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 of the pathogenesis of systemic lupus erythematosus (SLE), there are only a few drugs approved by the regulatory agencies across the world for the treatment of these patients; in fact, many of the compounds subjected to clinical trials have failed in achieving their primary endpoints. Current therapeutic options include antimalarials which should be used in all SLE patients unless they are strongly contraindicated, glucocorticoids 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 severe organ involvements or receiving high doses of steroids to control their disease. Despite improvement on the survival of SLE patients, damage accrual has not varied over the last few decades, reflecting a gap between these therapeutic options and the expectations of these patients and their treating physicians. Biologic compounds can be used in some refractory cases. However, their cost is of great concern for both the patients and the health system. Cost is of special importance in low-income countries, because low-income SLE patients tend to experience a more severe disease having an overall worse prognosis which is compounded by their limited access to the M. F. Ugarte-Gil (*) Servicio de Reumatología, Hospital Nacional Guillermo Almenara Irigoyen, EsSalud, Lima, Perú e-mail: [email protected] M. F. Ugarte-Gil Universidad Científica del Sur, Lima, Perú G. S. Alarcón Department of Medicine, Division of Clinical Immunology and Rheumatology, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA G. S. Alarcón Department of Medicine, Universidad Peruana Cayetano Heredia, Lima, Perú
health system. Although a treatment to target based on defined molecular pathways for specific disease subsets is appealing, this is not yet a reality. This review addressed current therapeutic options for SLE patients and the state of the art of investigational drugs targeting pathogenic pathways identified in these patients. Keywords Systemic lupus erythematosus . Treatment
Introduction The discovery and introduction of glucocorticoids (GC) and subsequently of immunosuppressive drugs in the management of patients with systemic lupus erythematosus (SLE) has a significant impact in the course and outcome of this disease [1, 2]. Nevertheless, patients with SLE still experience a diminished life expectancy which, at least in part, is due to the irreversible damage caused not only by the disease itself but also by same medications that have contributed to improve these patients overall outcome. Prognosis in SLE is affected by several factors including genetic and nongenetic ones. Genetic factors are important, because they can lead to a more severe disease; for example, African and Amerindian ancestral genes seem to be associated with renal involvement [3], but these genes alone do not fully explain the differences in the outcome of the disease between Caucasian and not Caucasian patients; in fact, socioeconomic factors, such as poverty, lower levels of education, and lack of or inadequate health insurance, are associated with worse intermediate (disease activity, damage, and health-related quality of life) and long-term (mortality) outcomes [2, 4–6]. These data are important when different treatment strategies are considered; for example, even though mycophenolate mofetil seems to be more effective in Hispanic patients with lupus nephritis [7], it is also more expensive than
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cyclophosphamide, so Hispanic patients with inadequate health insurance may not benefit from this finding.
Current options Antimalarials are currently used and indicated in almost all SLE patients, due to the many beneficial effects associated with their use as reported over the years; reduction in mortality, damage, flares, cardiovascular morbidity, and infections may occur due to the multiple immunomodulatory and metabolic effects of these compounds [8]. Glucocorticoids are still the cornerstone in the treatment of SLE and are included in almost all therapeutic schemes due to their proven efficacy; however, they have been associated with several adverse events including cardiovascular events, diabetes mellitus, osteoporosis, osteonecrosis, infections, glaucoma, cataracts, psychological disorders, among several other deleterious effects [9]. Several immunosuppressive drugs have been used in SLE as steroid-sparing or to augment their effect when steroids alone have not been able to abate the manifestations associated with severe organ system involvement. For example, cyclophosphamide has been shown to be efficacious in patients with lupus nephritis and neurological involvement [10–12]. However, as cyclophosphamide has been associated with various adverse events, there has been several proposals for reducing the time and dose of this medication [13]. Mycophenolate mofetil has emerged as another option for the treatment of lupus nephritis, being at least as effective as cyclophosphamide for the induction phase [14, 15] and better than azathioprine for the maintenance phase [16]. Other therapeutic options for these patients are azathioprine [17, 18], methotrexate [19, 20], cyclosporine [21, 22], tacrolimus [23–25], and leflunomide [26–28]; however, all these immunosuppressive drugs are also associated with several adverse events like infections and malignancies [13]. The indications and main safety issues of these immunosuppressive drugs are described in Table 1. Despite these treatments, SLE patients still have a threefold increase in all-cause mortality compared to the general population [29]. Furthermore, despite adequate control of disease activity, early disease damage has not changed during the last 35 years [30]. Since medications contribute significantly to damage, there is a clamor among those caring for patients with lupus to count with medications which exhibit a better safetytoxicity profile. With advances in the understanding of the pathogenesis of lupus, a number of different biological products have been tried in these patients with variable success. In 2011, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) granted regulatory approval for belimumab, a fully human monoclonal antibody against B-
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lymphocyte stimulator (BLyS), a cytokine important for the 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) involvement. In a post hoc analysis, the domains that improved with belimumab were the musculoskeletal and the mucocutaneous, the ones more frequently involved in these patients [31]. There is not enough information to evaluate the impact of belimumab in patients with more severe disease. Furthermore, it is important to point out that more than 40 % of patients do not respond to this compound; in fact, the ones more likely to respond are those who are serologically active and exhibit high degree of disease activity [31]. Another biologic agent used in SLE is rituximab, a chimeric monoclonal antibody against CD20, which is a B lymphocyte restricted molecule that is expressed from pre-B to memory B cells. Although the randomized clinical trials (RCTs) of rituximab in SLE failed to prove this agent’s efficacy, rituximab seems to be effective in SLE patients with refractory disease [32–34]. This apparent conflicting information may at least be partly due to trial design, and in fact, these trials prompted the lupus community to reassess how trials in lupus should be conducted [35]. Abatacept, a fusion protein analog of cytotoxic Tlymphocyte antigen 4 (CTLA-4), which is made of the extracellular domain of CTLA-4 and a fragment of the Fc portion of human IgG1, also failed to achieve primary or secondary end points [36]; however, some exploratory analyses suggest that abatacept could be useful in some SLE patients [37]. The main indications of these biologic compounds are described in Table 2. Of significant importance is the cost associated with these new treatment options, which is of great concern to patients and private and governmental insurance agencies across the world. However, if these and other more “intelligent” or targeted treatments would cause less adverse short- and long-term consequences, their cost could be significantly offset.
