Title: Improving evaluation and implementation of B cell targeted therapies in systemic lupus erythematosus
Funder: Department of Health and Social Care

Abstract: Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disease which causes significant morbidity and mortality despite treatment with immunosuppressive therapies. New biologic therapies may improve control of disease activity, but their development has been problematic with several negative randomised controlled trials for agents in widespread clinical use and shown to be effective in other trials. The best example of this problem is rituximab which depletes B-cells in peripheral blood and lymphoid tissues for about 6 months with variable B cell repopulation subsequently. It is licensed in other indications and widely used off label in the UK based on positive case series. This creates a dilemma, highlighted in a recent NICE review of an alternative biologic for SLE (belimumab) which was appealed in part due to the comparison with rituximab.The failure of these trials has been attributed to (i) difficulty applying outcome measures or trial endpoints, and (ii) the use of active comparators instead of placebo. In Workpackage 1 I will investigate new, objective outcome measures that may enable reliable assessment of efficacy of a biologic in smaller, shorter trials. These outcome measures will be applied to skin and musculoskeletal disease. For these non-lethal manifestations, the use of a true placebo is ethical.Skin disease in SLE is variable in morphology and severity. I have demonstrated a variable clinical response to B cell depletion, which was linked to morphology (submitted, JAMA dermatology). Skin SLE is usually linked to exposure to ultraviolet light, which induces apoptosis and therefore exposes the antigenic targets of pathogenic B cells in SLE. Controlled UV light exposure is used as a diagnostic test for SLE and other skin diseases and has been used to measure response to topical therapies in clinical trials. Musculoskeletal disease in SLE varies between some patients with severe synovitis similar to rheumatoid arthritis and others with pain that does not cause typical joint swelling, but may nevertheless respond to immunosuppressive therapy. In rheumatoid arthritis, high resolution ultrasound (HRUS) has been used extensively in Leeds to demonstrate subclinical synovitis that has long term clinical consequences and responds to therapy. Workpackage 1 will consist of a randomised controlled feasibility study of rituximab vs. placebo, with tightly controlled concomitant therapies, in 30 patients with active skin and musculoskeletal SLE. Patients will be assessed using existing clinical outcome measures and two novel endpoints: musculoskeletal ultrasound to assess inflammatory arthritis, and UV photoprovocation with biopsy to assess skin inflammation. These outcomes will be measured at baseline and 16 weeks. The feasibility and validitiy of the new outcome measures will be assessed according to OMERACT filter principles and the feasibility and acceptability of the overall trial approach will be evaluated prior to designing a definitive study. Although rituximab appears effective in open label series, its effects are temporary with highly variable duration of response[2]. Another area of uncertainty is therefore how often the treatment should be repeated this will be addressed in work package 2.The link between repopulation of B cells and response mentioned above will be confirmed using samples from patients in another clinical trial of rituximab vs. placebo in SLE with nephritis. The efficacy of intervention to control B cell repopulation will be tested in a further clinical trial to be developed in collaboration with Prof Isenberg and Prof Ehrenstein with separate funding to be sought.

Lay abstract: Systemic Lupus Erythematosus (SLE) is a disease in which the immune system attacks the body's own tissues. It can be controlled with treatment, but not all patients respond. New therapies could help more patients, but it is difficult to prove that they work. I will undertake a trial of a new treatment for SLE with specialised tests that may more accurately measure the disease to develop a new way to test treatments in a future trial. I will also investigate why treatment effects wear off over time and develop a future clinical trial to control disease activity long term.

Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM