THE APhA COMPLETE REVIEW FOR PHARMACY, 7th Ed

22. Rheumatoid Arthritis, Osteoarthritis, Gout, and Lupus - Kevin L. Freeman, PharmD, BCNSP

22-1. Rheumatoid Arthritis

Introduction

Rheumatoid arthritis (RA) is a highly variable, chronic autoimmune disorder of unknown etiology characterized by symmetric, erosive synovitis. Manifestations may extend to extra-articular sites.

Incidence

RA affects 1% of the population and is two to three times more common in women than in men. It has a peak incidence in women between 30 and 60 years of age. Certain families, monozygotic twins, and people with specific HLA (human leukocyte antigen) genetic markers have a greater incidence of RA, which suggests a genetic predisposition.

Clinical Presentation

The onset of RA is unpredictable and varies from rapid to insidious progression. The course of the disease is likewise variable: 10-20% of patients have a short course with remission, 70-80% have mild to moderate disease with cyclic exacerbations, and 10-20% develop progressively destructive disease.

RA usually affects diarthrodial joints such as the proximal interphalangeal (PIP) joints, metacarpophalangeal (MCP) joints, metatarsophalangeal (MTP) joints, wrists, and ankles. Also commonly involved are the elbows, shoulders, sternoclavicular joints, temporomandibular joints, hips, and knees.

The initial complaints may include generalized fatigue and multiple joint pain.

Morning stiffness is a hallmark of RA. Patients describe it as a gel-like sensation in the joints that occurs after attempting to move upon awakening.

Ulnar deviation, swan-neck deformities, boutonniere deformities, hammertoe formation, and ankylosis are common irreversible joint abnormalities that occur in RA.

The extra-articular features that occur in RA include rheumatoid nodules, vasculitis, anemia, thrombocytopenia, Felty's syndrome, and Sjogren's syndrome.

Etiology

The cause of RA remains a mystery. Factors that may be responsible are of environmental, genetic, endocrinologic, gastrointestinal, atmospheric, and infectious origin.

RA is widely held to have a strong genetic component. This assertion is supported by the fact that a greater prevalence of RA is found in patients with the major histocompatibility complex antigen HLA-DR4. This class II antigen is expressed on the surface of helper T-lymphocytes and macrophages. In combination with environmental factors, an inappropriate immune response may occur, resulting in chronic inflammation.

Patients with RA have been demonstrated to have increased antibody titers to Mycobacterium tuberculosis, Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae, normal human gut flora antigen, Epstein-Barr virus, and the superantigen staphylococcal enterotoxin B.

Female patients are at greater risk of RA after breast-feeding, which supports the theory that endocrinologic risk factors are involved.

Gastrointestinal (GI) factors may be responsible for hyperactivity of the immune system—that is, antibodies to enteric organisms and gluten develop in the GI tract.

Atmospheric changes are associated with symptomatic changes in the disease course.

Pathophysiology

Because of causes still unknown, the body's immune system (starting with macrophages) attacks the cells within the joint capsule, thereby causing synovitis (as indicated by the warmth, swelling, redness, and pain associated with RA). Specifically, helper T-lymphocytes stimulate B-cells to attack antigen (in this case, the body's own collagen). In addition, helper T-lymphocytes release cytokines (interleukins and tumor necrosis factor, or TNF), which cause further inflammation and injury in the joints. During the inflammatory process, the cells of the synovium grow and divide abnormally, causing a normally thin synovium to become thick (pannus). These abnormal synovial cells begin to invade and destroy the cartilage and bone within the joint. These effects are responsible for the pain and deformities seen in patients with RA.

Diagnostic Criteria

Patients meeting four of the following criteria are classified as having RA:

• Morning stiffness of or near joints lasting 1 hour before maximum improvement. This condition must be present for at least 6 weeks.

• Three or more joint areas, including the right or left PIP joint, MCP joint, wrist, elbow, MTP joint, ankle, or knee, must have arthritis, as demonstrated by soft tissue swelling or fluid. This condition must be present for at least 6 weeks and observed by a physician.

• Arthritis, as demonstrated by soft tissue swelling or fluid in the hand joints (MCP, PIP, or wrist), must be present for at least 6 weeks and observed by a physician.

• Symmetric arthritis must occur in the areas noted in the second criterion. This condition must be present for at least 6 weeks and observed by a physician.

• Subcutaneous nodules (rheumatoid nodules) over bony prominences, extensor surfaces, or in juxtaarticular regions must be present.

• Positive rheumatoid factor (antibodies that collect in the synovium of the joint) must be present, as demonstrated by a positive test in less than 5% of normal subjects.

• Radiologic changes of the hands or wrists (e.g., erosions or bone decalcification in or next to involved joints) must be present.

Treatment Goals

According to the American College of Rheumatology (ACR), the goals in managing RA are to prevent or control joint damage, prevent loss of function, and decrease pain.

Monitoring

At each visit, the patient should be evaluated for subjective evidence of active disease on the basis of the following criteria:

• Degree of joint pain

• Duration of morning stiffness

• Duration of fatigue

• Presence of actively inflamed joints on examination

• Limitation of function

Periodically, the patient should be evaluated for disease activity or progression:

• Evidence of disease progression on physical examination (loss of motion, instability, malalignment, deformity)

• Erythrocyte sedimentation rate or C-reactive protein elevation

• Progression of radiographic damage of involved joints

Other parameters for assessing response to treatment (outcomes):

• Physician's global assessment of disease activity

• Patient's global assessment of disease activity

• Functional status or quality-of-life assessment using standardized questionnaires

The majority of clinical studies use a benchmark of 20% improvement in the preceding criteria, also known as ACR 20.

Drug Therapy

Aggressive use of disease-modifying antirheumatic drugs (DMARDs) is suggested (

Table 22-1).

The ACR recommendations focus on the use of biologic and nonbiologic therapies for the treatment of RA. The use of nonmedical therapies and anti-inflammatory drugs as well as other analgesics is still a part of the optimal treatment regimen; however, it was not evaluated as part of the 2008 recommendations (

Figures 22-1 and

22-2).

The 2008 ACR recommendations for the initiation or reinstitution of biologic and nonbiologic therapies depend on three factors:

[Table 22-1. Disease-Modifying Antirheumatic Drugs]

• Disease duration:

• Early (< 6 months)

• Intermediate (6-24 months)

• Long or longer (> 24 months)

• Disease activity:

• Available indices:

• Disease Activity Score in 28 Joints

• Simplified Disease Activity Index

• Clinical Disease Activity Index

• Mild disease: typically fewer than six inflamed joints, no extra-articular disease, and no radiographic evidence of erosions

• Severe disease: typically more than 20 inflamed joints, elevation in C-reactive protein, and positive rheumatoid factor, extra-articular disease, or both

• Prognostic factors:

• Physical examination, health questionnaire, and laboratory analysis

• Poor prognosis: functional limitation, extra-articular disease, elevated rheumatoid factor or anti-cyclic citrullinated peptide (CCP) antibodies (anti-CCP may be more specific than rheumatoid factor)

Nonsteroidal anti-inflammatory drugs

Salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), and selective cyclooxygenase-2 (COX-2) inhibitors are agents with analgesic and anti-inflammatory properties useful in the management of RA. These agents reduce joint pain and swelling; however, they do not inhibit joint destruction or otherwise alter the course of the disease. For this reason, they should not be considered as a sole treatment option. These agents act by inhibiting prostaglandin synthesis and release. Cyclooxygenase is present in many cells, including platelets, endothelial cells, and cells of the gastric and intestinal mucosa. The initial choice of agent is based on the efficacy, safety, cost, and convenience for any given patient. A wide range of interpatient variability exists with regard to clinical effect; several NSAIDs may need to be tried before achieving patient satisfaction. See

Table 22-2.

Aspirin

Mechanism of action

Aspirin prevents prostaglandin formation by inhibiting the action of the enzyme cyclooxygenase. The

[Figure 22-1. Nonbiologic DMARD Use]

[Figure 22-2. Biological DMARD Use]

antithrombotic effect of aspirin occurs by an irreversible inhibition of platelet cyclooxygenase. This irreversible inhibition is unique to aspirin, because the remaining NSAIDs do so in a reversible manner.

Dosage

The usual daily dosage needed to achieve anti-inflammatory effects is 3-5 g per day.

Patient instructions

Aspirin should be taken with food or milk to decrease gastrointestinal intolerance. Patients should report any dark or black stools, abdominal pain, or swelling to their physician immediately.

Adverse drug events

Aspirin irreversibly inhibits platelet activity, and serious bleeding may result. Dyspepsia, GI bleeding, tinnitus, hepatitis, and renal damage have been reported.

Drug-drug and drug-disease interactions

• Warfarin: Aspirin may enhance the hypoprothrombinemic effects of warfarin.

[Table 22-2. Drug Therapy with Nonsteroidal Anti-Inflammatory Drugs]

• Uricosuric agents: The uricosuric effects of agents such as probenecid are antagonized by aspirin.

• Methotrexate: Aspirin may displace methotrexate from its protein binding sites, thereby increasing serum methotrexate concentrations.

