Drug therapy of rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune, inflammatory disorder that affects about 1% of the American population. Each year, the disease results in more than 9 million physician visits and over 250,000 hospitalizations. Although RA can develop at any age, initial symptoms usually appear during the third and fourth decades. Among younger patients, the incidence of RA in females is 3 times greater than in males. However, among patients over age 60, the incidence in men and women is equal. Rheumatoid arthritis follows a progressive course, and can eventually cripple its victim. In many cases, drug therapy can delay disease progression. In others, benefits are limited to symptomatic relief. Some of the drugs used for RA were introduced in preceding chapters. Additional drugs are introduced here.

Pathophysiology of rheumatoid arthritis

Onset of RA is heralded by symmetric joint stiffness and pain. Symptoms are most intense in the morning and abate as the day advances. Joints become swollen, tender, and warm. For some patients, periods of spontaneous remission occur. For others, injury progresses steadily. In addition to joint injury, RA has systemic manifestations, including fever, weakness, fatigue, weight loss, thinning of the skin, scleritis (inflammation of the sclera), corneal ulcers, vasculitis (which can be severe), and nodules under the skin and periosteum (connective tissue that surrounds all bones).

The progression of joint deterioration is depicted in Figure 73–1. Inflammation begins in the synovium—the membrane that encloses the joint cavity. As inflammation intensifies, the synovial membrane thickens and begins to envelop the articular cartilage. This overgrowth is referred to as pannus. Damage to the cartilage is caused by enzymes released from the pannus and by chemicals and enzymes produced by the inflammatory process raging within the synovial space. Ultimately, the articular cartilage undergoes total destruction, resulting in direct contact between bones of the joint, followed by eventual bone fusion. After this, inflammation subsides.

Figure 73–1 Progressive joint degeneration in rheumatoid arthritis.
A, Healthy joint. B, Inflammation of synovial membrane. C, Onset of pannus formation and cartilage erosion. D, Pannus formation progresses and cartilage deteriorates further. E, Complete destruction of joint cavity together with fusion of articulating bones.

Joint destruction is caused by an autoimmune process in which the immune system mounts an attack against synovial tissue. During the attack, mast cells, macrophages, and T lymphocytes produce cytokines and cytotoxins—compounds that promote inflammation and joint destruction. The cytokines of greatest importance are tumor necrosis factor, interleukin-1, interleukin-6, interferon gamma, platelet-derived growth factor, and granulocyte-macrophage colony-stimulating factor. Why the immune system attacks joints is unclear.

NSAID classification.

As discussed in Chapter 71, there are two main classes of NSAIDs: (1) first-generation NSAIDs, which inhibit COX-1 and COX-2; and (2) second-generation NSAIDs (coxibs), which selectively inhibit COX-2. Anti-inflammatory and analgesic effects result from inhibiting COX-2, whereas major adverse effects—especially gastroduodenal ulceration—result from inhibiting COX-1. Because of their selectivity, the coxibs may cause less GI ulceration than the first-generation NSAIDs, while producing equal therapeutic effects.

Drug selection.

Selection of an NSAID is based largely on efficacy, safety, and cost.

Efficacy.

All of the NSAIDs have essentially equal antirheumatic effects. However, individual patients may respond better to one NSAID than to another. Accordingly, it may be necessary to try more than one agent to achieve an optimal response.

Safety and cost.

The COX-2 inhibitors (eg, celecoxib [Celebrex]) appear somewhat safer than the first-generation NSAIDs, but are also more expensive. Hence, selection must balance these factors. If symptoms are controlled with a first-generation NSAID, and the drug is well tolerated, cost considerations would dictate using that drug. However, if a first-generation NSAID produces serious gastric ulceration, then switching to a COX-2 inhibitor might be appropriate—despite the increased cost.

Dosage.

Dosages employed for anti-inflammatory effects are considerably higher than those required for analgesia or fever reduction. For example, treatment of RA may require 5.2 gm (16 standard tablets) of aspirin a day, compared with only 2.6 gm for aches, pain, and fever. Dosages for RA are summarized in Table 73–1.

