B Cell Depletion in RA: The future is bright Save

The incredible potential of B cell depletion in rheumatic diseases was heralded by its activity in the treatment of rheumatoid arthritis (RA) over 20 years ago. Rituximab (RTX) was cemented into the armamentarium of RA by its efficacy in TNF-inhibitor inadequate responders (REFLEX). Subsequently, it was recognized that the clinical responses of RTX was greater in seropositive RA patients. In contrast to other biologics, RTX could be combined with TNF inhibitors without toxicity from increased infections.  

Moreover, repeated courses of RTX for RA were very well tolerated at 6 month intervals, without secondary loss of activity as seen with anti-TNF antibodies.  At the same time, unexpected durability of response was seen; some patients went into long-term (> 12 months) remissions following a single course of RTX. Curious effects were seen on the underlying pathophysiology. While substantive changes in Rheumatoid Factor (RF) levels were associated with clinical response, this effect was not reflected anti-citrullinated protein antibodies (ACPA).

Since its FDA approval for RA in March 2006, RTX has remained a critical component of our tool kit in the therapy of RA exhibiting both clinical and radiographic benefits. These studies led to the discovery of RTX for other rheumatic diseases, perhaps most notably in ANCA-associated therapy.

As alluded to above, the mechanism of action of RTX at both the cellular and systemic level remain enigmatic. RTX is mouse-human IgG1 chimeric antibody that, when infused, mediates profound depletion of circulating CD19+ B cells within 48-72 hours in all patients with RA.  CD19 is measured as a surrogate for CD20+ B cells in the context of circulating RTX levels that can block binding to CD20, falsely lowering apparent B cell depletion.  Despite a marked depletion in circulating B cells, clinical responses to RTX take weeks to months with peak improvement in disease activity at 16 weeks. Second, some patients exhibit little or no clinical response even with persistent B cell depletion. Finally, in patients who have responded to RTX, recurrence of synovitis is often seen in the context of persistent B cell depletion.

Understanding these seemingly anomalous relationships has been a persistent cipher despite several important insights derived from clinical and animal studies. 

Most important has been recognition that RTX mediated B cell reduction occurs through opsonized circulating B cells being targeted for clearance in the liver or spleen. This observation has led to the following model of its mechanism of action.  In this model, synovial inflammation in a given patient is dependent on B cell trafficking to the joint.  Thus, RTX interdicts circulating B cells from doing so thus resulting in resolution of synovitis as synovial B cells die or leave the joint. In contrast, in RA patients with predominantly myeloid synovial inflammation with low B cell numbers, RTX-mediated depletion of circulated B cells would be predicted to have little or no effect.

These models incorporate recognition that RTX does not efficiently mediate some IgG-dependent effector functions (complement mediated cytotoxicity, antibody mediated cellular cytotoxicity) that would be expected to locally deplete B cells in the joint.  Other anti-CD20 antibodies (ofatumumab, obinatuzumab) which have engineered to optimize these activities have been shown to be more efficacious than rituximab in Chronic Lymphocytic Leukemia (CLL) and are now in randomized controlled clinical trials for rheumatic diseases (Lupus).  

Finally, other antibodies targeting B cell antigens such as CD19 might turn out to be more effective than RTX, perhaps through a broader spectrum of B cell depletion.  CD19 expression occurs earlier (pre-B) and later (plasmablasts) in the B cell lineage than CD20.  Thus, antibody-mediated targeting of CD19 might induce a depth of depletion on circulating B cells not seen with RTX.  This strategy need not be limited to antibody-targeting of CD19.  Indeed, targeting of CD19 by CAR-T cell therapy has exhibited impressive responses in refractory lupus, dermatomyositis, and scleroderma. 

Thus, the discovery of the activity of RTX in RA may be remembered as that first conceptual step in the evolving potential and sophistication of B cell depletion in many rheumatic diseases.