Basic and Clinical Pharmacology, 13th Ed.

Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout

Nabeel H. Borazan, MD, & Daniel E. Furst, MD

CASE STUDY

A 48-year-old man presents with complaints of bilateral morning stiffness in his wrists and knees and pain in these joints on exercise. On physical examination, the joints are slightly swollen. The rest of the examination is unremarkable. His laboratory findings are also negative except for slight anemia, elevated erythrocyte sedimentation rate, and positive rheumatoid factor. With the diagnosis of rheumatoid arthritis, he is started on a regimen of naproxen, 220 mg twice daily. After 1 week, the dosage is increased to 440 mg twice daily. His symptoms are reduced at this dosage, but he complains of significant heartburn that is not controlled by antacids. He is then switched to celecoxib, 200 mg twice daily, and on this regimen his joint symptoms and heartburn resolve. Two years later, he returns with increased joint symptoms. His hands, wrists, elbows, feet, and knees are all now involved and appear swollen, warm, and tender. What therapeutic options should be considered at this time? What are the possible complications?

ACRONYMS

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THE IMMUNE RESPONSE

The immune response occurs when immunologically competent cells are activated in response to foreign organisms or antigenic substances liberated during the acute or chronic inflammatory response. The outcome of the immune response for the host may be deleterious if it leads to chronic inflammation without resolution of the underlying injurious process (see Chapter 55). Chronic inflammation involves the release of multiple cytokines and chemokines plus a very complex interplay of immunoactive cells. The whole range of autoimmune diseases (eg, RA, vasculitis, SLE) and inflammatory conditions (eg, gout) derive from abnormalities in this cascade.

The cell damage associated with inflammation acts on cell membranes to release leukocyte lysosomal enzymes; arachidonic acid is then liberated from precursor compounds, and various eicosanoids are synthesized (see Chapter 18). The lipoxygenase pathway of arachidonate metabolism yields leukotrienes, which have a powerful chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction and alterations in vascular permeability. During inflammation, stimulation of the neutrophil membranes produces oxygen-derived free radicals and other reactive molecules such as hydrogen peroxide and hydroxyl radicals. The interaction of these substances with arachidonic acid results in the generation of chemotactic substances, thus perpetuating the inflammatory process.

THERAPEUTIC STRATEGIES

The treatment of patients with inflammation involves two primary goals: first, the relief of symptoms and the maintenance of function, which are usually the major continuing complaints of the patient; and second, the slowing or arrest of the tissue-damaging process. In RA, several validated combined indices are used to define response (eg, Disease Activity Index [DAS], American College of Rheumatology Response Index [ACR Response]). These indices often combine joint tenderness and swelling, patient response, and laboratory data. Reduction of inflammation with NSAIDs often results in relief of pain for significant periods. Furthermore, most of the nonopioid analgesics (aspirin, etc) have anti-inflammatory effects, so they are appropriate for the treatment of both acute and chronic inflammatory conditions.

The glucocorticoids also have powerful anti-inflammatory effects and when first introduced were considered to be the ultimate answer to the treatment of inflammatory arthritis. Although there are data indicating that low-dose corticosteroids have disease-modifying properties, their toxicity makes them less favored than other medications, when it is possible to use the others. However, the glucocorticoids continue to have a significant role in the long-term treatment of arthritis.

Another important group of agents is characterized as DMARDs including biologics (a subset of the DMARDs). They decrease inflammation, improve symptoms, and slow the bone damage associated with RA. They affect more basic inflammatory mechanisms than do glucocorticoids or the NSAIDs. They may also be more toxic than those alternative medications.

image NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Salicylates and other similar agents used to treat rheumatic disease share the capacity to suppress the signs and symptoms of inflammation including pain. These drugs also exert antipyretic effects.

Since aspirin, the original NSAID, has a number of adverse effects, many other NSAIDs have been developed in attempts to improve upon aspirin’s efficacy and decrease its toxicity.

Chemistry & Pharmacokinetics

The NSAIDs are grouped in several chemical classes, as shown in Figure 36–1. This chemical diversity yields a broad range of pharmacokinetic characteristics (Table 36–1). Although there are many differences in the kinetics of NSAIDs, they have some general properties in common. All but one of the NSAIDs are weak organic acids as given; the exception, nabumetone, is a ketone prodrug that is metabolized to the acidic active drug.

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FIGURE 36–1 Chemical structures of some NSAIDs.

TABLE 36–1 PROPERTIES OF ASPIRIN AND SOME OTHER NONSTEROIDAL ANTI-INFLAMMATORY DRUGS.

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Most of these drugs are well absorbed, and food does not substantially change their bioavailability. Most of the NSAIDs are highly metabolized, some by phase I followed by phase II mechanisms and others by direct glucuronidation (phase II) alone. NSAID metabolism proceeds, in large part, by way of the CYP3A or CYP2C families of P450 enzymes in the liver (see Chapter 4). While renal excretion is the most important route for final elimination, nearly all undergo varying degrees of biliary excretion and reabsorption (enterohepatic circulation). In fact, the degree of lower gastrointestinal (GI) tract irritation correlates with the amount of enterohepatic circulation. Most of the NSAIDs are highly protein-bound (~ 98%), usually to albumin. Most of the NSAIDs (eg, ibuprofen, ketoprofen) are racemic mixtures, while one, naproxen, is provided as a single enantiomer and a few have no chiral center (eg, diclofenac).

All NSAIDs can be found in synovial fluid after repeated dosing. Drugs with short half-lives remain in the joints longer than would be predicted from their half-lives, while drugs with longer half-lives disappear from the synovial fluid at a rate proportionate to their half-lives.

Pharmacodynamics

NSAID anti-inflammatory activity is mediated chiefly through inhibition of prostaglandin biosynthesis (Figure 36–2). Various NSAIDs have additional possible mechanisms of action, including inhibition of chemotaxis, down-regulation of IL-1 production, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events. Aspirin irreversibly acetylates and blocks platelet COX, while the non-COX-selective NSAIDs are reversible inhibitors.

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FIGURE 36–2 Prostanoid mediators derived from arachidonic acid and sites of drug action. ASA, acetylsalicylic acid (aspirin); LT, leukotriene; NSAID, nonsteroidal anti-inflammatory drug.

Selectivity for COX-1 versus COX-2 is variable and incomplete for the older NSAIDs, but selective COX-2 inhibitors have been synthesized. The selective COX-2 inhibitors do not affect platelet function at their usual doses. The efficacy of COX-2-selective drugs equals that of the older NSAIDs, while GI safety may be improved. On the other hand, selective COX-2 inhibitors increase the incidence of edema, hypertension, and possibly, myocardial infarction. As of August 2011, celecoxib and the less selective meloxicam were the only COX-2 inhibitors marketed in the USA. Celecoxib has an FDA-initiated “black box” warning concerning cardiovascular risks. It has been recommended that all NSAID product labels be revised to mention cardiovascular risks.

The NSAIDs decrease the sensitivity of vessels to bradykinin and histamine, affect lymphokine production from T lymphocytes, and reverse the vasodilation of inflammation. To varying degrees, all newer NSAIDs are analgesic, anti-inflammatory, and antipyretic, and all (except the COX-2-selective agents and the nonacetylated salicylates) inhibit platelet aggregation. NSAIDs are all gastric irritants and can be associated with GI ulcers and bleeds as well, although as a group the newer agents tend to cause less GI irritation than aspirin. Nephrotoxicity, reported for all NSAIDs, is due, in part, to interference with the autoregulation of renal blood flow, which is modulated by prostaglandins. Hepatotoxicity can also occur with any NSAID.

Although these drugs effectively inhibit inflammation, there is no evidence that—in contrast to drugs such as methotrexate, biologics, and other DMARDs—they alter the course of any arthritic disorder.

Several NSAIDs (including aspirin) reduce the incidence of colon cancer when taken chronically. Several large epidemiologic studies have shown a 50% reduction in relative risk for this neoplasm when the drugs are taken for 5 years or longer. The mechanism for this protective effect is unclear.

Although not all NSAIDs are approved by the FDA for the whole range of rheumatic diseases, most are probably effective in RA, sero-negative spondyloarthropathies (eg, PA and arthritis associated with inflammatory bowel disease), OA, localized musculoskeletal syndromes (eg, sprains and strains, low back pain), and gout (except tolmetin, which appears to be ineffective in gout).

Adverse effects are generally quite similar for all of the NSAIDs:

1.Central nervous system: Headaches, tinnitus, dizziness, and rarely, aseptic meningitis.

2.Cardiovascular: Fluid retention, hypertension, edema, and rarely, myocardial infarction and congestive heart failure (CHF).

3.Gastrointestinal: Abdominal pain, dysplasia, nausea, vomiting, and rarely, ulcers or bleeding.

4.Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia.

5.Hepatic: Abnormal liver function test results and rare liver failure.

6.Pulmonary: Asthma.

7.Skin: Rashes, all types, pruritus.

8.Renal: Renal insufficiency, renal failure, hyperkalemia, and proteinuria.

ASPIRIN

Aspirin’s long use and availability without prescription diminishes its glamour compared with that of the newer NSAIDs. Aspirin is now rarely used as an anti-inflammatory medication and will be reviewed only in terms of its antiplatelet effects (ie, doses of 81–325 mg once daily).

1.Pharmacokinetics: Salicylic acid is a simple organic acid with a pKa of 3.0. Aspirin (acetylsalicylic acid; ASA) has a pKa of 3.5 (see Table 1–3). Aspirin is absorbed as such and is rapidly hydrolyzed (serum half-life 15 minutes) to acetic acid and salicylate by esterases in tissue and blood (Figure 36–3). Salicylate is nonlinearly bound to albumin. Alkalinization of the urine increases the rate of excretion of free salicylate and its water-soluble conjugates.

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FIGURE 36–3 Structure and metabolism of the salicylates. (Reproduced, with permission, from Meyers FH, Jawetz E, Goldfien A: Review of Medical Pharmacology, 7th ed. McGraw-Hill, 1980. Copyright © The McGraw-Hill Companies, Inc.)

2.Mechanisms of Action: Aspirin irreversibly inhibits platelet COX so that aspirin’s antiplatelet effect lasts 8–10 days (the life of the platelet). In other tissues, synthesis of new COX replaces the inactivated enzyme so that ordinary doses have a duration of action of 6–12 hours.

3.Clinical Uses: Aspirin decreases the incidence of transient ischemic attacks, unstable angina, coronary artery thrombosis with myocardial infarction, and thrombosis after coronary artery bypass grafting (see Chapter 34).

4.Epidemiologic studies suggest that long-term use of aspirin at low dosage is associated with a lower incidence of colon cancer, possibly related to its COX-inhibiting effects.

5.Adverse Effects: In addition to the common side effects listed above, aspirin’s main adverse effects at antithrombotic doses are gastric upset (intolerance) and gastric and duodenal ulcers. Hepatotoxicity, asthma, rashes, GI bleeding, and renal toxicity rarely if ever occur at antithrombotic doses.

