The ‘Alphabet’ of Rheumatoid Arthritis Treatment

NSAIDs, DMARDs, MTX, COX-2 inhibitors, anti-TNF therapy, IL-I receptor antagonists, and mAbs…these acronyms describe the various drugs used in treating rheumatoid arthritis (RA). A vast array of medications is used to treat RA, from anti-inflammatory to biologic agents. Combinations of different classes of drugs are the most effective treatment modality. Health care providers should be familiar with the classes of commonly prescribed medications for RA – a unique “alphabet’Of pharmacologie treatment.

Pathophysiology of RA

Rheumatoid arthritis is an immune-mediated, chronic inflammatory disease of the joints. Its cause is unknown and it has no cure; treatments can only reduce symptoms and progression of disease. RA affects approximately 1% of the world’s population, with women afflicted three times more often than men (Gabriel, 2001). In the United States, 2 million persons suffer from RA, 75% of whom are women (Arthritis Foundation, 2004a).

Recent research has led to a greater knowledge of the body’s inflammation cascade on a molecular level, and this new understanding of cytokine involvement in inflammation is revolutionizing the treatment of RA. Inflammation in RA most likely begins with a reaction to an inciting antigen. Because it is unknown whether this antigen is endogenous or exogenous, RA is called an autoimmune disease. Specific CD4-T cells initiate an immune response, which attracts leukocytes, macrophages, and fibroblasts to the synovial region of joints. B lymphocytes are also attracted to the site, liberating IgM antibody which can be measured in the serum as rheumatoid factor (RF). Leukocytes and macrophages release pro- inflammatory cytokines and enzymes that cause erosive tissue damage. Complement and other chemotaxins become part of the reaction, and inflammation is amplified and perpetuated (Olsen & Stein, 2004). Tumor necrosis factor alpha (TNF) and interleukin-1 (IL-I) are specific cytokines which perpetuate the inflammation cascade in RA. They are currently the focus of intense pharmacologie research.

Diagnosis of RA

The diagnosis of RA is based on several clinical criteria and laboratory tests. Clinical criteria include the presence of morning stiffness of the joints, polyarthritis which includes hand joints, symmetrical arthritis, and subcutaneous rheumatoid nodules for a minimum of 6 weeks (American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines, 2002). In the hands, characteristic involvement includes the metacarpal and proximal interphalangeal joints, with sparing of the distal interphalangeal joints of the fingers. The patient may also suffer systemic symptoms which include fever, fatigue, malaise, anorexia, and weight loss (American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines, 2002). Major diagnostic evidence includes elevated serum RF, erythrocyte sedimentation rate, and C-reactive protein, as well as radiologie evidence of joint changes (American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines, 2002). However, the serum RF assay may be negative in up to 30% of patients, making diagnosis difficult (Genovese & Davis, 2001).

Early diagnosis of RA is critical because therapy is most effective when begun in the disease’s initial stages. Initiation of therapy within the first 3 months of the appearance of symptoms is crucial to prevent joint damage (Emery & Seto, 2003; Genovese & Davis, 2001, O’Dell, 2004). At the time of diagnosis, 30% of patients have radiologie evidence of joint erosion; 60% have joint damage by 2 years (van der Heijde, 1995). However, early diagnosis of RA is challenging because initial signs and symptoms of many other syndromes can mimic RA. Initially, the presentation of RA can be indistinguishable from other inflammatory arthropathies, viral syndromes, fibromyalgia, polymyalgia rheumatica, and other autoimmune diseases.

Figure 1.

