Journal of Internal Medicine - 2020 - Klareskog - The Importance of Differences On Environment and Its Interactions With

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Review
doi: 10.1111/joim.13058
The importance of differences; On environment and its

interactions with genes and immunity in the causation of
rheumatoid arthritis
L. Klareskog1 , J. R€onnelid2, S. Saevarsdottir3,4, L. Padyukov1 & L. Alfredsson5
1
From the, Division of Rheumatology, Department of Medicine, Karolinska Institutet and Karolinska University Hospital (Solna), Stockholm;
2
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala; 3Division of Clinical Epidemiology, Department of
Medicine, Karolinska Institutet and Karolinska University Hospital (Solna); 4Faculty of Medicine, School of Health Sciences, University of
Iceland; and 5Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Abstract. Klareskog L, R€
onnelid J, Saevarsdottir S, RA. We also discuss how several other environ-
Padyukov L, Alfredsson L (Karolinska Institutet at mental and lifestyle factors, including microbial,
Karolinska University Hospital (Solna), Stockholm; neural and metabolic factors, can influence risk for
Uppsala University, Uppsala; Karolinska Institutet RA in ways that are different in different subsets of
at Karolinska University Hospital (Solna), RA.The description of these processes in RA pro-
Stockholm; Karolinska Institutet, Stockholm; and vides the best example so far in any immune-
Karolinska Institutet, Stockholm, Sweden). The mediated disease of how triggering of immunity at
importance of differences; On environment and one anatomical site in the context of known envi-
its interactions with genes and immunity in the ronmental and genetic factors subsequently can
causation of rheumatoid arthritis. J Intern Med; lead to symptoms that precede the classical inflam-
2020; 287: 514–533. matory disease symptoms and later contribute also
to the classical RA joint inflammation. The findings
The current review uses rheumatoid arthritis (RA) referred to in the review have led to a change of
as a prominent example for how studies on the paradigms for very early therapy and prevention of
interplay between environmental and genetic fac- RA and to efforts towards what we have named
tors in defined subsets of a disease can be used to ‘personalized prevention’. We believe that the pro-
formulate aetiological hypotheses that subse- gress described here for RA will be of relevance for
quently can be tested for causality using molecular research and practice also in other immune-medi-
and functional studies. Major discussed findings ated diseases.
are that exposures to airways from many different
noxious agents including cigarette smoke, silica Keywords: rheumatoid arthritis, personalized pre-
dust and more interact with major susceptibility vention, autoimmunity, disease prediction, disease
genes, mainly HLA-DR genetic variants in trigger- subsets, gene–environment interactions.
ing antigen-specific immune reactions specific for
This evolutionary perspective may be particularly

Introduction
useful in the study of diseases of the immune system,
Evolution is driven by natural selection where where infections historically have been the major
variable environments interact with variable driver of selection, favouring variability at many
genotypes in determining the fate of an individ- levels of the immune system; the major histocompat-
ual. This follows that combinations of some ibility region (MHC) is notably one of the most variable
variable genes and some variable environmental genetic regions in many species including humans [1]
determinants will determine the ‘immunological and the genes coding for T- and B-cell receptors [2] in
phenotype’ of an individual and thus influence the adaptive immune system provide us with exten-
the onset and course of immune-mediated sive both interindividual and intraindividual variants
diseases. A further correlate from the influence for immune defence.
of the environment is that both cause and
course of diseases will vary with time and As destruction and loss of function of an organ can
space. be the result of many kinds of dysregulation at
514 ª 2020 The Association for the Publication of the Journal of Internal Medicine
13652796, 2020, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13058 by Cochrane Colombia, Wiley Online Library on [11/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Environment and genes in RA / L. Klareskog et al.
many different levels in the immune and inflam- As different mechanisms may be responsible for
matory systems, it also follows that different com- the causation of different symptoms, and as these
binations of genes, environmental factors and mechanisms might differ between different genet-
chance may be active in different subsets of clin- ically or immunologically defined subgroups of the
ically defined diseases. However, also chance (or disease classified as RA, we need to investigate the
‘stochastic factors’) has a major impact as major determinants for each of these symptoms in sep-
variabilities in immune molecules are shaped also arate genetic and/or immunologic contexts, and
by random events as is the case for T- and B-cell not as signs of one homogeneous disease.
receptor where repertoires are unique in each
individual, also between monozygotic twins [3]. Notably, this reasoning goes not only in RA but also
Notably, also environmental exposures will shape for other antibody-associated immune-mediated
the composition of immune repertoires of the diseases such as vasculitis [8] and myositis [9]
immune system and differences in immune cell where subdivision based on immunophenotype
phenotypes between different monozygotic twins has provided more aetiological insights than sub-
have been shown to increase over time with differ- divisions based on clinical symptoms only.
ential environmental exposures [4]. A consequence
of this reasoning is that studies of cause, course
Subdivision of RA in subsets by means of serology
and remedies for immune-mediated diseases
should be based on information on how combina- The antibodies that are present in RA patients are
tions of genetic variants, environmental exposures typically present only in certain subsets of the
and random events enable the development of disease, with a complex pattern of partial overlaps
different disease subtypes. and cross-reactivity between the different antibod-
ies. The presence of agglutinating IgM rheumatoid
The current review aims to describe the results of factors (RF) [10] constitutes the classical hallmark
such efforts in rheumatoid arthritis. of the so-called ‘seropositive’ subset of RA. Subse-
quently, also IgG and IgA RF have been identified
and are typically present in subsets of the IgM RF-
Rheumatoid arthritis (RA) – a complex and heterogeneous disease
positive patient group [10]. A breakthrough in RA
As many other complex and chronic diseases, the research occurred with the discovery that antibod-
disease we call RA has since its first naming in the ies previously defined as anti-perinuclear, anti-
1850s [5] been defined by various clinical descrip- keratin or anti-filaggrin antibodies displayed a
tions and more recently by detailed classification distinct reactivity with peptides and proteins mod-
criteria [6]. These classification criteria have been ified by citrullination, later named anti-citrulli-
developed mainly to enable scientific investiga- nated protein/peptide antibodies (ACPA) [11,12].