6.The antiplatelet action of aspirin contraindicates its use by patients with hemophilia. Although previously not recommended during pregnancy, aspirin may be valuable in treating preeclampsia-eclampsia.

NONACETYLATED SALICYLATES

These drugs include magnesium choline salicylate, sodium salicylate, and salicyl salicylate. All nonacetylated salicylates are effective anti-inflammatory drugs, although they may be less effective analgesics than aspirin. Because they are much less effective than aspirin as COX inhibitors and they do not inhibit platelet aggregation, they may be preferable when COX inhibition is undesirable such as in patients with asthma, those with bleeding tendencies, and even (under close supervision) those with renal dysfunction.

The nonacetylated salicylates are administered in doses up to 3–4 g of salicylate a day and can be monitored using serum salicylate measurements.

COX-2 SELECTIVE INHIBITORS

COX-2 selective inhibitors, or coxibs, were developed in an attempt to inhibit prostaglandin synthesis by the COX-2 isozyme induced at sites of inflammation without affecting the action of the constitutively active “housekeeping” COX-1 isozyme found in the GI tract, kidneys, and platelets. COX-2 inhibitors at usual doses have no impact on platelet aggregation, which is mediated by thromboxane produced by the COX-1 isozyme. In contrast, they do inhibit COX-2-mediated prostacyclin synthesis in the vascular endothelium. As a result, COX-2 inhibitors do not offer the cardioprotective effects of traditional nonselective NSAIDs. Recommended doses of COX-2 inhibitors cause renal toxicities similar to those associated with traditional NSAIDs. Clinical data suggested a higher incidence of cardiovascular thrombotic events associated with COX-2 inhibitors such as rofecoxib and valdecoxib, resulting in their withdrawal from the market.

Celecoxib

Celecoxib is a selective COX-2 inhibitor—about 10–20 times more selective for COX-2 than for COX-1. Pharmacokinetic and dosage considerations are given in Table 36–1.

Celecoxib is associated with fewer endoscopic ulcers than most other NSAIDs. Probably because it is a sulfonamide, celecoxib may cause rashes. It does not affect platelet aggregation at usual doses. It interacts occasionally with warfarin—as would be expected of a drug metabolized via CYP2C9. Adverse effects are the common toxicities listed above.

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Meloxicam

Meloxicam is an enolcarboxamide related to piroxicam that preferentially inhibits COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as celecoxib and may be considered “preferentially” selective rather than “highly” selective. It is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, even at supratherapeutic doses, its blockade of thromboxane A2 does not reach levels that result in decreased in vivo platelet function (see common adverse effects above).

NONSELECTIVE COX INHIBITORS*

Diclofenac

Diclofenac is a phenylacetic acid derivative that is relatively nonselective as a COX inhibitor. Pharmacokinetic and dosage characteristics are set forth in Table 36–1.

Gastrointestinal ulceration may occur less frequently than with some other NSAIDs. A preparation combining diclofenac and misoprostol decreases upper gastrointestinal ulceration but may result in diarrhea. Another combination of diclofenac and omeprazole was also effective with respect to the prevention of recurrent bleeding, but renal adverse effects were common in high-risk patients. Diclofenac, 150 mg/d, appears to impair renal blood flow and glomerular filtration rate. Elevation of serum aminotransferases occurs more commonly with this drug than with other NSAIDs.

A 0.1% ophthalmic preparation is promoted for prevention of postoperative ophthalmic inflammation and can be used after intraocular lens implantation and strabismus surgery. A topical gel containing 3% diclofenac is effective for solar keratoses. Diclofenac in rectal suppository form can be considered for preemptive analgesia and postoperative nausea. In Europe, diclofenac is also available as an oral mouthwash and for intramuscular administration.

Diflunisal

Although diflunisal is derived from salicylic acid, it is not metabolized to salicylic acid or salicylate. It undergoes an enterohepatic cycle with reabsorption of its glucuronide metabolite followed by cleavage of the glucuronide to again release the active moiety. Diflunisal is subject to capacity-limited metabolism, with serum half-lives at various dosages approximating that of salicylates (Table 36–1). In RA the recommended dose is 500–1000 mg daily in two divided doses. It is claimed to be particularly effective for cancer pain with bone metastases and for pain control in dental (third molar) surgery. A 2% diflunisal oral ointment is a clinically useful analgesic for painful oral lesions.

Because its clearance depends on renal function as well as hepatic metabolism, diflunisal’s dosage should be limited in patients with significant renal impairment.

Etodolac

Etodolac is a racemic acetic acid derivative with an intermediate half-life (Table 36–1). The analgesic dosage of etodolac is 200–400 mg three to four times daily. The recommended dose in OA and RA is 300 mg twice or three times a day up to 500 mg twice a day initially followed by a maintenance of 600 mg/d.

Flurbiprofen

Flurbiprofen is a propionic acid derivative with a possibly more complex mechanism of action than other NSAIDs. Its (S)(−) enantiomer inhibits COX nonselectively, but it has been shown in rat tissue to also affect tumor necrosis factor-α (TNF-α) and nitric oxide synthesis. Hepatic metabolism is extensive; its (R)(+) and (S)(−) enantiomers are metabolized differently, and it does not undergo chiral conversion. It does demonstrate enterohepatic circulation.

Flurbiprofen is also available in a topical ophthalmic formulation for inhibition of intraoperative miosis. Flurbiprofen intravenously is effective for perioperative analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat.

Although its adverse effect profile is similar to that of other NSAIDs in most ways, flurbiprofen is also rarely associated with cogwheel rigidity, ataxia, tremor, and myoclonus.

Ibuprofen

Ibuprofen is a simple derivative of phenylpropionic acid (Figure 36–1). In doses of about 2400 mg daily, ibuprofen is equivalent to 4 g of aspirin in anti-inflammatory effect. Pharmacokinetic characteristics are given in Table 36–1.

Oral ibuprofen is often prescribed in lower doses (<2400 mg/d), at which it has analgesic but not anti-inflammatory efficacy. It is available over the counter in low-dose forms under several trade names.

Ibuprofen oral and IV is effective in closing patent ductus arteriosus in preterm infants, with much the same efficacy and safety as indomethacin. A topical cream preparation appears to be absorbed into fascia and muscle; ibuprofen cream was more effective than placebo cream in the treatment of primary knee OA. A liquid gel preparation of ibuprofen, 400 mg, provides prompt relief and good overall efficacy in postsurgical dental pain.

In comparison with indomethacin, ibuprofen decreases urine output less and also causes less fluid retention. The drug is relatively contraindicated in individuals with nasal polyps, angio-edema, and bronchospastic reactivity to aspirin. Aseptic meningitis (particularly in patients with SLE), and fluid retention have been reported. The concomitant administration of ibuprofen and aspirin antagonizes the irreversible platelet inhibition induced by aspirin. Thus, treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin. Furthermore, the use of ibuprofen concomitantly with aspirin may decrease the total anti-inflammatory effect. Common adverse effects are listed on pages 620-621; rare hematologic effects include agranulocytosis and aplastic anemia.

Indomethacin

Indomethacin, introduced in 1963, is an indole derivative (Figure 36–1). It is a potent nonselective COX inhibitor and may also inhibit phospholipase A and C, reduce neutrophil migration, and decrease T-cell and B-cell proliferation.

Indomethacin differs somewhat from other NSAIDs in its indications and toxicities. It has been used to accelerate closure of patent ductus arteriosus. Indomethacin has been tried in numerous small or uncontrolled trials for many other conditions, including Sweet’s syndrome, juvenile RA, pleurisy, nephrotic syndrome, diabetes insipidus, urticarial vasculitis, postepisiotomy pain, and prophylaxis of heterotopic ossification in arthroplasty.

An ophthalmic preparation is efficacious for conjunctival inflammation and to reduce pain after traumatic corneal abrasion. Gingival inflammation is reduced after administration of indomethacin oral rinse. Epidural injections produce a degree of pain relief similar to that achieved with methylprednisolone in postlaminectomy syndrome.

At usual doses, indomethacin has the common side effects listed above. The GI effects may include pancreatitis. Headache is experienced by 15–25% of patients and may be associated with dizziness, confusion, and depression. Renal papillary necrosis has also been observed. A number of interactions with other drugs have been reported (see Chapter 66).

Ketoprofen

Ketoprofen is a propionic acid derivative that inhibits both COX (nonselectively) and lipoxygenase. Its pharmacokinetic characteristics are given in Table 36–1. Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life.

The effectiveness of ketoprofen at dosages of 100–300 mg/d is equivalent to that of other NSAIDs. Its major adverse effects are on the GI tract and the central nervous system (see common adverse effects above).

Nabumetone

Nabumetone is the only nonacid NSAID in current use; it is given as a ketone prodrug (Figure 36–1) and resembles naproxen in structure. Its half-life of more than 24 hours (Table 36–1) permits once-daily dosing, and the drug does not appear to undergo enterohepatic circulation. Renal impairment results in a doubling of its half-life and a 30% increase in the area under the curve.

Its properties are very similar to those of other NSAIDs, though it may be less damaging to the stomach. Unfortunately, higher dosages (eg, 1500–2000 mg/d) are often needed, and this is a very expensive NSAID. Like naproxen, nabumetone has been associated with pseudoporphyria and photosensitivity in some patients.

Naproxen

Naproxen is a naphthylpropionic acid derivative. It is the only NSAID presently marketed as a single enantiomer. Naproxen’s free fraction is significantly higher in women than in men, but half-life is similar in both sexes (Table 36–1). Naproxen is effective for the usual rheumatologic indications and is available in a slow-release formulation, as an oral suspension, and over the counter. A topical preparation and an ophthalmic solution are also available.

The incidence of upper GI bleeding in over-the-counter use is low but still double that of over-the-counter ibuprofen (perhaps due to a dose effect). Rare cases of allergic pneumonitis, leukocytoclastic vasculitis, and pseudoporphyria as well as the common NSAID-associated adverse effects have been noted.

Oxaprozin

Oxaprozin is another propionic acid derivative NSAID. As noted in Table 36–1, its major difference from the other members of this subgroup is a very long half-life (50–60 hours), although oxaprozin does not undergo enterohepatic circulation. It is mildly uricosuric. Otherwise, the drug has the same benefits and risks that are associated with other NSAIDs.

Piroxicam

Piroxicam, an oxicam (Figure 36–1), is a nonselective COX inhibitor that at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function. Its long half-life (Table 36–1) permits once-daily dosing.

Piroxicam can be used for the usual rheumatic indications. When piroxicam is used in dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding is encountered—as much as 9.5 times higher than with other NSAIDs (see common adverse effects above).

Sulindac

Sulindac is a sulfoxide prodrug. It is reversibly metabolized to the active sulfide metabolite, which is excreted in bile and then reabsorbed from the intestine. The enterohepatic cycling prolongs the duration of action to 12–16 hours.

In addition to its rheumatic disease indications, sulindac suppresses familial intestinal polyposis and it may inhibit the development of colon, breast, and prostate cancer in humans. Among the more severe adverse reactions, Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia, agranulocytosis, and nephrotic syndrome have all been observed. It is sometimes associated with cholestatic liver damage.

Tolmetin

Tolmetin is a nonselective COX inhibitor with a short half-life (1–2 hours) and is not often used. It is ineffective (for unknown reasons) in the treatment of gout.

Other NSAIDs

Azapropazonecarprofenmeclofenamate, and tenoxicam are rarely used and are not reviewed here.

CHOICE OF NSAID

All NSAIDs, including aspirin, are about equally efficacious with a few exceptions—tolmetin seems not to be effective for gout, and aspirin is less effective than other NSAIDs (eg, indomethacin) for AS.

Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost-effectiveness. For example, the GI and renal side effects of ketorolac limit its use. Some surveys suggest that indomethacin and tolmetin are the NSAIDs associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen are least toxic. The selective COX-2 inhibitors were not included in these analyses.

For patients with renal insufficiency, nonacetylated salicylates may be best. Diclofenac and sulindac are associated with more liver function test abnormalities than other NSAIDs. The relatively expensive, selective COX-2 inhibitor celecoxib is probably safest for patients at high risk for GI bleeding but may have a higher risk of cardiovascular toxicity. Celecoxib or a nonselective NSAID plus omeprazole or misoprostol may be appropriate in patients at highest risk for GI bleeding; in this subpopulation of patients, they are cost-effective despite their high acquisition costs.

The choice of an NSAID thus requires a balance of efficacy, cost-effectiveness, safety, and numerous personal factors (eg, other drugs also being used, concurrent illness, compliance, medical insurance coverage), so that there is no best NSAID for all patients. There may, however, be one or two best NSAIDs for a specific person.

image DISEASE-MODIFYING ANTIRHEUMATIC DRUGS

RA is a progressive immunologic disease that causes significant systemic effects, shortens life, and reduces mobility and quality of life. Interest has centered on finding treatments that might arrest—or at least slow—this progression by modifying the disease itself. The effects of disease-modifying therapies may take 2 weeks to 6 months to become clinically evident.

These therapies include nonbiologic and biologic disease-modifying antirheumatic drugs (usually designated “DMARDs”). The nonbiologic agents include small molecule drugs such as methotrexate, azathioprine, chloroquine and hydroxychloroquine, cyclophosphamide, cyclosporine, leflunomide, mycophenolate mofetil, and sulfasalazine. Tofacitinib, though marketed as a biologic, is actually a well-tolerated nonbiologic DMARD. Gold salts, which were once extensively used, are no longer recommended because of their significant toxicities and questionable efficacy. Biologics are large-molecule therapeutic agents, usually proteins, that are often produced by recombinant DNA technology. The biologic DMARDs approved for RA include: a T-cell-modulating biologic (abatacept), a B-cell cytotoxic agent (rituximab), an anti-IL-6 receptor antibody (tocilizumab), IL-1-inhibiting agents (anakinra, rilonacept, canakinumab), and the TNF-α-blocking agents (five drugs).

The small-molecule DMARDs and biologics are discussed alphabetically, independent of origin.

ABATACEPT

1.Mechanism of action: Abatacept is a co-stimulation modulator biologic that inhibits the activation of T cells (see also Chapter 55). After a T cell has engaged an antigen-presenting cell (APC), a second signal is produced by CD28 on the T cell that interacts with CD80 or CD86 on the APC, leading to T-cell activation. Abatacept (which contains the endogenous ligand CTLA-4) binds to CD80 and 86, thereby inhibiting the binding to CD28 and preventing the activation of T cells.

2.Pharmacokinetics: The recommended dose of abatacept for the treatment of adult patients with RA is three intravenous infusion “induction” doses (day 0, week 2, and week 4), followed by monthly infusions. The dose is based on body weight; patients weighing less than 60 kg receiving 500 mg, those 60–100 kg receiving 750 mg, and those more than 100 kg receiving 1000 mg. Abatacept is also available as a subcutaneous formulation and is given as 125 mg subcutaneously once weekly.

JIA can also be treated with abatacept with an induction schedule at day 0, week 2, and week 4, followed by intravenous infusion every 4 weeks. The recommended dose for patients 6–17 years of age and weighing less than 75 kg is 10 mg/kg, while those weighing 75 kg or more follow the adult intravenous doses to a maximum not to exceed 1000 mg. The terminal serum half-life is 13–16 days. Co-administration with methotrexate, NSAIDs, and corticosteroids does not influence abatacept clearance.

Most patients respond to abatacept within 12–16 weeks after the initiation of the treatment; however, some patients can respond in as few as 2–4 weeks. A study showed equivalence between adalimumab and abatacept.

3.Indications: Abatacept can be used as monotherapy or in combination with methotrexate or other DMARDs in patients with moderate to severe RA or severe PJIA. It is being tested in early RA and methotrexate-naïve patients.

4.Adverse Effects: There is a slightly increased risk of infection (as with other biologic DMARDs), predominantly of the upper respiratory tract. Concomitant use with TNF-α antagonists or other biologics is not recommended due to the increased incidence of serious infection. All patients should be screened for latent tuberculosis and viral hepatitis before starting this medication. Live vaccines should be avoided in patients while taking abatacept and up to 3 months after discontinuation. Infusion-related reactions and hypersensitivity reactions, including anaphylaxis, have been reported but are rare. Anti-abatacept antibody formation is infrequent (<5%) and has no effect on clinical outcomes. There is a possible increase in lymphomas but not other malignancies when using abatacept.

AZATHIOPRINE

1.Mechanism of Action: Azathioprine is a synthetic nonbiologic DMARD that acts through its major metabolite, 6-thioguanine. 6-Thioguanine suppresses inosinic acid synthesis, B-cell and T-cell function, immunoglobulin production, and IL-2 secretion (see Chapter 55).

2.Pharmacokinetics: Azathioprine can be given orally or parenterally. Its metabolism is bimodal in humans, with rapid metabolizers clearing the drug four times faster than slow metabolizers. Production of 6-thioguanine is dependent on thiopurine methyltransferase (TPMT), and patients with low or absent TPMT activity (0.3% of the population) are at particularly high risk of myelosuppression by excess concentrations of the parent drug, if dosage is not adjusted.

3.Indications: Azathioprine is approved for use in RA at a dosage of 2 mg/kg/d. It is also used for the prevention of kidney transplant rejection in combination with other immune suppressants. Controlled trials show efficacy in PA, reactive arthritis, polymyositis, SLE, maintenance of remission in vasculitis, and Behçet’s disease. Azathioprine is also used in scleroderma; however, in one study, it was found to be less effective than cyclophosphamide in controlling the progression of scleroderma lung disease.

4.Adverse Effects: Azathioprine’s toxicity includes bone marrow suppression, GI disturbances, and some increase in infection risk. As noted in Chapter 55, lymphomas may be increased with azathioprine use. Rarely, fever, rash, and hepatotoxicity signal acute allergic reactions.

CHLOROQUINE & HYDROXYCHLOROQUINE

1.Mechanism of Action: Chloroquine and hydroxychloroquine are nonbiologic drugs mainly used for malaria (see Chapter 52) and in the rheumatic diseases. The following mechanisms have been proposed: suppression of T-lymphocyte responses to mitogens, inhibition of leukocyte chemotaxis, stabilization of lysosomal enzymes, processing through the Fc-receptor, inhibition of DNA and RNA synthesis, and the trapping of free radicals.

2.Pharmacokinetics: Antimalarials are rapidly absorbed and 50% protein-bound in the plasma. They are very extensively tissue-bound, particularly in melanin-containing tissues such as the eyes. The drugs are deaminated in the liver and have blood elimination half-lives of up to 45 days.

3.Indications: Antimalarials are approved for RA, but they are not considered very effective DMARDs. Dose-loading may increase rate of response. There is no evidence that these compounds alter bony damage in RA at their usual dosages (up to 6.4 mg/kg/d for hydroxychloroquine or 200 mg/d for chloroquine). It usually takes 3–6 months to obtain a response. Antimalarials are used very commonly in SLE because they decrease mortality and the skin manifestations, serositis, and joint pains of this disease. They have also been used in Sjögren’s syndrome.

4.Adverse Effects: Although ocular toxicity (see Chapter 52) may occur at dosages greater than 250 mg/d for chloroquine and greater than 6.4 mg/kg/d for hydroxychloroquine, it rarely occurs at lower doses. Nevertheless, ophthalmologic monitoring every 12 months is advised. Other toxicities include dyspepsia, nausea, vomiting, abdominal pain, rashes, and nightmares. These drugs appear to be relatively safe in pregnancy.

CYCLOPHOSPHAMIDE

1.Mechanism of Action: Cyclophosphamide is a synthetic nonbiologic DMARD. Its major active metabolite is phosphoramide mustard, which cross-links DNA to prevent cell replication. It suppresses T-cell and B-cell function by 30–40%; T-cell suppression correlates with clinical response in the rheumatic diseases. Its pharmacokinetics and toxicities are discussed in Chapter 54.

2.Indications: Cyclophosphamide is used regularly at 2 mg/kg/d to treat SLE, vasculitis, Wegener’s granulomatosis, and other severe rheumatic diseases.

CYCLOSPORINE

1.Mechanism of Action: Cyclosporine is a peptide antibiotic but is considered a nonbiologic DMARD. Through regulation of gene transcription, it inhibits IL-1 and IL-2 receptor production and secondarily inhibits macrophage-T-cell interaction and T-cell responsiveness (see Chapter 55). T-cell-dependent B-cell function is also affected.

2.Pharmacokinetics: Cyclosporine absorption is incomplete and somewhat erratic, although a microemulsion formulation improves its consistency and provides 20–30% bioavailability. Grapefruit juice increases cyclosporine bioavailability by as much as 62%. Cyclosporine is metabolized by CYP3A and consequently is subject to a large number of drug interactions (see Chapters 55 and 66).

3.Indications: Cyclosporine is approved for use in RA and retards the appearance of new bony erosions. Its usual dosage is 3–5 mg/kg/d divided into two doses. Anecdotal reports suggest that it may be useful in SLE, polymyositis and dermatomyositis, Wegener’s granulomatosis, and juvenile chronic arthritis.

4.Adverse Effects: Leukopenia, thrombocytopenia, and to a lesser extent, anemia are predictable. High doses can be cardiotoxic and sterility may occur after chronic dosing at anti-rheumatic doses, especially in women. Bladder cancer is very rare but must be looked for, even 5 years after cessation of use.

LEFLUNOMIDE

1.Mechanism of Action: Leflunomide, another nonbiologic DMARD, undergoes rapid conversion, both in the intestine and in the plasma, to its active metabolite, A77-1726. This metabolite inhibits dihydroorotate dehydrogenase, leading to a decrease in ribonucleotide synthesis and the arrest of stimulated cells in the G1 phase of cell growth. Consequently, leflunomide inhibits T-cell proliferation and reduces production of autoantibodies by B cells. Secondary effects include increases of IL-10 receptor mRNA, decreased IL-8 receptor type A mRNA, and decreased TNF-α-dependent nuclear factor kappa B (NF-κB) activation.

