proposition though no firm con- migratory activity (potentially even between joints), and local
clusions can yet be drawn as the critical pre-RA phase could well proliferation and release high levels of MMP and TIMPs (tissue
be Th17 cell driven but not manifest in the effector stages of dis- inhibitors of metalloproteinases), cytokines and chemokines
ease amenable to direct examination. Nevertheless, one report together with collagens and other ECM components (Filer
suggests that cytokine profiles in lavage fluid from early RA are 2013). They appear to be particularly dependent upon cadherin
paradoxically rich in IL-4, IL-13, and IL-15, whereas those 11 for their effector function (Kiener et al., 2009). As such they
T cells detected in established disease have features of both should be considered a critical component of the RA inflamma-
Th1 and Th17 (Raza et al., 2005). A recent study in which citrulli- tory response rather than as responding bystanders. Other
nated tetramer responses were explored in RA patients found studies suggest the existence subsets of FLS, although the
most T cells that were cit-specific were of Th1 cell phenotype functional significance of these remains uncertain. Further
(Snir et al., 2011). IL-17 targeting therapeutics including IL-17A complexity is emerging since FLS exhibit distinct features even
and IL-17RA inhibitors have as yet not been particularly effective across different diarthrodial joints, e.g., hips and knees,
in established RA trials despite remarkable responses being described above. FLS may also migrate across anatomically

Immunity
Review
Table 1. Major Drug Classes that Have Been Informative of the Pathogenesis of RA
Immune Target Drugs Key Modes of Action
TNF Adalimumab reduced endothelial, stromal cell, and chondrocyte activation
Etanercept reduced osteoclast differentiation/activation
Golimumab modified cellular migration
Certolizumab reduced cytokine expression, e.g., IL-6
Infliximab reduced metabolic/CVD risk
Biosimilars
IL-6 Tocilizumab reduced endothelial, stromal cell activation
Multiple Abs in development reduced osteoclast activation
reduced cytokine/chemokine expression
altered lipid metabolism
Co-stimulation (CD28-CD80/86) Abatacept reduced T cell activation
diminished dendritic cell activation, cytokine production,
and antigen presentation
reduced osteoclast activation
B cell depletion (anti-CD20) Rituximab depletion of CD20+ B cell lineages, sparing plasma cells
reduced cytokine production
reduced antigen presentation
JAK inhibitors Tofacitinib inhibition of pivotal cytokine receptors with predictable
Baricitinib downstream effects; JAK1, JAK2, and JAK3 thus far targeted
multiple compounds in development
IL-1 Anakinra decreased endothelial cell, stromal cell activation
decreased cellular migration
altered T cell differentiation
innate immunity activation
Other cytokines (GM-CSF, multiple multiple
IL-17, and others)
discrete articular sites (Lefèvre et al., 2009). Presumably re- cohort studies. Thus, subsets of patients can potentially be
flecting the epigenetic changes described above, FLS thus defined by myeloid, lymphoid, and stromal-rich synovial patho-
play a critical role in recruiting, retaining, activating, and sus- types (Dennis et al., 2014). The longer-term functional implica-
taining leukocytes, e.g., via type 1 interferons, CXCL12 (SDF-1) tions of these subsets are currently unclear but carry the poten-
in the synovium (e.g., Perlman et al., 2003). Finally, in combina- tial to offer subtype-specific therapeutics in due course—clinical
tion with endothelial cells, they may become permissive for trials are underway to test this hypothesis (Astorri et al., 2015;
ELS formation (Pitzalis et al., 2014) further enhancing an ‘‘autor- Kelly et al., 2015). If confirmed this would suggest that distinct
eactive-prone’’ articular microenvironment. pathologic processes can induce pathotypes that are patholog-
Articular destruction, often reflected in radiographic evi- ically discrete and of functional importance in identifying domi-
dence of bone erosion, is a further hallmark of RA. Mecha- nant effector pathways and tissue responses.
nisms driving damage are reviewed elsewhere (McInnes and
Schett, 2007). In brief, FLS drive damage primarily via MMP Lessons from Therapeutic Targeting as to the Hierarchy
(particularly MMP1 and MMP3), which mediates direct carti- of Pathways and Heterogeneity of Responses
lage damage or by promoting chondrocyte activation and tis- The utility of immune targeting in RA represents a major advance
sue catabolism through cytokine release in concert with mac- in disease management (Smolen et al., 2016; Smolen and Ale-
rophages. IL-1, TNF, and IL-17 are particularly relevant in this taha, 2015). Thus, inhibitors of TNF and IL-6 are particularly
respect. Bone damage arises from more complex interactions potent in delivering clinical responses. Co-stimulatory blockade
that sustain osteoclast precursor maturation mediated partic- with abatacept (CTLA4:Ig) is similarly effective, as is depletion of
ularly via RANKL, M-CSF, and TNF pathways. Recent insights CD20 lineages by rituximab (Nam et al., 2014; Schiff et al., 2014).
into the participation of sclerostin, DKK, ACPAs, and other Notably, those blocking IL-17, IL-1, BAFF, IL-21, and IL-20 (for
osteoclast and osteoblast co-regulators suggest the intriguing example) appear less effective. More recently, small molecule in-
possibility of promoting bone healing—this has not yet been hibitors of the JAK pathways, e.g., tofacinitib (targeting JAK1
possible on the basis of existing therapeutics (Diarra et al., and JAK3) and baricitinib (JAK1 and JAK2), have demonstrated
2007; McInnes and Schett, 2011). Other factors in the synovial considerable efficacy, especially if used in early disease (Geno-
milieu including ACPAs are also implicated via their ability to vese et al., 2016; Lee et al., 2014).
bind directly to osteoclasts and promote their differentiation Immune therapeutics have taught us much (Table 1): (1) critical
and activation. immune checkpoints or functional nodes must exist within the
One further development of note is the recent observation by complex synovial lesion that are amenable to blockade and pro-
some groups of synovial tissue micro-heterogeneity in several mote collapse of the majority of the lesion; (2) upstream immune

