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 Table of Contents  
Year : 2017  |  Volume : 12  |  Issue : 1  |  Page : 48-51

New treatments for systemic lupus erythematosus

Department of Medicine, Newark Beth Israel Medical Center, Rutgers, The NJ Medical School, Newark, New Jersey, USA

Date of Web Publication23-Feb-2017

Correspondence Address:
Robert George Lahita
Rutgers, New Jersey Medical School, Newark, New Jersey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_1_17

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New therapies for systemic lupus erythematosus are rare. This is because of the complexity of the disease and its varied presentations. There are many variables and a variety of measurement scales that must be satisfied before a new agent is approved for use in humans. Attempts are ongoing to develop biological treatments for the disease using three approaches: B cell modulation, T cell regulation and cytokine inhibition. This paper reviews the current state of these three critical areas.

Keywords: B cells, cytokine manipulation, lupus treatments, T cells

How to cite this article:
Lahita RG. New treatments for systemic lupus erythematosus. Indian J Rheumatol 2017;12:48-51

How to cite this URL:
Lahita RG. New treatments for systemic lupus erythematosus. Indian J Rheumatol [serial online] 2017 [cited 2023 Feb 5];12:48-51. Available from:

The morbidity and mortality in systemic lupus erythematosus (SLE) continues to be poor. The consistent uses of standard therapies such as corticosteroids and immunomodulators such as hydroxychloroquine, Imuran, cyclophosphamide, and mycophenolic acid have raised 10-year survival of this disease to >90%.[1] However, despite the use of these agents early, the morbidity of the disease in concert with the adverse effects of the available therapeutic agents is substantial. An example would be the use of prednisone where the side effects are daunting: Osteoporosis, avascular necrosis, and a 5 times greater increase of cardiac events than that seen with the general population. To obviate the adverse effects of many of these agents, there is emphasis on the development of targeted biologicals to treat SLE. To date, only one of these agents is approved for use in lupus; belimumab.[2],[3]

Every arm of the immune system is a possible target for therapeutic development in this disease; they include B-cells and T-cells, interferon (IFN), and cytokines. Both the innate and the adaptive immune systems are targets.

In the adaptive immune system, B-cells have captured the imagination of researchers. Clinical trials using rituximab, which targets CD20, resulted in an insignificant response to renal disease SLE [4] in both the Lupus Nephritis Assessment with Rituximab (LUNAR) Phase II and III and the Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trials.[5],[6] Uncontrolled studies suggests that rituximab might have steroid-sparing effects in the treatment of lupus patients. In the “EXPLORER” trial, using British Isles Lupus Assessment Group (BILAG) scores for the measurement of clinical activity in 257 British patients, the primary endpoints of this trial were not met; there was no difference between the placebo and treatment groups after 12 months. A pitfall could have been the use of daily oral prednisone based on BILAG scores which could have confounded the data.[5] The LUNAR trial looked at renal response, and again, there was no response between the placebo and drug groups.[6] However, again, steroids were used in the renal trial. Both of these trials highlight the difficulties of studying drugs in lupus patients.[7]

Ocrelizumab and epratuzumab are both anti-CD20 and anti-CD22 targeting therapies, respectively, and epratuzumab in the EMBODY I and II trial (Phase 3) showed no difference in disease improvement between drug and placebo.[8],[9],[10] Belimumab is approved by the US Food and Drug Administration as an agent directed to soluble B-lymphocyte-stimulating (BLYS) factor also known as B-cell activating factor (BAFF).[11],[12] Despite widespread use in nonrenal and noncentral nervous system, patients' results have been disappointing because there is an uneven response to the drug.[3],[12] An effort is underway to develop antisoluble and receptor bound BLYS soon. Tabalumab (an IgG4 monoclonal) neutralizes bound BAFF and the results so far have been modest.[13],[14] Blisibimod is a human peptibody, which also targets BAFF, and data on the effects of this agent are pending.[15] See [Table 1].[16]
Table 1: B-cell[16]

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Because B-lymphocyte therapy is less successful for all patients with active SLE, T-cell therapies, anti-IFN, and cytokines seemed logical directions to pursue. T-cells enhance autoantibody production and promote B-cell differentiation, proliferation, and maturation. They also support class switching of antibodies. For those reasons, anti-CD40 ligand therapies were attempted to affect T-cell function in lupus patients; a strategy that could work. There were two major agents developed by two companies: BG9588, a humanized anti-CD40 L monoclonal,[17] and IDEC-131,[18] an anti-CD40 L molecule. Some of the data for the agents were promising because BG9588 showed a 50% reduction of proteinuria in two patients without worsening renal function. The drug inhibited both T-cell activation and T-cell-dependent B-cell activation. However, there were safety issues with BG9588 that was thromboembolic in nature. The other drug IDEC-131 showed no significant change in the SLEDAI-SELENA score for the treatment cohort. Another agent dapirolizumab pegol, an anti-CD40 L Fab fragment, showed good scores for the SLE responder index (SRI) and the BILAG assessment and results are also pending.