2.Pharmacokinetics: Leflunomide is completely absorbed from the gut and has a mean plasma half-life of 19 days. Its active metabolite, A77-1726, has approximately the same half-life and is subject to enterohepatic recirculation. Cholestyramine can enhance leflunomide excretion and increases total clearance by approximately 50%.

3.Indications: Leflunomide is as effective as methotrexate in RA, including inhibition of bony damage. In one study, combined treatment with methotrexate and leflunomide resulted in a 46.2% ACR20 response compared with 19.5% in patients receiving methotrexate alone.

4.Adverse Effects: Diarrhea occurs in approximately 25% of patients given leflunomide, although only about 3–5% of patients discontinue the drug because of this side effect. Elevation in liver enzymes can occur. Both effects can be reduced by decreasing the dose of leflunomide. Other adverse effects associated with leflunomide are mild alopecia, weight gain, and increased blood pressure. Leukopenia and thrombocytopenia occur rarely. This drug is contraindicated in pregnancy.

METHOTREXATE

Methotrexate, a synthetic nonbiologic antimetabolite, is the first-line DMARD for treating RA and is used in 50–70% of patients. It is active in this condition at much lower doses than those needed in cancer chemotherapy (see Chapter 54).

1.Mechanism of Action: Methotrexate’s principal mechanism of action at the low doses used in the rheumatic diseases probably relates to inhibition of amino-imidazolecarboxamide ribonucleotide (AICAR) transformylase and thymidylate synthetase. AICAR, which accumulates intracellularly, competitively inhibits AMP deaminase, leading to an accumulation of AMP. The AMP is released and converted extracellularly to adenosine, which is a potent inhibitor of inflammation. As a result, the inflammatory functions of neutrophils, macrophages, dendritic cells, and lymphocytes are suppressed. Methotrexate has secondary effects on polymorphonuclear chemotaxis. There is some effect on dihydrofolate reductase and this affects lymphocyte and macrophage function, but this is not its principal mechanism of action. Methotrexate has direct inhibitory effects on proliferation and stimulates apoptosis in immune-inflammatory cells. Additionally, it inhibits proinflammatory cytokines linked to rheumatoid synovitis.

2.Pharmacokinetics: The drug is approximately 70% absorbed after oral administration (see Chapter 54). It is metabolized to a less active hydroxylated product. Both the parent compound and the metabolite are polyglutamated within cells where they stay for prolonged periods. Methotrexate’s serum half-life is usually only 6–9 hours. Hydroxychloroquine can reduce the clearance or increase the tubular reabsorption of methotrexate. Methotrexate is excreted principally in the urine, but up to 30% may be excreted in bile.

3.Indications: Although the most common methotrexate dosing regimen for the treatment of RA is 15–25 mg weekly, there is an increased effect up to 30–35 mg weekly. The drug decreases the rate of appearance of new erosions. Evidence supports its use in juvenile chronic arthritis, and it has been used in psoriasis, PA, AS, polymyositis, dermatomyositis, Wegener’s granulomatosis, giant cell arteritis, SLE, and vasculitis.

4.Adverse Effects: Nausea and mucosal ulcers are the most common toxicities. Additionally, many other side effects such as leukopenia, anemia, stomatitis, GI ulcerations, and alopecia are probably the result of inhibiting cellular proliferation. Progressive dose-related hepatotoxicity in the form of enzyme elevation occurs frequently, but cirrhosis is rare (<1%). Liver toxicity is not related to serum methotrexate concentrations. A rare hypersensitivity-like lung reaction with acute shortness of breath has been documented, as have pseudo-lymphomatous reactions. The incidence of GI and liver function test abnormalities can be reduced by the use of leucovorin 24 hours after each weekly dose or by the use of folic acid, although this may decrease the efficacy of the methotrexate by about 10%. This drug is contraindicated in pregnancy.

MYCOPHENOLATE MOFETIL

1.Mechanism of Action: Mycophenolate mofetil (MMF), a semisynthetic DMARD, is converted to mycophenolic acid, the active form of the drug. The active product inhibits inosine monophosphate dehydrogenase, leading to suppression of T- and B-lymphocyte proliferation. Downstream, it interferes with leukocyte adhesion to endothelial cells through inhibition of E-selectin, P-selectin, and intercellular adhesion molecule 1. MMF’s pharmacokinetics and toxicities are discussed in Chapter 55.

2.Indications: MMF is effective for the treatment of renal disease due to SLE and may be useful in vasculitis and Wegener’s granulomatosis. Although MMF is occasionally used at a dosage of 2 g/d to treat RA, there are no well-controlled data regarding its efficacy in this disease.

3.Adverse Effects: MMF is associated with nausea, dyspepsia, and abdominal pain. Like azathioprine, it can cause hepatotoxicity. MMF can also cause leukopenia, thrombocytopenia, and anemia. MMF is associated with an increased incidence of infections. It is only rarely associated with malignancy.

RITUXIMAB

1.Mechanism of Action: Rituximab is a chimeric monoclonal antibody biologic agent that targets CD20 B lymphocytes (see Chapter 55). Depletion of these cells takes place through cell-mediated and complement-dependent cytotoxicity and stimulation of cell apoptosis. Depletion of B lymphocytes reduces inflammation by decreasing the presentation of antigens to T lymphocytes and inhibiting the secretion of proinflammatory cytokines. Rituximab rapidly depletes peripheral B cells, although this depletion correlates neither with efficacy nor with toxicity.

2.Pharmacokinetics: Rituximab is given as two intravenous infusions of 1000 mg, separated by 2 weeks. It may be repeated every 6–9 months, as needed. Repeated courses remain effective. Pretreatment with acetaminophen, an antihistamine, and intravenous glucocorticoids (usually 100 mg of methylprednisolone) given 30 minutes prior to infusion decreases the incidence and severity of infusion reactions.

3.Indications: Rituximab is indicated for the treatment of moderately to severely active RA in combination with methotrexate in patients with an inadequate response to one or more TNF-α antagonists. Rituximab in combination with glucocorticoids is also approved for the treatment of adult patients with Wegener’s granulomatosis (also known as granulomatosis with polyangiitis) and microscopic polyangiitis and is used in other forms of vasculitis as well (see Chapter 54 for its use in lymphomas and leukemias).

4.Adverse Effects: About 30% of patients develop rash with the first 1000 mg treatment; this incidence decreases to about 10% with the second infusion and progressively decreases with each course of therapy thereafter. These rashes do not usually require discontinuation of therapy, although an urticarial or anaphylactoid reaction precludes further therapy. Immunoglobulins (particularly IgG and IgM) may decrease with repeated courses of therapy and infections can occur, although they do not seem directly associated with the decreases in immunoglobulins. Serious, and sometimes fatal, bacterial, fungal, and viral infections are reported for up to one year of the last dose of rituximab, and patients with severe and active infections should not receive rituximab. Rituximab is associated with reactivation of hepatitis B virus (HBV) infection, which requires monitoring before and several months after the initiation of the treatment. Rituximab has not been associated with either activation of tuberculosis or the occurrence of lymphomas or other tumors (see Chapter 55). Fatal mucocutaneous reactions have been reported in patients receiving rituximab. Different cytopenias can occur, which require complete blood cell monitoring every 2–4 months in RA patients. Other adverse effects, such as cardiovascular events, are rare.

SULFASALAZINE

1.Mechanism of Action: Sulfasalazine, a synthetic nonbiologic DMARD, is metabolized to sulfapyridine and 5-aminosalicylic acid. The sulfapyridine is probably the active moiety when treating RA (unlike inflammatory bowel disease, see Chapter 62). Some authorities believe that the parent compound, sulfasalazine, also has an effect. Suppression of T-cell responses to concanavalin and inhibition of in vitro B-cell proliferation are documented. In vitro, sulfasalazine or its metabolites inhibit the release of inflammatory cytokines produced by monocytes or macrophages, eg, IL-1, -6, and -12, and TNF-α.

2.Pharmacokinetics: Only 10–20% of orally administered sulfasalazine is absorbed, although a fraction undergoes enterohepatic recirculation into the bowel where it is reduced by intestinal bacteria to liberate sulfapyridine and 5-aminosalicylic acid (see Figure 62–8). Sulfapyridine is well absorbed while 5-aminosalicylic acid remains unabsorbed. Some sulfasalazine is excreted unchanged in the urine whereas sulfapyridine is excreted after hepatic acetylation and hydroxylation. Sulfasalazine’s half-life is 6–17 hours.

3.Indications: Sulfasalazine is effective in RA and reduces radiologic disease progression. It has also been used in juvenile chronic arthritis, PA, inflammatory bowel disease, AS, and spondyloarthropathy-associated uveitis. The usual regimen is 2–3 g/d.

4.Adverse Effects: Approximately 30% of patients using sulfasalazine discontinue the drug because of toxicity. Common adverse effects include nausea, vomiting, headache, and rash. Hemolytic anemia and methemoglobinemia also occur, but rarely. Neutropenia occurs in 1–5% of patients, while thrombocytopenia is very rare. Pulmonary toxicity and positive double-stranded DNA (dsDNA) are occasionally seen, but drug-induced lupus is rare. Reversible infertility occurs in men, but sulfasalazine does not affect fertility in women. The drug does not appear to be teratogenic.

TOCILIZUMAB

1.Mechanism of Action: Tocilizumab, a newer biologic humanized antibody, binds to soluble and membrane-bound IL-6 receptors, and inhibits the IL-6-mediated signaling via these receptors. IL-6 is a proinflammatory cytokine produced by different cell types including T cells, B cells, monocytes, fibroblasts, and synovial and endothelial cells. IL-6 is involved in a variety of physiologic processes such as T-cell activation, hepatic acute-phase protein synthesis, and stimulation of the inflammatory processes involved in diseases such as RA.

2.Pharmacokinetics: The half-life of tocilizumab is dose-dependent, approximately 11 days for the 4 mg/kg dose and 13 days for the 8 mg/kg dose. IL-6 can suppress several CYP450 isoenzymes; thus, inhibiting IL-6 may restore CYP450 activities to higher levels. This may be clinically relevant for drugs that are CYP450 substrates and have a narrow therapeutic window (eg, cyclosporine or warfarin), and dosage adjustment of these medications may be needed.

Tocilizumab can be used in combination with nonbiologic DMARDs or as monotherapy. In the USA the recommended starting dose for RA is 4 mg/kg intravenously every 4 weeks followed by an increase to 8 mg/kg (not exceeding 800 mg/infusion) dependent on clinical response. In Europe, the starting dose of tocilizumab is 8 mg/kg up to 800 mg. Tocilizumab dosage in SJIA or PJIA follows an algorithm that accounts for body weight. Additionally, dosage modifications are recommended on the basis of certain laboratory changes such as elevated liver enzymes, neutropenia, and thrombocytopenia.