Cyclooxygenase Pathways in Inflammation and Sites of Drug Action

Treatment of RA

Because there is no cure for RA, current treatment modalities focus on reducing pain, inducing remission, and increasing functional abilities of patients. Experts agree that early initiation of treatment can slow progression of the disease most effectively (Emery & Seto, 2003; Genovese & Davis, 2001; O’Dell, 2004). Three main classes of medications are used to treat RA:

1. Nonsteroidal antiinflammatory drugs (NSAIDs)

* Nonselective NSAIDs

* Selective NSAIDs

2. Disease-modifying antirheumatic drugs (DMARDs)

* Synthetic DMARDs

* Biologie DMARDs

3. Corticosteroids (steroids)

NSAIDS

Nonselective NSAIDs. Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are usually the first class of drugs prescribed for joint pain and stiffness until a definitive diagnosis of RA is made. Although somewhat effective for relieving the symptoms of RA, these do not slow progression of the disease. The nonselective, prototypical NSAID is ibuprofen (Motrin, Advil), which is available as an over-the-counter (OTC) medication. However, the OTC dosage is usually too weak to provide relief of the joint symptoms of RA. Naproxen (Aleve) is another nonselective NSAID available as an OTC medication of weak strength. Prescription NSAIDs include indomethacin (Indocin), naproxen (Anaprox, Naprosyn, Naprelan), ketoprofen (Oruvail), nabumetone (ReIafen), flurbiprofen (Ansaid), diclofenac (Arthrotec, Cataflam, Voltaren), etodolac (Lodine), meloxicam (Mobic), sulindac (Clinoril), oxaprozin (Daypro), and piroxicam (Feldene).

Nonselective NSAIDs inhibit the two cyclooxygenase (COX) pathways which produce prostaglandins in the inflammation cascade. These NSAlDs are called “nonselective” because they inhibit both the COX- 1 and COX-2 enzymes in the two cyclooxygenase pathways (see Figure 1). Prostaglandins produced via the COX-1 enzymatic pathway enable the stomach to produce mucous, which protects the gastric mucosa, and also enhance renal perfusion. Prostaglandins produced via the COX-2 enzymatic pathway cause pain, edema, and inflammation. Nonselective NSAIDs therefore block the formation of prostaglandins that cause inflammation as well as the prostaglandins which protect the stomach lining. The inhibition of the COX-1 pathway is the reason for the common adverse gastrointestinal effects of the nonselective NSAIDs: esophagitis, gastritis, and gastroduodenal ulceration. Each year 1.5% of patients with RA are hospitalized with gastrointestinal conditions related to NSAID use (Singh, 1998). Misoprostol (Cytotec) is a prostaglanclin analogue which can be used along with nonselective NSAIDs to protect the gastric mucosa. However, this drug can stimulate uterine contractions and is contraindicated in pregnant women, nursing mothers, and women planning pregnancy (Medical Economics, 2004; Silverstein et al., 1995). Alternatively, proton pump inhibitors such as omeprazole (Prilosec), lansoprazole (Prevacid), pantoprazole (Protonix), or rabeprazole (Aciphex) can be used along with nonselective NSAIDs to prevent gastric ulceration. Long-term use of nonselective NSAIDs can also cause renal impairment clue to the inhibition of the COX-1 enzymatic pathway (Medical Economics, 2004) (see Figure 1).

Selective NSAIDs: COX-2 inhibitors. COX-2 inhibitors are NSAIDs which selectively block the cyclooxygenase-2 enzymatic pathway in the inflammation cascade. In therapeutic doses, these medications block the pain, edema, and other negative consequences of inflammation without blocking the COX-1 pathway (see Figure 1). The COX-2 inhibitors, therefore do not inhibit stomach mucous production and should not cause gastrointestinal irritation. In high doses, however, these medications can exert inhibitory effects on the COX- 1 pathway and have the same side effects as nonselective NSAIDs. Celecoxib (Celebrex) and rofecoxib (Vioxx) are COX-2 inhibitors which have been marketed widely, directly to the public through the media when the safety of rofecoxib was questioned. In late 2004, the drug was withdrawn from the market by the parent company Merck Pharmaceuticals (2004). A 3-year multicenter clinical trial of rofecoxib use for treating adenomatous colon polyps was halted when the study revealed that participants endured an increased risk of cardiovascular events when using 25 mg of rofecoxib compared to placebo. The results of this clinical study do not necessarily apply to other COX-2 inhibitors; however, further study is warranted (U.S. Food and Drug Administration, 2004).

