A Clinically Qualified Biomarker of Response to anti-CD20 Therapy in Rheumatoid Arthritis

In the September 21^st issue of Science Translational Medicine (link), scientists at Genentech reveal their findings about a new, clinically qualified biomarker of non-response to antibody therapy to CD20 in rheumatoid arthritis (RA).  B cell depleting therapy using the anti-CD20 mAb rituximab in RA (link) is reserved for patients who have failed standard disease-modifying antirheumatic drugs (specifically methotrexate) and/or with inadequate response to anti-TNF antibody therapy.  Considering the cost, complexity, and relative risk associates with anti-CD20 therapy and considering that about 50% of RA patients do not respond to rituximab, there is a strong impetus to target this therapy to patients who are most likely to respond favorably.

Hypothesizing that RA patients with high frequency of antibody producing plasma B cells are less likely to respond to rituximab (plasma cells do not express CD20), the team at Genentech surveyed a set of B cell and plasma cell specific RNA transcripts in blood samples from a subgroup of patients who had been treated with rituximab (REFLEX study).  Using the American College of Rheumatology 50% improvement criteria (ACR50), they identified a clear association between failure to meet ACR50 and elevated levels of RNA for the immunoglobulin J chain (IgJ) at baseline.  They confirmed this observation using blood samples from patients enrolled in two additional independent rituximab studies (DANCER and SERENE), and one study of ocrelizumab (a second generation anti-CD20 mAb) in RA (SCRIPT).  When all four trials were combined, the ACR50 response rate in the active arms was 28% for the IgJ^lo group (n = 471) and 12% for the IgJ^hi group (n = 122) (Odd ratio: 2.7; 95% confidence interval: 1.5 to 5.3).  The predictive power of the IgJ RNA level was further refined by combining this parameter with the RNA levels for the B cell specific splice variant of Fc Receptor-like 5 (FCRL5).  Together, elevated levels of IgJ RNA and low levels of FCRL5 at baseline (biomarker positive: IgJ^lo / FCRL5^hi) were strongly associated with low probability of positive response to anti-CD20 mAbs therapy (figure 1).  Indeed, in the combined 4 clinical studies, 28% of biomarker-negative patients responded to treatment while only 9% of biomarker positive patients responded under the same conditions (Odd ratio: 3.6; 95% confidence interval: 1.8 to 8.4).  Of note, this combination biomarker does not appear to be an indicator of more severe diseases since it was not associated with different response rate in the placebo groups from those clinical studies.

Fig. 1

Beyond representing a major advance in the area of treatment decision in RA patients, this work represents a remarkable example of the power of well-planned, well-executed prospective retrospective studies for the discovery and clinical qualification of novel biomarkers

Thierry Sornasse for Integrated Biomarker Strategy