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Joint Bone Spine 79 (2012) 113–116

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ditorial

nterferon-alpha as a treatment target in systemic lupus erythematosus

r t i c l e i n f o

eywords:ystemic lupus erythematosusnterferon-alpha

In this era of biological therapies and therapeutic monoclonalntibodies, interferon is a crucial treatment target for autoimmuneiseases, including systemic lupus erythematosus (SLE) in partic-lar. The type I interferons are at the cross-roads between innate

mmunity and adaptive immunity, where they play a pivotal roleot only in controlling viral infections, tumor cell growth, andngiogenesis [1], but also in initiating and perpetuating SLE andjögren’s syndrome. As early as 2003, Mary Crow suggested in anditorial for Arthritis and Rheumatism that interferon-� may be areatment target in SLE [2]. Since then, progress has been slow andautious, given the antiviral and antitumoral effects of type 1 inter-erons. However, several molecules have completed Phase I studiesnd are being evaluated in Phase II studies. In addition to humanonoclonal antibodies against interferon-�, promising approaches

nclude antagonists of the interferon-� receptor and blockade of theoll-like receptors (TLRs) sensitive to ssRNA or dsDNA (TLR-7 andLR-9) such as nucleic acid analogs and tyrosine kinase inhibitorscting via the TLR signaling pathway. Finally, an original strategyonsists in vaccination with a kinoid that induces the productionf antibodies capable of neutralizing endogenous interferon-�.

. Rationale for targeting interferon-�

A 1979 study established that serum interferon-� levels werelevated in patients with SLE [3]. Interferon-� levels are also high inhe cerebrospinal fluid of patients with neurological lupus manifes-ations. As with all cytokines, interferon-� (13 different functional

olecules encoded by at least 17 genes at 9p21) binds to a mem-rane receptor, triggering intracellular signal transduction afterhosphorylation of the STAT-1 and STAT-2 proteins by the tyrosineinases JAK-1 and TYK-2 [1]. STAT-1/STAT-2 and interferon regu-atory factor 9 (IRF-9) form a complex (interferon-stimulated geneactor 3, ISGF3), which binds to the nuclear DNA at the interferon-timulated response element (ISRE) of the promoter region fornterferon-sensitive genes. The result is either activation or inhi-

ition of the transcription of these genes. The mRNAs produced bylternative splicing constitute the interferon signature, which cane evaluated by transcriptome analysis [4]. Many genes activatedy interferons encode proteins involved in granulopoiesis [5]. In

297-319X/$ – see front matter © 2011 Société francaise de rhumatologie. Published by Eoi:10.1016/j.jbspin.2011.10.013

cross-sectional studies, 50% of adults with SLE had an interferonsignature and this proportion was 80% or more in recent-onsetpediatric SLE. A good overall correlation has been reported betweenthe interferon score of peripheral blood cells and disease progres-sion as assessed based on the number of ACR classification criteriaand on the SLEDAI and SLAM values [4,6,7]. Several genes inducedby interferon-� encode chemokines such as IP-10 (CXCL-10), MIP-3� (CCL-19), and MCP-1 (CCL-2). Thus, the concentrations of thesechemokines in the peripheral blood or urine may also reflect theoverall activity of the disease and, more specifically, the poten-tial for renal disease progression (a possible biomarker for diseaseactivity) [8,9]. Longitudinal studies are under way to evaluate theusefulness of these biomarkers, which are easier to use than RNAtranscript measurements [10].