3.Indications: Tocilizumab is indicated for adult patients with moderately to severely active RA who have had an inadequate response to one or more DMARDs. It is also indicated in patients who are older than 2 years with active SJIA or active PJIA. A recent study showed that it is slightly more effective than adalimumab.

4.Adverse Effects: Serious infections including tuberculosis, fungal, viral, and other opportunistic infections have occurred. Screening for tuberculosis should be done prior to beginning tocilizumab. The most common adverse reactions are upper respiratory tract infections, headache, hypertension, and elevated liver enzymes.

Neutropenia and reduction in platelet counts occur occasionally, and lipids (eg, cholesterol, triglycerides, LDL, and HDL) should be monitored. GI perforation has been reported when using tocilizumab in patients with diverticulitis and in those using corticosteroids, although it is not clear that this adverse effect is more common than with TNF-α-blocking agents. Demyelinating disorders including multiple sclerosis are rarely associated with tocilizumab use. Fewer than 1% of the patients taking tocilizumab develop anaphylactic reaction. Anti-tocilizumab antibodies develop in 2% of the patients, and these can be associated with hypersensitivity reactions requiring discontinuation.

TNF-α-BLOCKING AGENTS

Cytokines play a central role in the immune response (see Chapter 55) and in RA. Although a wide range of cytokines are expressed in the joints of RA patients, TNF-α appears to be particularly important in the inflammatory process.

TNF-α affects cellular function via activation of specific membrane-bound TNF receptors (TNFR1, TNFR2). Five biologic DMARDs interfering with TNF-α have been approved for the treatment of RA and other rheumatic diseases (Figure 36–4). These drugs have many adverse effects in common; these effects are discussed at the end of this section.

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FIGURE 36–4 Structures of TNF-α antagonists used in rheumatoid arthritis. CH, constant heavy chain; CL, constant light chain; Fc, complex immunoglobulin region; VH, variable heavy chain; VL, variable light chain. Red regions, human derived; blue regions, mouse derived; green regions, polyethylene glycol (PEG).

Adalimumab

1.Mechanism of Action: Adalimumab is a fully human IgG1 anti-TNF monoclonal antibody. This compound complexes with soluble TNF-α and prevents its interaction with p55 and p75 cell surface receptors. This results in down-regulation of macrophage and T-cell function.

2.Pharmacokinetics: Adalimumab is given subcutaneously and has a half-life of 10–20 days. Its clearance is decreased by more than 40% in the presence of methotrexate, and the formation of human anti-monoclonal antibody is decreased when methotrexate is given at the same time. The usual dose in RA is 40 mg every other week, but dosing is frequently increased to 40 mg weekly. In psoriasis, 80 mg is given at week 0, 40 mg at week 1, and then 40 mg every other week thereafter. The initial dose in inflammatory bowel disease is higher; patients receive 160 mg at week 0, 80 mg 2 weeks later, followed by a 40 mg maintenance dose every other week. Patients with ulcerative colitis should continue maintenance treatment beyond 8 weeks if they show evidence of remission by that time. Adalimumab dose depends on the body weight in patients with JIA; 20 mg every other week for patients weighing 15–30 kg, and 40 mg every other week in patients weighing 30 kg or more.

3.Indications: The compound is approved for RA, AS, PA, JIA, plaque psoriasis, Crohn’s disease, and ulcerative colitis. It decreases the rate of formation of new erosions. It is effective both as monotherapy and in combination with methotrexate and other nonbiologic DMARDs. Based only on case reports and case series, adalimumab has also been found to be effective in the treatment of Behçet’s disease, sarcoidosis, and notably, noninfectious uveitis.

Certolizumab

1.Mechanism of Action: Certolizumab is a recombinant, humanized antibody Fab fragment conjugated to a polyethylene glycol (PEG) with specificity for human TNF-α. Certolizumab neutralizes membrane-bound and soluble TNF-α in a dose-dependent manner. Additionally, certolizumab does not contain an Fc region, found on a complete antibody, and does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro.

2.Pharmacokinetics: Certolizumab is given subcutaneously and has a half-life of 14 days. Methotrexate decreases the appearance of anti-certolizumab antibodies. The usual dose for RA is 400 mg initially and at weeks 2 and 4, followed by 200 mg every other week, or 400 mg every 4 weeks.

3.Indications: Certolizumab is indicated for the treatment of adults with moderately to severely active RA. It can be used as monotherapy or in combination with nonbiologic DMARDs. Additionally, certolizumab is approved in adult patients with Crohn’s disease, active PA and active AS.

Etanercept

1.Mechanism of Action: Etanercept is a recombinant fusion protein consisting of two soluble TNF p75 receptor moieties linked to the Fc portion of human IgG1 (Figure 36–4); it binds TNF-α molecules and also inhibits lymphotoxin-α.

2.Pharmacokinetics: Etanercept is given subcutaneously as 25 mg twice weekly or 50 mg weekly. In psoriasis, 50 mg is given twice weekly for 12 weeks and then is followed by 50 mg weekly. The drug is slowly absorbed, with peak concentration 72 hours after drug administration. Etanercept has a mean serum elimination half-life of 4.5 days. A recent study demonstrated a reduction of radiographic progression with the use of 50 mg of etanercept weekly.

3.Indications: Etanercept is approved for the treatment of RA, juvenile chronic arthritis, psoriasis, PA, and AS. It can be used as monotherapy, although over 70% of patients taking etanercept are also using methotrexate. Etanercept decreases the rate of formation of new erosions relative to methotrexate alone. It is also being used in other rheumatic syndromes such as scleroderma, granulomatosis with polyangiitis (Wegener’s granulomatosis), giant cell arteritis, Behçet’s disease, uveitis, and sarcoidosis.

Golimumab

1.Mechanism of Action: Golimumab is a human monoclonal antibody with a high affinity for soluble and membrane-bound TNF-α. Golimumab effectively neutralizes the inflammatory effects produced by TNF-α seen in diseases such as RA.

2.Pharmacokinetics: Golimumab is administered subcutaneously and has a half-life of approximately 14 days. Concomitant use with methotrexate increases golimumab serum levels and decreases anti-golimumab antibodies. The recommended dose for the treatment of RA, PA, and AS is 50 mg given every 4 weeks. A higher dose of golimumab is used for the treatment of ulcerative colitis as follows: 200 mg initially at week 0 followed by 100 mg at week 2 and every 4 weeks thereafter.

3.Indications: Golimumab with methotrexate is indicated for the treatment of moderately to severely active RA in adult patients. It is also indicated for the treatment of PA and AS and moderate to severe ulcerative colitis.

Infliximab

1.Mechanism of Action: Infliximab (Figure 36–4) is a chimeric (25% mouse, 75% human) IgG1 monoclonal antibody that binds with high affinity to soluble and possibly membrane-bound TNF-α. Its mechanism of action probably is the same as that of adalimumab.

2.Pharmacokinetics: Infliximab is given as an intravenous infusion with “induction” at 0, 2, and 6 weeks and maintenance every 8 weeks thereafter. Dosing is 3–10 mg/kg, and the usual dose is 3–5 mg/kg every 8 weeks. There is a relationship between serum concentration and effect, although individual clearances vary markedly. The terminal half-life is 9–12 days without accumulation after repeated dosing at the recommended interval of 8 weeks. After intermittent therapy, infliximab elicits human antichimeric antibodies in up to 62% of patients. Concurrent therapy with methotrexate markedly decreases the prevalence of human antichimeric antibodies.

3.Indications: Infliximab is approved for use in RA, AS, PA, Crohn’s disease, ulcerative colitis, pediatric inflammatory bowel disease, and psoriasis. It is being used off-label in other diseases, including granulomatosis with polyangiitis (Wegener’s granulomatosis), giant cell arteritis, Behçet’s disease, uveitis, and sarcoidosis. In RA, infliximab plus methotrexate decreases the rate of formation of new erosions. Although it is recommended that methotrexate be used in conjunction with infliximab, a number of other nonbiologic DMARDs, including antimalarials, azathioprine, leflunomide, and cyclosporine, can be used as background therapy for this drug. Infliximab is also used as monotherapy.

Adverse Effects of TNF-α-Blocking Agents

TNF-α-blocking agents have multiple adverse effects in common. The risk of bacterial infections and macrophage-dependent infection (including tuberculosis, fungal, and other opportunistic infections) is increased, although it remains very low. Activation of latent tuberculosis is lower with etanercept than with other TNF-α-blocking agents. Nevertheless, all patients should be screened for latent or active tuberculosis before starting TNF-α-blocking agents. The use of TNF-α-blocking agents is also associated with increased risk of HBV reactivation and screening for HBV is important before starting the treatment.

TNF-α-blocking agents increase the risk of skin cancers—including melanoma—which necessitates periodic skin examination, especially in high-risk patients. On the other hand, there is no clear evidence of increased risk of solid malignancies or lymphomas with TNF-α-blocking agents, and their incidence may not be different compared with other DMARDs or active RA itself.

A low incidence of newly formed dsDNA antibodies and antinuclear antibodies (ANAs) has been documented when using TNF-α-blocking agents, but clinical lupus is extremely rare and the presence of ANA and dsDNA antibodies per se does not contraindicate the use of TNF-α-blocking agents. In patients with borderline or overt heart failure (HF), TNF-α-blocking agents can exacerbate HF. TNF-α-blocking agents can induce the immune system to develop anti-drug antibodies in about 17% of cases. These antibodies may interfere with drug efficacy and correlate with infusion site reactions. Injection site reactions occur in 20–40% of patients, although they rarely result in discontinuation of therapy. Cases of alopecia areata, hypertrichosis, and erosive lichen planus have been reported. Cutaneous pseudo lymphomas are reported rarely with TNF-α-blocking agents, especially infliximab. TNF-α-blocking agents may increase the risk of gastrointestinal ulcers and large bowel perforation including diverticular and appendiceal perforation.

Nonspecific interstitial pneumonia, psoriasis, and sarcoidosis-like syndrome are among the rare reported toxicities associated with TNF-α blockers. Rare cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia have been reported. The precipitating drug should be discontinued in such cases.

TOFACITINIB

1.Mechanism of Action: Tofacitinib is a synthetic small molecule that selectively inhibits all members of the Janus kinase (JAK, see Chapter 2) family to varying degrees. At therapeutic doses, tofacitinib exerts its effect mainly by inhibiting JAK3, and to a lesser extent JAK1, hence interrupting the JAK-STAT signaling pathway. This pathway plays a major role in the pathogenesis of autoimmune diseases including RA. The JAK3/JAK1 complex is responsible for signal transduction from the common γ-chain receptor (IL-2RG) for IL-2, -4, -7, -9, -15, and -21, which subsequently influences transcription of several genes that are crucial for the differentiation, proliferation, and function of NK cells and T and B lymphocytes. In addition, JAK1 (in combination with other JAKs) controls signal transduction from IL-6 and interferon receptors. RA patients receiving tofacitinib rapidly reduce the C-reactive protein.

