Rheumatoid arthritis drug therapy

Muller-Ladner U, Gay S. The SCID mouse—a novel experimental model for gene therapy in human rheumatoid arthritis. Drugs Today (Barcelona) 1999 35 379-88. 

Chloroquine and other aminoquinolines are used in the prophylaxis or therapy of malaria and other parasitic diseases. Chloroquine and hydroxychloroquine are also used in the treatment of rheumatoid arthritis. Drugs in this class include chloroquine phosphate (Aralen ), amodiaquine hydrochloride (Camoquin ), hydroxychloroquine sulfate (Plaquenil ), mefloquine (Lariam" ), primaquine phosphate, and quinacrine hydrochloride (Atabrine ). Chloroquine overdose is common, especially in countries where malaria is prevalent, and the mortality rate is 10-30%. Quinine toxicity is described on p 326. 

MTX is part of curative therapeutic schedules for acute lymphoblastic leukemias (ALL), Burkitt s lymphoma, and choriocarcinoma. It was also used in adjuvant therapy of breast cancer. High dose MTX with leucovorin rescue can induce about 30% remissions in patients with metastatic osteogenic sarcoma. MTX is one of the few antineoplastic drugs that can be safely administered intrathecally for the treatment of meningeal metastases and leukemic infiltrations (routine prophylaxis in ALL). In addition, MTX can be used as an immunosuppressive agent for the treatment of severe rheumatoid arthritis and psoriasis. 

Promoting an Optimal Response to Therapy The patient with a musculoskeletal disorder may be in acute pain or have longstanding mild to moderate pain, which can be just as difficult to tolerate as severe pain. Along with pain, there may be skeletal deformities, such as the joint deformities seen with advanced rheumatoid arthritis. For many musculoskeletal conditions, drug therapy is a major treatment modality. Therapy with these drugs may keep the disorder under control (eg, therapy for gout), improve the patient s ability to carry out the activities of daily living, or make the pain and discomfort tolerable. 

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

TABLE 4-3 Clinical Monitoring of Drug Therapy in Rheumatoid Arthritis 1 ... 

Benorylate (315) [4 -(acetamido)phenyl-2-acetoxybenzoate] is another example. It is the ester between two well-known antiinflamatory drugs, aspirin and paracetamol, and is employed in rheumatoid arthritis therapy. In view of the chemical structure with three photolabile groups (two esters and one amide), its possible phototoxicity has been investigated. From the preparative irradiations, it has been concluded that the PFR takes place with breaking of the central C—O bond to yield 5-acetamido-2 -acetoxy-2-hydroxybenzophenone (316). This product undergoes transacetylation to 5 -acetamido-2 -acetoxy-2-hydroxy-benzophenone (318) (Scheme 80) [300]. 

Olsen NJ, Stein CM. Drug therapy new drugs for rheumatoid arthritis. N Engl ] Med 2004 350 2167-79. 

Rheumatoid arthritis Administer on an empty stomach at least 1 hour before meals and at least 1 hour apart from any other drug, food, or milk. initiai therapy A single daily dose of 125 or 250 mg. Thereafter, increase dose at 1-to 3-month intervals by 125 or 250 mg/day as patient response and tolerance indicate. If satisfactory remission is achieved, continue the dose. If there is no improvement and if there are no signs of potentially serious toxicity after 2 to 3 months with doses of 500 to 750 mg/day, continue increases of 250 mg/day at 2- to 3-month intervals until satisfactory remission occurs or toxicity develops. If there is no discernible improvement after 3 to 4 months of treatment with 1 to 1.5 g/day, assume the patient will not respond and discontinue the drug. 

Two compounds of the fenamate class of antiinflammatory drugs are marketed in the United States. Mefenamic acid (Ponstel) is indicated only for analgesia and primary dysmenorrhea when therapy will not exceed 1 week. Meclofenamate sodium (Meclomen) is prescribed for rheumatoid arthritis and osteoarthritis. 

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. 

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. 

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. 

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