Parameters to monitor

Complete blood count (CBC) as well as creatinine should be monitored at least yearly.

Other NSAIDs

Mechanism of action

The mechanism of action is the same as described for aspirin.

Patient instructions

Patient instructions are the same as described for aspirin. Studies indicate that the optimal times for taking an NSAID might be after the evening meal and immediately on awakening. Patients with a hypersensitivity to aspirin should not take NSAIDs.

Adverse drug events

Compared with patients with osteoarthritis, patients with RA on NSAID therapy are at increased risk for a serious complication.

As with aspirin, NSAIDs cause platelet dysfunction. Unlike aspirin, however, this effect is readily reversible with discontinuation of the medication.

All NSAIDs are capable of causing GI intolerance and peptic ulceration. Risk factors for the development of peptic ulcer disease include advanced age, history of previous ulcer, concomitant use of corticosteroids or anticoagulants, higher dosage of NSAID, use of multiple NSAIDs, or serious underlying disease. Options to decrease the risk of developing GI ulceration include adding a high-dose histamine blocker such as ranitidine or a proton pump inhibitor such as lansoprazole to the patient's regimen. Lansoprazole and esomeprazole both have U.S. Food and Drug Administration (FDA) approval for reducing the risk of NSAID-induced gastric ulcers in those patients who had a previous risk of ulceration and who continue to require NSAID treatment. Misoprostol, an oral prostaglandin analogue, may be added at a dose of 100-200 mcg four times daily to prevent ulceration. Misoprostol is available in combination with diclofenac and sold under the trade name Arthrotec. Some evidence exists that, compared with other NSAIDs, ibuprofen, nabumetone, and naproxen carry lower risks of ulceration and GI symptoms. Piroxicam, in contrast, appears to carry a higher risk of serious GI consequences. A 2008 joint consensus statement by the American College of Cardiology Foundation, the American Heart Association, and the American College of Gastroenterology recommends that patients with a history of ulcer disease or with risk factors for ulceration be treated with a proton pump inhibitor while on NSAID therapy.

Hepatic failure has been reported with NSAID use.

Renal blood flow can be decreased by NSAIDs, which may lead to permanent renal damage. Prostaglandins are responsible for maintaining the patency of the afferent renal tubule. Inhibition by NSAIDs decreases glomerular filtration pressure, resulting in decreased blood flow. Because of this mechanism, patients with hypertension, severe vascular disease, and kidney or liver problems and those taking diuretics must be monitored closely.

Central nervous system (CNS) side effects such as dizziness, drowsiness, and confusion may occur with all NSAIDs.

Within the class, some drug-specific adverse reactions occur. Meclofenamate, for example, has a high incidence (> 10%) of abdominal cramping and diarrhea. Paradoxically, indomethacin tends to have more severe CNS adverse effects, such as headache.

Concern exists about NSAIDs and their risk of cardiovascular events. The FDA now requires that manufacturers include a black box warning regarding the potentially serious cardiovascular and GI adverse events associated with these drugs.

Drug-drug interactions

Interactions are the same as those described for aspirin. Ibuprofen may diminish the antiplatelet mechanism of aspirin if it is taken before aspirin or taken daily on a scheduled basis. It is recommended that aspirin be taken 2 hours before taking ibuprofen.

COX-2 inhibitors

COX-1 is the isoenzyme constitutively found in most tissues that produce the prostaglandins PGI2 and PGE2, which protect the gastric barrier, and thromboxane A2, which is responsible for platelet function. COX-2 is the inducible isoenzyme present at sites of inflammation. COX-2 is also found in the brain, kidneys, and reproductive organs. Celecoxib (Celebrex) has been shown to have lower incidence of endoscopically demonstrated gastroduodenal lesions than do ibuprofen, naproxen, and diclofenac. The lower risk for GI complications is apparently eliminated when patients take low-dose aspirin concomitantly.

Celecoxib

Mechanism of action

Celecoxib selectively inhibits prostaglandin synthesis by specifically targeting the COX-2 isoenzyme.

Patient instructions

Patients with a history of allergic reaction to sulfonamides should avoid the use of celecoxib.

Adverse drug events

Although the rates of GI ulceration have been demonstrated to be lower with COX-2 inhibitors than with traditional NSAIDs, the risk is not completely eliminated. In addition, the risk of dyspepsia, abdominal pain, and nausea is not significantly less with COX-2 inhibitors than with traditional NSAIDs. Celecoxib now contains a black box warning regarding cardiovascular and GI risk associated with its use (as described later).

Drug-drug interactions

Interactions are the same as those associated with aspirin.

Parameters to monitor

CBC as well as creatinine should be monitored at least yearly.

Other aspects

The FDA recommended the voluntary removal of valdecoxib (Bextra) from the market in 2005 because of the lack of adequate data on the cardiovascular safety of its long-term use and the recent data demonstrating increased cardiovascular risk in short-term coronary artery bypass graft (CABG) patients. This risk is in addition to that of potentially life-threatening skin reactions. Merck removed rofecoxib (Vioxx) from the market in September 2004 because its use was shown to be associated with an increased cardiovascular risk in the VIGOR (Vioxx Gastrointestinal Outcomes Research), APPROVE (Adenomatous Polyp Prevention on Vioxx), and VICTOR (Vioxx in Colorectal Therapy, Definition of Optimal Regimen) trials. The FDA has concluded that the benefits of celecoxib outweigh the risks in properly selected and informed patients. Celecoxib contains a black box warning about cardiovascular and GI risk. Patients with a high risk of cardiovascular events should not use celecoxib, including CABG patients. Low doses of celecoxib (200 mg per day) do not seem to be associated with increased risk.

Disease-modifying antirheumatic drugs

Unlike the NSAIDs, DMARDs have the ability to reduce or prevent joint damage and preserve joint integrity and function. The ACR recommends that patients with an established diagnosis of RA be offered treatment with DMARDs. Biologic DMARDs are reserved for use after failure of nonbiologic agents, unless the patient has early disease with high activity and poor prognosis risk factors. Methotrexate is typically selected for initial therapy because of its track record to induce long-term response. Methotrexate or leflunomide may be used as monotherapy in patients with all disease durations and activity regardless of poor prognostic features. Unfortunately, all DMARDs tend to lose effectiveness over time. It is rare for a patient to use one medication for longer than 2 years.

Nonbiologic DMARDs

Hydroxychloroquine

Mechanism of action

Hydroxychloroquine (Plaquenil) may inhibit interleukin-1 release by monocytes, thereby decreasing macrophage chemotaxis and phagocytosis.

Patient instructions

Beneficial effect may not be seen until 1-6 months of use. Patients should report any changes in vision to their physician immediately.

Adverse drug events

The most serious potential adverse effect associated with hydroxychloroquine is retinal damage that can lead to vision loss. This damage is caused by the deposition of the drug in the melanin layer of the cones. A cumulative dose of 800 g and age > 70 years increase the risk. Hydroxychloroquine may also cause rash, abdominal cramping, diarrhea, myopathy, skin pigment changes, and peripheral neuropathy.

Parameters to monitor

Ophthalmic evaluations should be performed at baseline. If the patient has no risk factors (liver disease, retinal disease, age > 60) and the baseline exam is normal, the American College of Ophthalmology recommends no further testing for 5 years. High-risk patients should have annual exams.

Dose

The dose is 6.0-7.5 mg/kg of lean body weight daily or 200 mg bid (maximum dose).

Sulfasalazine

Mechanism of action

The intestinal flora breaks sulfasalazine (Azulfidine) down to 5-aminosalicylic acid and sulfapyridine, the active moiety in RA. Sulfapyridine likely inhibits endothelial cell proliferation, reactive oxygen species, and cytokines. In addition, it has been shown to slow radiographic progression of RA.

Patient instructions

Sulfasalazine may produce effects more quickly (within 1 month) than hydroxychloroquine. A coated tablet form may help reduce adverse GI effects.

Adverse drug events

The most common adverse reactions associated with sulfasalazine include headache, GI intolerance, dysgeusia, rash, leukopenia, and thrombocytopenia.

Drug-drug interactions

Sulfasalazine may inhibit the absorption of folic acid.

Parameters to monitor

Patient tests should include baseline CBC, liver function tests (LFTs), and glucose-6-phosphate dehydrogenase (G6PD) levels. Patients should then have a CBC every 2-4 weeks for the first 3 months and then once every 3 months thereafter. Patients should receive a pneumococcal vaccination prior to initiation.

Dose

Begin with 500 mg daily, titrated up to 1-3 g per day divided tid or qid.

Methotrexate

Mechanism of action

Methotrexate (Rheumatrex) inhibits dihydrofolate reductase. It reduces dihydrofolate to tetrahydrofolate, which can be used as a carrier of single carbon units for the synthesis of nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication.

Patient instructions

Patients should be instructed not to change the amount of methotrexate taken without first consulting their physician.

Adverse drug events

• Liver: Methotrexate may cause liver damage. People with diabetes, liver problems, obesity, and psoriasis and those who are elderly or alcoholic are at higher risk. If LFTs are more than three times the upper limit of normal, methotrexate should be discontinued.

• Bone marrow: Leukopenia, thrombocytopenia, and pancytopenia are rare but serious adverse events associated with methotrexate therapy.

