Breaking the Rules: Dual-Advanced Combinations in Rheumatology Save

For decades, the standard of care in rheumatology has been combination therapy - pairing methotrexate (MTX) with an advanced biologic or synthetic agent to achieve optimal outcomes. 

Because of early trials combining IL-1 and TNF inhibition, regulators have strongly warned against combining biologics or biologics with targeted synthetics with package insert warnings that would state - "XXXXXX is not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine."

More recently there are trials in inflammatory bowel disease and psoriatic disease utilizing combinations of biologic and advanced therapies. The preliminary data suggests benefit without increased toxicity or serious infections. 

A recent overview, detailed by IQVIA, examines the possibility of  "dual-advanced" therapy—combining two biologics or targeted synthetic DMARDs (tsDMARDs) to achieve synergistic outcomes. 

The rationale for Dual-Advanced Strategies is driven by: 

1. Mechanistic Complementarity: By targeting distinct but synergistic pathways—such as inhibiting cytokine production (upstream) alongside effector signaling (downstream)—clinicians may better manage the inherent heterogeneity and complexity of autoimmune diseases.

2. Addressing "Metaflammation": A compelling example of this is the recent readout of the TOGETHER trials (PsA4 and PsO5). These studies combined an IL-17 inhibitor (Taltz) with a GLP-1/GIP receptor agonist (Zepbound). By targeting the "obesity-inflammation axis," the combination significantly outperformed monotherapy in PASI 100 achievement (40.6% vs. 29%), demonstrating that treating co-morbid "metaflammation" can enhance primary disease control.

3. Precision vs. Broad Immunosuppression: Combination immunosuppressives, especially when combined with high-dose corticosteroids, has causes broad immunosuppression and poorly tolerated effects, while dual-advanced therapies offer mechanistic precision and potentially limited toxicity; resulting in a a more favorable risk-benefit profile.

The Future

The development pipeline is already pivoting. Dual-advanced therapy trials as a share of all combination trials doubled from 19% (2015-2020) to 40% (2021-2025). We are seeing a surge in mid-to-late-stage trials, particularly in Inflammatory Bowel Disease (IBD) and Psoriatic Arthritis, where multi-pathway blockade is becoming the preferred strategy for refractory or difficult-to-treat (D2T) populations.

We need trials, approvals and more safety data to go down this thereapeutic pathway.  Other significant hurdles include payers restrictions, costs, competition form biosimilars and new drugs iwth novel mechanisms of action.