Version May 2024
INTRODUCTION — Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by an inflammatory polyarthritis that preferentially affects the small joints. RA is a "multicausal" disease that most likely results from a combination of genetic predisposition and various environmental and lifestyle factors. Articular and systemic manifestations in RA can lead to poor long-term outcomes such as disability and death.
The epidemiology, risk factors, and causes of RA will be reviewed here. The pathogenesis, genetic basis, clinical manifestations, diagnosis, and treatment are presented separately. (See "Pathogenesis of rheumatoid arthritis" and "HLA and other susceptibility genes in rheumatoid arthritis" and "Clinical manifestations of rheumatoid arthritis" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis" and "Diagnosis and differential diagnosis of rheumatoid arthritis" and "General principles and overview of management of rheumatoid arthritis in adults" and "Initial treatment of rheumatoid arthritis in adults".)
EPIDEMIOLOGY — Rheumatoid arthritis (RA) is estimated to affect approximately 0.24 to 1 percent of the population and to be twice as common in women compared with men. A range of poor long-term outcomes can potentially occur, but these have been reduced to some degree with the use of more aggressive treatment strategies and more effective drug therapies. However, RA's financial burden on society remains substantial. (See 'Incidence and prevalence' below and 'Long-term outcomes' below and 'Economic burden' below.)
Incidence and prevalence — The worldwide prevalence of RA has been estimated as 0.24 percent based upon the Global Burden of Disease 2010 Study [1]. Estimates of RA prevalence in the United States and northern European countries are typically higher, usually between 0.5 to 1 percent [2,3]. The annual incidence of RA in the United States and northern European countries is estimated to be approximately 40 per 100,000 persons [2,4]. Most epidemiologic studies of RA have been conducted in United States or northern European populations. As a result, epidemiologic estimates of RA and identification of risk factors come largely from these populations. The incidence and prevalence of RA is much greater in some populations, such as in the Pima Native Americans, where rates are up to 10 times higher than those of most population groups [5].
RA has a predilection to affect women, in whom incidence and prevalence rates of RA are twice as high as in men. The lifetime risk of developing RA is 3.6 percent in women and 1.7 percent in men [6].
It is uncertain whether the incidence and prevalence of RA is changing over time. The incidence of RA increased from 1995 to 2007 in Olmstead County, Minnesota after declining over the prior four decades [2]. In the United Kingdom, the incidence of RA decreased an average of 1.6 percent per year from 1990 to 2014 [7]. From 1990 to 2010, the worldwide prevalence of RA appears to be stable [1].
Long-term outcomes — Patients with RA are at risk of developing several adverse long-term outcomes, although these outcomes can be improved by early identification and early, aggressive treatment with disease-modifying antirheumatic drugs (DMARDs). These long-term complications can include:
●Physical and work disability – Impairment in physical function leads to near-universal reporting of difficulty with valued life activities [8]. Nearly 40 percent of patients with RA will have work disability within 10 years of diagnosis [9].
●Reduced quality of life – Patients with RA have lower physical and mental health-related quality of life compared with the general population [10].
●Joint replacement surgeries – Up to 25 percent of patients with RA will have a joint replacement in the 20 years after disease onset [11]. (See "Surgical management of end-stage rheumatoid arthritis".)
●Development of other chronic diseases – RA increases the risk of many chronic diseases including cardiovascular disease [12], lung diseases [13,14], psychiatric disorders [15], osteoporosis and fractures [16], and some malignancies (eg, lymphoma, lung and nonmelanoma skin cancers) [17].
●Premature mortality – Survival is reduced in RA compared with the general population, with cardiovascular disease, respiratory disease, and cancer being the leading causes of death in RA [18,19].
Temporal trends show improving long-term outcomes. The prognosis of RA has improved substantially in association with treatment advances, including the earlier initiation of DMARD therapies, implementation of treat-to-target strategies, and the expansion of effective therapeutic options [20,21]. However, studies examining whether survival in RA has improved relative to improvements in the general population are conflicting, and results can vary by the cause of death [22-24].
