Highly sensitive B cell analysis predicts response to rituximab therapy in rheumatoid arthritis

Abstract

Objective. In rheumatoid arthritis (RA), B cell depletion occurs in all patients treated with rituximab, but the clinical responses to rituximab are variable. A highly sensitive assay was used to test the hypothesis that B cell depletion is variable, and that incomplete depletion leads to a poorer outcome.Methods. Sixty patients with active RA unresponsive to anti-tumor necrosis factor agents received two 1-gram infusions of rituximab. B cell numbers were measured by highly sensitive flow cytometry before and after each infusion and at 3-month intervals thereafter. A reduction in B cell levels below 0.0001 ؋ 10 9 /liter was defined as complete depletion (compared with 0.05 ؋ 10 9 /liter by conventional cytometry). Clinical responses were measured using the European League Against Rheumatism (EULAR) criteria.Results. At 6 months, 92% of patients had a moderate-to-good clinical response according to the EULAR criteria. B cells were detected in 63% of patients after the first infusion of rituximab (median level 0.0009 ؋ 10 9 /liter [range <0.0001-0.0015 ؋ 10 9 /liter), and these patients had poorer clinical outcomes than patients with complete depletion. At 9 months, 82% of patients with complete depletion had a moderate-togood EULAR response, compared with 43% of those with partial depletion (P ‫؍‬ 0.01). At 12 months, 59% of complete responders had a moderate-to-good EULAR response, compared with 21% of those with partial depletion (P ‫؍‬ 0.01). Patients in whom B cells were depleted only after the second infusion did no better than those in whom depletion was never complete and had poorer clinical outcomes than those in whom depletion was initially complete.Conclusion. This study is the first to show, using a highly sensitive analysis, that rituximab therapy is associated with variable diminution in B cell numbers. A lack of complete depletion of B cells after 1 infusion was associated with a poorer outcome.

Re‐treatment of rheumatoid arthritis patients who were initial nonresponders to rituximab: Comment on the article by Thurlings et al

“…This is consistent with the findings of our own studies (3) and the studies of other investigators (4) on synovium. It is also consistent with the results of our studies of peripheral blood (5). In fact, we have never observed nonresponse in patients with fast and complete B cell depletion, as measured by highly sensitive flow cytometry (5).…”

Relationship between the type I interferon signature and the response to rituximab in rheumatoid arthritis patients

“…This appears unlikely, since all patients in our study were RF positive and/or ACPA positive. Furthermore, current evidence suggests that nonresponse to rituximab is associated with the persistence of B cells (36,37). It is conceivable that higher inflammatory activity in patients with an IFN high signature may relatively protect B cells against the depleting effects of rituximab.…”

The value of rituximab treatment in primary Sjögren's syndrome

“…In RA, these factors are RF or anti-CCP positivity, elevated serum IgG, low IFN activity, lower serum levels of BAFF and lower numbers of circulating plasmablasts [54]. Furthermore, the degree of B cell depletion was positively associated with clinical response in both RA and SLE [55,56]. SLE patients with a low-affinity FcγRIIIa genotype have less effective B cell depletion, as antibody-dependent cellular cytotoxicity, mediated by FcγRIIIa-positive effector cells (mostly NK cells), is impaired [57].…”