Future options Given that the use of GC in lupus is clearly a main risk factor for damage, the possibility of using them at very low doses or not at all is gaining momentum. One such protocol, rituxilup, [38] for patients with lupus nephritis includes two doses of rituximab and methylprednisolone and mycophenolate mofetil, but not sustained oral GC. This trial conducted in a single center in Great Britain provided positive results, but the multicenter RCT to definitively address this option is still ongoing. There are several other potential targets for the treatment of SLE which are currently being investigated. They may target the innate immunity as is the case with type I interferons (IFN)
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Table 1 Nonbiologic immunosuppressive drugs currently used in SLE patients Drugs
Main indication
Other indications
Comment
Cyclophosphamide [10–12] MMF [14–16]
LN, CNS lupus LN (induction and maintenance therapy) LN (maintenance therapy)
Other severe clinical manifestations Hematological, dermatological and articular involvement GC sparing in patient with active SLE (without CNS and severe lupus nephritis) GC sparing
May induce premature ovarian failure Seems to be more effective than CYC in Hispanic patients with LN May induce hepatotoxicity
Azathioprine [17, 18]
Methotrexate [19, 20]
Cyclosporine [21, 22] Tacrolimus [23–25] Leflunomide [26–28]
Moderately active disease (musculoskeletal and dermatological involvement) Refractory LN Refractory LN (induction and maintenance therapy) Mild-to-moderate disease
SLE refractory to GC
Refractory LN
May induce hepatotoxicity
May induce nephrotoxicity Could be used in addition to MMF Mainly used in Asian population 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 drugs can be monoclonal antibodies against IFNα, such as sifalimumab, with a good tolerability in a phase I study [39]; phase II studies are still ongoing. Rontalizumab failed to achieve primary and secondary endpoints in phase II studies; however, it seems to be useful in a subset of patients [40]. AGS-009 has also completed its phase I study [41]. MEDI546, a monoclonal antibody against INFα receptor has phase II studies ongoing [42]. IFNα inhibition can also be achieved via a kinoid; this IFNα kinoid has promising results in its phase I study [43]. Another possible target is tumor necrosis factor α (TNFα); however, a trial of etanercept for patients with lupus nephritis was not continued due to safety issues [44], and a trial of infliximab failed to recruit patients [45]. Other possible signals that can act as therapeutic targets in lupus are the monocyte colony-stimulating factor (M-CSF) [46], the anti-macrophage inhibitory factor (anti-MIF) [47], the C5a receptor (C5aR) [48], the TNF-related weak inducer of apoptosis (TWEAK) [49], and CD74 [50]; all of them are currently in early phases of research. A phosphodiesterase type 4 inhibitor, apremilast, has also been used in discoid lupus in
an open label pilot study. This drug blocks the production of IL-12, IL-23, TNF-α, and IFN-γ, reducing Th1 and Th17 response [51]. Chaperonin 10 or heat shock protein 10 can modulate the innate and adaptive immune responses and is being evaluated in subjects with active SLE [52]. Innate immunity-targeted treatments are summarized in Table 3. Among molecules targeting the adaptive immunity, there are therapies directed to B cells including cell surfaces markers like CD20. In addition to rituximab, other drugs have been evaluated with variable success. For example, a phase III study of ocrelizumab [53] was terminated early due to a safety issue (increased frequency of serious infections), TRU-015 [54] and SBI-087 [55] are other anti-CD20 drugs under evaluation. Epratuzumab, an anti-CD22 drug, seemed to be effective in its phase II study [56], however, the initial phase III studies had to be terminated because of interruption of the drug’s supply [57], but new phase III studies are now being conducted. Another therapeutic option is the BLyS pathway; besides belimumab, tabalumab [58], and blisibimod [59] are BLyS inhibitors that are being evaluated. Atacicept, a BLyS and APRIL inhibitor, has been evaluated in SLE patients;
Table 2 Biologic immunosuppressive compounds currently used in SLE patients Drug
Main indication
Comment
Belimumab [31] Rituximab [32–34]
Active SLE (without LN or CNS involvement) Moderate-to-severe SLE, LN, CNS involvement.
