Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

72. Rheumatoid Arthritis

Kimberly Wahl and Arthur A. Schuna


KEY CONCEPTS

 Images Rheumatoid arthritis (RA) is a systemic disease characterized by symmetrical inflammation of joints, yet may involve other organ systems.

 Images Control of inflammation is the key to slowing or preventing disease progression as well as managing symptoms.

 Images Drug therapy should be only part of a comprehensive program for patient management, which would also include physical therapy, exercise, and rest. Assistive devices and orthopedic surgery may be necessary in some patients.

 Images Disease-modifying antirheumatic drugs (DMARDs) or biologic agents should be started early in the course of the disease and shortly after diagnosis of RA.

 Images Nonsteroidal antiinflammatory drugs and/or corticosteroids should be considered adjunctive therapy early in the course of treatment and as needed if symptoms are not adequately controlled with DMARDs.

 Images When DMARDs used singly are ineffective or not adequately effective, combination therapy with two or more DMARDs or a DMARD plus biologic agent may be used to induce a response.

 Images Patients require careful monitoring for toxicity and therapeutic benefit for the duration of treatment.


Rheumatoid arthritis (RA) is the most common systemic inflammatory disease characterized by symmetrical joint involvement. Extraarticular involvement, including rheumatoid nodules, vasculitis, eye inflammation, neurologic dysfunction, cardiopulmonary disease, lymphadenopathy, and splenomegaly, can be manifestations of the disease. Although the usual disease course is chronic, some patients will enter a remission spontaneously.

EPIDEMIOLOGY

RA is estimated to have a prevalence of 1% and does not have any racial predilections. It can occur at any age, with increasing prevalence up to the seventh decade of life. The disease is three times more common in women. In people ages 15 to 45 years, women predominate by a ratio of 6:1; the sex ratio is approximately equal among patients in the first decade of life and in those older than age 60 years.

Epidemiologic data suggest that a genetic predisposition and exposure to unknown environmental factors may be necessary for expression of the disease. The major histocompatibility complex molecules, located on T lymphocytes, appear to have an important role in most patients with RA. These molecules can be characterized using human lymphocyte antigen (HLA) typing. A majority of patients with RA have HLA-DR4, HLA-DR1, or both antigens in the major histocompatibility complex region. Patients with HLA-DR4 antigen are 3.5 times more likely to develop RA than those patients who have other HLA-DR antigens.1 Although the major histocompatibility complex region is important, it is not the sole determinant as patients can have the disease without these HLA types. RA is six times more common among dizygotic twins and nontwin children of parents with rheumatoid factor-positive, erosive RA when compared with children whose parents do not have the disease. If one of a pair of monozygotic twins is affected, the other twin has a 30 times greater risk of developing the disease.2,3

PATHOPHYSIOLOGY

Images Chronic inflammation of the synovial tissue lining the joint capsule results in the proliferation of this tissue. The inflamed, proliferating synovium characteristic of RA is called pannus. This pannus invades the cartilage and eventually the bone surface, producing erosions of bone and cartilage and leading to destruction of the joint. The factors that initiate the inflammatory process are unknown.

The immune system is a complex network of checks and balances designed to discriminate self from nonself (foreign) tissues. It helps rid the body of infectious agents, tumor cells, and products associated with the breakdown of cells. In RA, this system is no longer able to differentiate self from nonself tissues and attacks the synovial and other connective tissues.

In addition to the genetic factors mentioned above, environmental factors play a role. It is known that smoking and pulmonary disease may increase risk. Infectious agents (e.g., Epstein-Barr virus, Escherichia coli) and periodontal disease (Porphyromonas gingivalis) have been associated with RA.

The immune system has both humoral and cell-mediated functions (Fig. 72-1). The humoral component is necessary for the formation of antibodies. These antibodies are produced by plasma cells, which are derived from B lymphocytes. Most patients with RA form antibodies called rheumatoid factors. Rheumatoid factors have not been identified as pathogenic, nor does the quantity of these circulating antibodies always correlate with disease activity. Seropositive patients tend to have a more aggressive course of their illness than do seronegative patients. Anticitrullinated protein antibody (ACPA) is another antibody identified, which is produced in most patients with RA and has become an important diagnostic tool. Patients may develop ACPA long before they develop symptoms of RA, and those with positive antibodies have a poorer prognosis than those without.

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FIGURE 72-1 Pathogenesis of the inflammatory response. Antigen-presenting cells process and present antigens to T cells, which may stimulate B cells to produce antibodies and osteoclasts to destroy and remove bone. Macrophages stimulated by the immune response can stimulate T cells and osteoclasts to promote inflammation. They also can stimulate fibroblasts, which produce matrix metalloproteinases to degrade the bone matrix and produce proinflammatory cytokines. Activated T cells and macrophages release factors that promote tissue destruction, increase blood flow, and result in cellular invasion of synovial tissue and joint fluid. (APC, antigen-presenting cell; IL, interleukin; MMP, matrix metalloproteinase; TNF-α, tumor necrosis factor α.)

The invasion of the synovium and joint by leukocytes results in synovitis. These leukocytes migrate to the region directed by chemokines and adhesion molecules. Early in the inflammatory process, increased vascularity aids in cell trafficking. The synovium proliferates and fibroblasts are activated, and this promotes bone and connective tissue destruction.

Immunoglobulins can activate the complement system. The complement system amplifies the immune response by encouraging chemotaxis, phagocytosis, and the release of lymphokines by mononuclear cells, which are then presented to T lymphocytes. The processed antigen is recognized by major histocompatibility complex proteins on the lymphocyte, which activates it to stimulate the production of T and B cells. The proinflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6 are key substances in the initiation and continuance of rheumatoid inflammation. IL-17 can induce proinflammatory cytokines in fibroblasts and synoviocytes and stimulate the release of matrix metalloproteinases and other cytotoxic substances, which leads to cartilage destruction. Activated T cells produce cytotoxins, which are directly toxic to tissues, and cytokines, which stimulate further activation of inflammatory processes and attract cells to areas of inflammation. Macrophages are stimulated to release prostaglandins and cytotoxins.46 T-cell activation requires both stimulation by proinflammatory cytokines as well as interaction between cell surface receptors, called costimulation. One of these costimulation interactions is between CD28 and CD80/86. The binding of the CD80/86 receptor by the drug abatacept has proved to be an effective treatment for RA by preventing costimulation interactions between T cells.7


CLINICAL PRESENTATION Rheumatoid Arthritis

Symptoms

    • Joint pain and stiffness of more than 6 weeks’ duration. May also experience fatigue, weakness, low-grade fever, loss of appetite. Muscle pain and afternoon fatigue may also be present. Joint deformity is generally seen late in the disease.

Signs

    • Tenderness with warmth and swelling over affected joints usually involving hands and feet. Distribution of joint involvement is frequently symmetrical. Rheumatoid nodules may also be present.

Laboratory Tests

    • Rheumatoid factor (RF) detectable in 60% to 70%.

    • Anticyclic citrullinated peptide (anti-CCP) antibodies have similar sensitivity to RF (50% to 85%) but are more specific (90% to 95%) and are present earlier in the disease.

    • Elevated erythrocyte sedimentation rate and C-reactive protein are markers for inflammation.

    • Normocytic normochromic anemia is common as is thrombocytosis.

Other Diagnostic Tests

    • Joint fluid aspiration may show increased white blood cell counts without infection, crystals.

    • Joint radiographs may show periarticular osteoporosis, joint space narrowing, or erosions.

