REVIEW

Systemic Lupus Erythematosus (SLE) Therapy: The Oldand the New

Fabio Basta . Federica Fasola . Konstantinos Triantafyllias .

Andreas Schwarting

Received: April 16, 2020 / Published online: June 2, 2020� The Author(s) 2020

ABSTRACT

Despite recent improvements in the treatmentof systemic lupus erythematosus (SLE), diseaseactivity, comorbidities and drug toxicity signif-icantly contribute to the risk of progressiveirreversible damage accrual and increased mor-tality in patients with this chronic disease.Moreover, even lupus patients in remissionoften report residual symptoms, such as fatigue,which have a considerable impact on theirhealth-related quality of life. In recent decades,SLE treatment has moved from the use of

hydroxychloroquine, systemic glucocorticos-teroids and conventional immunosuppressivedrugs to biologic agents, of which belimumab isthe first and only biologic agent approved forthe treatment for SLE to date. Novel therapiestargeting interferons, cytokines and theirreceptors, intracellular signals, plasma cells, Tlymphocytes and co-stimulatory molecules arebeing evaluated. In the context of a holisticapproach, growing evidence is emerging of theimportance of correct lifestyle habits in themanagement of lupus manifestations andcomorbidities. The aim of this paper is to pro-vide an overview of current pharmacologicaland non-pharmacological treatment optionsand emerging therapies in SLE.

Keywords: Belimumab; Fatigue; Hydroxy-chloroquine; Lupus; Lupus nephritis;Management; Rituximab; SLE; Systemic lupuserythematosus; Therapy

Digital Features To view digital features for this articlego to: https://doi.org/10.6084/m9.figshare.12288038.

F. Basta (&) � F. Fasola � K. Triantafyllias �A. SchwartingAcura Rheumatology Center Rhineland Palatinate,Bad Kreuznach, Germanye-mail: fabiobasta@libero.it

A. SchwartingDivision of Rheumatology and ClinicalImmunology, University Medical Center, JohannesGutenberg University, Mainz, Germany

F. Basta � F. Fasola � K. Triantafyllias � A. SchwartingUniversity Center of Autoimmunity, JohannesGutenberg University, Mainz, Germany

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https://doi.org/10.1007/s40744-020-00212-9

Key Summary Points

Antimalarials are still considered to be thecornerstone of treatment for systemiclupus erythematosus (SLE).

Glucocorticosteroids are an importantcomponent of SLE treatment as theyrapidly ablate the autoimmune responsein organ-threatening manifestations, butthe risk for damage accrual increasesconsiderably at doese of[ 5–7.5 mg/day.

Belimumab, a fully humanizedmonoclonal antibody which inhibitsB-lymphocyte stimulator, is the onlytargeted biologic agent licensed for thetreatment of SLE to date.

Adjuvant treatments and non-pharmacological interventions arefundamental in the context of a holisticapproach to the treatment of patientswith SLE.

Among emerging therapies, anifrolumab,a fully human monoclonal antibody, hasshown positive results in a phase III trial,indicating the potential of anti-interferons in the treatment of SLE.

INTRODUCTION

Systemic lupus erythematosus (SLE; lupus) is acomplex autoimmune disease with a chronicrelapsing–remitting course and variable mani-festations leading to a spectrum of diseaseranging from mild to life-threatening illness.The clinical onset of SLE derives from theinteraction between genetic predisposition andenvironmental, immunological and hormonalfactors, with a strong predilection for women ofchildbearing age [1–3]. The manifestations ofSLE are associated with the presence of multipleautoantibodies (Ab) that cause the formationand deposition of immune complexes (ICs), aswell as other immune processes. Constitutional,

muco-cutaneous and musculoskeletal signsrepresent the earliest and most common com-plaints reported by the majority of SLE patients.However, any organ, including the skin,hematologic, renal, neuropsychiatric (NP), car-diovascular and/or respiratory systems, can beaffected. Not all manifestations perforce appearsimultaneously, and a time interval of monthsor years may exist between the appearance ofvarious symptoms [1]. As a consequence of thisheterogeneous clinical presentation and patho-genesis, SLE is a disease that is still difficult todefine. New classification criteria have beendesigned for research purposes but these cannotsubstitute for clinical judgment when makingthe diagnosis of SLE [4].