Abatacept [36, 37]
LN, articular involvement
More effective in serologically active patients RCT failed to achieve their primary end points. Data of efficacy is based on observational studies. 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
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Table 3 Potential drugs that can modulate the innate immunity Target IFN-α production and signaling IFN-α
IFN-α R IFN-α kinoid vaccine Inhibition of TNF-α signaling TNFα soluble receptor TNFα mononuclear antibodies Other signals M-CSF MIF C5aR TWEAK MHC-II CD74 Other targets PDE-4 inhibitor CPN-10
Agent
Status of development
Sifalimumab [39] Rontalizumab [40] AGS-009 [41] MEDI-546 [42] IFN-α kinoid [43]
Active SLE, phase IIb (completed and ongoing) Active SLE, phase II (completed) Active SLE, phase I (completed) SLE active, phase II (ongoing) Active SLE, phases I–II (completed)
Etanercept [44] Infliximab [45]
LN, phase II (terminated); DLE, phase II (unknown) Type V LN, phases II–III (terminated)
PD-0360324 [46] Anti-MIF [47] NNC 0151-0000-0000 [48] BIIB023 [49] Milatuzumab [50]
CLE, phase I (terminated) LN, phase I (terminated) Active SLE, phase I (terminated) LN, phase II (ongoing) Active SLE, phases I–II (not yet open for enrollment)
Apremilast [51]
CLE, phases I–II (completed)
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 prematurely terminated due to safety issues [60]; however, on further examination, it was felt that the increased number of infections observed in this trial were due to the background medication and thus this compound is still under study on active SLE patients [61]. Plasma-cell depletion can be achieved with a n onselective proteasome inhibitor like bortezomib; this drug can induce apoptosis of immune cells by several pathways [62] and is now being tested in lupus nephritis [63]. Induction of B cell tolerance, with abetimus [64] or edratide [65], have also been studied, but these trials failed to achieve their endpoints. Omalizumab, a monoclonal antibody against IgE, is also being evaluated in SLE patients [66]. Potential drugs that can modulate B cells are shown in Table 4. There are several compounds targeting T cells including co-estimulation blockade with CD40-L-targeted agents like IDEC-131 [67] and BG9588 [68]; the first failed to achieve its endpoints and the second was suspended due to safety issues (thromboembolic events). CDP7657, another agent against CD40L is also being evaluated in active SLE patients [69]. In addition to abatacept, RG2077, another CTLA-4 agonist, has been evaluated in patients with active SLE [70]. ICOSICOSL blockade by AMG557 is being evaluated in SLE patients with arthritis, subacute cutaneous lupus, and active SLE [71–73]. A trial of MEDI-570, another ICOS–
ICOSL-targeted agent, was terminated by the sponsor for unclear reasons [74]. Cytokine blockade is being evaluated by monoclonal antibodies against IL-6 (e.g., sirukumab [75] and PF-04236921 [76]), IL-6 receptor (MRA 003 US [77]), IL-21 (NNC0114-0006 [78]), and IFN-γ (AMG 811) [79], but these compounds are all in early phases of development (phases I–II studies). IL-10 blockage was evaluated in SLE patients over a decade ago; although there was a decrease in the SLEDAI, only six patients were included in this open labeled trial [80], but there has not been recent trials. Kinase inhibitors include syk inhibitors, such as R333 [81], which is being evaluated in cutaneous SLE patients, and fostamatinib, in which a business decision by the sponsor led to the early termination of the trial [82], and JAK inhibitors like GSK2586184 which is still under evaluation in SLE patients [83]. The benefit / risk profile of JNK inhibitor CC930 does not support continuing its study in patients with discoid lupus [84]. Other T cell-targeting therapies are quinolone-3carboxamide derivatives, immunomodulatory agents that might reduce the expression of MHC-II, adhesion molecules, and chemokines; in this group of compounds, we have laquinimod [85] and paquinimod [86]. Sphingosine-1-phosphate (S1P) analogs exert several functions on immune cells [87] including the expansion and activation of Treg cells [88]. KRP203, an S1P analog, has been used in subacute cutaneous lupus
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Table 4 Potential drugs that can modulate B cells Target B cell depletion AntiCD20
AntiCD22 Inhibition of B cell activation BLyS inhibitor BLyS and APRIL inhibitor Plasma cell depletion Nonselective proteasome inhibitors Induction of B cell tolerance Inhibitor of anti-DNAds antibodies Tolerogenic peptide IgE Mononuclear antibodies against IgE
Agent
Status of development
Ocrelizumab [53] TRU-015 [54] SBI-087 [55] Epratuzumab [56, 57]
LN, phase III (ongoing); Active SLE, phase III (terminated) Type V LN, phase I (terminated) Active SLE, phase I (completed) Active SLE, phase II and III (completed and terminated); Active SLE, phase III (ongoing)
Tabalumab [58] Blisibimod [59] Atacicept [60, 61]
Active SLE, phase III (ongoing) Active SLE, phase III (completed, ongoing) LN, phases II–III (terminated); Active SLE, phase II (completed and ongoing)
Bortezomib [63]
LN, phase IV (withdrawn)
Abetimus [64] Edratide [65]
LN, phase III (completed) Active SLE, phase II (terminated)
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 nuclear ribonucleoprotein 70 kDa phosphorylated at Ser140, has tolerogenic and immunomodulatory properties, preventing CD4+ T cells proliferation, but not the secretion of regulatory cytokines [90, 91]. Efalizumab, a monoclonal antibody against CD11a (α subunit of lymphocyte function-associated antigen 1), has been used in patients with discoid lupus erythematosus [92], and it is being evaluated in patients with active SLE [93]. BCL-2 inhibitor (ABT-199) can induce apoptosis of T- and Bcells, it has been used in hematologic neoplasms, and phase I study in SLE patients has been started [94]. T cell-targeted therapies are presented in Table 5. Despite the impressive number of new molecules targeting different cells and pathways in the immune system, it should be pointed out that the conduct of RCTs in SLE face tremendous difficulties related not only to the lack of a uniform definition of response but also to the heterogeneity of the disease with different clinical subsets, possibly representing 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 criteria like we do nowadays, patients should be identified based on which molecular pathway or pathways may be affected and consequently use the proper treatment which could alter them. Finally, the availability of eligible and willing patients to participate in these trials across different nations and continents is a consideration that cannot be dismissed.