COX-2 inhibitors can reduce the pain and inflammation of RA but cannot prevent progression of the disease. The efficacy of these medications has not been found to surpass older, nonselective NSAIDs in RA treatment (Fitzgerald & Patrono, 2001). Reduced gastrointestinal side effects are the main advantage of COX-2 inhibitors over older NSAIDs. Celecoxib can be taken as 100 mg to 200 mg doses twice a day in RA. Another COX-2 inhibitor, valdecoxib (Bextra), is prescribed in 10 mg to 20 mg once-daily doses (Medical Economics, 2004). The newest addition to this class of drugs to be released is etoricoxib (Arcoxia). As with nonselective NSAIDs, COX- 2 inhibitors are often administered with proton pump inhibitors to diminish risk of gastrointestinal ulceration. COX-2 inhibitors are most effective when used in combination with the class of RA drugs known as disease-modifying anti-rheumatic drugs (DMARDs) (American College of Rheumatol\ogy Subcommittee on Rheumatoid Arthritis Guidelines, 2002).

Synthetic DMARDs

Methotrexate (MTX). The DMARDs include the widest array of medications for RA. DMARDs are subdivided into synthetic and biologic agents. They can diminish the progression of disease and at least one-third of patients with RA are on a combination of drugs which include DMARDs (Mikuls &O’Dell, 2000). Establishing a diagnosis as early as possible and then starting the patient on combination DMARD therapy is the foundation of treatment of patients with RA (O’Dell, 2004). Most rheumatologists select methotrexate (MTX) (Rheumatrex Dose Pack) as the initial DMARD for most patients. Many experts regard MTX as the cornerstone of therapy, and the medication most likely to induce a long-term response in patients with RA (O’Dell, 2004). Methotrexate is a synthetic DMARD started at a dose of 7.5 mg to 15 mg orally once a week in tablet or liquid form. This dose can be increased by increments of 5 mg each month, to a total of 20 mg to 30 mg per week if active disease persists. Alternatively, MTX can be administered subcutaneously or intramuscularly if the desired effect is not achieved orally (O’Dell, 2004). Other DMARDs can be added to the regimen if active disease does not remit. MTX has potent immunosuppressant and anti- inflammatory effects. MTX inhibits the synthesis of purines, which are needed to make DNA. Activated lymphocytes also require synthesis of purines to proliferate. Activated lymphocytes are the key constituents of the inflammatory cycle that perpetuate the joint injury in RA. Because MTX specifically interferes with folic acid (part of purine synthesis), folate supplementation of 1 mg to 3 mg/ day is necessary when MTX is used (Medical Economics, 2004). Although the drug is well-tolerated by most patients, bone marrow suppression, hepatotoxicity, pulmonary fibrosis, and pneumonitis are potential side effects of MTX. Patients with renal insufficiency can experience toxic blood levels of MTX. Vigilant monitoring of liver function, serum creatinine, complete blood counts, platelet counts, and periodic chest x-rays are recommended. Women of childbearing age must be cautioned that MTX can cause fetal defects, and they should use reliable contraceptive methods. Abstinence from alcohol is recommended due to higher potential for liver impairment. Also, because MTX is an immunosuppressant, the patient has heightened susceptibility to infection (Fye, 1999; O’Dell, 2004).