Although it has been suggested that T cells play a key role in the pathogenesis of RA, B cells clearly have an equally important role. Evidence for this importance may be found in the effectiveness of B-cell depletion using the drug rituximab in controlling rheumatoid inflammation. Activated B cells produce plasma cells, which form antibodies. These antibodies in combination with the complement system result in the accumulation of polymorphonuclear leukocytes, which release cytotoxins, oxygen-free radicals, and hydroxyl radicals that promote cellular damage to synovium and bone. The benefits of B-cell depletion occur even though antibody formation is not suppressed with rituximab therapy; this suggests that other mechanisms play a role in reducing RA activity. B cells produce cytokines that may alter the function of other immune cells, and they also have the ability to process antigens and act as antigen-presenting cells, which interact with T cells to activate the immune process.811

In the synovial membrane, CD4+ T cells are abundant and communicate with macrophages, osteoclasts, fibroblasts, and chondrocytes either through direct cell–cell interactions using cell surface receptors or through proinflammatory cytokines such as TNF-α, IL-1, and IL-6. These cells produce metalloproteinases and other cytotoxic substances, which lead to the erosion of bone and cartilage. They also release substances promoting growth of blood vessels and adhesion molecules, which assists in proinflammatory cell trafficking and attachment of fibroblasts to cartilage and eventual synovial invasion and destruction.1215 TNF inhibitors are widely used to treat RA. Although anakinra inhibits IL-1 by attaching to receptors on cell surface, the benefits of this approach have not been as great as expected. Tocilizumab has proven effective as an inhibitor of IL-6 activity.

There are also a number of signaling molecules that are important for activating and maintaining inflammation. One of these is Janus kinase (JAK), which is a tyrosine kinase responsible for regulating leukocyte maturation and activation. JAK also has effects on the production of cytokines and immunoglobulins. Tofacitinib, an oral JAK inhibiting drug, has proven to be very effective in RA and appears to inhibit IL-6 activity as the major mechanism of action.

Vasoactive substances also play a role in the inflammatory process. Histamine, kinins, and prostaglandins are released at the site of inflammation. These substances increase both blood flow to the site of inflammation and the permeability of blood vessels. These substances cause the edema, warmth, erythema, and pain associated with joint inflammation and make it easier for granulocytes to pass from blood vessels to the site of inflammation.

The end results of the chronic inflammatory changes are variable. Loss of cartilage may result in a loss of the joint space. The formation of chronic granulation or scar tissue can lead to loss of joint motion or bony fusion (called ankylosis). Laxity of tendon structures can result in a loss of support to the affected joint, leading to instability or subluxation. Tendon contractures also may occur, leading to chronic deformity.12,16

The symptoms of RA usually develop insidiously over the course of several weeks to months. Prodromal symptoms include fatigue, weakness, low-grade fever, loss of appetite, and joint pain. Stiffness and muscle aches (myalgias) may precede the development of joint swelling (synovitis). Fatigue may be more of a problem in the afternoon. During disease flares, the onset of fatigue begins earlier in the day and subsides as disease activity lessens. Most commonly, joint involvement tends to be symmetrical; however, early in the disease some patients present with an asymmetrical pattern involving one or a few joints that eventually develops into the more classic presentation. Approximately 20% of patients develop an abrupt onset of their illness with fevers, polyarthritis, and constitutional symptoms (e.g., depression, anxiety, fatigue, anorexia, and weight loss).2,3

No single test or physical finding can be used to make the diagnosis of RA. In early disease, the diagnosis can be particularly challenging given that radiographic findings are usually absent and rheumatoid factor test can be undetectable. Duration of joint pain and swelling, morning stiffness lasting more than 1 hour, and involvement of three or more joints are important early predictors of the development of persistent erosive RA.17

JOINT INVOLVEMENT

The joints affected most frequently by RA are the small joints of the hands, wrists, and feet (Fig. 72-2). In addition, elbows, shoulders, hips, knees, and ankles may be involved. Patients usually experience joint stiffness that typically is worse in the morning. The duration of stiffness tends to be correlated directly with disease activity, usually exceeds 30 minutes, and may persist all day. Chronic inflammation with lack of an adequate exercise program results in loss of range of motion, atrophy of muscles, weakness, and deformity (Figs. 72-3 and 72-4).

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FIGURE 72-2 Patterns of joint involvement in rheumatoid arthritis and osteoarthritis.

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FIGURE 72-3 Deformities of rheumatoid arthritis, with marked ulnar deviation, swan-neck deformity, active synovitis, and nodules. (Reproduced with permission from Brunicardi FC, Anderson DK, Billiar TR, et al. Schwartz’s Principles of Surgery, 8th ed. New York: McGraw-Hill, 2005.)

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FIGURE 72-4 A. Preoperative view of metacarpophalangeal joints in rheumatoid arthritis. B. Following resection arthroplasty. (Reproduced with permission from Skinner H., ed. Current Diagnosis & Treatment in Orthopedics, 4th ed. New York: McGraw-Hill, 2006:592.)

On examination, the swelling of the joints may be visible or may be apparent only by palpation. The swelling feels soft and spongy because it is caused by proliferation of soft tissues or fluid accumulation within the joint capsule. The swollen joint may appear erythematous and feel warmer than nearby skin surfaces, especially early in the course of the disease. In contrast, the swelling associated with osteoarthritis usually is bony (caused by osteophytes) and infrequently is associated with signs of inflammation.

Involvement of the hands and wrists is common in RA. Hand involvement is manifested by pain, swelling, tenderness, and grip weakness during the acute phase and by subluxation, instability, deformity, and muscle atrophy in the chronic phase of the disease. Functional difficulties with clasp, grasp, and pinch alter both strength and fine motor movement.

Deformity of the hand may be seen with chronic inflammation. These changes may alter the mechanics of hand function, reducing grip strength and making it difficult to perform usual daily activity.

Pain in the elbow and shoulder may be the result of true joint inflammation or inflammation of soft-tissue structures such as tendons (tendonitis) or the bursa (bursitis). The knee also can be involved, with loss of cartilage, instability, and joint pain. Synovitis of the knee may cause the formation of a cyst behind the knee called a popliteal or Baker’s cyst. These cysts may become painful as they get tense, or they may rupture, producing a clinical picture similar to thrombophlebitis secondary to the release of inflammatory components into the area of the calf muscle (pseudothrombophlebitis syndrome). Chronic joint pain leads to muscle atrophy, which can result in a laxity of the ligamentous structures that support the knee, causing instability. Maintenance of an adequate range of motion of the knee is essential to normal gait.

Foot and ankle involvement in RA is common. The metatarsophalangeal joints are involved frequently in RA, making walking difficult. Subluxation of the metatarsal heads leads to “cock-up” or hammer toe deformities. Subluxation also may cause a flexion deformity at the proximal interphalangeal joint of the toe, leading to pressure necrosis of the skin over the joint secondary to irritation caused by shoes. Hallux valgus (lateral deviation of the digit) and bunion or callus formation may occur at the great toe. A widening of the foot occurs commonly with long-standing disease.

Involvement of the spine usually occurs in the cervical vertebrae; lumbar vertebral involvement is rare. Involvement of the first and second cervical vertebrae (C1 to C2) can lead to instability of this joint. Patients with this problem are at a greater risk for spinal cord compression, although this complication is rare.

The temporomandibular joint (jaw) can be affected, resulting in malocclusion and difficulty in chewing food. Inflammation of cartilage in the chest can lead to chest wall pain. Hip pain may occur as a result of destructive changes in the hip joint, soft-tissue inflammation (e.g., bursitis), or referred pain from nerve entrapment at the lumbar vertebrae.

EXTRAARTICULAR INVOLVEMENT

Although joint involvement in RA is a hallmark finding in RA, it is important to recognize that, as a systemic disease, other organ systems are often involved.

