Indications: Tofacitinib was originally developed to prevent solid organ allograft rejection. It has also been tested for the treatment of inflammatory bowel disease, spondyloarthritis, psoriasis, and dry eyes. To date, tofacitinib is approved in the United States for the treatment of adult patients with moderately to severely active RA who have failed or are intolerant to methotrexate. It is not approved in Europe for this indication. It can be used as a monotherapy or in combination with other csDMARDs, including methotrexate. Ongoing studies are evaluating its role in other rheumatic diseases such as PsA, psoriasis, and JIA.
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Adverse Effects: Tofacitinib slightly increases the risk of infection, and it has thus far not been used with potent immunosuppressants (eg, azathioprine, cyclosporine) or biologic bDMARDs because additive immunosuppression is feared, although it has not been tested in combinations. Upper respiratory tract infection and urinary tract infection represent the most common infections. More serious infections are also reported, including pneumonia, cellulitis, esophageal candidiasis, and other opportunistic infections. All patients should be screened for latent or active tuberculosis before the initiation of treatment. Lymphoma and other malignancies such as lung and breast cancer have been reported in patients taking tofacitinib, although some studies discuss the potential use of JAK inhibitors to treat certain lymphomas. Dose-dependent increases in the levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol have been found in patients receiving tofacitinib, often beginning about 6 weeks after starting treatment; therefore, lipid levels should be monitored. Although tofacitinib causes a dose-dependent increase in CD19 B cells and CD4 T cells plus a reduction in CD16/CD56 NK cells, the clinical significance of these changes remains unclear. Drug-related neutropenia and anemia occur, requiring drug discontinuation. Headache, diarrhea, elevation of liver enzymes, and gastrointestinal perforation are among the other reported effects of tofacitinib.
IL-1α plays a major role in the pathogenesis of several inflammatory and autoimmune diseases including RA. IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1RA) are other members of the IL-1 family. All three bind to IL-1 receptors in the same manner. However, IL1RA does not initiate the intracellular signaling pathway and thus acts as a competitive inhibitor of the proinflammatory IL-1α and IL-1β.
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Mechanism of Action: Anakinra is the oldest drug in this family but is now rarely used for RA.
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Pharmacokinetics: Anakinra is administered subcutaneously and reaches a maximum plasma concentration after 3–7 hours. The absolute bioavailability of anakinra is 95%, and it has a 4to 6-hour terminal half-life. The recommended dose in the treatment of RA is 100 mg daily. The dose of anakinra depends on the body weight in the treatment of cryopyrin-associated periodic syndrome (CAPS), starting with 1–2 mg/kg per day to a maximum of 8 mg/kg per day. Reduction in the frequency of administering anakinra to every other day is recommended in patients with renal insufficiency.
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Indications: Anakinra is approved for the treatment of moderately to severely active RA in adult patients, but it is rarely used for this indication. However, anakinra is the drug of choice for CAPS, particularly the neonatal-onset multisystem inflammatory disease (NOMID) subtype. Anakinra is effective in gout (see below) and is used for other diseases including Behçet’s disease and adult onset JIA. Its use for giant cell arteritis is controversial.
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