Abstract
B cells are believed to be central to the disease process in systemic lupus erythematosus (SLE), making them a target for new therapeutic intervention. In recent years there have been many publications regarding the experience in SLE of B-cell depletion utilising rituximab, an anti-CD20 mAb that temporarily depletes B cells, reporting promising results in uncontrolled open studies and in routine clinical use. However, the two large randomised controlled trials in extra-renal lupus (EXPLORER study) and lupus nephritis (LUNAR study) failed to achieve their primary endpoints. Based on the clinical experience with rituximab this failure was somewhat unexpected and raised a number of questions and concerns, not only into the true level of benefit of B-cell depletion in a broad population but also how to test the true level of effectiveness of an investigational agent as we seek to improve the design of therapeutic trials in SLE. A better understanding of what went wrong in these trials is essential to elucidate the underlying reasons for the disparate observations noted in open studies and controlled trials. In this review, we focus on various factors that may affect the ability to accurately and confidently establish the level of treatment effect of the investigational agent, in this case rituximab, in the two studies and explore hurdles faced in the randomised controlled trials investigating the efficacy of ocrelizumab, the humanised anti-CD20 mAb, in SLE. Further, based on the lessons learned from the clinical trials, we make suggestions that could be implemented in future clinical trial design to overcome the hurdles faced.
Highlights
B cells have been targeted in the treatment of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) owing to the central role they play in the pathogenesis of these disorders
More recently just one dose of cyclophosphamide has been used, and any subsequent need for immunosuppressive therapy is adjusted based on the merits of clinical response and disease manifestation activity that can be assessed using well-validated tools such as the British Isles Lupus Assessment Group (BILAG) 2004 index
(i) and (ii) no significant difference; (iii) placebo (50%) and rituximab (69%) (P
Summary
B cells have been targeted in the treatment of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) owing to the central role they play in the pathogenesis of these disorders. More recently just one dose of cyclophosphamide has been used, and any subsequent need for immunosuppressive therapy is adjusted based on the merits of clinical response and disease manifestation activity that can be assessed using well-validated tools such as the British Isles Lupus Assessment Group (BILAG) 2004 index (for example, using the BLIPS computer software program; LIMATHON, Sheffield, UK) Appreciating this robust clinical management focused on the individual patient – potentially involving multidisciplinary expert opinion, including rheumatologists, dermatologists and renal physicians – is important when comparing the results with those from large multicentre randomised controlled trials with variable quality observations in a broad population. Involving only small numbers, the observations from repeating the regimen showed that improvements in disease, including remission rates, were sustained in patients who responded to the initial treatment [20] This same group has previously demonstrated following B-cell depletion therapy (BCDT) that anti-double-stranded DNA (anti-dsDNA) and anti-nucleosome antibodies reduce to 30 to 40% of baseline, whereas other autoantibodies such as anti-Ro and antibodies to pneumococcal polysaccharide (protective) remain unaltered. In the intent-to-treat analysis of 257 patients, approximately 70% of patients completed the study in both arms
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
