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Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder
characterized by potentially deforming polyarthritis and a wide spectrum
of extra-articular manifestations. Diagnosis of RA is based on joint
involvement, serology, acute-phase reactants, and symptom duration.
Treatments for RA include nonpharmacologic (heat or cold therapy,
range-of-motion [ROM] exercises, physical therapy, and occupational
therapy) and pharmacologic options (nonsteroidal anti-inflammatory
drugs [NSAIDs], synthetic [conventional and targeted] and biologic
disease-modifying antirheumatic drugs [DMARDs], and
corticosteroids). NSAIDs are for symptom management only and must
be used cautiously, if at all, because of serious health risks, including
gastrointestinal complications and thromboembolic cardiovascular
Owing to the destructive nature of the disease, DMARDs should be
initiated as soon as possible once diagnosis has been established.
Methotrexate is the most common selection because of efficacy, safety,
rapid onset, and cost-effectiveness. Other traditional DMARDs and
combinations of traditional DMARDs are selected based on disease
severity, disease duration, and the presence of poor prognostic
indicators. Regardless of the DMARD chosen, all require diligent
Patients with RA, who experience an inadequate response to traditional
DMARD monotherapy or intolerable adverse effects, should consider
the addition of or switching to a biologic DMARD. Diligent monitoring is
also critical with biologic agents owing to the risk of serious adverse
effects such as infections and lymphoma.
Corticosteroids when used judiciously at the lowest effective doses and
for limited duration, are very effective at quickly controlling
inflammation while awaiting onset of DMARD therapy. Although
systemic corticosteroids can be prescribed for short-term flares of RA
disease activity, intra-articular corticosteroid injections are very
effective at managing flares that are limited to a few joints and are not
associated with the adverse effects of systemic therapy.
Juvenile idiopathic arthritis (JIA) describes an assortment of arthritis Case 44-11 (Questions 1, 2)
conditions affecting children and adolescents. Symptoms of JIA, such as
joint inflammation and ROM limitation, are present before 16 years of
age. As in RA, the diagnosis of JIA is based on clinical manifestations,
and all infectious, traumatic, and other etiologies must be ruled out.
Many nonpharmacologic treatment options are also available to
supplement JIA pharmacologic therapy, including exercise, massage,
and physical and occupational therapies.
Pharmacologic treatment options for JIA include NSAIDs, traditional
and biologic DMARDs, and corticosteroids.
Arthritis refers to more than 100 different joint diseases causing swelling, pain and
damage to joints and connective tissue.
1 Rheumatoid arthritis (RA) is the most
common chronic inflammatory arthritis and is characterized by potentially deforming
polyarthritis and a wide spectrum of extra-articular manifestations resulting from
abnormal systemic immune response. It has an estimated worldwide prevalence of
0.5 to 1%, although rates vary between geographic regions.
alone, RA afflicts 1.3 million adults, occurring 2 to 3 times more often in women than
3,4 RA prevalence increases with age, with the average age increasing from
63.3 years in 1965 to 66.8 years in 1995. These patterns predict that RA-associated
morbidity, mortality, and disability will rise in future years, especially as the United
States’ baby boomer generation ages.
The exact etiology of RA is unknown, but like many autoimmune diseases it involves
interplay among multiple factors including genetic susceptibility, environmental
influences, and effects of advancing age on somatic changes in the musculoskeletal
3 The onset of RA likely starts years before clinical symptoms
develop with activation of specific genes, resulting in innate immunity activity
leading the cascade of events.
It is suspected that genetics contribute 50% to 60% of
PTPN22 gene. Cigarette smoking increases the production of rheumatoid factor (RF)
and anti–cyclic citrullinated peptide antibody (anti-CCP), clinical markers
associated with RA, and has been shown to double the risk of developing RA.
Female sex hormones may also play a role in RA development. In women, peak
incidence occurs at the fifth decade, a time when many enter menopause or
perimenopause. Estrogen is known to stimulate the immune system; pregnant patients
often experience a remission of RA symptoms, and women who take oral
contraceptives appear to be somewhat protected against the development of RA.
Diets rich in fish, olive oil, and other omega-3 fatty acid sources are associated with
a lower risk of developing RA.
Pharmacologic therapy for RA targets components of the inflammatory cascade
which lead to persistent inflammation of the synovial lining and ultimately cause joint
7 This normally thin membrane proliferates and transforms into the
synovial pannus. The pannus, a highly erosive enzyme-laden inflammatory exudate,
invades articular cartilage (leading to narrowing of joint spaces), erodes bone
(resulting in osteoporosis), and destroys periarticular structures (ligaments, tendons),
resulting in joint deformities (Fig. 44-1).