Unmet needs Almost 30 % of SLE patients achieve disease quiescence (defined according to physician global assessments) during the first year of their disease; however, almost 50 % of them present flares in the subsequent years [95]. When a more strict definition of remission is used (SLEDAI 0, without concomitant GC and immunosuppressive drug use), only 6.5 % of the patients achieve remission at 1 year and not quite 2 % achieve long-term remission [96]. Furthermore, almost 50 % of the patients accrue at least one point in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index over 5 years [97]. These data suggest that we need more effective and safer treatments, and these new drugs or new schemes should help us not only on reducing disease activity but also on reducing the number of flares which would lead to higher damage.
Conclusions Despite advances in the treatment of SLE patients, there is still a big gap between what lupus patients need or expect and what current treatment options offer. Furthermore, better treatment options are going to come from a better understanding of the disease pathogenesis and eventually its cause. For the time being, antimalarials must be used in every SLE patient unless
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Table 5 Potential drugs that can modulate T cells Target Co-stimulation blockade CD40–CD40L
CD80/86–CD28 ICOS–ICOSL
Agent
Status of development
IDEC-131 [67] BG9588 [68] CDP7657 [69] RG2077 [70] AMG557 [71–73]
Active SLE, phase II (completed) LN, phase II (completed) Active SLE, phase I (ongoing) Severe SLE, phases I–II (completed) Lupus arthritis phase I (ongoing); SCLE phase I (terminated); Active SLE, phase I (completed) Active SLE, phase I (terminated)
MEDI-570 [74] Cytokine blockade IL-6
IL-6R IL-21 IFN-γ IL-10 Kinase inhibition Syk inhibitor JAK inhibitor JNK inhibitor Other targets Quinolone-3-carboxamide derivatives
Sphingosine-1-phosphate targeting agents Immune-modulating peptides Integrin LFA-1 BCL-2 inhibitor
Sirukumab [75]
Active SLE and CLE, phase I (completed); LN, phase II (completed)
PF-04236921 [76] MRA 003 US [77] NNC0114-0006 [78] AMG 811 [79] B-N10 [80]
Active SLE, phase II (ongoing) Active SLE, phase I (completed) Active SLE, phase I (ongoing) DLE, phase I (ongoing); Active SLE, phase I (ongoing) Active SLE, pilot trial
R333 [81] Fostamatinib [82] GSK2586184 [83] CC-930 [84]
DLE, phase II (completed) Active SLE, phase II (withdrawn) Active SLE, phase II (ongoing) DLE, phase II (terminated)
Laquinimod [85]
Lupus arthritis, phase II (completed); LN, phase II (completed) Active SLE, phase II (completed) SCLE, phase II (terminated) SLE active, phase IIb (completed) DLE, phase II (terminated) Active SLE, phase I (ongoing)
Paquinimod [86] KRP203 [89] Lupuzor [91] Efalizumab [93] ABT-199 [94]
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 lowest possible dose and for the shortest time to control the activity of the disease. Immunosuppressive drugs should be used in order to reduce disease activity and GC dosing taking into account their safety profile. Biologics should be used in patients with refractory disease and only after a careful assessment of the clinical manifestations which are likely or not to respond to these drugs. We do hope that in the not too distant future our lupus patients could be treated with safer and more effective compounds than the ones we currently use. Even if costly, these treatments may be cost-effective in the long run, if damage can be prevented and health-related quality of life and survival improved. Working on this direction, the Accelerating Medicines Partnership is a new US program of the National Institute of Health, ten biopharmaceutical companies, the Lupus
Foundation of America, and several other nonprofit organizations aimed at sharing information to speed up the creation and approval of new drugs for patients suffering from Alzheimer’s disease, type 2 diabetes, and autoimmune diseases (rheumatoid arthritis and SLE) [98]. SLE was selected due to the lack of effective therapies for the most severe forms of the diseases, mainly lupus nephritis and neurological involvement. Finally, as further advances are made in the understanding of lupus and new therapies do emerge, it is desirable that such treatment opportunities are made available to all patients regardless of their ethnic/racial origin, country of residence, or socioeconomic status.