Interferon-� overproduction in SLE is related to both geneticand environmental factors. Family studies showed type I inter-feron overproduction not only in patients with SLE, but alsoin their first-degree relatives. Genome-wide association studiesdemonstrated overrepresentation of several rare allelic variants inpatients with SLE. About 25 susceptibility genes have been identi-fied to date (accounting for about 10% of the genetic determinismof SLE). Their allelic variants identified using single-nucleotidepolymorphisms have individual odds ratios lower than 1.5, theonly exception being the gene for interferon regulatory factor5 (IRF-5), whose product is involved in TLR signal transductionand, probably to a lesser degree, in interferon-� signal transduc-tion. Several products of SLE susceptibility genes are involved ininnate immunity and, more specifically, in regulating the pro-duction of interferon-�. In addition to IRF-5, examples includeSTAT-4 (signal transducer and activator of transcriptor 4), SPP-1(osteopontin), IRAK-1 (interleukin-1 receptor-associated kinase, aserine/threonine protein kinase involved in TLR signal transduc-tion), and TREX-1 (3’ DNA repair exonuclease 1 also known asDNAse III, an enzyme capable of degrading DNA and therefore ofblocking interferon induction via stimulation of TLR-9 or othercytosolic DNA receptors [11,12]).

The environmental factors that stimulate interferon-� produc-tion are nucleoprotein complexes (histones in nucleosomes and theribonucleoproteins U-RNPs and Y-RNPs, i.e., Sm, U1-RNP, and SS-A/Ro52Kd or Ro60Kd) released during cell apoptosis and necrosis(e.g., keratinocytes damaged by ultraviolet radiation and lympho-cytes or neutrophils stimulated by various microorganisms such

as the Epstein-Barr virus) [13] and microparticles released by neu-trophil extracellular traps (NETs) and very rich in nucleic acids andribonucleoproteins [14,15]. Nucleic acids are potent interferon-�inducers via TLR pathway activation (TLR-3 for dsRNA, TLR-7 for

lsevier Masson SAS. All rights reserved.

114 Editorial / Joint Bone Spine 79 (2012) 113–116

Table 1Main immunostimulating effects of interferon-�.

Innate immunityMaturation of pDCsActivation of DCs: expression of CD-40, CD-80, CD-86, HLA moleculesProduction of the chemokines CXCL-8 (IL-8), CXCL-9 (MIG), CXCL-10 (IP-10),and CXCL-11 (I-TAC) and of their receptorsProduction of cytokines by mDCs: IL-12, IL-15, IL-18, IL-21, IL-23, and BAFFEnhancement of NK activity (Fas L)Production of NETs by neutrophilsActivation of macrophages and inducible NO synthaseFormation of foam cells via expression of the scavenger receptor-A (SR-A)

Adaptive immunityStimulation of the Th1 (IFN�), Th17 (IL-17), and Th2 (IL-10) (self-reactiveclones) responsesBlunting of the Treg Foxp3+ responseStimulation of follicular T-helper cells (auxiliary B-cells)Stimulation of the IgG and IgA switch by B-cells (self-reactive clones)

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Decrease in the B-cell receptor activation threshold by B-cellsIncreased TLR-7 expression

sRNA, TLR-9 for DNA with CpG repeat hypomethylation [16,17])r via other cytosolic DNA receptors such as RIG, MDA-5, and DAI18].

Overproduction of interferon-� is due mainly to immature plas-acytoid dendritic cells (pDCs) that selectively express TLR-7 and

LR-9. The excess interferon-� induces the expression of manyenes and stimulates both innate and adaptive immune responsesTable 1). The result is stimulation of self-reactive clones and pro-uction of autoantibodies to DNA and ribonucleoproteins, whichorm pathogenic immune complexes. A self-perpetuation loop isormed, as the immune complexes via the B-cell receptor, FC�RIIa,nd/or TLRs on B-cells and pDCs stimulate TLR-7 and TLR-9, leadingo continuous production of interferon-� [19] (Fig. 1).

Recent evidence shows that platelets having bound immuneomplexes via their Fc�RIIa (CD32) and CD40L (CD154) recep-ors increase the production of interferon-� in patients with SLE20]. This effect has also been demonstrated with the NETs, whoseroduction by neutrophils is dependent on transcripts found in

ncreased amounts in patients with active SLE [14].

