Emerging Trends
in Diagnosis and
Treatment of
Rheumatoid Arthritis
James T. Birch Jr, MD, MSPH*, Shelley Bhattacharya, DO, MPH
EPIDEMIOLOGY
Rheumatoid arthritis (RA) is a chronic inflammatory disease with multiple comorbidities and is a cause of disability for many children and adults worldwide. The role of
primary care is essential in early diagnosis and treatment of this debilitating disease.
The prevalence of RA is estimated to be 0.8% globally, with women 2 to 4 times as
likely as men to develop the disease. The incidence of RA in the United States is estimated at 25 per 100,000 men and 54 per 100,000 women, affecting approximately 2.1
million people.1,2 Age at onset is usually between 30 and 50 years of age; however,
juvenile RA and elderly onset RA (over age 65) also occur.1,2
In the United States, arthritis and other rheumatic conditions are the leading cause
of disability. Approximately 39% of adults with arthritis report limitations in their physical activities because of their condition. Patients with RA are more than 7 times as
likely to have greater than moderate disability as their sex- or age-matched counterparts. In addition, RA disability is linked with increased mortality. The Health Assessment Questionnaire (HAQ) disability index used to follow RA patients found that
a change of 1 standard deviation in the HAQ correlates to an odds ratio for mortality
of 2.3.2 After 10 to 20 years of having the disease, as many as 80% show a compromise of their activities of daily living. Beginning early treatment can reduce the potential for disability by more than 60%.3
In economic terms, RA accounts for an estimated 250,000 hospitalizations and 9
million physician office visits annually. Within 2 to 3 years of diagnosis, 20% to 30%
The investigators have nothing to disclose.
University of Kansas School of Medicine, Department of Family Medicine, Division of Geriatric
Medicine & Palliative Care, 3901 Rainbow Boulevard, MS-1005, Kansas City, KS 66160-0001, USA
* Corresponding author.
E-mail address: jbirch@kumc.edu
KEYWORDS
Rheumatoid arthritis Juvenile rheumatoid arthritis
Disease-modifying antirheumatic drugs Synovitis
Elderly onset rheumatoid arthritis
Prim Care Clin Office Pract 37 (2010) 779–792
doi:10.1016/j.pop.2010.07.001 primarycare.theclinics.com
0095-4543/10/$ – see front matter 2010 Elsevier Inc. All rights reserved.
of those with RA become permanently disabled from work because of pain, impaired
physical function, and transportation difficulties.1,2 The total costs of arthritis and other
rheumatologic conditions in the United States in 2003 was $128 billion ($80.8 billion
from direct medical costs and $47 billion from indirect costs such as lost earnings).
In addition, a reduced life expectancy of 5 to 15 years can occur.3
RISK FACTORS
Several environmental and genetic factors that potentially contribute to increased risk
of developing RA have been identified. There are no definitive risk factors.
Environmental factors include hormonal exposure, tobacco use, microbial exposure, smoking, and consumption of more than 3 cups of decaffeinated coffee daily.1,4
Among these, tobacco use has the most consistent evidence for an association.4
Genetic factors include female gender, positive family history, older age, and the
HLA genotype.1,4 In monozygotic twins, the concordance rate for the development
of RA is more than 30%.1 Siblings of patients with the disease are 2 to 4 times
more likely to develop the disease than persons who are not related.3 Among whites
who have RA, 80% express the HLA-DR1 or HLA-DR4 subtypes.1
Risk of RA is reduced through high vitamin D intake, tea consumption, use of oral
contraceptives, and with breast-feeding.1 Women who have never given birth seem
to have a slight to moderate risk of developing RA, and the evidence is mixed
regarding an association between RA and hormone replacement therapy.1
PATHOPHYSIOLOGY
The pathophysiology of RA essentially remains only partially understood. A complicated interaction between environmental and genetic factors eventually results in
the onset of disease. A viral infection or other biologic factor can initiate an abnormal
autoimmune inflammatory response in persons who are genetically predisposed to
RA. Where chronic inflammation exists in these cases of RA, there is an imbalance
among the mediators controlling the system’s response, resulting in eventual damage
to cartilage and bone.5 The pathophysiology of RA originates with inflammation of
the synovium at any joint location, possibly triggered by the presentation of an antigen,
autoantigen, or athrogenic peptide to the immune system. It appears that the subsequent cascade of inflammatory responses leads to proliferation of synovial macrophages, fibroblasts, and chondrocytes in the articular cartilage. These cells secrete
enzymes that degrade proteoglycans and collagen, which eventually precipitate synovial tissue destruction.5 Further infiltration by lymphocytes and other inflammatory
cells occurs and is accompanied by angiogenesis in the synovium, causing irregular
regrowth of the synovial tissue and eventually forming invasive pannus tissue. This
process stimulates the increased activity of osteoclasts, resulting in further inflammation, leading to more cartilage destruction and the characteristic bony erosion of RA
(Fig. 1).1 Continued ongoing release of inflammatory mediators along with interleukins,
tumor necrosis factor a (TNFa), cytokines, and proteinases, also contributes to the
development of systemic symptoms and the extra-articular manifestations of RA.1,5
There is suspected to be a “shared epitope,” possibly derived from the disease-associated HLA-DR4/1 allele that is initially presented by an antigen-presenting cell to the T
cell as a self-antigen.6 Later in life, these T cells could be activated by cross-reactive
antigens that display the shared epitope, leading to the inflammatory cascade.6
Multiple infectious agents are known to possess potentially cross-reactive peptides
so that possible reactivation of RA by these common and ubiquitous organisms might
occur.6
780 Birch & Bhattacharya
Research continues to elucidate the role of macrophages and their cytokines in
the synovitis of RA and to decipher the mechanisms of the apparent autonomous
and aggressive behavior of fibroblast-like synoviocytes.6 Greater understanding of
these elusive issues could have a significant impact on the therapeutic approach
to RA.