TABLE 73–1

Nonsteroidal Anti-inflammatory Drugs: Oral Dosage for Rheumatoid Arthritis

Generic Name	Trade Name	Daily Dosage
First-Generation NSAIDs
Salicylates
Aspirin (extended release)	Many trade names	800 mg 4 times/day
Magnesium salicylate	Magan	1090 mg 3 times/day
Salsalate	Disalcid, others	3–4 gm/day (in 2 or 3 doses)
Sodium salicylate	generic	3.6–5.4 gm/day (in divided doses)
Nonsalicylates
Diclofenac	Cambia, Cataflam, Voltaren, Zipsor	150–200 mg/day (in 3 or 4 doses)
Diclofenac/misoprostol	Arthrotec	50 mg diclofenac/200 mcg misoprostol 3 or 4 times daily
Diflunisal	generic	250–500 mg twice daily
Etodolac	generic	600–1200 mg/day (in 2–4 doses)
Fenoprofen	Nalfon	300–600 mg 3 or 4 times/day
Flurbiprofen	generic	200–300 mg/day (in 2–4 doses)
Ibuprofen	Motrin, Advil, others	600–800 mg 3 or 4 times/day
Indomethacin	Indocin	25–50 mg 3 times/day
Ketoprofen	generic	150–300 mg/day (in 3 or 4 doses)
Meclofenamate	generic	200–400 mg/day (in 3 or 4 doses)
Meloxicam	Mobic, Mobicox	7.5 mg once a day
Nabumetone	generic	1.5–2 gm/day (in 1 or 2 doses)
Naproxen	Naprosyn	250–500 mg twice daily
Naproxen sodium	Aleve, others	250–500 mg twice daily
Naproxen/esomeprazole	Vimovo	375–500 mg (naproxen) twice daily
Oxaprozin	Daypro	1.2 gm once a day
Piroxicam	Feldene	20 mg once a day
Sulindac	Clinoril	150–200 mg twice daily
Tolmetin	generic	200–400 mg 3 times/day
Second-Generation NSAIDs (COX-2 Inhibitors)
Celecoxib	Celebrex	100–200 mg twice daily

Glucocorticoids

The glucocorticoids are powerful anti-inflammatory drugs that can relieve symptoms of severe RA, and may also retard disease progression. For patients with generalized symptoms, oral glucocorticoids are indicated. However, if only one or two joints are affected, intra-articular injections may be employed. Because long-term oral therapy can cause serious toxicity (eg, osteoporosis, gastric ulceration, adrenal suppression), short-term therapy should be used whenever possible. Most often, glucocorticoids are used for temporary relief until drugs with more slowly developing effects (eg, methotrexate) can provide control. Long-term therapy should be limited to patients who have failed to respond adequately to all other options. The most commonly employed oral glucocorticoids are prednisone and prednisolone. When symptoms flare, patients may be given 10 to 20 mg/day until symptoms are controlled, followed by gradual drug withdrawal over 5 to 7 days. The pharmacology of the glucocorticoids is discussed at length in Chapter 72 (Glucocorticoids in Nonendocrine Disorders).

Nonbiologic (traditional) DMARDs

As noted, the nonbiologic DMARDs are small molecules produced using conventional synthetic procedures. With several of these drugs, benefits result from immunosuppression. Unlike the NSAIDs, whose benefits are limited to symptomatic relief, the nonbiologic DMARDs can retard disease progression. These drugs are much more toxic than the NSAIDs, and clinical responses develop more slowly. The nonbiologic DMARDs cost much less than the biologic DMARDS, largely because the nonbiologic agents are easier to make.

Methotrexate

Methotrexate [Rheumatrex, Trexall] acts faster than all other DMARDs. Therapeutic effects may develop in 3 to 6 weeks. At least 80% of patients improve with this drug. Benefits are the result of immunosuppression secondary to reducing the activity of B and T lymphocytes. Many rheumatologists consider methotrexate the DMARD of first choice, owing to its efficacy, relative safety, low cost, and extensive use in RA. Major toxicities are hepatic fibrosis, bone marrow suppression, GI ulceration, and pneumonitis. Periodic tests of liver and kidney function are mandatory, as are complete blood cell and platelet counts. Methotrexate can cause fetal death and congenital abnormalities, and therefore is contraindicated during pregnancy. Recent data suggest that patients using methotrexate for RA may have a reduced life expectancy, owing to increased deaths from cardiovascular disease, infection, and certain cancers (melanoma, lung cancer, and non-Hodgkin’s lymphoma). For treatment of RA, methotrexate is administered once a week, either orally or by injection. Oral dosage is 10 to 15 mg/wk initially, and then increased by 5 mg/wk every 2 to 4 weeks, up to a maintenance level of 20 to 30 mg/wk. Dosing with folic acid (at least 5 mg/wk) is recommended to reduce GI and hepatic toxicity. Methotrexate is discussed at length in Chapter 102 (Anticancer Drugs I: Cytotoxic Agents).

