These therapies include conventional synthetic (cs) and biologic (b) disease-modifying antirheumatic drugs (recently designated csDMARDs and bDMARDs, respectively). The conventional synthetic agents include small molecule drugs such as methotrexate, azathioprine, chloroquine and hydroxy-chloroquine, cyclophosphamide, cyclosporine, leflunomide, mycophenolate mofetil, and sulfasalazine. Tofacitinib, though marketed as a biologic, is actually a targeted synthetic DMARD (tsDMARD). Gold salts, which were once extensively used, are no longer recommended because of their significant toxicities and questionable efficacy. Nevertheless, they have found limited use for RA in Canada. Biologics are large-molecule therapeutic agents, usually proteins, which are often produced by recombinant DNA technology. The bDMARDs approved for RA include a T-cell–modulating biologic (abatacept), a B-cell cytotoxic agent (rituximab), an anti–IL-6 receptor antibody (tocilizumab), IL-1–inhibiting agents (anakinra, rilonacept, canakinumab), and the TNF-α–blocking agents (five drugs); bDMARDs are further divided into biological original (or legacy) products and biosimilar DMARDs (boDMARDs and bsDMARDs, respectively).
The small-molecule DMARDs and biologics are discussed alphabetically, independent of origin.
1.
Mechanism of action: Abatacept is a co-stimulation modulator biologic that inhibits the activation of T cells (see also Chapter 55). After a T cell has engaged an antigen-presenting cell (APC), a second 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.
2.
Pharmacokinetics: The recommended dose of abatacept for the treatment of adult patients with RA is three intravenous infusion “induction” doses (day 0, week 2, and week 4), followed by monthly infusions. The dose is based on body weight; 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. Abatacept is also available as a subcutaneous formulation and is given as 125 mg subcutaneously once weekly.
JIA can also be treated with abatacept with an induction schedule at day 0, week 2, and week 4, followed by intravenous infusion every 4 weeks. The recommended dose for patients 6–17 years of age and weighing less than 75 kg is 10 mg/kg, while those weighing 75 kg or more follow the adult intravenous doses to a maximum not to exceed 1000 mg. The terminal serum half-life is 13–16 days. Co-administration with methotrexate, NSAIDs, and corticosteroids does not influence abatacept clearance.
Most patients respond to abatacept within 12–16 weeks after the initiation of the treatment; however, some patients can respond in as few as 2–4 weeks. A study showed equivalence between adalimumab (see TNF-α Blocking Agents) and abatacept.
3.