• Lung: Pulmonary toxicity occurs in up to 5% of people who take methotrexate. Risk factors for the development of pulmonary toxicity include age, diabetes, rheumatoid involvement of the lungs, protein in the urine, and previous use of sulfasalazine, oral gold, or penicillamine.

• GI: Nausea, vomiting, and stomatitis occur with an incidence of 5-30%.

Drug-drug interactions

Aspirin and other NSAIDs may increase methotrexate concentrations by as much as 30-35%. Trimethoprim-sulfamethoxazole may cause additive hematologic abnormalities because of its similar affinity for dihydrofolate reductase.

Parameters to monitor

CBC, LFTs, albumin, and creatinine should be monitored every 2-4 weeks for the first 3 months and every 8-12 weeks thereafter. Patients at risk for hepatitis B and C should be screened prior to initiation.

Other aspects

Taking folate supplements may help minimize adverse effects such as liver toxicity. Folic acid in doses up to 3 mg per day has proven effective and does not diminish methotrexate activity. Patients should receive a pneumococcal vaccination prior to initiation.

Dose

The dose is 7.5-25.0 mg once weekly.

Leflunomide

Mechanism of action

Leflunomide (Arava) inhibits dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated its anti-inflammatory effect.

Patient instructions

Leflunomide is under pregnancy category X. Women taking leflunomide who wish to become pregnant should follow the drug elimination procedure outlined under "Other aspects."

Adverse drug events

Diarrhea, elevated LFTs, alopecia, hypertension, and rash have been reported with leflunomide therapy.

Drug-drug interactions

An increased risk of liver toxicity exists when leflunomide is used in conjunction with methotrexate. Rifampin causes a 40% increase in levels of leflunomide's active metabolite, M1.

Parameters to monitor

CBC, LFTs, albumin, and creatinine should be monitored every 2-4 weeks for the first 3 months and every 8-12 weeks thereafter. If alanine aminotransferase exceeds two times the upper limit of normal, reduce the dose of leflunomide to 10 mg per day. Patients at risk for hepatitis B and C should be screened prior to initiation.

Kinetics

After absorption, 80% of the parent compound is converted to the active metabolite, M1, which is responsible for all of leflunomide's activity. Because the half-life is 2 weeks, a loading dose is necessary. In addition, M1 undergoes extensive enterohepatic recirculation.

Other aspects

Begin the following drug elimination procedure if a patient decides to become pregnant: 8 g of cholestyramine three times daily for 11 days; plasma levels of M1 < 0.02 mg/L must be verified on two separate occasions at least 14 days apart.

Many randomized controlled trials have established leflunomide as an alternative to methotrexate as monotherapy.

Patients should receive a pneumococcal vaccination prior to initiation.

Dose

100 mg daily for 3 days (loading dose), then 20 mg daily

D-penicillamine

Mechanism of action

How penicillamine (Cuprimine) induces therapeutic effects in RA is currently unknown. It is known, however, that penicillamine significantly reduces immunoglobulin M rheumatoid factor and appears to suppress disease activity.

Patient instructions

Penicillamine should be taken on an empty stomach and at least 2 hours from any dose of antacids or iron supplements.

Adverse drug events

• Bone marrow: Penicillamine may cause thrombocytopenia and leukopenia approximately 6 months into therapy. Rarely, aplastic anemia develops and is associated with its use.

• Renal: Proteinuria may occur in up to 32% of patients on penicillamine therapy.

• Dermatologic: Skin rash may occur 6-9 months after therapy commences.

• Other: Penicillamine causes stomatitis, dysgeusia, and polymyositis.

Drug-drug interactions

Absorption decreases approximately 70% with concomitant administration of antacids, iron, and zinc. Penicillamine may increase digoxin levels. In addition, penicillamine's chelating effects in combination with oral gold compounds may cause gold from deep tissue compartments to mobilize, which can increase toxicity.

Parameters to monitor

Patients should have CBC, platelet count, creatinine, and urine dipstick for protein lab testing done before initiating therapy. Afterward, the patient should have a CBC and urine dipstick for protein every 2 weeks until the dosage is stable and then every 1-3 months.

Other aspects

Penicillamine may take up to 1 year to be effective. Note that more than half the patients who take it withdraw because of side effects.

Dose

Begin with 125-250 mg/d, and increase by 125-250 mg/d every 8-10 weeks, not to exceed a maximum dose of 750 mg/d.

Gold compounds

The intramuscular (IM) gold compounds are gold sodium thiomalate (Myochrysine) and aurothioglucose (Solganal). Auranofin (Ridaura) is given orally.

Mechanism of action

The mechanism of action of gold compounds is currently unknown; they appear to suppress the synovitis seen in RA. Current research indicates that they may stimulate specific protective factors, such as interleukin-6 and interleukin-10.

Patient instructions

Patients receiving gold therapy should avoid prolonged sun exposure, which may increase the risk of serious rash.

Adverse drug events

IM gold

Patients may experience an immediate "nitroid reaction" (i.e., flushing, weakness, dizziness, sweating, syncope, and hypotension). Rash is the single-largest adverse effect associated with gold therapy. The rash may range from simple erythema to exfoliative dermatitis. Gold therapy may also cause proteinuria or microscopic hematuria. Rarely, immunologic glomerulonephritis may occur, in which case gold therapy should be permanently discontinued. Leukopenia and thrombocytopenia occur with a 1-3% incidence.

Oral gold

Adverse reactions are similar to those associated with the IM formulation. However, GI complaints of nausea, diarrhea, emesis, and dysgeusia are higher.

Drug-drug interactions

Patients receiving concomitant penicillamine therapy may be subject to an increased risk of toxicity associated with gold therapy. The risk of rash is higher when gold therapy is used with hydroxychloroquine.

Parameters to monitor

At baseline, all patients should have a CBC, platelet count, creatinine, and urine dipstick for protein. For patients receiving IM therapy, a CBC, platelet count, and urine dipstick are recommended every 1-2 weeks for the first 20 weeks and then again at the time of each (or every other) injection. Those on oral therapy should have a CBC, platelet count, and urine dipstick for protein every 4-12 weeks.

Other aspects

Aurothioglucose may have a lower rate of injection reactions; its sesame seed formulation slows absorption.

Dosing

IM gold

A 10 mg test dose IM is followed by a 25 mg test dose on week 2 and then weekly 50 mg doses until a cumulative dose of 1 g is achieved. The maintenance regimen is 50 mg every 2 weeks for 3 months or until 1.5 g is given; then every 3 weeks; and then monthly.

Oral gold

The dose is 3 mg bid up to 3 mg tid.

Biologic DMARDs

Antitumor necrosis factor therapy

The drugs used in antitumor necrosis factor (anti-TNF) therapy are infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira).

Mechanism of action

Composed of human constant and murine variable regions, infliximab binds specifically to human tumor necrosis factor (TNF).

Similarly, by binding specifically to TNF, etanercept binds and blocks its interaction with the cell surface's TNF receptors. It is produced by recombinant technology in Chinese hamster ovaries.

Adalimumab is a recombinant human immunoglobulin G1 monoclonal antibody that binds to TNF with high affinity.

Patient instructions

Patients should not receive live vaccines during treatment. Therapy should be temporarily discontinued in the event of an acute infection.

Adverse drug events

Therapy has been associated with serious mycobacterial, fungal, and opportunistic infectious complications such as sepsis and tuberculosis, leading to requirement of an FDA black box warning to that effect in 2008. Other adverse reactions include rash, headache, nausea, and cough. Although rare, both etanercept and infliximab have been associated with nerve damage that resembles the disease process in multiple sclerosis. Lymphoma has been reported with all three TNF antagonists.

Drug-drug interactions

Live vaccines may interact with these drugs.

Parameters to monitor

Be clinically alert for tuberculosis, histoplasmosis, and other opportunistic infections.

Other aspects

Patients should be tested for tuberculosis (skin testing, chest radiograph, or both) and hepatitis B (if risk factors are present) before initiating therapy with any biologic agent. Currently, infliximab is approved for therapy only in combination with methotrexate. Increased mortality in heart failure patients taking infliximab has been shown. The ACR recommends against the use of anti-TNF agents in patients with class III-IV heart failure.

Dose

The dosage for infliximab is 3 mg/kg intravenous (IV) initially, at weeks 2 and 6, and then every 8 weeks in combination with methotrexate.

The dosage for etanercept is 25 mg subcutaneous (SC) twice weekly or 50 mg SC once weekly.

The dosage for adalimumab is 40 mg SC every second week.

Anakinra

Mechanism of action

Anakinra (Kineret) blocks the biologic activity of interleukin-1 by competitively inhibiting interleukin-1 binding to the interleukin-1 type I receptor.

Patient instructions

Kineret is supplied in a single-use, prefilled syringe that should be stored in the refrigerator. Any syringe left unrefrigerated for more than 24 hours should be discarded.

Adverse drug events

Like the anti-TNF agents, anakinra increases the risk of serious infections. Injection-site reactions are extremely common. Headache, nausea, diarrhea, sinusitis, flu-like symptoms, and abdominal pain have also been reported.

Drug-drug interactions

Live vaccines can interact with anakinra.

Parameters to monitor

Patients should have a CBC checked at baseline, then monthly for 3 months, and then once every 3 months for the first year of therapy.

Dose

The dose is 100 mg daily SC.

Abatacept

Mechanism of action

Abatacept (Orencia) selectively modulates T-cell activation causing downregulation and an anti-inflammatory effect.

Adverse drug events

Like the other biologic DMARDs, abatacept increases the risk of infections, especially upper respiratory infections. Nausea and headache are also frequently reported. In addition, patients with chronic obstructive pulmonary disease developed adverse effects more frequently than with placebo. More cases of lung cancer were observed in patients treated with abatacept than with placebo. The lymphoma rate was higher as well.

Drug-drug interactions

Use of abatacept is contraindicated with other biologic DMARDs because of increased risk of infection. Live vaccines are contraindicated as well.

Other aspects

Abatacept contains maltose and may falsely elevate blood glucose readings. Monitors that do not react to maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide, glucose oxidase, or glucose hexokinase test methods, are recommended.

Dose

Dose is based on weight (< 60 kg = 500 mg; 60-100 kg = 750 mg; > 100 kg = 1,000 mg). Infusions are given over 30 minutes. After the initial dose, give at 2 and 4 weeks, followed by every 4 weeks.

Rituximab

Mechanism of action

Rituximab (Rituxan) causes a transient depletion of B-lymphocytes by binding to the CD20 surface antigens.

Other aspects

Rituximab should be used only in patients with moderate to severe RA who have had an inadequate response or a contraindication to anti-TNF products.

Dose

Give 1,000 mg every 2 weeks for two doses; patients may be premedicated with a glucocorticoid to decrease infusion-related reactions.

Other agents

Azathioprine

Azathioprine (Imuran) is a purine analogue immunosuppressive agent that is generally reserved for refractory RA. It is associated with dose-related bone marrow suppression, stomatitis, diarrhea, rash, and liver failure. Patients must have a baseline CBC, creatinine, and liver profile. Patients should then have a CBC and platelet count every 1-2 weeks after any change in dosage and every 1-3 months thereafter. Azathioprine should not be administered with allopurinol because xanthine oxidase metabolizes 6-mercaptopurine.

Cyclosporine A

By blocking T-cell activation, cyclosporine A (Sandimmune) produces powerful immunosuppressive effects and is beneficial as monotherapy in the treatment of RA. Serious adverse effects such as hypertension, nephrotoxicity, glucose intolerance, and hepatotoxicity have limited its use.

Corticosteroids

Low-dose oral corticosteroids (< 10 mg per day of prednisone or the equivalent) and local injections of glucocorticoids are highly effective. Studies indicate that corticosteroids decrease the progression of RA. They may be useful for acute flare-ups and in patients with significant systemic manifestations of RA. RA is associated with an increased risk of osteoporosis (independent of steroid therapy), and the addition of steroidal anti-inflammatory agents increases the risk. Patients on glucocorticoids should receive 1,500 mg of elemental calcium per day and 400-800 international units (IU) of vitamin D per day.

Nondrug Therapy

Surgery

Prosorba column

A device called the Prosorba column removes inflammatory antibodies from the patient's blood.

Joint surgery

Patients may have arthroscopy performed to clean out the bone and cartilage fragments that cause pain within the joint capsule. Patients may eventually require complete joint replacement surgery.

Lifestyle modifications

A mild exercise regimen can be an effective therapy.

Some evidence suggests a moderate increase in daily protein intake may be beneficial in RA.

Patients with RA benefit from a formal support group.

22-2. Osteoarthritis

Introduction

Osteoarthritis (OA), a disease that affects the weight-bearing joints of the peripheral and axial skeleton, is the most common form of arthritis in the United States. OA is also known as degenerative joint disease.

Incidence

According to radiologic evidence, approximately 60-80% of people over the age of 65 have OA. Before the age of 50, men have a higher incidence; however, after the age of 50, women have a higher incidence.

Clinical Presentation

Pain is a common initial finding in patients with OA. This pain typically worsens with weight-bearing activity and improves with rest of the affected joint. Changes in weather and barometric pressure tend to influence the severity of pain.

Joint stiffness, including morning stiffness, is another common complaint. This stiffness differs from that of RA. It is relatively short in duration, is related to periods of inactivity, and resolves with movement.

Crepitus is common, especially when the knee joint is involved.

Joint deformities also occur in OA. Heberden's nodes, Bouchard's nodes, and osteophytes on the distal interphalangeal and proximal interphalangeal joints are commonly seen.

Pathophysiology

Although the causes of OA are not completely understood, biomechanical stresses affecting the articular cartilage and subchondral bone are thought to be the primary factors in the development of OA. In addition, inflammatory, biochemical, and immunologic components play a role. The function of the normal cartilage—that is, to dissipate the force and stress caused by normal weight-bearing activity—is impaired in OA.

• Collagen fibers are destroyed and subsequently release proteoglycans. The hydration of the cartilage increases, and the cartilage becomes thick.

• Metalloproteinases, which degrade the proteoglycans, are released to initiate the reparation process. This degradation causes an increase in chondrocyte activity.

• The resulting cartilage is thin because the chondrocyte activity cannot match the rate at which proteoglycan degradation occurs.

• With this ever-thinning layer of cartilage now exposing bone, the grinding motion stimulates osteoclast and osteoblast activity, thereby causing bone resorption and vascular changes. Ultimately, these changes lead to the formation of osteophytes.

Diagnostic Criteria

Osteoarthritis of the hip

According to the ACR classification criteria, osteoarthritis of the hip exists if the patient has hip pain and at least two of the following:

• Erythrocyte sedimentation rate < 20 mm/h

• Radiographic femoral or acetabular osteophytes

• Radiographic joint space narrowing

Other criteria include one of the following:

• Hip pain and radiographic femoral or acetabular osteophytes

• Hip pain and radiographic joint space narrowing and erythrocyte sedimentation rate < 20 mm/h

Osteoarthritis of the knee

According to ACR classification criteria, osteoarthritis of the knee exists if the patient has knee pain, radiographic osteophytes, and at least one of the following:

• Age > 50 years

• Morning stiffness ≤ 30 minutes in duration

• Crepitus on motion

Other criteria include one of the following:

• Knee pain and radiographic osteophytes

• Knee pain and age ≥ 40 years, morning stiffness ≤ 30 minutes in duration, and crepitus on motion

Treatment Principles

Treatment of patients with OA focuses on symptom control. Currently, no therapeutic options are known to change the course of the disease.

Drug Therapy

Pain relief is the primary treatment goal for patients with OA. The recommended initial drug of choice is acetaminophen. For those patients who do not respond fully, the addition of an NSAID (see discussion of this class in Section 22-1) is made. Box 22-1 outlines pharmacologic therapy for patients with osteoarthritis.

Acetaminophen

Mechanism of action

Acetaminophen centrally inhibits prostaglandin synthesis.

Patient instructions

Patients with hepatic disease or viral hepatitis are at risk of toxicity from chronic acetaminophen use.

Adverse drug events

Hepatotoxicity is the most severe side effect associated with acetaminophen therapy. For this reason, patients should not ingest more than 4 g of acetaminophen per day. Long-term therapy has also been linked to renal failure.

Box 22-1. Pharmacologic Therapy for Patients with Osteoarthritis

Oral

• Acetaminophen 4 g/d

• COX-2-specific inhibitor

• Nonselective NSAID plus misoprostol or a proton pump inhibitor

• Nonacetylated salicylate

• Other pure analgesics

   Tramadol (Ultram) 50 mg/dose (up to 400 mg/d)

   Ultracet 37.5 mg/dose (up to 300 mg/d)

• Alternative therapy: glucosamine 1,500 mg/d (alone or in combination with chondroitin)


Intra-articular

• Glucocorticoids

• Hyaluronan


Topical

• Capsaicin

• Methyl salicylate

Other aspects

Acetaminophen is generally considered the initial drug of choice; however, there have been no clinical trials comparing its side effects, potential toxicity, or pain-relieving properties with those of NSAIDs.

Tramadol

Tramadol is a central opioid agonist that binds to mu receptors and weakly inhibits norepinephrine and serotonin reuptake.

Adverse drug events

Nausea, vomiting, constipation, and seizures are associated with tramadol use. Withdrawal symptoms may occur with abrupt discontinuation.

Drug interactions

Tramadol is contraindicated in patients taking monoamine oxidase inhibitors because of the risk of serotonin syndrome.

Other aspects

Tramadol is available as an immediate-release product (Ultram), as an extended-release product (Ultram ER), and in combination with acetaminophen 325 mg (Ultracet).

Topical agents (capsaicin)

Mechanism of action

Derived from the pepper plant, capsaicin works by exciting the nociceptive C-afferent neurons, which, in turn, causes the release of substance P, which is responsible for transmitting pain from the peripheral to the central nervous system.

Patient instructions

Patients should avoid contact with eyes. It is important to wash hands thoroughly after use.

Adverse drug events

Patients will experience mild burning and stinging at the site of application.

