Background

• Rheumatoid arthritis (RA), an autoimmune condition, is a chronic inflammatory polyarthritis (arthritis that affects 5 or more joints)(2).
• The natural history of RA varies considerably with at least three possible disease courses (3-5):
• Monocyclic: Have one episode which ends within 2-5 years of initial diagnosis and did not reoccur. This may result from early diagnosis and/or aggressive treatment.
• Polycyclic: The levels of disease activity fluctuate over the course of the condition
• Progressive: RA continues to increase in severity and is unremitting
• Radiographic erosion is typically fastest in the first year of disease (4).
• One natural history study found that 75% of people with RA experienced remission within five years of diagnosis (5)

II. Diagnosis of RA

• Ideally, RA is diagnosed early – within 6 months of symptom onset – so that treatment can begin as soon as possible to slow or halt disease progression. Early diagnosis is challenging because the symptoms of early RA can be non-specific (e.g., malaise, fatigue, weakness, muscle soreness, low-grade fever, weight loss) and may actually be symptoms of other conditions (6).
• RA is diagnosed clinically, but classified according to the 2010 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis http://www.rheumatology.org/practice/clinical/classification/ra/ra_2010.asp(7, 8).
• Prior to the 2010 criteria, the 1987 ACR criteria were the standard for diagnosis and study of RA (http://www.rheumatology.org/practice/clinical/classification/ra/ra.asp) (9). Comparison of the 2010 and 1987 criteria indicate that the 2010 criteria are better at identifying people with early RA (7, 8).

III. Treatment

• Historically, treatment for most people started with corticosteroids/non-steroidal anti-inflammatory drugs (NSAIDs), then slowly progressed for fewer people to non-biologic disease-modifying antirheumatic drugs (DMARDs) and finally progressed for even fewer people to biologic DMARDs if people had not responded to the previous drugs.
• Today, a much more aggressive treatment approach is advocated for people with RA, with prescription of non-biologic DMARDs within three months of diagnosis to reduce disease activity and prevent joint deformity. (10)
• Treatment guidelines have also changed with the increasing array of biologic DMARDs available; in 2008, the American College of Rheumatology updated RA medical management guidelines http://www.rheumatology.org/practice/clinical/guidelines/recommendations.pdf (11). These guidelines describe which biologic DMARDs are indicated for specific RA disease profiles (e.g., features such as diease activity, signs and symptoms, and prognosis)
• The 2008 guidelines also recommend that treatment with nonbiologic and biologic therapies should be acocmpanyied by non-medical interventsions including physical and occupational therapy and anti-inflammatory pharmacologic articularns (e.g., treatment with NSAIDs, intraarticular and oral glucocorticoids) (11).

IV. Risk Factors

The etiology, or cause, of RA is unknown. Many cases are believed to result from an interaction between genetic factors and environmental exposures.
Socio-demographics: The incidence of RA is typically two to three times higher in women than men. The onset of RA, in both women and men, is highest among those in their sixties(2)

Genetics: There is longstanding evidence that specific HLA class II genotypes are associated with increase risk. Most attention has been given to the DR4 and DRB1 molecules of the major histocompatability complex HLA class II genes. The strongest associations have been found between RA and the DRB1*0401 and DRB1*0404 alleles (12). More recent investigations indicate that of the more than 30 genes studied, the strongest candidate gene is PTPN22, a gene that has been linked to several autoimmune conditions(12).
Modifiable: Several modifiable risk factors have been studied in association with RA including reproductive hormonal exposures, tobacco use, dietary factors, and microbial exposures.
Smoking
Among these risk factors, the strongest and most consistent evidence is for an association between smoking and RA. A history of smoking is associated with a modest to moderate (1.3 to 2.4 times) increased risk of RA onset (2). This relationship between smoking and RA is strongest among people who are ACPA-positive (anti-citrullinated protein/peptide antibodies), a marker of auto-immune activity (12).
Reproductive and breastfeeding history
Hormones related to reproduction have been studied extensively as potential risk factors for RA:

• Oral contraceptives (OC): Early studies found that women who had ever used Ocs had a modest to moderate decrease in risk of RA (13, 14). The decreased risk has not confirmed in recent studies (13, 15, 16). The estrogen concentration of contemporary Ocs is typically 80-90% less than the first Ocs introduced in the 1960s (15), which may account for the lack of association in recent studies (15).
• Hormone replacement therapy (HRT): There is mixed evidence of an association between HRT and RA onset (15-19)
• Live birth history: Most studies have found that women who have never had a live birth have a slight to moderately increased risk of RA (20-23).
• Breastfeeding: Recent population based studies have found that RA is less common among women who breastfeed (16, 24-26).
• Menstrual history: At least two studies have observed that women with irregular menses or a truncated menstrual history (e.g., early menopause) have an increased risk of RA (16, 20). Because women with polycystic ovarian syndrome (PCOS) have an articula risk of RA, the association with an articul menstrual history may result from PCOS (20).

V. Prevalence

• The prevalence of RA is believed to range from 0.5-1.0% in the general population (2). In 2005, an estimated 1.5 million US adults aged ≥ 18 (0.6%) had RA (27), a decrease from the previous 1990 estimate of 2.1 million (28). Prevalence estimates derived from 2001-2005 US ambulatory health care system data estimated that 1.5 million US adults have RA (29)
• In 1995 in the Rochester Epidemiology Project (Minnesota), the age-adjusted prevalence of RA among women was 7.7 per 1000 compared with 4.4 per 1000 among men). By 2005, the prevalence among women had increased (9.8 per 1000) but prevalence among men (4.1 per 1000) (30).

VI. Incidence

• The most recent US data on the incidence of RA is from the Rochester Epidemiology Project, a study that has provided the majority of population-based descriptive statistics on RA. In 1995-2007, 41 per 100,000 people were diagnosed with RA each year. Incidence rose with age (e.g., 8.7 per 100,000 people among those aged 18-34 compared with 54 per 100,000 among those aged ≥ 85 years); incidence peaked among people aged 65-74 years (89 per 100,000) (all estimates age-adjusted to 2000 US population). From 1995 to 2007, rates increased by 2.5% each year among women but there was a small decrease (0.5%) among men (30).
• Longitudinal study of RA incidence rates in the Rochester Epidemiology Project indicates that incidence among women and men was highest at the beginning of the project in 1955 but declined to its lowest in the late 1980s/early 1990s.
• At least one study have found incidence to be the same regardless of the definition (i.e., 1958 American Rheumatology Association, and 1987 American College of Rheumatology definitions) (31).

VII. Lifetime risk

• The lifetime risk of rheumatoid arthritis in the Rochester Minnesota Mayo Clinic Population was estimated 4% among women and 3% among men (32).

VIII. Mortality and comorbidities

• In 1997, RA accounted for 22% of all deaths due to arthritis and other rheumatic conditions (33)
• Mortality has been found to be increased among people with diagnosed RA in multiple studies. Over the past half century, many studies have found mortality to be increased in patients with established RA in comparison with the general population (34) Around 40% of all deaths in individuals with RA are attributable to cardiovascular causes, including ischemic heart disease and stroke. The most recent North American study of mortality among people with RA, based on data from 1965–1990, found a standardized mortality ratio of 2.3 among people with RA compared to the general population (35), that is, people with RA are more than twice as likely to die than people of the same age in the general population.
• Among people with RA, the presence of rheumatoid factor (RF) and/or anti-citrullinated protein antibody (ACPA) are potential markers of premature mortality (34).

IX. Co-morbidities

The four most common comorbidiities among people with arthritis, in order of prevalence are the following:

• Cardiovascular disease (CVD), in articular ischemic heart disease, is more common among people with RA (34). It is unclear whether the risk of CVD precedes the disease onset or results from the condition; a Rochester Epidemiology Project study found that people with RA were more likely to have a hospitalizations because of myocardial infarction prior to diagnosis (34). However, two longitudinal cohort studies have found no difference in presence of MI, congestive heart failure or angina prior to diagnosis of RA (34). People with RA have greater evidence of subclinical atherosclerotic disease (36), and risk of silent MI (37).
  
