09:37
Mani
DMARDs
Careful clinical and epidemiologic studies have shown that rheumatoid arthritis is an immunologic disease that causes significant systemic effects which shorten life in addition to the joint disease that reduces mobility and quality of life. NSAIDs offer mainly symptomatic relief; they reduce inflammation and the pain it causes and often preserve function, but they have little effect on the progression of bone and cartilage destruction. Interest has therefore 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 6 weeks to 6 months to become evident although some biologics are effective within 2 weeks; generally, they are slow-acting compared with NSAIDs.
These therapies include methotrexate, a T-cell-modulating biologic (abatacept), azathioprine, chloroquine and hydroxychloroquine, cyclophosphamide, cyclosporine, leflunomide, mycophenolate mofetil, a B-cell cytotoxic agent (rituximab), sulfasalazine, and the TNF- -blocking agents. These drugs comprise both biologically derived and nonbiologic agents and will be listed alphabetically, independent of origin. Gold salts, which were once extensively used, are no longer recommended because of their significant toxicities and questionable efficacy.
Abatacept
Abatacept is a costimulation modulator that inhibits the activation of T cells. After a T cell has engaged an antigen-presenting cell (APC), a 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.
Pharmacokinetics
Abatacept is given as an intravenous infusion in three initial doses (day 0, week 2, and week 4), followed by monthly infusions. The dose is based on body weight, with 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. Dosing regimens in any adult group can be increased if needed. The terminal serum half-life is 13–16 days. Coadministration with methotrexate, NSAIDs, and corticosteroids does not influence abatacept clearance.
Indications
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.
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- antagonists is not recommended due to the increased incidence of serious infection with this combination. 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. The incidence of malignancies is similar to placebo with the exception of a possible increase in lymphomas. The role of abatacept in this increase is unknown.
Mechanism of Action
Azathioprine acts through its major metabolite, 6-thioguanine. 6-Thioguanine suppresses inosinic acid synthesis, B-cell and T-cell function, immunoglobulin production, and interleukin-2 secretion.
Pharmacokinetics
The metabolism of azathioprine 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.
Indications
Azathioprine is approved for use in rheumatoid arthritis and is used at a dosage of 2 mg/kg/d. Controlled trials show efficacy in psoriatic arthritis, reactive arthritis, polymyositis, systemic lupus erythematosus, and Behçet's disease.
Adverse Effects
Azathioprine's toxicity includes bone marrow suppression, gastrointestinal disturbances, and some increase in infection risk, lymphomas may be increased with azathioprine use. Rarely, fever, rash, and hepatotoxicity signal acute allergic reactions.
Mechanism of Action
Chloroquine and hydroxychloroquine are used mainly in malaria and in the rheumatic diseases. The mechanism of the anti-inflammatory action of these drugs in rheumatic diseases is unclear. The following mechanisms have been proposed: suppression of T-lymphocyte responses to mitogens, decreased leukocyte chemotaxis, stabilization of lysosomal enzymes, inhibition of DNA and RNA synthesis, and the trapping of free radicals.
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.
Indications
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. Although antimalarials improve symptoms, there is no evidence that these compounds alter bony damage in rheumatoid arthritis 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 often used in the treatment of the skin manifestations, serositis, and joint pains of systemic lupus erythematosus, and they have been used in Sjögren's syndrome.
Adverse Effects
Although ocular toxicity 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 6–12 months is advised. Other toxicities include dyspepsia, nausea, vomiting, abdominal pain, rashes, and nightmares. These drugs appear to be relatively safe in pregnancy.
Mechanism of Action
Cyclophosphamide's 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
Indications
Cyclophosphamide is active against rheumatoid arthritis when given orally at dosages of 2 mg/kg/d but not when given intravenously. It is used regularly to treat systemic lupus erythematosus, vasculitis, Wegener's granulomatosis, and other severe rheumatic diseases.
Mechanism of Action
Through regulation of gene transcription, cyclosporine inhibits interleukin-1 and interleukin-2 receptor production and secondarily inhibits macrophage–T-cell interaction and T-cell responsiveness. T-cell-dependent B-cell function is also affected.
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.
Indications
Cyclosporine is approved for use in rheumatoid arthritis 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 systemic lupus erythematosus, polymyositis and dermatomyositis, Wegener's granulomatosis, and juvenile chronic arthritis.
Adverse Effects
Cyclosporine has significant nephrotoxicity, and its toxicity can be increased by drug interactions with diltiazem, potassium-sparing diuretics, and other drugs inhibiting CYP3A. Serum creatinine should be closely monitored. Other toxicities include hypertension, hyperkalemia, hepatotoxicity, gingival hyperplasia, and hirsutism.
Mechanism of Action
Leflunomide 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 production of autoantibodies by B cells. Secondary effects include increases of interleukin-10 receptor mRNA, decreased interleukin-8 receptor type A mRNA, and decreased TNF- –dependent nuclear factor kappa B (NF- B) activation.
Pharmacokinetics
Leflunomide is completely absorbed and has a mean plasma half-life of 19 days. A77-1726, the active metabolite of leflunomide, is thought to have approximately the same half-life and is subject to enterohepatic recirculation. Cholestyramine can enhance leflunomide excretion and increases total clearance by approximately 50%.
Indications
Leflunomide is as effective as methotrexate in rheumatoid arthritis, 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.
Adverse Effects
Diarrhea occurs in approximately 25% of patients given leflunomide, although only about 3–5% discontinue the drug because of this effect. Elevation in liver enzymes also occurs. 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.
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