Common adverse effects include the following

a. Skin and mucous membranes. Pruritus and skin rash represent the most common side effects, and dermatitis may occur at any time during the course of therapy. These may be controlled by administration of an antihistamine and a moderate reduction in dosage. If rash persists despite these measures, the drug should be stopped for at least 3 months. Repeated administration of low doses (125 mg) may be possible after this. A sudden febrile response, often associated with a generalized rash, may occur within the first 3 weeks of therapy; defervescence occurs when the drug is stopped. However, in this situation, rechallenge is not recommended. Stomatitis has been observed and often clears with decreased dosage. If oral ulcers persist, the drug should be stopped permanently. Blunting or alteration in taste perception (dysgeusia) may occur during the first 6 weeks of therapy. It may gradually disappear despite continuation of therapy or may persist even after therapy is stopped.

b. Hematologic toxicity is potentially dangerous and dictates the need for close follow-up. Mandatory testing includes complete blood cell counts, including platelet count, differential counts, and definition of the absolute neutrophil count, at 2-weekly intervals for the first 6 months of therapy and at least monthly thereafter. Recording laboratory data on flow sheets will permit early detection of downward trends in white blood cell or platelet counts. Hematologic toxicity may be sudden in onset and may occur in the interval between scheduled laboratory studies. Thus, patients must be aware that they need to report the development of sore throat, skin or mucous membrane bleeding, infection, or fever. Downward trends of white blood cell and platelet counts (specifically a white cell count £3,000/mm 3 or a platelet count <100,000/mm3) require immediate and permanent discontinuation of D-penicillamine therapy. Leukopenia associated with thrombocytopenia or thrombocytopenia alone may indicate impending aplastic anemia.

c. Renal toxicity. Proteinuria is encountered in up to 20% of patients on long-term therapy. If proteinuria of 2+ or more has persisted for 30 days and other causes of renal disease have been excluded, a 24-hour urine protein determination should be performed and repeated at monthly intervals. As long as the protein excretion does not exceed 1 g/d and creatinine clearance is stable, the drug may be continued. Proteinuria may clear completely with only a 125-mg reduction in the daily dose. Development of hypoalbuminemia, nephrotic syndrome, or significant hematuria requires discontinuation of the drug. Nephrosis is reversible, but urinary abnormalities may persist up to 1 year. Rechallenge will usually lead to recurrence of proteinuria.

d. Miscellaneous. Uncommon but severe side effects include autoimmune syndromes such as drug-induced lupus, Goodpasture's syndrome, and polymyositis. They require drug discontinuation and at times disease-specific treatment, and they usually resolve after the drug is stopped.

e. Immunosuppressive and immunomodulatory drugs. Five classes of immunosuppressive drugs are now being employed in the treatment of RA: the antimetabolite/antiinflammatory drug methotrexate (MTX), the purine analog azathioprine (AZA), the cyclic polypeptide cyclosporine (CyA), the pyrimidine inhibitor leflunomide, and the alkylating agent cyclophosphamide (CTX). Of all the DMARDs and immunosuppressive agents, MTX is now considered the central DMARD in single or multiple drug regimens.

1. Methotrexate. Given its safety profile and tolerance by patients, relatively rapid onset of action in 4 to 6 weeks, effectiveness, and the availability of various routes of administration (PO, IM, IV, or SC), MTX has dominated the therapeutic armamentarium as a first-or second-choice disease-modifying medication in the treatment of RA. Studies have demonstrated that RA patients remain on MTX longer than on other DMARDs (45% to 62% on MTX

for 3 years vs. 18% to 32% on IM gold, 35% on hydroxychloroquine, 11% to 39% on SSZ) because of a combination of effectiveness and safety.

Evidence that MTX retards bony damage is provided by many of the available studies.

a. Indications. Although MTX does not induce a complete remission, it is a highly effective drug in controlling the inflammatory process and markedly improving function in a majority of RA patients. Its position in the RA armamentarium is either as a first-line agent, started soon after the diagnosis is made, or as a powerful second-line drug added to or used in place of ineffective courses of antimalarial drugs or SSZ.

b. Mechanism of action. MTX inhibits dihydrofolate reductase, thus interrupting purine biosynthesis and synthesis of thymidilic and inosinic acids. However, MTX is metabolized intracellularly to MTX polyglutamates, and these long-lived metabolites inhibit dihydrofolate reductase plus other folate-dependent enzymes. Other antiinflammatory effects include reduced polymorphonuclear chemotaxis and decreased production of IL-1 and IL-2 production. In vivo and in vitro studies have demonstrated inhibition of intracellular activity of 5-aminoimidazole-4-carboxamidoribonucleotide transformylase. This inhibition is associated with increased release of adenosine into the extracellular milieu. Antiinflammatory properties of adenosine are mediated by specific receptors on the surface of cells. In inflammatory arthritis, the A 3 receptor occupancy inhibits cytokine release. This mechanism may be related to some adverse effects of MTX, such as nodulosis.

c. Therapeutic approach. The antiinflammatory effect of MTX has been repeatedly demonstrated, and one study has shown that the effect is dose-related. Although the initial dose of MTX continues to be 7.5 mg/wk, the dose at which most patients demonstrate a well-defined clinical improvement now ranges between 15 and 25 mg/wk. Most patients will profit from the addition of 1 mg of folic acid daily without any reduction in drug efficacy. The drug appears to have a steroid-like clinical effect with relatively rapid onset (4 to 6 weeks) and offset of action. The latter point must be appreciated because severe disease flares commonly occur when the drug is stopped, and at times it is difficult to regain disease control. If MTX is stopped for only 2 to 3 weeks (e.g., in the perioperative period or because of minor side effects), disease control can be maintained simply with the repeated administration of MTX. However, if MTX must be stopped permanently, an alternative DMARD, such as SSZ, hydroxychloroquine, AZA, or an anti-TNF biologic should be started to avoid disease exacerbation. Other issues that must be appreciated before MTX is started are the following:

i. Cost and route of administration. The cost of the oral medication is high, especially when the expense of monitoring is added. The cost of parenteral MTX is much lower, and many patients are switched from the oral to the SC, IM, or IV route because of lack of response or intolerance to the oral medication. Some physicians give the less expensive parenteral solution orally in orange juice. Bioavailability studies have demonstrated that approximately 80% of the drug is absorbed via the oral route, and more than 90% by other routes. Patient acceptance of the SC route is high, and the ability to inject it themselves at home avoids an office visit.

ii. Nodulosis. In patients both with and without a history of nodular disease, MTX can lead to the development of painful new nodules. This is particularly prominent on the fingers and can further limit function. The fact that a medication that is so effective in controlling the inflammation of RA can stimulate the formation of a characteristic inflammatory symbol of the disease underscores the incompleteness of our understanding of this disease and the actions of MTX.

iii. Liver toxicity in the form of fibrosis or cirrhosis was an early concern and evolved from prior clinical experience with a daily regimen of MTX in patients with psoriasis and psoriatic arthritis. However, with the use of weekly MTX dosing, the avoidance of MTX in high-risk patients, and an optimal monitoring approach, such liver problems are uncommon in RA patients treated with long-term MTX. Studies of MTX treatment in RA patients quantifying the risk for fibrosis/cirrhosis have shown that this problem occurs in only 1 in 1,000 patients.

iv. Oncogenicity. One of the reasons why MTX has supplanted AZA in the treatment of RA has been its lack of oncogenicity. However, MTX treatment has rarely been associated with the development of non-Hodgkin's B-cell lymphomas.

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