Susan P. Bruce
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Identify risk factors for developing rheumatoid arthritis (RA).
2. Describe the pathophysiology of RA, with emphasis on the specific immunologic components.
3. Discuss the comorbidities associated with RA.
4. Recognize the typical clinical presentation of RA.
5. Create treatment goals for a patient with RA.
6. Compare and contrast the available pharmacotherapeutic options, selecting the most appropriate regimen for a given patient.
7. Propose a patient education plan that includes nonpharmacologic and pharmacologic treatment measures.
8. Formulate a monitoring plan to evaluate the safety and efficacy of a therapeutic regimen designed for an individual patient with RA.
KEY CONCEPTS
Comorbidities with the greatest impact on morbidity and mortality associated with rheumatoid arthritis (RA) are: (a) cardiovascular disease; (b) infections; (c) malignancy; and (d) osteoporosis.
Both osteoarthritis and RA are prevalent in the U.S. population, but they differ significantly in presentation.
The most clinically important features associated with poor long-term outcomes include: (a) functional limitation (defined by use of standard measurement scales such as the Health Assessment Questionnaire [HAQ] score); (b) extraarticular disease; (c) positive rheumatoid factor; (d) positive anticyclic citrullinated peptide (anti-CCP) antibodies; and/or (e) bony erosions by radiography.
The goals of treatment for RA are to: (a) reduce or eliminate pain; (b) protect articular structures; (c) control systemic complications; (d) prevent loss of joint function; and (e) improve or maintain quality of life.
It is imperative that the initiation of one or more disease-modifying antirheumatic drugs (DMARDs) occurs in all patients within the first 3 months of diagnosis to reduce joint erosion.
Most clinicians favor the “step-down” approach to slow or reverse the early articular damage as soon as possible.
Methotrexate is the nonbiologic DMARD of choice because of its documented efficacy and safety profile when monitored appropriately.
The risk of infection in patients treated with biologic DMARDs must be considered when selecting and monitoring therapy.
Women of childbearing potential and their partners must be counseled to: (a) use proper birth control while undergoing treatment for RA; and (b) discontinue medications at least 3 months before conception.
In addition to designing an individualized therapeutic regimen to control the progression of RA, the clinician must evaluate the presence of comorbidities and implement measures to control the increased risk.
Introduction
Rheumatoid arthritis (RA) is a complex systemic inflammatory condition manifesting initially as symmetric swollen and tender joints of the hands and/or feet. Some patients may experience mild articular(joint) disease, whereas others may present with aggressive disease and/or extra-articular manifestations. The systemic inflammation of RA leads to joint destruction, disability, and premature death. Juvenile idiopathic arthritis (JIA), formerly known as juvenile rheumatoid arthritis (JRA), is the most common form of arthritis in children.
EPIDEMIOLOGY AND ETIOLOGY
RA affects approximately 1% of the U.S population and 1% to 2% of the world s population.1,2 RA arises from an immunologic reaction, and there is speculation that it is in response to a genetic or infectious antigen. Risk factors associated with the development of RA include the following:
• Female gender (3:1 females to males)
• Increasing age (peak onset 35–50 years of age)
• Current tobacco smoking. Studies have identified a direct relationship between tobacco use and RA disease severity.3 Tobacco users also have an increased risk of pulmonary manifestations of RA. This risk is reduced when a patient has remained tobacco-free for at least 10 years.
• Family history of RA. Genetic studies demonstrate a strong correlation between RA and the presence of major histocompatibility complex class II human leukocyte antigens (HLA), specifically HLA-DR1 and HLA-DR4.4,5 HLA is a molecule associated with the presentation of antigens to T lymphocytes.
• Potential environmental exposures. The number of RA cases has increased during industrialization, although a specific link to environmental factors has not been determined.6
• Oral contraceptive use and high ingestion of vitamin D and tea are associated with a decreased risk of RA.7
• Fewer than 300,000 children in the United States under age 16 are affected by JIA.8 There are no known risk factors for JIA.
PATHOPHYSIOLOGY
The characteristics of a synovium affected by RA are: (a) the presence of a thickened, inflamed membrane lining called pannus; (b) the development of new blood vessels; and (c) an influx of inflammatory cells in the synovial fluid, predominantly T lymphocytes. The pathogenesis of RA is driven by T lymphocytes, but the initial catalyst causing this response is unknown. Understanding specific components of the immune system and their involvement in the pathogenesis of RA will facilitate understanding of current and emerging treatment options for RA. The components of most significance are T lymphocytes, cytokines, and B lymphocytes.4,9
T Lymphocytes
The development and activation of T lymphocytes are important to maintain protection from infection without causing harm to the host.9 Activation of mature T lymphocytes requires two signals. The first is the presentation of an antigen by antigen-presenting cells to the T-lymphocyte receptor. Second, a ligand-receptor complex (i.e., CD80/CD86) on antigen-presenting cells binds to CD28 receptors on T lymphocytes. Once a cell successfully passes through all stages, the inflammatory cascade is activated.10 Activation of T lymphocytes: (a) stimulates the release of macrophages or monocytes, which subsequently causes the release of inflammatory cytokines; (b) activates osteoclasts; (c) activates the release of matrix metalloproteinases or enzymes responsible for the degradation of connective tissue; and (d) stimulates B lymphocytes and the production of antibodies.4,9
Cytokines
Cytokines are proteins secreted by cells that serve as intercellular mediators (see Table 57–1). An imbalance of proinflammatory and anti-inflammatory cytokines in the synovium leads to inflammation and joint destruction. The proinflammatory cytokines interleukin 1 (IL-1), tumor necrosis factor-α (TNF-α), IL-6, and IL-17 are found in high concentration in synovial fluid. These proinflammatory cytokines cause the activation of other cytokines and adhesion molecules responsible for the recruitment of lymphocytes to the site of inflammation. Anti-inflammatory cytokines and mediators (IL-4, IL-10, and IL-1 receptor antagonist) are present in the synovium, although concentrations are not high enough to overcome the effects of the proinflammatory cytokines.4,9
Table 57–1 Cytokines Involved in the Pathogenesis of RA
B Lymphocytes
In addition to serving as antigen-presenting cells to T lymphocytes, B lymphocytes may produce proinflammatory cytokines and antibodies.5,9 Antibodies of significance in RA are rheumatoid factors(antibodies reactive with the Fc region of IgG) and antibodies against cyclic citrullinated peptide (CCP).5 Rheumatoid factors are not present in all patients with RA, but their presence is indicative of disease severity, likelihood of extra-articular manifestations, and increased mortality.10 CCPs are produced early in the course of disease. High levels of anti-CCP antibodies are indicative of aggressive disease and a greater likelihood of poor outcomes. Monitoring anti-CCP antibodies may be useful to predict the severity of disease and match aggressive treatment appropriately.
