| Summary: | Background: Pathogenesis of systemic lupus erythematosus (SLE) is thought to be closely related to B-cell dysfunction, and accordingly this is the usual target for therapies. However, non-B-cell mechanisms such as tumour necrosis factor (TNF) and interferons may also be important in the onset as well as established disease. Objectives: (i) To assess biomarkers of progression from At-Risk (ANA-positive but limited symptoms) to connective tissue disease (AI-CTD); (ii) to identify predictors of non-response and serious infections with rituximab; and (iii) to assess new therapies to overcome rituximab deficiency with respect to anti-rituximab antibodies and B-cell-independent inflammation in discoid lupus erythematosus (DLE). Methods: Prospective observational studies were conducted in (i) At-Risk of AI-CTD and (ii) SLE patients treated with rituximab. Patients with anti-rituximab antibodies were treated with alternative humanised anti-CD20 agents. (iii) A single arm, phase II open label trial of intra-dermal injection of etanercept for remission induction in DLE (TARGET-DLE) was undertaken. Results: (i) Higher IFN-Score-B and a family history of autoimmune rheumatic diseases at baseline were predictive of progression from At-Risk to AI-CTD. (ii) B-cell depletion at 6 weeks post-rituximab was predictive of major response to rituximab and was not associated with increased serious infection post-therapy in SLE. During repeat rituximab cycles, 12% of SLE patients lost depletion, which was attributed to anti-rituximab antibodies. These patients were switched to humanised agents, and all depleted and responded. (iii) For TARGET-DLE, the primary and most of the key secondary endpoints were met. Therapy was tolerable without inducing systemic autoimmunity. Conclusion: In this thesis, a personalised approach to treatment based on immunopathogenesis in At-Risk and established SLE led to better outcomes for patients. The predictive values of the biomarkers presented may allow stratification of patients for disease progression. While results from the use of novel therapies presented support further development in multi-centre trials.
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