INTRODUCTION

Rheumatoid arthritis (RA) is a complex systemic inflamma tory condition manifesting

initially as symmetric swollen and tender joints of the hands and/or feet. Some patients -may
experience mild articular disease, whereas others may present with aggressive disease and/or
extraarticular manifestations. The systemic inflammation of RA leads to joint destruction,
disability, and premature death. Juvenile idiopathic arthritis (JIA) is the most common form
of arthritis in children.

EPIDEMIOLOGY AND ETIOLOGY

RA has a prevalence of 0.5% to 1%. Patients with RA have a 50% increased risk of premature
death and a decreased life expectancy of 3 to 10 years compared with individuals without
RA. The underlying causes of increased mortality are unclear. RA arises from an
immunologic reaction, perhaps in response to a genetic or infectious antigen. Risk factors
associated with the development of RA include the following:
Female gender (3:1 females to males)
Increasing age (peak onset 3550 years of age)
Current tobacco smoking. Tobacco users are more likely to have extraarticular
manifestations and to experience treatment nonresponsiveness. This risk is reduced when a
patient has remained tobacco-free for at least 10 years.
Family history of RA. Genetic studies demonstrate a strong correlation between RA and the
presence of major histocompatibility complex class II human leukocyte antigens (HLA),
specifically HLA-DR1 and HLA-DR4. HLA is a molecule associated with the presentation of
antigens to T lymphocytes.
Emerging evidence suggests that stress may influence RA onset and disease activity. It
appears that individual major stressful life events do not play a significant role. Instead,
chronic presence of minor stressors (daily hassles, work and relationship stress, financial
pressures) may affect the immune response and RA disease activity.
The prevalence of JIA is approximately 1 in 1000 children. There are no known risk factors
for JIA.

PATHOPHYSIOLOGY
The characteristics of a synovium affected by RA are: (a) the presence of a thickened,
inflamed membrane lining called pannus; (b) development of new blood vessels; and (c)
influx of inflammatory cells in the synovial fluid, predominantly T lymphocytes. The
pathogenesis of RA is driven by T lymphocytes, but the initial catalyst causing this response
is unknown. Understanding specific components of the immune system and their involvement
in the pathogenesis of RA will facilitate understanding of current and emerging treatment
options for RA. The components of most significance are T lymphocytes, cytokines,
B lymphocytes, and kinases.

T Lymphocytes
The development and activation of T lymphocytes are important to maintain protection from
infection without causing harm to the host. Activation of mature T lymphocytes requires
two signals. The first is the presentation of an antigen by antigen-presenting cells to the T
lymphocyte receptor. Second, a ligand-receptor complex (ie, CD80/CD86) on antigen-
presenting cells binds to CD28 receptors on T lymphocytes. Once a cell successfully passes
through both stages, the inflammatory cascade is activated. Activation of T lymphocytes: (a)
stimulates the release of macrophages or monocytes, which subsequently causes the release
of inflammatory cytokines; (b) activates osteoclasts; (c) activates release of matrix
metalloproteinases or enzymes responsible for the degradation of connective tissue; and (d)
stimulates B lymphocytes and the production of antibodies

Cytokines
Cytokines are proteins secreted by cells that serve as intercellular mediators (Table 571). An
imbalance of proinflammatory and anti-inflammatory cytokines in the synovium leads to
inflammation and joint destruction. Some of the proinflammatory cytokines are interleukin 1
(IL-1), tumor necrosis factor- (TNF-), IL-6, and IL-17. These proinflammatory cytokines
cause activation of other cytokines and adhesion molecules responsible for recruitment of
lymphocytes to the site of inflammation. Antiinflammatory cytokines and mediators (IL-4,
IL-10, and IL-1 receptor antagonist) are present in the synovium, although concentrations are
not high enough to overcome the effects of the proinflammatory cytokines.5,9,10

B Lymphocytes
In addition to serving as antigen-presenting cells to T lymphocytes, B lymphocytes may
produce proinflammatory cytokines and antibodies.6,9 Antibodies of significance in RA are
rheumatoid factors (antibodies reactive with the Fc region of IgG) and anticitrullinated
protein antibodies (ACPA).6 Rheumatoid factors are not present in all patients with RA, but
their presence is indicative of disease severity, likelihood of extraarticular manifestations, and
increased mortality.11 ACPA are produced early in the course of disease. High levels of
ACPA are indicative of aggressive disease and a greater likelihood of poor outcomes.
Monitoring ACPA may be useful to predict the severity of disease and match aggressive
treatment appropriately.