Leflunomide (Arava). Leflunomide inhibits a key enzyme in pyrimidine synthesis. Pyrimidines and purines are building blocks of DNA. Activated proliferating lymphocytes require constant synthesis of DNA, and leflunomide inhibits this process. This drug therefore acts as an immunosuppressant by blocking the formation of the lymphocytes that liberate damaging inflammatory mediators in RA (Fye, 1999). The combination of leflunomide (which blocks pyrimidines) with MTX (which blocks purine synthesis) exerts a synergistic effect on inhibiting DNA synthesis. Leflunomide is recommended in patients who cannot tolerate MTX. Leflunomide reduces inflammation and erosive joint damage within a short term of therapy. Typically, patients show a therapeutic response within days to 1 month. The recommended dosing schedule is an oral loading dose of 100 mg for 3 days with a maintenance dose of 20 mg/day begun on day 4 (Fye, 1999). A recent study demonstrated that, when compared to placebo, leflunomide slowed progression of joint damage as measured radiologically over a period of 6 to 12 months. After 2 years, more than 80% of the subjects had no new erosions (Cohen et al., 2001).

Leflunomide has a long halflife; it can take up to 2 years for this drug to be eliminated from the plasma. Because it is largely excreted by the liver, hepatotoxicity is a significant potential adverse effect. Therefore, persons with history of alcohol abuse or hepatitis should not be treated with leflunomide. Persons on the combination of MTX and leflunomide also have higher risk of hepatotoxicity. Other side effects which have been reported include weight loss, diarrhea, hypertension, and reversible alopecia (Medical Economics, 2004).

Because this drug can also cause fetal death or defects, women of childbearing potential must be counseled about contraception. Discontinuing treatment long before conception is necessary because of leflunomide’s prolonged half-life. The drug is also contraindicated in nursing mothers. If pregnancy develops during treatment, a protocol of oral cholestyramine (Questran) 8 mg three times a day for 11 days is recommended to hasten elimination of the drug (Fye, 1999; Olsen & Stein, 2004). Cholestyramine binds the active metabolite of leflunomide in the gastrointestinal tract, preventing entry into the enterohepatic circulation. This protocol also should be followed by hypersensitive individuals and by male patients who wish to father a child. Plasma levels need to diminish to less than 0.2 mg/L by two separate tests at least 14 days apart (Olsen & Stein, 2004). While a patient is taking leflunomide, vigilant monitoring of liver function, CBC, platelet count, serum creatinine, and blood pressure is necessary. A pregnancy test is needed to exclude the possibility of pregnancy in female patients (Medical Economics, 2004).

Biologic DMARDs

TNF-alpha antagonists. Tumor necrosis factor-alpha (TNF-alpha) is a natural occurring cytokine which is released by activated monocytes, macrophages, and lymphocytes in the normal inflammation reaction of the body (Choy & Panayi, 2001) (see Figure 2). Patients with RA have high levels of TNF-alpha in the synovial fluid, and this is associated with erosion of bone. Numerous studies show that blocking the action of TNF-alpha significantly ameliorates the damaging effects of RA (Chu, Field, Feldmann, & Maini, 1991; Elliot et al., 1994). Inhibiting the effects of TNF is achieved by drugs which block TNF itself or the TNF receptor on cell surfaces. Available TNF-blocking drugs include etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira).

Etanercept. Etanercept is a biologic DMARD which blocks TNF receptors on cell surfaces. Etanercept is administered as a subcutaneous injection of 25 mg twice a week or 50 mg once weekly (Keystone et al., 2004). The patient can administer this subcutaneous injection independently after appropriate education. A clinical response has been apparent within 1 to 2 weeks after initiation of therapy and by 3 months in most patients (Keystone et al., 2004a). Investigations have demonstrated that compared to placebo, etanercept arrests progression of disease significantly. In comparison studies with MTX, etanercept showed patients achieved a more rapid response within the first 2 weeks of therapy. Although patients on MTX took more time to report significant benefits, both drugs showed similar therapeutic effects after 12 months (Korth- Braclley, Rubin, Hanna, Simcoe, & Lebsack, 2000; Moreland et al, 1999; Weinblatt et al., 1999). Studies also indicate that patients with an inadequate response to MTX receive benefits when etanercept is added to their regimen (Olsen & Stein, 2004).