2.Pharmacokinetics: Tofacitinib is an oral, targeted DMARD. The recommended dose in the treatment of RA is 5 mg twice daily; there is a clear trend to increased response (and increased toxicity) at double this dose. Tofacitinib has an absolute oral bioavailability of 74%, high-fat meals do not affect the AUC, and the elimination half-life is about 3 hours. Metabolism (of 70%) occurs in the liver, mainly by CYP3A4 and to a lesser extent by CYP2C19. The remaining 30% is excreted unchanged by the kidneys. Patients taking CYP enzyme inhibitors and those with moderate hepatic or renal impairment require dose reduction to 5 mg once daily. It should not be given to patients with severe hepatic disease.

3.Indications: Tofacitinib was originally developed to prevent solid organ allograft rejection. It has also been tested for the treatment of inflammatory bowel disease, spondyloarthritis, psoriasis, and dry eyes. To date, tofacitinib is approved in the USA for the treatment of adult patients with moderately to severely active RA who have failed or are intolerant to methotrexate. It is not approved in Europe for this indication. It can be used as a monotherapy or in combination with other nonbiologic DMARDs, including methotrexate.

4.Adverse Effects: As with biologic DMARDs, tofacitinib slightly increases the risk of infection, and it should not be used with potent immunosuppressants or biologic DMARDs due to added immunosuppressive effects. Upper respiratory tract infection and urinary tract infection represent the most common infections. More serious infections are also reported, including pneumonia, cellulitis, esophageal candidiasis, and other opportunistic infections. All patients should be screened for latent or active tuberculosis before the initiation of treatment. Lymphoma and other malignancies such as lung and breast cancer have been reported in patients taking tofacitinib, although some studies discuss the potential use of JAK inhibitors to treat certain lymphomas. Dose-dependent increases in the levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol have been found in patients receiving tofacitinib, often beginning about 6 weeks after starting treatment; therefore, lipid levels should be monitored. Although tofacitinib causes a dose-dependent increase in CD19 B cells and CD4 T cells plus a reduction in CD16/CD56 NK cells, the clinical significance of these changes remains unclear. Drug-related neutropenia and anemia occur, requiring drug discontinuation. Headache, diarrhea, elevation of liver enzymes, and gastrointestinal perforation are among the other reported effects of tofacitinib.

INTERLEUKIN-1 INHIBITORS

IL-1α plays a major role in the pathogenesis of several inflammatory and autoimmune diseases including RA. IL-1β and IL-1 receptor antagonist (IL-1RA) are other members of the IL-1 family. All three bind to IL-1 receptors in the same manner. However, IL-1RA does not initiate the intracellular signaling pathway and thus acts as a competitive inhibitor of the proinflammatory IL-1α and IL-1β.

Anakinra

1.Mechanism of Action: Anakinra is the oldest drug in this family but is now rarely used for RA. Anakinra is a recombinant IL-1RA; it blocks the effect of IL-1α and IL-1β on IL-1 receptors, hence decreasing the immune response in inflammatory diseases.

2.Pharmacokinetics: Anakinra is administered subcutaneously and reaches a maximum plasma concentration after 3–7 hours. The absolute bioavailability of anakinra is 95%, and it has a 4- to 6-hour terminal half-life. The recommended dose in the treatment of RA is 100 mg daily. The dose of anakinra depends on the body weight in the treatment of cryopyrin-associated periodic syndrome (CAPS), starting with 1–2 mg/kg/d to a maximum of 8 mg/kg/d. Reduction in the frequency of administering anakinra to every other day is recommended in patients with renal insufficiency.

3.Indications: Anakinra is approved for the treatment of moderately to severely active RA in adult patients, but it is not very effective and is rarely used for this indication. However, anakinra is the drug of choice for CAPS, particularly the neonatal-onset multisystem inflammatory disease (NOMID) subtype. Anakinra is effective in gout (see below) and is used for other diseases including Behçet’s disease and adult onset JIA. Its use for giant cell arteritis is controversial.

Canakinumab

1.Mechanism of Action: Canakinumab is a human IgG1/κ monoclonal antibody against IL-1β. It forms a complex with IL-1β, preventing its binding to IL-1 receptors.

2.Pharmacokinetics: Canakinumab is given as subcutaneous injections. It reaches peak serum concentrations 7 days after a single subcutaneous injection. Canakinumab has an absolute bioavailability of 66% and a 26-day mean terminal half-life. The recommended dose for patients with SJIA who weigh more than 7.5 kg is 4 mg/kg every 4 weeks. There is a weight-adjusted algorithm for treating CAPS.

3.Indications: Canakinumab is indicated for active SJIA in children 2 years or older. It is also used to treat CAPS, particularly the familial cold autoinflammatory syndrome and Muckle-Wells syndrome subtypes for adults and children 4 years or older. Canakinumab is also used to treat gout (see below).

Rilonacept

1.Mechanism of Action: Rilonacept is the ligand-binding domain of the IL-1 receptor. It binds mainly to IL-1β and binds with lower affinity to IL-1α and IL-1RA. Rilonacept neutralizes IL-1β and prevents its attachment to IL-1 receptors.

2.Pharmacokinetics: The subcutaneous dose of rilonacept for CAPS is age-dependent. In patients 12–17 years of age, 4.4 mg/kg (maximum of 320 mg) is the loading dose, with a maintenance dose of 2.2 mg/kg (maximum of 160 mg) weekly. Those 18 years and older receive 320 mg as a loading dose and 160 mg weekly thereafter. The steady-state plasma concentration is reached after 6 weeks.

3.Indications: Rilonacept is approved to treat CAPS subtypes: familial cold autoinflammatory syndrome and Muckle-Wells syndrome in patients 12 years or older. Rilonacept is also used to treat gout (see below).

Adverse Effects of Interleukin-1 Inhibitors

The most common adverse effects are injection site reactions (up to 40%) and upper respiratory tract infections. Serious infections occur rarely in patients given IL-1 inhibitors. Headache, abdominal pain, nausea, diarrhea, arthralgia, and flu-like illness have all been reported, as well as hypersensitivity reactions. Patients taking IL-1 inhibitors may experience transient neutropenia, which requires regular monitoring of neutrophil counts.

BELIMUMAB

Belimumab is an antibody that specifically inhibits B-lymphocyte stimulator (BLyS). It is administered as an intravenous infusion. The recommended dose is 10 mg/kg at weeks 0, 2, 4, and every 4 weeks thereafter. Belimumab has a distribution half-life of 1.75 days and a terminal half-life of 19.4 days.

Belimumab is approved only for the treatment of adult patients with active, seropositive SLE who are receiving standard treatment. The drug was approved after a protracted series of clinical trials, and its place in the SLE armamentarium is not clear. Belimumab should not be used in patients with active renal or neurological manifestations of SLE, as there are no data for these conditions. In addition, the efficacy of belimumab has not been tested in combination with other biologic DMARDs or cyclophosphamide.

The most common adverse effects of belimumab are nausea, diarrhea, and respiratory tract infection. As with other biologic DMARDs, there is a slight increase in the risk of infection including serious infections. Cases of depression and suicide have been reported in patients receiving belimumab, although these patients may have had neurologic SLE, thus confounding the causal relationship. Infusion reactions including anaphylaxis are among the other adverse effects. A very small percentage of patients develop antibodies toward belimumab; their clinical significance however is not clear.

COMBINATION THERAPY WITH DMARDS

In a 1998 survey, approximately half of North American rheumatologists treated moderately aggressive RA with combination therapy, and the use of drug combinations is probably much higher now. Combinations of DMARDs can be designed rationally on the basis of complementary mechanisms of action, nonoverlapping pharmacokinetics, and nonoverlapping toxicities.

When added to methotrexate background therapy, cyclosporine, chloroquine, hydroxychloroquine, leflunomide, infliximab, adalimumab, rituximab, and etanercept have all shown improved efficacy. Triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine appears to be as effective as etanercept and methotrexate. In contrast, azathioprine or sulfasalazine plus methotrexate results in no additional therapeutic benefit. Other combinations have occasionally been used.

While it might be anticipated that combination therapy could result in more toxicity, this is often not the case. Combination therapy for patients not responding adequately to monotherapy is now the rule in the treatment of RA.

GLUCOCORTICOID DRUGS

The general pharmacology of corticosteroids, including mechanism of action, pharmacokinetics, and other applications, is discussed in Chapter 39.

Indications

Corticosteroids have been used in 60–70% of RA patients. Their effects are prompt and dramatic, and they are capable of slowing the appearance of new bone erosions. Corticosteroids may be administered for certain serious extra-articular manifestations of RA such as pericarditis or eye involvement or during periods of exacerbation. When prednisone is required for long-term therapy, the dosage should not exceed 7.5 mg daily, and gradual reduction of the dose should be encouraged. Alternate-day corticosteroid therapy is usually unsuccessful in RA.

Other rheumatic diseases in which the corticosteroids’ potent anti-inflammatory effects may be useful include vasculitis, SLE, Wegener’s granulomatosis, PA, giant cell arteritis, sarcoidosis, and gout. Intra-articular corticosteroids are often helpful to alleviate painful symptoms and, when successful, are preferable to increasing the dosage of systemic medication.

Some of the symptoms of RA, especially morning stiffness and joint pain, follow a circadian rhythm, probably due to an increase in proinflammatory cytokines in the early morning. A recent approach uses delayed-release prednisone for the treatment of early morning stiffness and pain in RA. The tablet contains an inactive outer layer and a core of the active drug. The outer layer dissolves over 4–6 hours, releasing the prednisone. Taking the drug at 9–10 pm results in a small pulse of prednisone at 2–4 am, decreasing the circadian inflammatory cytokines. At low doses of 3–5 mg prednisone, the adrenal-pituitary axis does not seem to be impacted.

Adverse Effects

Prolonged use of corticosteroids leads to serious and disabling toxic effects as described in Chapter 39. Many of these adverse effects occur at doses below 7.5 mg prednisone equivalent daily and many experts believe that even 3–5 mg/d can cause adverse effects in susceptible individuals when this class of drugs is used over prolonged periods.

image OTHER ANALGESICS

Acetaminophen is one of the most important drugs used in the treatment of mild to moderate pain when an anti-inflammatory effect is not necessary. Phenacetin, a prodrug that is metabolized to acetaminophen, is more toxic and should not be used.

ACETAMINOPHEN

Acetaminophen is the active metabolite of phenacetin and is responsible for its analgesic effect. It is a weak COX-1 and COX-2 inhibitor in peripheral tissues and possesses no significant anti-inflammatory effects.

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1.Pharmacokinetics: Acetaminophen is administered orally. Peak blood concentrations are usually reached in 30–60 minutes. Acetaminophen is poorly bound to plasma proteins and is partially metabolized by hepatic microsomal enzymes to the inactive sulfate and glucuronide (see Figure 4–5). Less than 5% is excreted unchanged. A minor but highly reactive metabolite (N-acetyl-p-benzoquinone) is important in large doses because it is toxic to both liver and kidney (see Chapter 4). The half-life of acetaminophen is 2–3 hours and is relatively unaffected by renal function. With toxic doses or liver disease, the half-life may be increased twofold or more.