Economic burden — RA poses a substantial burden to health care systems and society. Regular health care visits, long-term treatment with DMARDs, increased disability and work loss, reduced quality of life, and premature mortality result in total (direct, indirect, and intangible) annual societal costs estimated to exceed $39 billion 2005 United States dollars [25]. A similar economic burden has been suggested by studies from several European countries, although the individual contribution of drug costs, other medical costs, and indirect costs to these totals varies substantially by country [26].
RISK FACTORS FOR AND POTENTIAL CAUSES OF RA — A series of genetic, demographic, lifestyle, environmental, and physiologic risk factors for rheumatoid arthritis (RA) have been identified in epidemiologic and related studies, though many have not been externally validated and appear to have small effect sizes. (See 'Familial and genetic risk factors' below and 'Demographic risk factors' below and 'Lifestyle factors' below and 'Environmental risk factors' below and 'Physiologic risk factors or identifiers of preclinical RA' below.)
Familial and genetic risk factors — Familial and genome-wide association studies have provided evidence of the hereditability of RA and identified genetic risk loci, as emphasized by the following:
●Family history – A large, Swedish nested case-control study estimated RA hereditability to be 40 percent [27]. Familial risk was higher for seropositive and early-onset RA. A family history of RA affected the risk of RA as follows:
•First-degree relative (eg, mother, father, sibling) – Threefold higher odds
•Second-degree relative (eg, grandparent, aunt, uncle) – Twofold higher odds
●Genetics – Over 100 risk loci for RA have been identified, primarily in studies of White populations [28]. The genetics of RA is described in more detail separately. (See "HLA and other susceptibility genes in rheumatoid arthritis".)
Briefly, the following associations are of particular note:
•Human leukocyte antigen (HLA)-DRB1 – The strongest genetic predisposition for RA is within the HLA-DRB1 region. Within the HLA-DRB1 region, a shared sequence of amino acids at positions 70 to 74 termed the "shared epitope" has been consistently identified as a risk factor for RA [29]. Further studies have identified 16 HLA-DRB1 haplotypes based upon amino acid positions 11, 71, and 74 in the HLA-DRB1 region that may better predict RA risk and disease course than shared epitope status [30]. (See "HLA and other susceptibility genes in rheumatoid arthritis", section on 'HLA alleles and susceptibility to rheumatoid arthritis'.)
•Other susceptibility genes – Several genetic loci outside of the HLA-DRB1 region affect the predisposition to developing RA [28]. These include protein tyrosine phosphatase N22 (PTPN22), STAT4, TRAF1-C5, PADI4, and CTLA4, among others. (See "HLA and other susceptibility genes in rheumatoid arthritis", section on 'Rheumatoid arthritis severity genes outside the HLA region'.)
•Interactions between HLA-DRB1 and non-HLA genes – An analysis of genome-wide association data from two independent case-control studies identified interactions between HLA-DRB1 shared epitope alleles and a large number of non-HLA single-nucleotide polymorphisms for the risk of anti-citrullinated protein antibody (ACPA)-positive RA [31].
Demographic risk factors — Demographic factors associated with a higher risk of RA include older age, female sex, North American and Western European ethnicities and selected smaller ethnic groups, and lower socioeconomic status:
●Age – RA typically occurs in middle-aged and older individuals with peak incidence rates between the ages of 65 and 80 years [2,4]. "Elderly-onset RA" (diagnosed after age 60 to 65 years) is often accompanied by constitutional symptoms and proximal joint involvement [32].
●Sex – Incidence rates of RA are nearly twice as high among females compared with males [2]. Expression of disease varies by sex, with males more likely to develop extraarticular features such as subcutaneous nodules and interstitial lung disease [33]. The degree to which these sex differences relate to differences in environmental factors such as cigarette smoking remains unknown.
●Geographic regions and populations – Globally, RA is most common in Australasian, Western Europe, and North American regions and least common in east/southeast Asia and North Africa/the Middle East [1]. Among the highest rates of RA observed have been in Native Americans, including the Pima [5].
●Socioeconomic status – Lower socioeconomic status and education levels are associated with a higher risk of RA [34,35].