Rheumatoid Nodules

Rheumatoid nodules occur in 20% of patients with RA. These nodules are seen most commonly on the extensor surfaces of the elbows, forearms, and hands but also may be seen on the feet and at other pressure points. They also may develop in the lung or pleural lining of the lung and, rarely, in the meninges. Rheumatoid nodules usually are asymptomatic and do not require any special intervention. Nodules are observed more commonly in patients with erosive disease.18

Vasculitis

Vasculitis usually is seen in patients with long-standing RA. Vasculitis may result in a wide variety of clinical presentations. Invasion of blood vessel walls by inflammatory cells results in an obliteration of the vessel, producing infarction of tissue distal to the area of involvement. Most commonly, small-vessel vasculitis produces infarcts near the ends of the fingers or toes, especially around the nail beds. These infarcts are usually of little consequence.

Vasculitis also may cause the breakdown of skin, especially in the lower extremities, producing ulcers that may be indistinguishable in appearance from stasis ulcers. However, these ulcers do not heal with the usual modes of treatment used for stasis ulcers. Involvement of larger vessels with vasculitis can result in life-threatening complications. Infarction of vessels supplying blood to nerves can cause irreversible motor deficits. Involvement of vessels supplying other organ systems can lead to visceral involvement and a polyarteritis nodosa-like illness. Aggressive treatment of the inflammatory process is necessary in these patients. Fortunately, vasculitis has become much less frequently seen since the advent of methotrexate and biologic therapy.

Pulmonary Complications

RA may involve the pleura of the lung, which is often asymptomatic, although pleural effusions may result. Pulmonary fibrosis also may develop as a result of rheumatoid involvement; smoking appears to increase the risk of this complication. Rheumatoid nodules may develop in lung tissue and appear similar to neoplasms on chest radiographs. Interstitial pneumonitis and arteritis are rare, potentially life-threatening complications of RA.

Ocular Manifestations

Ocular manifestations include keratoconjunctivitis sicca and inflammation of the sclera, episclera, and cornea. Atrophy of the lacrimal duct may result in a decrease in tear formation, causing dry and itchy eyes, termed keratoconjunctivitis sicca. When this is observed in association with RA, it is referred to as Sjögren’s syndrome. Artificial tears may be used to relieve symptoms. The salivary glands may also be involved in Sjögren’s syndrome, resulting in dry mouth (xerostomia). Inflammation of the superficial layers of the sclera (episcleritis) is generally self-limiting. Involvement of deeper tissues (scleritis) usually results in a more serious, painful, and chronic inflammation. Rheumatoid nodules may develop on the sclera.

Cardiac Involvement

The heart is sometimes affected by RA. RA is associated with an increased risk of cardiovascular mortality. This risk appears to be higher in those with more active inflammation and is reduced with treatment, particularly with methotrexate.19,20 Pericarditis may occur, resulting in the accumulation of fluid. Although many patients show evidence of previous pericarditis at autopsy, the development of clinically evident pericarditis with tamponade is a rare complication. Cardiac conduction abnormalities and aortic valve incompetence, caused by aortic root dilation, may occur. Myocarditis is a rare complication of RA.

Felty’s Syndrome

RA in association with splenomegaly and neutropenia is known as Felty’s syndrome. Thrombocytopenia also may be a manifestation of the syndrome. Patients with Felty’s syndrome and severe leukopenia are more susceptible to infection. The decrease in granulocytes appears to be mediated by the immune system because splenectomy does not result in improvement of the patient.18

Other Complications

Lymphadenopathy may occur in patients with RA, particularly in nodes proximal to more actively involved joints. Renal involvement is rare but can be associated with treatment, including nonsteroidal antiinflammatory drugs (NSAIDs), gold salts, and penicillamine. Amyloidosis is a rare complication of longstanding RA. It appears to be more common in Europe than in the United States.

LABORATORY FINDINGS

Hematologic tests often reveal a mild-to-moderate anemia with normocytic, normochromic indices. The hematocrit may fall as low as 30%. The anemia is usually inversely related to inflammatory disease activity and is referred to as an anemia of chronic disease. This type of anemia does not respond to iron therapy and can present a diagnostic dilemma because NSAIDs may induce gastritis and chronic blood loss, leading to iron-deficiency anemia. Laboratory tests useful in differentiating these anemias include stool guaiac (or other stool tests for occult blood), serum iron-to-iron-binding capacity ratio (decreased in iron deficiency), ferritin (decreased in iron deficiency), and mean corpuscular volume (more likely to be decreased in iron deficiency). Other causes of anemia also must be considered in the differential diagnosis (see Chaps. 80 and 82).

Thrombocytosis is another common hematologic finding with active RA. Platelet counts rise and fall in direct correlation with disease activity in many patients. Thrombocytopenia may result from toxicity of immunosuppressive therapy. Thrombocytopenia also may be observed in Felty’s syndrome or vasculitis.

Although leukopenia is associated with Felty’s syndrome, it also may result from toxicity of methotrexate, gold, sulfasalazine, penicillamine, and immunosuppressive drugs. Leukocytosis is seen commonly as a result of corticosteroid treatment.

The erythrocyte sedimentation rate (ESR) is usually elevated in patients with RA and other inflammatory diseases. This test is very nonspecific, and although the ESR usually falls as patients respond to therapy, there is a large variability among patients in response to treatment. C-reactive protein (CRP) is another nonspecific marker for inflammatory arthritis when it is elevated. This protein is produced by the liver in response to certain cytokines.

Rheumatoid factor (RF) is present in 60% to 70% of patients with RA. The usual laboratory test for RF is an antibody specific for immunoglobulin (Ig)M RF. Patients with RA and a negative test for RF may have IgG or IgA RFs, but tests for these are not routinely available. RF tests may be reported positive at a specific serum dilution. Serum is diluted to a standard series of dilutions; the greatest dilution that yields a positive test result will be reported (e.g., RF positive at 1:640). Some laboratories quantify RF rather than using titers. Higher dilutional titers or serum concentrations of RFs usually indicate a more severe disease, but like the ESR, the large interpatient variability makes this test unreliable as a means of assessing patient progress. RF may be positive in patients without RA (Table 72-1).

TABLE 72-1 Diseases Associated with a Positive Rheumatoid Factor

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ACPA has similar sensitivity for RA, being found in 50% to 85% of patients with the disease, but is more specific (90% to 95%) and is detectable very early in the disease. Many rheumatologists will do both tests in evaluating new patients.

Antinuclear antibodies (ANAs) are detected in 25% of patients with RA. These antibodies usually have a diffuse pattern of immunofluorescence. Tests for antibodies to double-stranded DNA (usually positive in systemic lupus erythematosus) are negative. Serum complement is usually normal, although complement concentrations of joint fluid often are depressed from consumption secondary to the inflammatory process. In patients with vasculitis, serum complement concentrations may be low.21,22

Synovial fluid usually is turbid because of the large number of leukocytes in inflammatory fluid. White cell counts of 5,000 to 50,000/mm3 (5 × 109 to 50 × 109/L) are not uncommon in inflamed joints. The fluid is usually less viscous than that in normal joints or fluid associated with osteoarthritis. Glucose concentrations of joint fluid are normal or low compared with those in serum drawn at the same time as synovial aspirates. The decrease is not as profound as the decrease associated with joint infection or systemic lupus erythematosus.

Early radiographic manifestations of RA include soft-tissue swelling and osteoporosis near the joint (periarticular osteoporosis). Joint space narrowing occurs as a result of cartilage degradation. Erosions tend to occur later in the course of the disease and usually are seen first in the metacarpophalangeal and proximal interphalangeal joints of the hands and the metatarsophalangeal joints of the feet. Periodic joint radiographs are a useful way of evaluating disease progression.

Diagnostic Criteria

The American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) revised criteria for the diagnosis of RA.23 These criteria were developed to be used for patients early in their disease; they, therefore, emphasize early manifestations of the disease. Late manifestations of RA such as erosive disease or nodules are no longer in the diagnostic criteria, but these patients would have previously met these criteria based on retrospective data.

