Systemic Lupus Erythematosus: a Therapeutic Challenge for the XXI Century

Clin Rheumatol (2014) 33:441–450 DOI 10.1007/s10067-014-2531-4

REVIEW ARTICLE

Systemic lupus erythematosus: a therapeutic challenge for the XXI century

Manuel F. Ugarte-Gil & Graciela S Alarcón

Received: 6 February 2014 /Revised: 9 February 2014 /Accepted: 9 February 2014 /Published online: 28 February 2014 # Clinical Rheumatology 2014

Abstract Despite significant advances in our understanding health system. Although a treatment to target based on defined of the pathogenesis of systemic lupus erythematosus (SLE), molecular pathways for specific disease subsets is appealing, there are only a few drugs approved by the regulatory agencies this is not yet a reality. This review addressed current thera- across the world for the treatment of these patients; in fact, peutic options for SLE patients and the state of the art of many of the compounds subjected to clinical trials have failed investigational drugs targeting pathogenic pathways identified in achieving their primary endpoints. Current therapeutic op- in these patients. tions include antimalarials which should be used in all SLE patients unless they are strongly contraindicated, glucocorti- Keywords Systemic lupus erythematosus . Treatment coids which should be used at the lowest possible dose and for the shortest possible time, and immunosuppressive drugs which should be used judiciously, mainly in patients with Introduction severe organ involvements or receiving high doses of steroids to control their disease. Despite improvement on the survival The discovery and introduction of glucocorticoids (GC) and of SLE patients, damage accrual has not varied over the last subsequently of immunosuppressive drugs in the management few decades, reflecting a gap between these therapeutic op- of patients with systemic lupus erythematosus (SLE) has a tions and the expectations of these patients and their treating significant impact in the course and outcome of this disease [1, physicians. Biologic compounds can be used in some refrac- 2]. Nevertheless, patients with SLE still experience a dimin- tory cases. However, their cost is of great concern for both the ished life expectancy which, at least in part, is due to the patients and the health system. Cost is of special importance in irreversible damage caused not only by the disease itself but low-income countries, because low-income SLE patients tend also by same medications that have contributed to improve to experience a more severe disease having an overall worse these patients overall outcome. prognosis which is compounded by their limited access to the Prognosis in SLE is affected by several factors including genetic and nongenetic ones. Genetic factors are important, M. F. Ugarte-Gil (*) because they can lead to a more severe disease; for example, Servicio de Reumatología, Hospital Nacional Guillermo Almenara African and Amerindian ancestral genes seem to be associated Irigoyen, EsSalud, Lima, Perú with renal involvement [3], but these genes alone do not fully e-mail: [email protected] explain the differences in the outcome of the disease between M. F. Ugarte-Gil Caucasian and not Caucasian patients; in fact, socioeconomic Universidad Científica del Sur, Lima, Perú factors, such as poverty, lower levels of education, and lack of or inadequate health insurance, are associated with worse G. S. Alarcón Department of Medicine, Division of Clinical Immunology and intermediate (disease activity, damage, and health-related Rheumatology, School of Medicine, The University of Alabama at quality of life) and long-term (mortality) outcomes [2, 4–6]. Birmingham, Birmingham, AL, USA These data are important when different treatment strategies are considered; for example, even though mycophenolate G. S. Alarcón Department of Medicine, Universidad Peruana Cayetano Heredia, mofetil seems to be more effective in Hispanic patients with Lima, Perú lupus nephritis [7], it is also more expensive than 442 Clin Rheumatol (2014) 33:441–450 cyclophosphamide, so Hispanic patients with inadequate lymphocyte stimulator (BLyS), a cytokine important for the health insurance may not benefit from this finding. survival of B lymphocytes. Belimumab has shown efficacy on reducing disease activity in SLE patients with mild–moderate disease, without severe renal or central nervous system (CNS) Current options involvement. In a post hoc analysis, the domains that improved with belimumab were the musculoskeletal and the Antimalarials are currently used and indicated in almost all mucocutaneous, the ones more frequently involved in these SLE patients, due to the many beneficial effects associated patients [31]. There is not enough information to evaluate the with their use as reported over the years; reduction in mortal- impact of belimumab