Comorbidities Associated With RA
RA reduces a patient’s average life expectancy by 5 to 10 years, but RA alone rarely causes death.11,12 Instead, specific comorbidities contribute to premature death independent of safety issues surrounding the use of immunomodulating medications. The comorbidities with the greatest impact on morbidity and mortality associated with RA are: (a) cardiovascular disease; (b) infections; (c) malignancy; and (d) osteoporosis.11,12
Cardiovascular Disease
Half of all deaths in RA patients are cardiovascular related.11 Because a patient with RA experiences inflammation and swelling in his or her joints, it is likely that there is inflammation elsewhere, such as in the blood vessels, termed vasculitis. C-reactive protein (CRP), a nonspecific marker of inflammation, is associated with an increased risk of cardiovascular disease; CRP is elevated in patients with RA. Chronic systemic inflammation may contribute to the relationship between RA and cardiovascular disease, but the exact mechanism is still under investigation.11,12 Uncontrolled hypertension is common in patients with RA. Clinicians should screen for and aggressively treat elevated blood pressure in this population.13
Infections
RA itself leads to changes in cellular immunity and causes a disproportionate increase in pulmonary infection and sepsis.12 Because medications that alter the immune system are linked to an increased risk of infection, it is difficult to distinguish between an increased risk of infection secondary to RA and the medications used to treat RA. Patients and clinicians must pay close attention to signs and symptoms of infection because of this increased risk.12
Malignancy
Patients with RA have an increased risk of developing lymphoproliferative malignancy (e.g., lymphoma, leukemia, and multiple myeloma) and a decreased risk of developing cancer of the digestive tract.12,14,15 The relationship between RA and cancer is not clear. To confound the issue, medications for the treatment of RA may contribute to increased cancer risk. Patients presenting with new onset of symptoms (e.g., fevers, night sweats, chills, or anorexia) out of proportion with disease activity and patients not responding to conventional RA treatment should be evaluated further for lymphoproliferative malignancy.12,15
Osteoporosis
Osteoporosis associated with RA follows a multifaceted pathogenesis, but the primary mechanism likely is mediated by increased osteoclast activity.12 The cytokines involved in the inflammatory process directly stimulate osteoclast and inhibit osteoblast activity. Additionally, arthritis medications can lead to increased bone loss. Bone mineral density should be evaluated at baseline and routinely using dual-energy x-ray absorptiometry.12
CLINICAL PRESENTATION AND DIAGNOSIS
Both osteoarthritis and RA are prevalent in the American population, but they differ significantly in presentation (Table 57–2). Figure 57–1 illustrates the typical joint involvement for patients with RA and osteoarthritis.
Diagnosis
Seven criteria must be met to diagnose RA appropriately:1
1. Morning joint stiffness lasting more than 1 hour before disappearing
2. Involvement of three or more joint areas
3. Arthritis of hand joints
4. Symmetric joint involvement
5. Presence of rheumatoid nodules
6. Elevated rheumatoid factor
7. Radiographic changes
A patient may be diagnosed with RA if four or more of these are present. Criteria 1 through 4 must be present for at least 6 weeks. Criteria 2 through 5 must be observed by a clinician.
Table 57–2 Comparison of RA and Osteoarthritis
FIGURE 57–1. Patterns of joint involvement in rheumatoid arthritis and osteoarthritis. (From DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy, 7th ed. New York: McGraw-Hill; 2008, Fig. 92–3, p. 1507, with permission.)
Clinical Presentation and Diagnosis of RA
General
• About 60% of patients develop symptoms gradually over several weeks to months.
• Patients may present with systemic findings, joint findings, or both.
Symptoms
• Nonspecific systemic symptoms may include fatigue, weakness, anorexia, and diffuse musculoskeletal pain.
• Patients complain of pain in involved joints and prolonged morning joint stiffness.
Signs
• The metacarpophalangeal (MCP), proximal interphalangeal (PIP), metatarsophalangeal (MTP), and wrist joints are involved frequently.
• Joint involvement is usually symmetric.
• There is often limited joint function.
• Signs of joint inflammation are present (tenderness, warmth, swelling, and erythema).
• Low-grade fever may be present.
• Extraarticular manifestations:
• Skin: Subcutaneous nodules
• Ocular: Keratoconjunctivitis sicca, scleritis
• Pulmonary: Interstitial fibrosis, pulmonary nodules, pleuritis, pleural effusions
• Vasculitis: ischemic ulcers, skin lesions, leukocytoclastic vasculitis
• Neurologic: Peripheral neuropathy, Felty’s syndrome
• Hematologic: Anemia, thrombocytosis
Laboratory Tests
• Positive rheumatoid factor (the test is negative in up to 30% of patients)
• Elevated ESR (Westergren ESR: greater than 20 mm/h in men; greater than 30 mm/h in women)
• Elevated C-reactive protein (CRP) (greater than 0.7 mg/dL or 7 mg/L)
• CBC: Slight elevation in WBC count with a normal differential; slight anemia; thrombocytosis
• Positive anti-CCP antibodies
Other Diagnostic Tests
• Synovial fluid analysis: Straw colored, slightly cloudy, WBC 5 to 25 × 103/mm3 (5–25 × 109/L), no bacterial growth if cultured.