tions, particularly clinical trials for patients with The presence of these antibodies as measured by
similar symptoms. Interestingly, descriptions of the standard anti-circular citrullinated peptides
what is RA as well as the classification criteria have (anti-CCP) assay [13] was mainly seen in the IgM
changed over time, recently to enable earlier diag- RF-positive group, but there are also smaller
nosis of the disease, but also to take biomarkers as subsets of patients who are RF+/anti-CCP- and
well as variations in clinical manifestations over anti-CCP+/RF- [14-16]. Whereas the anti-CCP
time into account [6]. Studies such as those assay captures most ACPAs, there is a notable
described below are therefore valid for the variants heterogeneity in reactivity to distinct citrullinated
of RA that are present in our present time, and in peptides and proteins with a large number of
certain geographical regions and in the context of overlapping subsets being formed [17-20] (see also
environments and lifestyles that are under rapid Figure 1). Subsequent to the recognition of reac-
change. tivity against epitopes modified by citrullination,
RA autoantibodies have been shown to also react
We also have to acknowledge that RA is a chronic with proteins/peptides modified by additional
disease, where symptoms typical for the disease post-translational modifications, including homo-
(pain, fatigue) often occur before the onset of joint citrullination (or carbamylation) [21-24] as well as
inflammation [7], and where other symptoms and acetylation [25,26]. Although most of these anti-
comorbidities may add on over time, for example bodies are seen in ACPA-positive patients, there
joint destruction, subcutaneous nodules, lung and are also smaller subsets of RA with antibodies
cardiovascular symptoms, lymphomas and more. against these alternative modifications, while being
ª 2020 The Association for the Publication of the Journal of Internal Medicine 515
Journal of Internal Medicine, 2020, 287; 514–533
negative for ACPA or RF [18,20]. Collectively anti- proportion of asialylated sugars has been observed
bodies against post-translationally modified pep- in the Fc part of antibodies during the emergence of
tides are denoted anti-modified peptide antibodies RA [31], and a very high glycosylation of specific
(AMPA). parts of the Fab region has been observed on IgG
ACPAs [32]. The perceived functional relevance of
Several other antibody reactivities have been these findings will be discussed in the sections on
shown to be present in smaller groups of RA functional effects of antibodies below.
patients, some being rather specific for RA, other
being shared with other inflammatory diseases Taken together, several RA subsets can be defined
such as antibodies to SSA and SSB often in from the presence of different patterns of antibod-
conjunction with RF [27]. Notably, antibodies to ies, implicating that different mechanisms are
cartilage-derived collagen II (anti-CII) are present involved in the generation of defined subsets of
in one specific but rather small subsets of RA with this criterion-defined disease.
a clinical acute onset phenotype [28-30]. Antibod-
ies against citrullinated collagen II peptides are
Genetics
included in the broader group of ACPAs [20,29,30].
While genome-wide association studies have
Notably, antibodies associated with the develop- defined more than 100 SNPs that have significant
ment of RA show interesting features not only differences in allelic frequencies between RA
concerning their specificity, but also concerning patients and healthy controls [33,34], the long-
other properties such as glycosylation of the Fc and known association with several alleles in the HLA
Fab parts. Thus, the emergence of an increasing locus remains dominant [35]. The initial demon-
stration that the association between certain HLA-
DR alleles, often grouped together under the con-
cept of ‘shared epitope’ (SE) [36], and RA was
confined almost exclusively to the RF-positive and
anti-CCP-positive subsets of disease [14,37,38],
indicating that the MHC class II-dependent
immune events are involved mainly or only in
serologically defined subsets of disease. Later, also
the second most prominent genetic variant associ-
ation with RA, a missense variation in the PTPN22
gene [39] was also found to be mainly associated
with ACPA-positive RA [40,41]. Further detailed
analysis of the effects of HLA-DR genes in subsets
defined combinations of RF and anti-CCP antibod-
ies have shown that the association with HLA-DR
SE alleles is confined to subsets of disease that are
anti-CCP+/RF+ or anti-CCP+/RF-negative but are
not present in the anti-CCP-/RF+ subset, impli-
cating different pathogenic mechanisms in the
single RF-positive as compared to the anti-CCP-
Figure 1 Overlap between presence of different anti- positive subsets (more about the functional impli-
body specificities in the incident RA cohort named EIRA cations of these findings below) [16].
(epidemiological investigation of rheumatoid arthritis). The
colours denote the presence of antibodies to specific Studies in the antibody-negative subset of RA have
annotated target molecules, and the figures denote num- over the years been challenging. Thus, whereas the
bers of individuals scored positive for the antibodies
subset defined by the presence of one or several
marked by colour in the specific section of the picture.
antibodies has some common functional denomi-
Data for 1706 patients with data for all investigated
autoantibodies are depicted; 465 patients did not express nator, there is no reason to believe that such
any of the autoantibodies. Note that numbers of patients common denominators would be present in the
with the respective antibody-defined subphenotypes are broad group of antibody-negative RA patients.
provided in sections of the figure where only the relevant Rather, the identification only of relatively weak
overlaps are seen. genetic associations [42,43] in the ACPA/RF-
negative subset suggests that this subset may be peptides. A recent analysis using this approach
heterogeneous with regard to genetics and related indeed demonstrated that aspartic acid in position
pathogenic mechanisms. 9 of HLA-B preferably associated with RA subsets
defined by the presence of antibodies against
In contrast to the situation for the MHC and distinct citrullinated peptides (defined as ‘non-
PTPN22 gene, where the polymorphisms associ- canonical’ specificities), whereas valine in position
ated with RA are present in protein-coding regions, 11 of the HLA-DR beta chain associated with the
most other polymorphisms are present in noncod- presence of a large group of mostly cross-reactive
ing regions of the genome [33,34]. Different antibodies against several citrullinated peptides
approaches have been used in order to get an and proteins (defined as ‘canonical’ specificities)
understanding of the potential functional role of [50]. When this analysis of serologically defined
these polymorphisms in disease development. subsets was extended to the anti-CCP-negative
These studies include investigations on differen- subset, it was also shown that a small group of
tially methylated sites in the genome, e-QTLs, individuals positive for antibodies against certain
associations with chromatin structure change, fibrinogen, vimentin and enolase-derived citrulli-
and involvement of long noncoding RNA. These nated peptides associated with HLA-DR SE alleles
approaches have produced more accurate esti- [20]. This finding further demonstrated that sub-
mates of genes involved in RA pathogenesis as setting of RA by means of reactivity to peptides and
compared to earlier studies that most often protein fragments from distinct autoantigens may
described the identity of genes close to the initially define an extended group of ACPA-positive RA
identified SNP. The assignment of genes identified patients as compared to the group defined only
in these functional ways has enabled descriptions from the occurrence of anti-CCP.
of molecular pathways active in particular cell
populations where several RA-associated genes are Concerning genetic associations with other anti-
involved [44,45]. An overall conclusion from such body-defined subsets, the small subsets defined by
analyses of non-HLA genes has been that a signif- the presence of antibodies to carbamylated pep-
icant part of the genetic contributions to ACPA- tides/proteins only are not associated with any
positive RA arises from variations related to the defined MHC alleles [51]. Further, the distinct but
regulation of T cells and in particular T helper cells still small subset defined by antibodies against
[20,46-48]. native collagen type II does not associate with the
major HLA-DR SE-associated alleles but shows a
A major improvement of the model of MHC class II- weak association with HLA-DRB1*03 allele [29,30],
dependent T-cell activation in HLA-DR SE-associ- again implicating a different pathogenesis of this
ated subsets of disease occurred from an investi- subset as compared with the major ACPA-associ-
gation where the presence of different amino acids ated RA groups.
(aa) in the antigen-binding grove of MHC class II
and class I molecules was analysed in anti-CCP-
The relative importance of genes vs. environment as determinants
positive RA patients as compared to healthy con-
of RA development in different subsets of the disease.
trols. This analysis showed that variations in
neutral vs. positively charged aa residues (mainly Results from twin studies can be used to obtain a
aa 11 and 13 of the HLA-DR Beta chain) in the crude picture of the relative importance of genetics
antigen-binding grove of the HLA-DR molecule on one hand, and environment, lifestyle and
accounted for most of the previously shown asso- stochastic factors (chance) on the other. Some
ciation between RA and anti-CCP-positive RA [49]. studies, which have identified RA cases by active
However, also variations in aa residues in the recruitment, have found a monozygotic twin con-
peptide-binding groves of HLA-DP and the class I cordance of around 15% [52,53], and in one of
molecule HLA-A and HLA-B contributed indepen- these studies, also subdivision of cases by serology
dently to RA susceptibility [49]. was performed [54]. However, more recent popula-
tion-based studies have found a monozygotic twin
The use of this aa- and antigen-binding grove- concordance of about 10% for seropositive (ACPA
centric analysis was further utilized to analyse and/or RF-positive) RA and around 5% for
whether there was any preference for certain vari- seronegative RA [55]. Thus, the influence of envi-
ants in the antigen-binding groves and presence of ronment/lifestyle and stochastic factors must be
antibody reactivity to different citrullinated substantial in both subsets of the disease.
Moreover, these studies indicate a distinct genetic subset [16]. Another smaller study without infor-
component also in the seronegative subsets of RA, mation of dose of smoking confirmed the associa-
which is not yet fully captured in GWAS analyses. tion with cigarette smoking in the RF+/anti-CCP+
and RF+/anti-CCP- subsets, but not with the anti-
Another approach to quantify the influence of CCP+/RF- subset [15]. Collectively, these studies
genetic vs. nongenetic factors in the causation of imply that RF associate more strongly with smok-
RA is to use multigeneration registers with enough ing, compared to anti-CCP with the strongest
good assignment of diagnosis. One such study on effects being seen for the anti-CCP+/RF+ subset.
‘familial heritability’ of RA has been performed
using the Swedish nationwide multigeneration A special observation of aetiological interest was
register together with national disease registers the observation that the (IgG) anti-CCP-positive
that provide diagnostic information (for methodol- subset could be further subdivided into IgA anti-
ogy, see [56]). This study showed that only about CCP-positive and anti-CCP-negative groups, and
30% of the ‘familial heritability’ can be defined by that smoking was almost exclusively associated
as yet identified genetic polymorphisms [57]. It is with risk for the IgA anti-CCP+/IgG anti-CCP
thus likely that many more genetic polymorphisms double-positive subset [73], constituting about 2/
than those hitherto defined may influence the 3 of the IgG anti-CCP-positive group (very few
development of RA. patients express only IgA anti-CCP). Notably, the
genetic association with HLA-DR SE variants was
seen in all IgG anti-CCP-positive patients and was
Impact of environment and lifestyle
not related to the presence of IgA anti-CCP [73].