Lifestyle factors — Cigarette smoking, poor diet quality, obesity, and physical inactivity are lifestyle factors that may increase RA risk. The effect of these lifestyle factors, as well as genetic risk alleles discussed, may be mediated at least in part by epigenetic changes such as deoxyribonucleic acid (DNA) methylation and histone modifications among others [36]. (See 'Cigarette smoking' below and 'Other lifestyle factors' below.)
Cigarette smoking — Cigarette smoking is the strongest known lifestyle or environmental risk factor for RA [37]. The dose-dependent relationship between cigarette smoking and RA is more closely linked to seropositive RA and interacts with the presence of shared epitope alleles [38-40]. The relative risks (RR) for ACPA-positive RA in a Swedish study, analyzed based upon smoking history and shared epitope allele presence and copy number, were [38]:
●Never smoker, negative shared epitope – Referent group
●Ever smoker, negative shared epitope – RR 1.5 (95% CI 0.8-2.6)
●Never smoker, one copy shared epitope – RR 3.3 (95% CI 1.8-5.9)
●Ever smoker, one copy shared epitope – RR 6.5 (95% CI 3.8-11.4)
●Never smoker, two copies shared epitope – RR 5.4 (95% CI 2.7-10.8)
●Ever smoker, two copies shared epitope – RR 21.0 (95% CI 11.0-40.2)
There is conflicting evidence on whether passive cigarette smoke exposure increases the risk of developing RA, with childhood passive smoke exposure being more closely linked to RA risk [41-43]. In addition to the well-described gene-smoking interaction and the consistency of observations linking cigarette smoking to RA risk [37], other factors supporting a causal role of smoking in RA development include: (1) the induction of citrullination in the lungs by cigarette smoking [44], (2) identification of RA autoantibodies in bronchoalveolar fluid [45] and identification of RA autoantibodies in individuals with chronic lung diseases and without RA [46,47], and (3) risk reduction that follows long term smoking cessation [48-50]. (See 'Modifiable risk factors' below.)
Other lifestyle factors — The association of other lifestyle factors with RA risk is less well established for most of these exposures or habits than it is for cigarette use:
●Alcohol – Moderate intake of alcohol has been associated with a lower risk of RA in some [51,52], but not all [53], cohort studies.
●Nutrition and diet – Observational studies of diet and RA risk have been inconclusive. Adherence to a higher-quality diet and higher intake of fish and long-chain n-3 polyunsaturated fatty acids may be associated with a modestly lower risk of RA [54-56]. Adhering specifically to a Mediterranean diet is not associated with a lower risk of RA [57,58]. There are conflicting results regarding coffee increasing RA risk [59-61], antioxidants lowering RA risk [62,63], and consumption of red meat increasing RA risk [64,65]. Consumption of sugar-sweetened soda was associated with a higher risk of RA in the Nurses' Health Studies [66].
●Vitamin D intake – There are conflicting findings regarding a possible inverse association between vitamin D intake and RA risk [67,68].
●Physical activity – Higher levels of leisure-time physical activity may be associated with a lower risk of RA, though this has not been consistently observed [53,69].
●Obesity – Several observational studies have suggested that obesity is a risk factor for RA. A meta-analysis of 11 observational studies estimated a 30 percent increased risk of RA for individuals with an obese body mass index (BMI >30 kg/m2) and 15 percent increased risk for those with an overweight BMI (25 to 29.9 kg/m2) versus those with normal body weight [70].
●Hormonal and reproductive factors – Breast feeding has been associated with a lower risk of RA, while parity and oral contraceptives are not significantly associated with RA risk [71,72]. Conflicting findings have been reported in other cohorts [73]. Early age at menopause has been reported to confer higher RA risk, and menopausal factors are more closely related to seronegative RA risk [74,75]. In post-hoc analyses from the Women's Health Initiative randomized trial, there were nonsignificant trends towards lower RA risk with postmenopausal hormone therapy [76]. In men, lower testosterone levels have been associated with a higher risk of seronegative RA [77].
Environmental risk factors — Chronic mucosal inflammation, particularly of the oral mucosa and the lung; microbial dysbiosis and bacterial and viral infections; and inhalant exposures are environmental risk factors associated with increased risk for RA. (See 'Chronic inflammatory mucosal conditions' below and 'Infections' below and 'Occupational exposures and inhalants' below and 'Psychologic and other factors' below.)