2.Indications: Although said to be equivalent to aspirin as an analgesic and antipyretic agent, acetaminophen lacks anti-inflammatory properties. It does not affect uric acid levels and lacks platelet-inhibiting effects. The drug is useful in mild to moderate pain such as headache, myalgia, postpartum pain, and other circumstances in which aspirin is an effective analgesic. Acetaminophen alone is inadequate therapy for inflammatory conditions such as RA. For mild analgesia, acetaminophen is the preferred drug in patients allergic to aspirin, when salicylates are poorly tolerated. It is preferable to aspirin in patients with hemophilia, in those with a history of peptic ulcer, and in those in whom bronchospasm is precipitated by aspirin. Unlike aspirin, acetaminophen does not antagonize the effects of uricosuric agents.

3.Adverse Effects: In therapeutic doses, a mild reversible increase in hepatic enzymes may occasionally occur. With larger doses, dizziness, excitement, and disorientation may occur. Ingestion of 15 g of acetaminophen may be fatal, death being caused by severe hepatotoxicity with centrilobular necrosis, sometimes associated with acute renal tubular necrosis (see Chapters 4 and 58).

4.Present data indicate that even 4 g acetaminophen is associated with increased liver function test abnormalities. Doses greater than 4 g/d are not usually recommended and a history of alcoholism contraindicates even this dose. Early symptoms of hepatic damage include nausea, vomiting, diarrhea, and abdominal pain. Cases of renal damage without hepatic damage have occurred, even after usual doses of acetaminophen. Therapy for overdose is much less satisfactory than that for aspirin overdose. In addition to supportive therapy, one should provide sulfhydryl groups in the form of acetylcysteine to neutralize the toxic metabolites (see Chapter 58).

5.Hemolytic anemia and methemoglobinemia are very rare adverse events. Interstitial nephritis and papillary necrosis—serious complications of phenacetin—have not occurred, and GI bleeding also has not occurred. Caution is necessary in patients with any type of liver disease.

6.Dosage: Acute pain and fever may be effectively treated with 325–500 mg four times daily and proportionately less for children. Dosing in adults is now recommended not to exceed 4 g/d, in most cases.

KETOROLAC

Ketorolac is an NSAID promoted for systemic use mainly as a short-term analgesic (not longer than 1 week), not as an anti-inflammatory drug (although it has typical NSAID properties). Pharmacokinetics are presented in Table 36–1. The drug is an effective analgesic and has been used successfully to replace morphine in some situations involving mild to moderate postsurgical pain. It is most often given intramuscularly or intravenously, but an oral formulation is available. When used with an opioid, it may decrease the opioid requirement by 25–50%. Toxicities are similar to those of other NSAIDs (see pages 620-621), although renal toxicity is more common with chronic use.

TRAMADOL

Tramadol is a centrally acting synthetic analgesic, structurally related to opioids. Since naloxone, an opioid receptor blocker, only inhibits 30% of the analgesic effect of tramadol, the mechanism of action of this drug must involve both nonopioid and opioid receptors. Tramadol does not have significant anti-inflammatory effects. The drug may exert part of its analgesic effect by enhancing 5-hydroxytryptamine (5-HT) release and inhibiting the reuptake of norepinephrine and 5-HT (see Chapter 31).

image DRUGS USED IN GOUT

Gout is a metabolic disease characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage. Uric acid renal calculi, tophi, and interstitial nephritis may also occur. Adverse cardiovascular outcomes are becoming more clear as well. Gout is usually associated with a high serum uric acid level (hyperuricemia), a poorly soluble substance that is the major end product of purine metabolism. In most mammals, uricase converts uric acid to the more soluble allantoin; this enzyme is absent in humans. While clinical gouty episodes are associated with hyperuricemia, most individuals with hyperuricemia may never develop a clinical event from urate crystal deposition.

The treatment of gout aims to relieve acute gouty attacks and prevent recurrent gouty episodes and urate lithiasis. Therapies for acute gout are based on our current understanding of the pathophysiologic events that occur in this disease (Figure 36–5). Clinical gout is dependent on a macromolecular complex of proteins, called NLRP3, which regulates the activation of IL-1. Urate crystals activate NLRP3, resulting in release of prostaglandins and lysosomal enzymes by synoviocytes. Attracted by these chemotactic mediators, polymorphonuclear leukocytes migrate into the joint space and amplify the ongoing inflammatory process. In the later phases of the attack, increased numbers of mononuclear phagocytes (macrophages) appear, ingest the urate crystals, and release more inflammatory mediators.

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FIGURE 36–5 Pathophysiologic events in a gouty joint. Synoviocytes phagocytose urate crystals and then secrete inflammatory mediators, which attract and activate polymorphonuclear leukocytes (PMN) and mononuclear phagocytes (MNP) (macrophages). Drugs active in gout inhibit crystal phagocytosis and polymorphonuclear leukocyte and macrophage release of inflammatory mediators. PG, prostaglandin; IL-1, interleukin-1; LTB4, leukotriene B4.

Before starting chronic urate-lowering therapy for gout, patients in whom hyperuricemia is associated with gout and urate lithiasis must be clearly distinguished from individuals with only hyperuricemia. The efficacy of long-term drug treatment in an asymptomatic hyperuricemic person is unproved. Although there are data suggesting a clear relationship between the degree of uric acid elevation and the likelihood of clinical gout, in some individuals, uric acid levels may be elevated up to 2 standard deviations above the mean for a lifetime without adverse consequences. Many different agents have been used for the treatment of acute and chronic gout. However, non-adherence to these drugs is exceedingly common; adherence has been documented to be 18%–26% in younger patients. Providers should be aware of compliance as an important issue.

COLCHICINE

Although NSAIDs, corticosteroids, or colchicine are first-line drugs for acute gout, colchicine was the primary treatment for many years. Colchicine is an alkaloid isolated from the autumn crocus, Colchicum autumnale. Its structure is shown in Figure 36–6.

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FIGURE 36–6 Colchicine and uricosuric drugs.

1.Pharmacokinetics: Colchicine is absorbed readily after oral administration, reaches peak plasma levels within 2 hours, and is eliminated with a serum half-life of 9 hours. Metabolites are excreted in the intestinal tract and urine.

2.Pharmacodynamics: Colchicine relieves the pain and inflammation of gouty arthritis in 12–24 hours without altering the metabolism or excretion of urates and without other analgesic effects. Colchicine produces its anti-inflammatory effects by binding to the intracellular protein tubulin, thereby preventing its polymerization into microtubules and leading to the inhibition of leukocyte migration and phagocytosis. It also inhibits the formation of leukotriene B4 and IL-1β. Several of colchicine’s adverse effects are produced by its inhibition of tubulin polymerization and cell mitosis.

3.Indications: Colchicine is indicated for gout and is also used between attacks (the “intercritical period”) for prolonged prophylaxis (at low doses). It prevents attacks of acute Mediterranean fever and may have a mild beneficial effect in sarcoid arthritis and in hepatic cirrhosis. Colchicine is also used to treat and prevent pericarditis, pleurisy, and coronary artery disease, probably due to its anti-inflammatory effect. Although it has been given intravenously, this route is no longer approved by the FDA (2009).

4.Adverse Effects: Colchicine often causes diarrhea and may occasionally cause nausea, vomiting, and abdominal pain. Hepatic necrosis, acute renal failure, disseminated intravascular coagulation, and seizures have also been observed. Colchicine may rarely cause hair loss and bone marrow depression, as well as peripheral neuritis, myopathy, and, in some cases, death. The more severe adverse events have been associated with the intravenous administration of colchicine.

5.Dosage: In prophylaxis (the most common use), the dosage of colchicine is 0.6 mg one to three times daily. For terminating a gouty attack, a regimen of 1.2 mg followed by a single 0.6 mg oral dose was as effective as higher dose regimens and adverse events were less with this lower dose regimen. In 2008, the FDA requested that intravenous preparations containing colchicine be discontinued in the USA because of their potential life-threatening adverse effects. Therefore, intravenous colchicine is no longer available.

In 2009, the FDA approved a new oral formulation of colchicine for the treatment of acute gout, allowing Colcrys (a branded colchicine) marketing exclusivity in the USA. Generic colchicine rather than Colcrys is available throughout the rest of the world.

NSAIDS IN GOUT

In addition to inhibiting prostaglandin synthase, NSAIDs inhibit urate crystal phagocytosis. Aspirin is not used because it causes renal retention of uric acid at low doses (≤ 2.6 g/d). It is uricosuric at doses greater than 3.6 g/d. Indomethacin is commonly used in the initial treatment of gout as a replacement for colchicine. For acute gout, 50 mg is given three times daily; when a response occurs, the dosage is reduced to 25 mg three times daily for 5–7 days.

All other NSAIDs except aspirin, salicylates, and tolmetin have been successfully used to treat acute gouty episodes. Oxaprozin, which lowers serum uric acid, is theoretically a good choice. These agents appear to be as effective and safe as the older drugs.

URICOSURIC AGENTS

Probenecid and sulfinpyrazone are uricosuric drugs employed to decrease the body pool of urate in patients with tophaceous gout or in those with increasingly frequent gouty attacks. In a patient who excretes large amounts of uric acid, the uricosuric agents should not be used. Lesinurad (RDEA594) is a promising new uricosuric agent that is currently in phase 3 trials.

1.Chemistry and Pharmacokinetics: Uricosuric drugs are organic acids (Figure 36–6) and, as such, act at the anion transport sites of the renal tubule (see Chapter 15). Probenecid is completely reabsorbed by the renal tubules and is metabolized slowly with a terminal serum half-life of 5–8 hours. Sulfinpyrazone or its active hydroxylated derivative is excreted by the kidneys. Even so, the duration of its effect after oral administration is almost as long as that of probenecid, which is given once or twice daily.

2.Pharmacodynamics: Uricosuric drugs—probenecid, sulfinpyrazone, fenofibrate, and losartan—inhibit active transport sites for reabsorption and secretion in the proximal renal tubule so that net reabsorption of uric acid in the proximal tubule is decreased. Because aspirin in doses of less than 2.6 g daily causes net retention of uric acid by inhibiting the secretory transporter, it should not be used for analgesia in patients with gout. The secretion of other weak acids (eg, penicillin) is also reduced by uricosuric agents.

3.As the urinary excretion of uric acid increases, the size of the urate pool decreases, although the plasma concentration may not be greatly reduced. In patients who respond favorably, tophaceous deposits of urate are reabsorbed, with relief of arthritis and remineralization of bone. With the ensuing increase in uric acid excretion, a predisposition to the formation of renal stones is augmented rather than decreased; therefore, the urine volume should be maintained at a high level, and at least early in treatment, the urine pH should be kept above 6.0 by the administration of alkali.

4.Indications: Uricosuric therapy should be initiated in gouty patients with underexcretion of uric acid when allopurinol or febuxostat is contraindicated or when tophi are present. Therapy should not be started until 2–3 weeks after an acute attack.