We and others have used population-based and These results provided additional support to the
other broad case–control studies to identify a large notion that an anti-citrulline immune response is
number of environmental and lifestyle factors as formed at mucosal surfaces after exposure to
risk factors for the disease, summarized in Table 1. smoke in the airways. The demonstration that
Results from case–control studies have been com- exposure to nicotine in users of smoke-free tobacco
pared with results from cohort studies, where the associates neither with RA nor with increased
Nurses’ Health Study cohort study [58] has consti- levels of ACPA or RF [74,75] shows that compo-
tuted a major source. As also described in Table 1, nents in the smoke per se are responsible for the
results from the Nurses’ Health Study and different now described effects (more about mechanisms
case–control studies are highly reproducible for below).
major exposures such as smoking [59-67], hor-
monal factors [68-70] and modifying factors such Also, other environmental/occupational exposures
as alcohol consumption [71,72], whereas other and have been investigated, with silica exposure as an
more rare exposures have so far been investigated interesting example. Thus, silica exposure has
in fewer studies and mainly in case–control set- been identified as a risk factor both for RA as a
tings. whole (before appropriate subdivisions into sub-
sets was done) [76] and later found to be restricted
mainly but not exclusively to the seropositive (RF
Smoking and other airway exposures
and/or ACPA-positive) subsets [77-79]. Interest-
The risk of smoking is dependent on the amount of ingly, a significant interaction between the two
cigarette smoking before onset of disease and, environmental exposures smoking and silica expo-
interestingly, the risk persists several years after sure was observed in providing risk for ACPA-
cessation of smoking [59,60,66,67], indicating that positive RA [77,81]. An additional exposure with
disease-causing events triggered by smoking may possible effects both in airways and elsewhere was
occur long before onset of joint inflammation observed in textile workers in Malaysia, where an
classified as RA. When subjected to analysis of increased risk was seen both for anti-CCP-positive
which serologically defined subsets of disease that and anti-CCP-negative patients [80]. More recently,
are associated with exposure to cigarette smoke, we have obtained indications that also heavy
we and others have found a strong effect of occupational exposure to asbestos may provide
smoking in the anti-CCP+/RF+ subset [14-16], a an increased risk for RA [79]. Also, exposure to
smaller but highly significant effect in the anti- more general air pollution has been investigated,
CCP-/RF+ subset and a weaker effect, visible but provided variable results. Thus, results from
mainly in heavy smokers, in the RF-/anti-CCP+ NHS and elsewhere have indicated an increased
Table 1. Environmental factors associated with risk of developing RA
Exposure RA overall Seropositive RA Seronegative RA References

Smoking and other airway exposures
Smoking + + +/ [59-67]
Passive smoking (as adult) [202,203]
Snuff use [74,75]
Occup. exp to silica + + +/ [76-79]
Occup. exp to asbestos + + + [79]
Occup. exp to coal +/ ? ? [86,87]
Occup. exp to textile dust + + + [80]
Air pollution (traffic) [82-85]
Hormonal factors
Breastfeeding + ? ? [99-105]
Oral contraceptive +/ ? ? [100,107,196]
Dietary factors, including alcohol use
Healthy eating pattern /reduced /reduced ? (203,204)
Fatty fish reduced ? ? [111-116]
Moderate alcohol consumption reduced reduced reduced [71-72,119-121]
Physical exercise +/ ? ? [137,138]
Infections
Viral infection ? ? ? [127]
Bacterial infections
P. Gingivalis + + ? [128-132]
Effects are shown for RA without any subsetting, and for the ‘seropositive’ and ‘seronegative’ subsets; ‘seropositive’ is in
this context patients positive for ACPA and/or RF; for many exposures, differentiation between RF-positive and ACPA-
positive groups has not been possible. In the table, (+) means that exposure for the environmental and/or lifestyle factor(s)
has been shown to increase risk for RA, whereas ( ) means that no risk has been observed. For some exposures, data are
conflicting with different results from different studies and such exposures are denoted (+/ ). A few exposures have been
shown to mediate a reduced risk for RA. These cases are denoted ‘reduced’. In still other cases, no well-documented
studies exist and such exposures for RA or RA subset are assigned with (?).
risk in individuals living close to roads with heavy triggering agents may be limited to individuals
traffic [82,83], whereas our own studies in the with a particular occupation, thus mandating
relatively clean environment in Stockholm did not follow-up of studies on occupation and RA with
observe any clear effects on RA risk of variations in more targeted approaches. Occupations repro-
amounts and size of particles and chemicals used ducibly associated with increased RA risk are
to monitor air pollution [84]. In a nationwide study characterized by airway exposure to various forms
from Taiwan, signs of an increased risk of RA in of organic or nonorganic noxious agents among
residents exposed to NO2 were observed [85]. farmers (dust), construction workers and mechan-
Finally, also exposure to coal dust has been ics [88-91].
associated with seropositive RA in a context some-
times denoted Caplan’s syndrome [86,87].
Other environmental risk factors
In studies without serological subsetting, a num-
Occupation and risk for RA
ber of physical and psychosocial factors have been
Analyses of the relationship between certain occu- reported to associate with an increased risk for RA
pations and risk for RA are limited by the fact that [92-94]. The most prominent factor is general
actual exposures to certain potential disease- socio-economic status. Thus, even after correction
for specific known risk factors (smoking, alcohol such a diet is combined with cigarette smoking
and other lifestyle factors) socio-economic status [117,118]. However, the role of diet in RA continues
measured as length of education is a very repro- to be of large interest to patients and public, but
ducible risk factor for disease [95]. When investi- requires more and stringent studies before any
gating other psychosocial factors such as stress general recommendations can be issued.
and social networks, small or no effects were seen
after correction for smoking and other known risk Several studies have shown a dose-dependent
factors [94]. However, some physical exposures protective effect of alcohol consumption on risk
such as joint load expressed as certain repetitive for RA, also when correcting for other known
movements [96], working in the cold [97] or being environmental and lifestyle factors [71-72,119-
involved in shift/night work [98] have been 120,123]. Interestingly, this protective effect
reported to be associated with a moderately appears to increase with amounts of alcohol con-
increased risk for RA. sumption up to a certain level [72,121], after which
effects are difficult to evaluate and possibly
decrease. The notion that alcohol itself, rather
Hormonal factors
than other factors associated with alcohol con-
The striking gender difference has led to the sumption, would cause the protective effect is
hypothesis that hormonal/reproductive factors strengthened by the observation that also experi-
are involved in the aetiology of RA. Several studies mental arthritis in mice is ameliorated from alcohol
have investigated these factors, however mostly added to the drinking water [122]. A crude analysis
without considering serology or genetics. of mechanisms responsible for the ameliorating
effects indicates that alcohol downregulates the
Breastfeeding has been dose dependently associ- NfjB-dependent inflammatory pathways [122].
ated with a decreased risk of RA in many [99-104], Such a broad anti-inflammatory effect is also
but not all [105] studies, whereas most investiga- compatible with the observation that the effects of
tions have reported no association between the use alcohol were similar for ACPA-positive and ACPA-
of oral contraceptives (OC) and RA risk [106,107]. negative RA [123].