Chronic inflammatory mucosal conditions — Chronic inflammation of mucosal sites, including the oral mucosa and lung, appears to be a risk factor for RA. Evidence from a large case-control study with detailed periodontal exams and adjustment for several confounders demonstrated 35 percent higher likelihood of the presence of periodontitis in RA compared with patients with osteoarthritis [78]. However, cohort studies have suffered from inconsistent approaches of classifying periodontitis and from limited adjustments for confounders [79,80].
RA autoantibody responses have been detected in the serum of patients with bronchiectasis and cystic fibrosis in the absence of RA [46,47]. Airway abnormalities are significantly more common in high-risk individuals (those with RA autoantibodies but without inflammatory arthritis) than controls [81].
Infections — There has long been interest in identifying infections that may trigger the onset of RA. Building off a growing understanding of chronic inflammation of mucosal sites driving autoimmunity, studies of the microbiome and its interface with mucosal immunity have been of particular interest. The following microbial and infection-related findings are of note:
●Dysbiosis of mucosal sites – Periodontal, gut, and distal airway microbial dysbiosis occurs more commonly in RA patients than controls [82,83]. While global dysbiosis (ie, perturbation of normal bacterial flora) has been more consistently identified as a risk factor than specific individual pathogens, several candidate bacterial pathogens have been reported in RA.
In the oral cavity, candidate pathogens have included Porphyromonas gingivalis, Prevotella species, and Aggregatibacter actinomycetemcomitans, among others [84-86]. P. gingivalis is of particular interest since this pathogen expresses a peptidylarginine deiminase that may drive citrullination of peptides and ACPA responses. The most consistent individual bacterial pathogen identified in gut microbiome studies in RA is Prevotella copri [87,88]. A 2022 study implicated the Lachnospiraceae/Ruminococcaceae genus Subdoligranulum as another gut microbe that has the potential to drive initial tolerance loss in RA [89].
●Viral infections – Polyarthritis can accompany many viral infections, including those related to parvovirus B19, hepatitis B and C, and rubella, providing plausibility that viral infections could serve as triggers of RA. Molecular mimicry has been proposed as a potential link between Epstein-Barr virus (EBV) and RA, with EBV-encoded proteins sharing homology with the shared epitope and ACPAs from patients with RA targeting citrullinated EBV-encoded peptides [90,91]. However, a meta-analysis of 23 case-control studies of EBV serologies and RA did not find a consistent association [92]. Outbreaks of Chikungunya virus have demonstrated a high prevalence of infected patients developing persistent inflammatory arthritis, including cases of seropositive, erosive RA [93]. It is unknown whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination may affect RA risk [94,95]. Other viruses implicated as risk factors for RA are parvovirus B19, rubella, cytomegalovirus, and human T-lymphotropic virus type 1. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis" and "COVID-19: Care of adult patients with systemic rheumatic disease" and "Viral arthritis: Causes and approach to evaluation and management".)
●Other infections – Greater serologic responses to Mycoplasma pneumoniae, Proteus mirabilis, and Escherichia coli have also been reported in RA compared with controls [96,97].
Occupational exposures and inhalants — A range of airborne inhalant exposures has been associated with increased risk for RA:
●Occupational – Occupations with exposure to airborne inhalants, including silica, appear to confer greater risk of RA, especially in men [98,99]. Prolonged work exposure at the World Trade Center site following the 9/11 attacks was associated with greater risk of developing autoimmune disease, the most common of which was RA [100,101]. Farming and exposure to chemical fertilizers and solvents have also been associated with increased RA risk [102,103]. Select military inhalant exposures have also been associated with autoantibody expression and RA risk in United States veterans [104,105]. Occupational inhalant exposures appear to interact with genetic risk factors and/or cigarette smoking to potentiate RA risk [104,106].
●Pollution – Residential proximity to traffic has been associated with higher risk of RA [107,108]. However, exposure to air pollution measured by particulate matter and gaseous pollutants has not been consistently associated with disease risk in all studies [109,110].