in patients with more severe disease. ity, damage, flares, cardiovascular morbidity, and infections Furthermore, it is important to point out that more than 40 % may occur due to the multiple immunomodulatory and meta- of patients do not respond to this compound; in fact, the ones bolic effects of these compounds [8]. more likely to respond are those who are serologically active Glucocorticoids are still the cornerstone in the treatment of and exhibit high degree of disease activity [31]. SLE and are included in almost all therapeutic schemes due to Another biologic agent used in SLE is rituximab, a chime- their proven efficacy; however, they have been associated ric monoclonal antibody against CD20, which is a B lympho- with several adverse events including cardiovascular events, cyte restricted molecule that is expressed from pre-B to mem- diabetes mellitus, osteoporosis,osteonecrosis,infections, ory B cells. Although the randomized clinical trials (RCTs) of glaucoma, cataracts, psychological disorders, among several rituximab in SLE failed to prove this agent’s efficacy, rituxi- other deleterious effects [9]. mab seems to be effective in SLE patients with refractory Several immunosuppressive drugs have been used in SLE disease [32–34]. This apparent conflicting information may as steroid-sparing or to augment their effect when steroids at least be partly due to trial design, and in fact, these trials alone have not been able to abate the manifestations associat- prompted the lupus community to reassess how trials in lupus ed with severe organ system involvement. For example, cy- should be conducted [35]. clophosphamide has been shown to be efficacious in patients Abatacept, a fusion protein analog of cytotoxic T- with lupus nephritis and neurological involvement [10–12]. lymphocyte antigen 4 (CTLA-4), which is made of the extra- However, as cyclophosphamide has been associated with cellular domain of CTLA-4 and a fragment of the Fc portion various adverse events, there has been several proposals for of human IgG1, also failed to achieve primary or secondary reducing the time and dose of this medication [13]. end points [36]; however, some exploratory analyses suggest Mycophenolate mofetil has emerged as another option for that abatacept could be useful in some SLE patients the treatment of lupus nephritis, being at least as effective as [37]. The main indications of these biologic compounds cyclophosphamide for the induction phase [14, 15] and better are described in Table 2. than azathioprine for the maintenance phase [16]. Other ther- Of significant importance is the cost associated with these apeutic options for these patients are azathioprine [17, 18], new treatment options, which is of great concern to patients and methotrexate [19, 20], cyclosporine [21, 22], tacrolimus private and governmental insurance agencies across the world. [23–25], and leflunomide [26–28]; however, all these immu- However, if these and other more “intelligent” or targeted nosuppressive drugs are also associated with several adverse treatments would cause less adverse short- and long-term con- events like infections and malignancies [13]. The indications sequences, their cost could be significantly offset. and main safety issues of these immunosuppressive drugs are described in Table 1. Despite these treatments, SLE patients still have a threefold Future options increase in all-cause mortality compared to the general population [29]. Furthermore, despite adequate control of disease Given that the use of GC in lupus is clearly a main risk factor activity, early disease damage has not changed during the last for damage, the possibility of using them at very low doses or 35 years [30]. Since medications contribute significantly to not at all is gaining momentum. One such protocol, rituxilup, damage, there is a clamor among those caring for patients with [38] for patients with lupus nephritis includes two doses of lupus to count with medications which exhibit a better safety- rituximab and methylprednisolone and mycophenolate mofe- toxicity profile. til, but not sustained oral GC. This trial conducted in a single With advances in the understanding of the pathogenesis of center in Great Britain provided positive results, but the lupus, a number of different biological products have been multicenter RCT to definitively address this option is tried in these patients with variable success. In 2011, the US still ongoing. Food and Drug Administration (FDA) and the European There are several other potential targets for the treatment of Medicines Agency (EMA) granted regulatory approval for SLE which are currently being investigated. They may target belimumab, a fully human monoclonal antibody against B- the innate immunity as is the case with type I interferons (IFN) Clin Rheumatol (2014) 33:441–450 443

