Abatacept

Introduction to Abatacept

Abatacept is a selective T-cell costimulation modulator, classified as a biologic disease-modifying antirheumatic drug (DMARD). It was first approved by the FDA in 2005 for the treatment of rheumatoid arthritis and has since gained approval for other indications, including pediatric polyarticular juvenile idiopathic arthritis (pJIA). Abatacept is a soluble fusion protein consisting of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G1 (IgG1).

Mechanism of Action

Abatacept works by modulating T-cell activation, which plays a crucial role in the pathogenesis of autoimmune diseases. The mechanism of action involves:

  • Binding to CD80 and CD86 on antigen-presenting cells (APCs)
  • Inhibiting the costimulatory signal required for full T-cell activation
  • Preventing the interaction between CD28 on T-cells and CD80/CD86 on APCs
  • Reducing T-cell proliferation and inhibiting the production of inflammatory cytokines

By modulating this costimulatory pathway, abatacept helps to reduce inflammation and joint damage in autoimmune conditions such as rheumatoid arthritis and juvenile idiopathic arthritis. Unlike TNF inhibitors, abatacept does not directly target inflammatory cytokines but instead interferes with the upstream process of T-cell activation.

Indications

Abatacept is FDA-approved for the following indications:

  • Adult Rheumatoid Arthritis (RA): Reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA
  • Polyarticular Juvenile Idiopathic Arthritis (pJIA): In patients 2 years of age and older
  • Adult Psoriatic Arthritis (PsA): Treatment of adult patients with active PsA

Of particular interest to pediatricians is the indication for polyarticular JIA, which makes abatacept an important option in the treatment of children with this condition. It's often used in patients who have had an inadequate response to other treatments, including methotrexate and TNF inhibitors.

Dosage and Administration

Abatacept is available in two formulations: intravenous (IV) infusion and subcutaneous (SC) injection. The dosage varies depending on the indication, patient's age, and weight:

Intravenous Administration:

  • Adult RA and PsA:
    • < 60 kg: 500 mg
    • 60-100 kg: 750 mg
    • > 100 kg: 1000 mg
    Given at weeks 0, 2, and 4, then every 4 weeks thereafter
  • Pediatric pJIA (6 years and older):
    • 6 to 17 years and < 75 kg: 10 mg/kg
    • 6 to 17 years and ≥ 75 kg: Adult dosing, not to exceed 1000 mg
    Given at weeks 0, 2, and 4, then every 4 weeks thereafter

Subcutaneous Administration:

  • Adult RA and PsA: 125 mg once weekly
  • Pediatric pJIA (2 years and older):
    • 10 to < 25 kg: 50 mg once weekly
    • 25 to < 50 kg: 87.5 mg once weekly
    • ≥ 50 kg: 125 mg once weekly

For subcutaneous administration in pJIA, abatacept may be initiated without an IV loading dose. For patients transitioning from IV to SC administration, the first SC dose should be given instead of the next scheduled IV dose.

Adverse Effects

Common adverse effects of abatacept include:

  • Headache
  • Upper respiratory tract infections
  • Nasopharyngitis
  • Nausea
  • Infusion-related reactions (with IV administration)
  • Injection site reactions (with SC administration)
  • Dizziness
  • Cough
  • Back pain
  • Hypertension

More serious adverse effects, although less common, may include:

  • Serious infections, including pneumonia, cellulitis, and urinary tract infections
  • Malignancies (although the overall incidence has not been shown to be increased compared to the general population)
  • Hypersensitivity reactions
  • Autoimmune disorders (rare cases of lupus-like syndrome)
  • Liver enzyme elevations

In pediatric patients with JIA, the safety profile has been generally similar to that observed in adults, with infections being the most common serious adverse events. However, the frequency of some adverse events may differ in children compared to adults.

Drug Interactions

Abatacept has fewer drug interactions compared to many other medications, but there are some important considerations:

  • TNF antagonists: Concurrent use is not recommended due to increased risk of serious infections
  • Other biologic DMARDs: Combination has not been studied and is not recommended due to potential increased immunosuppression
  • Live vaccines: Should not be given concurrently with abatacept or within 3 months of its discontinuation
  • Blood glucose testing: Certain blood glucose monitors (BGMs) falsely interpret maltose in ORENCIA® for IV use as glucose. This could result in falsely elevated glucose readings on the day of infusion.

Unlike some other DMARDs, abatacept does not significantly affect cytochrome P450 enzymes, reducing the potential for interactions with drugs metabolized by these pathways. However, as with all immunomodulatory agents, caution should be exercised when combining abatacept with other medications that affect the immune system.

Pediatric Considerations

Abatacept's approval for use in pediatric patients with pJIA makes it an important treatment option for pediatricians managing this condition. Key considerations include:

  • Age and Weight-based Dosing: Accurate weight measurements are crucial for proper dosing in pediatric patients
  • Route of Administration: The availability of both IV and SC formulations allows for flexibility in administration, which can be particularly important in pediatric patients
  • Immunizations: Live vaccines should be avoided in patients receiving abatacept. It's important to update vaccinations before initiating therapy
  • Growth and Development: Regular monitoring of growth and development is crucial in pediatric patients receiving abatacept
  • Infections: Children may be at higher risk for certain infections. Careful monitoring and prompt treatment of infections is essential
  • Long-term Safety: While long-term safety data in children is accumulating, continued vigilance for potential long-term effects is important
  • Transition of Care: For adolescents on long-term abatacept therapy, planning for transition to adult care is important
  • Quality of Life: The impact of regular medication administration (whether IV infusions or SC injections) on the child's quality of life should be considered

Pediatricians should work closely with pediatric rheumatologists when managing children on abatacept to ensure optimal care and monitoring. The choice to use abatacept in pJIA is often made after considering factors such as disease severity, prior treatment response, and patient/family preferences.



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