Journal of Autoimmunity 35 (2010) 10e14

Contents lists available at ScienceDirect

Journal of Autoimmunity
journal homepage: www.elsevier.com/locate/jautimm

The environment, geo-epidemiology, and autoimmune disease:

Rheumatoid arthritis
Gabriel J. Tobón, Pierre Youinou, Alain Saraux*
EA2216, IFR148, Université de Bretagne Occidentale, Brest, and Service de Rhumatologie, Centre Hospitalier Universitaire de Brest, Brest, France

a b s t r a c t

Keywords: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by a distinctive pattern of
Rheumatoid arthritis bone and joint destruction. RA patients have an increased risk of death. The incidence and prevalence of RA
Epidemiology vary across populations, statistical methods, and disease definitions. In North America and Northern Europe,
Incidence
the incidence of RA is estimated at 20e50 cases per 100,000 population and the prevalence at 0.5e1.1%.
Prevalence
Lower incidences and prevalences have been reported in Southern Europe, and few data are available for
Environmental factors
developing countries. Some studies showed declining incidences and prevalences after the 1960s. RA is
a multifactorial disease that results from interactions between genetic and environmental factors. The main
genetic factors are HLA-DRB1 and the tyrosine-phosphatase gene PTPN22. Among environmental factors
implicated in the development of RA, smoking shows the strongest association with RA susceptibility and is
also linked to worse outcomes. The aim of this review is to discuss the available data on the incidence and
prevalence of RA, as well as the genetic and environmental risk factors associated with RA.
Ó 2010 Elsevier Ltd. All rights reserved.

Take-home messages 1. Introduction

The incidence and prevalence of rheumatoid arthritis (RA)
vary across populations, methodologies, and case-ascertain-
ment criteria.

The incidence and prevalence of RA are higher in North
America and Northern Europe than in Southern Europe and
developing countries.

Both the prevalence and the incidence of RA have declined
over the last four decades.

RA is a multifactorial disease that involves both genetic and
environmental factors.

HLA-DRB1 and PTPN22 are the main genetic factors associated
with the development of RA. RA patients who carry these
genes are likely to produce anti-cyclic citrullinated peptide
antibodies.

Environmental factors whose potential role in RA has been
investigated include infections, smoking, pollutant, and die-
tary factors. Smoking is the main environmental factor
associated with RA.
Rheumatoid arthritis (RA) is a chronic inflammatory joint
disease characterized by a distinctive pattern of bone and joint
destruction. RA is also a systemic disease, and several patient
subsets can be distinguished based on the presence of extra-artic-
ular manifestations. For example, the concomitant presence or
absence of anti-cyclic citrullinated peptide antibody (ACPA) and
rheumatoid factor (RF) defines two important patient subsets [1].
Several epidemiological studies of RA have been published. They
show variations in the incidence and prevalence of RA across
populations. Further variation include occurs as a result of differ-
ences in statistical methods and case-ascertainment criteria.
Several large prospective studies have improved our knowledge of
the risk factors for RA. Unfortunately, the available epidemiological
data often come from retrospective studies and underpowered
case-control studies. Here, we review the main data on the epide-
miology of RA and on the environmental factors involved in the
disease.
2. Epidemiology

2.1. Incidence
* Correspondence to: Alain Saraux, Rheumatology Unit, Brest University Medical
School, BP 824, F29609 Brest, France. Tel.: þ33 298 347 267; fax: þ33 298 493 627. The incidence of RA varies across populations. Estimates from
E-mail address: alain.saraux@chu-brest.fr (A. Saraux). North America and Northern Europe range from 20e50 cases per

