Rheumatoid arthritis DMARDs

FIGURE 4-1. Algorithm for treatment of rheumatoid arthritis. (DMARD, diseasemodifying antirheumatic drug MIX, methotrexate NSAID, nonsteroidal antiinflammatory drug Rx, therapy.)... 

The most recent treatment paradigm calls for earher, more aggressive treatment of rheumatoid arthritis. DMARDs are frequently employed along with NSAIDs in the initial treatment of the disease. The COX-2 inhibitors are often used because they are less likely to cause serious GI toxicity than are the nonspecihc COX inhibitors. The usual DMARD of choice for patients with mild rheumatoid arthritis is hydroxychloroquine or sulfasalazine methotrexate is used for those with moderate to serious disease. Other DMARDs are used if these agents are poorly tolerated or do not produce suf-hcient response. Combination therapy of methotrexate and another agent is also used to treat disease that is not responsive to individual DMARDs. 

Polyarticular-course juvenile rheumatoid arthritis (JRA) For reducing signs and symptoms of moderately to severely active polyarticular-course JRA in patients who have had an inadequate response to at least 1 disease-modifying antirheumatic drug (DMARD). 

Darmawan J, Nasution AR, Rasker JJ, Zhao DB, Soorosh GS, Chen SL et al. Sustained clinical and radiological remission in DMARD refractory rheumatoid arthritis treated with step-down bridge combination therapy of five immunosuppressants without corticosteroids in a 6 years observation in Asia - WHO-ILAR COPCORD Stage II Treatment. APLAR J Rheumatol 2007 10 in press. 

Of the DMARDs, methotrexate (Rheumatrex) is the most widely prescribed. It is indicated for the treatment of rheumatoid arthritis and psoriasis it is also used for psoriatic arthritis, systemic lupus erythematosus, and... 

Sulfasalazine (Azulfidine) is approved for the treatment of rheumatoid arthritis and ulcerative colitis. It is also used to treat ankylosing spondylitis and Crohn s disease. Comparisons of sulfasalazine with other DMARDs suggest that it is more effective than hydroxychloroquine, azathioprine, and oral gold compounds. It is at least as effective as intramuscular gold and penicillamine. It has a greater degree of toxicity than hydroxychloroquine but less than gold compounds and penicillamine. After 5 years, approximately 75% of patients have discontinued sulfasalazine therapy, primarily because of a lack of efficacy as opposed to intolerable side effects. 

Hydroxychloroquine Plaquenil) and chloroquine Ara-len) are 4-aminoquinoline antimalarial drugs that possess modest DMARD activity. They are indicated for the treatment of rheumatoid arthritis and systemic lupus erythematosus their use as antimalarials is detailed in Chapter 53. The onset of action of these drugs is longer than that of other DMARDs, and their side effects are relatively mild. Because of this, these agents show promise as ingredients of combination therapies for rheumatoid arthritis. 

Leflunomide (Arava) is an isoxazole derivative approved for the treatment of rheumatoid arthritis in 1998. Limited data suggest that it is comparable in efficacy to sulfasalazine and produces fewer adverse effects. It has a faster onset of action (4 weeks) than other DMARDs. 

Two recently introduced biological therapies were designed to interfere with the inflammatory cascade initiate by TNF-a. Etanercept (Enbrel) is indicated for the treatment of moderate to severe rheumatoid arthritis in individuals over age 4. Infliximab in conjunction with methotrexate (Remicade) is approved for use by adults in the treatment of rheumatoid arthritis. It is also indicated for therapy of Crohn s disease. Over the short term, the efficacy of these drugs in the treatment of rheumatoid arthritis appears to be superior to that of methotrexate alone however, their ability to prevent bone erosion for longer than 24 months must be further studied. The cost of both drugs is significantly higher than that of the other DMARDs. 

Anakinra (Kineret) is the first antirheumatic agent that acts by blocking the action of IL-1. This drug was recently approved for the treatment of moderately to severely active rheumatoid arthritis in adults who have not responded to therapy with one or more DMARDs. Anakinra may be used alone or in combination with DMARDs other than the TNF antagonists. Clinical trials have shown anakinra to be more effective than placebo, either alone or in conjunction with methotrexate. 