The field is still open, however as a recent large
population-based case–control study observed that
Effects of microbial agents, including the microbiome
ever and past use of OC were significantly associ-
ated with a decreased risk of developing ACPA- The concept that microbial agents, including both
positive RA and that this association was stronger viruses and bacteria, would contribute to the
for a longer duration of use [100]. Interestingly, in a development of RA has been investigated for a very
study based on first-degree relatives of RA patients, long time. Indeed, the use of gold injections for the
OC use was observed to be associated with a treatment of RA was partly initiated from the
decreased rate of RF positivity, giving further suspicion that tuberculosis bacteria might trigger
support to the notion that OC use may be differ- RA and that gold might work as a treatment against
ently associated with the major RA subsets [108]. tuberculosis [124]. Later, extensive studies on
relationships between gut flora and RA were made,
however, without conclusive results with technolo-
Effects of obesity, diet and alcohol
gies available before 1980 [125,126].
Most studies on the effects of obesity on risk to
develop RA have demonstrated a certain increased For viruses, a recently published systematic review
risk for RA in individuals with obesity [109,110]. concluded that studies of RA after viral exposures
Dietary factors have for a long time been in the generally have poor quality and few conclusions
focus of many studies on development and disease can be drawn [127]. However, the authors also
course of RA, but results have in most cases mentioned some evidence in support of an
remained inconclusive and difficult to reproduce. increased risk of RA after Parvo B19, HCV and
Protective effects have, however, been observed in possibly EBV infection.
several studies after consumption of fat fish [111-
114] and large amounts of omega-3 fatty acids Concerning bacterial infections and risk for RA, the
[115,116]. A few recent studies have reported an most tangible results have been obtained for peri-
enhancing effect on RA risk from consumption of odontitis-associated bacteria, mainly Porphy-
food with high sodium content, in particular when romonas gingivalis, where citrullination by
endogenous citrullinating enzymes from this bac- disease. Several statistical approaches exist to
terium has been shown to generate citrullinated study such gene–environment interactions, and
bacterial as well as host proteins, including P. the most biologically relevant is considered to be
gingivalis-derived enolase [128-132]. ACPAs from the model that analyses the specific contribution of
ACPA-positive RA patients have been shown to two risk factors as single exposures as compared to
cross-react with these bacterium-derived citrulli- the combined effects of these two factors with
nated molecules [131], and it has been suggested interaction being defined as departure from addi-
that the presence of these bacteria in an immuno- tivity of the separate effects (i.e. interaction on the
genic context in the gums might be responsible for additive scale). The relevance of this approach, also
the triggering of some of the ACPAs in RA patients called Rothman’s pie model (or sufficient-cause
[130]. However, the relationships between peri- model) [139], has been further developed by Van-
odontitis and RA are complex, and available data derWeele [140] and used in several epidemiological
suggest that periodontitis and the presence of P. studies and in many different disease contexts. The
gingivalis per se may not be responsible for trig- relevance of this model has, however, been ques-
gering of ACPA production in RA, but that immune tioned in some theoretical modelling experiments
activation rather occurs in a context of inflamma- where the pie model may provide false-positive
tion and genetics, where P. gingivalis and other results due to a particular ‘spiking’ procedure
bacteria including Aggregatibacter actinomycetem- [141]. As this modelling procedure does not mimic
comitans may be involved [133]. the situations discussed in the present and previ-
ous case–control and cohort studies, we continue
Re-investigations of the gut [134,135] as well as to consider the Rothman model as a valuable and
other microbiomes including the lung [136] have relevant tool for calculation of the strength of gene–
produced interesting results concerning associa- environment interactions. There are several ways
tions between different compositions of the micro- to quantify such additive interaction, the most
biome and presence of RA. So far, however, no usual being relative excess risk due to interaction
distinct properties of the gut or lung microbiomes (RERI) and attributable proportion due to interac-
have been observed prior to the development of RA tion (AP) [142]. In the present context, the AP is
or any distinct subset of RA; something that makes most frequently used since it has a more straight-
it difficult to determine whether the observed forward interpretation; that is, it measures the
differences in microbiomes between RA cases and proportion of incidence among the double exposed
controls are involved in the causation of RA or are that is due to the interaction per se (for details of
consequences of the RA phenotype. the procedure and examples of its use, see Figure 2
and references [14,37,41,143-145]). In some cases,
we and others also used departure from multi-
Effects of exercise
plicativity as a measure of interaction, with confir-
Only very few studies have been performed inves- mation of interactions between HLA-DR SE alleles
tigating effects of exercise on risk for RA develop- and smoking in the ACPA-positive subsets also
ment, and the largest one so far from our own with this procedure [41].
groups failed to demonstrate any protective effects
on disease incidence, but showed that individuals Investigation of gene–environment interactions
involved with regular exercise programmes before between major environmental and major genetic
onset of RA had a significantly milder disease at variants provides a most powerful way to formulate
onset as compared with individuals with a seden- testable aetiological hypotheses of disease devel-
tary lifestyle [137]. In a recent study from the opment in various subsets of disease. We and
Nurses’ Health Study, higher levels of physical others have used this opportunity in the serolog-
activity were, however, associated with reduced RA ically defined RA subsets describe above. The very
risk [138]. first observations of an interaction between smok-
ing and HLA-DR alleles were seen in seropositive
RA both when defined first by RF positivity [37] and
Gene–environment interactions
thereafter by the presence of anti-CCP antibodies
The aetiology of complex diseases like RA depends [14], in both cases with large attributable propor-
on both genes and environment, and there is an tions due to interaction. These observations were
obvious need to investigate interactions between also rapidly reproduced in several studies in Cau-
genes and environment in relevant subsets of casian populations [143,144]. The same analyses
Figure 2 Schematic illustration of the principle for calculating gene–environment interaction using the Rothman additive
model (see ref 139,140,142-147). The figure illustrates how the effect of interaction is calculated using information from the
odds ratio calculated for each of the risk factors alone and the odds ratio for the two risk factors combined.