• Joint x-rays: To establish baseline and evaluate joint damage.
• MRI: May detect erosions earlier in the course of disease than x-rays but is not required for diagnosis.
Several clinical features of RA are associated with a worse long-term prognosis. The presence of these poor prognostic features should be considered at the time initial treatment decisions are made; more aggressive treatment may be warranted if these features are present. The most clinically important features associated with poor long-term outcomes include: (a) functional limitation (defined by use of standard measurement scales such as the Health Assessment Questionnaire [HAQ] score); (b) extra-articular disease; (c) positive rheumatoid factor; (d) positive anti-CCP antibodies; and/or (e) bony erosions by radiography.
Diagnostic criteria for JIA include: (a) age less than 16 years at disease onset; (b) arthritis in one or more joints for more than 6 weeks; (c) exclusion of other types of arthritis. JIA can be divided into three types:
1. Systemic (approximately 10% of cases): occurs equally in girls and boys. There are characteristic fever spikes twice daily (greater than 38.3°C or 101°F) and the presence of a pale, pink, transient rash. The peak onset is between ages 1 and 6 years.
2. Polyarticular (approximately 40% of cases): more likely to affect girls than boys (3:1). Arthritis is present in five or more joints. The disorder resembles adult RA more than the other types of JIA.
3. Pauciarticular (approximately 50% of cases): more likely to affect girls than boys (5:1). Uveitis is more likely to be present. Arthritis is present in four or fewer joints. Categories are further divided into early onset and late onset. Early onset is more likely to occur in girls, whereas late onset is more common in boys.16
Patient Encounter, Part 1
AL is a 46-year-old woman who speaks only Spanish. She presents to her physician with a 2-month history of pain and inflammation in her hands and feet. She is accompanied by her daughter, who serves as her interpreter. On questioning, the patient indicates that she experiences joint pain, stiffness, and swelling for at least an hour in the morning. AL is an artist and avid runner, and she wonders if her activities are causing this pain.
What information is suggestive of RA?
What risk factors does she have for RA?
What additional information is necessary to differentiate between osteoarthritis and RA?
What additional information do you need before creating a treatment plan for this patient?
What are the advantages and disadvantages of having a family member serve as an interpreter for the patient?
TREATMENT
Desired Outcomes
The goals of treatment in RA are to: (a) reduce or eliminate pain; (b) protect articular structures; (c) control systemic complications; (d) prevent loss of joint function; and (e) improve or maintain quality of life.1,7 The goals for JIA are the same with the added goals of maintaining normal growth, development, and activity level.17 It is a common misconception that patients with JIA grow out of the disease. Many children with JIA become adults with JIA. Knowing this, it is essential that early, aggressive treatment is initiated to achieve the goals of therapy.
General Approach to Treatment
The clinician must evaluate patient-specific factors and select appropriate treatment to maximize the care of an individual patient. Thirty percent of all patients with RA have radiographic evidence of erosions at the time of diagnosis; therefore, all patients should be treated early and aggressively to reduce disease progression and to prevent joint erosions.1 Aggressive treatment is defined as one or more disease-modifying antirheumatic drugs (DMARDs) at effective doses. Delaying treatment will result in more destructive disease that is very difficult to delay or reverse to preserve joint function. Specialty care by a rheumatologist may reduce the likelihood of disease progression and joint damage.1
It is imperative that the initiation of one or more DMARDs occurs in all patients within the first 3 months of diagnosis to reduce joint erosion. Depending on disease severity and whether poor prognostic features are present, combination therapy may be initiated at the time of diagnosis or after an adequate trial of a DMARD initiated as monotherapy. Starting combination therapy initially is referred to as the step-down approach, wherein one or more agents are discontinued once the disease is controlled. Adding a second or third agent after an adequate trial of DMARD monotherapy is considered a step-up approach. 
Most clinicians favor the “step-down” approach to slow or reverse the early articular damage as soon as possible.7 The following medication classes are prescribed commonly for the treatment of RA: (a) nonsteroidal anti-inflammatory drugs (NSAIDs); (b) glucocorticoids; (c) nonbiologic DMARDs; and (d) biologic DMARDs. Table 57–3 highlights dosing, safety, monitoring, and patient counseling information for the common nonbiologic and biologic DMARDs.
Figures 57-2 and 57-3 outline the course of treatment according to the American College of Rheumatology (ACR) 2008 Recommendations.18 The recommendations are based on the activity level of the patient’s disease, the presence or absence of poor prognostic features, and the duration of disease activity. Figures 57–2 and 57–3 apply to patients who have had RA for less than 6 months. Please consult the ACR guidelines18 for treatment recommendations for patients having RA for 6 months or longer.
Table 57–3 FDA-Approved Nonbiologic and Biologic DMARDs for Treatment of RA
FIGURE 57–2. Recommendations for the use of nonbiologic disease-modifying antirheumatic drugs (DMARDs) in RA patients who have never received DMARDs and who have had RA for less than 6 months. These recommendations do not specifically include the potential role of glucocorticoids or NSAIDs in the management of patients with RA. aSee Ref. 18 for definitions of disease activity. b Includes functional limitation (defined using standard measurement scales such as HAQ score or variations of this scale), extraarticular disease (e.g., presence of rheumatoid nodules, secondary Sjogren’s syndrome, RA vasculitis, Felty’s syndrome, and RA lung disease), rheumatoid factor positivity, positive anti-CCP antibodies, or bony erosions by radiography. cOnly recommended for patients with high disease activity with features of poor prognosis. (HCQ, hydroxychloroquine; LEF, leflunomide; MIN, minocycline; MTX, methotrexate; SSZ, sulfasalazine.) (From Ref. 18.)