Immunity
Review
dysregulation apparently manifests primarily in cytokine (espe- Processes Driving Co-morbidities

cially TNF and IL-6)-mediated effector mechanisms; and (3) RA is associated with increased cardiovascular risk, metabolic
murine models, despite offering exquisite mechanistic insight syndrome, psychosocial deficit including psychiatric disease,
and proof of possibility, poorly reflect the complexity of the hu- osteoporosis, and increased cancer rates. The mechanisms
man RA state and therefore the therapeutic potential of any given underlying these are increasingly understood to depend on
agent. Moreover, the discrete effects of cytokine inhibitors cytokines and other circulating immune moieties, primarily us-
across the wider range of chronic inflammatory diseases is ing immune therapeutics as molecular scalpels. For example,
increasingly pointing to a new molecular disease taxonomy IL-6 and to some extent TNF directly regulate cholesterol
that can be therapeutically defined—RA might represent a TNF metabolism, such that active RA is associated with paradoxical
and IL-6-dependent axis whereas psoriasis might reflect more low cholesterol levels that are replenished with effective ther-
TNF, IL-23, and IL-17-dependent pathways. apy—the latter appears to operate via direct IL-6-mediated,
The diversity of responses to highly targeted agents like STAT3-dependent modulation of cholesterol ester catabolism
cytokine inhibition, B cell depletion, or co-stimulation blockade (Charles-Schoeman et al., 2015; Robertson et al., 2013).
suggest that RA is not a single disease entity. Instead, it is a Similarly, the atherosclerotic lesion and RA synovium exhibit
syndrome with a common clinical presentation but multiple remarkable similarities leading to the suggestion that TNF and
pathogenic pathways, any one of which (or combination) might IL-6-driven pathways may enhance the progression of vascular
be relevant for a particular patient (Firestein, 2014). One of the disease. TNF inhibition in patients leads to reduced vascular
key challenges going forward will be how we can stratify pa- dysfunction and to improved vascular mortality commensurate
tients so that we can make better treatment selections. Thus with this notion (McKellar et al., 2009). Moreover, RA athero-
far there are no studies that have separated responder RA sclerotic plaques exhibit exaggerated cytokine expression
populations to distinct interventions. A variety of molecular compared to non-RA controls (Ahmed et al., 2016). Similarly,
and cellular profiling approaches in peripheral blood have not circulating TNF, RANKL, and IL-1 are implicated in systemic
been successful as yet. As noted above, preliminary studies osteoporosis (McInnes and Schett, 2011), and TNF has been
suggest that synovial histologic patterns might correlate with implicated in the hippocampal dysfunction that likely underlies
responses to therapy, although other careful assessments of depression in RA (Krishnadas et al., 2016).
synovial structure and biomarkers have not demonstrated suf-
ficient power for clinical utility (Dennis et al., 2014). These in
Concluding Remarks
turn could presage the advent of biomarkers that enrich for
RA represents a remarkable example of successful immunologic
response. We also need to begin considering more robust
interrogation of tissue culture cells, pre-clinical models, and
clinical trial instruments to take into account joint-specific
human translational studies that has delivered enormous thera-
differences in clinical responses.
peutic advances. The penumbra of these advances has also
Kinetically distinct phases of immune pathway utilization as
benefited many other immune-mediated disease, such as psori-
RA progresses also should be considered—in essence we use
asis, spondyloarthropathies, inflammatory bowel disease (IBD),
all immune therapeutics across the various phases of RA devel-
and inflammatory eye disease. It has taught us much about im-
opment without consideration to the dominant pathogenesis at
mune pathogenetic mechanisms in the context of human auto-
that time point (McInnes et al., 2016). Immunologic adaptation
immunity and chronic inflammation, not least in unraveling the
is a characteristic of chronic infectious responses and it seems
complex multi-hit sequence of events that ultimately overcome
plausible that similar alterations in effector pathways will evolve
immune homeostasis to manifest as tissue-destructive disease.
as damage accrues in patients. Should we now consider ‘‘path-
Despite such successes there remains much unmet need, not
ogenesis-appropriate’’ timing of therapeutic interventions? For
least in the current absence of the capacity to predict, prevent,
example, could there be a role for immune tolerance-inducing
and cure the disease or even predict which patients will respond
therapies in very early RA, or even pre-RA? This supposes that
to a particular therapy. It is clear that further pathogenetic dis-
pre-RA can be identified in a meaningful population and at a
covery must drive such progress and lead ultimately to the deliv-
stage when immune homeostasis or re-programming can be
ery of agents with homeostatic activity, used within a precision
achieved and that molecular outcome measures can be derived
medicine-based therapeutic culture.
to define therapeutic success. Various therapeutics are being
explored in this respect, including B cell depletion or co-stimula-
tory blockade in high-risk populations. The PRAIRI study admin- REFERENCES
istered a single dose of rituximab to people at high risk of devel-
Ahmed, A., Hollan, I., Curran, S.A., Kitson, S.M., Riggio, M.P., Mikkelsen, K.,
oping RA—formal reporting of outcome is awaited (NTR2442 Almdahl, S.M., Aukrust, P., McInnes, I.B., and Goodyear, C.S. (2016). Brief
Netherlands Trial Register). A similar study is ongoing in which report: Proatherogenic cytokine microenvironment in the aortic adventitia of
abatacept is being given to high risk pre-RA (APIPRA Study; patients with rheumatoid arthritis. Arthritis Rheumatol. 68, 1361–1366.
ISRCTN46017566). Finally, a broader approach to identification Ai, R., Whitaker, J.W., Boyle, D.L., Tak, P.P., Gerlag, D.M., Wang, W., and Fire-
of pre-RA comprises the StopRA study in which hydroxychloro- stein, G.S. (2015). DNA methylome signature in synoviocytes from patients
with early rheumatoid arthritis compared to synoviocytes from patients with
quine is being given to healthy subjects with an elevated ACPA longstanding rheumatoid arthritis. Arthritis Rheumatol. 67, 1978–1980.
(NCT02603146). Finally, exciting cell transfer clinical trials using
tolerogenic dendritic cells, with thus far encouraging results in Ai, R., Hammaker, D., Boyle, D.L., Morgan, R., Walsh, A.M., Fan, S., Firestein,
G.S., and Wang, W. (2016). Joint-specific DNA methylation and transcriptome
terms of immune function modulation, are also ongoing (Benham signatures in rheumatoid arthritis identify distinct pathogenic processes. Nat.
et al., 2015). Commun. 7, 11849.

