Table 1. Overview of the potential reasons for clinical success or clinical failure of targeted RA therapies.

Clinical approved	Target	Potential reasons and lessens
Success	TNF-α	✓ First approved bDMARD for RA
		✓ Multipotent and central role of TNF-α in RA pathophysiology
	IL-6	✓ Pleiotropic activity of IL-6 in RA pathogenesis
		✓ Low incidence of anti-drug Ab
		✓ Rapid reduction of inflammation
	CD80/CD86	✓ Blockade of upstream immune-synapse in the inflammatory cascade
		✓ Relatively less susceptible to infection by mainly suppressing activated T cells rather than naive T cells
	JAK/STAT	✓ Blockade of upstream signal transduction
		✓ Blockade of signaling pathways across multiple cytokine axes simultaneously
		✓ Oral formulation; convenient to take medicines
Failure	IL-1β	✓ Short half-life and need for daily injection
		✓ Higher risk of infection compared to efficacy
	IL-17A	✓ Disease heterogeneity of RA with variable expression of IL-17A
		✓ Meaningful roles of IL-17A only in the early phase of RA, but not in the established phase
		✓ Blocks not only pathologic Th17 but also regulatory Th17
	MAPK p38α	✓ Compensatory activation of upstream kinase pathways upon p38α
		✓ Blocks not only pro-inflammatory p38α but also anti-inflammatory p38α
		✓ Pro-inflammatory roles of additional isoforms of p38