0896-8411/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jaut.2009.12.009
 G.J. Tobón et al. / Journal of Autoimmunity 35 (2010) 10e14
Table 1
Incidence and prevalence of rheumatoid arthritis in various populations.
Populations Incidence (cases per Prevalence (cases per
100,000 population) 100 population)
Northern Europe 29 (24e36) 0.5 (0.44e0.8)
Southern Europe 16.5 (9e24) 0.33 (0.31e0.5)
North America 38 (31e45) 0.5
Developing countries No data 0.35 (0.24e0.36)
100,000 population. In Southern Europe, lower incidences of 9e24
cases per 100,000 population have been reported. The incidence of
RA in developing countries is unknown [2e5].
2.2. Prevalence and geographic variation
Studies done in North America and Northern Europe have
shown prevalences of 0.5e1.1%. In Southern Europe, lower preva-
lences of 0.3e0.7% have been found [6e9]. Table 1 reports inci-
dence and prevalence data in various populations. Prevalence data
by gender and country are shown in Table 2.
We used an original case-ascertainment method to study the
epidemiology of RA in the Brittany region of western France [6].
Possible cases were first identified in the general population by
phone interviews conducted by trained patients with RA or other
joint diseases. These possible cases were then evaluated by rheu-
matologists, who confirmed or refuted the diagnosis. The prevalence
of RA in this study was 0.5% [6]. The case-ascertainment method was
then refined and validated through a nationwide survey [10].
The few prevalence studies performed in developing countries
based on the 1987 American College of Rheumatology (ACR)
criteria [11] suggest significantly lower prevalences than in
Northern Europe and North America, of about 0.1e0.5% [12,13].
Although this finding may indicate that RA is less common in
developing countries, it may also reflect age distribution differ-
ences between developing countries and North America/Northern
Europe. In addition, cases of mild RA may escape detection more
easily in developing countries where access to medical care is
limited, leading to underestimation of the prevalence of RA in
studies that rely on retrospective chart review [5].
In some geographic areas, the prevalence and incidence of RA
vary across ethnic groups. For example, the prevalence of RA is high
among Pima Indians [14] and low in some areas of rural Africa [15].
Within ethnic groups, the incidence and prevalence of RA vary
according to the geographic area of residence [16].
2.3. Time trends in the epidemiology of rheumatoid arthritis
Limited data are available on time trends of the incidence and
prevalence of RA. Several longitudinal studies suggest declines in
both the prevalence and the incidence of RA after the 1960s. A recent
systematic review found substantial fluctuations across time
periods within studies. A substantial decline in the incidence of RA
over time with a shift toward an older age at onset was noted in
several studies. A population-based study done in Rochester, Min-
nesota (US) over the 40-year period from 1955 to 1994 showed
Table 2
Prevalence of RA by gender in various countries.
Country Females
United States 1.4%
United Kingdom 1.16%
Spain 0.8%
Italy 0.51%
France 0.51%
Greece 0.45%
11
a decline in the incidence of RA from 61.2/100,000 in the first decade
to 32.7/100,000 in the last decade [17]. In addition, there were
indications of cyclical trends over time. In five districts of Finland,
the annual incidence of RA declined by about 15% between 1980 and
1990, and the decline was largest for RF-negative disease [18].
Three factors may explain the changes in RA epidemiology over
time. First, changes in study methodologies and case-ascertainment
criteria may be involved. Several studies were conducted before the
1987 ACR classification criteria were issued. Also, RA is difficult to
differentiate from unspecified polyarthritis, and the resulting
misclassification may affect incidence figures. For example, among
patients with inflammatory arthritis, only one seventh in Kuopio,
Finland [19], and one-fourth in southern Sweden met 1987 ACR
criteria for RA. Second, geographic and ethnic factors influence
incidence and prevalence data. For instance, the incidence of RA is
markedly higher among Pima Indians than among other populations
of North America and Europe [14]. Finally, there may be true changes
in the incidence and prevalence of RA over time. Studies conducted