Immunity
Review
Anzilotti, C., Merlini, G., Pratesi, F., Tommasi, C., Chimenti, D., and Migliorini, Diarra, D., Stolina, M., Polzer, K., Zwerina, J., Ominsky, M.S., Dwyer, D., Korb,
P. (2006). Antibodies to viral citrullinated peptide in rheumatoid arthritis. A., Smolen, J., Hoffmann, M., Scheinecker, C., et al. (2007). Dickkopf-1 is a
J. Rheumatol. 33, 647–651. master regulator of joint remodeling. Nat. Med. 13, 156–163.
Arend, W.P., and Firestein, G.S. (2012). Pre-rheumatoid arthritis: predisposi- Ekwall, A.K., Whitaker, J.W., Hammaker, D., Bugbee, W.D., Wang, W., and
tion and transition to clinical synovitis. Nat. Rev. Rheumatol. 8, 573–586. Firestein, G.S. (2015). The rheumatoid arthritis risk gene LBH regulates growth
in fibroblast-like synoviocytes. Arthritis Rheumatol. 67, 1193–1202.
Astorri, E., Nerviani, A., Bombardieri, M., and Pitzalis, C. (2015). Towards a
stratified targeted approach with biologic treatments in rheumatoid arthritis: El-Gabalawy, H.S., Robinson, D.B., Hart, D., Elias, B., Markland, J., Peschken,
role of synovial pathobiology. Curr. Pharm. Des. 21, 2216–2224. C.A., Smolik, I., Montes-Aldana, G., Schroeder, M., Fritzler, M.J., et al. (2009).
Immunogenetic risks of anti-cyclical citrullinated peptide antibodies in a
Benham, H., Nel, H.J., Law, S.C., Mehdi, A.M., Street, S., Ramnoruth, N., Pa- North American Native population with rheumatoid arthritis and their first-de-
hau, H., Lee, B.T., Ng, J., Brunck, M.E., et al. (2015). Citrullinated peptide den- gree relatives. J. Rheumatol. 36, 1130–1135.
dritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis
patients. Sci. Transl. Med. 7, 290ra87. Ferreira, R.C., Freitag, D.F., Cutler, A.J., Howson, J.M., Rainbow, D.B., Smyth,
D.J., Kaptoge, S., Clarke, P., Boreham, C., Coulson, R.M., et al. (2013). Func-
Bombardieri, M., Kam, N.W., Brentano, F., Choi, K., Filer, A., Kyburz, D., tional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influ-
McInnes, I.B., Gay, S., Buckley, C., and Pitzalis, C. (2011). A BAFF/APRIL- ences risk of diverse inflammatory diseases. PLoS Genet. 9, e1003444.
dependent TLR3-stimulated pathway enhances the capacity of rheumatoid
synovial fibroblasts to induce AID expression and Ig class-switching in B cells. Filer, A. (2013). The fibroblast as a therapeutic target in rheumatoid arthritis.
Ann. Rheum. Dis. 70, 1857–1865. Curr. Opin. Pharmacol. 13, 413–419.
Bottini, N., and Firestein, G.S. (2013a). Epigenetics in rheumatoid arthritis: a Firestein, G.S. (1996). Invasive fibroblast-like synoviocytes in rheumatoid
primer for rheumatologists. Curr. Rheumatol. Rep. 15, 372. arthritis. Passive responders or transformed aggressors? Arthritis Rheum.
39, 1781–1790.
Bottini, N., and Firestein, G.S. (2013b). Duality of fibroblast-like synoviocytes in
RA: passive responders and imprinted aggressors. Nat. Rev. Rheumatol. Firestein, G.S. (2003). Evolving concepts of rheumatoid arthritis. Nature 423,
9, 24–33. 356–361.
Byng-Maddick, R., and Ehrenstein, M.R. (2015). The impact of biological ther- Firestein, G.S. (2014). The disease formerly known as rheumatoid arthritis.
apy on regulatory T cells in rheumatoid arthritis. Rheumatology (Oxford) 54, Arthritis Res. Ther. 16, 114.
768–775.
Firestein, G.S., and Zvaifler, N.J. (2002). How important are T cells in chronic
Catrina, A.I., Ytterberg, A.J., Reynisdottir, G., Malmström, V., and Klareskog, rheumatoid synovitis?: II. T cell-independent mechanisms from beginning to
L. (2014). Lungs, joints and immunity against citrullinated proteins in rheuma- end. Arthritis Rheum. 46, 298–308.
toid arthritis. Nat. Rev. Rheumatol. 10, 645–653.
Firestein, G.S., Echeverri, F., Yeo, M., Zvaifler, N.J., and Green, D.R. (1997).
Catrina, A.I., Joshua, V., Klareskog, L., and Malmström, V. (2016). Mechanisms Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis
involved in triggering rheumatoid arthritis. Immunol. Rev. 269, 162–174. synovium. Proc. Natl. Acad. Sci. USA 94, 10895–10900.
Charles-Schoeman, C., Fleischmann, R., Davignon, J., Schwartz, H., Turner, Fonseca, J.E., Cavaleiro, J., Teles, J., Sousa, E., Andreozzi, V.L., Antunes, M.,
S.M., Beysen, C., Milad, M., Hellerstein, M.K., Luo, Z., Kaplan, I.V., et al. Amaral-Turkman, M.A., Canhão, H., Mourão, A.F., Lopes, J., et al. (2007).
(2015). Potential mechanisms leading to the abnormal lipid profile in patients Contribution for new genetic markers of rheumatoid arthritis activity and