The tetracycline antibiotic minocycline (Minocin) is modestly effective in the treatment of rheumatoid arthritis and is generally well tolerated. Radiographic evidence of its efficacy as a DMARD is lacking, although clinical symptoms do abate. It can be useful in the treatment of early, mild disease. A more detailed description of the pharmacology and chnical uses of minocycline is found in Chapter 47. 

In previous decades, a pyramid model dominated the treatment of rheumatoid arthritis. Early in the course of the disease, sahcylates were used to control pain and stiffness. If sahcylates were poorly tolerated or began to lose efficacy, they were discontinued and a different NSAID was used. As the efficacy of NSAID therapy waned and joint deterioration progressed, treatment with a DMARD was added. DMARDs were employed... 

E. Treatment guidelines suggest the use of DMARDs early in the course of rheumatoid arthritis to slow the joint deterioration associated with the disease. Methotrexate is the DMARD of choice for people with moderate to severe forms of rheumatoid arthritis. Although NSAIDs can decrease methotrexate clearance, NSAIDs can be safely used with the low doses of methotrexate used in the therapy of rheumatoid arthritis. Methotrexate is highly teratogenic and should not be used by women who are or may become pregnant. 

Currently recommended for management of rheumatoid arthritis after failure of other DMARD agents... 

Mechanism of Action A DMARD that inhibits dihydroorotate dehydrogenase, the enzyme involved in autoimmune process that leads to rheumatoid arthritis. Therapeutic Effect Reduces signs and symptoms of rheumatoid arthritis and slows structural damage. 

B. Indications and use Kineret is indicated for the reduction in signs and symptoms of moderately to severely active rheumatoid arthritis in patients 18 years of age or older who have failed one or more disease-modifying antirheumatic drugs (DMARDs). Kineret can be used alone or in combination with DMARDs other than tumor necrosis factor (TNF) blocking agents. 

Another important group of agents is characterized as disease-modifying antirheumatic drugs (DMARDs). They decrease inflammation, usually improve symptoms, and slow the bone damage associated with rheumatoid arthritis. They are thought to affect more basic inflammatory mechanisms than do glucocorticoids or the NSAIDs. They may also be more toxic than those alternative medications. 

Abatacept can be used as monotherapy or in combination with other DMARDs in patients with moderate to severe rheumatoid arthritis who have had an inadequate response to other DMARDs. It reduces the clinical signs and symptoms of rheumatoid arthritis, including slowing of radiographic progression. It is also being tested in early rheumatoid arthritis. 

Antimalarials are approved for rheumatoid arthritis, but they are not considered very effective DMARDs. Dose-response and serum concentration-response relationships have been documented for hydroxychloroquine and dose-loading may increase rate of response. 

Methotrexate is now considered the DMARD of first choice to treat rheumatoid arthritis and is used in 50-70% of patients. It is active in this... 

The compound is approved for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, juvenile idiopathic arthritis, plaque psoriasis, and Crohn s disease. It decreases the rate of formation of new erosions. It is effective both as monotherapy and in combination with methotrexate and other DMARDs. 

In a 1998 study, approximately half of North American rheumatologists treated moderately aggressive rheumatoid arthritis 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. 

Disease-modifying agents currently used in treating rheumatoid arthritis are listed in Table 16-3. As the name implies, DMARDs attempt to induce remission by modifying the pathologic process inherent to rheumatoid arthritis. In general, DMARDs inhibit certain aspects of the immune response thought to... 

Originally used in the treatment of malaria, the drugs chloroquine (Aralen) and hydroxychloroquine (Pla-quenil) have also been used to treat rheumatoid arthritis. In the past, these drugs have been used reluctantly because of the fear of retinal toxicity (see Adverse Side Effects ).25 There is now evidence, however, that these agents can be used safely, but they are only marginally effective when compared to other DMARDs. These drugs are therefore not usually the first choice, but they can be used in patients who cannot tolerate other DMARDs, or in combination with another DMARD (e.g., methotrexate) for more comprehensive treatment. 

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