Ta b l e 1 Nonbiologic immunosuppressive drugs currently used in SLE patients

Drugs Main indication Other indications Comment

Cyclophosphamide [10–12] LN, CNS lupus Other severe clinical manifestations May induce premature ovarian failure MMF [14–16] LN (induction and maintenance Hematological, dermatological Seems to be more effective than therapy) and articular involvement CYC in Hispanic patients with LN Azathioprine [17, 18] LN (maintenance therapy) GC sparing in patient with active May induce hepatotoxicity SLE (without CNS and severe lupus nephritis) Methotrexate [19, 20]ModeratelyactivediseaseGC sparing May induce hepatotoxicity (musculoskeletal and dermatological involvement) Cyclosporine [21, 22] Refractory LN SLE refractory to GC May induce nephrotoxicity Tacrolimus [23–25] Refractory LN (induction and Could be used in addition to MMF maintenance therapy) Mainly used in Asian population Leflunomide [26–28] Mild-to-moderate disease Refractory LN May cause subacute cutaneous lupus and lupus-like syndrome and hepatotoxicity

GC glucocorticoids, SLE systemic lupus erythematosus, LN lupus nephritis, CNS central nervous system, MMF mycophenolate mofetil, CYC cyclophosphamide in which production or signaling is being inhibited. These an open label pilot study. This drug blocks the produc- drugs can be monoclonal antibodies against IFNα,suchas tion of IL-12, IL-23, TNF-α,andIFN-γ,reducingTh1 sifalimumab, with a good tolerability in a phase I study [39]; and Th17 response [51]. Chaperonin 10 or heat shock phase II studies are still ongoing. Rontalizumab failed to protein 10 can modulate the innate and adaptive im- achieve primary and secondary endpoints in phase II studies; mune responses and is being evaluated in subjects with however, it seems to be useful in a subset of patients [40]. active SLE [52]. Innate immunity-targeted treatments are AGS-009 has also completed its phase I study [41]. MEDI- summarized in Table 3. 546, a monoclonal antibody against INFα receptor has phase Among molecules targeting the adaptive immunity, there II studies ongoing [42]. IFNα inhibition can also be achieved are therapies directed to B cells including cell surfaces via a kinoid; this IFNα kinoid has promising results in its markers like CD20. In addition to rituximab, other drugs have phase I study [43]. been evaluated with variable success. For example, a phase III Another possible target is tumor necrosis factor α study of ocrelizumab [53] was terminated early due to a safety (TNFα); however, a trial of etanercept for patients with issue (increased frequency of serious infections), TRU-015 lupus nephritis was not continued due to safety issues [54] and SBI-087 [55] are other anti-CD20 drugs under eval- [44], and a trial of infliximab failed to recruit patients uation. Epratuzumab, an anti-CD22 drug, seemed to be effec- [45]. Other possible signals that can act as therapeutic tive in its phase II study [56], however, the initial phase III targets in lupus are the monocyte colony-stimulating studies had to be terminated because of interruption of factor (M-CSF) [46], the anti-macrophage inhibitory the drug’s supply [57], but new phase III studies are factor (anti-MIF) [47], the C5a receptor (C5aR) [48], now being conducted. the TNF-related weak inducer of apoptosis (TWEAK) Another therapeutic option is the BLyS pathway; besides [49],andCD74[50]; all of them are currently in early belimumab, tabalumab [58], and blisibimod [59] are BLyS phases of research. A phosphodiesterase type 4 inhibi- inhibitors that are being evaluated. Atacicept, a BLyS and tor, apremilast, has also been used in discoid lupus in APRIL inhibitor, has been evaluated in SLE patients;

Ta b l e 2 Biologic immunosuppressive compounds currently used in SLE patients

Drug Main indication Comment

Belimumab [31] Active SLE (without LN or CNS involvement) More effective in serologically active patients Rituximab [32–34] Moderate-to-severe SLE, LN, CNS involvement. RCT failed to achieve their primary end points. Data of efficacy is based on observational studies. Abatacept [36, 37] LN, articular involvement RCT failed to achieve its primary end point. Data of efficacy is based on observational studies.