Other aspects

Patients usually derive benefit after several weeks of application. Capsaicin is often used in conjunction with oral agents.

Glucosamine sulfate and chondroitin

Mechanism of action

Glucosamine is found naturally in articular cartilage and acts as a substrate in the synthesis of proteoglycans. Chondroitin, another constituent in the cartilage, attracts and retains water, which provides shock absorption. In addition, chondroitin prevents the breakdown of cartilage and stimulates RNA (ribonucleic acid) synthesis of chondrocytes.

Patient instructions

Patients taking anticoagulants concomitantly may be at increased risk of bleeding.

Adverse drug events

Adverse events tend to be mild but include dyspepsia and euphoria.

Other aspects

This combination is available over the counter and has some clinical literature to support its use. The Arthritis Foundation, however, does not currently recognize it as a treatment for OA.

Other agents

The FDA has approved hyaluronic acid derivatives for the treatment of pain associated with OA of the knee. These agents may be an option after all conventional therapies for OA have been exhausted. The injection of this product into the synovium appears to replenish the viscosity to the space, thus enabling normal tissue to regenerate.

Nondrug Therapy

Nondrug therapy for OA consists of the following:

• Patient education

• Self-management programs (e.g., Arthritis Foundation Self-Management Program)

• Personalized social support through telephone contact

• Weight loss (if overweight)

• Aerobic exercise programs

• Physical therapy (i.e., range-of-motion exercises)

• Muscle-strengthening exercises

• Assistive devices for ambulation

• Patellar taping

• Appropriate footwear

• Lateral-wedged insoles (for genu varum)

• Bracing

• Occupational therapy

• Joint protection and energy conservation

• Assistive devices for activities of daily living

22-3. Gout

Introduction

Gout, a systemic disease caused by the buildup of uric acid in the joints, causes inflammation, swelling, and pain. Hyperuricemia is defined as a urate level > 8 mg/dL in men and 7 mg/dL in women.

Incidence

Gout has been known as "the disease of kings and the king of diseases" and can be traced to the time of Hippocrates. Gout occurs in approximately 1% of the population. The vast majority of gout patients are men.

Clinical Presentation

Pain in one joint of the lower extremity is the most common first symptom of gout. The initial period of pain, usually monarticular and self-limiting, is followed by a period in which the patient is completely asymptomatic.

Termed intercritical periods, the time between acute gouty arthritis attacks may be 3 months to 2 years. The length of time shortens as the disease progresses.

The first attack is typically at night or in the early morning.

Gout commonly affects the ankle, heel, knee, wrist, finger, elbow, and instep. The most common site of the initial attack is the first MTP joint and is known as podagra.

The patient may experience fever, chills, and malaise during an acute gouty arthritis attack. Left untreated, the attack may last 1-2 weeks.

The skin over the affected joint becomes red, hot, swollen, and tender. As the patient recovers from the attack, local desquamation may occur.

Pathophysiology

Uric acid is the end product of purine metabolism (

Figure 22-3). Xanthine oxidase is the rate-limiting step in the formation of uric acid. Uric acid, which serves no known biological function, has a body content of 1.0-1.2 g.

Approximately 70% of uric acid is excreted via the kidneys. At physiologic pH, uric acid primarily exists as monosodium urate (MSU) salt.

Approximately 95% of serum uric acid is filtered across the glomerulus. Of this filtered amount, almost 100% is reabsorbed in the early part of the proximal tubule, only to be secreted back into the lumen in the more distal part of the tubule.

Primary gout is a result of an innate defect in purine metabolism or uric acid excretion. In this case,

[Figure 22-3. Ribose-Uric Acid Pathway]

hyperuricemia may result from uric acid overproduction (in "overproducers"), impaired renal clearance of uric acid (in "underexcreters"), or a combination of both. In rare instances, enzyme defects of either hypoxanthine guanine phosphoribosyltransferase or 5-phosphoribosyl-1-pyrophosphate may cause primary gout (Figure 22-3).

Secondary gout is associated with increased nucleic acid turnover, decreased renal function, increased purine production, or drug-induced decreased elimination of uric acid. Hematologic disorders that are lymphoproliferative and myeloproliferative in nature are known causes of secondary hyperuricemia. Salicylates such as aspirin may inhibit tubular secretion of uric acid at low doses. All diuretics, with the exception of spironolactone, may cause hyperuricemia. Ethambutol, pyrazinamide, nicotinic acid, ethanol, niacin, and cyclosporine are known to cause an increase in serum uric acid.

Acute gout attacks are caused by the deposition of monosodium urate (MSU) in the synovium of the joint. This deposition results in the stimulation of the body's inflammatory cascade. The MSU crystals undergo phagocytosis by polymorphonuclear leukocytes. These leukocytes, damaged by the sharp crystals, burst and release their contents (interleukin-1, lysosomes, and prostaglandins) into the synovium, resulting in the inflammatory reaction—that is, pain, swelling, and erythema.

If left untreated, deposits of MSU crystals, also known as tophi, lead to joint deformity and disability. Ultimately, patients may develop one of two types of renal disease: urate nephropathy or uric acid nephropathy. Urate nephropathy results from the deposition of MSU crystals in the renal interstitium. Uric acid nephropathy results from the deposition of uric acid in the collecting tubules.

Diagnostic Criteria

The American Rheumatism Association lists the following criteria for the diagnosis of gout:

• Definite: Sodium urate crystals in the affected joint appear negatively birefringent when viewed through a polarized light source.

• Suggestive: A minimum of six of the following criteria should be met.

• More than one attack of arthritis

• Development of maximum inflammation within 1 day

• Oligoarthritis attack

• Redness over joint

• Painful or swollen first MTP joint

• Unilateral attack on first MTP joint

• Unilateral attack on tarsal joint

• Tophus

• Hyperuricemia

• Asymptomatic swelling within a joint

Ruling out pseudogout is also important. In pseudogout, crystals deposited into the joint synovium cause intense pain and inflammation, but the culprit is calcium pyrophosphate dihydrate, not monosodium urate.

Treatment Goals

• Relieve pain and inflammation.

• Reduce serum uric acid concentration.

• Prevent recurrent gout attacks.

Drug Therapy

Drugs for the treatment of gout are outlined in

Table 22-3.

Acute gouty arthritis attack

Three treatments are available: colchicine, NSAIDs (indomethacin in particular), and corticosteroids. Avoiding treatments that affect serum uric acid concentrations is best during an acute attack.

Colchicine

Mechanism of action

Colchicine inhibits the phagocytosis of urate crystals by leukocytes. Colchicine also inhibits the release of chemotactic factor, thus reducing the adhesion of polymorphonuclear leukocytes. The net result makes colchicine an anti-inflammatory agent without analgesic activity.

Patient instructions

Patients should immediately stop taking colchicine if abdominal cramping or diarrhea occurs. Patients should never exceed a total of 8 mg during an acute gouty arthritis attack.

Adverse drug events

Nausea, bloating, emesis, and diarrhea occur in up to 80% of patients taking colchicine. Rarely, it may cause bone marrow suppression. This effect occurs with a higher incidence in those patients with underlying renal or hepatic dysfunction. When colchicine is given intravenously, possible extravasation may cause local skin necrosis. In addition, the intravenous route has been associated with bone marrow suppression,

[Table 22-3. Drugs for the Treatment of Gout]

disseminated intravascular coagulation, seizures, and death.

Drug-drug and drug-disease interactions

Patients with active peptic ulcer disease should not take colchicine.

Parameters to monitor

With long-term therapy, patients should have a serum creatinine test, liver function test, and complete white blood cell count check periodically.

Dose

For the treatment of an acute gouty arthritis attack, patients should take 1.2 mg orally followed by 0.6 mg in 1 hour. Maximum dose is 1.8 mg.

Other aspects

Colchicine is most effective when initiated within 12-36 hours of the attack.

Indomethacin

Indomethacin is the most extensively studied NSAID in the treatment of an acute gouty arthritis attack. Unlike colchicine, indomethacin is effective at any point during the acute attack. For more information, see the review of NSAIDs in Section 22-1.

Corticosteroids

For the treatment of acute gout pain, corticosteroids are effective when given intra-articularly, intravenously, or orally. Their use is limited to treatment failures of colchicine and NSAIDs. Intramuscular corticotropin (adrenocorticotropic hormone) is also effective when given (40 units) to treat an acute gouty arthritis attack.

Gout prophylaxis (intercritical period)

Patients with asymptomatic hyperuricemia should not be routinely treated with pharmacologic agents. These patients should undergo a workup to determine the cause of hyperuricemia. The use of low-dose (0.6-1.2 mg/d) colchicine can prevent subsequent attacks of gout. Patients in the intercritical period (after an acute gouty arthritis attack) are candidates for long-term prophylactic therapy directed at affecting serum uric acid levels. Choice of therapy is based on the patient's pathophysiologic cause of hyperuricemia. Patients are generally classified as overproducers or underexcreters. Placing the patient on a purine-restricted diet and performing a 24-hour urine collection to measure uric acid concentration may identify overproducers of uric acid. Those patients who excrete more than 600 mg of uric acid are considered overproducers. Once this diagnosis is made, patients are treated with one of two classes of agents: xanthine oxidase inhibitors or uricosurics.