. Targeting interferon-�

Table 2 shows the main treatment strategies under develop-ent as means of controlling interferon-� overproduction. Some of

able 2reatments against interferon-� that are being developed or considered for the treatmen

Agent Target

Sifalimumab (MEDI-545) IFN�

Rontalizumab IFN�

NNC0152-0000-0001 (humab) IFN�AGS-009IgG4 anti-IFN�

IFN�

IFN� kinoid (vaccine) IFN�MEDI-546 (humab) IFN� receptor blocker

CpG-52364 TLR-7/9 antagonistDV 1179 TLR-7/9 antagonist

IMO-3100 TLR-7/9 antagonistHydroxychloroquine TLR-9 antagonist (±7)Tasocitinib (JAK-3/JAK-1 inhibitor) JAK/STAT kinasesINCB 28050 (JAK-1/KAK-2 inhibitor) JAK/STAT kinasesVX-509 (JAK-3 inhibitor) JAK/STAT kinasesmiRNA inhibitor miR-155* (TLR-7)miRNA stimulator miR-146a

Fig. 1. Model of chronic activation of the type 1 interferon pathway in systemiclupus erythematosus.

these strategies target interferon-� or the type 1 interferon recep-tors, whereas others are directed against the activation of genesencoding interferon-�. This last group of strategies includes TLR

blockade (TLR-7 and TLR-9) and the use in the future of microRNAscontrolling the mRNAs for TLR proteins [21]. However, as men-tioned above, other families of cytosol receptors can recognize RNAand DNA, thereby leading to interferon production. Thus, blocking

t of systemic lupus erythematosus.

Pharmaceuticalcompany

Development phase

MedimmuneAstra Zeneca

II

GenentechRoche

II

Novo Nordisk IArgos Therapeutics I

Néovacs I/IIMedimmuneAstra Zeneca

I (scleroderma)

Pfizer IDynavaxGlaxo Smith Kline

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Idera ISanofi Aventis IVPfizer III (PR RA)Incyte, Eli Lilly IIb (RA)Vertex II (RA)– –– –

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Editorial / Joint Bone

nly the TLR-7/9 pathway may fail to suppress the production ofnterferon [22]. Most of the compounds listed in Table 2 are in thearly phases of development for SLE. The most advanced prelim-nary clinical results available as abstracts presented at meetingsr press releases are for either human monoclonal antibodies thateutralize interferon-� or the vaccine against interferon-�.

Rontalizumab is a humanized monoclonal antibody developedy Roche and Genentech. A Phase I study was done in the USA in 20enters in 60 patients with moderately active SLE requiring no morehan 20 mg of prednisone per day and no immunosuppressants. Theontalizumab doses ranged from 0.3 to 10 mg/kg intravenously orubcutaneously. Tolerance was satisfactory with no difference inhe infection rate compared to the placebo arm. During the study, 1atient had appendicitis and another was diagnosed with leukemia.bout 50% of the study patients had the interferon signature, which

aded in proportion to the rontalizumab dose, with the highest dosenducing the strongest response. Given the type of SLE in the studyatients and small sample size, the results do not constitute prooff efficacy on the clinical symptoms. A Phase II trial (ROSE) that isnder way in the USA, South America, and Europe will include 210atients with moderate-to-high disease activity.

Sifalimumab is a fully human monoclonal IgG1 againstnterferon-� that has been used both intravenously and subcu-aneously. Sifalimumab binds to specific amino acid residues ofnterferon-�-2a involved in binding to subunit-1 of the IFNAR1eceptor for interferons-� and -�. This event prevents formationf the interferon-�-2a/IFNAR1/2 heterotrimer. Sifalimumab alsoinds to the IFNAR2 receptor in the presence of interferon-�-2and prevents the internalization of interferon-�-2a. It partiallyntagonizes interferon-� and -� [23]. A multicenter randomizedour-arm Phase Ib trial tested three sifalimumab doses (0.3, 3,nd 10 mg/kg) in 161 patients with moderate-to-severe SLE (meanaseline SLEDAI, 10). Sifalimumab was given intravenously everyweeks for 26 weeks. At baseline, 75% of patients had an inter-

