Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder that predominantly affects women of child-bearing age with a ~9:1 female-to-male ratio. Patients with SLE suffer an impaired health-related quality of life (HRQoL), and experience fatigue and pain as major problems.
The pathogenesis of SLE is multifactorial and its aetiology is largely unknown.1 Genes, hormones and environmental factors have been implicated among the causes of the disease. Multiple organs may be involved, including the skin, joints, kidneys and the central nervous system, with renal and neuropsychiatric SLE probably constituting the most severe manifestations. Considerable variations in severity can be observed during the course of the disease, with periods of remission and flares, the intensity of the latter ranging from mild to severe, to sometimes organ- or life-threatening. Mortality during the early course of the disease is associated with activity grade and infections, but comorbidities, especially cardiovascular disease, are considerable causes of death at later stages.2
In SLE, both the innate and the adaptive immunity may be aberrant, and defective apoptotic cell clearance is hypothesised to be a central phenomenon underlying the initiation of autoreactive responses. The type I interferon pathway has a central role in the pathogenesis of SLE,3 and the hyperactivity of the B cell lineage also has pivotal significance. The disease is characterised by a prominent production of autoantibodies to nuclear components and immune complex depositions, resulting in inflammation and damage in organs and/or tissues. There is now a better understanding of autoimmunity in SLE, which has led to improved therapeutic strategies, but revolutionary treatments have yet to be discovered.
Management of SLE
The management of SLE and the development of new therapies have been challenging because of the prominent heterogeneity of the disease in clinical presentation and underlying immunopathology, as well as its unpredictable course. For these reasons, the treatment of SLE varies and is highly individualised. Commonly used therapies include corticosteroids, antimalarial agents, immunosuppressive agents and non-steroidal anti-inflammatory drugs (NSAIDs).4,5 Several immune components have been identified as potential targets of novel treatments. Unfortunately, the majority of trials have failed. In 2011, drug agencies in several countries approved belimumab, an anti-BAFF (B cell-activating factor belonging to the TNF family) monoclonal antibody, for the treatment of SLE.6,7 The introduction of belimumab has contributed to improved management; however, it is still unclear which patient groups are expected to benefit most from this drug. Considering the cost and potential toxicity of biologic therapies, further survey towards identification of predictors of treatment response is of utmost importance.
Therapeutic strategies in SLE
The management of SLE has traditionally been non-specific, with symptomatic therapeutic approaches. As mentioned above, the reasons for this can be traced to: (i) the lack of therapies targeting specific immune components, with the possible exceptions of belimumab, rituximab and cyclosporine; and (ii), the wide spectrum of clinical manifestations. The treatment strategies are therefore individual, depending on the organ involvement, the severity of the disease and the complications. Non-major organ involvement may be treated with for example, glucocorticoids, antimalarial agents, and NSAIDs. In more severe or non-responsive cases, azathioprine, mycophenolate mofetil and methotrexate are commonly used. Despite their widespread use, not all of these drugs have been approved for SLE.
The use of antimalarial agents in SLE is coupled to a wide variety of beneficial effects, making this drug class the cornerstone of SLE therapy.8,9 The modulatory effects of antimalarial agents on immune responses are mediated by several mechanisms, for example, through interference with antigen processing. The use of antimalarial agents in SLE has been associated with remission maintenance effects,8 as well as prevention of flares and decreased corticosteroid use during pregnancy.10 Hydroxychloroquine
has been shown to improve renal prognosis in patients with lupus nephritis.11 Based on their atheroprotective effects, antimalarial agents are expected to be beneficial in SLE patients at high risk for thrombotic events; for example, patients with the antiphospholipid syndrome or high titres of antiphospholipid antibodies. It is recommended that all SLE patients receive adequate doses of antimalarial agents unless it is contraindicated due to, for example, retinopathy.
Glucocorticoids have rapid and powerful anti-inflammatory and immunosuppressive effects,12 and are used for most SLE manifestations, from mild cutaneous disease to life-threatening conditions, often in combination with other drugs. Pulse methylprednisolone therapy is commonly used during severe exacerbations to induce remission, followed by high doses of oral corticosteroids with a gradual taper. Low-dose oral corticosteroids are used in the vast majority of SLE patients as a long-term remission maintenance therapy. Fortunately, the glucocorticoid-induced harm has received increasing recognition in recent years.
