# To target or not to target APRIL in systemic lupus erythematosus: that is the question!

J. Morel, M. Hahne

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## To cite this version:

J. Morel, M. Hahne. To target or not to target APRIL in systemic lupus erythematosus: that is the question!. Arthritis Research and Therapy, 2013, 15 (1), pp.107. 10.1186/ar4160. hal-02192892

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Submitted on 25 May 2021

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EDITORIAL

To target or not to target APRIL in systemic lupus
erythematosus: that is the question!

Jacques Morel*<fnref n="1" />,²,³ and Michael Hahne²,³,⁴

See related research by Treamtrakanpon *et al*., http://arthritis-research.com/content/14/6/R252

**Abstract**

Among the cytokines that regulate B-cell homeostasis
are the TNF-like ligands B-lymphocyte stimulator
(BLyS; also B-cell activation factor) and a proliferation-
inducing ligand (APRIL). BLyS and APRIL share two
receptors; that is, B-cell maturation antigen and
transmembrane activator and CAML interactor.
Therapeutic approaches using biologics are limited for
treatment of lupus patients. One previously approved
drug is belimumab, which antagonizes the B-cell
stimulator BLyS. Atacicept, another biologic inhibiting
BLyS and APRIL, was terminated for serious adverse
events – raising the question of whether APRIL should
be neutralized in autoimmune diseases.

Treamtrakanpon and coworkers analyzed B-lymphocyte
stimulator (BLyS; also B-cell activation factor) and a
proliferation-inducing ligand (APRIL) expression in
patients with lupus nephritis and observed a correlation
with renal disease activity and APRIL serum levels [1]. In
addition, the authors describe that, upon treatment with
immunosuppressors, nonresponding patients had higher
APRIL serum levels. They thus concluded that APRIL
could be a potential biomarker for predicting difficult-to-
treat cases of lupus nephritis, and propose the use of
APRIL antagonists such as atacicept for treatment of
lupus nephritis patients with high APRIL serum levels.

These conclusions might be premature, as Treamtra-
kanpon and coworkers have not found a correlation
between the level of APRIL in kidney tissue and renal
disease activity. Another hypothesis could be that APRIL
has a protective effect in autoimmune diseases. Indeed,
the crucial role of BLyS in B-cell maintenance became

evident by the analysis of BLyS-deficient mice displaying
lower numbers of mature B cells and of BLyS transgenic
mice developing severe B-cell hyperplasia. Although
APRIL can trigger different B-cell responses *in vitro*,
including proliferation and survival of human and murine
B cells, it is less critical than BLyS in B-cell maintenance
as APRIL knockout and transgenic mice reveal no gross
abnormalities in lymphoid homeostasis [2]. In fact,
APRIL was found to modulate specific B-cell responses
such as IgA isotype switching, increased IgM secretion
and B1 cell activity.

Meanwhile, BLyS is an established promoter of B-cell-
triggered autoimmune diseases such as systemic lupus
erythematosus and rheumatoid arthritis, whereas the
role of APRIL in these pathologies is rather controversial.
Neutralizing BLyS with the mAb belimumab displayed a
modest, although statistically significant, therapeutic
effect in systemic lupus erythematosus [3,4]. But blocking
both BLyS and APRIL with atacicept (TACI-Fc) was
associated with a pronounced reduction of immuno-
globulins, and occurrence of serious infections led to a
premature termination of a phase II/III trial in lupus
nephritis [5]. The combination of mycofenolate mofetil
with atacicept may have contributed to the decrease of
immunoglobulins. However, atacicept combined with
another drug such as methotrexate in patients with
rheumatoid arthritis was also associated with a significant
reduction of immunoglobulins (especially IgM). In this
autoimmune disease, atacicept failed to demonstrate
efficacy on American College of Rheumatology 20 criteria
[6]. In contrast, administration of belimumab showed a
modest but significant efficacy using the same evaluation
criteria in rheumatoid arthritis [7].

These findings suggest distinct roles for BLyS and
APRIL in lupus and other B-cell-mediated autoimmune
diseases. Elevated serum levels are found for both
cytokines in lupus patients, and for BLyS there is a
consensus in the literature that this reflects its disease-
promoting activity. Elevated APRIL serum levels, how-
ever, have been – depending on the respective study –
either positively or negatively correlated with disease
features [8]. One possible explanation for this discrepancy

<footnote>*Correspondence: j-morel@chu-montpellier.fr</footnote>

<footnote n="1">¹Department of Rheumatology, CHU Lapeyronie, 191 avenue du Doyen Gaston, Giraud, 34295 Montpellier, Cedex 5, France</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
could be differences in the patient cohorts analyzed. A recent study by Jacob and colleagues analyzed a murine lupus model in APRIL-deficient mice and observed elevated numbers of splenocytes, increased autoantibody production and a tendency towards increased IgG production [9]. Notably, ectopic APRIL expression does not result – in contrast to BLyS transgenic mice – in lupus-like symptoms. In fact, we found that APRIL does dampen collagen-induced arthritis, the most common mouse model for human arthritis [10].