Patients with synovitis of at least one joint and no other explanation for the finding are candidates for these criteria. The criteria use a scoring system with a score of >6 out of a possible total score of 10 as being diagnostic for RA. More points are given for patients presenting with more actively involved joints. Positive laboratory tests including RF, ACPA, CRP, and ESR result in additional points.

Duration of symptoms ≥6 weeks results in an additional point. It is important to note that not all patients with RA may have a score >6 initially, particularly if seen very early in their disease but may evolve to higher scores over time. Reassessment should be considered for those with ongoing symptoms.

Seronegative Inflammatory Arthritis

Although RA may have a negative RF titer, a number of other systemic inflammatory arthritic conditions exist including psoriatic arthritis, reactive arthritis, ankylosing spondylitis, and arthritis associated with inflammatory bowel disease. These conditions often tend to be less aggressive than what is typically seen with RA. Detailed discussion about these conditions is beyond the scope of this chapter, but further information may be found elsewhere.2Management principles are similar to those for RA.

TREATMENT

Rheumatoid Arthritis

Desired Outcome

Images The primary objective in the treatment of RA is to improve or maintain functional status, thereby improving quality of life. The ultimate goal is to achieve complete disease remission or low disease activity, although this goal may not be possible to achieve in some patients. Additional goals of treatment include controlling disease activity and joint pain, maintaining the ability to function in daily activities or work, slowing destructive joint changes, and delaying disability.

General Approach to Treatment

The multifaceted treatment approach includes pharmacologic and nonpharmacologic therapies with recent emphasis being placed on aggressive treatment early in the disease course. Early aggressive treatment may prevent irreversible joint damage and disability. As many pharmacologic agents are available for the treatment of RA, the recommended drug therapy is based on disease duration, activity, and prognosis.24,25 In general, patients with less active disease and good prognostic indicators may be treated with oral agents as monotherapy. Those with high disease activity and/or poor prognostic features are candidates for combination therapy and biologics to suppress inflammation. Controlling inflammation with therapeutic interventions improves symptoms, slows the disease course, and prevents disease progression.

Nonpharmacologic Therapy

Images Rest, occupational therapy, physical therapy, use of assistive devices, weight reduction, and surgery are the most useful types of nonpharmacologic therapy used in patients with RA. Rest is an essential component of a nonpharmacologic treatment plan. It relieves stress on inflamed joints and prevents further joint destruction. Rest also aids in alleviation of pain. Too much rest and immobility, however, may lead to decreased range of motion and, ultimately, muscle atrophy, and contractures.

Occupational and physical therapy can provide the patient with skills and exercises necessary to increase or maintain mobility. These disciplines may also supply patients with supportive and adaptive devices such as canes, walkers, and splints.

Other nonpharmacologic therapeutic options include weight loss and surgery. Weight reduction helps to alleviate stress on inflamed joints. This should be instituted and monitored with close supervision of a healthcare professional. Tenosynovectomy, tendon repair, and joint replacements are surgical options for patients with RA. Such management is reserved for patients with severe disease.2627

Pharmacologic Therapy

Images Images Pharmacologic agents that reduce RA symptoms and impede radiographic joint damage can be categorized as either nonbiologic disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs, which include TNF-α inhibitor biologics or non-TNF biologics. DMARDs are a treatment cornerstone and should be started as soon as possible after disease onset as early introduction results in more favorable outcomes2830 and reduces mortality rates comparable to patients without the disease.19,31 NSAIDs and/or corticosteroids may be used for symptomatic relief if needed. They provide relatively rapid improvement in symptoms compared with DMARDs, which may take weeks to months before benefit is seen; however, NSAIDs have no impact on disease progression and the long-term complication risks of corticosteroids make them less desirable.28

DMARDs and biologic agents slow RA disease progression. DMARDs commonly used include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide. The biologic agents with disease-modifying activity include the anti-TNF drugs (etanercept, infliximab, adalimumab, certolizumab, golimumab, tofacitinib), the costimulation modulator abatacept, the IL-6 receptor antagonist tocilizumab, and rituximab, which depletes peripheral B cells. Agents less frequently used because of reduced efficacy, greater toxicity, or both include the IL-1 receptor antagonist anakinra, azathioprine, D-penicillamine, gold (including auranofin), minocycline, cyclosporine, and cyclophosphamide.

DMARDs, either as monotherapy or in combination, are first-line agents for most patients with RA. The order in which these agents are used is not clearly defined, although methotrexate is often chosen because long-term data suggest superior outcomes with methotrexate than with other DMARDs. There is also good documentation for better outcomes with methotrexate in combination therapy if methotrexate monotherapy does not achieve an adequate response. Leflunomide appears to have similar long-term efficacy as that of methotrexate.32

Images Combination therapy with two or more DMARDs may be effective when single-DMARD treatment is unsuccessful.29,3335 One study suggests that initial combination therapy with either methotrexate, sulfasalazine plus prednisone, or infliximab plus methotrexate was superior to more conventional sequential monotherapy or step-up combinations of DMARDs in early RA.33 For patients with moderate-to-high disease activity, ACR recommends dual DMARD combinations of methotrexate plus hydroxychloroquine, methotrexate plus leflunomide, or methotrexate plus sulfasalazine. They also recommend the triple combination of sulfasalazine, hydroxychloroquine, and methotrexate.24

The anti-TNF and non-TNF biologic agents have proven effective for patients who fail treatment with other DMARDs and were previously reserved for this population subset, partly due to cost. However, ACR now endorses the use of anti-TNF biologics in patients with early disease of high activity and presence of poor prognostic factors, regardless of previous DMARD use.24 Features of poor prognosis include functional limitation, extraarticular disease (e.g., rheumatoid nodules, vasculitis), positive RF or ACPA, or bone erosions. Anti-TNF biologics can be used as either monotherapy or in combination with other DMARDs.25 Use of biologics in combination with methotrexate is more effective than biologic monotherapy and the combination is frequently used. Infliximab, specifically, should be given in combination with methotrexate to prevent development of antibodies that may reduce drug efficacy or induce allergic reactions.24

ACR published recommendations for use of nonbiologic and biologic DMARDs in 2008 and updated them in 2012. These recommendations are not intended to be prescriptive but provide guidance for treatment choice. Recommendations are given based on disease duration, degree of disease activity, and likely prognosis. The recommendations take into account barriers to treatment, including cost and insurance restrictions, by suggesting treatment options with and without expensive biologic agents. Simplified algorithms summarizing these treatment recommendations are provided in Figures 72-5 and 72-6. For more details, see the published recommendations.24,25

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FIGURE 72-5 Algorithm for treatment of rheumatoid arthritis (RA) in early RA (<6 months). Poor prognosis is defined as limitation in function, extraarticular findings (rheumatoid nodules, vasculitis, Felty’s syndrome, Sjögren’s syndrome, rheumatoid lung findings, erosions on radiograph), bone erosions, and positive rheumatoid factor or anticitrullinated protein antibody. (DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; NSAID, nonsteroidal antiinflammatory drug.)

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FIGURE 72-6 Algorithm for treatment of rheumatoid arthritis (RA) in established RA (>6 months). Poor response is defined as a deterioration of disease activity or the patient continues with moderate to high disease activity after 3 months of therapy.

Corticosteroids can be used in various ways in the treatment of RA but should not be used as monotherapy. Corticosteroids are valuable in controlling symptoms before DMARDs take effect and are used in acute RA flares as burst therapy. Additionally, continuous low doses of corticosteroids may be used as adjunct therapy when DMARDs do not provide adequate disease control. Corticosteroids may be injected into joints and soft tissues to control local inflammation. There are data to suggest they have disease-modifying activity;33,34,36 however, it is preferable to avoid chronic use when possible to avoid long-term complications. NSAIDs and DMARDs have steroid-sparing properties that permit corticosteroid dose reductions.