have subsequently been performed in subsets Gene–environment interactions similar to those

defined by various patterns of antibodies and between smoking and HLA-DR susceptibility alleles
found that gene–environment interactions between in ACPA-positive RA patients have been described
smoking and HLA-DR SE alleles are present in all also for a few other airway exposures, including
subsets defined by the presence of ACPAs, whereas silica dust [77,78] and textile dust [80] in Malaysia.
no such interaction is present in the RF+/anti-
CCP- groups or in the overall seronegative subsets
Triggering of RA-associated immunity in the context of genes,
[16]. Interestingly, this gene–environment interac-
environment and time
tion has subsequent to the first studies in Cau-
casian populations and has been identified also in A major observation in RA as well as in several
Malaysian [145] and Korean [146] populations other immune-mediated and antibody-associated
where ‘Asian’ HLA-DR SE alleles, in particular diseases is that the disease-associated immunity
HLA-DRB*0405, interact with smoking. The func- occurs a long time before the emergence of any
tional relevance of this finding was further empha- disease symptoms. In RA, the emergence of RF as
sized from the observations that differences in well as antibodies to citrullinated perinuclear
amino acids in critical parts of the peptide-binding antigens and filaggrin before onset of joint inflam-
groove of HLA-DRB described above also showed mation was first shown in Finland [152,153] and
interactions with smoking in ACPA-positive RA provided the basis for a still expanding field of
[147]. Taken together, these studies form the basis studies aiming to understand the gradual evolution
for the hypothesis that smoking may contribute to of immunity and symptoms associated with RA (see
the formation of citrullinated peptides that bind also [7]). The development of this field including the
specifically to the HLA-DR variants with certain recognition that not only ACPAs but also antibod-
amino acids in the antigen-binding groove and that ies to other post-translational modifications
this complex may in certain contexts, such as in (AMPAs) and RF emerge long before onset of RA
the lung, be recognized by T-cell receptors and lead [154-156] and that epitope spreading as well as
to T-cell activation and subsequent autoantibody changes in glycosylation of these antibodies hap-
formation [148-151] (Figures 3 and 4). The obser- pen during the transition from autoimmunity to
vation that the interaction between SE and smok- autoimmune disease [31-32,156-159] has been
ing is even stronger in the ACPA-positive subset covered in an excellent recent review in Journal of
that is also positive for RF, than in the ACPA- Internal Medicine [160].
positive, but RF-negative subset [16], indicates
that RF has an enhancing role in the biological A major task for the investigations of RA patho-
events that provide the basis for the gene–environ- genesis has been consequently to understand how
ment interactions. and where this immunity that precede joint
Figure 3 Schematic illustration of how many different environmental agents may affect organs distant from joints, in
particular at mucosal surfaces, and initiate immune reactions that subsequently contribute to symptoms associated with
arthritis.
inflammation is triggered; ample evidence exists constitutively expressed in the lungs, whereas
that it is not initiated in joints, where no immune PAD4 appears to be subject to induction after
cells and no evidence of local immune activation exposure of noxious agents to the lung [162,163].
are seen at times of high levels of AMPAs and RF Increased levels of citrullinated proteins have
[161]. indeed been found in biopsies from the bronchial
tree [163] as well as in cells from bronchoalveolar
Here, the evidence of gene–environment interac- fluids [14] in smokers as compared to nonsmokers.
tions between HLA-DR risk alleles and the findings Of potential relevance is that exposure to smoke
so far indicate that smoking and other noxious may also induce other post-translational modifica-
agents associated with risk for seropositive RA may tions including homo-citrullination (by nonenzy-
induce citrullination in several cell types in the matic procedures [164]), and may also enhance the
lung via activation of the citrullinating enzymes formation of other neo-antigens involved in
peptidyl arginine deiminases (PAD), especially immune-mediated diseases. Smoking and other
PAD4 and PAD2 [162]; PAD2 appears to be noxious agents in the airways may also change the
Figure 4 Schematic illustration of molecular events at mucosal sites where arthritis-associated immune reactions can be
triggered (left part of the figure) and how these immune reactions may target different cells in joints and bones and give rise
to functional effects such as bone loss and arthralgia and potentially also to joint inflammation – arthritis.
oral and lung microbiome [136], and are associated from several laboratories and described in other
with an increased frequency of periodontitis review articles [171,172]. One particular challenge
[165,166]. There are thus many ways whereby in these studies will be to explain the impact of
smoking may make self and nonself molecules rheumatoid factors in the process that give rise to
available for antigen processing and presentation the most pronounced gene–environment interac-
in the lungs and associated mucosal surfaces, and tions in the RA subpopulations positive for both
whereby immune reactions may be initiated. Which ACPA and RF. Notably, smoking has in other
immune reactions that will ultimately be triggered contexts been shown to activate RF production in
depend on both local conditions for immune acti- a non-T cell- and non-MHC-dependent manner
vation and on genetic constitution, mainly in MHC [173]. Such a T cell-independent mode of RF
genes expressed by the host. Of interest in the production is further supported from single-cell
context of local immune activation is that smoke studies of RA-derived RF-producing B cells where
(containing char and other agents) as well as silica very few somatic mutations in immunoglobulin
dust can activate dendritic cells as well as mono- genes are present – in contrast to extensive somatic
cytes/macrophages as antigen-presenting cells by mutations in ACPA-producing B cells from the
effects mediated via pattern recognition molecules, same RA patients [174]. Also, complement activa-
including TLR4 [167-169]. That such events hap- tion might be involved in RF-enhanced inflamma-
pen also in vivo in patients is indicated from the tion induced by ACPA [175]. An attractive
demonstration of germinal centre-like structures in possibility is thus that smoke and possibly other
the lungs of ACPA-positive newly diagnosed RA airway exposures may initiate RF production in a T
patients [163,170]. These features provide a pos- cell-independent manner and that RF-expressing B
sible context for immune activation against both cells and RF-containing immune complexes may
post-translationally modified, including citrulli- enhance antigen presentation and immune activa-
nated, molecules as well as to microbial proteins tion against other antigens, in particular in the
present in the lungs or in the gums. Indeed, levels context of T-cell recognition of peptides binding to
of ACPAs measured in BAL fluid of newly diagnosed RA-associated MHC class II molecules.