Despite recent improvements in the man-agement of the disease, patients with lupus stillhave a high risk of morbidity and mortality. Forexample, in lupus nephritis (LN), nearly 10% ofthe patients progress towards end-stage kidneydisease. Persistent disease activity, comorbidi-ties and drug toxicity significantly contribute tothe risk of progressive irreversible damageaccrual and increased mortality [5, 6].

In the recent years, sustained remission hasbeen proposed as the ultimate goal of themanagement of SLE, but it is rare to achieve [7].Indeed, the Lupus Low Disease Activity State(LLDAS), which combines both low SLE activityand a low prednisone (PDN) doses (B 7.5 mgdaily), is emerging as a more realistic target state[8]. The LLDAS is associated with a lower risk ofnew damage accrual and better health-relatedquality of life (HRQoL) [9, 10]

In summary, the therapeutic goals forpatients with SLE have changed over the past 20years. While in the first decades the focus wason patient survival, recent efforts have beendirected towards the reduction of therapy-re-lated side effects and organ damage with grow-ing attention focused on HRQoL [11]. It istherefore crucial, in the context of a modernapproach to the management of SLE, to com-bine global control of the disease with an ade-quate tolerability and safety of all availabletreatments.

This article is based on previously conductedstudies and does not contain any studies with

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human participants or animals performed byany of the authors.

CURRENT TREATMENT OPTIONS

Antimalarials

Antimalarials are among the oldest drugs usedto treat SLE, but they are still rightfully consid-ered to be the cornerstone of SLE therapy. Theyare particularly effective in the management ofskin manifestations and arthritis but should beincluded in the treatment regimen of everypatient, unless there is a clear contraindication.The first use of antimalarial drugs in a patientwith SLE probably occurred in 1894, when J.S.Payne described features of the lupus rash suc-cessfully treated with quinine. During the Sec-ond World War, quinacrine, used as malariaprophylaxis, improved various rheumatic com-plaints among soldiers. These observations ledto studies on the use of antimalarial drugs inpatients with rheumatic diseases, whichdemonstrated improvements in arthritis andcutaneous lupus among patients treated withquinacrine. Chloroquine was subsequentlyintroduced in 1953, followed by hydroxy-chloroquine (HCQ) in 1955. HCQ showed thegreatest efficacy and patient tolerability andbecame the most common antimalarial medi-cation administered to patients with SLE [12]. Inthe 1990s, the role of HCQ in decreasing lupusflares, disease activity and glucocorticoid (GC)doses was further ascertained [13]. In 2007,Alarcon et al. showed that the use of HCQimproved survival in patients with SLE and wasassociated with a long-term protective effect onend-organ damage [14]; subsequent cohortstudies have continued to support these find-ings. HCQ has also been found to exert pleio-tropic favorable effects on endothelialdysfunction and the metabolic profile, thusreducing cardiovascular and thrombotic risk. Inaddition, HCQ has been shown to have a ben-eficial effect on pregnancy outcomes (includingthe prevention of congenital heart block), ratesof infections and osteoporosis, and may ulti-mately play a role in preventing neoplasia [15].Poor adherence or underdosing is the main

issue associated with the use of HCQ, often dueto concerns of retinal toxicity, which is, how-ever, a rare complication that appears only afterlong-term treatment.

Glucocorticosteroids

The efficacy of GCs in the acute control of SLE iswell established, and the use of high-dose or‘‘pulsed’’ GCs to rapidly ablate the autoimmuneresponse in organ-threatening manifestations isan important component of SLE treatmentregimens. GCs were introduced in the 1950s fortreating autoimmune diseases, with an over-whelming effect (‘‘miracle drug’’), and havecontributed to an increase in the survival ratesof patients with SLE [5]. However, soon aftertheir introduction, it became clear that dose-dependent side effects could occur in patientsreceiving GC treatment, and a series of studiessubsequently demonstrated that their long-term use could have deleterious effects. In 2000,Zonana-Nacach and coworkers reported thatGC use leads to permanent damage in multipleorgan systems [16]. Gladman et al. found thatup to 80% of the damage accrued wasattributable to GC use [17], and a study byThamer and colleagues showed that GC doses of6–12 mg/day increase the risk of damage accrualto 50% [18]. Most studies have used 5–-7.5 mg/day as a cut-off range, above which therisk for damage accrual considerably increases,but even low doses, over time, increase the riskfor cataracts, osteoporosis, fractures and coro-nary artery disease [19].