SLE systemic lupus erythematosus, LN lupus nephritis, CNS central nervous system, RCT randomized clinical trial 444 Clin Rheumatol (2014) 33:441–450

Ta b l e 3 Potential drugs that can modulate the innate immunity

Target Agent Status of development

IFN-α production and signaling IFN-α Sifalimumab [39] Active SLE, phase IIb (completed and ongoing) Rontalizumab [40] Active SLE, phase II (completed) AGS-009 [41] Active SLE, phase I (completed) IFN-α R MEDI-546 [42] SLE active, phase II (ongoing) IFN-α kinoid vaccine IFN-α kinoid [43] Active SLE, phases I–II (completed) Inhibition of TNF-α signaling TNFα soluble receptor Etanercept [44] LN, phase II (terminated); DLE, phase II (unknown) TNFα mononuclear antibodies Infliximab [45] Type V LN, phases II–III (terminated) Other signals M-CSF PD-0360324 [46] CLE, phase I (terminated) MIF Anti-MIF [47] LN, phase I (terminated) C5aR NNC 0151-0000-0000 [48] Active SLE, phase I (terminated) TWEAK BIIB023 [49] LN, phase II (ongoing) MHC-II CD74 Milatuzumab [50] Active SLE, phases I–II (not yet open for enrollment) Other targets PDE-4 inhibitor Apremilast [51] CLE, phases I–II (completed) CPN-10 Ala-Cpn10 [52] Active SLE, phases I–II (ongoing)

INF interferon, TNF tumor necrosis factor, M-CSF monocyte colony-stimulating factor, MIF macrophage migration inhibitory factor, C5aR C5a receptor, TWEAK tumor necrosis factor-like weak inducer of apoptosis, MHC major histocompatibility complex, PDE phosphodiesterase, CPN chaperonin, SLE systemic lupus erythematosus, LN lupus nephritis, CLE cutaneous lupus erythematosus, DLE discoid lupus erythematosus however, its phases II–III lupus nephritis study was prema- ICOSL-targeted agent, was terminated by the sponsor for turely terminated due to safety issues [60]; however, on further unclear reasons [74]. Cytokine blockade is being evaluated examination, it was felt that the increased number of infec- by monoclonal antibodies against IL-6 (e.g., sirukumab [75] tions observed in this trial were due to the background med- and PF-04236921 [76]), IL-6 receptor (MRA 003 US [77]), ication and thus this compound is still under study on active IL-21 (NNC0114-0006 [78]), and IFN-γ (AMG 811) [79], but SLE patients [61]. Plasma-cell depletion can be achieved these compounds are all in early phases of development with a nonselective proteasome inhibitor like (phases I–II studies). IL-10 blockage was evaluated in SLE bortezomib; this drug can induce apoptosis of immune patients over a decade ago; although there was a decrease in cells by several pathways [62] and is now being tested the SLEDAI, only six patients were included in this open in lupus nephritis [63]. Induction of B cell tolerance, labeled trial [80], but there has not been recent trials. with abetimus [64]oredratide[65], have also been Kinase inhibitors include syk inhibitors, such as R333 [81], studied, but these trials failed to achieve their endpoints. which is being evaluated in cutaneous SLE patients, and Omalizumab, a monoclonal antibody against IgE, is also fostamatinib, in which a business decision by the sponsor being evaluated in SLE patients [66]. Potential drugs led to the early termination of the trial [82], and JAK inhibitors that can modulate B cells are shown in Table 4. like GSK2586184 which is still under evaluation in SLE There are several compounds targeting T cells includ- patients [83]. The benefit / risk profile of JNK inhibitor CC- ing co-estimulation blockade with CD40-L-targeted 930 does not support continuing its study in patients with agents like IDEC-131 [67] and BG9588 [68]; the first discoid lupus [84]. failed to achieve its endpoints and the second was Other T cell-targeting therapies are quinolone-3- suspended due to safety issues (thromboembolic events). carboxamide derivatives, immunomodulatory agents that CDP7657, another agent against CD40L is also being might reduce the expression of MHC-II, adhesion mol- evaluated in active SLE patients [69]. In addition to ecules, and chemokines; in this group of compounds, abatacept, RG2077, another CTLA-4 agonist, has been we have laquinimod [85] and paquinimod [86]. evaluated in patients with active SLE [70]. Sphingosine-1-phosphate (S1P) analogs exert several ICOSICOSL blockade by AMG557 is being evaluated in functions on immune cells [87] including the expansion SLE patients with arthritis, subacute cutaneous lupus, and andactivationofTregcells[88]. KRP203, an S1P active SLE [71–73]. A trial of MEDI-570, another ICOS– analog, has been used in subacute cutaneous lupus Clin Rheumatol (2014) 33:441–450 445