Patients who have had RA for less than 6 months and have been determined to have low disease activity and no poor prognostic features may be treated with a single-agent nonbiologic DMARD (hydroxychloroquine, minocycline, leflunomide, methotrexate, or sulfasalazine) (Fig. 57–2). If patients with low disease activity do have poor prognostic features, treatment should be started with leflunomide, methotrexate, or sulfasalazine. Patients with moderate or high disease activity but without poor prognostic features may receive initial treatment with sulfasalazine, leflunomide, methotrexate, or the combination of methotrexate and hydroxychloroquine. Patients with moderate or high disease activity and evidence of poor prognostic features may receive initial single-drug therapy with leflunomide or methotrexate; however, combination therapy may also be started initially in these patients using methotrexate/hydroxychloroquine, methotrexate/sulfasalazine, or methotrexate/sulfasalazine/hydroxychloroquine.
Biologic DMARDs are usually considered after failure of nonbiologic DMARDs. Patients with early RA (less than 6 months) and low or moderate disease activity are generally not candidates for biologic DMARDs. In contrast, patients who have had RA for less than 6 months but have had high disease activity for less than 3 months and features of poor prognosis should be considered for treatment with a TNF antagonist (etanercept, infliximab, adalimumab, golimumab, or certolizumab pegol) plus methotrexate (Fig. 57–3). Because of treatment expense, this option should be considered only in patients who have no limitations due to cost or insurance coverage. Other biologic DMARDs may be considered under certain circumstances.
Nonpharmacologic Therapy
All patients should receive education about the nonpharmacologic and pharmacologic measures to help manage RA and JIA. Empowered patients take an active role in care by participating in therapy-related decisions. Certain forms of nonpharmacologic therapy benefit all levels of severity, whereas others (i.e., surgery) are reserved for severe cases only.
Occupational and physical therapy may help patients preserve joint function, extend joint range of motion, and strengthen joints and muscles through strengthening exercises. Patients with joint deformities may benefit from the use of mobility or assistive devices that help to minimize disability and allow continued activities of daily living. In situations where the disease has progressed to a severe form with extensive joint erosions, surgery to replace or reconstruct the joint may be necessary.1
Pharmacologic Therapy
Nonsteroidal Anti-Inflammatory Drugs
NSAIDs provide analgesic and anti-inflammatory benefits for joint pain and swelling. However, they do not prevent joint damage or change the underlying disease.1 It is appropriate for a patient to begin taking an NSAID along with a DMARD for “bridge therapy” to provide symptomatic relief until the therapeutic effect of the DMARD is observed. Because of interpatient variability in response, patients may find relief from one NSAID and not another. For this reason, if a patient does not receive relief from one NSAID, it is acceptable to try a second one. Selecting another NSAID depends on multiple patient-specific factors including cardiovascular risk, potential for GI-related adverse events, adherence to medication regimens, and insurance coverage or lack thereof. Clinicians must weigh these factors carefully to determine if the patient will benefit from another NSAID, if he or she should receive a cyclooxygenase-2 (COX-2) inhibitor, or if another medication class should be considered.
FIGURE 57–3. Recommendations for the use of biologic DMARDs in patients who have had RA for less than 6 months. These recommendations do not specifically include the potential role of glucocorticoids or NSAIDs in the management of patients with RA. aSee Ref. 18 for definitions of disease activity. bIncludes functional limitation (defined using standard measurement scales such as HAQ score or variations of this scale), extraarticular disease (e.g., presence of rheumatoid nodules, secondary Sjogren’s syndrome, RA vasculitis, Felty’s syndrome, and RA lung disease), rheumatoid factor positivity, positive anti-CCP antibodies, or bony erosions by radiography. (DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; TNF, tumor necrosis factor.) (From Ref. 18.)
NSAID use is associated with an increased risk of GI ulcers or hemorrhage, fluid retention, exacerbation of existing hypertension, and decreased renal function in certain patient populations.7,1 9 Factors that place a patient at a higher risk of GI-related adverse reactions include: (a) history of peptic ulcer disease, (b) high doses of NSAIDs, (c) concomitant use of other medications with an increased risk of GI hemorrhage or ulcers (e.g., anticoagulants, corticosteroids, use of multiple NSAIDs), (d) age greater than 75 years, and (e) serious underlying diseases.1 If a patient has an increased risk of NSAID-induced adverse reactions, gastroprotection should be considered by coinitiation of a proton pump inhibitor, histamine-2 receptor blocker, or misoprostol. Misoprostol is effective in reducing the occurrence of gastric and duodenal ulcers. However, its tolerability is limited by adverse effects, specifically diarrhea. Histamine-2 receptor blockers effectively prevent duodenal ulcers (but not gastric ulcers) that occur more readily as a result of NSAID therapy. Proton pump inhibitors are the preferred gastroprotective agents due to greater acid suppression, prevention of both gastric and duodenal ulcers, and a tolerable adverse-effect profile.20 Changing treatment to low-dose prednisone, a nonacetylated salicylate, or a COX-2 inhibitor are additional options.1
NSAIDs may accentuate the increased risk of cardiovascular events inherent in patients with RA. Increases in blood pressure and fluid retention may exacerbate existing cardiovascular disease. With the evidence associating COX-2 inhibitors with cardiovascular disease, clinicians must carefully evaluate the potential risks of NSAID therapy against the potential benefits.2 See Chapter 58 for additional discussion of NSAID therapy.
NSAIDs are the treatment of choice in children with JIA of mild severity. As in adults, adverse effects of NSAID therapy should be anticipated and treated accordingly in pediatrics.
Glucocorticoids
Low-dose glucocorticoid treatment (equivalent to prednisone 10 mg/day or less) effectively reduces inflammation through inhibition of cytokines and inflammatory mediators and prevents disease progression.19,21 The goal of glucocorticoid use is to minimize adverse drug events by keeping doses low and using the drugs as infrequently as possible. Patients may receive glucocorticoids for a brief time as “bridge therapy” following DMARD initiation or via intra-articular injections to relieve symptoms of active disease. Patients taking more than 10 mg/day prednisone or equivalent are at an increased risk for clinically significant adverse reactions, especially bone loss leading to osteoporosis. Other glucocorticoid-related adverse reactions include Cushing’s syndrome, peptic ulcer disease, hypertension, weight gain, infection, mood changes, cataracts, dyslipidemia, and hyperglycemia.2,21
Systemic glucocorticoids should be avoided in patients with JIA due to the adverse effects mentioned above and growth suppression.
Nonbiologic DMARDs
Nonbiologic and biologic DMARDs are the mainstay of RA treatment because they modify the disease process and prevent or reduce joint damage. In addition to relying on safety and efficacy data, the initial DMARD choice depends on disease severity, patient characteristics (i.e., comorbidities, likelihood of adherence), cost, and clinician experience with the medication.1,7,18 Methotrexate alone or in combination therapy is the initial treatment of choice for patients with aggressive disease. Patients with early, mild disease may receive monotherapy with sulfasalazine, leflunomide or hydroxychloroquine. Agents such as azathioprine, D-penicillamine, gold salts, and anakinra are used rarely today because of concerns about toxicity and reduced efficacy.1,18,19
Methotrexate
Methotrexate is the nonbiologic DMARD of choice in RA because of its documented efficacy and safety profile when monitored appropriately.1,22 Methotrexate exerts its anti-inflammatory effect through inhibition of dihydrofolate reductase, which causes the inhibition of purines and thymidylic acid, and by inhibiting the production of certain cytokines.2 Unless the patient has contraindications to methotrexate, once-weekly doses should be initiated within 3 months of diagnosis and increased steadily until the patient has symptomatic improvement or a maximum dose of 20 mg/week is reached. Concomitant folic acid is given routinely to reduce the risk of folate-depleting reactions induced by methotrexate therapy (e.g., stomatitis, diarrhea, nausea, alopecia, myelosuppression, and elevations in liver function tests).1,23
Serious adverse reactions include pulmonary fibrosis and hepatotoxicity. Patients should be counseled to avoid the use of alcohol, take folic acid as directed, adhere to the laboratory monitoring schedule, and immediately report symptoms of pulmonary fibrosis (e.g., cough or dyspnea) and hepatotoxicity (e.g., jaundice or abdominal pain). If monotherapy does not produce complete resolution of symptoms, methotrexate may be used in combination with other nonbiologic or biologic DMARDs. In situations where the clinician suspects RA but a diagnosis has not yet been made, initiation of methotrexate was found to delay the diagnosis and halt joint damage without untoward adverse effects.24
Methotrexate is considered a second-line treatment of JIA. The usual dose is 5 to 15 mg/m2 (based on body surface area) once weekly. There are insufficient published data to assess the risk of serious toxicity in children receiving doses greater than 20 mg/m2/wk. Patients will begin to notice a response in 3 to 4 weeks with maximal response in 3 to 6 months. Methotrexate therapy in pediatric patients should be monitored the same way that is recommended in adults.25
Hydroxychloroquine and Sulfasalazine
The exact mechanism of action of these drugs is unknown, but both agents are fairly well tolerated. Hydroxychloroquine or sulfasalazine may be initiated on diagnosis of mild disease. Because of their slow onset of action, each drug must be given at therapeutic doses for at least 6 months before it can be deemed a treatment failure. Hydroxychloroquine and sulfasalazine are relatively inexpensive compared with the new biologic agents. If patients do not respond to methotrexate monotherapy, adding one of these agents may provide the benefit necessary to reduce symptoms satisfactorily.2,18
Hydroxychloroquine may cause retinal toxicity, and patients must have their eyes examined at least annually to detect this abnormality. It is not associated with renal, hepatic, or bone marrow suppression and therefore may be an acceptable treatment option for patients with contraindications to other DMARDs because of their toxicities.
Starting sulfasalazine at low doses and titrating slowly will minimize the nausea and abdominal discomfort caused by the drug. Patients receiving sulfasalazine must undergo routine blood work to monitor for leukopenia.1Patients with a sulfa allergy should not receive sulfasalazine.
Hydroxychloroquine and sulfasalazine can be used to treat JIA if methotrexate is not appropriate for the patient.17 The pediatric dose of hydroxychloroquine is 3 to 5 mg/kg/day divided in 1 to 2 doses. The dose of sulfasalazine for children older than 6 years is 30 to 50 mg/kg/day in two divided doses.
Leflunomide
Leflunomide inhibits dihydroorotate dehy-drogenase, an enzyme within the mitochondria that supplies T lymphocytes with the necessary components to respond to cytokine stimulation.26 Thus, leflunomide inhibits the T-lymphocyte response to various stimuli and halts the cell cycle. Its efficacy is similar to that of moderate doses of methotrexate or sulfasalazine.19 Because of its extended half-life, leflunomide therapy begins with a loading dose followed by a maintenance dose. Patients with pre-existing hepatic disease or a history of heavy alcohol ingestion should not receive leflunomide.26 Leflunomide may be used in combination with methotrexate, but the added efficacy comes with a dramatic rise in the risk of hepatotoxicity. Liver function tests must be followed closely to prevent or minimize liver damage.1 If therapy requires abrupt discontinuation (e.g., due to toxicity or pregnancy), administering cholestyramine will accelerate removal of leflunomide from the body.