Disclosures None
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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 of the pathogenesis of systemic lupus erythematosus (SLE), there are only a few drugs approved by the regulatory agencies across the world for the treatment of these patients; in fact, many of the compounds subjected to clinical trials have failed in achieving their primary endpoints. Current therapeutic options include antimalarials which should be used in all SLE patients unless they are strongly contraindicated, glucocorticoids 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 severe organ involvements or receiving high doses of steroids to control their disease. Despite improvement on the survival of SLE patients, damage accrual has not varied over the last few decades, reflecting a gap between these therapeutic options and the expectations of these patients and their treating physicians. Biologic compounds can be used in some refractory cases. However, their cost is of great concern for both the patients and the health system. Cost is of special importance in low-income countries, because low-income SLE patients tend to experience a more severe disease having an overall worse prognosis which is compounded by their limited access to the M. F. Ugarte-Gil (*) Servicio de Reumatología, Hospital Nacional Guillermo Almenara Irigoyen, EsSalud, Lima, Perú e-mail: [email protected] M. F. Ugarte-Gil Universidad Científica del Sur, Lima, Perú G. S. Alarcón Department of Medicine, Division of Clinical Immunology and Rheumatology, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA G. S. Alarcón Department of Medicine, Universidad Peruana Cayetano Heredia, Lima, Perú
health system. Although a treatment to target based on defined molecular pathways for specific disease subsets is appealing, this is not yet a reality. This review addressed current therapeutic options for SLE patients and the state of the art of investigational drugs targeting pathogenic pathways identified in these patients. Keywords Systemic lupus erythematosus . Treatment
Introduction The discovery and introduction of glucocorticoids (GC) and subsequently of immunosuppressive drugs in the management of patients with systemic lupus erythematosus (SLE) has a significant impact in the course and outcome of this disease [1, 2]. Nevertheless, patients with SLE still experience a diminished life expectancy which, at least in part, is due to the irreversible damage caused not only by the disease itself but also by same medications that have contributed to improve these patients overall outcome. Prognosis in SLE is affected by several factors including genetic and nongenetic ones. Genetic factors are important, because they can lead to a more severe disease; for example, African and Amerindian ancestral genes seem to be associated with renal involvement [3], but these genes alone do not fully explain the differences in the outcome of the disease between Caucasian and not Caucasian patients; in fact, socioeconomic factors, such as poverty, lower levels of education, and lack of or inadequate health insurance, are associated with worse intermediate (disease activity, damage, and health-related quality of life) and long-term (mortality) outcomes [2, 4–6]. These data are important when different treatment strategies are considered; for example, even though mycophenolate mofetil seems to be more effective in Hispanic patients with lupus nephritis [7], it is also more expensive than
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cyclophosphamide, so Hispanic patients with inadequate health insurance may not benefit from this finding.
Current options Antimalarials are currently used and indicated in almost all SLE patients, due to the many beneficial effects associated with their use as reported over the years; reduction in mortality, damage, flares, cardiovascular morbidity, and infections may occur due to the multiple immunomodulatory and metabolic effects of these compounds [8]. Glucocorticoids are still the cornerstone in the treatment of SLE and are included in almost all therapeutic schemes due to their proven efficacy; however, they have been associated with several adverse events including cardiovascular events, diabetes mellitus, osteoporosis, osteonecrosis, infections, glaucoma, cataracts, psychological disorders, among several other deleterious effects [9]. Several immunosuppressive drugs have been used in SLE as steroid-sparing or to augment their effect when steroids alone have not been able to abate the manifestations associated with severe organ system involvement. For example, cyclophosphamide has been shown to be efficacious in patients with lupus nephritis and neurological involvement [10–12]. However, as cyclophosphamide has been associated with various adverse events, there has been several proposals for reducing the time and dose of this medication [13]. Mycophenolate mofetil has emerged as another option for the treatment of lupus nephritis, being at least as effective as cyclophosphamide for the induction phase [14, 15] and better than azathioprine for the maintenance phase [16]. Other therapeutic options for these patients are azathioprine [17, 18], methotrexate [19, 20], cyclosporine [21, 22], tacrolimus [23–25], and leflunomide [26–28]; however, all these immunosuppressive drugs are also associated with several adverse events like infections and malignancies [13]. The indications and main safety issues of these immunosuppressive drugs are described in Table 1. Despite these treatments, SLE patients still have a threefold increase in all-cause mortality compared to the general population [29]. Furthermore, despite adequate control of disease activity, early disease damage has not changed during the last 35 years [30]. Since medications contribute significantly to damage, there is a clamor among those caring for patients with lupus to count with medications which exhibit a better safetytoxicity profile. With advances in the understanding of the pathogenesis of lupus, a number of different biological products have been tried in these patients with variable success. In 2011, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) granted regulatory approval for belimumab, a fully human monoclonal antibody against B-
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lymphocyte stimulator (BLyS), a cytokine important for the 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) involvement. In a post hoc analysis, the domains that improved with belimumab were the musculoskeletal and the mucocutaneous, the ones more frequently involved in these patients [31]. There is not enough information to evaluate the impact of belimumab in patients with more severe disease. Furthermore, it is important to point out that more than 40 % of patients do not respond to this compound; in fact, the ones more likely to respond are those who are serologically active and exhibit high degree of disease activity [31]. Another biologic agent used in SLE is rituximab, a chimeric monoclonal antibody against CD20, which is a B lymphocyte restricted molecule that is expressed from pre-B to memory B cells. Although the randomized clinical trials (RCTs) of rituximab in SLE failed to prove this agent’s efficacy, rituximab seems to be effective in SLE patients with refractory disease [32–34]. This apparent conflicting information may at least be partly due to trial design, and in fact, these trials prompted the lupus community to reassess how trials in lupus should be conducted [35]. Abatacept, a fusion protein analog of cytotoxic Tlymphocyte antigen 4 (CTLA-4), which is made of the extracellular domain of CTLA-4 and a fragment of the Fc portion of human IgG1, also failed to achieve primary or secondary end points [36]; however, some exploratory analyses suggest that abatacept could be useful in some SLE patients [37]. The main indications of these biologic compounds are described in Table 2. Of significant importance is the cost associated with these new treatment options, which is of great concern to patients and private and governmental insurance agencies across the world. However, if these and other more “intelligent” or targeted treatments would cause less adverse short- and long-term consequences, their cost could be significantly offset.
