Rheumatoid Arthritis

 Background

• Rheumatoid arthritis (RA), an autoimmune condition, is a chronic inflammatory polyarthritis.¹
   
• Natural history studies of RA suggests that RA follows one of three courses
  • Monocyclic in 20% of people initially diagnosed with RA (i.e., had one episode which abated within two years of initial presentation and did not reoccur).
  • Polycyclic in 70% (i.e., fluctuating levels of disease activity).
  • Progressive and unremitting condition in 10%.³

Another natural history study found that 75% of people with RA experienced remission after five years.⁴  

• Historically, pharmacologic treatment of RA has traditionally followed the pyramid approach. That is, treatment starts with corticosteroids/non-steroidal anti-inflammatory drugs, then progresses to disease-modifying antirheumatic drugs (DMARD) and finally to biologic response modifiers (BRM) if persons are non-responsive to the previous drugs. Today, a more aggressive treatment approach is being advocated for people with early RA, with prescription of DMARDs within three months of diagnosis.¹
   
• Diagnosis
  • The 1987 American College of Rheumatology* criteria are used in the clinical diagnosis of RA, and to define RA in epidemiologic studies. Persons must meet four of seven ACR criteria;⁵ these criteria are based on clinical observation (e.g., number of joints affected), laboratory tests (e.g., positive rheumatoid factor), and radiographic examination (e.g., X-rays evidence of joint erosion).⁵
  • Early RA is typically defined as RA that is diagnosed within 6 months of symptom onset. There is extensive interest in early diagnosis of RA because early treatment may improve disease prognosis. The only U.S. study to examine time between symptom onset and diagnosis reported a median lag time of approximately 4 weeks between symptom onset and medical encounter, and a median time of 18 weeks between medical encounter and RA diagnosis (A total median lag time of 36 weeks)⁶. These authors noted that there was even a delay in diagnosing patients with most identifiable features of RA (e.g., morning stiffness and seropositive rheumatoid factor), and concluded that early disease recognition is challenging as only half of those who eventually develop RA initially present with features specific to the condition.
     
• Risk factors
  • A range of environmental and genetic variables have been evaluated as potential risk factors for RA (e.g. hormonal exposures, tobacco use, dietary components, HLA genotype, and microbial exposures), but to date no definitive risk factors for RA have been identified.
  • Of the environmental factors examined, the most consistent evidence exists for an association between tobacco use and RA; most studies of this risk factor have found a history of smoking is associated with RA onset with increased risks ranging from 1.3 to 2.4.²
  • The role of the following four estrogenic factors in RA etiology has been studied extensively:
    • Oral contraceptives(OC) — Early studies found a decreased risk of RA among women who had ever used OCs, a relationship that has not been confirmed in recent studies.^19-21
    • Hormone replacement therapy (HRT) — There is mixed evidence of an association between HRT and RA onset.^20-25
    • 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.^21,24,26,27
    • Breastfeeding — The most recent studies have found that RA is less common among women who breastfeed; this is in contrast with earlier studies which found an increased risk associated with breastfeeding.^21,28-30
  • Genetic susceptibility markers. 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.²

II. Prevalence

• An estimated 1.293 million adults aged 18 and older (0.6%) had RA in 2005, down from the previous 1990 estimate of 2.1 million.⁴⁰ This is partly due to a more restrictive definition of RA, but in part reflects well established declines in RA prevalence around the world.
   
• The prevalence among women in 1995 was approximately double that in men (1.06% versus 0.61%).⁴⁰
   
• This study observed almost a 2:1 ratio in prevalence for women to men (1,367 per 100,000 (95% CI=1,175-1,558) among women compared with 736 per 100,000 (95% CI=561-912) in men.⁸)
   
• Prevalence decreasing.