Probenecid

Mechanism of action

Probenecid (Benemid) is a uricosuric agent that promotes the excretion of uric acid by blocking its reuptake at the proximal convoluted tubule.

Patient instructions

Patients should drink at least 2 liters of water per day to decrease the risk of uric acid stone formation. Patients should take probenecid with food if GI intolerance occurs.

Adverse drug events

Probenecid is generally well tolerated and is associated with very few adverse side effects. Up to 10% of patients receiving probenecid therapy develop uric acid stones. Probenecid may cause abdominal discomfort, but patients can often avoid it by taking probenecid with food.

Drug-drug interactions

Because probenecid prevents the tubular secretion of many weak organic acids, it has potential drug interactions—for example, with the penicillins, cephalosporins, nitrofurantoin, and rifampin. Although the interaction between probenecid, penicillins, and cephalosporins has been used therapeutically, the interaction with nitrofurantoin reduces nitrofurantoin's effectiveness. Using probenecid and aspirin together, even in low doses, is not advisable because aspirin blocks uric acid excretion. A crossover study in patients with gouty arthritis concluded that low-dose aspirin did not significantly interfere with the uricosuric effects of probenecid. Avoiding the combination would be reasonable, however. Additionally, the diuretic effects of furosemide and hydrochlorothiazide are magnified when probenecid is taken concomitantly. Finally, patients receiving sulfonylureas should be monitored closely for hypoglycemia when started on probenecid.

Other aspects

Patients should never begin uricosuric therapy during an acute gouty arthritis attack because of the risk of exacerbating the attack. Probenecid should not be used in patients with a creatinine clearance less than 50 mL/min.

Sulfinpyrazone

Mechanism of action

Sulfinpyrazone (Anturane) is a uricosuric agent that promotes the excretion of uric acid by blocking its reuptake at the proximal convoluted tubule.

Patient instructions

Patients should drink at least 2 liters of water per day to decrease the risk of uric acid stone formation. Patients should take sulfinpyrazone with food if GI intolerance occurs. Patients who are sensitive to aspirin should not take this agent because of the risk of bronchoconstriction.

Adverse drug events

Like probenecid, sulfinpyrazone is generally well tolerated. The most common reported adverse effects are GI discomfort and uric acid stone formation. In addition, rarely, sulfinpyrazone has been associated with bone marrow suppression and immunoallergic interstitial nephritis.

Drug-drug interactions

Sulfinpyrazone decreases the effectiveness of nitrofurantoin. When sulfinpyrazone is taken with aspirin, the effect of sulfinpyrazone is lessened.

Parameters to monitor

Patients should have complete blood work periodically because of the rare risk of bone marrow suppression associated with sulfinpyrazone therapy.

Other aspects

Patients should never start uricosuric therapy during an acute gouty arthritis attack; uricosuric therapy may exacerbate the attack. When increasing the dose of sulfinpyrazone, titrate upward slowly to minimize the risk of uric acid stone formation. Because uricosuric therapy may precipitate an acute gouty arthritis attack, patients should take an NSAID or colchicine for the first 6-12 months of therapy. Patients with a creatinine clearance of less than 50 mL/min should not use sulfinpyrazone.

Allopurinol

Mechanism of action

Allopurinol (Zyloprim) and its metabolite, oxypurinol, inhibit xanthine oxidase formation (the rate-limiting step in uric acid synthesis), thereby facilitating the clearance of the more water-soluble precursors of uric acid, oxypurines.

Patient instructions

Patients should immediately report any signs of rash to their health care providers. Allopurinol should be taken with food to minimize GI discomfort.

Adverse drug events

Allopurinol is generally well tolerated; the overall occurrence of adverse effects is less than 1%. Patients should be advised that rash, the most common adverse effect, might occur at any time during therapy. The rash may be as simple as a maculopapular eruption or as serious as the life-threatening Stevens-Johnson syndrome (which is exfoliative and erythematous). Rarely, allopurinol may cause alopecia, neutropenia, and hepatitis.

Drug-drug interactions

The chemotherapeutic agents azathioprine and 6-mercaptopurine are metabolized via the xanthine oxidase pathway; therefore, allopurinol and its metabolite oxypurinol may increase serum levels of these agents. The concomitant administration of ampicillin or amoxicillin with allopurinol increases the risk of rash to approximately 20%.

Parameters to monitor

Patients should be encouraged to report the first signs of rash to their physicians immediately. Patients should have serum creatinine as well as liver function tests drawn periodically.

Kinetics

With a half-life of 30 hours, allopurinol is rapidly converted to its active metabolite (oxypurinol). This speed allows for once-daily dosing.

Other aspects

To reduce the risk of precipitating an acute gouty arthritis attack, allopurinol should be initiated at a dose of 100 mg per day and increased at 100 mg intervals weekly to an average dose of 300 mg per day. Patients with renal insufficiency require a dose adjustment. Assuming the target dose is 300 mg per day, patients with a creatinine clearance of 10-20 mL/min should receive 200 mg per day. Those with a clearance of less than 10 mL/min should receive 100 mg per day.

Febuxostat (Uloric) was approved in February 2009 for the chronic management of hyperuricemia in patients with gout. It is also a xanthine oxidase inhibitor; however, unlike allopurinol, it is not a purine-based analogue.

Secondary hyperuricemia

As discussed earlier, hyperuricemia may be caused by lymphoproliferative and myeloproliferative disorders, as well as their chemotherapeutic treatments (e.g., tumor lysis syndrome). Allopurinol is commonly added to the prescribed chemotherapeutic regimen to prevent complications of hyperuricemia, for example, an acute gouty arthritis attack. Rasburicase (Elitek) is an approved therapeutic agent that is used to prevent hyperuricemia in children with leukemia, lymphoma, and solid-tumor malignancies. Rasburicase is a recombinant urate oxidase enzyme that converts uric acid to allantoin, thereby allowing it to be eliminated. Patients with G6PD deficiency should not use rasburicase.

22-4. Systemic Lupus Erythematosus

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder that can affect any system in the body, including the skin, joints, and internal organs.

Classification

The workup of SLE must include the consideration of an alternative diagnosis. Because other autoimmune diseases have similar characteristics and because the features of SLE, RA, and scleroderma overlap, a thorough assessment is warranted. Drug-induced lupus must be ruled out as well.

Clinical Presentation

Signs and symptoms consistent with SLE include the following:

• Malar rash (a butterfly-shaped rash over the cheeks and across the bridge of the nose)

• Discoid rash (scaly, disk-shaped sores on the face, neck, or chest)

• Photosensitivity

• Oral ulcers

• Arthritis

• Serositis (inflammation of the lining around the heart, lungs, or abdomen that causes pain and shortness of breath)

• Proteinuria

• Central nervous system problems

• Antinuclear antibodies (autoantibodies that react against the body's own cells)

• Anemia

• Fatigue

• Fever

• Skin rash

• Muscle aches

• Nausea

• Vomiting and diarrhea

• Anorexia

• Raynaud's phenomenon

• Weight loss

Patients typically present with chronic fatigue and depression. Dermatitis and arthritis (in multiple joints) are the most common clinical manifestations. The arthritic pain patients describe is generally out of proportion to the amount of synovitis present. Although it is rare, serious renal abnormalities can occur in patients with SLE. CNS involvement, also rare, can be serious. Lupus-related encephalopathy may occur from scarring of arterioles in the subcortical white matter. In addition, patients with SLE are at risk of stroke because of the thromboembolic nature of the antiphospholipid antibody.

Pathophysiology

The exact pathophysiology of SLE remains unknown. It is an autoimmune disease (type III hypersensitivity) in which patients have an overactivity of B cells. The result is hypergammaglobulinemia that ultimately precipitates immune complexes on the vascular membranes, thereby causing activation of complement. Drugs, procainamide being the most predominant, may also cause SLE. Other such medications include phenytoin, chlorpromazine, hydralazine, quinidine, methyldopa, and isoniazid.

Diagnostic Criteria

Criteria for diagnosing SLE are as follows:

• Characteristic rash across the cheeks

• Discoid lesion rash

• Photosensitivity

• Oral ulcers

• Arthritis

• Inflammation of membranes in lungs, heart, or abdomen

• Evidence of kidney disease

• Evidence of severe neurologic disease

• Blood disorders, including low red blood cell, white blood cell, and platelet counts

• Immunologic abnormalities

• Positive antinuclear antibody

A patient must experience four of the criteria before a classification of SLE can be made. These criteria, proposed by the ACR, should not be the sole characteristics for diagnosis, however.

Therapy

Therapy for each case of SLE is based on the particular symptoms of any given patient. Arthritis is commonly treated with NSAIDs or glucocorticoids. Dermatologic complications can be treated with hydroxychloroquine (see Section 22-1). Hydroxychloroquine may also be used for musculoskeletal manifestations that do not respond to NSAIDs. Thrombocytopenia generally responds to glucocorticoid therapy. Immunosuppressive agents are used in patients with lupus nephritis. Most commonly, cyclophosphamide is used, sometimes in combination with glucocorticoids.

