Elsevier

Autoimmunity Reviews

Volume 13, Issue 11, November 2014, Pages 1094-1101
Autoimmunity Reviews

Review
The efficacy of novel B cell biologics as the future of SLE treatment: A review

https://doi.org/10.1016/j.autrev.2014.08.020Get rights and content

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with wide ranging multi-systemic effects. Current understanding centralises B cells in SLE pathogenesis with clinical features resulting from autoantibody formation, immune complex deposition, antigen presentation and cytokine activation. Existing standard of care therapies generates adverse side effects; secondary to corticosteroid use and untargeted immunosuppression. The inability to uphold remission and abolish the disease process, in addition to the increasing numbers of patients seen with refractory disease with these therapies, has provoked the development of novel B cell biologics targeting specific pathogenic pathways fundamental to the SLE disease process.

Current evidence highlighting the efficacy of Rituximab, Ocrelizumab and Epratuzumab in inducing B cell depletion and achieving disease amelioration through specific B cell surface receptor antagonism is discussed. We review the efficacy of Atacicept, Briobacept and Belimumab in antagonising B lymphocyte stimulator (BLyS) and A proliferation inducing ligand (APRIL), two stimulatory cytokines crucial to B cell survival, growth and function. Two large multicentre randomised controlled trials, BLISS-52 and BLISS-76, have led to FDA approval of Belimumab. Following this breakthrough, other anti-BLyS therapies, Blisibimod and Tabalumab, are currently under Phase III evaluation. Similarly, murine models and Phase I/II trials have demonstrated significant efficacy of Rituximab, Epratuzumab, Briobacept and Atacicept as potential future therapies and we now eagerly await results from Phase III trials. Future research must compare the efficacy of different biologics amongst different patient subpopulations and SLE manifestations, in order to develop clinically and cost effective therapies.

Introduction

SLE is a relapsing and remitting, chronic autoimmune inflammatory disease with wide ranging multi-systemic effects. Clinical features develop through autoantibody formation, immune complex deposition and cytokine activation. Symptoms vary from general malaise, fever, lethargy and depression to more severe musculoskeletal, cutaneous, pulmonary, renal, haematopoietic, cardiac and nervous system manifestations [1]. (See Fig. 1, Fig. 2.)

African–American (AA) women are the highest risk sub-population affected by SLE with 1 in 500 people affected [2]. 80% of patients are females of childbearing age, with males 9 times less likely to develop SLE [2], [3]. Klinefelter's syndrome (47 XXY) patients, as well as SLE females on hormone replacement therapy have been shown to have an increased risk of relapsing lupus — together suggesting an aetiological role for oestrogen [4], [5]. Hereditary factors (40% rate of concordance seen in monozygotic twins), environmental trigger factors (Epstein–Barr virus, UV light and drug interventions such as isoniazid, penicillamine and hydralazine) as well as genetic influences (approximately 200 different genetic loci coding for HLA variants and complement deficiencies have been described) also play a complex multifactorial role in the aetiology of SLE [6], [7], [8], [9].

Section snippets

Pathogenesis

Following triggers such as EBV infection or UV radiation, inherent abnormalities in the innate and adaptive immune systems result in the collection of ineffectively cleared apoptotic nuclear fragments. These include double and single stranded DNAs (dsDNA, ssDNA), RNA binding nuclear antigens (Ro, La and Smith antigens) and non-nuclear fragments, which are then processed by Antigen Presenting Cells (APCs) such as B cells or plasmacytoid dendritic cells (pDCs) [10]. Self-antigens are presented on

Therapeutics in SLE: current and future medications

The existing standard of care for SLE depends primarily on disease severity and has been in place for over 60 years. NSAIDS (Aspirin, Ibuprofen and Diclofenac) and anti-malarials (hydroxychloroquine) are used in mild disease. Corticosteroids are vital in moderate–severe disease with additional immunosuppressives such as Mycophenolate mofetil (MMF), Azathioprine (AZT), Cyclophosphamide and Cyclosporine effective in severe cases of SLE [15].

The efficacy of current SLE medication has been

Anti-CD20: Rituximab

CD20 is a surface antigen expressed throughout B cell maturation and is involved in B cell activation by aiding Ca2 + influx [19]. CD20 is not expressed on haematopoietic lymphoid stem cells or pre-B cells and is lost upon terminal differentiation into plasma B cells — thus antagonism would not prevent B cell regeneration [20].

Rituximab is an anti-CD20 human-murine monoclonal chimeric antibody that causes selective short-term depletion of matured B cells through three mechanisms: induction of

B lymphocyte stimulator (BLyS) & A proliferation inducing ligand (APRIL)

Two of the key B cell stimulatory cytokines include components of the TNF ligand superfamily, member 13 or APRIL and member 13b or BLyS (B cell activating factor, BAFF) [18].

Several studies have deduced the vital role of BLyS in B cell survival, proliferation and antibody secretion, through actions upon three main receptors: the transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), the BLyS receptor (BAFF-R) and the B cell maturation antigen (BCMA). APRIL, a

Cost effectiveness

The cost burden of SLE morbidity was recently assessed in the UK amongst 86 lupus patients with a mean SLEDAI score of 7.7 [60]. The mean total cost for severe and non-severe lupus patients was £4652 and £2105 per year respectively (p < 0.001). For both groups, immunosuppressive therapies accounted for the majority of the cost, £1187 (25.5%) and £523 (24.8%) (p = 0.003), whereas biological therapies cost £532 (11.4%) and £109 (5.2%) for severe and non-severe groups respectively (p = 0.007). These

Conclusion

Recent advances in SLE research have begun to deduce the intricate pathogenesis underlying this autoimmune condition highlighting the critical role of auto-B cells in autoantibody formation, antigen presentation and T cell interaction. Standard of care therapy drawbacks has initiated the quest for SLE disease pathway specific biologics to ameliorate the condition with minimal side effects.

In 2011 the FDA signified a new direction for SLE by approving Belimumab as the first novel therapy for

Take Home Messages

  • Standard of care therapies produces adverse side effects through untargeted actions.

  • B cell biologics are an attractive therapeutic option specific to SLE pathogenesis.

  • Early phase trials have been successful and Belimumab has been FDA approved.

  • Other B cell depletion and anti-cytokine treatments are under Phase III assessment.

  • Different subpopulations and manifestations may respond differently to treatment.

Conflict of Interest

There are no conflicts of interest to declare and no funding or grants have been received for this research.

Acknowledgements

None.

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