at various time points within the same geographic regions suggest
that the incidence of RA is declining over time and that this decline is
greatest among women [17]. One explanation for the decline in
women may be exposure to the oral contraceptives, which decreases
the incidence of RA [20]. Other studies suggest a shift over time in RA
onset toward older age groups. Data from the last decade suggest
that that the incidence of RA may be rising after four decades of
decline [21].
2.4. Mortality
Mortality rates are higher among RA patients than in the general
population. The life expectancy decrease is about 3 to 10 years. The
excess mortality associated with RA has remained unchanged over
the last two to three decades. In addition, recent studies show that RA
patients have not experienced the survival gains seen in the general
population, so that the gap between the two has widened [22]. The
main causes of death in RA patients are cardiovascular, infectious,
haematological, gastrointestinal, and pulmonary complications.
3. Risk factors for rheumatoid arthritis
RA is a multifactorial disease that results from interactions
between genetic and environmental factors. Personal and lifestyle
factors influence the course of the disease. A comparison of
smoking history between twins with RA and their unaffected co-
twins established that smoking was closely associated with RA [23].
In this study, of the 13 pairs of monozygotic twins discordant for RA
and smoking history, the twin who had RA was also the twin with
a history of smoking in 12 of the pairs. Below we discuss the main
factors believed to influence the development and/or course of RA.
3.1. Genetic factors
Genetic factors contribute 50e60% of the risk of developing RA.
The gene most strongly associated with RA is the HLA-DRB1 gene in
the major histocompatibility complex, where specific alleles within
the DRB1*04 and *01 clusters encode the “shared-epitope”
sequences within the expressed DRB1 molecule [24]. HLA-DRB1 may
contribute up to one-third of the genetic susceptibility to RA. Among
Males
other genes, the main RA susceptibility factor is the tyrosine-
phosphatase gene PTPN22 on chromosome 1. A missense C-to-T
0.74%
0.44% substitution at nucleotide position 1856 of this gene leads to
0.2% substitution of tryptophan (W) for arginine (R) at residue 620 of the
0.13% protein product. The resulting gain of function, with enhanced
0.09% regulation of T-cell receptor (TCR) signalling during thymic selec-
0.19%
tion, permits autoantigen-specific T cells to escape clonal deletion,
12 G.J. Tobón et al. / Journal of Autoimmunity 35 (2010) 10e14
thereby predisposing to autoimmunity [25]. This PTPN22 poly-
morphism is not seen in Asian populations. A vast collaborative
epidemiological study duplicated the findings in Swedish, Dutch,
and US populations, showing multiplicative effects between
smoking and the shared-epitope, as well as between the PTPN22
polymorphism and the shared-epitope. The HLA-DRB1 shared-
epitope and PTPN22 risk alleles are associated only with the RA
pattern characterized by the presence of ACPA, RF, or both.
Polymorphisms of TRAF1-C5 and TNFAIP3 have also been
described in RA. Other non-HLA genetic risk factors such as STAT4
[26] and CTLA-4 [27] have been identified in European populations,
although not with genome-wide significance.
A case-control study in a Dutch cohort was conducted to assess
the impact on RA susceptibility of three recently described loci,
namely, STAT4, IL2/IL21, and CTLA4. These loci were genotyped in
877 RA patients and 866 healthy individuals. The results showed
that each of these three loci was associated with RA (odds ratios,
1.19 [P ¼ 0.031], 0.84 [P ¼ 0.051], and 0.87 [P ¼ 0.041], respectively).
These results constitute convincing evidence that STAT4 and CTLA4
are associated with RA and highly suggestive evidence that IL2/IL21
is associated with RA in Caucasian individuals [28].
Substantial differences in genetic RA susceptibility factors have
been found between European and Asian populations. HLA-DRB1 is
the only known genetic factor that is associated with RA in all the
populations studied to date [29]. PTPN22 polymorphisms have been
identified in European populations but are rarely found in Asian
populations. On the contrary, polymorphisms of PADI4 (which
encodes an enzyme that converts the arginine residues of proteins
