Systemic lupus erythematosus (SLE) is characterized by multisystem immune-mediated injury in the setting of autoimmunity to nuclear antigens. The clinical heterogeneity of SLE, the absence of universally agreed clinical trial end points, and the paucity of validated therapeutic targets have, historically, contributed to a lack of novel treatments for SLE. However, in 2011, a therapeutic monoclonal antibody that neutralizes the cytokine TNF ligand superfamily member 13B (also known as B-cell-activating factor of the TNF family [BAFF]), belimumab, became the first targeted therapy for SLE to have efficacy in a randomized clinical trial. Because of its specificity, the efficacy of belimumab provides an opportunity to increase understanding of SLE pathophysiology. Although belimumab depletes B cells, this effect is not as powerful as that of other B-cell-directed therapies that have not been proven efficacious in randomized clinical trials. In this article, therefore, we review results suggesting that neutralizing BAFF can have effects on the immune system other than depletion of B cells. We also identify aspects of the BAFF system for which data in relation to SLE are still missing, and we suggest studies to investigate the pathogenesis of SLE and ways to refine anti-BAFF therapies. The role of a related cytokine, TNF ligand superfamily member 13 (also known as a proliferation-inducing ligand [APRIL]) in SLE is much less well understood, and hence this review focuses on BAFF.

/pdf/the-baff-april-system-in-sle-pathogenesis-32yzyv6khd.pdf

The BAFF/APRIL system in SLE pathogenesis

Since their discovery in 1998, the two TNF family members APRIL and BLyS/BAFF have received increasing attention. In addition to regulating normal B-cell development and immune responses, these molecules might be crucial in a diverse set of diseases, including autoimmunity and cancer. Although more has been published about the general biology of BLyS/BAFF than that of APRIL, many recent articles have described novel APRIL biology. Here we focus on APRIL, exploring its normal and pathological functions, and comparing the therapeutic molecules currently under development that target BLyS/BAFF alone, or APRIL and BLyS/BAFF together.

An APRIL to remember: novel TNF ligands as therapeutic targets

SUMMARY Interleukin-21 (IL-21) belongs to a family of cytokines that includes IL-2, IL-4, IL-7, IL-9, and IL-15, all of which bind to private (or shared) receptors as well as the common cytokine receptor gamma-chain as a component. Most cytokines in this family are critically important for both the maintenance and function of T cells and B cells. The receptor for IL-21 is widely distributed on lymphohematopoietic cells, and IL-21 plays many biologic roles, including maintenance and function of CD8(+) memory T cells and natural killer cells, as well as promoting the generation of Th17 cells in the mouse. One principal non-redundant role of IL-21 is the promotion of B-cell activation, differentiation or death during humoral immune responses. Furthermore, increased IL-21 production is characteristic of certain autoimmune diseases and is likely to contribute to autoantibody production as well as pathologic features of autoimmune disease. In contrast, IL-21 may function as a co-adjuvant to enhance antibody responses and thereby facilitate host defense to malignances and infectious diseases. The critical role of IL-21 in promoting humoral immune responses makes it an important focus of potential therapeutic interventions in conditions characterized by either overproduction of pathogenic autoantibodies or under production of protective antibodies.

The role of IL-21 in regulating B-cell function in health and disease.

Objective
To evaluate the efficacy and safety of atacicept, an antagonist of BLyS/APRIL-mediated B cell activation, in patients with systemic lupus erythematosus (SLE).

Methods
ADDRESS II was a phase IIb, multicentre study (NCT01972568). Patients with active, autoantibody-positive SLE receiving standard therapy were randomized (1:1:1) to atacicept (75 or 150 mg) or placebo for 24 weeks. The primary endpoint was the SLE responder index (SRI)-4 at Week 24.

Results
The ITT population included 306 patients. There was a trend towards improved SRI-4 response rate with atacicept 75 mg (57.8% [adjusted OR 1.78], P = 0.045) and 150 mg (53.8% [adjusted OR 1.56], P = 0.121) versus placebo (44.0%) at Week 24 (primary analysis; screening visit as baseline). In a pre-specified sensitivity analysis using study Day 1 as baseline, a significantly larger proportion of patients receiving atacicept 75 mg (55.9% [adjusted OR 1.88], P = 0.029) and 150 mg (55.8% [adjusted OR 1.96], P = 0.020) achieved SRI-4 response at Week 24 versus placebo (41%). In pre-defined subpopulations with baseline high disease activity (HDA), serologically active disease (SA), or both, statistically significant improvements in SRI-4 and SRI-6 response rates were seen with atacicept versus placebo. Severe flare risk was reduced with atacicept in both the ITT and HDA populations. The risks of serious adverse events and serious or severe infection were not increased with atacicept versus placebo.