with rheumatoid arthritis versus healthy volunteers and reversal by tofacitinib. severity: sequencing of the tumor necrosis factor-alpha gene promoter.
Arthritis Rheumatol. 67, 616–625. Arthritis Res. Ther. 9, R37.
Christophorou, M.A., Castelo-Branco, G., Halley-Stott, R.P., Oliveira, C.S., Franz, J.K., Pap, T., Hummel, K.M., Nawrath, M., Aicher, W.K., Shigeyama, Y.,
Loos, R., Radzisheuskaya, A., Mowen, K.A., Bertone, P., Silva, J.C., Zer- Mu€ller-Ladner, U., Gay, R.E., and Gay, S. (2000). Expression of sentrin, a novel
nicka-Goetz, M., et al. (2014). Citrullination regulates pluripotency and histone antiapoptotic molecule, at sites of synovial invasion in rheumatoid arthritis.
H1 binding to chromatin. Nature 507, 104–108. Arthritis Rheum. 43, 599–607.
Corsiero, E., Bombardieri, M., Carlotti, E., Pratesi, F., Robinson, W., Migliorini, Genovese, M.C., Kremer, J., Zamani, O., Ludivico, C., Krogulec, M., Xie, L.,
P., and Pitzalis, C. (2016). Single cell cloning and recombinant monoclonal Beattie, S.D., Koch, A.E., Cardillo, T.E., Rooney, T.P., et al. (2016). Baricitinib
antibodies generation from RA synovial B cells reveal frequent targeting of in patients with refractory rheumatoid arthritis. N. Engl. J. Med. 374,
citrullinated histones of NETs. Ann. Rheum. Dis. 75, 1866–1875. 1243–1252.
Croft, A.P., Naylor, A.J., Marshall, J.L., Hardie, D.L., Zimmermann, B., Turner, Hammaker, D., Whitaker, J.W., Maeshima, K., Boyle, D.L., Ekwall, A.H., Wang,
J., Desanti, G., Adams, H., Yemm, A.I., Mu €ller-Ladner, U., et al. (2016). Rheu- W., and Firestein, G.S. (2016). Limb bud and heart development gene tran-
matoid synovial fibroblasts differentiate into distinct subsets in the presence of scription is regulated by the interplay of an enhancer risk allele and DNA
cytokines and cartilage. Arthritis Res. Ther. 18, 270. methylation in rheumatoid arthritis. Arthritis Rheumatol. 68, 2637–2645.
de Aquino, S.G., Abdollahi-Roodsaz, S., Koenders, M.I., van de Loo, F.A., Harre, U., Georgess, D., Bang, H., Bozec, A., Axmann, R., Ossipova, E.,
Pruijn, G.J., Marijnissen, R.J., Walgreen, B., Helsen, M.M., van den Bersselaar, Jakobsson, P.J., Baum, W., Nimmerjahn, F., Szarka, E., et al. (2012). Induction
L.A., de Molon, R.S., et al. (2014). Periodontal pathogens directly promote of osteoclastogenesis and bone loss by human autoantibodies against citrulli-
autoimmune experimental arthritis by inducing a TLR2- and IL-1-driven Th17 nated vimentin. J. Clin. Invest. 122, 1791–1802.
response. J. Immunol. 192, 4103–4111.
Hill, J.A., Southwood, S., Sette, A., Jevnikar, A.M., Bell, D.A., and Cairns, E.
de Hair, M.J., van de Sande, M.G., Ramwadhdoebe, T.H., Hansson, M., Land- (2003). Cutting edge: the conversion of arginine to citrulline allows for a
ewé, R., van der Leij, C., Maas, M., Serre, G., van Schaardenburg, D., Klareskog, high-affinity peptide interaction with the rheumatoid arthritis-associated
L., et al. (2014). Features of the synovium of individuals at risk of developing HLA-DRB1*0401 MHC class II molecule. J. Immunol. 171, 538–541.
rheumatoid arthritis: implications for understanding preclinical rheumatoid
arthritis. Arthritis Rheumatol. 66, 513–522. Horiuchi, M., Morinobu, A., Chin, T., Sakai, Y., Kurosaka, M., and Kumagai, S.
(2009). Expression and function of histone deacetylases in rheumatoid arthritis
Deane, K.D., O’Donnell, C.I., Hueber, W., Majka, D.S., Lazar, A.A., Derber, synovial fibroblasts. J. Rheumatol. 36, 1580–1589.
L.A., Gilliland, W.R., Edison, J.D., Norris, J.M., Robinson, W.H., and Holers,
V.M. (2010). The number of elevated cytokines and chemokines in preclinical Huber, L.C., Brock, M., Hemmatazad, H., Giger, O.T., Moritz, F., Trenkmann,
seropositive rheumatoid arthritis predicts time to diagnosis in an age-depen- M., Distler, J.H., Gay, R.E., Kolling, C., Moch, H., et al. (2007). Histone deace-
dent manner. Arthritis Rheum. 62, 3161–3172. tylase/acetylase activity in total synovial tissue derived from rheumatoid
arthritis and osteoarthritis patients. Arthritis Rheum. 56, 1087–1093.
Dennis, G., Jr., Holweg, C.T., Kummerfeld, S.K., Choy, D.F., Setiadi, A.F.,
Hackney, J.A., Haverty, P.M., Gilbert, H., Lin, W.Y., Diehl, L., et al. (2014). Joosten, L.A., Leoni, F., Meghji, S., and Mascagni, P. (2011). Inhibition of
Synovial phenotypes in rheumatoid arthritis correlate with response to biologic HDAC activity by ITF2357 ameliorates joint inflammation and prevents carti-
therapeutics. Arthritis Res. Ther. 16, R90. lage and bone destruction in experimental arthritis. Mol. Med. 17, 391–396.