Ta b l e 4 Potential drugs that can modulate B cells

Target Agent Status of development

Bcelldepletion AntiCD20 Ocrelizumab [53] LN, phase III (ongoing); Active SLE, phase III (terminated) TRU-015 [54] Type V LN, phase I (terminated) SBI-087 [55] Active SLE, phase I (completed) AntiCD22 Epratuzumab [56, 57] Active SLE, phase II and III (completed and terminated); Active SLE, phase III (ongoing) Inhibition of B cell activation BLyS inhibitor Tabalumab [58] Active SLE, phase III (ongoing) Blisibimod [59] Active SLE, phase III (completed, ongoing) BLyS and APRIL inhibitor Atacicept [60, 61] LN, phases II–III (terminated); Active SLE, phase II (completed and ongoing) Plasma cell depletion Nonselective proteasome inhibitors Bortezomib [63] LN, phase IV (withdrawn) Induction of B cell tolerance Inhibitor of anti-DNAds antibodies Abetimus [64] LN, phase III (completed) Tolerogenic peptide Edratide [65] Active SLE, phase II (terminated) IgE Mononuclear antibodies against IgE Omalizumab [66] Active SLE, phase I (ongoing)

BLyS B lymphocyte stimulator, APRIL a proliferation-inducing ligand, SLE systemic lupus erythematosus, LN lupus nephritis

[89]. Lupuzor, a 21-aminoacid-fragment of U1 small Unmet needs nuclear ribonucleoprotein 70 kDa phosphorylated at Ser140, has tolerogenic and immunomodulatory proper- Almost 30 % of SLE patients achieve disease quies- ties, preventing CD4+ T cells proliferation, but not the cence (defined according to physician global assess- secretion of regulatory cytokines [90, 91]. Efalizumab, a ments) during the first year of their disease; however, monoclonal antibody against CD11a (α subunit of lym- almost 50 % of them present flares in the subsequent phocyte function-associated antigen 1), has been used in years [95]. When a more strict definition of remission is patients with discoid lupus erythematosus [92], and it is used (SLEDAI 0, without concomitant GC and immu- being evaluated in patients with active SLE [93]. BCL-2 nosuppressive drug use), only 6.5 % of the patients inhibitor (ABT-199) can induce apoptosis of T- and B- achieve remission at 1 year and not quite 2 % achieve cells, it has been used in hematologic neoplasms, and long-term remission [96]. Furthermore, almost 50 % of phase I study in SLE patients has been started [94]. T the patients accrue at least one point in the Systemic cell-targeted therapies are presented in Table 5. Lupus International Collaborating Clinics/American Col- Despite the impressive number of new molecules targeting lege of Rheumatology (SLICC/ACR) damage index over different cells and pathways in the immune system, it should 5 years [97]. These data suggest that we need more be pointed out that the conduct of RCTs in SLE face tremen- effective and safer treatments, and these new drugs or dous difficulties related not only to the lack of a uniform new schemes should help us not only on reducing definition of response but also to the heterogeneity of the disease activity but also on reducing the number of disease with different clinical subsets, possibly representing flares which would lead to higher damage. not only different pathogenic pathways but also different responses to treatments. Some authors, in fact, have argued that rather than distinguishing patients based on clinical Conclusions criteria like we do nowadays, patients should be identified based on which molecular pathway or pathways may be Despite advances in the treatment of SLE patients, there is still affected and consequently use the proper treatment which a big gap between what lupus patients need or expect and what could alter them. Finally, the availability of eligible and current treatment options offer. Furthermore, better treatment willing patients to participate in these trials across dif- options are going to come from a better understanding of the ferent nations and continents is a consideration that disease pathogenesis and eventually its cause. For the time cannot be dismissed. being, antimalarials must be used in every SLE patient unless 446 Clin Rheumatol (2014) 33:441–450