Psychologic and other factors — Other proposed risk factors for RA have included stress, including post-traumatic stress disorder, and selected medications, including statins:
●Psychologic factors – Stress is thought to dysregulate the immune system, and supporting this notion, individuals with post-traumatic stress disorder have been found to have an increased risk of developing RA [111,112]. One prospective study found that higher levels of perceived stress were associated with an increased risk of developing inflammatory arthritis among ACPA-positive individuals, all of whom were without active arthritis at study enrollment [113].
●Statins – There are conflicting data regarding whether statins (HMG-CoA reductase inhibitors) influence the risk of RA, with both higher and lower risk of RA reported [114,115]. Treatment with atorvastatin did not prevent the development of clinical arthritis in autoantibody-positive individuals with arthralgias in a small randomized trial [116].
Physiologic risk factors or identifiers of preclinical RA — Autoantibodies and inflammatory responses characteristic of RA can be detected in the blood prior to RA onset; these may be considered risk factors, but more likely represent the early biologic processes that precede and subsequently lead to clinically apparent RA. This phase of disease, when RA autoantibodies are detected but inflammatory arthritis is not present, has been termed "preclinical RA" or "prediagnostic RA," and these individuals are thought to be at high risk for developing the clinical disorder. The following changes have been observed:
●Autoantibodies – Rheumatoid factor (RF), an antibody to the Fc portion of an immunoglobulin G (IgG), and ACPAs are the two autoantibodies of primary clinical relevance in RA. The specificity of commercially available anti-cyclic citrullinated peptide (anti-CCP) antibodies and RF for the diagnosis of RA are 95 and 85 percent respectively [117]. These autoantibodies are detectable in the blood on average 3 to 5 years (ranging to >12 years) prior to the development of clinically apparent RA [118,119]. Anti-CCP positivity appears to have greater predictive ability for the onset of RA than RF. While the specificity of these autoantibodies is high for RA prior to disease onset, positive predictive values in the general population are modest given the low prevalence of RA.
●Systemic inflammation – Proinflammatory cytokine production accompanies the expansion of ACPA responses and also precedes RA onset [120]. Given very low specificity, there is little clinical utility in measuring acute phase responses (C-reactive protein or erythrocyte sedimentation rate) for predicting the onset of RA [121].
PREVENTION OF RA — Given the potentially poor long-term outcomes and substantial economic burden posed by rheumatoid arthritis (RA), there is considerable interest in developing strategies aimed at disease prevention. Two approaches that have been proposed are targeting of modifiable risk factors and administering preventive immunomodulating therapies in individuals at high risk for developing RA. (See 'Modifiable risk factors' below and 'Clinical trials examining preventive therapies' below.)
Modifiable risk factors — Independent observational studies have found that smoking cessation lowers the risk of RA over time, though the rates still appear to be modestly higher 20 to 30 years after quitting than for lifetime nonsmokers [48-50]. Data suggesting that addressing other modifiable risk factors might also lower RA risk are lacking.
Thus, research is needed to determine which individuals likely to be at increased risk of RA (based upon genetics, family history, and environmental exposures) should be targeted for risk factor modification measures, and what strategies might be effective in modifying those factors; there will then also be a need to assess what the outcomes of such strategies are for general health and for the development of RA.
In pursuit of such efforts, behaviors that might reduce the likelihood of RA in at-risk individuals and that are of general health benefit include:
●Smoking cessation
●Eating a well-balanced diet
●Achieving and maintaining a healthy body weight
●Regular physical activity
●Good dental hygiene and regular dental visits
●Wearing respiratory protective equipment when exposed to potentially noxious inhalants
Given challenges that patients often have in adopting and maintaining these behaviors, there is a need for strategies to improve adoption of healthy behaviors, including in individuals at risk of RA. As an example of one approach, a randomized trial, involving 238 subjects, showed that use of a web-based risk estimator for RA, personalized with genotype/biomarker results and behaviors, increased motivation to improve behaviors among first-degree relatives of patients with RA who did not have the disease themselves [122].