Immunity
Review
Juarez, M., Bang, H., Hammar, F., Reimer, U., Dyke, B., Sahbudin, I., Buckley, Investigators (2014). Tofacitinib versus methotrexate in rheumatoid arthritis.
C.D., Fisher, B., Filer, A., and Raza, K. (2016). Identification of novel antiacety- N. Engl. J. Med. 370, 2377–2386.
lated vimentin antibodies in patients with early inflammatory arthritis. Ann.
Rheum. Dis. 75, 1099–1107. Lefèvre, S., Knedla, A., Tennie, C., Kampmann, A., Wunrau, C., Dinser, R.,
Korb, A., Schna €ker, E.M., Tarner, I.H., Robbins, P.D., et al. (2009). Synovial
Ka€llberg, H., Ding, B., Padyukov, L., Bengtsson, C., Rönnelid, J., Klareskog, L., fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med. 15,
and Alfredsson, L.; EIRA Study Group (2011). Smoking is a major preventable 1414–1420.
risk factor for rheumatoid arthritis: estimations of risks after various exposures
to cigarette smoke. Ann. Rheum. Dis. 70, 508–511. Linn-Rasker, S.P., van der Helm-van Mil, A.H., van Gaalen, F.A., Kloppenburg,
M., de Vries, R.R., le Cessie, S., Breedveld, F.C., Toes, R.E., and Huizinga,
Kaminsky, Z.A., Tang, T., Wang, S.C., Ptak, C., Oh, G.H., Wong, A.H., Feld- T.W. (2006). Smoking is a risk factor for anti-CCP antibodies only in rheumatoid
camp, L.A., Virtanen, C., Halfvarson, J., Tysk, C., et al. (2009). DNA methylation arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann. Rheum.
profiles in monozygotic and dizygotic twins. Nat. Genet. 41, 240–245. Dis. 65, 366–371.
€ngel, A., Kolling, C., Gay, R.E., Michel, B.A., Tak,