As immunosuppression may reduce the ability to mount an antibody response, the need for immunizations should be assessed, and these should be administered if needed before nonbiologic or biologic DMARDs are started.25Postvaccination antibody titers seem to be only minimally affected by conventional DMARDs and TNF antagonists. Rituximab and abatacept seem to reduce the ability to develop antibodies after vaccination. Live vaccines are not recommended for patients taking biologic DMARDs.37

Some biologic agents are contraindicated in the setting of hepatitis or malignancies because of immunosuppression. Etanercept, an anti-TNF biologic, is the only agent recommended for possible treatment of RA in patients with hepatitis C. No biologic agent should be used in patients with untreated hepatitis B or treated hepatitis B with liver dysfunction (Child-Pugh class B or higher). Rituximab is preferred in patients with previously treated solid malignancies, skin cancers, or lymphoproliferative malignancies. For patients with solid or nonmelanoma skin cancers treated more than 5 years ago, any biologic agent can be initiated or restarted.24

Images Tables 72-272-3, and 72-4 provide monitoring parameters and dosing guidelines for DMARDs and NSAIDs used in RA.

TABLE 72-2 Usual Doses for Antirheumatic Drugs

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TABLE 72-3 Clinical Monitoring of Drug Therapy in Rheumatoid Arthritis

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TABLE 72-4 Dosage Regimens for Nonsteroidal Antiinflammatory Drugs

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Nonsteroidal Antiinflammatory Drugs

NSAIDs should seldom be used as monotherapy for RA because they do not alter the course of the disease; instead, they should be viewed as adjuncts to DMARD treatment. NSAIDs possess both analgesic and antiinflammatory properties and reduce stiffness associated with RA. These agents mainly inhibit prostaglandin synthesis, which is only a small portion of the inflammatory cascade. For details on these agents see Chapter 71, Osteoarthritis.

Methotrexate

Methotrexate is now considered the nonbiologic DMARD of choice by many rheumatologists for treating RA. It inhibits cytokine production, inhibits purine biosynthesis, and may stimulate release of adenosine, all of which may lead to its antiinflammatory properties. The drug has a fairly rapid onset of action; results may be seen as early as 2 to 3 weeks after starting therapy. Some 45% to 67% of patients remain on methotrexate therapy in studies ranging from 5 to 7 years.38

Absorption of methotrexate is variable and averages approximately 70% of an oral dose. Methotrexate is 35% to 50% bound to albumin; it may be displaced by highly protein-bound drugs such as NSAIDs, but the clinical importance of this interaction in the relatively low doses of methotrexate used in RA is unknown. Methotrexate is extensively metabolized intracellularly to polyglutamated derivatives. It is excreted by the kidney, 80% unchanged, by glomerular filtration and active transport. Some methotrexate may be reabsorbed, but this transport process may be saturated even with low doses, resulting in increased renal clearance.

Methotrexate is contraindicated in pregnant and nursing women as it is teratogenic. Patients should use contraception to avoid pregnancy and discontinue the drug if conception is planned. It is also contraindicated in patients with chronic liver disease, immunodeficiency, pleural or peritoneal effusions, leukopenia, thrombocytopenia, preexisting blood disorders, and a creatinine clearance of less than 40 mL/min (0.67 mL/s).

The toxicities of methotrexate therapy are mainly gastrointestinal, hematologic, pulmonary, and hepatic. Stomatitis occurs in 3% to 10% of patients and may be painful or painless. Diarrhea, nausea, and vomiting may occur in up to 10% of patients. The most common hematologic toxicity is thrombocytopenia in 1% to 3% of patients. Leukopenia also may occur, but in a smaller number of patients. Although pulmonary fibrosis and pneumonitis can be severe adverse effects, they are rare.

Elevated liver enzymes may occur in up to 15% of patients; cirrhosis is rare. Liver function tests, aspartate aminotransferase or alanine aminotransferase, should be performed periodically. Methotrexate should be discontinued if these test values show sustained results greater than twice the upper limits of normal. Albumin should also be checked periodically as a sign of liver toxicity because some patients may not have liver inflammation manifested by aspartate aminotransferase or alanine aminotransferase elevation. Liver biopsy is now recommended before beginning methotrexate therapy only for patients with a history of excessive alcohol use, ongoing hepatitis B or C infection, or recurring elevation of aspartate aminotransferase. Biopsies during methotrexate therapy are recommended only for patients who develop consistently abnormal liver function tests.26

Because it is a folic acid antagonist, methotrexate can induce a folic acid deficiency. This deficiency is thought to be partly responsible for methotrexate toxicity, and supplementation with folic acid does alleviate some adverse effects. Addition of folic acid to a methotrexate regimen for RA does not compromise drug efficacy.26,24,39

Methotrexate may be given intramuscularly, subcutaneously, or orally. Doses greater than 15 mg per week generally are given parenterally because of decreased oral bioavailability of larger doses.

Leflunomide

Leflunomide is a DMARD that inhibits pyrimidine synthesis, leading to a decrease in lymphocyte proliferation and modulation of inflammation. It has efficacy similar to methotrexate for treating RA. The drug may cause liver toxicity and is contraindicated in patients with preexisting liver disease. Patients taking the drug should have alanine aminotransferase monitored monthly initially and periodically thereafter as long as they continue treatment. Leflunomide may cause bone marrow toxicity and complete blood count with platelets is recommended monthly for 6 months and then every 6 to 8 weeks thereafter.

The drug is teratogenic, and appropriate contraceptive measures are recommended to avoid pregnancy for all sexually active male and female patients who are taking leflunomide. If conception is desired, leflunomide must be discontinued. Because leflunomide undergoes enterohepatic circulation, the drug takes many months to drop to a plasma concentration considered safe during pregnancy (<0.02 μg/mL [<0.02 mg/L; 74 nmol/L]). Cholestyramine may be used to rapidly clear the drug from plasma. In addition to pregnancy, cholestyramine use may be warranted to rapidly clear the drug in the event of severe toxicity.

Leflunomide may be given as a loading dose of 100 mg daily for 3 days, followed by a maintenance dose of 20 mg daily. Lower doses may be used if patients have gastrointestinal intolerance, complain of hair loss, or have other signs of dose-related toxicity. The loading dose allows the patient to achieve a more rapid therapeutic response, usually within the first month. The long elimination half-life of the drug (14 to 16 days) would require the patient to take the drug for several months to achieve steady state without a loading dose. Some rheumatologists prefer to begin with maintenance dosing as the loading dose may put the patient at increased risk for toxicity.32,40,41

Hydroxychloroquine

Hydroxychloroquine is often used in mild RA or as an adjuvant in combination DMARD therapy in more progressive disease. The pharmacokinetics and mechanism of action of this drug are poorly understood, but it is thought to dampen antigen–antibody reactions at sites of inflammation.27 It is well absorbed orally and widely distributed to body tissues. Hydroxychloroquine is partially metabolized in the liver and is excreted by the kidney. The onset of action of hydroxychloroquine may be delayed up to 6 weeks, but the drug is considered a therapeutic failure only when 6 months of therapy without a response has elapsed.