Kinases
The role of intracellular signaling is an emerging area of interest. Kinases are enzymes
involved in communication or signaling activities within and between cells. Activated kinases
lead to cell activation and proliferation. Examples include Janus-associated kinases (JAKs)
and spleen tyrosine kinase. Research is ongoing to identify therapeutic targets to interrupt
signaling and thereby halt the inflammatory process.

Comorbidities Associated with RA

RA reduces a patients average life expectancy, but RA alonerarely causes death. Instead,
specific comorbidities contribute to premature death independent of safety issues surrounding
the use of immunomodulating medications. The comorbidities with the greatest impact on
morbidity and mortality associated with RA are: (a) cardiovascular disease, (b) infections,
(c) malignancy, and (d) osteoporosis.
\
Cardiovascular disease
More than half of all deaths in RA patients are cardiovascular related. Because a patient with
RA experiences inflammation and swelling in joints, it is likely that there is inflammation
elsewhere, such as in the blood vessels, termed vasculitis. C-reactive protein (CRP), a
nonspecific marker of inflammation, is associated with an increased risk of cardiovascular
disease; CRP is elevated in patients with RA. Traditional cardiovascular risk factors alone
cannot explain the increased cardiovascular mortality in patients with RA. Increasing
evidence suggests that the presence of RA is a cardiovascular risk similar to diabetes.
Aggressive management of systemic inflammation and traditional cardiovascular risk factors
(eg, blood pressure, cholesterol, tobacco use) may reduce cardiovascular mortality in this
population.

Infections
RA itself leads to changes in cellular immunity and causes a disproportionate increase in
infections.15 Because medications that alter the immune system increase infection risk, it is
difficult to distinguish between an increased risk due to RA and the immunosuppressive
therapy. Patients and clinicians must pay close attention to signs and symptoms of infection.
 Malignancy
Cancer is the second most common cause of death in RA patients. There is increased risk of
developing lymphoproliferative malignancy (eg, lymphoma, leukemia, multiple myeloma),
skin, and lung cancer but decreased risk of developing cancer of the breast and digestive
tract. The relationship between RA and cancer is not clear. To confound the issue,
medications for treating RA are undergoing review to determine whether use independently
increases cancer risk. Current evidence suggests that the use of biologic medications does not
increase the baseline risk associated with disease alone.

Osteoporosis
Osteoporosis associated with RA follows a multifaceted pathogenesis, but the primary
mechanism likely is mediated by increased osteoclast activity.15 The cytokines involved in
the inflammatory process directly stimulate osteoclast and inhibit osteoblast activity.
Additionally, arthritis medications can lead to increased bone loss. Bone mineral density
should be evaluated at baseline and routinely using dual-energy x-ray absorptiometry.

CLINICAL PRESENTATION AND DIAGNOSIS

See the box on next page for the clinical presentation of RA.

Diagnosis
Both osteoarthritis and RA are prevalent in the U.S. population, but they differ in presentation
(Table 572). Because management of the two conditions differs significantly, early
evaluation and diagnosis are essential to maximize an individual patients
care. In 2010, The American College of Rheumatology (ACR) and European League Against
Rheumatism (EULAR) released new classification criteria for RA (Table 573).1 The goal
was to identify a subset of patients with undifferentiated synovitis who were at high risk for
chronic and erosive disease. The criteria are intended to help identify patients earlier in the
course of disease. This will allow researchers to determine whether earlier introduction of
medications alters the disease process. The criteria were developed as a tool for research
purposes, but they are also helpful to guide clinical diagnosis. Patients with at least one joint
with definite clinical synovitis that is not explained by another disease should be tested for
RA. Several clinical features of RA are associated with a worse long-term prognosis. The
presence of these poor prognostic features should be considered at the time initial treatment
decisions are made; more aggressive treatment may be warranted if these features are present.
The most clinically important features associated with poor long-term outcomes include: (a)
functional limitation (defined by use of standard measurement scales such as the Health
Assessment Questionnaire [HAQ] score),
 Diagnosis of Juvenile Idiopathic Arthritis
Diagnostic criteria for JIA include: (a) age less than 16 years at disease onset, (b) arthritis in
one or more joints for more than 6 weeks, (c) exclusion of other types of arthritis. JIA can be
divided into three main types:
1. Systemic (4%17% of cases): Occurs equally in girls and boys. There are characteristic
fever spikes twice daily (greater than 38.3C or 101F) and the presence of a pale, pink,
transient rash. The peak onset is between ages 1 and 6 years.
2. Polyarticular (approximately 40% of cases): More likely to affect girls than boys (3:1).
Arthritis is present in five or more joints. The disorder resembles adult RA more than
the other types of JIA.
3. Oligoarticular (about 50% of cases): More likely to affect girls than boys (5:1). Uveitis is
more likely to be present. Arthritis is present in four or fewer joints. The peak onset is
between ages 1 and 3 years.