RA patients are higher than in blood (after correc-
tion for total IgG concentrations) indicating local Of large interest is the evidence that this scenario
ACPA production [163]. of mucosa-associated immune activation may
occur long before onset of RA. This concept is well
Mechanisms, specificities and potential local supported from studies on ACPA- and RF-positive
pathogenic effects of such immune activation in individuals at risk for RA, but so far without any
lungs and other mucosal surfaces including gums joint symptoms [175-177]. The mechanisms and
and teeth are presently subject to active studies implications of these findings have been
extensively described in several recent reviews as being positive for ACPA using the anti-CCP
[178-180]. assay, 2/3 of these individuals were without any
arthritis at the screening visit, whereas 1/3 had a
diagnosed RA [55]. Interestingly, both the presence
Development of RA-associated symptoms in the context of genes,
of ACPAs without RA and the presence of criterion-
environment and immunity
defined RA associated with smoking as well as with
As indicated in the introduction to this review, RA HLA-DR SE, but the relative impact of smoking was
is a heterogeneous disease also concerning which higher in the antibody-positive and RA-negative
symptoms that emerge and when such symptoms group as compared to the impact of HLA-DR SE
are present. Accumulating data indicate that dif- genes. The opposite was the case for ACPA-positive
ferent mechanisms may be responsible for different RA [55]. This study thus provides suggestive
symptoms. evidence that a partly MHC class II independent,
but smoking-dependent process may be active in
In support of this concept, several RA-associated the early process of immune activation, whereas an
symptoms, in particular joint pain (arthralgia) and MHC class II and T cell-dependent process may be
bone loss, have been described in ACPA- and RF- critical in the transition from autoimmunity to
positive individuals years before onset of joint autoimmunity-associated joint inflammation in
inflammation [177,181,182]. Additional studies some individuals. This observation is also in line
have demonstrated that antibodies, including with the findings of a gradual and T cell-dependent
ACPAs derived from RA patients, may induce bone broadening of the antibody repertoire towards
loss as well as pain when transferred to mice [183- reactivity against larger sets of both citrullinated
187]. As has been discussed in previous reviews and otherwise modified peptides and proteins
[178,179], some of these effects are suggested to be (156-158; 189,190).
due to an activation and chemokine production
from osteoclasts after exposure to ACPA [184- A major remaining question is whether the anti-
185,187]. body responses described here contribute to the
actual joint inflammation, which is characterized
In some but not all individuals carrying ACPAs, by massive proliferation of synovial fibroblasts and
other AMPAs and/or RF, joint inflammation will macrophages that invade and destroy cartilage and
follow, whereas most individuals with AMPAs/RF bone in the joints. Notably, recent studies have
will not develop RA, and in many of them, the pointed out the differential behaviour of different
autoantibodies will disappear without future sets of synovial fibroblasts in this process
sequelae [188]. It thus becomes of interest to [191,192] however, without providing leads to
understand which symptoms that depend on anti- which factors in the pre-existing immune reactions
bodies without the simultaneous presence of joint that may contribute to the development of these
inflammation and which additional mechanisms phenotypes of synovial fibroblasts. A recently
may be responsible for the transformation from published report from our own group provided
autoimmunity to autoimmunity-associated joint evidence that certain ACPAs may indeed activate
inflammation, and ultimately arthritis classified synovial fibroblasts into a migratory behaviour
as RA. So far, only limited studies have been after binding to citrullinated targets on their cell
performed aimed at understanding how genes, surface [193]; notably, only synoviocytes that had
environment and gene–environment interactions previously been activated by various stimuli,
contribute to the emergence of antibodies without including pro-inflammatory cytokines and
symptoms, to a state of antibody-associated pain chemokines, were targeted by the ACPAs, thereby
and bone loss and to joint inflammation, respec- providing additional but still circumstantial sup-
tively. This is partly due to the fact that the port for a two-step model of the development of
identification of individuals with AMPAs and/or joint inflammation in ACPA- and RF-positive indi-
RF but without joint inflammation requires screen- viduals [193]. Whether also other mechanisms
ing of a large population without any signs of joint involving ACPAs that cross-react with post-trans-
inflammation. One study from our group has lationally modified cartilage molecules, including
addressed this question in a large population- collagen II, CILP, tenascin and more [194-197],
based group of twins, with available blood samples, contribute to joint inflammation remains an addi-
genotypes and environment/lifestyle information. tional possibility in need of exploration using
While identifying approximately 2.5% of the twins polyclonal as well as monoclonal antibodies from
RA patients. Importantly, however, we must recog- are responsible for the development of different
nize that multiple regulating events happen over subsets of this disease.
time after initial triggering of potentially pathogenic
immunity. A recent report highlighted this fact by What has enabled the research producing the
showing that many individuals with ACPA and/or results summarized in this review has to a large
RF actually seroconverted back to a nonimmune extent been the opportunity to combine analysis of
state spontaneously [188]. Further investigation of genes, environment and gene–environment inter-
such processes may provide leads to how to actions for forming a testable hypothesis on where,
modulate potentially pathogenic immune reactions when and how potentially pathogenic immune
to instead become preventive. reactions are being generated. The shaping of the
‘mucosal hypothesis’ for generation of the RA-
Of interest in that context is that another smaller associated immunity, together with knowledge of
subset of RA characterized by the presence of the gradual evolvement of immunity and disease,
antibodies to native type II collagen (anti-CII) has helped to formulate a model of how triggering
seems to have a relationship to genes and envi- and perpetuation of pathogenic immunity may
ronment that is entirely different from what is the occur [178,193,200]. Building further on this
case for RF and AMPAs. Notably, these anti-CII model, testable hypotheses have been formulated
antibodies do not appear in the pre-RA phase on how immunity triggered at sites different from
[198]. Instead, anti-CII levels are high in a sub- the joints may after some further time and immune
group of RA patients at the time of diagnosis and evolvement target cells and structures in joints and
thereafter decline during the first year [28-30]. cause symptoms associated with RA [179,180].