Conventional Immunosuppressive Agents

The increasing concerns about the toxicity andsevere side effects of GC have fostered thedevelopment of alternative therapeutic strate-gies. Conventional immunosuppressive (IS)drugs became a fundamental part of the thera-peutic armamentarium for treating SLE. Alongwith their immunomodulatory properties, theyalso allow a more rapid and successful taperingof GC dose.

Early randomized controlled trials showedthat combined therapy with GCs and

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cyclophosphamide (CYC), compared to GCmonotherapy, led to a better renal outcome andto a higher remission rate in patients with LN,but at the expense of a very high rate of infec-tions and ovarian failure [20]. Houssiau et al.then conducted the pioneering Euro-LupusNephritis Trial (EuroLupus), which showed thatlow-dose CYC (cumulative dosage of 3 g) wasequally efficient for induction therapy of LN asthe original high-dose CYC; thus low-dose CYCbecame the standard therapy for Caucasianpatients with diffuse proliferative type III andtype IV LN [21]. Other approaches to reducetreatment-related toxicities are based on the useof IS drugs, such as azathioprine (AZA),methotrexate (MTX), cyclosporine A (CsA) andmycophenolate mofetil (MMF). MMF has beenshown not to be inferior to CYC for inductiontherapy of LN and even seems to be the prefer-able agent in African and Hispanic patients.Multi-target therapy has been recently proposedfor induction therapy in LN [22]. In one study,the combination of tacrolimus with MMF andprednisolone (PDN) was superior to CYC andPDN when renal response was analyzed at 6months, but not at 18 months [23]. In a furtherphase II trial, the addition of low-dose voclos-porin, a new calcineurin inhibitor (CNI) with amore stable pharmacokinetic profile, to treat-ment with MMF resulted in a better renalresponse, but higher rates of adverse events,including death, were observed [24]. A phase IIItrial (AURORA) is ongoing.

MMF is considered to be the drug of choicefor maintenance treatment, unless there is anongoing pregnancy, in which case AZA is con-sidered. CNIs and tacrolimus can also be used asuseful adjunctive therapy in LN [22]. Amongpatients with non-renal disease, the choice ofthe IS drug is largely empirical: MTX whenarthritis and cutaneous involvement are thepredominant manifestations, and AZA or CsA inhematological disease or when pregnancy iscontemplated. CYC is the treatment of choicefor severe neuropsychiatric (NP) involvement inSLE and is also reserved for the treatment of anysevere organ-threatening disease manifestations[25]. Sirolimus, an inhibitor of the mammaliantarget of rapamycin (mTOR), a serine-threoninekinase involved in T-cell proliferation, has

recently emerged as a promising therapy inpatients with clinically active SLE, particularlyin those presenting musculoskeletal involve-ment [26, 27].

IS drugs are also burdened by their associa-tion to side effects, such as severe infections,malignancies, teratogenity and infertility,potentially leading to additional organ damageand mortality.

Targeted Therapies: Biologic Agents

In recent years, a better understanding of SLEetiopathogenesis has led to the introduction ofa number of biologic agents that specificallytarget disease pathways underlying the devel-opment and progression of lupus. Some of thesetherapies, such as rituximab (RTX) and beli-mumab, are available in clinical practice, whileothers are being tested in ongoing clinical trials.

RTX is a chimeric monoclonal Ab whichselectively targets B cell-specific surface mole-cule CD20. Two large, phase III, randomizedplacebo-controlled trials in non-renal lupus(EXPLORER) [28] and renal lupus (LUNAR) [29]failed to meet their primary endpoints; thusRTX still remains unlicensed. Despite the lack oftrial evidence, the efficacy of RTX in the treat-ment of refractory LN and in severe non-renalSLE manifestations has been shown in manyobservational studies [30, 31]. The EuropeanLeague Against Rheumatism (EULAR) hasrecently stated that therapy with RTX should beconsidered in the treatment of organ-threaten-ing, refractory lupus [32].