The main advantage of hydroxychloroquine is the lack of myelosuppressive, hepatic, and renal toxicities that may be seen with other DMARDs, which simplifies monitoring. Short-term toxicities of hydroxychloroquine include gastrointestinal effects such as nausea, vomiting, and diarrhea, which can be managed by taking doses with food. Ocular toxicity includes accommodation defects, benign corneal deposits, blurred vision, scotomas (small areas of decreased or absent vision in the visual field), and night blindness. Although the risk of true retinopathy with hydroxychloroquine approaches zero, preretinopathy may occur in 2.7% of patients. All patients must understand the importance of adhering to hydroxychloroquine monitoring guidelines, as delineated in Table 72-2. Any visual change must be reported immediately. Dermatologic toxicities include rash, alopecia, and increased skin pigmentation; neurologic adverse effects such as headache, vertigo, and insomnia usually are mild.35,42,43

Sulfasalazine

Sulfasalazine, a prodrug, is cleaved by bacteria in the colon into sulfapyridine and 5-aminosalicylic acid. It is believed that the sulfapyridine moiety is responsible for the agent’s antirheumatic properties, although the exact mechanism of action is unknown. Once the colonic bacteria have cleaved sulfasalazine, sulfapyridine and 5-aminosalicylic acid are absorbed rapidly from the gastrointestinal tract. Sulfapyridine distributes rapidly throughout the body, but higher concentrations are found in certain tissues such as serous fluid, liver, and intestines. Both sulfasalazine and its metabolites are excreted in the urine. Antirheumatic effects should be seen in 2 months.

Use of sulfasalazine is often limited by its adverse effects. Gastrointestinal adverse effects such as nausea, vomiting, diarrhea, and anorexia are the most common. These can be minimized by initiating therapy with low doses and titrating gradually to higher doses, dividing the dose more evenly throughout the day, or using enteric-coated preparations. Rash, urticaria, and serum sickness-like reactions can be managed with antihistamines and, if indicated, corticosteroids. If a hypersensitivity reaction occurs, therapy should be stopped immediately and another DMARD substituted. Sulfasalazine is associated with leukopenia, alopecia, stomatitis, and elevated hepatic enzymes. It also may cause the patient’s urine and skin to turn a yellow-orange color, which is of no clinical consequence however; patients should be educated about this to avoid premature discontinuance.

Sulfasalazine’s absorption can be decreased when antibiotics are used that destroy the colonic bacteria. Sulfasalazine also binds iron supplements in the gastrointestinal tract that can lead to a decreased absorption of sulfasalazine. The administration of these two agents should be separated temporally to avoid this interaction. Sulfasalazine can potentiate warfarin’s effects by displacing it from protein-binding sites. Close monitoring of the patient’s international normalized ratio is indicated.44,45

Minocycline

The tetracycline derivative minocycline has been suggested as a treatment alternative for patients with mild disease and without features of poor prognosis. While the mechanism of action is not completely understood, inhibition of metalloproteinases active in damaging articular cartilage is thought to play a role.27 A meta-analysis of 10 clinical trials using tetracyclines for more than 3 months found mild reductions in tender and swollen joint counts and ESR but no effect on erosion progression; however, the number of patients and treatment duration in the two trials that looked at erosions were limited. The dose of minocycline for RA treatment is 100 to 200 mg daily. Adverse effects are uncommon and were reported no more frequently than placebo control groups.46

Tofacitinib

Tofacitinib (Xeljanz) is a JAK inhibitor for use in patients with moderate to severe RA who have failed, or have intolerance to methotrexate.

JAK is a tyrosine kinase, which mediates signal transduction from cytokines responsible for leukocyte functioning. Thus, inhibition of JAK results in modulation and suppression of the immune system through cytokine signal reduction.

In clinical trials, oral doses of tofacitinib 5 mg twice daily resulted in 55% to 59% of patients achieving at least a 20% improvement in RA symptoms at 3 months. An improvement in symptoms of 50% occurred in approximately 30% of patients.47,48 The FDA-approved dosing of tofacitinib is 5 mg twice daily as monotherapy or in combination with other nonbiologic DMARDs.

Risks, for which black box warnings exist, include serious infections, lymphomas, and other malignancies. Patients should be tested and treated for latent tuberculosis before therapy with tofacitinib. Monitoring for reductions in lymphocytes, neutrophils, and hemoglobin should be completed at baseline and periodically throughout therapy at 4 to 8 weeks postinitiation and every 3 months thereafter.

Tofacitinib therapy has been associated with elevated plasma liver enzymes and lipids. Live vaccinations should not be given during treatment. Further data assessing long-term safety and impact on radiographic joint damage are needed before tofacitinib’s place in the treatment of RA will be clear.

Other Disease-Modifying Antirheumatic Drugs

Gold salts, azathioprine, D-penicillamine, cyclosporine, and cyclophosphamide have all been used to treat RA. Although these drugs can be effective and they may be of value in certain clinical settings, they are used less frequently today because of toxicity, lack of long-term benefit, or both. Tables 72-2 and 72-3 provide dosing information and toxicity information.

Biologic Agents

Biologic agents are genetically engineered protein molecules that block the proinflammatory cytokines TNF-α (infliximab, etanercept, adalimumab, golimumab, and certolizumab), IL-1 (anakinra), and IL-6 (tocilizumab), deplete peripheral B cells (rituximab), or bind to CD80/86 on T cells to prevent the costimulation needed to fully activate T cells (abatacept). These drugs may be effective when nonbiologic DMARDs fail to achieve adequate responses but are considerably more expensive to use. Other than anakinra and tocilizumab, these agents have no toxicities requiring laboratory monitoring, but they do carry a small increased risk for infection. There is an increased incidence of tuberculosis in patients treated with these agents. Tuberculin skin testing is recommended prior to treatment with biologic agents so that latent tuberculosis can be detected.25 Patients with a history of significant tuberculosis exposure or recurrent infection may not be good candidates for these drugs. Those who develop infections while on biologic agents should at least temporarily discontinue them until the infection is cured. Live vaccines should not be given to patients taking biologic agents.

TNF-α Inhibitors

While the anti-TNF biologics have differing structures, pharmacokinetics, and dosing, their side effects and contraindications are similar in that they all block TNF. Chronic heart failure (CHF) is a relative contraindication for anti-TNF agents. Increased cardiac mortality has been seen in patients treated with infliximab and etanercept-associated heart failure exacerbations have been documented.41,49 Patients with New York Heart Association class III or IV and an ejection fraction of 50% or less should not use anti–TNF-α therapy. Patients whose CHF worsens while taking anti–TNF-α therapy should discontinue the drug.24

Anti–TNF-α therapy has also been reported to induce a multiple sclerosis-like illness or exacerbate multiple sclerosis in patients with the disease. Patients with neurologic symptoms suggestive of multiple sclerosis should discontinue therapy. TNF inhibitors may predispose patients to increased cancer risk, especially lymphoproliferative cancer, as TNF plays a role in ridding the body of cancer cells. The U.S. Food and Drug Administration (FDA) added a black box warning to product labeling for anti-TNF drugs alerting prescribers of increased lymphoproliferative and other cancers in children and adolescents treated with these drugs.50

Etanercept Etanercept is a fusion protein consisting of two p75-soluble TNF receptors linked to an Fc fragment of human IgG1. The drug binds to TNF, making it biologically inactive and preventing it from interacting with the cell-surface TNF receptors that would lead to cell activation.

The drug is given by subcutaneous injection, 50 mg once weekly or 25 mg twice weekly, usually through self-injections or administration by a caregiver. Aside from local injection-site reactions, adverse effects are rare. There are case reports of pancytopenia and neurologic demyelinating syndromes like multiple sclerosis associated with use of etanercept, but these are rare. No laboratory monitoring is required. Clinical trials have used etanercept in patients who failed DMARDs. Response was seen in 60% to 75% of patients. The drug has also been FDA approved for the treatment of juvenile RA, ankylosing spondylitis, psoriatic arthritis, and moderate-to-severe psoriasis. Clinical trials have shown that it slows erosive disease progression to a greater degree than oral methotrexate therapy.5153

Infliximab Infliximab is a chimeric antibody combining portions of mouse and human IgG1. Approximately 25% of the antibody is derived from mouse amino acids. This antibody, when injected in humans, binds to TNF and prevents its interaction with TNF receptors on inflammatory cells.