Because TNF is a component of the body’s natural inflammatory reaction and defense against infection, there is an increased risk of infection with use of etanercept. This drug is not recommended, therefore, for patients with active or chronic infection, or underlying conditions such as diabetes mellitus. In clinical studies, the most common type of infection which developed among subjects was an upper-respiratory infection (Hamilton, 2004; Khanna, McMahon, & Furst, 2004). Patients who develop infection should discontinue the drug and persons should not receive live vaccines while taking this drug (Medical Economics, 2004). It is not known whether this drug is safe in pregnancy or nursing mothers. It has demonstrated therapeutic effects in children over 4 years old with juvenile rheumatoid arthritis. Children treated with etanercept should have their immunizations up to date and avoid exposure to varicella (Medical Economics, 2004).

Figure 2.

Joint Inflammatory Mediators and Drug Action in RA

Infliximab. Infliximab is a monoclonal antibody (mAb) which directly binds to TNFalpha. This biologic DMARD is a genetically engineered IgG antibody synthesized from mouse (murine) and human antibody components. The resultant mAb, infliximab, attaches to TNF and impairs its ability to bind to receptors on cell surfaces. This mAb also incites cytotoxic reactions which directly kill the inflammatory cells that express TNF (Chu et al., 1991; Elliot et al., 1994; Williams, Feldmann, & Maini, 1992).

Infliximab has shown clinical efficacy in RA and Crohn’s disease (Medical Economics, 2005). In RA, clinical studies have focused on the efficacy of a combination of infliximab and MTX (Lipsky et al., 2000). Monotherapy with infliximab was superior to placebo; however, singular therapy frequently stimulated development of anti- infliximab antibodies in research subjects. Subsequent studies showed decreased development of this side effect when infliximab was used in combination with MTX (Lipsky et al, 2000; Maini et al., 1998). Investigations showed that a regimen of infliximab at a dose of 3 mg to 10 mg/kg every 4 or 8 weeks combined with methotrexate resulted in superior therapeutic benefits than MTX alone in RA (St. Clair et al., 2002). Improvement in signs and symptoms of RA can be obtained within 2 weeks of initiating this combination of drugs.

The recommended dose of infliximab is 3 mg/kg given as an intravenous infusion over at least 2 to 3 hours followed by similar doses at 2 and 6 weeks, then every 8 weeks thereafter. Infliximab should be given with MTX. For patients who do not respond, the dosage can be increased up to 10 mg/kg as often as every 4 weeks (Lipsky et al., 2000). An acute infusion reaction of nausea, flushi\ng, dyspnea, fever, chills, and rash can occur in some patients during the infusion or within 1 to 2 hours of treatment (Khana et al., 2004). Slowing the infusion rate and administering antihistamines can ameliorate these symptoms. Patients who develop anti-infliximab antibodies are most susceptible to sustaining an infusion reaction (Khana et al., 2004). In general, anaphylactic reactions are uncommon. However, acetaminophen (Tylenol), antihistamines, epinephrine, and corticosteroids should be readily available during infusion (Medical Economics, 2004).

Infliximab is contraindicated in patients with heart failure (FDA Center for Drug Evaluation and Research, Arthritis Advisory Committee, 2003). The drug has not been investigated thoroughly for use in pregnant or nursing women. Safety in children also has not been established. Patients are susceptible to infection due to the immunosuppressant effects of infliximab. cases of tuberculosis, histoplasmosis, listeriosis, and pneumocystis pneumonia have been reported in persons on infliximab and other immunosuppressive drugs. It has been proposed that cases of tuberculosis (TB) arise primarily in patients with latent TB infection. Therefore, this drug is contraindicated in patients with a history of TB and all candidates for infliximab treatment should be screened for TB (Furst, Cush, Kaufmann, Siegel, & Kurth, 2002). Upper-respiratory infection is the most commonly reported infection associated with infliximab (Hamilton, 2004). Any serious infection is cause for discontinuation of the drug; persons receiving this drug should not be given live vaccines. This drug should not be used in patients with demyelinating disease. Exacerbations of previously quiescent multiple sclerosis in some patients have been reported (FDA Center for Drug Evaluation and Research, Arthritis Advisory Committee, 2003; Medical Economics, 2004).

A recent investigation revealed that patients taking infliximab had a 3 times greater incidence of lymphoma than the general public (FDA Medwatch, 2004) Centocor, a Johnson & Johnson subsidiary, recently announced label revisions to reflect this lymphoma risk. These label warnings will be applied to the other TNF antagonists, etanercept (Enbrel) (Wyeth and Amgen Pharmaceuticals) and adalumib (Humira) (Abbot Laboratories), as well.

Adalimumab. Adalimumab is another mAb which directly binds to the cytokine TNF-alpha. This genetically engineered IgG antibody is constructed using solely human antibody components. Like infliximab, this biologic DMARD attaches to TNF and impairs its ability to bind to receptors on cell surfaces. It also incites cytotoxic reactions which directly lyse inflammatory cells that express TNF (Emery, 2003; Maini et al., 1998; Neidel, Schulze, & Lindschau, 1995). Adalimumab is administered subcutaneously and absorbed slowly, reaching peak levels after 130 hours. The standard dose is 40 mg every other week, and the drug can be used alone or in combination with other DMARDs such as MTX (Bang & Keating, 2004; Emery, 2003). Adalimumab has been well tolerated by subjects of clinical studies; however, it does increase risk for infection. Tuberculosis has been reported less frequently in patients using adalimumab as compared to infliximab (Hamilton, 2004). Skin reactions, such as redness and itching at the site of injection, are common (Bang & Keating, 2004). As with other antiTNF agents, this drug should not be used in patients with heart failure, demyelinating disease, or active or chronic infection. Safety in pregnant women and children has not been established. Live vaccines are contraindicated with all TNF antagonists (Olsen & Stein, 2004).

Co-Stimulatory Blockers

Abatacept. Abatacept (CTLA 4Ig) is the first in a new class of biologic DMARDs known as costimulatory or second-signal blockers. These agents work by a different mechanism than TNF inhibition. Abatacept is an engineered monoclonal antibody which inhibits the stimulation of antigen-presenting cells in the activation of T lymphocytes. Clinical trials have shown abatacept’s efficacy in patients with RA who are nonresponsive to TNF blockade (Keystone et al., 2004b). A recent trial of 234 patients with RA showed a therapeutic response after administration of a 10 mg/kg dose of IV abatacept every 2 weeks for 12 months in combination with methotrexate (Keystone et al., 2004b). Diminished inflammation and symptom reduction were reported by 51% of patients at 12 months. The combination treatment was most effective when given early in the course of disease. Adverse effects included upper-respiratory infection, gastrointestinal symptoms, rash, and dizziness in less than 2% of patients (Jancin, 2004; Keystone et al., 2004b).

Interleukin Antagonists

Anakinra (Kineref). lnterleukin-1, produced by monocytes and macrophages, is a pro-inflammatory cytokine which contributes to the erosive damage of joints in RA. The body also produces a natural interleukin-1 antagonist to dampen the inflammatory stimulus of this cytokine (Bresnihan & Cunane, 1998). In RA, studies show that there is an imbalance between the pro-inflammatory interleukin-1 cytokine and its natural antagonist which leads to the persistence of inflammation (Bresnihan & Cunane, 1998). Anakinra, a biologic DMARD, is a genetically engineered interleukin-1 antagonist. It blocks cellular receptors of interleukin-1 and thereby diminishes the inflammation of RA. This DMARD is metabolized rapidly and excreted by the kidney. Its short half-life requires daily dosing and it is administered as 100 mg subcutaneously once a day (Campion, Lebsack, Lookabaugh, Gordon, & Catalano, 1996). Anakinra alone or in combination with MTX has been more effective than placebo in multiple clinical studies (Cohen et al., 2002; Fleischman et al., 2003).

