There are 2 major categories of DMARDs: nonbiologic and biologic agents. See Table 9-5 for the classification, mechanism, and toxicities of these drugs.
Methotrexate A structural analogue of folic acid, methotrexate interferes both with folatedependent metabolic pathways, such as purine, and with pyrimidine metabolism. Its disease-modifying effect may be mediated partly through increased extracellular adenosine, which has intrinsic anti-inflammatory activity. Methotrexate is given weekly, usually beginning at a dose of 7.5–10 mg, gradually increasing to a maximum dose of 25 mg, depending on disease response. All patients are supplemented with folic acid to decrease adverse effects associated with methotrexate use. Major adverse effects include hepatic fibrosis, interstitial lung disease, bone marrow toxicity, teratogenicity, sterility, and, in higher dosages, renal toxicity. Baseline and periodic monitoring should include blood counts, liver enzymes, and albumin and creatinine levels.
Leflunomide The immunosuppressive agent leflunomide targets rapidly dividing cell populations such as activated lymphocytes. It is most commonly used to treat RA, although it has also been effective in managing other conditions including psoriatic arthritis, juvenile polyarthritis, refractory dermatomyositis, and SLE. This drug is similar in efficacy to methotrexate, and the 2 are sometimes combined if methotrexate alone is ineffective. Adverse reactions include GI side effects, hepatotoxicity, and hypertension (especially if taken with NSAIDs). Close monitoring of patients is advised.
Hydroxychloroquine An antimalarial compound, hydroxychloroquine is also commonly used to treat rheumatologic diseases. In addition to its anti-inflammatory activity, the drug raises the pH of various cellular compartments, which decreases both cytokine production and lymphocyte proliferation. Response to treatment may take weeks to months, in part because of the drug’s long half-life (1–2 months) and the time required to achieve steady-state levels.
Hydroxychloroquine is one of the safest immunosuppressive drugs used in managing rheumatologic disease. Retinopathy (bull’s-eye maculopathy) due to hydroxychloroquine use is a relatively unusual complication, but it can cause irreversible vision loss if not detected early.
Sulfasalazine Although its exact mechanism of action is unclear, sulfasalazine is effective in treating RA. It is often used in combination with other drugs, such as hydroxychloroquine and methotrexate.
Azathioprine An antimetabolite, azathioprine interferes with purine metabolism. Its use, especially in inflammatory bowel disease, is limited due to its toxicity. The most common adverse effects are gastrointestinal symptoms, risk of infection, and bone marrow suppression. Patients treated with this drug have up to a 4-fold increase in the risk of lymphoma.
Cyclophosphamide and chlorambucil are alkylating agents that are very potent immunosuppressive drugs. Their primary mechanism of action involves cross-linking DNA molecules, which blocks DNA replication. They also have potentially severe adverse effects, including infertility, bone marrow suppression, increased risk of infection, and late malignancy. Consequently, these drugs are reserved for very resistant or life-threatening diseases such as granulomatosis with polyangiitis, for which the benefits outweigh the risks. Cyclophosphamide is available as an oral or intravenous agent. The oral form is associated with increased rates of bladder cancer.
Cyclosporine and tacrolimus block calcineurin, thereby inhibiting the transcription of IL-2 and other cytokines, primarily in helper T cells. These drugs are used chiefly to prevent rejection in patients who have undergone transplants, but clinicians are increasingly recognizing their benefit in treating autoimmune diseases. The main adverse effects of both drugs are nephrotoxicity and hypertension. Other potential problems include infections and nonmelanoma skin cancers. Because of such risks, these agents are reserved for recalcitrant cases that do not respond to standard therapies.
Mycophenolate Initially used as an antirejection drug in the United States, mycophenolate mofetil is increasingly being employed in patients with immunologic diseases. It inhibits the production of guanosine in lymphocytes, thereby decreasing cellular proliferation and antibody production. Primary adverse effects include gastrointestinal symptoms, bone marrow suppression, and increased risk of infection. An enteric-coated formulation of mycophenolate sodium typically reduces the incidence of gastrointestinal adverse effects. Overall, the drug seems to be well tolerated by patients and may serve as an adjunct to other medications.
Biologic and other anticytokine agents
TNF-α inhibitors Research that facilitated improved understanding of the immune response has led to the development of drugs targeting specific mediators. Cytokines, which are cell-signaling proteins generated by activated immune cells, can enhance or inhibit the immune response. Tumor necrosis factor (TNF)-α is a major proinflammatory cytokine involved in the pathogenesis of inflammatory diseases. The US Food and Drug Administration (FDA) has approved 5 TNF-α antagonists: adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab. Certolizumab pegol is unique in this group as being an FDA category B drug and, therefore, is a treatment option for patients who are pregnant or nursing.
The drugs are usually well tolerated, but there is potential for severe adverse effects (see Table 9-5). Although not established, there may be a link between TNF-α inhibition and demyelinating disease, including optic neuritis, as well as potential risk of various malignancies. All patients on immunosuppressive therapy require close monitoring for the development of serious adverse effects. The cost of these drugs can also become a barrier for patients.
Interleukin inhibitors Biologic agents have been developed to block several types of interleukin (IL). Although these agents are not as potent as the TNF-α inhibitors, IL-1 drugs, including anakinra, canakinumab, and rilonacept, are used in many autoimmune disorders. The IL-6 inhibitor tocilizumab is used primarily for RA and JIA but may also be effective in treating giant cell arteritis and polymyalgia rheumatica. The drugs secukinumab and ixekizumab block the IL-17 pathway and are mainly used in psoriatic arthritis, as is the IL-12/23 inhibitor, ustekinumab.
Other biologic agents
Abatacept is used in the treatment of RA and JIA. This drug blocks the CD28 receptor, which is involved in T-cell activation. It can be very effective in treating refractory disease.
Rituximab is a B-cell–depleting monoclonal antibody used primarily in chemotherapy but also in cases of RA that are unresponsive to other agents.
Belimumab is a human monoclonal antibody that inhibits B-cell activation. It was approved by the FDA for the treatment of SLE, but it may also be helpful for other immune disorders.
Alemtuzumab is a monoclonal antibody that binds to CD52, a protein on mature lymphocytes. The drug is used to treat chronic lymphocytic leukemia and has shown promise in the treatment of autoimmune diseases.
JAK inhibitors Kinase inhibitors are another group of immunosuppressive agents showing promise in treating rheumatologic disease. Janus kinase is one such enzyme these drugs target. Tofacitinib is a small-molecule oral agent that inhibits JAK-1 and JAK-3. Baricitinib inhibits JAK-1 and JAK-2. Both are approved by the FDA for rheumatoid arthritis. Their role may be in cases that are refractory to other classes of agents, including nonbiologic agents and TNF-α inhibitors.
Biosimilar agents The expiration of patent protection on some biologic agents has led to the development of biosimilar agents. A biosimilar has amino acid sequencing that is analogous (not identical) to the original compound (reference product) on which it is based. The FDA requires a biosimilar to be “highly similar to” and to have “no clinically meaningful differences” from the reference product for approval. The use of infliximab-dyyb, the biosimilar for infliximab, has grown worldwide and is particularly effective in treating inflammatory bowel disease. This agent, along with the biosimilars for etanercept and adalimumab, was approved in 2016 by the FDA for the treatment of RA, psoriatic arthritis, and ankylosing spondylitis. Other biosimilar agents continue to be developed.
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Excerpted from BCSC 2020-2021 series: Section 1 - Update on General Medicine. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.