Ta b l e 5 Potential drugs that can modulate T cells

Target Agent Status of development

Co-stimulation blockade CD40–CD40L IDEC-131 [67] Active SLE, phase II (completed) BG9588 [68] LN, phase II (completed) CDP7657 [69] Active SLE, phase I (ongoing) CD80/86–CD28 RG2077 [70] Severe SLE, phases I–II (completed) ICOS–ICOSL AMG557 [71–73] Lupus arthritis phase I (ongoing); SCLE phase I (terminated); Active SLE, phase I (completed) MEDI-570 [74] Active SLE, phase I (terminated) Cytokine blockade IL-6 Sirukumab [75] Active SLE and CLE, phase I (completed); LN, phase II (completed) PF-04236921 [76] Active SLE, phase II (ongoing) IL-6R MRA 003 US [77] Active SLE, phase I (completed) IL-21 NNC0114-0006 [78] Active SLE, phase I (ongoing) IFN-γ AMG 811 [79] DLE, phase I (ongoing); Active SLE, phase I (ongoing) IL-10 B-N10 [80] Active SLE, pilot trial Kinase inhibition Syk inhibitor R333 [81] DLE, phase II (completed) Fostamatinib [82] Active SLE, phase II (withdrawn) JAK inhibitor GSK2586184 [83] Active SLE, phase II (ongoing) JNK inhibitor CC-930 [84] DLE, phase II (terminated) Other targets Quinolone-3-carboxamide derivatives Laquinimod [85] Lupus arthritis, phase II (completed); LN, phase II (completed) Paquinimod [86] Active SLE, phase II (completed) Sphingosine-1-phosphate targeting agents KRP203 [89] SCLE, phase II (terminated) Immune-modulating peptides Lupuzor [91] SLE active, phase IIb (completed) Integrin LFA-1 Efalizumab [93] DLE, phase II (terminated) BCL-2 inhibitor ABT-199 [94] Active SLE, phase I (ongoing)

IFN interferon, LFA lymphocye function-associated antigen, SLE systemic lupus erythematosus, LN lupus nephritis, DLE discoid lupus erythematosus, SCLE subcutaneous lupus erythematosus

they are strongly contraindicated. GC should be used at the Foundation of America, and several other nonprofit organiza- lowest possible dose and for the shortest time to control the tions aimed at sharing information to speed up the creation activity of the disease. Immunosuppressive drugs should be and approval of new drugs for patients suffering from used in order to reduce disease activity and GC dosing taking Alzheimer’s disease, type 2 diabetes, and autoimmune into account their safety profile. Biologics should be used in diseases (rheumatoid arthritis and SLE) [98]. SLE was patients with refractory disease and only after a careful assess- selected due to the lack of effective therapies for the ment of the clinical manifestations which are likely or not to most severe forms of the diseases, mainly lupus nephri- respond to these drugs. tis and neurological involvement. Finally, as further We do hope that in the not too distant future our lupus advances are made in the understanding of lupus and patients could be treated with safer and more effective com- new therapies do emerge, it is desirable that such treat- pounds than the ones we currently use. Even if costly, these ment opportunities are made available to all patients treatments may be cost-effective in the long run, if damage can regardless of their ethnic/racial origin, country of resi- be prevented and health-related quality of life and survival dence, or socioeconomic status. improved. Working on this direction, the Accelerating Medi- cines Partnership is a new US program of the National Insti- tute of Health, ten biopharmaceutical companies, the Lupus Disclosures None Clin Rheumatol (2014) 33:441–450 447

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