III. Incidence

• The incidence of RA is typically two to three times higher in women than men. Incidence studies from three populations show that incidence of RA in both women and men peaks in their sixties.²
   
• The observed incidence of RA in the United States ranges from 42 people per 100,000 (95% CI=23-60) (years 1987–1990)⁹ to 68.3 persons per 100,000 (95% CI=57.2-79.5) (years 1975–1985)⁸ depending on the definition used. Another study found incidence to be the same regardless of the definition (i.e., 1958 American Rheumatology Association, and 1987 American College of Rheumatology definitions).¹⁰
   
• Incidence has ranged from 24 persons per 100,000 (95% CI=19-30)¹⁰ to 88.1 persons per 100,000 (95% CI=71.0-105.3)⁸ among women,⁸ and rates of 22 persons per 100,000 (95% CI=13-32)⁹ to 46.8 persons per 100,000 (95% CI=32.4-61.2) among men.⁸
   
• There is some evidence that the incidence of RA in the United States is declining. Between 1955–1964 the annual incidence of RA in the Olmsted County population was 90.2 persons per 100,000 (95% CI=75.1-105.3) whereas the annual incidence declined to 68.3 persons per 100,000 for the interval 1975–1985 (95% CI=57.2-79.5).⁸

IV. Mortality

• In 1997, RA accounted for 22% of all deaths due to arthritis and other rheumatic conditions.¹¹
   
• The most recent North American study of mortality among people with RA, based on data from 1965–1990, found a standardized mortality ratio of 2.26 among people with RA compared to the general population.¹² That is, people with RA are two times more likely to die than people of the same age in the general population.
   
• Co-morbidities
  • Cardiovascular disease (CVD) is responsible for approximately half of all deaths among people with RA.¹⁷ The incidence of CVD among people with RA is similar to that of people without the condition,¹⁷ although people with RA have greater evidence of subclinical atherosclerotic disease.¹⁸ It is unknown whether the increase in CVD mortality is due to 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.^17,18
  • Infections have also been cited as another important and primary cause of death among people with RA; infections may be responsible for one-quarter of deaths among people with RA. 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.^17,18
  • 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.¹⁷

V. Hospitalizations

• In 2004, there were 20,000 hospitalizations with RA as the principal diagnosis in the Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample.³⁵ Eighty-five percent of these hospitalizations were among people aged 45 years or older. Women accounted for 15,000 of the hospitalizations.

VI. Ambulatory Care

• In 1997, there were 3,978,000 ambulatory care visits in the United States among people with RA. This comprised 10.9% of all visits among people with arthritis and other rheumatic diseases.³⁶ [These estimates were drawn from the National Ambulatory Medical Care and National Hospital Ambulatory Medical Care Surveys.]
   
• The majority of these ambulatory care visits were to physician offices (3,566,000 visits) while the remaining were outpatient visits (392,000 visits).³⁶

VII. Costs

Direct and indirect costs

• A study of direct (i.e., medical) costs among people with RA at the Mayo Clinic found an average cost of $3,802.05 (in U.S. dollars) per person in the year 1987 ($5,763.32 in U.S. 2000 dollars).³¹ 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. These charges were not just for musculoskeletal disorders but for care of disorders of most body systems.
   
• Gabriel et al., reported, in a 1992 study of indirect costs, that indirect and non-medical expenditures for a person with RA were $2269 per year ($2784.90 in U.S. 2000 dollars) compared to $824 ($1011.35 in U.S. 2000 dollars) for a person with osteoarthritis, and $816 ($1001.53 in U.S. 2000 dollars) per persons without arthritis.³²
   
• In the same study, they reported 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 due to illness: 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%).³²
   
• A recent 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).³³ 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).³⁴

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

• The functional status of people with RA has been observed to be compromised relative to those without the condition. People with RA have worse functional status than those with osteoarthritis, and those without arthritis.³²
   
• One study examining the self-reported quality of life among people with RA compared to people without arthritis those found that those 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)³⁷ compared with those without arthritis.
   
• 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.³⁸ 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.³⁹

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