  It is unknown whether the increase in CVD mortality is due to the disease, the risk factor profile of people with RA (e.g., presence of hypertension, more likely to be smokers), or the effects of the drugs used to treat the condition (36, 38).
• Infections, most commonly tuberculosis, are another important and primary cause of death among people with RA may be responsible for one-quarter of deaths among people with RA (37). It is unclear whether this increased susceptibility arising from immunosuppression is due to the intrinsic immune dysfunction in people with RA, the effects of the drugs used to treat it, or both (36, 38).
• Mental health conditions: The high prevalence of anxiety and depression has been documented in several clinical populations of people with RA. Both conditions are associated with increased disease activity and decreased physical function and adherence to medical and non-medical interventions (39-42).
• Malignancies: An increased incidence of lymphoproliferative malignancies (such as leukemia and multiple myeloma) has also been reported among people with RA. The cause of this increase is unknown (38).

X. Hospitalizations

In 2009, there were 15,600 hospitalizations with RA listed as the principal diagnosis with total hospital charges of $545 milion (mean charge of $35,000 per person) (2009 Nationwide Inpatient Survey)(43). Women and people aged 45 years and older accounted for the majority of these stays. This is decrease from 19,900 hospitalizations in 2004(43)

XI. Ambulatory Care

• In 2007, there were 2.9 million ambulatory care visits in the United States among people with RA. Most of these were physician office visits (2.6 million) with 1.9 million visits to medical specialty offices (e.g., rheumatologists) (44)[2007 National Ambulatory Medical Care and National Hospital Ambulatory Medical Care Surveys.] This is a decrease from 4.0 million visits in 1997 of which 3.6 million were physician office visits)(45).

XII. Costs

Direct and indirect costs

• A study of direct (i.e., medical) costs among people with RA in the Rochester Epidemiology Project found an average cost of $3,802 (in U.S. dollars) per person in the year 1987 ($5,763 in U.S. 2000 dollars) (46). These authors also reported that people with RA were approximately six times (odds ratio=6.4, 95% CI=5.4-7.7) more likely than people without arthritis to incur medical charges, independent of RA.
• A 1992 study found that indirect and non-medical expenditures for a person with RA were $2269 per year ($2785 in U.S. 2000 dollars) compared to $824 ($1011 in U.S. 2000 dollars) for a person with osteoarthritis, and $816 ($1002 in U.S. 2000 dollars) per persons without arthritis (47).
• The same study indicated that the typical work experience of people with RA differed substantially from that of someone without arthritis. Compared with people without arthritis, people with RA were more likely to do the following: change occupation (3.3% vs 0%), reduce work hours (12.2% vs 1.7%), lose their job (3.3% vs 0%), retire early (26.3% vs 5.2%), and be unable to find a job (15.3% vs 5.2%) (47).
• A Canadian survey found that the average direct and indirect costs among people with RA were $6777 ($4679 in direct costs and $2098 in indirect costs) (in U.S. 2000 dollars) (48). This study was based on a population sample of family physicians and rheumatologists. Costs associated with RA were almost twice of those for osteoarthritis.

Lifetime costs

• Gabriel et al., (1998) also estimated the median lifetime costs (i.e., 25 years following a diagnosis of RA) of RA to be $61,000 to $122,000 (U.S. 1995 dollars) (lifetime costs were highest among younger people with RA) (49)

XIII. Impact on health-related quality of life (HRQOL)

• People with RA have worse functional status than thosewith osteoarthritis, and those without arthritis (47).
• One study examining the self-reported quality of life found that compared with those without arthritis, people with RA were 40% more likely to report fair or poor general health (OR=1.4, 95% CI=1.2, 1.6), 30% more likely to need help with personal care (OR=1.3, 95% CI=1.1, 1.5), and twice as likely to have a health-related activity limitation (OR=2.0, 95% CI=1.7, 2.4) (50)
• People with RA have been reported to experience more losses in function than people without arthritis in every domain of human activity including work, leisure and social relations (51). Work loss among people with RA has observed to be highest among persons among service workers, and lower among those in jobs with few physical demands, or in jobs where they have influence over the job pace and activities (52).
• In 1996, RA was the 19th most common cause for years lost to disability in the United States (53). This is particularly notable given that RA is a very low prevalence condition.