5.Adverse Effects: Both of these organic acids cause equivalent GI irritation, but sulfinpyrazone is more active in this regard. A rash may appear after the use of either compound. Nephrotic syndrome has occurred after the use of probenecid. Both sulfinpyrazone and probenecid may rarely cause aplastic anemia.

6.Contraindications and Cautions: It is essential to maintain a large urine volume to minimize the possibility of stone formation.

7.Dosage: Probenecid is usually started at a dosage of 0.5 g orally daily in divided doses, progressing to 1 g daily after 1 week. Sulfinpyrazone is started at a dosage of 200 mg orally daily, progressing to 400–800 mg daily. It should be given in divided doses with food to reduce adverse GI effects.

ALLOPURINOL

The preferred and standard-of-care therapy for gout during the period between acute episodes is allopurinol, which reduces total uric acid body burden by inhibiting xanthine oxidase.

1.Chemistry and Pharmacokinetics: The structure of allopurinol, an isomer of hypoxanthine, is shown in Figure 36–7. Allopurinol is approximately 80% absorbed after oral administration and has a terminal serum half-life of 1–2 hours. Like uric acid, allopurinol is metabolized by xanthine oxidase, but the resulting compound, alloxanthine, retains the capacity to inhibit xanthine oxidase and has a long enough duration of action so that allopurinol is given only once a day.

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FIGURE 36–7 Inhibition of uric acid synthesis by allopurinol occurs because allopurinol and alloxanthine inhibit xanthine oxidase. (Reproduced, with permission, from Meyers FH, Jawetz E, Goldfien A: Review of Medical Pharmacology, 7th ed. McGraw-Hill, 1980. Copyright © The McGraw-Hill Companies, Inc.)

2.Pharmacodynamics: Dietary purines are not an important source of uric acid. Quantitatively important amounts of purine are formed from amino acids, formate, and carbon dioxide in the body. Those purine ribonucleotides not incorporated into nucleic acids and derived from nucleic acid degradation are converted to xanthine or hypoxanthine and oxidized to uric acid (Figure 36–7). Allopurinol inhibits this last step, resulting in a fall in the plasma urate level and a decrease in the overall urate burden. The more soluble xanthine and hypoxanthine are increased.

3.Indications: Allopurinol is often the first-line agent for the treatment of chronic gout in the period between attacks and it tends to prolong the intercritical period. As with uricosuric agents, the therapy is begun with the expectation that it will be continued for years if not for life. When initiating allopurinol, colchicine or NSAID should be used until steady-state serum uric acid is normalized or decreased to less than 6 mg/dL and they should be continued for 6 months or longer. Thereafter, colchicine or the NSAID can be cautiously stopped while continuing allopurinol therapy.

4.Adverse Effects: In addition to precipitating gout (the reason to use concomitant colchicine or NSAID), GI intolerance (including nausea, vomiting, and diarrhea), peripheral neuritis and necrotizing vasculitis, bone marrow suppression, and aplastic anemia may rarely occur. Hepatic toxicity and interstitial nephritis have been reported. An allergic skin reaction characterized by pruritic maculopapular lesions occurs in 3% of patients. Isolated cases of exfoliative dermatitis have been reported. In very rare cases, allopurinol has become bound to the lens, resulting in cataracts.

5.Interactions and Cautions: When chemotherapeutic purines (eg, azathioprine) are given concomitantly with allopurinol, their dosage must be reduced by about 75%. Allopurinol may also increase the effect of cyclophosphamide. Allopurinol inhibits the metabolism of probenecid and oral anticoagulants and may increase hepatic iron concentration. Safety in children and during pregnancy has not been established.

6.Dosage: The initial dosage of allopurinol is 50–100 mg/d. It should be titrated upward until serum uric acid is below 6 mg/dL; this level is commonly achieved at 300–400 mg/d but is not restricted to this dose; doses as high as 800 mg/d may be needed.

As noted above, colchicine or an NSAID should be given during the first months of allopurinol therapy to prevent the gouty arthritis episodes that sometimes occur.

FEBUXOSTAT

Febuxostat is a non-purine xanthine oxidase inhibitor that was approved by the FDA in 2009.

1.Pharmacokinetics: Febuxostat is more than 80% absorbed following oral administration. With maximum concentration achieved in approximately 1 hour and a half-life of 4–18 hours, once-daily dosing is effective. Febuxostat is extensively metabolized in the liver. All of the drug and its inactive metabolites appear in the urine, although less than 5% appears as unchanged drug.

2.Pharmacodynamics: Febuxostat is a potent and selective inhibitor of xanthine oxidase, thereby reducing the formation of xanthine and uric acid without affecting other enzymes in the purine or pyrimidine metabolic pathway. In clinical trials, Febuxostat at daily dosing of 80 mg or 120 mg was more effective in lowering serum urate levels than allopurinol at a standard 300 mg daily dose. The urate-lowering effect was comparable regardless of the pathogenic cause of hyperuricemia—overproduction or underexcretion.

3.Indications: Febuxostat is approved at doses of 40 or 80 mg for the treatment of chronic hyperuricemia in gout patients. Although it appeared to be more effective then allopurinol as urate-lowering therapy, the allopurinol dosing was limited to 300 mg/d, thus not reflecting the actual dosing regimens used in clinical practice. At this time, the dose equivalence of allopurinol and febuxostat is unknown.

4.Adverse Effects: As with allopurinol, prophylactic treatment with colchicine or NSAIDs should be started at the beginning of therapy to avoid gout flares. The most frequent treatment-related adverse events are liver function abnormalities, diarrhea, headache, and nausea. Febuxostat is well tolerated in patients with a history of allopurinol intolerance. There does not appear to be an increased risk of cardiovascular events.

5.Dosage: The recommended starting dose of febuxostat is 40 mg daily. Because there was concern for cardiovascular events in the original phase 3 trials, the FDA approved only 40 mg and 80 mg dosing. No dose adjustment is necessary for patients with renal impairment since it is highly metabolized into an inactive metabolite by the liver.

PEGLOTICASE

Pegloticase is the newest urate-lowering therapy to be approved for the treatment of refractory chronic gout.

1.Chemistry: Pegloticase is a recombinant mammalian uricase that is covalently attached to methoxy polyethylene glycol (mPEG) to prolong the circulating half-life and diminish immunogenic response.

2.Pharmacokinetics and Dosage: The recommended dose for pegloticase is 8 mg every 2 weeks administered as an intravenous infusion. It is a rapidly acting drug, achieving a peak decline in uric acid level within 24–72 hours. The serum half-life ranges from 6 to 14 days. Several studies have shown earlier clearance of PEG-uricase (mean of 11 days) due to antibody response when compared to PEG-uricase antibody-negative subjects (mean of 16.1 days).

3.Pharmacodynamics: Urate oxidase enzyme, absent in humans and some higher primates, converts uric acid to allantoin. This product is highly soluble and can be easily eliminated by the kidney. Pegloticase has been shown to maintain low urate levels for up to 21 days after a single dose at doses of 4–12 mg, allowing for IV dosing every 2 weeks. Pegloticase should not be used for asymptomatic hyperuricemia.

4.Adverse Effects: Gout flare can occur during treatment with pegloticase, especially during the first 3–6 months of treatment, requiring prophylaxis with NSAIDs or colchicine. Large numbers of patients show immune responses to pegloticase. The presence of antipegloticase antibodies is associated with shortened circulating half-life, loss of response leading to a rise in plasma urate levels, and a higher rate of infusion reactions and anaphylaxis. Anaphylaxis occurs in more than 6–15% of patients receiving pegloticase. Monitoring of plasma uric acid level, with rising level as an indicator of antibody production, allows for safer administration and monitoring of efficacy. In addition, other oral urate-lowering agents should be avoided in order not to mask the loss of pegloticase efficacy. Nephrolithiasis, arthralgia, muscle spasm, headache, anemia, and nausea may occur. Other less frequent side effects noted include upper respiratory tract infection, peripheral edema, urinary tract infection, and diarrhea. There is some concern for hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency because of the formation of hydrogen peroxide by uricase; therefore, pegloticase should be avoided in these patients.

GLUCOCORTICOIDS

Corticosteroids are sometimes used in the treatment of severe symptomatic gout, by intra-articular, systemic, or subcutaneous routes, depending on the degree of pain and inflammation.

The most commonly used oral corticosteroid is prednisone. The recommended oral dose is 30–50 mg/d for 1–2 days, tapered over 7–10 days. Intra-articular injection of 10 mg (small joints), 30 mg (wrist, ankle, elbow), and 40 mg (knee) of triamcinolone acetonide can be given if the patient is unable to take oral medications.

INTERLEUKIN-1 INHIBITORS

Drugs targeting the IL-1 pathway, such as anakinra, canakinumab, and rilonacept, are used for the treatment of gout. Although the data are limited, these agents may provide a promising treatment option for acute gout in patients with contraindications to, or who are refractory to, traditional therapies like NSAIDs or colchicine. A recent study suggests that canakinumab, a fully human anti-IL-1β monoclonal antibody, can provide rapid and sustained pain relief at a dose of 150 mg subcutaneously. These medications are also being evaluated as therapies for prevention of gout flares while initiating urate-lowering therapy.

PREPARATIONS AVAILABLE

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Zouali M, Uy EA: Belimumab therapy in systemic lupus erythematosus. BioDrugs 2013;27:3.

Other Analgesics

Chandrasekharan NV et al: COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. Proc Natl Acad Sci USA 2002;99:13926.

Lee CR, McTavish D, Sorkin EM: Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 1993;46:2.

Drugs Used in Gout

Becker MA et al: Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353:2450.

Getting SJ et al: Activation of melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis. Arthritis Rheum 2002;46:2765.

Schumacher HR: Febuxostat: A non-purine, selective inhibitor of xanthine oxidase for the management of hyperuricaemia in patients with gout. Expert Opin Investig Drugs 2005;14:893.

So A et al: A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 2007;9:R28.

Wallace SL, Singer JZ: Systemic toxicity associated with intravenous administration of colchicine—Guidelines for use. J Rheumatol 1988;15:495.

http://www.fda.gov/cder/drugs/unapproved_drugs/colchicine_qa.htm  (Restriction on drugs containing colchicine)

CASE STUDY ANSWER

This patient had good control of his symptoms for 1 year but now has a prolonged flare, probably denoting worsening disease (not just a temporary flare). In addition to physical findings and measurement of acute-phase reactants such as sedimentation rate or C-reactive protein, it would be wise to get hand and feet radiographs to document whether he has developed joint damage. Assuming such damage is found, the appropriate approach would be either a combination of nonbiologic DMARDs (eg, adding sulfasalazine and hydroxychloroquine) or adding a biologic medication, usually a TNF inhibitor. Follow-up should be every 1–3 months to gauge response and toxicity. Adverse events requiring caution are an increased risk of infection, possible appearance of lymphoma and rare liver function test or hematologic abnormalities. Importantly, close follow-up should ensue, including changing medications every 3–6 months until full disease control is achieved.

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* Listed alphabetically.