Nonsteroidal Anti Inflammatory Drugs

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NSAIDs provide analgesic and anti-inflammatory benefits for joint pain and swelling. However, they do not prevent joint damage or change the underlying disease.1 It is appropriate for a patient to begin taking an NSAID along with a DMARD for "bridge therapy" to provide symptomatic relief until the therapeutic effect of the DMARD is observed. Because of interpatient variability in response, patients may find relief from one NSAID and not another. For this reason, if a patient does not receive relief from one NSAID, it is acceptable to try a second one. Selecting another NSAID depends on multiple patient-specific factors including cardiovascular risk, potential for GI-related adverse events, adherence to medication regimens, and insurance coverage or lack thereof. Clinicians must weigh these factors carefully to determine if the patient will benefit from another NSAID, if he or she should receive a cyclooxygenase-2 (COX-2) inhibitor, or if another medication class should be considered.

FIGURE 57-3. Recommendations for the use of biologic DMARDs in patients who have had RA for less than 6 months. These recommendations do not specifically include the potential role of glucocorticoids or NSAIDs in the management of patients with RA. aSee Ref. 18 for definitions of disease activity. ^Includes functional limitation (defined using standard measurement scales such as HAQ score or variations of this scale), extraarticular disease (e.g., presence of rheumatoid nodules, secondary Sjogren's syndrome, RA vasculitis, Felty's syndrome, and RA lung disease), rheumatoid factor positivity, positive anti-CCP antibodies, or bony erosions by radiography. (DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; TNF, tumor necrosis factor.) (From Ref. 18.)

FIGURE 57-3. Recommendations for the use of biologic DMARDs in patients who have had RA for less than 6 months. These recommendations do not specifically include the potential role of glucocorticoids or NSAIDs in the management of patients with RA. aSee Ref. 18 for definitions of disease activity. ^Includes functional limitation (defined using standard measurement scales such as HAQ score or variations of this scale), extraarticular disease (e.g., presence of rheumatoid nodules, secondary Sjogren's syndrome, RA vasculitis, Felty's syndrome, and RA lung disease), rheumatoid factor positivity, positive anti-CCP antibodies, or bony erosions by radiography. (DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; TNF, tumor necrosis factor.) (From Ref. 18.)

NSAID use is associated with an increased risk of GI ulcers or hemorrhage, fluid retention, exacerbation of existing hypertension, and decreased renal function in certain patient populations.7,1 9 Factors that place a patient at a higher risk of GI-re-lated adverse reactions include: (a) history of peptic ulcer disease, (b) high doses of NSAIDs, (c) concomitant use of other medications with an increased risk of GI hemorrhage or ulcers (e.g., anticoagulants, corticosteroids, use of multiple NSAIDs), (d) age greater than 75 years, and (e) serious underlying diseases.1 If a patient has an increased risk of NSAID-induced adverse reactions, gastroprotection should be considered by coinitiation of a proton pump inhibitor, histamine-2 receptor blocker, or misoprostol. Misoprostol is effective in reducing the occurrence of gastric and duodenal ulcers. However, its tolerability is limited by adverse effects, specifically diarrhea. Histamine-2 receptor blockers effectively prevent duodenal ulcers (but not gastric ulcers) that occur more readily as a result of NSAID therapy. Proton pump inhibitors are the preferred gastroprotective agents due to greater acid suppression, prevention of both gastric and duodenal ulcers, and a tolerable adverse-effect profile. Changing treatment to low-dose prednisone, a nonacetylated salicylate, or a COX-2 inhibitor are additional options.1

NSAIDs may accentuate the increased risk of cardiovascular events inherent in patients with RA. Increases in blood pressure and fluid retention may exacerbate existing cardiovascular disease. With the evidence associating COX-2 inhibitors with cardiovascular disease, clinicians must carefully evaluate the potential risks of NSAID therapy against the potential benefits. See Chapter 58 for additional discussion of NSAID therapy.

NSAIDs are the treatment of choice in children with JIA of mild severity. As in adults, adverse effects of NSAID therapy should be anticipated and treated accordingly in pediatrics.

Glucocorticoids

Low-dose glucocorticoid treatment (equivalent to prednisone 10 mg/day or less) effectively reduces inflammation through inhibition of cytokines and inflammatory mediators and prevents disease progression.19,21 The goal of glucocorticoid use is to minimize adverse drug events by keeping doses low and using the drugs as infrequently as possible. Patients may receive glucocorticoids for a brief time as "bridge therapy" following DMARD initiation or via intra-articular injections to relieve symptoms of active disease. Patients taking more than 10 mg/day prednisone or equivalent are at an increased risk for clinically significant adverse reactions, especially bone loss leading to osteoporosis. Other glucocorticoid-related adverse reactions include Cushing's syndrome, peptic ulcer disease, hypertension, weight gain, infection, mood changes, cataracts, dyslipidemia, and hyperglycemia.