TREATMENT
Desired Outcomes
The goals of treatment in RA are to: (a) reduce or eliminate pain, (b) protect articular
structures, (c) control systemic complications, (d) prevent loss of joint function, and (e)
improve or maintain quality of life. The goals for JIA are the same, with the added goals of
maintaining normal growth, development, and activity level.17,18 It is a common
misconception that patients with JIA grow out of the disease. Many children with JIA become
adults with JIA. Knowing this, it is essential that early, aggressive treatment is initiated to
achieve the goals of therapy.

General Approach to Treatment

The clinician must evaluate patient-specific factors and select appropriate treatment to
maximize the care of each patientJoint damage accumulates over time; therefore, early
diagnosis and early aggressive treatment are necessary to reduce disease progression and
prevent joint damage. Aggressive treatment is defined as one or more disease-modifying
antirheumatic drugs (DMARDs) at effective doses. Delaying treatment will result in
more destructive disease that is very difficult to delay or reverse to preserve joint function.
It is imperative that the initiation of one or more DMARDs occurs in all patients within the
first 3 months of diagnosis to reduce joint erosion. Depending on disease severity and
whether poor prognostic features are present, combination therapy may be initiated at the
time of diagnosis or after an adequate trial of a DMARD initiated as monotherapy. If a patient
has more aggressive disease, a more aggressive treatment plan may be warranted. The
following medication classes are prescribed commonly for treatment of RA: (a) nonsteroidal
anti-inflammatory drugs (NSAIDs), (b) glucocorticoids, (c) conventional synthetic DMARDs
(csDMARDs), (d) biological originator DMARDs (boDMARDs), and (e) targeted synthetic
DMARDs (tsDMARDs). An emerging drug category is biosimilar DMARDs (bsDMARDs).
This category will include biological DMARDs that are a copy of the original biologic
compound and demonstrate similar efficacy and safety. boDMARDs are currently in
development and not yet available for general use. The nomenclature for DMARDs was
proposed by an international leader in rheumatology to distinguish the different types of
DMARDs. Figures 571 and 572 outline the course of treatment for adult RA according to
the ACR 2012 Recommendations. The recommendations are based on the disease activity
level, presence or absence of poor prognostic features, and duration of disease activity (early
vs established). Figure 571 applies to patients who have had RA for less than 6 months.
csDMARD monotherapy includes hydroxychloroquine, leflunomide, methotrexate,
minocycline, or sulfasalazine. Examples of combination therapy for patients with moderate or
high disease activity with evidence of poor prognostic features are
methotrexate/hydroxychloroquine, methotrexate/sulfasalazine, or methotrexate/
sulfasalazine/hydroxychloroquine. Figure 572 outlines the course of treatment for patients
with established RA (disease duration 6 months or longer). boDMARDs are usually
considered in patients with established RA following inadequate response to csDMARDs.
figure 572 establishes a progression for switching from one agent to another in a patient
who experiences an inadequate response or adverse event. Because of treatment expense,
boDMARDs should be considered only in patients who have no limitations due to cost
or insurance coverage. There is no evidence that the benefits of combination boDMARD
therapy outweigh the potential risks, especially the increased risk of infections.

Nonpharmacologic Therapy
All patients should receive education about the nonpharmacologic and pharmacologic
measures to help manage RA and JIA. Empowered patients take an active role in care by
participating in therapy-related decisions. Certain forms of nonpharmacologic therapy benefit
all levels of severity, whereas others (ie, surgery) are reserved for severe cases only.
Occupational and physical therapy may help patients preserve joint function, extend joint
range of motion, and strengthen joints and muscles through strengthening exercises.
Patients with joint deformities may benefit from the use of mobility or assistive devices
that help to minimize disability and allow continued activities of daily living. When
appropriate, patients should also be counseled about stress management (ie, cognitive
behavioral therapy, emotional disclosure, tai chi). In situations where the disease has
progressed to a severe form with extensive joint erosions, surgery to replace or
reconstruct the joint may be necessary