The only targeted biologic agent licensed forlupus to date is belimumab (Benlysta�;GlaxoSmithKline), a fully humanized mono-clonal antibody which inhibits B lymphocytestimulator (BlyS), also known as B-cell activat-ing factor (BAFF). Belimumab takes intoaccount the pathophysiological significance ofBAFF in autoimmune diseases. BAFF belongs tothe tumor necrosis factor (TNF) family and wasoriginally discovered in 1999 as a B-cell growthfactor [33, 34]. Its central role in autoimmunityis well established. Elevated levels of BAFF cor-relate with autoimmune disease in humans,mice and dogs [35]. Transgenic over-expression

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of BAFF was found to lead to an acceleratedlymphoproliferative disorder in mice, whereasBAFF-deficient mice were protected from SLE[33]. Two phase III trials, BLISS-52 and BLISS-76,studied the efficacy of intravenous belimumabon active SLE; both studies excluded patientswith severe active LN and severe central nervoussystem (CNS) manifestations. A significantimprovement of disease activity was achieved inthe treatment arm compared with the placeboarm, and the trials thus met the primary end-point. Belimumab also resulted in a reduction offlares and steroid use, as well as an improve-ment in HRQoL and levels of fatigue [36]. Thisled in 2011 to the approval of the use of beli-mumab to treat SLE [37, 38]. The efficacy andsafety of belimumab administered subcuta-neously were confirmed in another trial [39].Based on the results of randomized clinical trials(RCTs) and real-life experience, belimumab isparticularly effective in patients with activedisease, serological activity and high PDNintake, with earlier use achieving a better clini-cal response [40, 41]. The role of belimumab inLN is still being debated and will become clearerwhen the results of the ongoing BLISS-LN phaseIII RCT are published. In this context, a pooledpost hoc analysis of the BLISS studies, with theaim to determine the effect of belimumab onpatients with renal involvement, showed agreater improvement in renal disease in patientswith serologic activity at baseline or receivingMMF, as has been confirmed in the real-lifesetting [42, 43]. The finding of renal tubularepithelial cell-derived BAFF expression thatmediated kidney damage and correlated withLN activity in the mouse and humans furthersupports the efficacy of belimumab in LN [44].However, it must be noted that cases of newonset of LN in patients who received beli-mumab have been reported [45, 46], and pre-liminary retrospective observational data from aSwedish cohort showed increased risk and/orshorter time to de novo LN onset in non-renalpatients undergoing therapy with belimumab[47]. Indeed, as the authors of these studiesstated, the selection of patients suitable forbelimumab therapy based on serological activ-ity could be troublesome as these patients maybe at high risk of developing LN.

Regarding conventional IS, combinationtherapies designed to target two or more com-plementary pathways could be an effectivestrategy for the treatment of lupus, even withbiologics. Two ongoing trials, BLISS-BELIEVE[48] and BEAT [49], are evaluating the efficacyof combined RTX and belimumab therapy.There is a strong rationale for this combinedtherapeutic approach. First, treatment withbelimumab leads to the mobilization of mem-ory B cells from tissues despite an overalldecrease in peripheral B-cell levels, making tis-sue-resident B cells more susceptible to deple-tion by RTX. Second, blocking the effects ofhigh BAFF levels in the serum might havefavorable effects on B-cell reconstitution afterdepletion. The synergistic or additive effects ofsuch a combination have been demonstrated inpreclinical studies in lupus-prone mice and incase reports [50, 51].

Adjuvant Treatments

Intravenous immunoglobulins (IVIGs), whichare purified from the plasma of healthy humandonors, represent a valid therapeutic option forthose patients with SLE with concomitantinfections or for those who have contraindica-tions or are refractory to conventional thera-pies. In some cases, for example in cases ofneurological or hematological involvement,IVIGs can be given as first-line therapy [52].Despite being used since the 1980s, IVIG ther-apy is still considered to be experimental with-out any clear indications. A systematic review ofobservational studies highlighted the associa-tion of IVIG administration with significantimprovement in disease activity scores andcomplement levels [53].

Therapeutic plasma exchange (TPE) is ablood purification technique used for theremoval of pathological substances, such asmonoclonal para-proteins and auto-Ab, as wellas for the replacement of deficient plasmacomponents. This therapeutic option is helpfulwhen treatment with other agents fails or inpresence of leucopenia and psychosis, but it hasbeen profiled as an effective therapeutic optionespecially for patients with SLE with thrombotic

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thrombocytopenic purpura and catastrophicantiphospholipid syndrome [54].