Fig. 1. Pathogenesis of RA. (Reprinted from Pope RM. Apoptosis as a therapeutic tool in
rheumatoid arthritis. Nat Rev Immunol 2002;2(7):527–35; with permission from Nature
Publishing Group.)
Diagnosis and Treatment of Rheumatoid Arthritis 781
DIAGNOSIS
No single test confirms the diagnosis of RA. Diagnosis is largely based on clinical findings and patient history, which is challenging because the symptoms are similar to
many other potential causes of joint inflammation and pain.3 There are several tests
that can be used to increase diagnostic probability and monitor disease progression.
It is imperative that a diagnosis be established as early as possible, because a delay as
much as 4 to 6 months in initiation of treatment could result in long-term joint injury.5
In 1987, the American College of Rheumatology (ACR), in conjunction with the
American Rheumatism Association, established 7 diagnostic criteria to aid in the clinical diagnosis of RA.5 These criteria are also used to define RA in epidemiologic
studies.4 Any patient who presents with at least 4 of the listed criteria for 6 weeks
or longer is considered to have RA (Table 1).7 Early RA is the classification of disease
that is diagnosed within 6 months of symptom onset. There is considerable focus in
this area because early treatment has been demonstrated to have a positive impact
on disease progression and prognosis.4
Efficient diagnosis of RA requires vigilant attention to the patient’s medical history.3
Signs of early synovitis in the absence of obvious joint deformity might be uncovered
by the squeeze test of the metacarpophalangeal (MCP) joints or the metatarsophalangeal (MTP) joints.3 A key sign of RA at the time of the onset is symmetric joint swelling
Table 1
1987 Criteria for the classification of acute arthritis of RA
Criterion Definition
Morning stiffness Morning stiffness in and around the joints, lasting at least 1 h
before maximal improvement
Arthritis of 3 or more
joint areas
At least 3 joint areas simultaneously have had soft tissue swelling
or fluid (not bony overgrowth alone) observed by a physician.
The 14 possible areas are right or left PIP, MCP, wrist, elbow,
knee, ankle, and MTP joints
Arthritis of hand joints At least 1 area swollen (as defined above) in a wrist, MCP, or PIP
joint
Symmetric arthritis Simultaneous involvement of the same joint areas (as defined in 2)
on both sides of the body (bilateral involvement of PIPs, MCPs,
or MTPs is acceptable without absolute symmetry)
Rheumatoid nodules Subcutaneous nodules, over bony prominences, or extensor
surfaces, or in juxta-articular regions, observed by a physician
Serum RF Demonstration of abnormal amounts of serum RF by any method
for which the result has been positive in <5% of normal control
subjects
Radiographic changes Radiographic changes typical of RA on posteroanterior hand and
wrist radiographs, which must include erosions or unequivocal
bony decalcification localized in or most marked adjacent to the
involved joints (osteoarthritis changes alone do not qualify)
For classification purposes, a patient shall be said to have RA if he or she has satisfied at least 4 or
these 7 criteria. Criteria 1 through 4 must have been present for at least 6 weeks. Patients with 2
clinical diagnoses are not excluded. Designation as classic, definite, or probable RA is not to be
made.
Abbreviations: MCP, metacarpophalangeal; MTP, metatarsophalangeal; PIP, proximal interphalangeal; RF, rheumatoid factor.
Adapted form Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association
1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1998;31(3):315–24;
with permission.
782 Birch & Bhattacharya
with local heat and erythema. In the early phase there is usually no clinical evidence of
joint disease and no evidence of cartilage or bone loss on plain radiographs. The
physician or diagnostic clinician also needs to evaluate the patient for extra-articular
features of RA, which will determine the potential course of the disease and guide
treatment options.3
SYMPTOMS
Patients with RA typically present with pain and stiffness in multiple joints. However,
one-third of patients have initial symptoms at a solitary location. The most common
presentation of RA is that of an insidious onset of morning stiffness or diffuse aching
that lasts for at least 1 hour or longer, followed by involvement of the small peripheral
joints such as the MCP, MTP, and proximal interphalangeal (PIP).3 It is not unusual for
the larger joints to be affected first. Symptoms usually occur over weeks to months,
yet in 15% of patients onset can occur more rapidly over days to weeks. Most patients
have accompanying prodromal symptoms of weakness, fatigue, or anorexia. In 8% to
15% of patients, symptoms begin soon after a trigger event, such as a viral illness.1
Characterizing the pain often helps distinguish RA from other forms of arthritis, as
does a positive family history for RA. Determination of disability and ability to perform
activities of daily living facilitates monitoring the effects of treatment.
The joints that are usually affected are those with the highest ratio of synovium to
articular cartilage, such as the wrist, PIP, and MCP joints. The distal interphalangeal