Under normal circumstances, the body can distinguish between self (i.e., proteins
found within the body) and nonself (i.e., foreign substances such as bacteria and
viruses). On occasion, immune cells (T or B lymphocytes) can react to a self-protein
while developing in the thymus or bone marrow. These developing cells are usually
killed or inactivated before release from their place of formation; sometimes,
however, a self-targeted immune cell can escape destruction and become activated
years later to initiate an autoimmune response. Some experts believe the activation of
RA is initiated by bacteria (possibly Streptococcus) or a virus containing a protein
with an amino acid sequence similar to tissue protein, but this assertion remains
5 When the activation source (i.e., the self-targeted immune cell) reaches
the joint, complex cell–cell interactions take place, leading to the pathology
CD4-lineage T cell lymphocytes (Fig. 44-2). In addition, B cells (previously thought
to have little to do with the inflammatory response) can become activated, leading to
antibody formation (including RF and anti-CCP), proinflammatory cytokine
production, and accumulation of polymorphonuclear leukocytes that release
cytotoxins and other substances destructive to the synovium and joint structures. B
cells also act as APCs, leading to T cell activation and acceleration of the
a T cell receptor and (2) binding of CD39 on the T cell to either CD80 or CD86 on
the APC. T cell activation leads to activation of macrophages and secretion of
cytokines, polypeptides that serve as important mediators of inflammation, and
cytotoxins, which can directly destroy cells and tissues. Proinflammatory cytokines,
such as interleukin (IL) 1 and TNF-α, stimulate both synovial fibroblasts and
chondrocytes in neighboring articular cartilage to secrete enzymes that cause
degradation of proteoglycan and collagen tissues. In healthy individuals, the
inflammatory process is regulated by balancing the ratios of proinflammatory
cytokines (e.g., IL-1, IL-6, and TNF-α) with anti-inflammatory cytokines––for
example, IL-1 receptor antagonist (IL-1Ra), IL-4, IL-10, and IL-11. In the synovium
of patients with RA, however, this balance is heavily weighted toward the
proinflammatory cytokines, which results in sustained inflammation and tissue
Figure 44-1 Overview of joint changes in rheumatoid arthritis.
degradation. Tumor necrosis factor-α and IL-1 also induce RANK expression on macrophages, which when
nuclear factor-κB; RANKL, RANK ligand; RF, rheumatoid factor; TCR, T cell receptor. Reprinted with
Clinical Presentation, Diagnosis, and Disease Course
QUESTION 1: T.W., a previously healthy 42-year-old, 60-kg woman, has been suffering from morning
(PIP) joints of the hands and the metatarsophalangeal (MTP) joints of the feet.
Pertinent laboratory findings include the following:
ESR, 52 mm/hour (reference range: males 0 to 15 mm/hour, females 0 to 20 mm/hour)
CRP, 2.1 mg/dL (reference range: 0 to 0.5 mg/dL)
Total iron-binding capacity, 275 mg/dL
Positive anti-CCP at 82 units (reference range: <20 units/mL)
Positive RF performed by latex fixation method in a dilution of 1:320 (reference range: <1:80)
More than 50% of RA cases, like that seen in T.W., will have slow onset of
symptoms may be either articular or systemic, including nonspecific complaints such
as fatigue, weakness, muscle pains, weight loss, and low-grade fever. Joint
complaints include pain and stiffness in multiple joints. Classically, as illustrated by
T.W., presentation is symmetrical involving wrists, proximal interphalangeal joints,
and metacarpophalangeal joints, although asymmetrical joint involvement also occurs
with symmetry developing later in the disease course. The peripheral joints of the
hands, wrists, and feet are usually involved first. Reflective of joint inflammation,
patients usually experience prolonged morning stiffness on awakening lasting at least
30 to 45 minutes, but it can be present all day with decreasing intensity after
10,11 Morning stiffness lasting for more than 1 hour rarely occurs in other
metacarpophalangeal joints; MTPs, metatarsophalangeal joints; PIPs, proximal interphalangeal joints.
Ultimately, any or all of the diarthrodial joints (elbows, knees, shoulders, ankles,
hips, temporomandibular joints, sternoclavicular joints, and glenohumeral joints) can
be involved (Fig. 44-3). Progressive disease is characterized by irreversible joint
deformities, such as ulnar deviation of the fingers (Fig. 44-4), boutonniere
deformities (hyperextension of the DIP joint and flexion of the PIP joint), or swan
neck deformities (hyperextension of the PIP joint and flexion of the DIP joint) (Fig.