into citrullines, which can then be recognized by ACPAs in the sera
of RA patients) have been found more consistently in Asian than in
European populations [29].
3.2. Age and gender
RA is far more common in women than in men, the female-to-
male ratio being 3:1. However, the mechanism by which gender
influences the susceptibility to RA remains unclear. Differences in
sex hormones may be involved. The peak age at RA onset is the fifth
decade, which is a time of hormonal changes in women. However,
recent studies suggest a shift toward an older age at onset in recent
years, with this change being greater in women than in men.
3.3. Socioeconomic factors
Socioeconomic factors affect the course and outcome of RA but
do not seem to influence the risk of developing RA.
3.4. Hormonal factors
The predominance of RA in females suggests a role for hormonal
factors. In addition, estrogens stimulate the immune system. Low
testosterone levels have been reported in men with RA [30]. A
history of child-bearing may protect against RA. In patients with
RA, pregnancy often leads to a remission, followed by a flare-up
after delivery. Hormone replacement therapy (HRT) may decrease
the RA risk in women who carry the HLA-DRB1*01 and/or *04
alleles [31]. One possible explanation to this finding is that HRT
protects against the production of ACPA (OR ¼ 0.43; 95%CI,
0.24e0.77; P < 0.006). Nevertheless, these results must be
confirmed in other populations.
3.5. Ethnicity
Some ethnic and racial groups are at higher risk for RA than
others. This high risk may be related to differences in the
distribution and interactions of genetic and environmental factors.
Comparisons of populations with similar genetic backgrounds but
different lifestyles can shed light on the influence of non-genetic
factors. We used a standardized questionnaire to screen the nuns of
the nine largest Roman Catholic communities in Brittany, as well as
1706 adult females from the general population. We found similar
prevalences of RA in these two groups (1.66% vs. 1.33%) [32].
3.6. Environmental factors
The effects of several environmental factors on the risk and
outcome of RA have been studied. Environmental factors that affect
RA may act many years before the disease becomes clinically
apparent. Here, we discuss the main environmental factors impli-
cated in the development of RA.
3.6.1. Smoking
Among environmental factors, smoking has by far the strongest
association with RA. Smoking increases susceptibility to RA and
adversely affects the clinical course of the disease, as shown by
cross-sectional and longitudinal studies [33].
Smoking is associated with RF and ACPA production. In addition,
smoking multiples the adverse effect of the HLA-DRB1 shared-
epitope alleles. Heavy cigarette smoking has been linked to
a substantial increase in the susceptibility to RA. The risk of RA
increases after 10 pack-years of smoking and remains elevated up
to 20 years after smoking discontinuation. The effect of smoking
may be related to tetrachlorodibenzo-P-dioxin (TCDD), which up-
regulates the expression of IL-1beta, IL-6, and IL-8 by binding to the
arylhydrocarbone receptor, whose effect is transmitted via the
nuclear factor-kB and extracellular signal-regulated kinase signal-
ling cascades. TCDD induces inflammatory cytokines and may
therefore exacerbate the pathophysiological mechanisms involved
in RA [34]. Other potential factors include silica dust, mineral oils,
and other airborne exposures.
3.6.2. Infections
Several microorganisms have been implicated in the develop-
ment of RA (Table 3) based on higher titres of the relevant
antibodies in patients with RA. One possibility is that these
microorganisms trigger the development of RA in individuals who
carry genetic susceptibility factors to the disease.
However, the role for microorganisms as initiating factors of RA
remains controversial. Clearly, no single microorganism is respon-
sible for the development of RA. Evidence supporting a role for
parvovirus B19 includes the presence of viral DNA in the synovial
fluid, synovial cells, and/or synovial tissue of RA patients. Sera from
RA patients contain high titres of Epstein-Barr virus (EBV) antigens
and of antibodies to latent and replicative EBV antigens. In addition,
EBV RNA has been identified in B cells in synovial tissue from
Table 3
Infectious agents reported to trigger rheumatoid arthritisa.