There is also evidence that this transient appear-
ance of anti-CII in early RA is pathogenic. Thus, The capacity to use epidemiology and the combined
production of inflammatory cytokines has been analysis of genes, environment and immunity in
shown to be driven by anti-CII-containing immune the context of the longitudinal course of a disease
complexes via ligation of the Fc gamma RIIa depends on the capture of a vast amount of
receptor on monocytes/macrophages [199], in a epidemiological as well as biological data. Further,
process that is enhanced by granulocytes and these data need to be captured in ways that enable
involving the receptor TLR4 [199]. There is also a unbiased recruitment of cases and controls, and
close association between changes in anti-CII also enable a cohort approach with information
levels measured in vivo, production of pro-inflam- being generated on the gradual evolvement of
matory cytokines induced by anti-CII-containing immunity and disease. One rather cost-effective
immune complexes in vitro, and levels of ESR and way of accomplishing this goal is to perform
CRP in vivo [30]. Consequently, RA patients with population-based case–control studies using inci-
high anti-CII levels at the time of diagnosis have dent cases that are included in longitudinal regis-
high disease activity at diagnosis, but the anti-CII- ters, such as was the case for our Swedish EIRA
induced inflammation wears off as anti-CII levels study [201]. Another powerful but more resource-
drop, giving anti-CII-positive patients a favourable demanding approach is to rely on large longitudi-
long-term prognosis [29,30]. Although anti-CII is nal general cohort studies such as the Nurses’
associated with an acute onset RA phenotype, this Health Study where now more than 1000 cases of
association seems to be RA specific, as no RA have been identified amongst close to 200.000
increase in anti-CII levels is found in diagnosis US nurses followed for up to 40 years [68]. Opti-
sera from patients with other arthritides with mally, these different approaches should be com-
onset characterized by acute inflammation, like bined and results used to formulate testable
reactive arthritis, gouty arthritis and remitting biological hypotheses as has also been the case
seronegative symmetric synovitis with pitting for the RA studies described in this review.
oedema [30].
A major claim in this review is thus that studies of
aetiologies of complex diseases like RA need to
Concluding remarks
consider differences not only in genetics, but also
This review has aimed to describe how an immune- in environment and immunity between different
mediated disease, defined by traditional, mainly individuals who can be categorized into different
clinical, classification criteria, can be understood subsets of a disease. As importantly, the same
as a syndrome where several different mechanisms insights should provide support for efforts aimed at
prevention, recognizing that different approaches constituent of antigenic determinants recognized by

will be needed for different individuals and in rheumatoid arthritis-specific autoantibodies. J Clin Invest
1998; 101: 273–81.
different phases of disease development. We sug-
12 Girbal-Neuhauser E, Durieux JJ, Arnaud M, et al. The
gest the term ‘personal prevention’ as a potential epitopes targeted by the rheumatoid arthritis-associated
term for such strategies. antifilaggrin autoantibodies are posttranslationally gener-
ated on various sites of (pro)filaggrin by deimination of
arginine residues. J Immunol 1999; 162: 585–94.
Acknowledgements 13 Schellekens GA, Visser H, de Jong BA, et al. The diagnostic
properties of rheumatoid arthritis antibodies recognizing a
The studies referred to from the laboratories and
cyclic citrullinated peptide. Arthritis Rheum 2000; 43: 155–
clinics of the authors were support by grants from 63.
the Swedish Research Council, the Swedish 14 Klareskog L, Stolt P, Lundberg K, et al. A new model for an
Rheumatism Association (patient organization), etiology of rheumatoid arthritis: smoking may trigger HLA-
King Gustaf 80-year Jubilee Research Foundation, DR (shared epitope)-restricted immune reactions to
the Stockholm Region, the European Research autoantigens modified by citrullination. Arthritis Rheum
Council and the EU/IMI grants BTCure 115142 2006; 54: 38–46.
15 van Wesemael TJ, Ajeganova S, Humphreys J, et al. Smoking
and RTCure 777357 and Karolinska Institutet. We
is associated with the concurrent presence of multiple
thank Vijay Joshua for help with graphics of the autoantibodies in rheumatoid arthritis rather than with
figures in the manuscript. anti-citrullinated protein antibodies per se: a multicenter
cohort study. Arthritis Res Ther 2016; 18: 285.
16 Hedstr€ om AK, R€ onnelid J, Klareskog L, Alfredsson L. Com-
Conflicts of interest plex relationships of smoking, HLA-DRB1 Genes, and sero-
logic profiles in patients with early rheumatoid arthritis:
No conflicts of interest are declared for any of the
update from a swedish population-based case-control study.
authors. Arthritis Rheumatol 2019; 71: 1504–11.
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13652796, 2020, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/joim.13058 by Cochrane Colombia, Wiley Online Library on [11/02/2023].

The importance of differences; On environment and its

This evolutionary perspective may be particularly

Table 1. Environmental factors associated with risk of developing RA

Exposure RA overall Seropositive RA Seronegative RA References

have subsequently been performed in subsets Gene–environment interactions similar to those

prevention, recognizing that different approaches constituent of antigenic determinants recognized by

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