eron signature. The infection rates were similar in the treatmentrms and placebo arm (2.1 and 2.2 patients/year, respectively). Theain side effects were urinary tract infections, nausea, diarrhea,

pper airway infections, arthralgia, headaches, and a decline inhe hemoglobin level [24]. The patients with the highest SLEDAInd BILAG index values were also those with the strongest inter-eron signatures [25]. Inhibition of the interferon signature wasroportional to the sifalimumab dose and persisted throughout thereatment period in both the peripheral blood and the skin lesionamples [26]. Importantly, the SLEDAI decrease was not signifi-antly larger with the study drug than with the placebo. Antibodieso sifalimumab developed in 21% of patients. A Phase IIa multicenterandomized double-blind placebo-controlled trial with five treat-ent arms was conducted in 87 SLE patients (60% of Caucasians

nd 30% of blacks). Sifalimumab was given subcutaneously onceweek, once every 2 weeks, or once every 4 weeks, for 13 weeks.

he side effects were the same as in the Phase Ib trial. The once-a-eek regimen induced a 40% decrease in the interferon signature

s evaluated using proteomics. In this preliminary study, no clini-al benefits were recorded during the 3-month observation period27].

Anti-interferon vaccination using the IFN-K kinoid is at thehase I/II stage and is therefore not yet available [28]. Interferon--2b is injected in combination with the KLH carrier protein anddjuvant to induce the production of anti- interferon-� antibodiesapable of neutralizing the effects of all 13 subtypes of endogenousnterferon-� without interfering with the activity of interferon-�r � [29].

Thus, more than 30 years after learning that interferon con-ributes to the pathophysiology of SLE, we will soon know whethernhibiting this cytokine is a valid therapeutic strategy. Transla-ional research must be slow and cautious, since the crucial role

[

79 (2012) 113–116 115

for interferons in protecting against infections and tumors must bepreserved in order to minimize the risk of serious adverse eventsthat might limit the development of these innovative treatments[30].

Disclosure of interest

The author declares that he has no conflicts of interest concern-ing this article.

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[2] Crow MK. Interferon-alpha: a new target for therapy in systemic lupus erythe-matosus? Arthritis Rheum 2003;48:2396–401.

[3] Hooks JJ, Moutsopoulos HM, Geis SA, et al. Immune interferon in the circulationof patients with autoimmune disease. N Engl J Med 1979;301:5–8.

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20] Duffau P, Seneschal J, Nicco C, et al. Platelet CD154 potentiates interferon-alphasecretion by plasmacytoid dendritic cells in systemic lupus erythematosus. SciTransl Med 2010;2:47ra63.

21] Zhou H, Huang X, Cui H, et al. miR-155 and its star-form partner miR-155*cooperatively regulate type I interferon production by human plasmacytoiddendritic cells. Blood 2010;116:5885–94.

22] Barrat FJ, Meeker T, Chan JH, et al. Treatment of lupus-prone mice with a dualinhibitor of TLR7 and TLR9 leads to reduction of autoantibody production andamelioration of disease symptoms. Eur J Immunol 2007;37:3582–6.

23] Riggs JM, Cibotti R, Liang M, et al. Mechanism of action of sifalimumab, ahuman neutralizing IFN alpha specific monoclonal antibody. Ann Rheum Dis2011;70:123.

24] Petri M, Wallace DJ, Spindler A, et al. Sifalimumab, a fully human anti-interferon-alpha monoclonal antibody in subjects with systemic lupuserythematosus (SLE): results of a phase 1B randomized, placebo-controlled,

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E-mail address: olivier.meyer@bch.aphp.fr

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79 (2012) 113–116

Olivier Meyer ∗

Service de rhumatologie, CHU Bichat, 46, rueHenri-Huchard, 75018 Paris, France

∗ Corresponding author. Tel.: +33 1 40 25 74 03;fax: +33 1 42 29 06 88.

5 October 2011

Available online11 December 2011