Human parvovirus B19

Rubella virus

Human Retrovirus 5

Alphaviruses

Hepatitis B virus

EpsteineBarr Virus

Borrelia burgdorferi

Mycoplasma

Mycobacterium tuberculosis

Escherichia coli

Proteus mirabilis

Porphyromonas gingivalis
a
All unsubstantiated based on evidence-based research.
 G.J. Tobón et al. / Journal of Autoimmunity 35 (2010) 10e14
RA patients [35]. Despite these findings, the evidence that
microorganisms are involved in the development of RA remains
inconclusive.
3.6.3. Dietary factors
A diet rich in fish, olive oil, and cooked vegetables has been
shown to protect against RA, an effect ascribed to the high content
in these foods of omega 3 fatty acids. Several studies found that
populations of southern Europe had milder forms of RA, with fewer
extra-articular and radiological manifestations, compared to other
populations. This difference may be ascribable in part to the
Mediterranean diet.
A high vitamin D intake has been associated with a lower risk of
RA. Vitamin K, which is found primarily in legumes and other
vegetables, may inhibit the proliferation of fibroblast-like syno-
viocytes, thereby diminishing the severity of inflammation in RA.
A recent systematic review of the literature evaluated the effects
of dietary manipulation in patients with RA [36]. The interventions
included vegetarian, Mediterranean, elemental, and elimination
diets. The results were inconclusive, because the studies were small
and had substantial risks of bias. In addition, there was often
a single study available for a given intervention. Weight loss was an
adverse effect in the dietary intervention groups [36].
3.6.4. Pollutants
Pollutants may affect the risk of developing RA. As with cigarette
smoke, inhaled particulate matter may induce both local lung
inflammation and systemic inflammation. Indirect support for this
hypothesis comes from the established link between air pollution
and diseases involving pulmonary and systemic inflammation such
as asthma and chronic bronchitis, cardiovascular disease, and lung
and laryngeal cancers. A recent study [37] nested in the Nurse's
Health Study examined the distance between the place of residence
in 2000 and the nearest road, which served as an indicator of
exposure to traffic pollution. The required data were available for
90,297 nurses. The statistical models were adjusted for age,
calendar year, race, cigarette smoking, parity, lactation, menopausal
status and hormone use, oral contraceptive use, body mass index,
physical activity, and census-tract-level median income and house
value. Women living within 50 m of a road had an increased risk of
RA (hazard ratio, 1.31; 95%CI, 0.98e1.74), compared to women
living 200 m or farther from a road. Thus, exposure to traffic
pollution in adulthood may be a newly identified environmental
risk factor for RA.
3.6.5. Urbanization
Urbanization has been associated with an increased prevalence
of RA. For example, in the Xhosa tribe of South Africa, the preva-
lence of RA is higher among individuals living in an urban rather
than a rural environment. Similar findings have been obtained in
urban, suburban, and rural populations in Taiwan [38]. These
results suggest that environmental factors may affect RA suscepti-
bility in individuals who share the same genetic background.
3.6.6. Early environmental factors and birth weight
The risk of developing RA may be influenced by early environ-
mental factors such as growth and diet. In one study, high birth
weight was positively associated with RA (OR, 3.3), whereas breast
feeding was protective (OR, 0.2). The risk of RA associated with high
birth weight was evaluated in 87,077 women followed prospec-
tively as part of the Nurses' Health Study [39]. RA was diagnosed in
619 women between 1976 and 2002. After adjustment for age and
potential confounders, birth weight greater than 4.54 kg was
associated with a 2-fold increase in the risk of RA compared to birth
weight in the 3.2e3.85 kg range (relative risk, 2.1; 95%CI, 1.4e3.3).
13
Studies suggest that a history of infections in infancy may
protect against RA in adulthood.
Another factor that may influence the risk of RA is micro-
chimerism, which is the persistence in the body of cells and/or DNA
that travelled from the foetus to the mother during pregnancy. These
cells can persist in the mother for several decades and may contribute
to the development of autoimmunity. In one study, DRB1*01 or
DRB1*04 microchimerism was looked for in 33 women with RA and
in 46 healthy women who had no RA-associated genes such as HLA-
DRB1*01 (n ¼ 33 and n ¼ 46, respectively) and/or HLA-DRB1*04
(n ¼ 48 and n ¼ 64, respectively) [40]. Compared to the control
groups, the RA groups had significantly higher rates of DRB1*04
microchimerism (8% vs. 42%; P ¼ 0.00002) and DRB1*01 micro-
chimerism (4% vs. 30%; P ¼ 0.0015). Thus, RA patients had higher
rates of microchimerism with RA-associated HLA alleles, but not with
non-RA-associated HLA alleles, compared to healthy women.
3.7. Geneeenvironment interactions
One of the most important findings from epidemiological and
risk factor studies of RA is the interaction between the HLA shared-
epitope and smoking. In a population-based caseecontrol study,
the risk of developing RF-positive RA was substantially higher in
smokers carrying two copies of shared-epitope genes (RR, 15.7)
than in smokers with no copies of shared-epitope genes (RR, 2.4)
[33]. Studies have also shown an additive interaction between
PTPN22 and smoking [33]. These studies establish that both genetic
and environmental factors are important to the development and
clinical outcome of RA.
4. Conclusions
Epidemiological studies have found substantial variations in the
incidence and prevalence of RA across time periods and geographic
regions. A substantial decline in RA incidence over time, with a shift
toward an older age at onset, was found in several studies. There are
virtually no epidemiologic data from developing countries. ACPA-
positive patients with RA differ from ACPA-negative patients
regarding genetic (HLA-DRB1 and PTPN22) and environmental
(smoking) risk factors for RA.
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