Anakinra should not be used in combination with TNF antagonists because this combination increases risk of serious infection. There is less risk of serious infection when anakinra is used as indicated; however, monitoring of the patient’s CBC and platelet count is recommended because neutropenia and thrombocytopenia have occurred in a small number of patients (Keystone et al., 2004b). This drug has not been sufficiently tested in children, or pregnant or nursing women. Injection site reactions, headache, and gastrointestinal upset have been reported as side effects. Patients with active or chronic infections should not receive this drug, and live vaccines should not be administered concurrently (Prescribing Reference, 2004).

Drug Under Investigation

Rituximab (Rituxan). Rituximab is another monoclonal antibody, genetically engineered using mouse (murine) and human components. This mAb targets specific surface antigens on circulating B lymphocytes. B lymphocytes are participants in the inflammatory process of RA that synthesize the IgM antibodies measured as rheumatoid factor. Rituximab has been used in treating lymphoma and is under investigation for treating RA (Arthritis Foundation, 2004b). A recent multicenter investigation studied the effect of rituximab monotherapy and combination therapy in patients with severe RA (Arthritis Foundation, 2004b). Rituximab in combination with MTX and rituximab with cyclophosphamide were combination therapies compared to MTX and rituximab alone. Patients showed marked improvement in symptoms when given a single course of two infusions of rituximab alone or in combination with either cyclophosphamide or MTX. Patients in this study endured profound and prolonged peripheral B lymphocyte depletion, with some suffering severe infection. Investigators confirmed that the role of rituximab in RA therapy shows promise but warrants further research (Arthritis Foundation, 2004b).

Nursing Implications of RA Drug Therapy

Currently most patients with RA are on MTX in combination with a biologic DMARD. Generally, these drugs aim to suppress cells and mediators in the inflammation cascade. Some of the DMARDs inhibit purines or pyrimidines, building blocks in DNA synthesis. This inhibition in turn blocks proliferating lymphocytes involved in the RA joint erosion but also inhibits other white blood cells in the body.

It is important for the nurse to recognize that suppression of the inflammation defenses diminish the infection-fighting ability of the body as a side effect. There is no cure for RA and immunosuppression is the major pharmacologie strategy used to slow the progression of the joint pathology. However, this is not without significant risk.

Upper respiratory infection is the most commonly reported side effect in patients on DMARDs due to immunosuppression. These drugs are not recommended for patients with active or chronic infection or underlying conditions such as diabetes mellitus, heart failure, or demyelinating disease (Arthritis Foundation, 2004a). Reactivation of latent tuberculosis infection has been reported in patients using DMARDs; therefore, TB testing is necessary in recipients of these drugs. Reactivation of multiple sclerosis has been reported in patients on certain DMARDs as well. Any serious infection is cause for discontinuation of the drug and persons receiving these drugs should not be given live vaccines. Most of the DMARDs are not used in children and are contraindicated in pregnancy and nursing mothers. Site reactions and infusion reactions are possible with all parenterally administered drugs. Acetaminophen, antihistamines, epinephrine, and corticosteroids should be available to treat possible infusion and allergic reactions.

Nurses need to understand dosing, routes of administration, and contraindications of each specific DMARD. These drugs can be administered orally, intramuscularly, intravenously, and subcutaneously. Dosing can be on a daily, once a week, twice a week, twice a month, or monthly. Each drug has specific contraindications and potential side effects.

Selective NSAIDS, known as COX-2 inhibitors, u\sed by patients with RA can cause gastric irritation, ulceration, and renal impairment. Proton pump inhibitors such as omeprazole or lansoprazole can be used along with NSAIDS to prevent gastrointestinal side effects. Rofecoxib should not be used because it has recently been withdrawn from the market due to adverse cardiovascular side effects.