Systemic glucocorticoids should be avoided in patients with JIA due to the adverse effects mentioned above and growth suppression.

Nonbiologic DMARDs

Nonbiologic and biologic DMARDs are the mainstay of RA treatment because they modify the disease process and prevent or reduce joint damage. In addition to relying on safety and efficacy data, the initial DMARD choice depends on disease severity, patient characteristics (i.e., comorbidities, likelihood of adherence), cost, and clinician

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experience with the medication. ' ' Methotrexate alone or in combination therapy is the initial treatment of choice for patients with aggressive disease. Patients with early, mild disease may receive monotherapy with sulfasalazine, leflunomide or hydroxychloroquine. Agents such as azathioprine, D-penicillamine, gold salts, and anakinra are used rarely today because of concerns about toxicity and reduced efficacy.1,18,19

Methotrexate

Methotrexate is the nonbiologic DMARD of choice in RA because of its documented efficacy and safety profile when monitored appropriately. ' Methotrexate exerts its anti-inflammatory effect through inhibition of dihydrofolate reductase, which causes the inhibition of purines and thymidylic acid, and by inhibiting the production of certain cytokines. Unless the patient has contraindications to methotrexate, once-weekly doses should be initiated within 3 months of diagnosis and increased steadily until the patient has symptomatic improvement or a maximum dose of 20 mg/week is reached. Concomitant folic acid is given routinely to reduce the risk of folate-de-pleting reactions induced by methotrexate therapy (e.g., stomatitis, diarrhea, nausea,

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alopecia, myelosuppression, and elevations in liver function tests). '

Serious adverse reactions include pulmonary fibrosis and hepatotoxicity. Patients should be counseled to avoid the use of alcohol, take folic acid as directed, adhere to the laboratory monitoring schedule, and immediately report symptoms of pulmonary fibrosis (e.g., cough or dyspnea) and hepatotoxicity (e.g., jaundice or abdominal pain). If monotherapy does not produce complete resolution of symptoms, methotrexate may be used in combination with other nonbiologic or biologic DMARDs. In situations where the clinician suspects RA but a diagnosis has not yet been made, initiation of methotrexate was found to delay the diagnosis and halt joint damage without

untoward adverse effects.

Methotrexate is considered a second-line treatment of JIA. The usual dose is 5 to 15 mg/m (based on body surface area) once weekly. There are insufficient published data to assess the risk of serious toxicity in children receiving doses greater than 20 mg/m2/wk. Patients will begin to notice a response in 3 to 4 weeks with maximal re sponse in 3 to 6 months. Methotrexate therapy in pediatric patients should be monitored the same way that is recommended in adults. 5

Hydroxychloroquine and Sulfasalazine

The exact mechanism of action of these drugs is unknown, but both agents are fairly well tolerated. Hydroxychloroquine or sulfasalazine may be initiated on diagnosis of mild disease. Because of their slow onset of action, each drug must be given at therapeutic doses for at least 6 months before it can be deemed a treatment failure. Hy-droxychloroquine and sulfasalazine are relatively inexpensive compared with the new biologic agents. If patients do not respond to methotrexate monotherapy, adding one of

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these agents may provide the benefit necessary to reduce symptoms satisfactorily.

Hydroxychloroquine may cause retinal toxicity, and patients must have their eyes examined at least annually to detect this abnormality. It is not associated with renal, hepatic, or bone marrow suppression and therefore may be an acceptable treatment option for patients with contraindications to other DMARDs because of their toxicit-ies.

Starting sulfasalazine at low doses and titrating slowly will minimize the nausea and abdominal discomfort caused by the drug. Patients receiving sulfasalazine must undergo routine blood work to monitor for leukopenia.1 Patients with a sulfa allergy should not receive sulfasalazine.

Hydroxychloroquine and sulfasalazine can be used to treat JIA if methotrexate is not appropriate for the patient.17 The pediatric dose of hydroxychloroquine is 3 to 5 mg/kg/day divided in 1 to 2 doses. The dose of sulfasalazine for children older than 6 years is 30 to 50 mg/kg/day in two divided doses.