Leflunomide was shown to effectively treat JIA in clinical trials, but it does not have an FDA-approved indication for this use.17
Biologic DMARDs
Biologic DMARDs are indicated in patients who have failed an adequate trial of DMARD therapy or in combination with nonbiologic DMARDs in patients with early, aggressive disease.1 These agents may be added to nonbiologic DMARD monotherapy (e.g., methotrexate) or replace ineffective nonbiologic DMARD therapy.18 The decision to select a particular agent generally is based on the prescriber’s comfort level with monitoring the safety and efficacy of the medications, severity of disease activity, presence of factors suggestive of poor prognosis, the frequency and route of administration, the patient’s comfort level or manual dexterity to self-administer subcutaneous injections, the cost, and the availability of insurance coverage.18,27 In general, biologic DMARDs should be avoided in patients with serious infections, demyelinating disorders (e.g., multiple sclerosis or optic neuritis) or hepatitis. TNF antagonists should be avoided in patients with heart failure.18
Tumor Necrosis Factor Antagonists
Etanercept is a recombinant form of human T receptor.28 Etanercept provides a therapeutic effect by binding to soluble TNF and preventing its binding with TNF receptors. It is administered subcutaneously once or twice weekly; noticeable symptomatic improvement is seen in 1 to 4 weeks. Etanercept is very effective as monotherapy or in combination with other DMARDs, except anakinra.28 There is no evidence to suggest a benefit to combination with anakinra, and there is an increased infection risk. The most common adverse reactions with etanercept are injection-site reactions. If such reactions are bothersome, patients should be advised to place ice on the injection-site before and after administration or apply a topical anesthetic or corticosteroid to the affected area.29 Etanercept has an FDA-approved indication for treatment of JIA. The pediatric dose of etanercept is 0.8 mg/kg subcutaneously once weekly.
Infliximab is a chimeric IgGl monoclonal antibody that binds to soluble and bound TNF-α.30 Methotrexate typically is given with it to suppress antibody production against the mouse-derived portion of the molecule. Infliximab is delivered via IV infusion every 4 to 8 weeks; however, patients may notice benefit within 1 to 4 weeks of receiving the first infusion. Infusion-related reactions including rash, urticaria, flushing, headache, fever, chills, nausea, tachycardia, and dyspnea may occur during treatment. Qualified health care personnel must be present during the infusion to respond to the infusion-related reactions, if they occur. If patients experience any of these symptoms, the reaction may be treated by: (a) temporarily discontinuing the infusion, (b) slowing the infusion rate, or (c) administering corticosteroids or antihistamines.29 Clinicians may prescribe pretreatment regimens with corticosteroids or antihistamines if the patient continues to experience infusion reactions.29 Infliximab was shown in clinical trials to be effective for treatment of JIA, but it has not yet received FDA approval for this indication.
Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human TNF.31 Adalimumab binds to soluble and bound TNF-α. Patients may experience symptomatic relief in as early as 1 week. Adalimumab can be administered in combination with methotrexate or other DMARDs.2 Adalimumab has an FDA-approved indication for JIA.
Golimumab is a human monoclonal antibody that binds to membrane-bound and soluble TNF. Golimumab can be administered in combination with methotrexate in patients with moderate to severe RA. One advantage of this agent over others in the class may be the once-monthly dosing. Golimumab is not FDA-approved for use in JIA.
Certolizumab is a humanized antibody Fab fragment conjugated to polyethylene glycol, which delays the metabolism and elimination of the medication. Certolizumab can be administered as monotherapy or in combination with methotrexate in patients with moderate to severe RA. Certolizumab is not FDA-approved for use in JIA.
Interleukin 1 Receptor Antagonist
Anakinra is a recombinant form of human IL-1 receptor antagonist. Anakinra inhibits the activity of IL-1 by binding to it and preventing cell signaling. It is indicated for adults with RA who have failed one or more nonbiologic DMARDs. Patients must administer a subcutaneous injection every day, which may be less desirable than other treatment options. Anakinra may be used in combination with other nonbiologic DMARDs in patients not responding to or unable to tolerate nonbiologic DMARDs or TNF antagonists. Anakinra should not be used in combination with TNF antagonists due to the increased risk of infection. Anakinra is not included in the algorithms outlined in the 2008 treatment guidelines due to its infrequent use in RA.
Costimulation Modulators
Abatacept is the first agent in this class of medications. It interferes with T-cell signaling, ultimately blocking T-cell activation and leading to anergy, or lack of response to an antigen.32 Trials conducted in patients refractory to methotrexate and anti-TNF therapy demonstrated significant clinical benefit after administration of abatacept every 28 days with a dose approximating 10 mg/kg.32 Adverse reactions reported in clinical trials were low and similar to those of placebo, with the exception of an increased incidence of headache, infections, and infusion-related reactions in the treatment group.32 Abatacept is indicated as monotherapy or in combination with nonbiologic DMARDs. Its exact place in therapy is not yet clear; however, clinicians see a window of opportunity for patients who were intolerant to or did not receive therapeutic benefit from other nonbiologic or biologic DMARDs or developed antibodies to adequate trials of anti-TNF agents, specifically infliximab.32
Anti-CD20 Monoclonal Antibody
Rituximab is a genetically engineered chimeric anti-CD20 monoclonal antibody that causes B-lymphocyte depletion.33 Although the exact role of B lymphocytes in the pathogenesis of RA is not clear, a small study in patients with RA demonstrated noticeable efficacy. Further clinical trials showed a sustained therapeutic effect lasting for at least 48 weeks after the initial treatment.33–35 Adverse effects occurring during or up to 24 hours after the first infusion included changes in blood pressure (increases or decreases), cough, rash, and pruritus. The infusion-related reactions subsided with subsequent infusions. Serious infections occurred in a small number of rituximab-treated patients.