22-5. Key Points

Rheumatoid Arthritis

• RA, a highly variable autoimmune disease characterized by symmetric, erosive synovitis, often affects extra-articular sites.

• RA usually affects diarthrodial joints (e.g., PIP joints, MCP joints, MTP joints, wrists, and ankles). Also commonly involved are the elbows, shoulders, sternoclavicular joints, temporomandibular joints, hips, and knees.

• Morning stiffness is the hallmark of RA.

• According to the ACR, the goals in managing RA are to prevent or control joint damage, prevent loss of function, and decrease pain.

• The ACR recommends the aggressive use of DMARDs.

• Unlike the NSAIDs, DMARDs can reduce or prevent joint damage and preserve joint integrity and function. DMARDs carry the risk of various toxicities, and they must be monitored on a regular basis.

Osteoarthritis

• OA is the most common form of arthritis in the United States.

• Joint stiffness, a common complaint in osteoarthritis, differs from that in RA because it is relatively short in duration and resolves with movement.

• Unlike RA, pain relief is the primary treatment goal in OA. The initial drug of choice is acetaminophen.

Gout

• Gout, a systemic disease caused by the buildup of uric acid in the joints, causes inflammation, swelling, and pain.

• Primary gout is a result of an innate defect in purine metabolism or uric acid excretion.

• Patients with gout are classified as overproducers or underexcreters on the basis of 24-hour uric acid concentration levels.

• Treatment of an acute gouty arthritis attack involves the use of colchicine, NSAIDs, or glucocorticoids.

• Uricosuric agents, xanthine oxidase inhibitors, or both are used to prevent further gout attacks. These agents should not be used during an acute gouty arthritis attack.

Systemic Lupus Erythematosus

• SLE is a chronic autoimmune inflammatory disorder that can affect any system in the body.

• Therapy for SLE is primarily driven by the clinical manifestations of the disease.

22-6. Questions

1.

A 45-year-old man presents to his local physician with a complaint of extreme stiffness in the morning that lasts until noon on most days for the past 2 months. He also states that he feels "drained" all the time and that both of his knees are swollen and painful. On examining the patient, the physician documents the presence of rheumatoid nodules. The patient's laboratory workup is significant for thrombocytopenia and a positive rheumatoid factor. He states that he has been taking over-the-counter ibuprofen at a dose of 200 mg two or three times daily without relief. Which of the following represents the best drug therapy option for this patient?

A. Increase the dose of ibuprofen to 800 mg three times daily.

B. Increase the dose of ibuprofen and add methotrexate 25 mg twice daily.

C. Increase the dose of ibuprofen and add celecoxib 100 mg twice daily.

D. Increase the dose of ibuprofen and add leflunomide at a dose of 100 mg daily for 3 days, followed by 20 mg daily.

 

2.

Which of the following represents the best way to decrease potential liver toxicity with methotrexate while achieving optimal therapeutic benefit?

A. Add 1-3 mg of folic acid per day to the patient's regimen.

B. Decrease the dose of methotrexate to 25 mg once monthly.

C. Add monthly injections of leucovorin to the patient's regimen.

D. Add leflunomide to the patient's regimen.

 

3.

Because combination DMARD therapy may be more efficacious in the refractory RA population, which of the following represents the best choice for combination therapy?

A. Arava 20 mg once daily + Rheumatrex 25 mg once weekly

B. Remicade 3 mg/kg IM + Rheumatrex 25 mg once weekly

C. Myochrysine IM + Plaquenil 200 mg twice daily

D. Remicade 3 mg/kg IV + Rheumatrex 25 mg once weekly

 

4.

A physician inquires about the recommended monitoring parameters for patients started on Ridaura. Which of the following represents the most appropriate response?

A. Baseline ophthalmologic exam, CBC, and serum creatinine, followed by a yearly CBC, serum creatinine, and ophthalmologic exam

B. Baseline liver function tests, CBC, and albumin, followed by monthly liver function tests

C. Baseline CBC, serum creatinine, and urine dipstick for protein, followed by a CBC and urine dipstick for protein every 1-2 months

D. No recommended monitoring parameters at this time

 

5.

All of the following represent methods used to decrease the GI toxicity associated with NSAIDs except

A. changing patients from a nonselective cyclooxygenase inhibitor to a type II-specific inhibitor such as Celebrex.

B. adding a proton pump inhibitor such as Prevacid to the patient's NSAID.

C. adding Cytotec to the patient's NSAID.

D. instructing the patient to take his or her NSAID at night, when acid secretion is limited.

 

6.

Which of the following is (are) true concerning diclofenac?

I. It is available as an extended-release product, Voltaren XR.

II. It is available as an injectable product, Voltaren IM.

III. It is available in combination with misoprostol, Arthrotec.

A. I only

B. I and II only

C. I, II, and III

D. I and III only

 

7.

Which of the following would be a contraindication for the use of Enbrel?

A. Renal insufficiency

B. Active infection

C. Patient over the age of 65

D. Patient with class I or II congestive heart failure

 

8.

Regarding the biologic DMARDs, the following statements are correct except

A. Kineret is packaged as a single-use prefilled syringe that should be kept in the refrigerator.

B. patients should have a tuberculin skin test completed before initiation.

C. it is acceptable to use FluMist for influenza prevention.

D. patients receiving therapy are at increased risk for opportunistic infections.

 

9.

The use of glucocorticoids is associated with numerous adverse effects and long-term consequences. All of the following are initiatives to treat, prevent, or minimize these adverse effects except

A. instructing patients to take the glucocorticoid once daily instead of dividing the total daily dose into two to four doses.

B. instructing patients on long-term therapy to add 1,500 mg of elemental calcium and 400-800 IU of ergocalciferol to their regimen.

C. suggesting adding a bisphosphonate to their therapy.

D. informing patients that stopping glucocorticoid abruptly is contraindicated.

 

10.

A young lady enters your pharmacy and informs you that she plans on becoming pregnant and would like you to review her medication profile to see if any would be potentially harmful. On reviewing her profile, you notice that she is taking Arava for RA. Which is the most appropriate response?

A. Arava is a category C drug and could potentially harm the fetus. She should discuss the risks and benefits of becoming pregnant with her physician first.

B. Arava is a category X drug, and she should undergo the drug elimination procedure with cholestyramine before trying to become pregnant.

C. Arava is a category X drug with no active metabolites and a short half-life; therefore, she should discontinue the drug and wait 1-2 weeks before trying to become pregnant.

D. Arava is a category B drug, and the risk of toxicity to the fetus is extremely low.

 

11.

R. Y. is a 67-year-old man with chief complaints of a swollen big left toe and extreme pain. The area is erythematous and tender. Laboratory analysis reveals a uric acid level of 10 mg/dL. Review of R. Y.'s past medical history reveals hypertension and congestive heart failure. A diagnosis of gout is made. Which is the best choice for the treatment of R. Y.'s acute gouty arthritis attack?

A. Probenecid 500 mg now, followed by 500 mg twice daily

B. Indomethacin 50 mg now, followed by 50 mg three to four times daily

C. Allopurinol 100 mg once daily

D. Colchicine 1.2 mg followed by 0.6 mg in 1 hour if symptoms persist

 

12.

The following symptoms are consistent with the diagnosis of gout except

A. the presence of negatively birefringent crystals in the affected synovial joint fluid.

B. the presence of calcium pyrophosphate in the affected synovial joint fluid.

C. the presence of tophi.

D. the presence of hyperuricemia.

 

13.

Which of the following best describes Benemid?

A. Like allopurinol, it decreases the body's production of uric acid.

B. Like Anturane, it is a uricosuric agent that aids in the tubular reabsorption of uric acid.

C. It blocks the excretion of uric acid in the urine.

D. Like Anturane, it is a uricosuric agent that blocks reuptake of uric acid at the proximal convoluted tubule.

 

14.

Which of the following represents a therapeutically ineffective combination that should be avoided?

A. Benemid + penicillin G

B. Benemid + cephalexin

C. Anturane + Macrobid

D. Benemid + colchicine

 

15.

All of the following statements are true regarding Zyloprim except

A. it works to decrease the formation of uric acid by inhibiting xanthine oxidase.

B. it does not require dosage adjustment in patients with renal insufficiency.

C. skin reactions, including Stevens-Johnson syndrome, have been reported with its use.

D. it should not be used for the treatment of an acute gouty arthritis attack.

 

16.

Which of the following represent potentially dangerous drug interactions with Zyloprim?

I. Amoxicillin

II. Imuran

III. Essidrex

A. I only

B. I and II only

C. I, II, and III

D. III only

 

17.

All of the following are consistent with the diagnosis of osteoarthritis except

A. the presence of morning stiffness that is not associated with immobility and may last for several hours.

B. a common initial finding of pain that typically worsens with weight-bearing activity and subsides with rest.

C. it commonly occurs in the knees or the hips.

D. crepitus is common.

 

18.

Which of the following medication combinations is (are) contraindicated?

I. Tylenol + Ultram

II. Glucosamine sulfate and chondroitin

III. Ultram + Parnate

A. All of the above

B. II only

C. III only

D. I and II only

 

19.

Concerning treatment of osteoarthritis, which of the following statements is incorrect?