Apart from complications, recent indications of harmful effects of glucocorticoids on SLE itself have contributed to a scepticism towards the acceptance of long-term use, and a need for a paradigm shift has emerged.13
Moderate to severe flares in major organs are usually managed with an initial induction therapy using methylprednisolone, cyclophosphamide, mycophenolate mofetil, or combinations thereof.14–16 In lupus nephritis, the low-dose regimen proposed in the Euro-Lupus Nephritis Trial17 is the most commonly used cyclophosphamide regimen, and comprises six pulses of 0.5g cyclophosphamide, one every second week for a total of three months, followed by maintenance therapy with azathioprine. Together with mycophenolate mofetil, this regimen has replaced the initial high dose NIH cyclophosphamide protocol,18–20 mainly because of severe infections and toxicity concerns, for example, associations with premature gonadal failure.21 In patients with nephritis who have not responded to this management, the anti-CD20 monoclonal antibody rituximab may be an alternative.22
Calcineurin inhibitors have received growing attention as potential therapeutic agents in SLE, especially in lupus nephritis.23 Low doses of tacrolimus are effective and well tolerated in patients with renal SLE who have failed treatment with cyclophosphamide,24 and an open-label prospective study showed non-inferiority of tacrolimus as an induction therapy of active biopsy-proven nephritis compared with mycophenolate mofetil and cyclophosphamide.25 Later, a meta-analysis of nine studies demonstrated that tacrolimus was superior to cyclophosphamide but not to mycophenolate mofetil in inducing complete renal remission in lupus nephritis.26 Results from recent studies of voclosporine are awaited.
In recent years, more targeted therapies have been investigated, and biological agents have been used either following approval or as off-label therapies. Future strategies that may prove promising include small molecules modifying intracellular signal pathways, for example, through targeting Lyn, Syk, PI3Ks and Btk. The proteasome inhibitor bortezomib, approved for the treatment of multiple myeloma, was recently shown to improve the disease activity and reduce the numbers of peripheral blood and bone marrow plasma cells in twelve refractory SLE patients.27
Lupuzor, also known as P140 peptide and IPP-201101, is a 21-mer linear peptide originating from the small nuclear ribonucleoprotein U1-70K, phosphorylated at the Ser140 position. The mechanism of action of lupuzor is not fully elucidated, but studies in lupus-prone mice have shown promising immunomodulatory effects,28–33 and a Phase IIb trial evaluating 149 SLE patients documented greater response rates in patients receiving lupuzor than in patients receiving placebo.34
Biologics in SLE
Biologic agents have been the focus of research towards the development of modern therapies. Due to its important role in B cell homeostasis, BAFF has been of central interest as a target molecule. Belimumab is the first drug to be licensed for use in SLE in more than 50 years, and the first biologic agent approved for the disease.
The efficacy of belimumab in reducing SLE activity has been shown in Phase III randomised placebo-controlled clinical trials.35,36 Belimumab is a recombinant human IgG1-λ monoclonal antibody that specifically binds to the soluble BAFF fragment, and prevents the binding of BAFF to its receptors on the surface of B cells. Normally, the binding of BAFF to B cells prolongs their survival and promotes their maturation and differentiation towards immunoglobulin production.37 BAFF signalling also leads to increases in anti-apoptotic proteins. As defective clearance of apoptotic cells is implicated in the pathogenesis of SLE and the stimulation of autoantibody production, the reductions in anti-apoptotic proteins as a result of BAFF inhibition is expected to hamper this B cell-driven component in the pathogenesis of the disease.
Rituximab is a chimeric anti-CD20 monoclonal antibody, widely used for the treatment of non-Hodgkin lymphoma, rheumatoid arthritis, vasculitis and other autoimmune diseases, and also as an off-label therapy in refractory SLE, mostly for therapy-resistant lupus nephritis.38,39
Several centres have reported uncontrolled experiences with rituximab for the treatment of severe and refractory SLE, including cohorts of lupus nephritis.22,40–50 Studies of refractory renal SLE treated with rituximab combined with cyclophosphamide reported beneficial effects on various outcomes.22,41,42,51–53 However, randomised controlled trials of rituximab treatment in patients with SLE failed to show efficacy.54,55 Despite the negative results of the clinical trials, rituximab has been included in European and American recommendations for the management of renal SLE.56,57 Apart from refractory renal SLE, the use of rituximab has also been documented in other organ manifestations, such as severe arthritis, haematological abnormalities, and neuropsychiatric SLE when conventional treatments have failed.38,58–60
Atacicept, another biologic agent, which blocks the effects of both BAFF and its homologous molecule APRIL (a proliferation-inducing ligand),61 has also been studied as a candidate drug for SLE. A clinical trial of atacicept in lupus nephritis was terminated prematurely, due to adverse events, that is, hypogammaglobulinaemia and infections.62 Blisibimod is a fusion protein consisting of four high-affinity BAFF-binding domains and the Fc domain of human IgG1, targeting both soluble and membrane-bound BAFF. A dose-ranging Phase IIb clinical trial of blisibimob63 determined a safe and effective dose to further be studied in a Phase III trial, which unfortunately was not successful.
