Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by symmetric polyarthritis and joint changes, including erythema, effusion, and tenderness. The course of RA is characterized by remissions and exacerbations. RA can affect several organs, but it usually involves synovial tissue changes in the freely movable joints (diarthroses). RA most commonly affects small joints, including the wrists, second through fifth metatarsophalangeal joints, proximal interphalangeal joints, and metacarpophalangeal joints. RA may also affect large joints, including the elbows, shoulders, neck, hips, knees, and ankles.
In 2008, approximately 0.6% of the adult population in the United States had RA, with the prevalence in women about twice of that in men (Helmick et al., 2008
). New onset of RA is seen throughout the life span, including infancy, but most cases occur in the fifth or sixth decade. Recent data have shown that diagnosis is occurring later in life, and the overall prevalence is decreasing. Previous data have shown that patients with RA have a higher rate of disability and mortality compared to patients of similar age without RA. However, with the increased use of disease-modifying antirheumatic drugs (DMARDs), especially early in the disease process, these risks appear to have normalized (Kroot et al., 2000
The cause of RA continues to be the subject of research. Theories of causation include genetic factors, infectious agents, environmental factors, and an antigen-antibody response. It is unlikely that a single factor is responsible for all cases of RA.
In 2010, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) collaborated on defining classification criteria for RA (Table 37.1
). The goal of the criteria is to identify patients early who have a high probability of persistent RA and in whom early treatment would be beneficial. The emphasis of the classification criteria is on new patients with synovitis not explained by other conditions. Components of these criteria include joint involvement, serologic testing, acute phase reactants, and duration of symptoms.
The serology test can be either RF or ACPA, and the acute phase reactant test can be either erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). For serology tests, results are divided into three categories: negative, low positive (above normal but less than three times the upper limit of normal [ULN]), or high positive (greater than three times the ULN). The acute phase reactants are either normal or abnormal. None of these tests alone are sufficient to diagnose RA, but each is a component of diagnosis.
Other classic symptoms experienced by patients with RA include morning stiffness in involved joints persisting for at least 1 hour and subsiding with activity, symmetric joint involvement, and painful, swollen joints. Although RA characteristically affects joint structures, it is a systemic disease with potential extra-articular manifestations. Throughout the disease, the patient also may have generalized symptoms such as weakness, fatigue, mild fever, anorexia, and weight loss. Endorgan involvement may occur in patients with high RF titers.
The most common extra-articular manifestation of RA is joint nodules. These occur in 15% to 20% of patients with RA and are most commonly seen in patients with erosive disease. These subcutaneous nodules may develop in any area of the body exposed to pressure. Some of these areas are the olecranon bursa, knuckles, ischial spines, Achilles tendon, extensor surfaces of the forearm, and the bridge of the nose (in patients who wear glasses). These nodules may also form internally on the heart, lungs, and intestinal tract. The nodules are firm and rubbery, occur in clusters, and may be either freely mobile or attached to underlying connective tissue. The treatment of the nodules is confined to the treatment of the underlying disease. These nodules may occur in other connective tissue diseases (e.g., systemic lupus erythematosus), so alone they are not criteria for diagnosing RA.
An ocular manifestation of RA is sicca syndrome; patients have a sensation of grittiness in the eyes, accumulation of dried mucus, and decreased tear production. Scleritis and episcleritis are occasional sequelae of sicca syndrome. Additional extraarticular manifestations of RA include vasculitis, pulmonary fibrosis, and pericarditis.
INITIATING DRUG THERAPY
Physical and occupational therapies are considered mainstays of nonpharmacologic therapy in patients with RA. These therapies help protect the joints and maintain strength, function, and mobility. Reduction of joint stress is an additional goal of therapy. Patients should engage in activity to their fullest possible extent with adequate rest after activity, but they should avoid vigorous exercise and heavy labor during acute exacerbations of the disease. Hydrotherapy and hot and cold packs may be used to relax muscle spasms and facilitate joint movement. Warm showers and paraffin treatments may help relieve morning stiffness.
In 2012, the ACR updated their guidelines for the use of nonbiologic and biologic DMARDs, and in 2013, the EULAR provided updated recommendations for the treatment of RA. Both organizations indicated the importance of starting patients on DMARDs as early in the disease process as possible. Evidence has shown that the earlier in the disease process that DMARDs are started, the greater the chance of reducing disability and disease progression. Ideally, patients should be started on DMARD therapy within 3 months of diagnosis. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) can still be considered for symptom control, but these do not have disease-modifying characteristics.
Goals of Drug Therapy
The goals of drug therapy for RA include reducing pain, stiffness, and swelling; preserving mobility and joint function; and preventing further joint damage. Due to advancements in the treatment of RA, the ACR and EULAR now recommend treating
to a goal of remission or if remission is not possible then low disease activity. In 2011, the ACR and EULAR developed a definition for remission, which includes a swollen joint count, tender joint count, CRP level and patient global assessment of ≤1 each, or a simplified Disease Activity Score of ≤3.3. Low disease activity can be assessed in a variety of ways via the Patient Activity Scale (0.28 to 3.7), Clinical Disease Activity Index (greater than 2.8 to 10.0), Disease Activity Score in 28 joints (2.6 to 3.2), or the simplified Disease Activity Index (greater than 3.3 to 11).