Sulfasalazine

Sulfasalazine [Azulfidine, Azulfidine EN-tabs] has been used for decades to treat inflammatory bowel disease (see Chapter 80) and is now used for RA too. Benefits may result from anti-inflammatory and immunomodulatory actions. In patients with RA, sulfasalazine can slow the progression of joint deterioration, sometimes with just 1 month of treatment. Gastrointestinal reactions (nausea, vomiting, diarrhea, anorexia, abdominal pain) are the most common reasons for stopping treatment. These reactions can be minimized by using an enteric-coated formulation and by dividing the daily dosage. Dermatologic reactions (pruritus, rash, urticaria) are also common. Fortunately, serious adverse effects—hepatitis and bone marrow suppression—are rare. To ensure early detection, periodic monitoring for hepatitis and bone marrow function (complete blood counts, platelet counts) should be performed. Because of its structure, sulfasalazine should not be given to patients with sulfa allergy. The initial dosage for RA is 1000 mg/day. The usual maintenance dosage is 1000 mg 2 or 3 times a day. Sulfasalazine is discussed further in Chapter 80 (Other Gastrointestinal Drugs).

Leflunomide

Actions and uses.

Leflunomide [Arava] is a powerful immunosuppressant indicated for adults with active RA. In clinical trials, the drug decreased signs and symptoms and slowed disease progression. Compared with methotrexate, leflunomide is about equally effective, but more dangerous and more expensive. Accordingly, the drug is often reserved for second-line use.

Leflunomide is a prodrug that undergoes conversion to its active form—metabolite 1 (M1)—in the body. Metabolite 1 inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme needed for de novo synthesis of pyrimidines, which in turn are needed for T-cell proliferation and antibody production. In vitro, leflunomide inhibits T-cell proliferation. In animals, it suppresses inflammation.

Pharmacokinetics.

Following oral dosing, leflunomide is converted to M1 by enzymes in the intestine and liver. Levels of M1 peak in 6 to 12 hours. The active form undergoes further metabolism followed by excretion in the urine and bile. The half-life is prolonged: 16.5 days. As a result, a series of loading doses is needed to achieve steady state quickly.

Adverse effects.

The most common adverse effects are diarrhea (17%), respiratory infection (15%), reversible alopecia (10%), rash (10%), and nausea (9%). The drug has also been associated with much more serious reactions: pancytopenia, Stevens-Johnson syndrome, and severe hypertension.

Leflunomide is hepatotoxic. Elevation of liver enzymes occurs in about 10% of patients. In postmarketing reports, the drug has been associated with over 130 cases of severe liver injury, including 14 that were fatal. Liver function should be assessed at baseline, every month for the first 6 months of treatment, and every 6 to 8 weeks thereafter. Leflunomide should be avoided in patients with liver impairment, hepatitis B, or hepatitis C. Patients should be informed about signs of liver injury—abdominal pain, fatigue, dark urine, and jaundice—and advised to report them immediately.

Leflunomide may increase the risk of serious infection. The drug is immunosuppressive and can suppress the bone marrow. Rarely, patients experience sepsis and other severe infections, including tuberculosis. Deaths have occurred. If an infection develops, it may be necessary to interrupt leflunomide use. To reduce risk, platelet counts and blood cell counts should be conducted at baseline, every month for the first 6 months of treatment, and every 6 to 8 weeks thereafter. If evidence of bone marrow suppression is detected, leflunomide should be discontinued. Patients should be screened for tuberculosis before starting this drug.

Leflunomide is carcinogenic in animals, but has not been associated with cancer in humans.

Leflunomide and pregnancy.