Another agent used in SLE is the co-stimulatory inhibitor abatacept normally of use in rheumatoid arthritis (RA), which is now being considered for the use in SLE.[19] CD28 with CD80/86 on B-cells is a second signal for T-cells, and three clinical trials showed some efficacy for abatacept in nonlife-threatening SLE. In one study of SLE nephritis, there were no significant differences between treatment arms. A Euro-lupus regimen that includes abatacept, high-dose oral prednisone, and IV cyclophosphamide in biopsy proven Grade III and IV glomerulonephritis did not achieve significance [Table 2].[20]
Table 2: New therapies for systemic lupus erythematosus T-cell[20]

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T-cell proliferation has a role in the control of SLE because tacrolimus/mycophenolate mofetil (MMF) showed higher rates of remission at 24 weeks, which was better than those on cyclophosphamide treatment.

T-reg cells are suppressive to autoreactive T-cells. T-reg survival and function depend on interleukin (IL-2). Lack of IL-2 results in suppression of activation-induced cell death and increased longevity of autoreactive T-cells in patients with SLE. IL-2 is necessary for T-cell activation and proliferation and the use of IL-2 inhibitors to subvert the continued presence of autoreactive T-cells seemed like a good plan of therapy.[21],[22] In fact, an open-label trial using this cytokine showed reduction in SELENA-SLEDAI score from a baseline value of 11 to 4 at week 12 and an 89.5% SRI response.

Another useful agent is leflunomide [23] which inhibits pyrimidine synthesis in T-cells and widely used in RA patients. When it is used with prednisone, it is as effective as cyclophosphamide in controlling SLE flares. MMF inhibits inosine monophosphate dehydrogenase for the synthesis of guanosine nucleotides. In certain ethnic groups like the African-American, this agent is better than cyclophosphamide.

A very viable target in SLE is IFN-alpha [24] and several IFN inhibitors have shown promise. Anifrolumab [25] is an anti-IFN-alpha receptor monoclonal antibody. Use of this antibody met its primary endpoints after 12 months of therapy (34–54.6 drug vs. 17% for placebo). As an integral part of the innate immune system, the downregulation of IFN-alpha may have great potential as a means of therapy.[26],[27],[28],[29] IFN-alpha or type 1 can break tolerance by activating antigen-presenting cells. Toll-like receptors 7 and 9 on B-cells and plasma dendritic cells (pDC) recognize self-nucleic acids and help produce tremendous amounts of IFN signature. Hydroxychloroquine and high-dose steroids (30 mg/kg/day for several days) have therapeutic effects by inhibiting pDC production of IFN. Realizing the potential of using IFN inhibitors, a variety of newer agents have been developed against INF: Rontalizumab (anti-IFN IgG1) which did not meet its primary endpoint and sifalimumab (IgG1 kappa) which also failed to meet its primary endpoint. However, anifrolumab (IgG1 kappa) studied in patients without lupus nephritis seemed to show some promise and has gone on to Phase III clinical studies.[25] See [Table 3].[30]
Table 3: Anticytokine[30]

Click here to view

Immunomodulatory peptides are of potential importance with regard to control of SLE.[31] The first of these is edratide which downregulates autoreactive T-cell responses to peripheral blood monocytes in SLE. Unfortunately, there seems to be no response in humans in contradistinction to data from mice. Another agent a P140 peptide known as rigerimod shows a good therapeutic response in human studies. Another agent laquinimod [32] showed promise by improving renal function when used in conjunction with MMF. Rapamycin or mammalian target of rapamycin (M-TOR) is a kinase [33] which regulates transmembrane potentials in patients with SLE and it and N-acetyl cysteine inhibits M-TOR in mice and works by enhancing apoptosis of autoreactive B-cells. We shall have to wait for more data before making claims of success in lupus.

Finding an appropriate therapy for a complex disease like Systemic Lupus Erythematosus is difficult. At issue is the nature of lupus itself, which is a disease of unyielding complexity involving more than the immune system and of course the complexities of the immune system itself with its many cytokines and effecctve cell populations and autoantiobdies. The disease presents in many ways and involves many organ systems, not just the immune system. It was once believed that SLE is more than one disease, depending on the organs involved. A clinical researcher tries to quantify changes of the clinical activity in the context of a stochastic immune system in the face of other immunomodulators. These all highlight the fact that the etiology of SLE, which remains to be fully elucidated, is perhaps the biggest stumbling block in the new drug development for SLE.

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Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3]

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