Infliximab is given by IV infusion at a dose of 3 mg/kg at 0, 2, and 6 weeks and then every 8 weeks. To prevent the formation of an antibody response to this foreign protein, oral methotrexate should be given concurrently in doses typically used to treat RA for as long as the patient continues on infliximab. Antibodies develop in 14% to 40% of patients, which leads to a greater risk of infusion reactions and also may reduce the efficacy of the drug. Loss of response may be seen in patients with RA who have good initial response requiring increased doses or shorter intervals between doses to maintain response. Infusion reactions may occur in any patient treated with the drug. Both acute (within 24 hours of infusion) and delayed (24 hours to 14 days) reactions following infusion have been identified. An acute infusion reaction with symptoms including fever, chills, pruritus, and rash may occur during infusion or within 1 to 2 hours after giving the drug. Treatment includes slowing infusion rates and administering acetaminophen, diphenhydramine, or corticosteroids, depending on the severity of symptoms. Fortunately these reactions are rarely severe or anaphylactic in nature.54 The drug may increase the risk of infection. Autoantibodies and lupus-like syndrome also have been reported. In addition to RA, infliximab is indicated for the treatment of psoriatic arthritis and ankylosing spondylitis.5556

Adalimumab Adalimumab is a human IgG1 antibody to TNF. Because it has no foreign protein components, it is less antigenic than infliximab. The drug is provided as either premixed syringes or injection pens containing 40 mg, which is administered by subcutaneous injection every 14 days. It has similar response rates to those seen with the other TNF inhibitors. Local injection-site reactions were the most common adverse reactions noted in clinical trials. It has the same precautions regarding tuberculosis and other infections as the other biologics.5759

Golimumab Golimumab is a human antibody to TNF-α. In addition to RA, this agent is also indicated for treatment of psoriatic arthritis and ankylosing spondylitis. The drug is available as an injection pen, through which a dose of 50 mg is given monthly by subcutaneous injection. Precautions are similar to other TNF-α inhibitors.60

Certolizumab Certolizumab is a humanized antibody specific for human TNF-α. For RA, dosing recommendations are for 400 mg (2 doses of 200 mg) given by subcutaneous injection at weeks 0, 2, and 4 followed by 200 mg every 2 weeks. Precautions and side effects are similar to other TNF-α inhibitors.61

Non-TNF Biologics

Abatacept Abatacept is a costimulation modulator approved for the treatment of RA in patients with moderate to severe disease who fail to achieve an adequate response from one or more DMARDs. By binding to CD80/CD86 receptors on antigen-presenting cells, abatacept inhibits interactions between the antigen-presenting cells and T cells. This prevents T-cell activation to promote the inflammatory process, thus resulting in reductions in cytokines, T-cell proliferation, and other consequences of T-cell activation.

Abatacept is a fusion protein made using the extracellular domain of human cytotoxic T lymphocyte antigen 4 (the binding portion of the drug) and a fragment of the Fc domain of human IgG modified to prevent complement fixation. The drug is given by IV infusion based on patient weight (<60 kg [<132 lb]: 500 mg; 60 to 100 kg [132 to 220 lb]: 750 mg; >100 kg [>220 lb]: 1,000 mg) every 2 weeks for two doses after the initial dose and then every 4 weeks. Alternatively, the drug may be given by subcutaneous injection with the first dose of 125 mg given within 24 hours of a single IV infusion and every 7 days after that. Abatacept may be used as monotherapy or in combination with nonbiologic DMARDs.

The adverse effects include headache, nasopharyngitis, dizziness, cough, back pain, hypertension, dyspepsia, urinary tract infection, rash, and extremity pain reported more frequently than placebo in clinical trials. Infusion reactions were 50% more likely with abatacept than with placebo and there was a slightly higher rate of serious infections with active treatment.6264 In patients who failed to achieve adequate responses with TNF-α inhibitors, half had a clinical response to abatacept.84 Live vaccines should not be given to patients during and for 3 months after the completion of abatacept therapy.65

Rituximab Rituximab is a monoclonal chimeric antibody consisting of mostly human protein with the antigen-binding region derived from a mouse antibody to CD20 protein found on the cell surface of mature B lymphocytes. The binding of rituximab to B cells results in nearly complete depletion of peripheral B cells. Although its mechanism of action in RA is not completely known, it is thought that this depletion in B cells decreases antigen presentation to T cells, thus decreasing symptoms and delaying structural damage. After administration of rituximab, it takes several months for B cell recovery. This prolonged effect on B cells results in a variable duration of action that allows for intermittent therapy based on reactivation of arthritis symptoms.

Rituximab is useful in patients who failed methotrexate or TNF inhibitors.6670 Two infusions of 1,000 mg are given 2 weeks apart. Methylprednisolone 100 mg should be given 30 minutes prior to rituximab to reduce the incidence and severity of infusion reactions. Acetaminophen and antihistamines may also be of benefit in patients who have a history of reactions. Methotrexate should be given concurrently in the usual doses used for RA, as the combination has proved to provide the best therapeutic outcomes. Duration of benefit is variable after a course of rituximab and patients will need retreatment with reactivation of their disease. Live vaccines should not be given to patients given rituximab.

Tocilizumab IL-6 is a major cytokine believed to have a role in promoting inflammation in RA. Tocilizumab is a humanized monoclonal antibody that attaches to IL-6 receptors, preventing the cytokine from interacting with the IL-6 receptor. It is approved for use in adults with moderately to severely active RA who have failed to respond to one or more anti-TNF biologic agents. It is used as either monotherapy or in combination with methotrexate or another DMARD. The initial starting dose is 4 mg/kg given IV every 4 weeks with dose escalation to 8 mg/kg IV every 4 weeks based on clinical response and tolerance.

The rates of adverse events are generally low but higher with combination therapy as compared to monotherapy. The most serious adverse effects reported include infusion reactions, increased infection risk, elevated plasma lipids, elevated liver enzymes, and gastrointestinal perforation. Tocilizumab use may also lead to increased metabolism of concomitant cytochrome P450 (CYP)3A4 substrate medications. It is recommended to monitor agents with narrow therapeutic window such as warfarin. Oral contraceptives and CYP3A4 statins may also be affected.71

Anakinra Anakinra is a naturally occurring IL-1 receptor antagonist. Results of clinical trials suggest it to be less effective than other biologic DMARDs.72 The ACR did not include anakinra in their RA treatment recommendations because of limited use of this drug, but select patients with refractory disease could benefit from treatment with this drug.24


Clinical Controversy…

The order of DMARD or biologic agent choice is not clearly defined. No direct comparative studies exist for biologics to guide in the determination of optimal treatment order.

Treatment Strategies for Patients with Suboptimal Response to Biologics

TNF-α antagonists are generally the first biologic agents chosen for use in patients with RA. Approximately 30% of patients discontinue treatment with these drugs because of lack of efficacy or adverse effects. Lack of efficacy can further be defined as a primary failure (failure to see a treatment response 3 to 6 months after therapy initiation) or secondary failure (loss of response after an initial improvement is observed).

In such situations, addition of a nonbiologic DMARD may be beneficial if the patient is not already taking one. Dose escalation or decreased interval between infusions may be useful for those patients taking infliximab; higher doses of other TNF-α inhibitors have not been demonstrated to be effective. Choosing an alternative TNF-α inhibitor after failure of the initial anti-TNF agent may be beneficial for some patients; however, no randomized controlled trials have compared the effectiveness of cycling among agents in this class. One observational study found both decreased response and persistence rates with a second anti-TNF agent compared with the first TNF-agent.73Treatment with rituximab, abatacept, or tocilizumab may also prove to be effective in TNF-α treatment failures.64,66 Combination biologic DMARD therapy is not recommended because of the increased risk for infection.74


Clinical Controversy…

After failure of an initial anti-tumor necrosis factor (TNF) agent, subsequent treatment may include trialing an alternative anti-TNF agent or changing to a non-TNF biologic. Is more benefit seen with a second anti-TNF agent based on the reason for discontinuation of the original anti-TNF agent?