Clinical trials examining preventive therapies — Trials evaluating drug therapies to prevent RA are ongoing that typically identify individuals at high risk for RA based upon the presence of RA autoantibodies in the absence of inflammatory arthritis; however, these trials have had inconclusive results. The implications of these trials for other risk reduction efforts are uncertain. As examples:
●Glucocorticoids – A randomized trial comparing an intramuscular injection of 100 mg of dexamethasone and placebo in 83 individuals with arthralgias and positive RA autoantibodies found no difference in the rate of developing RA over a median follow-up of 26 months [123].
●Rituximab – In the PRAIRI study, a randomized trial assessing a single infusion of 1000 mg of rituximab for the prevention of RA in 81 individuals with RA autoantibodies but no arthritis, rituximab delayed the onset of RA by 12 months but did not significantly decrease the risk of developing RA over a mean follow-up of 29 months [124].
●Atorvastatin – The STAPRA trial was a randomized trial that evaluated the ability of atorvastatin to prevent the onset of clinical arthritis in patients with RA autoantibodies and arthralgias [116]. While this trial was stopped early due to insufficient patient recruitment, atorvastatin did not show any protective effect.
●Methotrexate – In the TREAT EARLIER trial, which included 236 patients with arthralgias who were suspected of progressing to RA based on magnetic resonance imaging (MRI)-detected subclinical joint inflammation, patients who were randomly assigned to receive a single intramuscular glucocorticoid injection plus a one-year course of oral methotrexate had similar rates of developing clinical arthritis compared with those who took placebo, up to one year after the one-year treatment period (19 percent in the treatment group versus 18 percent in the placebo group; hazard ratio 0.81 [95% CI 0.45-1.48]) [125]. However, there were greater improvements in physical functioning, pain, morning stiffness, and MRI-detected joint inflammation in the treatment group, which supports the role of methotrexate as an effective disease-modifying treatment among patients in the early phases of the disease.
●Hydroxychloroquine – Interim results from the STOP RA trial, a double-blind, randomized controlled trial of one year of hydroxychloroquine treatment in adults who were anti-cyclic citrullinated peptide 3 (anti-CCP3) positive but lacked inflammatory arthritis (n = 144) did not reveal efficacy for preventing or delaying RA onset [126].
●Abatacept – The double-blind, randomized, controlled APIPPRA trial found that one year of abatacept treatment in autoantibody positive adults with arthralgias (n = 213 randomized) reduced the incidence of inflammatory arthritis while on treatment. However, after discontinuing treatment, incidence rates approached those in the placebo group [127].
SUMMARY
●Epidemiology – Rheumatoid arthritis (RA) affects 0.2 to 1 percent of the developed world’s population and is a multicausal disease resulting from genetic predisposition and various lifestyle and environmental factors. (See 'Incidence and prevalence' above.)
●Outcomes – Long-term outcomes that can affect patients with RA include disability, reduced quality of life, a need for joint replacement surgery, development of other chronic conditions, and premature mortality. (See 'Long-term outcomes' above.)
●Genetic risk factors – Human leukocyte antigen (HLA)-DRB1 genes represent the strongest genetic risk factor for RA, and having a first-degree relative with RA increases the risk of RA approximately threefold. (See 'Familial and genetic risk factors' above.)
●Environmental risk factors – Cigarette smoking represents the strongest environmental risk factor for RA and interacts with HLA-DRB1 shared epitope alleles to markedly increase the risk of anti-citrullinated protein antibody (ACPA)-positive RA. (See 'Cigarette smoking' above.)
●Microbiome risk factors – Mucosal inflammation and dysbiosis of the periodontal, gut, and lung microbiota may represent disease risk factors and could be involved in the evolution of early generation of RA-related autoimmunity at extraarticular sites. (See 'Chronic inflammatory mucosal conditions' above and 'Infections' above.)
●Prevention – The identification of RA autoantibodies (rheumatoid factor [RF] and ACPA) may herald the future onset of RA and has allowed studies of high-risk individuals aimed at RA prevention. However, optimal strategies for reducing the risk of RA are not known; smoking cessation is important in risk reduction and healthy lifestyle behaviors are likely to be beneficial. (See 'Prevention of RA' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Peter Schur, MD, Cynthia S Crowson, PhD, and Sherine Gabriel, MD, MSc, who contributed to an earlier version of this topic review.
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