Leflunomide

Leflunomide inhibits dihydroorotate dehy-drogenase, an enzyme within the mitochondria that supplies T lymphocytes with the necessary components to respond to cytokine stimulation.26 Thus, leflunomide inhibits the T-lymphocyte response to various stimuli and halts the cell cycle. Its efficacy is similar to that of moderate doses of methotrexate or sulfasalazine.19 Because of its extended half-life, leflunomide therapy begins with a loading dose followed by a maintenance dose. Patients with pre-existing hepatic disease or a history of heavy alcohol ingestion should not receive leflun-omide26 Leflunomide may be used in combination with methotrexate, but the added efficacy comes with a dramatic rise in the risk of hepatotoxicity. Liver function tests must be followed closely to prevent or minimize liver damage.1 If therapy requires ab rupt discontinuation (e.g., due to toxicity or pregnancy), administering cholestyramine will accelerate removal of leflunomide from the body.

Leflunomide was shown to effectively treat JIA in clinical trials, but it does not have an FDA-approved indication for this use.17

Biologic DMARDs

Biologic DMARDs are indicated in patients who have failed an adequate trial of DMARD therapy or in combination with nonbiologic DMARDs in patients with early, aggressive disease.1 These agents may be added to nonbiologic DMARD monotherapy (e.g., methotrexate) or replace ineffective nonbiologic DMARD therapy.18 The decision to select a particular agent generally is based on the prescriber's comfort level with monitoring the safety and efficacy of the medications, severity of disease activity, presence of factors suggestive of poor prognosis, the frequency and route of administration, the patient's comfort level or manual dexterity to self-administer subcu-

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taneous injections, the cost, and the availability of insurance coverage. ' In general, biologic DMARDs should be avoided in patients with serious infections, demyelinat-ing disorders (e.g., multiple sclerosis or optic neuritis) or hepatitis. TNF antagonists should be avoided in patients with heart failure.18

Tumor Necrosis Factor Antagonists

Etanercept is a recombinant form of human T receptor.28 Etanercept provides a therapeutic effect by binding to soluble TNF and preventing its binding with TNF receptors. It is administered subcutaneously once or twice weekly; noticeable symptomatic improvement is seen in 1 to 4 weeks. Etanercept is very effective as monotherapy or in combination with other DMARDs, except anakinra.28 There is no evidence to suggest a benefit to combination with anakinra, and there is an increased infection risk. The most common adverse reactions with etanercept are injection-site reactions. If such reactions are bothersome, patients should be advised to place ice on the injection-site before and after administration or apply a topical anesthetic or corticosteroid to the affected area.29 Etanercept has an FDA-approved indication for treatment of JIA. The pediatric dose of etanercept is 0.8 mg/kg subcutaneously once weekly.

Infliximab is a chimeric IgGl monoclonal antibody that binds to soluble and bound

TNF-a. Methotrexate typically is given with it to suppress antibody production against the mouse-derived portion of the molecule. Infliximab is delivered via IV infusion every 4 to 8 weeks; however, patients may notice benefit within 1 to 4 weeks of receiving the first infusion. Infusion-related reactions including rash, urticaria, flush ing, headache, fever, chills, nausea, tachycardia, and dyspnea may occur during treatment. Qualified health care personnel must be present during the infusion to respond to the infusion-related reactions, if they occur. If patients experience any of these symptoms, the reaction may be treated by: (a) temporarily discontinuing the infusion,

(b) slowing the infusion rate, or (c) administering corticosteroids or antihistamines. Clinicians may prescribe pretreatment regimens with corticosteroids or antihistam-

ines if the patient continues to experience infusion reactions. Infliximab was shown in clinical trials to be effective for treatment of JIA, but it has not yet received FDA approval for this indication.

Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human TNF.31 Adalimumab binds to soluble and bound TNF-a. Patients may experience symptomatic relief in as early as 1 week. Adalimumab can be administered in combination with methotrexate or other DMARDs.2 Adalimumab has an FDA-approved indication for JIA.

Golimumab is a human monoclonal antibody that binds to membrane-bound and soluble TNF. Golimumab can be administered in combination with methotrexate in patients with moderate to severe RA. One advantage of this agent over others in the class may be the once-monthly dosing. Golimumab is not FDA-approved for use in JIA.

Certolizumab is a humanized antibody Fab fragment conjugated to polyethylene glycol, which delays the metabolism and elimination of the medication. Certolizumab can be administered as monotherapy or in combination with methotrexate in patients with moderate to severe RA. Certolizumab is not FDA-approved for use in JIA.