In contrast with plasma exchange,immunoadsorption (IAS), a more specific formof extracorporeal treatment, leads to a specificand nearly complete clearance of circulatingIgG and ICs, while neither removing otherplasma proteins or necessitating substitutionwith fresh frozen plasma or albumin. In the pasttwo decades IAS has emerged as a valuableoption in the treatment of SLE, showing bene-ficial effects in patients with refractory diseaseor contraindications to standard immunosup-pression, or during pregnancy [55]. Availablestudies have shown that short-term use of IASreduces proteinuria and improves global diseaseactivity, enabling GC dosages to be lowered[56]. In addition, prolonged IAS treatment hasbeen shown to provide additional therapeuticbenefits and to maintain an acceptable safetyprofile [55]. Additional evidence is needed tobetter define the clinical utility of IAS forspecific SLE manifestations.

In the context of a holistic approach to lupuspatients, there is an emerging body of evidencesupporting the importance of correct lifestylehabits in the management of the disease, withparticular attention to smoking cessation,physical activity and vitamin D supplementa-tion [57]. According to the results of a recentmeta-analysis, tobacco smoking, in addition toits well-known adverse effects, significantlyreduces the effectiveness of HCQ and beli-mumab in cutaneous lesions and systemicmanifestations. Cigarette smoking also appearsto be a risk factor of SLE, negatively influencingthe course of the disease [58]. Physical activity isemerging as pivotal in the reduction of cardio-vascular risk and has also been shown to havepositive effects on fatigue and mental health[59]. Vitamin D deficiency is common inpatients with SLE, and a large body of evidencesupports the negative impact of vitamin Ddeficiency on disease activity, fatigue and risk ofthrombosis [57].

EMERGING THERAPIES

There are currently 125 registered studies onSLE that are recruiting participants; theseinclude studies on targeting B cells, plasmacells, co-stimulation, cytokines and theirreceptors, chemokines and their receptors andcomplement factors or interferons. Clinicalphase II or phase III RCTs on molecules target-ing BAFF, such as tabalumab (IgG4 antibody tosoluble and membrane BAFF), blisibimod (Fcfusion protein of 4 BAFF binding domains) oratacicept (APRIL [a proliferation-inducingligand] and BAFF target) did not reach therespective endpoints [60–63]. Obinutuzumab(OBZ), a new-generation, glycoengineered typeII anti-CD20 monoclonal Ab, induced superiorB-cell cytotoxicity in patients with lupusin vitro, as demonstrated in whole blood assays[64], so further investigations on OBZ areongoing.

B-cell receptor (BCR) signaling is believed toplay a pivotal role in the development andmaintenance of autoimmunity. The decrease ofLyn tyrosine kinase and spleen tyrosine kinase(Syk) in response to BCR stimulation in patientswith active SLE further supports the hypothesisthat B cells are under constant activationthrough BCR signaling [65]. Since it wasthought that CD22 engagement would imposenegative regulation of BCR signaling, epratuzu-mab, an anti-CD22 monoclonal antibody, wastested in SLE, but with negative results [66].

Other clinical approaches, such as withabatacept or CD40-CD40L, use T-/B-cell cos-timulatory pathways as the target. However, thephase II RCTs with abatacept in patients withSLE arthritis did not meet the primary end-points [67, 68] and were stopped. CD40-CD40Lblockade is currently being tested in patientswith LN after a successful phase IIa RCT inpatients with rheumatoid arthritis [69].

Long-lived plasma cells producing auto-Abappear to be an interesting target of lupusresearch. As a consequence, a proteasomeblocker, such as bortezomib, was used in a RCT,showing a good response [70]. However, therewas a substantial rate of side effects [71]. Further

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clinical studies with other less toxic proteasomeblockers are ongoing (e.g. ixazomib).

The Janus kinase/signal transducer and acti-vator of transcription (JAK/STAT) pathway,which mediates the signal transduction of morethan 50 cytokines and growth factors in manydifferent cell types, has been found to have anemerging pathogenic relevance in SLE patho-genesis [72]. Baricitinib, a low-molecular-weightcompound targeting JAK 1 and 2, met the pri-mary endpoint at the dosage of 4 mg/day in aninternational phase IIb clinical trial whichinvolved patients with highly active SLEexhibiting skin and joint symptoms despitehaving received the standard treatment. Thesafety profile was consistent with that reportedin previous studies, and serious infections wereobserved in a dose-dependent manner [73].Baricitinib is currently under investigation in aphase III trial.