TABLE 37.1 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis
Target population (Who should be tested?): patients who
Have at least one joint with definite clinical synovitis (swelling)*
With synovitis not better explained by another disease†
Classification criteria for RA (score-based algorithm: add score of categories A-D; a score ≥6/10 is needed for classification of a patient as having definite RA)‡
A. Joint involvement§
1 large joint||
2-10 large joints
1-3 small joints#
4-10 small joints
>10 joints with at least 1 small joint**
B. Serology (at least one test is needed for classification)††
Negative RF and negative ACPA
Low-positive RF or low-positive ACPA
High-positive RF or high-positive ACPA
C. Acute phase reactants (at least 1 test results is needed for classification)‡‡
Normal CRP and ESR
Abnormal CRP or abnormal ESR
D. Duration of symptoms§§
* The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease typical of RA with a history compatible with prior fulfillment of the 2010 criteria should be classified as having RA. Patients with long-standing disease, including those whose disease is inactive (with or without treatment) and who, based on retrospectively available data, have previously fulfilled the 2010 criteria, should be classified as having RA.
† Differential diagnosis varies among patients with different presentations but may include conditions such as systemic lupus erythematosus, psoriatic arthritis, and gout. If it is unclear about the relevant differential diagnoses to consider, an expert rheumatologist should be consulted.
‡ Although patients with a score <6/10 are not classifiable as having RA, their status can be reassessed and the criteria might be fulfilled cumulatively over time.
§ Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment. Categories of joint distribution are classified according to the location and number of involved joints, with placement into the highest category possible based on the patter of joint involvement.
|| Large joints refer to shoulders, elbows, hips, knees, and ankles.
# Small joints refer to metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.
** In this category, at least one of the involved joints must be a small joint; the other joints can include any combination of large and additional small joints, as well as other joints not specifically listed elsewhere (e.g., temporomandibular, acromioclavicular, sternoclavicular, etc.).
†† Negative refers to IU values that are less than or equal to the ULN for the laboratory and assay; low positive refers to IU values that are higher than the ULN but less than or equal to three times the ULN for the laboratory and assay; high positive refers to IU values that are greater than three times the ULN for the laboratory and assay. When RF is only available as positive or negative, a positive result should be score as low positive for RF.
‡‡ Normal/abnormal is determined by local laboratory standards.
§§ Duration of symptoms refers to patient self-report of the duration of signs and symptoms of synovitis (e.g., pain, swelling, tenderness) of joints that are clinically involved at the time of assessment, regardless of treatment status.
RF, rheumatoid factor; ACPA, anticitrullinated protein antibody; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
Redrawn with permission from Aletaha, D., Neogi, T., Silman, A. J., et al. (2010). 2010 rheumatoid arthritis classification criteria. Arthritis and Rheumatism, 62(9), 2569-2581.
Low-dose corticosteroids (prednisone 10 mg or equivalent) are beneficial in patients who are beginning DMARD therapy. Because the therapeutic effect of DMARDs may not be seen until several weeks to months after initiating therapy, corticosteroids may be used to provide almost immediate symptom relief. Corticosteroids are also indicated in elderly patients with recent onset of RA. Last, higher doses of corticosteroids are beneficial in acute flares to regain control of inflammation and pain.
Corticosteroids have been proven to slow the progression of erosions when initiated early in treatment. Most of the trials have examined this benefit in combination with other DMARD therapy, and monotherapy is only recommended if patients have contraindications to other DMARD therapy. The extended-release prednisone has been examined for use in RA patients. The hypothesis is that if the extended-release prednisone is dosed at night, then the medication would be released at the time when proinflammatory cytokines become activated. The studies showed that this formulation resulted in reduced morning stiffness and a reduction in IL-6.
The difficulty in therapy with corticosteroids lies in the fine dosing line that divides therapeutic effects from long-term side effects. Low doses, such as prednisone 5 to 7.5 mg every morning, may be beneficial. The lowest dose possible should be given by gradually decreasing the dose in 1-mg decrements.
Injectable corticosteroids can be used if symptoms are restricted to one or two joints that have not responded to first-line treatment. They may also be of limited benefit for acute flare-ups of RA.
The most common adverse events of corticosteroid therapy include cataracts, glaucoma, mild glucose intolerance, and cutaneous atrophy. Less common adverse events include myopathy, hypothalamic-pituitary-adrenal axis dysfunction, and osteoporosis. Osteoporosis may be avoided by taking a calcium supplement (1,500 mg/d) along with vitamin D (800 mg/d).