Future options Given that the use of GC in lupus is clearly a main risk factor for damage, the possibility of using them at very low doses or not at all is gaining momentum. One such protocol, rituxilup, [38] for patients with lupus nephritis includes two doses of rituximab and methylprednisolone and mycophenolate mofetil, but not sustained oral GC. This trial conducted in a single center in Great Britain provided positive results, but the multicenter RCT to definitively address this option is still ongoing. There are several other potential targets for the treatment of SLE which are currently being investigated. They may target the innate immunity as is the case with type I interferons (IFN)
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Table 1 Nonbiologic immunosuppressive drugs currently used in SLE patients Drugs
Main indication
Other indications
Comment
Cyclophosphamide [10–12] MMF [14–16]
LN, CNS lupus LN (induction and maintenance therapy) LN (maintenance therapy)
Other severe clinical manifestations Hematological, dermatological and articular involvement GC sparing in patient with active SLE (without CNS and severe lupus nephritis) GC sparing
May induce premature ovarian failure Seems to be more effective than CYC in Hispanic patients with LN May induce hepatotoxicity
Azathioprine [17, 18]
Methotrexate [19, 20]
Cyclosporine [21, 22] Tacrolimus [23–25] Leflunomide [26–28]
Moderately active disease (musculoskeletal and dermatological involvement) Refractory LN Refractory LN (induction and maintenance therapy) Mild-to-moderate disease
SLE refractory to GC
Refractory LN
May induce hepatotoxicity
May induce nephrotoxicity Could be used in addition to MMF Mainly used in Asian population 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 drugs can be monoclonal antibodies against IFNα, such as sifalimumab, with a good tolerability in a phase I study [39]; phase II studies are still ongoing. Rontalizumab failed to achieve primary and secondary endpoints in phase II studies; however, it seems to be useful in a subset of patients [40]. AGS-009 has also completed its phase I study [41]. MEDI546, a monoclonal antibody against INFα receptor has phase II studies ongoing [42]. IFNα inhibition can also be achieved via a kinoid; this IFNα kinoid has promising results in its phase I study [43]. Another possible target is tumor necrosis factor α (TNFα); however, a trial of etanercept for patients with lupus nephritis was not continued due to safety issues [44], and a trial of infliximab failed to recruit patients [45]. Other possible signals that can act as therapeutic targets in lupus are the monocyte colony-stimulating factor (M-CSF) [46], the anti-macrophage inhibitory factor (anti-MIF) [47], the C5a receptor (C5aR) [48], the TNF-related weak inducer of apoptosis (TWEAK) [49], and CD74 [50]; all of them are currently in early phases of research. A phosphodiesterase type 4 inhibitor, apremilast, has also been used in discoid lupus in
an open label pilot study. This drug blocks the production of IL-12, IL-23, TNF-α, and IFN-γ, reducing Th1 and Th17 response [51]. Chaperonin 10 or heat shock protein 10 can modulate the innate and adaptive immune responses and is being evaluated in subjects with active SLE [52]. Innate immunity-targeted treatments are summarized in Table 3. Among molecules targeting the adaptive immunity, there are therapies directed to B cells including cell surfaces markers like CD20. In addition to rituximab, other drugs have been evaluated with variable success. For example, a phase III study of ocrelizumab [53] was terminated early due to a safety issue (increased frequency of serious infections), TRU-015 [54] and SBI-087 [55] are other anti-CD20 drugs under evaluation. Epratuzumab, an anti-CD22 drug, seemed to be effective in its phase II study [56], however, the initial phase III studies had to be terminated because of interruption of the drug’s supply [57], but new phase III studies are now being conducted. Another therapeutic option is the BLyS pathway; besides belimumab, tabalumab [58], and blisibimod [59] are BLyS inhibitors that are being evaluated. Atacicept, a BLyS and APRIL inhibitor, has been evaluated in SLE patients;
Table 2 Biologic immunosuppressive compounds currently used in SLE patients Drug
Main indication
Comment
Belimumab [31] Rituximab [32–34]
Active SLE (without LN or CNS involvement) Moderate-to-severe SLE, LN, CNS involvement.