In recent years, one cytokine has been foundtobe of particular interest: type I interferon alpha(IFNa) [74]. The accumulation of evidenceshowing that IFN-activated genes play a signifi-cant role in the pathophysiology of SLEhas led tothe testing of different therapeutic approaches.Although rontalizumab, a recombinant humanmonoclonal Ab against all 12 subtypes of IFNa,did not meet the primary endpoint in a phase IIclinical study, a subgroup analysis revealed pos-itive effects that was dependent on the plasmaIFNa levels [75]. The anti-IFNa receptor antibodyanifrolumab has recently shown promisingresults [76, 77], leading to the good possibilitythat a second biologic for the therapy of activeSLE will be approved in 2020. At the same time,this also means a step towards precision medi-cine, especially for SLE patients with a high IFNaactivity who can benefit from this therapy.

Mitochondrial dysfunction recently emergedas a pivotal factor in the immune dysregulationand development of organ damage in SLE. Ide-benone, a coenzyme Q10 synthetic quinoneanalog, has been found to ameliorate diseaseactivity and the severity of organ damage,including glomerular inflammation and fibrosisin a murin model of SLE, suggesting a potentialtherapeutic role in humans [78]. Oxidative stressis increased in SLE, contributing to immune sys-tem dysregulation and comorbidities [79].

Reversal of glutathione depletion by applicationof its amino acid precursor, N-acetylcysteine,safely improves disease activity in lupus patientsby blockingmTOR in T lymphocytes, but furtherresearch is needed [80].

The loss of tolerance to self-antigens in SLEpatients is associated with dysregulation ofT-cell signaling, including the depletion of totallevels of lymphocyte-specific protein kinasefrom sphingolipid-cholesterol-enriched mem-brane microdomains (lipid rafts). Atorvastatinhas emerged as an effective therapy by targetinglipid raft-associated signaling abnormalities inautoreactive T cells [81].

Chimeric antigen receptor (CAR) T-celltherapy is an emergent approach in cancerimmunotherapy and has shown efficacy in thetreatment of B-cell malignancies throughspecific targeting of the B-cell surface antigenCD19 [82, 83]. CARs are fusion proteins con-sisting of a single-chain fragment from a mon-oclonal Ab specific for the target antigen ofinterest and T-cell receptor intracellular signal-ing domains. The treatment involves the isola-tion of a patient’s autologous T cells, the geneticmodification of these cells to express the anti-gen-specific CARs, cell expansion, and finallyre-infusion of the modified cells into the patient[84]. Very recent data suggest that CAR T cellsmight also be a feasible strategy for the treat-ment of SLE. Using CD19-targeted CAR T cells,Kansal et al. showed sustained B-cell depletionin a murine lupus model [85]. Of note, CAR Tcells targeting the BAFF receptor (BAFF-R) haveproved to be effective in preclinical lymphomaand leukemia models [83]. Considering theencouraging results of current anti-BAFF thera-pies in SLE (reviewed above), BAFF-R-targetedCAR T cells might be a promising novel thera-peutic approach in patients suffering from SLE.

Interleukin-2 (IL-2) is involved in theexpansion of immune tolerance by increasingregulatory T cells and suppressing effector Tcells, including T helper 17 and T follicularhelper cells. When used at high doses, IL-2demonstrated efficacy in certain types of solidtumors, also contributing to the establishmentof the concept of its use in cancerimmunotherapy, while at low doses it wasfound to increase anti-infectious immune

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response [86]. A double-blind and placebo-con-trolled trial recently displayed the efficacy oflow-dose IL-2 in the treatment of SLE, with alower rate of infections, although not statisti-cally significant, recorded in the IL-2 groupcompared to placebo [87].

The most relevant SLE therapies accordingto their different mechanisms of action areshown in Fig. 1.