Corticosteroids

Corticosteroids are used in RA for their antiinflammatory and immunosuppressive properties. They interfere with antigen presentation to T lymphocytes, inhibit prostaglandin and leukotriene synthesis, and inhibit neutrophil and monocyte superoxide radical generation. Corticosteroids also impair cell migration and cause redistribution of monocytes, lymphocytes, and neutrophils, thus blunting the inflammatory and autoimmune responses.

Oral corticosteroids are absorbed rapidly and completely from the gastrointestinal tract. They are metabolized and inactivated primarily by the liver and excreted in the urine. The elimination half-life of most corticosteroids is sufficiently long that once-daily dosing is possible.

Oral corticosteroids can be used in several ways. They can be used in bridging therapy, continuous low-dose therapy, and short-term, high-dose bursts to control flares. Oral steroids (e.g., prednisone, methylprednisolone) can be used to control pain and synovitis while DMARDs are taking effect. This is termed bridging therapy and is often used in patients with debilitating symptoms when DMARD therapy is initiated. Patients with difficult-to-control disease may be placed on low-dose, long-term corticosteroid therapy to control their symptoms. Prednisone doses below 7.5 mg daily are well tolerated but are not devoid of the long-term adverse effects associated with corticosteroids. The lowest dose of corticosteroid that controls symptoms should be used to reduce adverse effects. Alternate-day dosing of low-dose oral corticosteroids usually is ineffective in RA; symptoms usually flare on days without medication. High-dose corticosteroid bursts often are used to suppress disease flares. High doses are sustained for several days until symptoms are controlled, followed by a taper to the lowest effective dose.

Corticosteroids also may be delivered by injection. The intramuscular route may be preferable in patients with adherence problems for short-term therapy. Long-acting depot forms of corticosteroids include triamcinolone acetonide, triamcinolone hexacetonide, and methylprednisolone acetate. This provides the patient with 2 to 6 weeks of symptomatic control. The depot effect provides a physiologic taper, avoiding withdrawal reaction associated with hypothalamic–pituitary axis suppression. IV corticosteroids may be used to provide the patient with large amounts of drug during a steroid burst to control severe symptoms. Intraarticular injections of depot forms of corticosteroids can be useful in treating synovitis and pain when a small number of joints are affected. The onset and duration of symptomatic relief are similar to those of intramuscular injection. The intraarticular route often is preferred because it is associated with the fewest number of systemic adverse effects. If efficacious, intraarticular injections may be repeated every 3 months. No one joint should be injected more than two to three times per year because of the risk of accelerated joint destruction and atrophy of tendons. Soft tissues such as tendons and bursae also may be injected. This may help control the pain and inflammation associated with these structures. The onset and duration of symptomatic relief are similar to those of intramuscular and intraarticular injections.

The major limitation to the long-term use of corticosteroids is adverse effects. They include hypothalamic-pituitary–adrenal suppression, Cushing’s syndrome, osteoporosis, myopathies, glaucoma, cataracts, gastritis, hypertension, hirsutism, electrolyte imbalances, glucose intolerance, skin atrophy, and increased susceptibility to infections. To minimize these effects, use the lowest effective corticosteroid dose and limit the duration of use. Prednisolone 7.5 mg daily results in an average of 9.5% loss of bone density from the spine. Corticosteroids double the risk for osteoporosis in patients.75 Patients on long-term therapy should be given calcium and vitamin D to minimize bone loss. Alendronate is effective in preventing bone loss in corticosteroid-treated patients and should be considered prophylactically for patients when long-term corticosteroid therapy is anticipated, particularly for patients who are at high risk of bone loss (e.g., postmenopausal women, elderly).7679 There is no evidence that corticosteroids alone increase the risk of gastrointestinal ulcerations, although they often have been implicated. Consequently, gastrointestinal protective measures usually are not indicated.8082


Clinical Controversy…

Even the best therapy available today does not completely eliminate all the signs, symptoms, or progression of disease for most patients. How much treatment is enough?

PERSONALIZED PHARMACOTHERAPY

With various pathways involved leading to inflammation in RA and an increasing number of agents available, it is important to consider patient-specific factors when making therapeutic decisions. Disease activity and the presence of poor prognostic (see Fig. 72-5 for explanation of poor prognostic feature) features may help guide treatment and lead to early aggressive therapy in patients with more severe disease.

Therapy must be tailored for various comorbidities the patient may have (Table 72-5). Hepatitis and other liver diseases, heart failure, renal failure, and history of cancer are among the comorbidities that influence treatment choice. Individual patients may also significantly differ in their response to a specific agent; currently, there are no clear predictors of response to therapeutic interventions.

TABLE 72-5 Rheumatoid Arthritis Therapy Recommendations Based on Comorbidity

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Pharmacokinetic parameters should be taken into consideration when determining therapeutic options for specific patients. NSAIDs should be avoided in patients with renal impairment or in patients at high risk for NSAID-induced renal injury including the elderly, those with congestive heart failure or cirrhosis, or patients at risk for volume depletion such as those using diuretics.83 Dose adjustments are recommended in patients with renal dysfunction for methotrexate and anakinra. Dose reductions are also recommended with tofacitinib in patients with moderate or severe renal impairment, moderate hepatic dysfunction, or patients treated concomitantly with CYP3A4 inhibitors.

While azathioprine is now used less frequently for RA, genetic testing for null or decreased thiopurine S-methyltransferase (TPMT) activity is available to help predict those patients with a higher risk of myelosuppression due to reduced metabolism of the drug, and dosage reductions may be made in those patients.84

EVALUATION OF THERAPEUTIC OUTCOMES

The evaluation of therapeutic outcomes is based primarily on improvements of clinical signs and symptoms of RA. Clinical signs of improvement include a reduction in joint swelling, decreased warmth over actively involved joints, and decreased tenderness to joint palpation. Improvement in RA symptoms includes reduction in perceived joint pain and morning stiffness, longer time to onset of afternoon fatigue, and improvement in ability to perform activities of daily living. Improvement of activities of daily living may be assessed objectively using a health assessment questionnaire score. Joint radiographs may be of some benefit in assessing the progression of the disease and should show little or no evidence of disease progression if treatment is effective.

Laboratory monitoring is of little value in monitoring individual patient response to therapy. Tables 72-2 and 72-3 provide monitoring of drug toxicity information. Routine monitoring of patients is essential to the safe use of these drugs. In addition, patients should be questioned about symptoms of the adverse effects outlined in the drug section of this chapter.

CONCLUSIONS

RA is the most common inflammatory arthritis, affecting approximately 1% of the population. The disease is characterized by symmetrical swelling and stiffness of the involved joints. The stiffness is usually more prominent in the morning. Extraarticular features of RA include rheumatoid nodules, vasculitis, and ocular, cardiac, and pulmonary complications. The course of the disease is highly variable. Treatment is aimed at relieving pain and inflammation and maintaining and preserving joint function. Nondrug therapy, including exercise and adequate rest periods, should also be used early in the course of treatment. Early use of a DMARD or biologic agent results in better patient outcomes. Methotrexate, sulfasalazine, and hydroxychloroquine are often considered for initial therapy. Biologics have also been shown to be effective in these patients but may be considered second choice because of cost considerations; however, they are effective in patients who fail to achieve adequate response from nonbiologic DMARDs. Combination DMARDs or biologics may be considered in those who fail adequate trials of single-agent therapy. Corticosteroids and NSAIDs may be useful adjuncts for treatment, but because of adverse effects and limited impact on long-term outcomes, they should not be considered as sole treatment for most patients.

ABBREVIATIONS

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