The exact role of rituximab in RA is not clearly defined, but it is indicated for patients with moderate to severe active RA and a history of inadequate response to one or more TNF antagonist therapies. Rituximab carries a black-box warning of fatal infusion reactions and severe mucocutaneous reactions even though these events did not occur during the RA clinical trials. The benefits of rituximab must be tempered against the safety concerns reported with use of rituximab in the oncology setting. Fully humanized anti-CD20 monoclonal antibodies are under development.
Anti-interleukin-6 Receptor Antibody
Interleukin-6 (IL-6) is produced in high amounts in patients with RA. High levels are indicative of joint damage and disease activity. In addition, IL-6 plays a significant role in the pathogenesis of anemia of chronic disease.36Tocilizumab, an anti-IL-6 receptor monoclonal antibody, inhibits the binding of IL-6 to the IL-6 receptor.22 Studies in patients not responding to methotrexate or TNF antagonists have demonstrated safety and efficacy of tocilizumab administration.2,22,37 The tocilizumab dose is 8 mg/kg IV every 4 weeks. Adverse reactions include nasopharyngitis, infection, and elevated lab values including liver function tests and cholesterol parameters. The exact place in therapy of tocilizumab is not yet known. Tocilizumab is not included in the 2008 recommendations from the ACR because the drug was still investigational at the time of writing.
Selecting a Biologic DMARD
Developments in the treatment of RA are tempered by the lack of evidence of the long-term safety and efficacy of the biologic DMARDs. In addition, high costs can be a deterrent to use. Longer term data are emerging that suggest that patients receiving therapy with these agents early in the course of disease (within 3 years) for a defined time period have reduced disease activity and less joint destruction. If additional evidence proves this to be true, concerns regarding the cost of biologic DMARDs may be alleviated. Cost analyses may indicate that the increased expenses associated with these drugs are offset by the costs avoided for treatment of advanced RA.
The risk of infection in patients treated with biologic DMARDs must be considered when selecting and monitoring therapy.18,38,39 Influencing the immune response to reduce symptoms of RA may influence the body’s response to pathogens. Of particular concern is the use of TNF antagonists in patients with a history of tuberculosis exposure. TNF is important in the formation of granulomas that wall off tuberculosis infection. In theory, if TNF is inhibited, patients with latent tuberculosis may have a reactivated infection. Patients receiving biologic DMARD therapy should be screened for tuberculosis and other infections. Prophylaxis should be initiated in patients with previous tuberculosis exposure or in patients at high risk of developing tuberculosis.18 Biologic DMARDs should not be initiated during an acute, serious infection and should be discontinued temporarily during times of infection.39
Patient Encounter, Part 2: Medical History, Physical Examination, and Laboratory Tests
PMH: Exercise-induced asthma; allergic rhinitis; carpal tunnel syndrome
FH: Father has hypertension, diabetes, dyslipidemia; mother has RA and a history of MI; two siblings (one brother, one sister) alive and well.
SH: She is a successful artist and works from home. She drinks alcohol occasionally and does not smoke or use illicit drugs.
Allergies: NKDA
Meds: Albuterol (salbutamol) 2 puffs 15 to 20 minutes before exercise; ortho Tri-Cyclen by mouth once daily; budesonide nasal spray one spray each nostril daily; calcium (with vitamin D) 600 mg orally twice daily; ibuprofen 400 mg by mouth every 4 hours daily as needed
ROS: (+) fatigue, (-) N/V/D, HA, SOB, chest pain, cough
PE:
VS: BP 126/74, P 70, RR 18, T 38°C (100.4°F); ht 5’6” (168 cm), wt 72.3 kg (159 lb)
Skin: Warm, dry
HEENT: NC/AT, PERRLA, TMs intact
CV: RRR, normal S1 and S2, no m/r/g
Chest: CTA
Abd: Soft, NT/ND
Neuro: A & O × 3; CN II to XII intact
Ext: Bilateral tender and swollen PIPs, MCPs, and MTPs (symmetric)
Labs: ESR 66 mm/h, RF (+), HLA-DR4 (+), anti-CCP (+)
Synovial fluid analysis: Yellow, cloudy, decreased viscosity.
Hand x-rays: Soft-tissue swelling, joint space narrowing, no evidence of erosions.
Given this additional information, what is your assessment of the patient’s condition?
Identify your treatment goals for this patient.
What nonpharmacologic and pharmacologic alternatives are available for this patient?
Use of biologic DMARDs is associated with an increased risk of malignancy, specifically lymphoma and skin cancer.14,40 Patients should be monitored closely for signs and symptoms suggestive of malignancy. Therapy should be discontinued once the risks outweigh the potential benefits of treatment.
Fertility, Pregnancy, and Fetal Development
Women of childbearing age should be counseled about the impact of antirheumatic drugs on fertility, pregnancy, fetal development, and lactation. Some women may experience a reduction in disease symptoms during pregnancy; however, many agents used to treat RA are known teratogens. Women desiring motherhood must consult with their physicians to carefully plan for the pregnancy and reduce risks to the developing fetus.41 Low-dose corticosteroids generally are safe and effective. Certain NSAIDs, hydroxychloroquine, and azathioprine may be considered in severe disease.
Methotrexate use (FDA pregnancy category X) is associated with spontaneous abortion, fetal myelosuppression, limb defects, and CNS abnormalities; therefore, pregnancy must be avoided.41 Sulfasalazine, on the other hand, may be the drug of choice in women who are pregnant or planning to become pregnant due to its safety profile.41 There is limited evidence of safety and long-term effects of the use of biologic DMARDs in pregnant women. Case reports of pregnancy during biologic DMARD therapy show no increased risk of fetal toxicity, but long-term data are needed.28,41
Male patients with RA must receive counseling about the effects of certain medications on their fertility and potential harm to the fetus. It is difficult to establish causality between use of a medication by a male and the effect on fertility or fetal development; therefore, a conservative approach must be taken. 
