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Title: Determinants of response to B cell depletion in rheumatic diseases
Author: Vital, Edward Marc John
ISNI:       0000 0004 2745 7596
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2011
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Background: Determinants of response and relapse to B cell depletion in rheumatic diseases is poorly understood, but necessary to improve its clinical use. Objectives: The aims of this study were (1) to test peripheral blood biomarkers for non-response in RA and systemic lupus erythematosus; (2) to evaluate variations in treatment regimen using these biomarkers; (3) to correlate peripheral blood findings with synovial tissue Results: In both RA and SLE, peripheral blood B cell subsets were predictive of response and relapse. Increase numbers of.memory B cells and plasma blasts before or immediately after rituximab were predictive of worse responses, and numbers of these subsets in early repopulation were predictive of relapse. Differences in pattern of depletion and re population were observed between these diseases. These markers correlated with improved response when combining rituximab with alternative DMARDs, when altering rituximab dose, or using early retreatment to improve poor response. Changes in antibodies were studied: these did not correlate with clinical response, but persistently high levels of rheumatoid factor after rituximab were predictive of earlier relapse, as was persistence of synovial plasma cells. Baseline levels of BAFF and IL-6 were predictive of clinical response. Abnormalities ofT cell homeostasis were partially reversed by rituximab, which also correlated with clinical response. Pilot data indicate changes in B cell phenotype in some patients whose importance in clinical response is as yet undetermined. In SLE, some subtypes of disease were less responsive to rituximab. Conclusions: Increased B cell numbers before and after rituximab predict worse clinical response, but this can be overcome by dose, combination DMARD or retreatment interval. Markers of B cell activation prior to rituximab predict good response to treatment. However, after rituximab, these markers, as well as B cell repopulation, also predict earlier relapse and the need for retreatment. These observations provide a rationale for future attempts to improve clinical use of rituximab.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available