Abatacept [36, 37]
LN, articular involvement
More effective in serologically active patients RCT failed to achieve their primary end points. Data of efficacy is based on observational studies. 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
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Table 3 Potential drugs that can modulate the innate immunity Target IFN-α production and signaling IFN-α
IFN-α R IFN-α kinoid vaccine Inhibition of TNF-α signaling TNFα soluble receptor TNFα mononuclear antibodies Other signals M-CSF MIF C5aR TWEAK MHC-II CD74 Other targets PDE-4 inhibitor CPN-10
Agent
Status of development
Sifalimumab [39] Rontalizumab [40] AGS-009 [41] MEDI-546 [42] IFN-α kinoid [43]
Active SLE, phase IIb (completed and ongoing) Active SLE, phase II (completed) Active SLE, phase I (completed) SLE active, phase II (ongoing) Active SLE, phases I–II (completed)
Etanercept [44] Infliximab [45]
LN, phase II (terminated); DLE, phase II (unknown) Type V LN, phases II–III (terminated)
PD-0360324 [46] Anti-MIF [47] NNC 0151-0000-0000 [48] BIIB023 [49] Milatuzumab [50]
CLE, phase I (terminated) LN, phase I (terminated) Active SLE, phase I (terminated) LN, phase II (ongoing) Active SLE, phases I–II (not yet open for enrollment)
Apremilast [51]
CLE, phases I–II (completed)
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 prematurely terminated due to safety issues [60]; however, on further examination, it was felt that the increased number of infections observed in this trial were due to the background medication and thus this compound is still under study on active SLE patients [61]. Plasma-cell depletion can be achieved with a n onselective proteasome inhibitor like bortezomib; this drug can induce apoptosis of immune cells by several pathways [62] and is now being tested in lupus nephritis [63]. Induction of B cell tolerance, with abetimus [64] or edratide [65], have also been studied, but these trials failed to achieve their endpoints. Omalizumab, a monoclonal antibody against IgE, is also being evaluated in SLE patients [66]. Potential drugs that can modulate B cells are shown in Table 4. There are several compounds targeting T cells including co-estimulation blockade with CD40-L-targeted agents like IDEC-131 [67] and BG9588 [68]; the first failed to achieve its endpoints and the second was suspended due to safety issues (thromboembolic events). CDP7657, another agent against CD40L is also being evaluated in active SLE patients [69]. In addition to abatacept, RG2077, another CTLA-4 agonist, has been evaluated in patients with active SLE [70]. ICOSICOSL blockade by AMG557 is being evaluated in SLE patients with arthritis, subacute cutaneous lupus, and active SLE [71–73]. A trial of MEDI-570, another ICOS–
ICOSL-targeted agent, was terminated by the sponsor for unclear reasons [74]. Cytokine blockade is being evaluated by monoclonal antibodies against IL-6 (e.g., sirukumab [75] and PF-04236921 [76]), IL-6 receptor (MRA 003 US [77]), IL-21 (NNC0114-0006 [78]), and IFN-γ (AMG 811) [79], but these compounds are all in early phases of development (phases I–II studies). IL-10 blockage was evaluated in SLE patients over a decade ago; although there was a decrease in the SLEDAI, only six patients were included in this open labeled trial [80], but there has not been recent trials. Kinase inhibitors include syk inhibitors, such as R333 [81], which is being evaluated in cutaneous SLE patients, and fostamatinib, in which a business decision by the sponsor led to the early termination of the trial [82], and JAK inhibitors like GSK2586184 which is still under evaluation in SLE patients [83]. The benefit / risk profile of JNK inhibitor CC930 does not support continuing its study in patients with discoid lupus [84]. Other T cell-targeting therapies are quinolone-3carboxamide derivatives, immunomodulatory agents that might reduce the expression of MHC-II, adhesion molecules, and chemokines; in this group of compounds, we have laquinimod [85] and paquinimod [86]. Sphingosine-1-phosphate (S1P) analogs exert several functions on immune cells [87] including the expansion and activation of Treg cells [88]. KRP203, an S1P analog, has been used in subacute cutaneous lupus
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445
Table 4 Potential drugs that can modulate B cells Target B cell depletion AntiCD20
AntiCD22 Inhibition of B cell activation BLyS inhibitor BLyS and APRIL inhibitor Plasma cell depletion Nonselective proteasome inhibitors Induction of B cell tolerance Inhibitor of anti-DNAds antibodies Tolerogenic peptide IgE Mononuclear antibodies against IgE
Agent
Status of development
Ocrelizumab [53] TRU-015 [54] SBI-087 [55] Epratuzumab [56, 57]
LN, phase III (ongoing); Active SLE, phase III (terminated) Type V LN, phase I (terminated) Active SLE, phase I (completed) Active SLE, phase II and III (completed and terminated); Active SLE, phase III (ongoing)
Tabalumab [58] Blisibimod [59] Atacicept [60, 61]
Active SLE, phase III (ongoing) Active SLE, phase III (completed, ongoing) LN, phases II–III (terminated); Active SLE, phase II (completed and ongoing)
Bortezomib [63]
LN, phase IV (withdrawn)
Abetimus [64] Edratide [65]
LN, phase III (completed) Active SLE, phase II (terminated)
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 nuclear ribonucleoprotein 70 kDa phosphorylated at Ser140, has tolerogenic and immunomodulatory properties, preventing CD4+ T cells proliferation, but not the secretion of regulatory cytokines [90, 91]. Efalizumab, a monoclonal antibody against CD11a (α subunit of lymphocyte function-associated antigen 1), has been used in patients with discoid lupus erythematosus [92], and it is being evaluated in patients with active SLE [93]. BCL-2 inhibitor (ABT-199) can induce apoptosis of T- and Bcells, it has been used in hematologic neoplasms, and phase I study in SLE patients has been started [94]. T cell-targeted therapies are presented in Table 5. Despite the impressive number of new molecules targeting different cells and pathways in the immune system, it should be pointed out that the conduct of RCTs in SLE face tremendous difficulties related not only to the lack of a uniform definition of response but also to the heterogeneity of the disease with different clinical subsets, possibly representing 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 criteria like we do nowadays, patients should be identified based on which molecular pathway or pathways may be affected and consequently use the proper treatment which could alter them. Finally, the availability of eligible and willing patients to participate in these trials across different nations and continents is a consideration that cannot be dismissed.