Women of childbearing potential and their partners must be counseled to: (a) use proper birth control while undergoing treatment for RA; and (b) discontinue medications at least 3 months before conception.41
OUTCOME EVALUATION
• Rheumatologists rely on standardized criteria to assess treatment interventions through measurement of disease activity. The ACR uses criteria for improvement based on percentage improvement in tender and swollen joint count and the presence of at least three or more of the following measures: (a) pain; (b) patient global assessment; (c) physician global assessment; (d) self-assessed physical disability; and (e) acute-phase reactants.42 ACR20, ACR50, and ACR70 are common efficacy endpoints in clinical trials. The number corresponds with the percentage improvement. As drug discovery continues to evolve, the acceptable criteria for 20% improvement may be too low. For example, if a patient has 10 tender and swollen joints, reducing that by 20% to 8 tender and swollen joints is, by definition, an improvement by ACR20 criteria. However, further reduction in symptoms or disease remission may have greater clinical significance and effect on the patient’s quality of life.
• Physical disability from RA can be measured through the Stanford HAQ.43,44 This patient self-assessment tool was developed to evaluate patient outcomes in five dimensions of chronic conditions: (a) disability; (b) discomfort; (c) drug adverse effects; (d) dollar costs; and (e) death. Clinicians and clinical studies in rheumatology use HAQ to assess longitudinally changes that influence the patient’s quality of life.43,44
• Disease activity can be measured through the Disease Activity Score in 28 joints (DAS 28). Components involved in the calculation are the number of swollen and tender joints, ESR or CRP, and a subjective measure of the patient’s general health. A DAS 28 score of 3.2 or less indicates low disease activity, between 3.2 and 5.1 is considered moderate activity, and 5.1 or more is considered to be high activity.18,45Remission is defined as a DAS 28 score of less than 2.6.
• Before starting treatment for RA, assess the subjective and objective evidence of disease. For joint findings, this includes the number of tender and swollen joints, pain, limitations on use, duration of morning stiffness, and presence of joint erosions. Systemic findings may include fatigue and the presence of extraarticular manifestations. Obtain laboratory measurements of CRP and ESR. The impact of the disease on quality of life and functional status is also important.
• At follow-up visits, compare the patient’s status to baseline or previous visits using standardized criteria for improvement of disease activity and the HAQ to assess longitudinally the influence on quality of life.
• Assess the patient’s response to initiation of nonbiologic or biologic DMARD therapy after allowing adequate time for the medication to achieve its therapeutic effect.
• Determine whether any adverse reactions associated with each antirheumatic medication are present.
Patient Encounter, Part 3: Creating a Care Plan
Based on the information available, create a care plan for this patient’s RA. The plan should include:
(a) a statement of the drug-related needs and/or problems;
(b) the goals of therapy; (c) a patient-specific detailed therapeutic plan; and (d) monitoring parameters to assess safety and efficacy.
Six months later, the patient comes back and mentions that she would like to become pregnant.
Does this change your treatment plan?
If yes, devise a new treatment plan for AL.
Patient Care and Monitoring
1. Assess the patient’s symptoms to determine if they are consistent with RA. Evaluate the duration of symptoms and their impact on daily living.
2. Review available diagnostic data to determine the severity of disease and whether the patient is at risk of experiencing poor outcomes.
3. Obtain a thorough medication history, including prescription drugs, over-the-counter drugs, and dietary supplement use.
4. Educate the patient on nonpharmacologic measures that will improve symptoms.
5. Formulate a therapeutic plan, taking into consideration patient-specific factors.
6. Evaluate the patient for the presence of adverse drug reactions, drug allergies, and drug interactions.
7. Develop a plan to assess safety and efficacy of the pharmacologic treatment plan. Determine if the appropriate doses of antirheumatic medications were used and if all medication were given a sufficient trial to achieve therapeutic benefit.
8. Stress importance of adherence with the therapeutic regimen, including required laboratory monitoring, medication dosing and administration. Recommend a therapeutic regimen that is convenient and consistent with the patient’s lifestyle.
9. Longitudinally evaluate the patient’s clinical response to therapy and the impact on quality of life and mobility.
10. Evaluate the presence of comorbidities and implement measures to control the increased risk.
• Cardiovascular: Keep doses of NSAIDs and glucocorticoids low, consider initiation of folic acid to reduce homocysteine level elevations induced by methotrexate, consider initiation of low-dose aspirin and/or HMG-CoA reductase inhibitors (statins), and encourage smokers to discontinue tobacco use and assist with the development of a tobacco-cessation plan.11,12 Screen and aggressively treat elevated blood pressure.13
• Infection: Wash hands routinely, limit contact with individuals who are ill, and report signs and symptoms of infection immediately (e.g., fever, weight loss, and night sweats).
• Malignancy: Report new onset of signs and symptoms (e.g., fever, chills, anorexia, and night sweats) immediately.15
• Osteoporosis: Encourage patients to ingest adequate amounts of calcium and vitamin D, encourage smokers to discontinue tobacco use, and consider initiation of medications for osteoporosis (e.g., bisphosphonates, calcitonin, and parathyroid hormone) if the patient is taking glucocorticoids chronically or if the patient has evidence of low bone mineral density19,46.
11. Provide patient education with regard to RA, lifestyle modifications, and drug therapy:
• What causes RA?
• What are the comorbidities associated with RA?
• How will lifestyle modifications affect RA?
• What are the goals of therapy in the treatment of RA?
• When and how should the medications be administered?
• What potential adverse drug reactions may occur?
• Which drugs may interact with therapy?
• What are the warning signs to report to the physician?
• Monitor laboratory parameters to ensure patient safety and reduce the risk of adverse reactions.
In addition to designing an individualized therapeutic regimen to control the progression of RA, the clinician must evaluate the presence of comorbidities and implement measures to control the increased risk.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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