WHAT HAS ALREADY BEEN DONEAND WHAT REMAINS TO DO

Advances in the treatment of SLE have beenmade in recent decades, leading to an increasein patient survival worldwide. Nevertheless,lupus currently is associated with a 2.4-foldincrease in all-cause mortality. Patients with SLEhave a higher risk of cardiovascular disease

Fig. 1 Main mechanisms of systemic lupus erythematosus(lupus) pathogenesis with related targeted therapies. BAFFB-cell-activating factor, APRIL a proliferation-inducingligand, BCMA B-cell maturation antigen, TACI

T-lymphocyte activation, JAK Janus kinase, TYK2 tyrosinekinase 2, IFN-a interferon alpha, IL-2 interleukin-2, H-2T helper 2, Treg regulatory T cells, CAR-T chimericantigen receptor redirected

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(CVD) compared to the general population dueto a complex interplay between traditional car-diovascular risk factors and SLE-specific condi-tions. CVD still represents the major cause ofpremature mortality in patients with SLE [5],but its effect remains underestimated amongclinicians and treatment requires an interdisci-plinary approach.

Patients with SLE also present a higher risk ofinfections, both as a consequence of their dis-ease and of the therapies used in their clinicalmanagement. Live attenuated vaccines arecontraindicated in patients receiving IS drugs,biologics and GCs at a dose[10 mg whereasinactivated vaccines can be used at any time.The risk of lupus flare deriving from vaccinationhas never been never confirmed, but vaccina-tion rates remain low [88]. Further efforts aretherefore needed to reinforce the immunizationcoverage of patients with SLE.

Lupus is known to cause a significant andsometimes severe neurological involvement,resulting in a number of diverse symptoms,referred to as NP-SLE. This heterogeneity inneurological and psychiatric symptoms occur-ring in SLE poses both diagnostic and thera-peutic challenges with a substantial risk ofeither over- or under-treatment. It is wellknown that lupus patients with CNS involve-ment often present a more significant impair-ment of HRQoL when compared with thosewho have other serious manifestations of thedisease (e.g. renal involvement) [1]. No decisivetreatments for NP-SLE are as yet available, andthere is only weak evidence on which to baserecommendations [32].

Fatigue is the most common complaint ofpatients with SLE, reported by 80–100% ofpatients. It is the result of a multifactorial eti-ology and leads to a strong reduction of theHRQoL [89] and work productivity [90]. Therelationship between several psychosocial fac-tors, mainly pain, mood and sleep disorders,and comorbidities, such as fibromyalgia, ane-mia and vitamin D deficiency, is well estab-lished and can explain why fatigue isdetectable even in patients in remission or withlow disease activity. However, the relationshipbetween fatigue and disease activity is still amatter of debate. We recently reported a

significant correlation between the titer of theanti-NR2 Ab, severity of fatigue, disease activityand anti-double stranded DNA Ab—indepen-dently from the presence of NP lupus manifes-tations. In addition, treatment with belimumabfor at least 6 months affected both the severityof fatigue and the levels of anti-NR2 Ab [91].This finding highlights NMDAR (N-methyl-D-aspartate) autoantibodies as a potential bio-marker for fatigue in SLE and also provides aplausible explanation of belimumab efficacy inthe treatment of fatigue, as observed in BLISStrials [36]. Physical activity and vitamin D sup-plementation [92] have also been shown toimprove fatigue levels in patients with SLE.Despite these findings, relieving fatigue remainsan unmet need for lupus patients and a chal-lenge for their physicians, and new effectiveapproaches are needed.

Over the last 30 years, advances in treatmenthave improved the life expectancy and HRQoLof SLE patients, but much more remains to bedone. The heterogeneity of SLE, the differentforms of progression and the concomitantmedications have limited the approval of newtherapies, despite major efforts of the scientificcommunity and associated industries. A moreprecise characterization of disease phenotypesbased on molecular and clinical features isexpected to lead to the development of moreeffective and less toxic regimens in the man-agement of SLE.

ACKNOWLEDGEMENTS

We wish to thank Vincenza Pellegrino for hercontribution to the realization of Fig. 1.

Funding. We wish to thank the RARENETEU-Interreg for supporting the study. No RapidService Fee was received by the journal for thepublication of this article.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity of

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the work as a whole, and have given theirapproval for this version to be published.

Disclosures. Fabio Basta, Federica Fasola andKonstantinos Triantafyllias have nothing todisclose. Andreas Schwarting is a member of theEditorial Board of Rheumatology and Therapy.

Compliance with Ethical Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by any of theauthors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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