Unmet needs Almost 30 % of SLE patients achieve disease quiescence (defined according to physician global assessments) during the first year of their disease; however, almost 50 % of them present flares in the subsequent years [95]. When a more strict definition of remission is used (SLEDAI 0, without concomitant GC and immunosuppressive drug use), only 6.5 % of the patients achieve remission at 1 year and not quite 2 % achieve long-term remission [96]. Furthermore, almost 50 % of the patients accrue at least one point in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index over 5 years [97]. These data suggest that we need more effective and safer treatments, and these new drugs or new schemes should help us not only on reducing disease activity but also on reducing the number of flares which would lead to higher damage.
Conclusions Despite advances in the treatment of SLE patients, there is still a big gap between what lupus patients need or expect and what current treatment options offer. Furthermore, better treatment options are going to come from a better understanding of the disease pathogenesis and eventually its cause. For the time being, antimalarials must be used in every SLE patient unless
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Table 5 Potential drugs that can modulate T cells Target Co-stimulation blockade CD40–CD40L
CD80/86–CD28 ICOS–ICOSL
Agent
Status of development
IDEC-131 [67] BG9588 [68] CDP7657 [69] RG2077 [70] AMG557 [71–73]
Active SLE, phase II (completed) LN, phase II (completed) Active SLE, phase I (ongoing) Severe SLE, phases I–II (completed) Lupus arthritis phase I (ongoing); SCLE phase I (terminated); Active SLE, phase I (completed) Active SLE, phase I (terminated)
MEDI-570 [74] Cytokine blockade IL-6
IL-6R IL-21 IFN-γ IL-10 Kinase inhibition Syk inhibitor JAK inhibitor JNK inhibitor Other targets Quinolone-3-carboxamide derivatives
Sphingosine-1-phosphate targeting agents Immune-modulating peptides Integrin LFA-1 BCL-2 inhibitor
Sirukumab [75]
Active SLE and CLE, phase I (completed); LN, phase II (completed)
PF-04236921 [76] MRA 003 US [77] NNC0114-0006 [78] AMG 811 [79] B-N10 [80]
Active SLE, phase II (ongoing) Active SLE, phase I (completed) Active SLE, phase I (ongoing) DLE, phase I (ongoing); Active SLE, phase I (ongoing) Active SLE, pilot trial
R333 [81] Fostamatinib [82] GSK2586184 [83] CC-930 [84]
DLE, phase II (completed) Active SLE, phase II (withdrawn) Active SLE, phase II (ongoing) DLE, phase II (terminated)
Laquinimod [85]
Lupus arthritis, phase II (completed); LN, phase II (completed) Active SLE, phase II (completed) SCLE, phase II (terminated) SLE active, phase IIb (completed) DLE, phase II (terminated) Active SLE, phase I (ongoing)
Paquinimod [86] KRP203 [89] Lupuzor [91] Efalizumab [93] ABT-199 [94]
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 lowest possible dose and for the shortest time to control the activity of the disease. Immunosuppressive drugs should be used in order to reduce disease activity and GC dosing taking into account their safety profile. Biologics should be used in patients with refractory disease and only after a careful assessment of the clinical manifestations which are likely or not to respond to these drugs. We do hope that in the not too distant future our lupus patients could be treated with safer and more effective compounds than the ones we currently use. Even if costly, these treatments may be cost-effective in the long run, if damage can be prevented and health-related quality of life and survival improved. Working on this direction, the Accelerating Medicines Partnership is a new US program of the National Institute of Health, ten biopharmaceutical companies, the Lupus
Foundation of America, and several other nonprofit organizations aimed at sharing information to speed up the creation and approval of new drugs for patients suffering from Alzheimer’s disease, type 2 diabetes, and autoimmune diseases (rheumatoid arthritis and SLE) [98]. SLE was selected due to the lack of effective therapies for the most severe forms of the diseases, mainly lupus nephritis and neurological involvement. Finally, as further advances are made in the understanding of lupus and new therapies do emerge, it is desirable that such treatment opportunities are made available to all patients regardless of their ethnic/racial origin, country of residence, or socioeconomic status.
Disclosures None
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