44-5). Similar irreversible deformities can also involve the feet. Patients with more
aggressive disease (multiple joint involvement, positive RF) have a greater than 70%
probability of developing joint damage or erosions within 2 years of disease onset.
deviation with subluxation of the extensor tendons (right finger; right).
metacarpophalangeal joint; PIP, proximal interphalangeal joint.
CASE 44-1, QUESTION 2: Which laboratory values in T.W. could be used to monitor her RA disease
Physical assessment of an RA patient is fundamental to monitoring and evaluating
patient course. For instructions on how to perform a basic musculoskeletal
examination, go to http://meded.ucsd.edu/clinicalmed/joints.htm and scroll to
select either knee, shoulder, hand, hip, or lower back examinations.
In 2010, the American College of Rheumatology (ACR) and European League
Against Rheumatism (EULAR) developed new classification criteria for RA. In
comparison to criteria previously outlined in 1987, the intent of the new
classification was to identify patients early in disease development so that
therapeutic intervention can be initiated as soon as possible, ultimately decreasing
disease progression and improving clinical outcomes.
Because no single chemical or laboratory finding is specific for the disease, the
diagnosis of RA is based on multiple clinical criteria (Table 44-1). Individuals
presenting with clinical synovitis (swelling) not explained by other differential
diagnoses such as systemic lupus erythematosus, psoriatic arthritis, or gout, among
others, should be tested for RA. RA criteria in the new classification system include
quantifying joint involvement and symptom duration as well as detecting presence of
autoantibodies and acute-phase reactants.
11,14–16 Using a score-based algorithm based
on these four categories, a summative score of 6 or more out of a total possible score
of 10, as seen in T.W., suggests RA.
Individually, each of the laboratory findings is characteristic for chronic systemic
inflammatory disease with no test being specific for RA, although rheumatoid factor
(RF) and anti–citrullinated peptide (anti-CCP) are more definitive than erythrocyte
sedimentation rate (ESR) or C-reactive protein (CRP).
diseases are frequently characterized by autoantibodies, with 50% to 80% of RA
individuals having RF, anti-CCP, or both.
RF, an IgM or IgG autoantibody, abnormally reacts with the Fc portion of IgG to
form an immune complex. It is found in 75% to 80% of patients with RA. It may also
present in up to 5% of healthy individuals and in patients with diseases other than
RA, including almost any condition associated with either immune complex
formation or with hypergammaglobulinemia (e.g., chronic infections,
lymphoproliferative and hepatic diseases, systemic lupus erythmatosus, and
Sjogren’s syndrome). An RF titer of at least 1:160 is considered a positive test and
most patients with RA, such as T.W., typically have titers of at least 1:320.
Overall, RF is neither sensitive nor specific enough to independently diagnose RA,
but it is found in the majority of patients and a higher titer early in disease generally
correlates with increased disease severity and progression.
Criteria for Diagnosis of Rheumatoid Arthritis
Negative RF and negative anti-CCP 0
Low-positive RF or low-positive anti-CCP 2
High-positive RF or high-positive anti-CCP 3
Abnormal CRP or abnormal ESR 1
bShoulders, elbows, hips, knees, and ankles.
Source: Aletaha D et al. 2010 rheumatoid arthritis classification criteria: an American College of
Rheum Dis. 2010;69:1892]. Ann Rheum Dis. 2010;69:1580.
rheumatoid arthritis; RF, rheumatoid factor.
Citrulline, a nonstandard amino acid, is also established as a key component of RA
antigenicity and is more specific for RA than RF. Citrullinated proteins and anti-CCP
antibodies are abundant in inflamed RA synovium. Anti-CCP antibodies can be
detected in 50% to 60% of early RA patients, and the specificity of anti-CCP is very
9 Anti-CCP is present as early as 1.5 to 9 years before symptom
presentation, suggesting a pathogenic role for these antibodies in RA.
anti-CCP also correlates with an increased likelihood of a more erosive course of
a marker for an erosive disease course, and in combination with positive RF also
correlates with 99.5% specificity for RA, making the likelihood of T.W. not having
The nonspecific markers for inflammation include ESR and CRP, but unfortunately
these acute-phase responses are also not
disease-specific. T.W.’s hematologic findings are consistent with a mild anemia of
chronic inflammation. Although her serum iron concentration is decreased, her
normal iron-binding capacity makes a diagnosis of iron-deficiency anemia unlikely.
Her anemia probably results from a failure of iron release from the
reticuloendothelial tissues and would not be expected to respond to iron therapy. The
mild thrombocytosis is additional evidence of a systemic inflammatory response. The
laboratory manifestations of inflammation should improve with effective drug therapy
and, along with many of the clinical features of RA, are useful parameters for
monitoring disease activity and response to therapy.
Finally, the test for ANA rules out systemic lupus erythematosus in T.W. The
ANA, however, can be positive in 10% to 70% patients with RA.
EXTRA-ARTICULAR MANIFESTATIONS AND
The classic RA presentation involves joint findings; however, RA is a systemic
disease reflected by accompanying extra-articular and organ system manifestations
that, chronically, can occur in up to 46% of patients. These manifestations are also
associated with higher disease activity,
22 and those with systemic involvement have
higher mortality rates than those without, suggesting that early treatment may lower
both the risk and severity of RA complications.
Rheumatoid nodules occur in 15% to 20% of patients and are typically found on
extensor surfaces, pressure points, and tendons. Pleuropulmonary manifestations
include pulmonary nodules, fibrosis, and pleuritis; interstitial pneumonitis and
neuropathy, and arteritis of organs.
Some extra-articular manifestations occur as syndromes. Sjögren syndrome
includes dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia), and
connective tissue disease. T.W.’s eye complaints may be an extra-articular
manifestation of her RA. Felty syndrome is characterized by chronic arthritis,
splenomegaly, and neutropenia; thrombocytopenia, anemia, and lymphadenopathy
Individuals with RA have a median life expectancy that is 3 to 10 years shorter
than non-RA populations, with lower life expectancy associated with more severe
5,24 The excess mortality has been attributed primarily to accelerated
cardiovascular disease, responsible for one-third to one-half of deaths among adults
compared with one-fourth to one-fifth of deaths among adults without RA. RA is
associated with a twofold to threefold increased rate of myocardial infarction (MI),
as well as lower MI survival. Management of cardiovascular risk include annual
cardiovascular risk evaluations for all patients, multiplying risk scores by 1.5 for
patients with more than one marker of severe disease activity, use of statins and
cardiovascular medications known to reduce cardiovascular risk, caution when
prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) owing to associated
cardiovascular risk, and smoking cessation (Table 44-2).
myocarditis, while rare, may also occur.
Recommendations for Reducing Cardiovascular Risk
Rheumatoid Arthritis (Evidence/Strength Rating)
both an increased prevalence of traditional cardiovascular risk factors and the inflammatory burden.
To lower cardiovascular risk, adequate control of arthritis disease activity is necessary (2b–3/B).
For patients with rheumatoid arthritis, risk score models should be adapted by introducing a 1.5
extra-articular manifestations (3–4/C).
When using the Systematic Coronary Risk Evaluation model for determination of cardiovascular risk,
triglyceride to high-density lipoprotein cholesterol ratio should be used (3/C).
Intervention for cardiovascular risk factor management should be performed according to national
risk is not completely determined and should be studied further. Clinicians should therefore be very
cautious in prescribing these drugs, especially to patients with cardiovascular risk factors or with
documented cardiovascular disease (2a–3/C).
When corticosteroids are prescribed, this should be at the lowest possible dose (3/C).
Patients should be actively encouraged to stop smoking (3/C).
“moderate” that is established for each country (i.e., either 10% or 20%).
extrapolated recommendations from category 1 evidence; C, category 3 evidence or extrapolated
Source: Peters MJ et al. EULAR evidence-based recommendations for cardiovascular risk management in
The treatment goals of RA are to maximize functional status through maintenance or
improvement of symptoms (e.g., joint pain and swelling), preserve joint function, and
prevent deformity to ultimately improve quality of life and delay disability.
Treatment to achieve remission or lowest possible disease activity involves a
combination of interventions. Early initiation of pharmacologic therapy starting at the
point of diagnosis is critical to quality RA care.
26–28 Other supportive interventions
include rest, exercise and physical therapy, occupational therapy, and emotional
CASE 44-1, QUESTION 3: What nonpharmacologic therapy should be included in the management of
Systemic and articular rest (achieved by splinting the affected joints) can reduce
inflammation significantly. Restful and adequate sleep are particularly important in
chronic, fatigue-inducing diseases such as RA. Therefore, T.W. should rest often
especially when experiencing acute inflammation, but daytime rest periods should be
limited to 30 to 60 minutes each as prolonged rest can also induce rapid losses in
strength and endurance. Splinting of joints is typically prescribed throughout the day
and night during periods of active inflammation, then only at night for several weeks
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