Conclusion
Atacicept showed evidence of efficacy in SLE, particularly in HDA and SA patients. Reductions in disease activity and severe flare were observed with atacicept treatment, along with an acceptable safety profile.

This article is protected by copyright. All rights reserved.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.40360

Efficacy and Safety of Atacicept in Patients With Systemic Lupus Erythematosus: Results of a Twenty-Four-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Arm, Phase IIb Study.

The objective of this study was to investigate the interaction between levels of BAFF (B-cell activation factor of the tumour necrosis factor [TNF] family) and APRIL (a proliferation-inducing ligand) and B-cell frequencies in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) treated with the B-cell-depleting agent rituximab Ten patients with SLE were treated with rituximab in combination with cyclophosphamide and corticosteroids They were followed longitudinally up to 6 months after B-cell repopulation Nine patients with RA, resistant or intolerant to anti-TNF therapy, treated with rituximab plus methotrexate were investigated up to 6 months after treatment The B-cell frequency was determined by flow cytometry, and serum levels of BAFF and APRIL were measured by enzyme-linked immunosorbent assays BAFF levels rose significantly during B-cell depletion in both patient groups, and in patients with SLE the BAFF levels declined close to pre-treatment levels upon B-cell repopulation Patients with SLE had normal levels of APRIL at baseline, and during depletion there was a significant decrease In contrast, patients with RA had APRIL levels 10-fold higher than normal, which did not change during depletion At baseline, correlations between levels of B cells and APRIL, and DAS28 (disease activity score using 28 joint counts) and BAFF were observed in patients with RA In summary, increased BAFF levels were observed during absence of circulating B cells in our SLE and RA patient cohorts In spite of the limited number of patients, our data suggest that BAFF and APRIL are differentially regulated in different autoimmune diseases and, in addition, differently affected by rituximab treatment

/pdf/differential-effects-on-baff-and-april-levels-in-rituximab-1w3xbiiqcp.pdf

Differential effects on BAFF and APRIL levels in rituximab-treated patients with systemic lupus erythematosus and rheumatoid arthritis

Objective: To assess longitudinal expression of a proliferation-inducing ligand (APRIL) in patients with systemic lupus erythematosus (SLE) and its correlation with B lymphocyte stimulator (BLyS) expression, serum anti-dsDNA titres, and clinical disease activity. 

Methods: Sixty eight patients with SLE were longitudinally followed up for a median of 369 days. At each visit the physician assessed disease activity by SLEDAI, and blood was collected for determination of serum APRIL and BLyS levels and of blood APRIL and BLyS mRNA levels. Fifteen normal control subjects underwent similar laboratory evaluation. 

Results: Dysregulation of APRIL was not as great as that of BLyS. Changes in serum levels of APRIL and BLyS over time were usually discordant, whereas blood levels of APRIL and BLyS mRNA strongly paralleled each other. Serum APRIL levels modestly, but significantly, inversely correlated with serum anti-dsDNA titres in anti-dsDNA positive patients analysed in aggregate. Moreover, serum APRIL levels modestly, but significantly, inversely correlated with clinical disease activity in all patients analysed in aggregate. 

Conclusion: Serum levels of APRIL and BLyS are differentially regulated. APRIL may serve as a down modulator of serological and/or clinical autoimmunity in patients with SLE. This may have important ramifications for BLyS targeted treatment, and it remains to be determined whether agents which neutralise only BLyS will be preferable to agents which neutralise both BLyS and APRIL.

https://ard.bmj.com/content/annrheumdis/63/9/1096.full.pdf

Inverse association between circulating APRIL levels and serological and clinical disease activity in patients with systemic lupus erythematosus.

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Inverse association between circulating APRIL levels and serological and clinical disease activity in patients with systemic lupus erythematosus.