Karouzakis, E., Rengel, Y., Ju Liu, X., Zeng, B., Zhang, J., Li, W., Mou, F., Wang, H., Zou, Q., Zhong, B., Wu,
P.P., Gay, S., Neidhart, M., and Ospelt, C. (2011). DNA methylation regulates L., Wei, H., and Fang, Y. (2016). Role of the gut microbiome in modulating
the expression of CXCL12 in rheumatoid arthritis synovial fibroblasts. Genes arthritis progression in mice. Sci. Rep. 6, 30594.
Immun. 12, 643–652.
Lubberts, E. (2015). The IL-23-IL-17 axis in inflammatory arthritis. Nat. Rev.
Rheumatol. 11, 415–429.
Kelly, S., Humby, F., Filer, A., Ng, N., Di Cicco, M., Hands, R.E., Rocher, V.,
Bombardieri, M., D’Agostino, M.A., McInnes, I.B., et al. (2015). Ultrasound- €llberg, H., Alfredsson, L., Klareskog, L., and Padyukov, L.
Lundström, E., Ka
guided synovial biopsy: a safe, well-tolerated and reliable technique for obtain-
(2009). Gene-environment interaction between the DRB1 shared epitope
ing high-quality synovial tissue from both large and small joints in early arthritis
and smoking in the risk of anti-citrullinated protein antibody-positive rheuma-
patients. Ann. Rheum. Dis. 74, 611–617.
toid arthritis: all alleles are important. Arthritis Rheum. 60, 1597–1603.
Kiener, H.P., Niederreiter, B., Lee, D.M., Jimenez-Boj, E., Smolen, J.S., and Makrygiannakis, D., Hermansson, M., Ulfgren, A.K., Nicholas, A.P., Zendman,
Brenner, M.B. (2009). Cadherin 11 promotes invasive behavior of fibroblast- A.J., Eklund, A., Grunewald, J., Skold, C.M., Klareskog, L., and Catrina, A.I.
like synoviocytes. Arthritis Rheum. 60, 1305–1310. (2008). Smoking increases peptidylarginine deiminase 2 enzyme expression
in human lungs and increases citrullination in BAL cells. Ann. Rheum. Dis.
Kim, K., Bang, S.Y., Lee, H.S., and Bae, S.C. (2017). Update on the genetic 67, 1488–1492.
architecture of rheumatoid arthritis. Nat. Rev. Rheumatol. 13, 13–24.
Matsumoto, I., Maccioni, M., Lee, D.M., Maurice, M., Simmons, B., Brenner,
Kinslow, J.D., Blum, L.K., Deane, K.D., Demoruelle, M.K., Okamoto, Y., Parish, M., Mathis, D., and Benoist, C. (2002). How antibodies to a ubiquitous cyto-
M.C., Kongpachith, S., Lahey, L.J., Norris, J.M., Robinson, W.H., and Holers, plasmic enzyme may provoke joint-specific autoimmune disease. Nat. Immu-
V.M. (2016). Elevated IgA plasmablast levels in subjects at risk of developing nol. 3, 360–365.
rheumatoid arthritis. Arthritis Rheumatol. 68, 2372–2383.
McInnes, I.B., and Schett, G. (2007). Cytokines in the pathogenesis of rheuma-
Kirschmann, D.A., Duffin, K.L., Smith, C.E., Welply, J.K., Howard, S.C., Schwartz, toid arthritis. Nat. Rev. Immunol. 7, 429–442.
B.D., and Woulfe, S.L. (1995). Naturally processed peptides from rheumatoid
arthritis associated and non-associated HLA-DR alleles. J. Immunol. 155, McInnes, I.B., and Schett, G. (2011). The pathogenesis of rheumatoid arthritis.
5655–5662. N. Engl. J. Med. 365, 2205–2219.
Klarenbeek, P.L., de Hair, M.J., Doorenspleet, M.E., van Schaik, B.D., Esveldt, McInnes, I.B., Mease, P.J., Kirkham, B., Kavanaugh, A., Ritchlin, C.T., Rah-
R.E., van de Sande, M.G., Cantaert, T., Gerlag, D.M., Baeten, D., van Kampen, man, P., van der Heijde, D., Landewé, R., Conaghan, P.G., Gottlieb, A.B.,
A.H., et al. (2012). Inflamed target tissue provides a specific niche for highly et al.; FUTURE 2 Study Group (2015). Secukinumab, a human anti-inter-
expanded T-cell clones in early human autoimmune disease. Ann. Rheum. leukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE
Dis. 71, 1088–1093. 2): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet
386, 1137–1146.
Konig, M.F., Abusleme, L., Reinholdt, J., Palmer, R.J., Teles, R.P., Sampson, K.,
Rosen, A., Nigrovic, P.A., Sokolove, J., Giles, J.T., et al. (2016a). Aggregati- McInnes, I.B., Buckley, C.D., and Isaacs, J.D. (2016). Cytokines in rheumatoid
bacter actinomycetemcomitans-induced hypercitrullination links periodontal arthritis - shaping the immunological landscape. Nat. Rev. Rheumatol.
infection to autoimmunity in rheumatoid arthritis. Sci. Transl. Med. 8, 369ra176. 12, 63–68.
Konig, M.F., Giles, J.T., Nigrovic, P.A., and Andrade, F. (2016b). Antibodies to McKellar, G.E., McCarey, D.W., Sattar, N., and McInnes, I.B. (2009). Role for
native and citrullinated RA33 (hnRNP A2/B1) challenge citrullination as the TNF in atherosclerosis? Lessons from autoimmune disease. Nat. Rev. Cardiol.
inciting principle underlying loss of tolerance in rheumatoid arthritis. Ann. 6, 410–417.
Rheum. Dis. 75, 2022–2028.
Miossec, P., and Kolls, J.K. (2012). Targeting IL-17 and TH17 cells in chronic
inflammation. Nat. Rev. Drug Discov. 11, 763–776.
Krishnadas, R., Nicol, A., Sassarini, J., Puri, N., Burden, A.D., Leman, J., Com-
bet, E., Pimlott, S., Hadley, D., McInnes, I.B., and Cavanagh, J. (2016). Circu- €ller-Ladner, U., Kriegsmann, J., Franklin, B.N., Matsumoto, S., Geiler, T.,
Mu
lating tumour necrosis factor is highly correlated with brainstem serotonin
Gay, R.E., and Gay, S. (1996). Synovial fibroblasts of patients with rheumatoid
transporter availability in humans. Brain Behav. Immun. 51, 29–38.
arthritis attach to and invade normal human cartilage when engrafted into
SCID mice. Am. J. Pathol. 149, 1607–1615.
Krishnamurthy, A., Joshua, V., Haj Hensvold, A., Jin, T., Sun, M., Vivar, N.,
Ytterberg, A.J., Engström, M., Fernandes-Cerqueira, C., Amara, K., et al. Mydel, P., Wang, Z., Brisslert, M., Hellvard, A., Dahlberg, L.E., Hazen, S.L., and
(2016). Identification of a novel chemokine-dependent molecular mechanism Bokarewa, M. (2010). Carbamylation-dependent activation of T cells: a novel
underlying rheumatoid arthritis-associated autoantibody-mediated bone mechanism in the pathogenesis of autoimmune arthritis. J. Immunol. 184,
loss. Ann. Rheum. Dis. 75, 721–729. 6882–6890.
Langley, R.G., Elewski, B.E., Lebwohl, M., Reich, K., Griffiths, C.E., Papp, K., Nakamachi, Y., Kawano, S., Takenokuchi, M., Nishimura, K., Sakai, Y., Chin,
Puig, L., Nakagawa, H., Spelman, L., Sigurgeirsson, B., et al.; ERASURE Study T., Saura, R., Kurosaka, M., and Kumagai, S. (2009). MicroRNA-124a is a
Group; FIXTURE Study Group (2014). Secukinumab in plaque psoriasis–re- key regulator of proliferation and monocyte chemoattractant protein 1 secre-
sults of two phase 3 trials. N. Engl. J. Med. 371, 326–338. tion in fibroblast-like synoviocytes from patients with rheumatoid arthritis.
Arthritis Rheum. 60, 1294–1304.
Law, S.C., Street, S., Yu, C.H., Capini, C., Ramnoruth, S., Nel, H.J., van Gorp,
E., Hyde, C., Lau, K., Pahau, H., et al. (2012). T-cell autoreactivity to citrulli- Nakano, K., Whitaker, J.W., Boyle, D.L., Wang, W., and Firestein, G.S. (2013a).
nated autoantigenic peptides in rheumatoid arthritis patients carrying HLA- DNA methylome signature in rheumatoid arthritis. Ann. Rheum. Dis. 72,
DRB1 shared epitope alleles. Arthritis Res. Ther. 14, R118. 110–117.
Lee, E.B., Fleischmann, R., Hall, S., Wilkinson, B., Bradley, J.D., Gruben, D., Nakano, K., Boyle, D.L., and Firestein, G.S. (2013b). Regulation of DNA
Koncz, T., Krishnaswami, S., Wallenstein, G.V., Zang, C., et al.; ORAL Start methylation in rheumatoid arthritis synoviocytes. J. Immunol. 190, 1297–1303.

Immunity
Review
Nam, J.L., Ramiro, S., Gaujoux-Viala, C., Takase, K., Leon-Garcia, M., Emery, Scher, J.U., Sczesnak, A., Longman, R.S., Segata, N., Ubeda, C., Bielski, C.,
P., Gossec, L., Landewe, R., Smolen, J.S., and Buch, M.H. (2014). Efficacy of Rostron, T., Cerundolo, V., Pamer, E.G., Abramson, S.B., et al. (2013). Expan-
biological disease-modifying antirheumatic drugs: a systematic literature re- sion of intestinal Prevotella copri correlates with enhanced susceptibility to
view informing the 2013 update of the EULAR recommendations for the man- arthritis. eLife 2, e01202.
agement of rheumatoid arthritis. Ann. Rheum. Dis. 73, 516–528.
Schiff, M., Weinblatt, M.E., Valente, R., van der Heijde, D., Citera, G., Elegbe, A.,
Okada, Y., Wu, D., Trynka, G., Raj, T., Terao, C., Ikari, K., Kochi, Y., Ohmura, Maldonado, M., and Fleischmann, R. (2014). Head-to-head comparison
K., Suzuki, A., Yoshida, S., et al.; RACI consortium; GARNET consortium of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-
(2014). Genetics of rheumatoid arthritis contributes to biology and drug dis- year efficacy and safety findings from AMPLE trial. Ann. Rheum. Dis. 73, 86–94.
covery. Nature 506, 376–381.
Shi, J., Knevel, R., Suwannalai, P., van der Linden, M.P., Janssen, G.M., van
Pap, T., Franz, J.K., Hummel, K.M., Jeisy, E., Gay, R., and Gay, S. (2000). Acti- Veelen, P.A., Levarht, N.E., van der Helm-van Mil, A.H., Cerami, A., Huizinga,
vation of synovial fibroblasts in rheumatoid arthritis: lack of expression of the T.W., et al. (2011). Autoantibodies recognizing carbamylated proteins are pre-
tumour suppressor PTEN at sites of invasive growth and destruction. Arthritis sent in sera of patients with rheumatoid arthritis and predict joint damage.
Res. 2, 59–64. Proc. Natl. Acad. Sci. USA 108, 17372–17377.
Perlman, H., Bradley, K., Liu, H., Cole, S., Shamiyeh, E., Smith, R.C., Walsh, K., Shi, J., van de Stadt, L.A., Levarht, E.W., Huizinga, T.W., Hamann, D., van
Fiore, S., Koch, A.E., Firestein, G.S., et al. (2003). IL-6 and matrix metallopro- Schaardenburg, D., Toes, R.E., and Trouw, L.A. (2014). Anti-carbamylated
teinase-1 are regulated by the cyclin-dependent kinase inhibitor p21 in syno- protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis. Ann.
vial fibroblasts. J. Immunol. 170, 838–845. Rheum. Dis. 73, 780–783.
Pitzalis, C., Jones, G.W., Bombardieri, M., and Jones, S.A. (2014). Ectopic Smolen, J.S., and Aletaha, D. (2015). Rheumatoid arthritis therapy reappraisal:
lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. strategies, opportunities and challenges. Nat. Rev. Rheumatol. 11, 276–289.
Immunol. 14, 447–462.
Smolen, J.S., Aletaha, D., and McInnes, I.B. (2016). Rheumatoid arthritis.
Randen, I., Brown, D., Thompson, K.M., Hughes-Jones, N., Pascual, V., Victor, Lancet 388, 2023–2038.
K., Capra, J.D., Førre, O., and Natvig, J.B. (1992). Clonally related IgM rheuma-
toid factors undergo affinity maturation in the rheumatoid synovial tissue. Snir, O., Rieck, M., Gebe, J.A., Yue, B.B., Rawlings, C.A., Nepom, G., Malm-
J. Immunol. 148, 3296–3301. ström, V., and Buckner, J.H. (2011). Identification and functional characteriza-
tion of T cells reactive to citrullinated vimentin in HLA-DRB1*0401-positive
Rawlings, D.J., Dai, X., and Buckner, J.H. (2015). The role of PTPN22 risk humanized mice and rheumatoid arthritis patients. Arthritis Rheum. 63,
variant in the development of autoimmunity: finding common ground between 2873–2883.
mouse and human. J. Immunol. 194, 2977–2984.
Sokolove, J., Zhao, X., Chandra, P.E., and Robinson, W.H. (2011). Immune
Raychaudhuri, S., Sandor, C., Stahl, E.A., Freudenberg, J., Lee, H.S., Jia, X., complexes containing citrullinated fibrinogen costimulate macrophages via
Alfredsson, L., Padyukov, L., Klareskog, L., Worthington, J., et al. (2012). Toll-like receptor 4 and Fcg receptor. Arthritis Rheum. 63, 53–62.
Five amino acids in three HLA proteins explain most of the association be-
tween MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296. Stanczyk, J., Ospelt, C., Karouzakis, E., Filer, A., Raza, K., Kolling, C., Gay, R.,
Buckley, C.D., Tak, P.P., Gay, S., and Kyburz, D. (2011). Altered expression of
Raza, K., Falciani, F., Curnow, S.J., Ross, E.J., Lee, C.Y., Akbar, A.N., Lord, microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibro-
J.M., Gordon, C., Buckley, C.D., and Salmon, M. (2005). Early rheumatoid blast activation. Arthritis Rheum. 63, 373–381.
arthritis is characterized by a distinct and transient synovial fluid cytokine pro-
file of T cell and stromal cell origin. Arthritis Res. Ther. 7, R784–R795. Suzuki, A., Yamada, R., Chang, X., Tokuhiro, S., Sawada, T., Suzuki, M., Naga-
saki, M., Nakayama-Hamada, M., Kawaida, R., Ono, M., et al. (2003). Functional
Reynisdottir, G., Karimi, R., Joshua, V., Olsen, H., Hensvold, A.H., Harju, A., haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase
Engström, M., Grunewald, J., Nyren, S., Eklund, A., et al. (2014). Structural 4, are associated with rheumatoid arthritis. Nat. Genet. 34, 395–402.
changes and antibody enrichment in the lungs are early features of anti-citrul-
linated protein antibody-positive rheumatoid arthritis. Arthritis Rheumatol. Tan, E.M., and Smolen, J.S. (2016). Historical observations contributing in-
66, 31–39. sights on etiopathogenesis of rheumatoid arthritis and role of rheumatoid
factor. J. Exp. Med. 213, 1937–1950.
Reynisdottir, G., Olsen, H., Joshua, V., Engström, M., Forsslund, H., Karimi, R.,
Sköld, C.M., Nyren, S., Eklund, A., Grunewald, J., and Catrina, A.I. (2016). Tran, C.N., Davis, M.J., Tesmer, L.A., Endres, J.L., Motyl, C.D., Smuda, C.,
Signs of immune activation and local inflammation are present in the bronchial Somers, E.C., Chung, K.C., Urquhart, A.G., Lundy, S.K., et al. (2007). Presen-
tissue of patients with untreated early rheumatoid arthritis. Ann. Rheum. Dis. tation of arthritogenic peptide to antigen-specific T cells by fibroblast-like syn-
75, 1722–1727. oviocytes. Arthritis Rheum. 56, 1497–1506.
Robertson, J., Peters, M.J., McInnes, I.B., and Sattar, N. (2013). Changes in Tsaprouni, L.G., Yang, T.P., Bell, J., Dick, K.J., Kanoni, S., Nisbet, J., Viñuela,
lipid levels with inflammation and therapy in RA: a maturing paradigm. Nat. A., Grundberg, E., Nelson, C.P., Meduri, E., et al. (2014). Cigarette smoking re-
Rev. Rheumatol. 9, 513–523. duces DNA methylation levels at multiple genomic loci but the effect is partially
reversible upon cessation. Epigenetics 9, 1382–1396.
Rodrı́guez-Carrio, J., Ha €hnlein, J.S., Ramwadhdoebe, T.H., Semmelink, J.F.,
Choi, I.Y., van Lienden, K.P., Maas, M., Gerlag, D.M., Tak, P.P., Geijtenbeek, van Beers, J.J., Willemze, A., Jansen, J.J., Engbers, G.H., Salden, M., Raats,
T.B., and van Baarsen, L.G. (2016). Altered innate lymphoid cells subsets in hu- J., Drijfhout, J.W., van der Helm-van Mil, A.H., Toes, R.E., and Pruijn, G.J.
man lymph node biopsies during the at risk and earliest phase of rheumatoid (2013). ACPA fine-specificity profiles in early rheumatoid arthritis patients do
arthritis. Arthritis Rheumatol. 69, 70–76. not correlate with clinical features at baseline or with disease progression.
Arthritis Res. Ther. 15, R140.
Rombouts, Y., Ewing, E., van de Stadt, L.A., Selman, M.H., Trouw, L.A.,
Deelder, A.M., Huizinga, T.W., Wuhrer, M., van Schaardenburg, D., Toes, van der Helm-van Mil, A.H., Verpoort, K.N., Breedveld, F.C., Huizinga, T.W.,
R.E., and Scherer, H.U. (2015). Anti-citrullinated protein antibodies acquire a Toes, R.E., and de Vries, R.R. (2006). The HLA-DRB1 shared epitope alleles
pro-inflammatory Fc glycosylation phenotype prior to the onset of rheumatoid are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and
arthritis. Ann. Rheum. Dis. 74, 234–241. are not an independent risk factor for development of rheumatoid arthritis.
Arthritis Rheum. 54, 1117–1121.
Rossetti, M., Spreafico, R., Consolaro, A., Leong, J.Y., Chua, C., Massa, M.,
Saidin, S., Magni-Manzoni, S., Arkachaisri, T., Wallace, C.A., et al. (2017). Vassallo, R., Luckey, D., Behrens, M., Madden, B., Luthra, H., David, C., and
TCR repertoire sequencing identifies synovial Treg cell clonotypes in the Taneja, V. (2014). Cellular and humoral immunity in arthritis are profoundly
bloodstream during active inflammation in human arthritis. Ann. Rheum. Dis. influenced by the interaction between cigarette smoke effects and host
76, 435–441. HLA-DR and DQ genes. Clin. Immunol. 152, 25–35.
Scally, S.W., Petersen, J., Law, S.C., Dudek, N.L., Nel, H.J., Loh, K.L., Wijeye- Wang, Y., Shaked, I., Stanford, S.M., Zhou, W., Curtsinger, J.M., Mikulski, Z.,
wickrema, L.C., Eckle, S.B., van Heemst, J., Pike, R.N., et al. (2013). A Shaheen, Z.R., Cheng, G., Sawatzke, K., Campbell, A.M., et al. (2013). The
molecular basis for the association of the HLA-DRB1 locus, citrullination, autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven,
and rheumatoid arthritis. J. Exp. Med. 210, 2569–2582. type 1 interferon-dependent immunity. Immunity 39, 111–122.

