Table 3.

Rituximab/belimumab paradox.

Paradigm	Hypothesis
Trial design	Liberal use of CS in EXPLORER and concurrent MMF use in LUNAR may have blunted the differences between placebo and RTX, while BEL trials had stricter requirements for background SOC therapy.
	Rigorous composite response in LUNAR may have been too conservative to detect significance, while BEL's primary outcome (SRI-4) was able to detect subtle changes in disease activity.
	Large numbers of patients in BEL trials resulted in adequate powering, while RTX trials may have not enrolled enough patients for adequate powering.
	The SRI-4 used in BEL trials was based on analysis and assessment of prior phase II trials; a similar approach was not taken for RTX trials.
SLE phenotype	SLE phenotypes with aggressive and refractory manifestations may be highly B cell-driven and respond dramatically to RTX, whereas those with more mild phenotypes may respond less well.
	BEL's more widespread effects on the immune system (including on T cells) may allow for better control of mild-moderate disease phenotypes.
B regulatory cells (Bregs)	Bregs are involved in regulatory functions of the immune system. Depletion by RTX may aggravate autoimmune response, whereas they may be spared by BEL.
Plasma cells	RTX spares plasma cells, thereby allowing continued pathogenic autoantibody production. Receptors for BAFF are present on plasma cells, so plasma cell function may be inhibited by BEL.
B cell depletion	B cells may require “priming” by certain factors prior to become sensitive to RTX. No such “priming” may be needed for sensitivity to BEL.
Effect on non-B cells	BEL may modulate non-B-cell elements of the immune system that contribute to SLE activity, whereas RTX is B-cell specific.

CS, corticosteroids; EXPLORER, exploratory phase II/III SLE evaluation of rituximab; MMF, mycophenolate mofetil; LUNAR, Lupus nephritis assessment with rituximab; RTX, rituximab; BEL, belimumab; BEL, belimumab; SRI-4, systemic lupus erythematosus responder index.