Interleukin 1 Receptor Antagonist

Anakinra is a recombinant form of human IL-1 receptor antagonist. Anakinra inhibits the activity of IL-1 by binding to it and preventing cell signaling. It is indicated for adults with RA who have failed one or more nonbiologic DMARDs. Patients must administer a subcutaneous injection every day, which may be less desirable than other treatment options. Anakinra may be used in combination with other nonbiologic DMARDs in patients not responding to or unable to tolerate nonbiologic DMARDs or TNF antagonists. Anakinra should not be used in combination with TNF antagonists due to the increased risk of infection. Anakinra is not included in the algorithms outlined in the 2008 treatment guidelines due to its infrequent use in RA.

Costimulation Modulators

Abatacept is the first agent in this class of medications. It interferes with T-cell signaling, ultimately blocking T-cell activation and leading to anergy, or lack of response

to an antigen. Trials conducted in patients refractory to methotrexate and anti-

TNF therapy demonstrated significant clinical benefit after administration of abata-

cept every 28 days with a dose approximating 10 mg/kg. Adverse reactions reported in clinical trials were low and similar to those of placebo, with the exception of an increased incidence of headache, infections, and infusion-related reactions in the

treatment group. Abatacept is indicated as monotherapy or in combination with non-biologic DMARDs. Its exact place in therapy is not yet clear; however, clinicians see a window of opportunity for patients who were intolerant to or did not receive therapeutic benefit from other nonbiologic or biologic DMARDs or developed antibodies

to adequate trials of anti-TNF agents, specifically infliximab. Anti-CD20 Monoclonal Antibody

Rituximab is a genetically engineered chimeric anti-CD20 monoclonal antibody that

causes B-lymphocyte depletion. Although the exact role of B lymphocytes in the pathogenesis of RA is not clear, a small study in patients with RA demonstrated noticeable efficacy. Further clinical trials showed a sustained therapeutic effect lasting

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for at least 48 weeks after the initial treatment. Adverse effects occurring during or up to 24 hours after the first infusion included changes in blood pressure (increases or decreases), cough, rash, and pruritus. The infusion-related reactions subsided with subsequent infusions. Serious infections occurred in a small number of rituximab-treated patients.

The exact role of rituximab in RA is not clearly defined, but it is indicated for patients with moderate to severe active RA and a history of inadequate response to one or more TNF antagonist therapies. Rituximab carries a black-box warning of fatal infusion reactions and severe mucocutaneous reactions even though these events did not occur during the RA clinical trials. The benefits of rituximab must be tempered against the safety concerns reported with use of rituximab in the oncology setting. Fully humanized anti-CD20 monoclonal antibodies are under development.

Anti-interleukin-6 Receptor Antibody

Interleukin-6 (IL-6) is produced in high amounts in patients with RA. High levels are indicative of joint damage and disease activity. In addition, IL-6 plays a significant role in the pathogenesis of anemia of chronic disease.36 Tocilizumab, an anti-IL-6 re ceptor monoclonal antibody, inhibits the binding of IL-6 to the IL-6 receptor. Studies in patients not responding to methotrexate or TNF antagonists have demonstrated safety and efficacy of tocilizumab administration.2,22,37 The tocilizumab dose is 8 mg/ kg IV every 4 weeks. Adverse reactions include nasopharyngitis, infection, and elevated lab values including liver function tests and cholesterol parameters. The exact place in therapy of tocilizumab is not yet known. Tocilizumab is not included in the 2008 recommendations from the ACR because the drug was still investigational at the time of writing.

Selecting a Biologic DMARD

Developments in the treatment of RA are tempered by the lack of evidence of the long-term safety and efficacy of the biologic DMARDs. In addition, high costs can be a deterrent to use. Longer term data are emerging that suggest that patients receiving therapy with these agents early in the course of disease (within 3 years) for a defined time period have reduced disease activity and less joint destruction. If additional evidence proves this to be true, concerns regarding the cost of biologic DMARDs may be alleviated. Cost analyses may indicate that the increased expenses associated with these drugs are offset by the costs avoided for treatment of advanced RA.

© The risk of infection in patients treated with biologic DMARDs must be considered when selecting and monitoring therapy.18,38,39 Influencing the immune response to reduce symptoms of RA may influence the body's response to pathogens. Of particular concern is the use of TNF antagonists in patients with a history of tuberculosis exposure. TNF is important in the formation of granulomas that wall off tuberculosis infection. In theory, if TNF is inhibited, patients with latent tuberculosis may have a reactivated infection. Patients receiving biologic DMARD therapy should be screened for tuberculosis and other infections. Prophylaxis should be initiated in patients with previous tuberculosis exposure or in patients at high risk of developing tuberculosis.18 Biologic DMARDs should not be initiated during an acute, serious in-

fection and should be discontinued temporarily during times of infection.

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