A thorough history is necessary prior to initiating DMARD therapy. Patients need to be assessed for any underlying conditions aside from RA. Such conditions as heart failure, demyelinating disease, diabetes mellitus, liver impairment, renal insufficiency, or chronic infections such as hepatitis or tuberculosis are contraindications to certain RA drugs.

Periodic lab testing is needed in patients taking medications for RA. To monitor the inflammatory effects of RA and progression of disease, providers evaluate the results of lab tests such as C- reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF). Because immunosuppression is the mechanism of many of the drugs, neutropenia, anemia, and thrombocytopenia are potential side effects. This requires periodic monitoring of a CBC with differential and platelet count. Liver function studies are required because hepatotoxicity has been reported with some drugs, particularly MTX. Serum folate levels need to be measured because MTX depletes body stores of folic acid; the patient typically requires supplementation. Serum creatinine measurement is necessary to ensure optimal renal excretion of drug metabolites. Chest x-ray and TB testing are needed prior to administration of immunosuppressive drugs. Periodic pregnancy testing may be necessary, because many of these drugs are teratogenic.

The nurses should understand that the patient with RA has chronic pain and other systemic complications. Fever, fatigue, malaise, anorexia, weight loss, swollen joints, and stiffness can cause significant physical and emotional disability. The nurse can assess the patient’s pain level periodically using various pain scales to gauge treatment efficacy. The patient also needs emotional support and education to learn to live with exacerbations and remissions of RA. In conjunction with counseling provided by the nurse, the patient should be referred to support groups through the Arthritis Foundation. Patient education materials can be obtained from the Arthritis Foundation Web site (www.arthritis.org).

Specific RA drugs require particular nursing interventions. Some drugs are teratogenic and require that the patient use contraception vigilantly to ensure pregnancy does not occur. Counseling of the RA patient of childbearing age about methods of contraception is an important nursing intervention. The DMARD leflunomide can cause fetal defects or fetal death. Both male and female RA patients need to recognize the teratogenic effects of this DMARD, should pregnancy occur.

Abstinence from alcohol is important because hepatoxicity is possible, particularly with MTX. Liver impairment of any kind is a contraindication for MTX. The patient should be screened for hepatitis and have liver enzymes measured periodically.

In summary, treatment goals for the patient with RA include:

* diagnosing the disease process early

* initiating pharmacologie intervention early

* alleviating the patient’s pain and systemic symptoms

* arresting the progression of inflammation and joint destruction

* maximizing the patient’s independent function

* assessing the patient for drug side effects

* minimizing the risks of drug therapy

* providing education and emotional support for the patient The nurse is integral to the achievement of all these goals, particularly in assessing side effects, minimizing risks of drug therapy, and providing patient education, and emotional support.

Conclusion

The nurse can be instrumental in the assessment and relief of the patient’s pain and disability in RA. Early treatment is key in arresting the progression of disease. MTX, NSAIDS, DMARDs, mAbs, anti-TNF alpha agents, and IL-I blockers make up the “alphabet” of different drugs in RA therapy. These agents can enhance the quality of life for the patient with RA, alleviating pain and slowing disease progression.

Immunosuppression is the mechanism of most pharmacologie agents used in RA. This drug mechanism can cause serious side effects for patients. Increased susceptibility to infection, bone marrow suppression, hepatotoxicity, and teratogenicity are among the serious side effects. The nurse can help prevent side effects through vigilant patient assessment and patient education. Health care providers must constantly weigh the risks and benefits of drug therapy in RA. It is imperative that the nurse who treats patients with RA keep abreast of the latest drug safety updates.

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Ten Capriotti, DO, MSN, CRNP, is a Clinical Associate Professor, Villanova University, College of Nursing, Villanova, PA.

Copyright Anthony J. Jannetti, Inc. Dec 2004