Only one of the two Phase III trials of tabalumab, a fully human monoclonal antibody targeting soluble and membrane-bound BAFF, met its primary endpoint,64,65 being the reason why no further development of the drug was planned for SLE. However, no dose-ranging Phase II studies had preceded the Phase III trials, and several outcomes in both trials justify the rationale of targeting BAFF in SLE.66,67
Phase II68 and Phase IIb69 clinical trials of epratuzumab, a humanised monoclonal antibody against CD22, demonstrated favourable effects on SLE disease activity, prompting the initiation of two Phase III trials, which unfortunately failed to meet their primary clinical efficacy endpoints.70 Experimental inhibition of IL-6 in murine lupus impedes autoreactive B cell activity and ameliorate nephritis features,71,72 but a proof-of-concept study of the human anti-IL-6 monoclonal antibody sirukumab failed to demonstrate superiority of the drug to placebo in patients with active nephritis.73 A Phase I trial of the IL-6 receptor antagonist tocilizumab showed improved SLE disease activity and decreased autoantibody production, but the observed dose-related decreases in absolute neutrophil counts raised concerns.74
The importance of the type I IFN pathway in the pathogenesis of SLE has prompted the investigation of anti-IFN antibodies as potential drugs.75 The first data supporting the efficacy of IFN-α inhibition came from a Phase IIb trial of sifalimumab;76 the results were modest but in favour of sifalimumab. However, another phase II study of the monoclonal anti-IFN-α antibody rontalizumab demonstrated superiority to placebo in patients with low IFN-regulated gene expression, but not in patients with high IFN gene signature,77 contrary to what was expected considering the biologic mechanism of the drug. A Phase II trial of the type I IFN receptor antagonist anifrolumab has been successful, meriting further development of this agent. Anifrolumab was more efficacious than placebo, especially in patients with a high IFN gene signature; however, no dose response was displayed.78 Results from ongoing trials, including a trial in lupus nephritis, are awaited.
Abatacept, a soluble fusion protein comprising the extracellular domain of the human cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and a fragment of the Fc portion of human IgG1, has also been investigated as a potential treatment for SLE. T cell activation relies on co-stimulatory interactions. The interaction of CD80/86 on antigen-presenting cells with CD28 on T cells is one of the most important co-stimulatory pathways. The CLTA-4 molecule is homologous to CD28, but binds to CD80 and CD86 with higher affinity, resulting in competitive inhibition of the binding of CD28 to CD80/CD86. Abatacept is approved for use in rheumatoid arthritis and has also been studied in other autoimmune diseases.
Two randomised clinical trials in SLE patients have been conducted. Patients with a current mucocutaneous, musculoskeletal or serositis flare were included in the first trial;79 unfortunately, abatacept did not prove more efficient than placebo. Later discussions raised the concern whether the choice of the primary endpoint in this trial concealed the inferiority of abatacept to placebo.80 The second trial of abatacept in SLE was a Phase II/III trial comprising 298 patients with active biopsy-proven proliferative lupus nephritis.81 The patients were randomised to receive abatacept or placebo in addition to glucocorticoids and mycophenolate mofetil. The time to attain complete response did not differ between the treatment arms, but greater improvements were seen in favour of abatacept regarding serologic markers and proteinuria. Later, a reanalysis with different definitions of renal response unveiled inferiority of abatacept to placebo,82 highlighting that the choice of outcomes in clinical trials might be determinant of their success.
Conclusions
The heterogeneity of SLE makes the design of clinical trials and the choice of adequate outcome measures challenging. Moreover, sufficient numbers of SLE patients in clinical trials can only be guaranteed by joint efforts, for example, within the frame of international multicentre collaborations. For these reasons, it is not surprising that drug development in SLE has not been as expeditious as in more common and less heterogeneous rheumatic diseases, such as rheumatoid arthritis.
Towards optimisation of the management of SLE, it is important that research focuses on: (i) a better understanding of autoimmunity underlying clinical phenotypes in order to identify adequate drug targets; (ii) in depth investigation of the effects of currently available therapies in order to improve their use; and (iii) better trial designs, including the choice of coherent outcome measures. In order to achieve these goals, it is important to remain receptive to new classification concepts. For example, studying new drugs in patients showing specific clinical patterns rather than in SLE at large might conceivably result in more homogeneous study populations. Another example might be stratification of SLE patients into subsets based on distinct immunological profiles such as interferon signature genes or autoantibody expression patterns.
Last, but not least, the patients’ perspective should be taken into consideration when studying drug effects. Self-perceptions of HRQoL, fatigue, pain and functional disability should be an integral part of the clinical assessment. A new drug cannot be considered effective if it does not significantly improve the patients’ HRQoL.
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