What is the efficacy of combination biologics for immunosuppression?

From the Guidelines

Combination biologic immunosuppression is generally not recommended in clinical practice due to increased risks of serious infections and other adverse events without clear evidence of superior efficacy. The most recent and highest quality study, 1, published in 2024, does not provide clear evidence to support the use of combination biologic immunosuppression.

Key Considerations

• The use of biologics, such as TNF inhibitors (adalimumab, infliximab, etanercept), IL-6 inhibitors (tocilizumab), IL-17 inhibitors (secukinumab), IL-12/23 inhibitors (ustekinumab), and B-cell depleting agents (rituximab), should typically be as monotherapy or combined with conventional synthetic DMARDs like methotrexate (7.5-25mg weekly) 1.
• The rationale against combining biologics is that targeting multiple immune pathways simultaneously significantly increases immunosuppression, leading to disproportionate infection risk compared to potential therapeutic benefit.
• In rare cases where combination therapy is considered, such as in severe refractory inflammatory conditions, it should only be done in specialized centers with close monitoring for infections, cytopenias, and other complications.

Monitoring and Precautions

• Regular laboratory monitoring (CBC, liver function, renal function) and screening for latent infections before initiation are essential regardless of regimen chosen.
• The potential health economic impact and overall safety of combination biologic immunosuppression should be taken into consideration, as noted in 1.
• The lack of clear studies demonstrating superior efficacy of combination therapy with biologics and an immunosuppressant makes proper guidance difficult, as stated in 1.

From the FDA Drug Label

The other two controlled studies compared two 20-mg doses of Simulect with placebo, each administered intravenously as a bolus injection, as part of a standard triple-immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED), corticosteroids and either azathioprine or mycophenolate mofetil (Study 3 and Study 4, respectively) In Study 3,340 patients were concomitantly treated with cyclosporine, USP (MODIFIED), corticosteroids and azathioprine (AZA), of which 168 patients were treated with Simulect and 172 patients were treated with placebo In Study 4,123 patients were concomitantly treated with cyclosporine, USP (MODIFIED), corticosteroids and mycophenolate mofetil (MMF), of which 59 patients were treated with Simulect and 64 patients were treated with placebo

The use of combination biologics immunosuppression is supported by the studies, which used Simulect in combination with:

• Dual-immunosuppressive regimens: cyclosporine and corticosteroids
• Triple-immunosuppressive regimens: cyclosporine, corticosteroids, and either azathioprine or mycophenolate mofetil The studies demonstrated the efficacy of Simulect in preventing acute rejection in renal transplant patients when used in combination with these immunosuppressive regimens 2. Key points:
• Simulect was used in combination with other immunosuppressive agents to prevent acute rejection
• The combination regimens included cyclosporine, corticosteroids, and either azathioprine or mycophenolate mofetil
• The studies demonstrated the efficacy of Simulect in preventing acute rejection in renal transplant patients when used in combination with these regimens 2

From the Research

Combination Biologics Immunosuppression

• The combination of etanercept and methotrexate has been shown to be effective in the treatment of rheumatoid arthritis, with studies demonstrating improved clinical response and reduced joint damage compared to monotherapy with either drug 3, 4, 5.
• A study published in the Lancet found that the combination of etanercept and methotrexate was significantly better than methotrexate or etanercept alone in reducing disease activity, improving functional disability, and retarding radiographic progression in patients with rheumatoid arthritis 3.
• Another study published in Clinical Rheumatology found that etanercept monotherapy was effective in reducing disease activity, but that the combination of etanercept and methotrexate was marginally more effective in some outcomes measured 4.
• A study published in the New England Journal of Medicine found that etanercept was more effective than methotrexate in reducing disease activity and slowing joint damage in patients with early active rheumatoid arthritis 5.
• The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study found that initial use of methotrexate monotherapy with the addition of sulfasalazine plus hydroxychloroquine (or etanercept, if necessary, after 6 months) is a reasonable therapeutic strategy for patients with early RA, and that treatment with the combination of MTX plus etanercept resulted in a statistically significant radiographic benefit compared with oral triple therapy 6.

Treatment Options after Methotrexate Failure

• For patients who do not respond to methotrexate, the addition of other DMARDs or biologics such as etanercept may be considered 7.
• The choice of treatment after methotrexate failure depends on various factors, including the patient's disease activity, comorbidities, and previous treatment history 7.
• Studies have shown that the combination of etanercept and methotrexate can be an effective treatment option for patients with rheumatoid arthritis who have failed methotrexate monotherapy 3, 4, 5.