A. Tylenol is generally considered the initial drug of choice.

B. Tylenol is considered safe and effective, and it has minimal adverse effects, especially in doses greater than 4 g per day.

C. Muscle-strengthening exercises may be helpful.

D. Hyaluronic acid derivatives have been approved by the FDA for the treatment of pain associated with osteoarthritis.

 

20.

The following medications are considered to be DMARDs except

A. Plaquenil.

B. Cuprimine.

C. Myochrysine.

D. Nalfon.

 

22-7. Answers

1.

D. Although the patient currently has room to increase his dose of the NSAID, he would benefit from the addition of a DMARD. This patient has a disease duration of less than 6 months with moderate disease and poor prognostic factors. Methotrexate represents a viable option; however, the dose of 25 mg twice daily is excessive (it should be dosed once weekly). The addition of leflunomide is the best choice.

 

2.

A. The addition of folic acid to the methotrexate regimen has been demonstrated to reduce the risk of liver toxicity. Lowering the dose of methotrexate is likely to decrease risk but is also likely to decrease its effectiveness. Leucovorin, an injectable formulation of folate, is used only to reverse methotrexate toxicity.

 

3.

D. Arava plus methotrexate (Rheumatrex) may be a very efficacious combination, but it increases the risk of liver toxicity significantly. Gold therapy in combination with Plaquenil increases the risk of rash. Remicade, approved only for use in combination with Rheumatrex, is given IV and not IM; this combination represents the best choice.

 

4.

C. Gold therapy is associated with glomerulonephritis, thrombocytopenia, and leukopenia; therefore, a baseline renal evaluation and periodic testing should occur during the entire course of therapy.

 

5.

D. Adding a proton pump inhibitor, adding Cytotec, or changing to a selective COX-II inhibitor has been demonstrated to lower the risk of significant GI adverse effects. Timing of the dose of an NSAID has never been demonstrated to affect the risk of GI toxicity.

 

6.

D. Diclofenac is available as an immediate-release product, an extended-release product, and in combination with misoprostol. It is not available in an injectable formulation.

 

7.

B. Because of its effects on tumor necrosis factor, Enbrel may decrease a patient's ability to fight infection. Enbrel is contraindicated in patients with an active infection. Its use should be temporarily discontinued until the acute process has resolved.

 

8.

C. FluMist is a live weakened flu vaccine. Live vaccines are contraindicated in patients receiving biologic DMARDs.

 

9.

A. Patients taking glucocorticoids are at risk of developing osteoporosis. Efforts to minimize this adverse effect include the addition of calcium and vitamin D to the patient's regimen as well as adding a bisphosphonate (e.g., Fosamax) to suppress bone resorption. Because of adrenal suppression that occurs with long-term glucocorticoid therapy, patients should taper off the agent.

 

10.

B. Because Arava is a teratogenic agent with an active metabolite with a long half-life, a drug elimination procedure should be performed before becoming pregnant.

 

11.

D. Both probenecid and allopurinol may exacerbate an acute gouty arthritis attack and should be reserved for the prevention of further attacks only. Indomethacin is an option for the treatment of an acute gouty arthritis attack; however, because of NSAIDs' tendency to cause fluid retention in the renal tubules, it would not be the ideal agent in a patient with congestive heart failure. Colchicine represents the best option from this list.

 

12.

B. The presence of calcium pyrophosphate is consistent with the diagnosis of pseudogout, not gout.

 

13.

D. Benemid is a uricosuric agent that blocks reuptake of uric acid at the proximal convoluted tubule. It does not affect the body's ability to produce uric acid. Answer B is incorrect because Benemid does not promote the reabsorption of uric acid.

 

14.

C. Benemid does prevent the tubular secretion of penicillin and cephalexin. However, these interactions are used therapeutically to increase the duration of action of a single dose. The combination of Benemid and colchicine (marketed under the trade name Colbenemid) has been used therapeutically to prevent the manifestation of an acute gouty arthritis attack. Finally, a combination of Anturane and Macrobid will inhibit Macrobid from reaching its site of action, thus diminishing its therapeutic efficacy.

 

15.

B. Zyloprim must be adjusted in patients with renal insufficiency. Its use has been associated with serious skin reactions that may occur at any point during therapy. Zyloprim should never be used in the treatment of an acute gouty arthritis attack.

 

16.

B. The coadministration of amoxicillin and allopurinol increases the risk of rash up to 20%. Imuran is metabolized via xanthine oxidase, whose activity is inhibited by allopurinol, thus increasing the risk of toxicity associated with Imuran. Although Essidrex may increase uric acid levels, there is no direct drug-drug interaction associated with allopurinol.

 

17.

A. The morning stiffness associated with osteoarthritis is usually of short duration, is associated with periods of inactivity, and resolves with movement.

 

18.

C. Tylenol + Ultram is marketed therapeutically as Ultracet. Glucosamine sulfate with or without chondroitin is recommended as an alternative therapy in the treatment of osteoarthritis. The combination of Ultram and Parnate, a monoamine oxidase inhibitor, is contraindicated because of the risk of serotonin syndrome.

 

19.

B. Tylenol is generally considered to be safe and effective; however, its use is associated with hepatic failure and the rare incidence of renal failure. Patients should be advised to take less than 4 g per day to limit the risk of hepatic failure.

 

20.

D. Nalfon, also known as fenoprofen, is an NSAID, not a DMARD.

 

22-8. References

Rheumatoid Arthritis

American College of Rheumatology. Recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59:762-84.

Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Am J Gastroenterol. 2008; 103:2890-907.

Boyce EG. Rheumatoid arthritis. In: Helms RA, Quan DJ, Herfindal ET, et al., eds. Textbook of Therapeutics: Drugs and Disease Management. 8th ed. Baltimore: Lippincott Williams & Wilkins; 2006:1705-36.

Goekoop YP, Allaart CF, Breedveld FC, et al. Combination therapy in rheumatoid arthritis. Curr Opin Rheumatol. 2001;30:249-54.

Kremer JM. Rational use of new and existing disease-modifying agents in rheumatoid arthritis. Ann Intern Med. 2001;134:695-706.

Kwoh CK, Anderson LG, Greene JM, et al. Guidelines for the management of rheumatoid arthritis. Arthritis Rheum. 2002;46:328-46.

Olsen NJ, Stein CM. New drugs for rheumatoid arthritis. N Engl J Med. 2004;21:2167-79.

Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59:762-84.

Sims RW, Kwoh CK, Anderson LG, et al. Guidelines for monitoring drug therapy in rheumatoid arthritis. Arthritis Rheum. 1996;39:723-31.

Wolfe F, Rehman W, Lane NE, et al. Starting a disease-modifying antirheumatic drug or a biologic agent in rheumatoid arthritis: Standards of practice for RA treatment. J Rheumatol. 2001;28:1704-11.

Osteoarthritis

Altman RD, Hochberg MC, Moskowitz RW, et al. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum. 2000;43:1905-15.

Boh LE. Osteoarthritis. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 4th ed. New York: McGraw-Hill; 1997:1441-59.

Roberts LJ, Morrow JD. Analgesic-antipyretic and anti-inflammatory agents and drugs employed in the treatment of gout. In: Hardman JG, Limbird LE, Gilman AG, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001:687-732.

Small RE. Osteoarthritis. In: Helms RA, Quan DJ, Herfindal ET, et al., eds. Textbook of Therapeutics: Drugs and Disease Management. 8th ed. Baltimore: Lippincott Williams & Wilkins; 2006:1737-52.

Gout

American College of Rheumatology. 2008. Gout. www.rheumatology.org/public/factsheets/diseases_and_conditions/gout.asp.

Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005; 353:2450-61.

Emmerson BT. The management of gout. N Engl J Med. 1996;334:445-51.

Harris M, Bryant LR, Danaher, et al. Effect of low-dose aspirin on serum urate levels and urinary excretion in patients receiving probenecid for gouty arthritis. J Rheumatol. 2000;27:2873-6.

Hawkins DW, Rahn DW. Gout and hyperuricemia. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 4th ed. New York: McGraw-Hill; 1997:1460-5.

McCloskey WW, Kostka-Rokosz MD. Gout and hyperuricemia. In: Helms RA, Quan DJ, Herfindal ET, et al., eds. Textbook of Therapeutics: Drugs and Disease Management. 8th ed. Baltimore: Lippincott Williams & Wilkins; 2006:1753-66.

Terkeltaub RA, Edwards NL, Pratt PW, et al. Gout. In: Klippel JH, Weyand CM, Wortmann RL, eds. Primer on the Rheumatic Diseases. 11th ed. Atlanta: Arthritis Foundation; 1998:230-43.

Systemic Lupus Erythematosus

Burlingame MB, Delafuente JC. Systemic lupus erythematosus. In: Dipiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach. 4th ed. New York: McGraw-Hill; 1997:1378-92.

Krikoria S. Systemic lupus erythematosus. In: Helms RA, Quan DJ, Herfindal ET, et al., eds. Textbook of Therapeutics: Drugs and Disease Management. 8th ed. Baltimore: Lippincott Williams & Wilkins; 2006:1767-87.

Lupus Foundation of America. Lupus. www.lupus.org/.