Immunity
Review
Wegner, N., Wait, R., Sroka, A., Eick, S., Nguyen, K.A., Lundberg, K., Kinloch, Yang, Z., Shen, Y., Oishi, H., Matteson, E.L., Tian, L., Goronzy, J.J., and
A., Culshaw, S., Potempa, J., and Venables, P.J. (2010). Peptidylarginine de- Weyand, C.M. (2016). Restoring oxidant signaling suppresses proarthrito-
iminase from Porphyromonas gingivalis citrullinates human fibrinogen and genic T cell effector functions in rheumatoid arthritis. Sci. Transl. Med. 8,
a-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis 331ra38.
Rheum. 62, 2662–2672.
Zhang, X., Zhang, D., Jia, H., Feng, Q., Wang, D., Liang, D., Wu, X., Li, J., Tang,
Weyand, C.M., Hicok, K.C., Conn, D.L., and Goronzy, J.J. (1992). The influ- L., Li, Y., et al. (2015). The oral and gut microbiomes are perturbed in rheuma-
ence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann. toid arthritis and partly normalized after treatment. Nat. Med. 21, 895–905.
Intern. Med. 117, 801–806.
Zvaifler, N.J., Boyle, D., and Firestein, G.S. (1994). Early synovitis–synovio-
Yamamoto, K., Okada, Y., Suzuki, A., and Kochi, Y. (2015). Genetics of rheu- cytes and mononuclear cells. Semin. Arthritis Rheum. 23 (6, Suppl
matoid arthritis in Asia–present and future. Nat. Rev. Rheumatol. 11, 375–379. 2), 11–16.

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Immunity

Immunopathogenesis of Rheumatoid Arthritis

Immunity 46, February 21, 2017 ª 2017 Elsevier Inc. 183

citrullinated peptides are also character-

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providing an enticing route to subse-

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Figure 3. Mechanisms that Drive the Chronicity of RA

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dysregulation apparently manifests primarily in cytokine (espe- Processes Driving Co-morbidities

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Immunity 46, February 21, 2017 193

€ngel, A., Kolling, C., Gay, R.E., Michel, B.A., Tak,

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