Experimental mouse models for autoimmune diseases obviously cannot entirely mimic human diseases. Nevertheless, *in vivo* data are accumulating that do not support a disease-supporting role for APRIL in B-cell-mediated autoimmunity. The study by Treamtrakanpon and colleagues is putting forward the need to better elucidate the role of APRIL in B-cell-driven diseases before concluding a therapeutic approach.

**Abbreviations**

APRIL, a proliferation-inducing ligand; BLyS, B-lymphocyte stimulator; mAb, monoclonal antibody; TNF, tumor necrosis factor.

**Competing interests**

The authors declare that they have no competing interests.

**Author details**

¹Department of Rheumatology, CHU Lapeyronie, 191 Avenue du Doyen Gaston, Giraud, 34295 Montpellier, Cedex 5, France. ²Institut de Génétique Moléculaire de Montpellier, CNRS, UMR5535, 1919 route de Mende, 34293 Montpellier, France. ³Université Montpellier 1, 5 Boulevard Henri IV, 34000 Montpellier, Cedex 5, France. ⁴Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier, Cedex 5, France.

Published: 25 February 2013

**References**

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2. Stein JV, López-Fraga M, Elustondo FA, Carvalho-Pinto CE, Rodríguez D, Gómez-Caro R, De Jong J, Martínez-A C, Medema JP, Hahne M: APRIL modulates B and T cell immunity. *J Clin Invest* 2002, **109**:1587-1598.

3. Manzi S, Sánchez-Guerrero J, Merrill JT, Furie R, Gladman D, Navarra SV, Ginzler EM, D'Cruz DP, Doria A, Cooper S, Zhong ZJ, Hough D, Freimuth W, Petri MA; BLISS-52 and BLISS-76 Study Groups: Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. *Ann Rheum Dis* 2012, **71**:1833-1838.

4. Navarra SV, Guzmán RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, Li EK, Thomas M, Kim HY, León MG, Tanasescu C, Nasonov E, Lan JL, Pineda L, Zhong ZJ, Freimuth W, Petri MA; BLISS-52 Study Group: Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. *Lancet* 2011, **377**:721-731.

5. Ginzler EM, Wax S, Rajeswaran A, Copt S, Hillson J, Ramos E, Singer NG: Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. *Arthritis Res Ther* 2012, **14**:R33.

6. Genovese MC, Kinnman N, de La Bourdonnaye G, Pena Rossi C, Tak PP: Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: results of a phase II, randomized, placebo-controlled, dose-finding trial. *Arthritis Rheum* 2011, **63**:1793-1803.

7. McKay J, Chwalinska-Sadowska H, Boling E, Valente R, Limanni A, Racewicz A, Wierzbinska-Zarowny D, Fernandez V, Zhong J, Zilberstein M, et al.; LBRA01 Study Group: Belimumab, a fully human monoclonal antibody to B-lymphocyte stimulator, combined with standard care of therapy reduces the signs and symptoms of rheumatoid arthritis in a heterogeneous subject population. *Arthritis Rheum* 2005, **52**:S710-S711.

8. Morel J, Roubille C, Panelles L, Rocha C, Fernandez L, Lukas C, Hahne M, Combe B: Serum levels of tumour necrosis factor family members a proliferation-inducing ligand (APRIL) and B lymphocyte stimulator (BLyS) are inversely correlated in systemic lupus erythematosus. *Ann Rheum Dis* 2009, **68**:997-1002.

9. Jacob CO, Guo S, Jacob N, Pawar RD, Putterman C, Quinn WJ 3rd, Cancro MP, Migone TS, Stohl W: Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice. *Arthritis Rheum* 2012, **64**:1610-1619.

10. Fernandez L, Salinas GF, Rocha C, Carvalho-Pinto CE, Yeremenko N, Papon L, Medema JP, Combe B, Morel J, Baeten D, Hahne M: The TNF family member APRIL dampens collagen-induced arthritis. *Ann Rheum Dis* 2012. [Epub ahead of print]

doi:10.1186/ar4160

Cite this article as: Morel J, Hahne M: To target or not to target APRIL in systemic lupus erythematosus: that is the question! *Arthritis Research & Therapy* 2013, **15**:107.