A phase 2 clinical trial investigating the treatment of systemic lupus erythematosus (SLE) with ustekinumab has demonstrated a significant reduction in severe flares in SLE patients with active disease.1,2 The reduction of flares was sustained over a year. Concurrent biomarker analyses of the same data reconfirmed the positive outcome of ustekinumab in SLE.3 The data were presented at the 2019 Annual European Congress of Rheumatology (EULAR 2019) held in Madrid, Spain from 12th to 19th June 2019.
Pathogenesis of SLE
SLE is a disease of immune dysregulation characterized by variable clinical manifestations that can affect many organ systems resulting in progressive organ damage. The pathogenesis of SLE is characterized by the activation of various inflammatory pathways, stimulating the activation of autoantibodies.4 Although numerous immunological abnormalities present as manifestations of the disease, the demarcation between the initiation of immune reaction and its consequences remains unclear.4
However, the heterogeneity of the disease’s clinical and biological presentation challenges the understanding of the disease. Conventional therapy for patients with moderate to severe SLE uses glucocorticoids for the rapid control of inflammation and clinical outcomes. For long term suppression of the disease, antimalarial medications or immunosuppressive drugs are used.
The need for new therapies in SLE
In recent years, advances in the quality of SLE care have led to higher overall survival rates. This was as a result of improvement in general outcomes, and better control of some of the more common organ-threatening complications, such as lupus nephritis.5 Nevertheless, treatments for SLE have not achieved many of the other therapeutic goals that are widely accepted as treatment targets in other autoimmune diseases. For example, durable remission is achieved in only a minority of patients, the risk for flares remains substantial, progression to end-stage renal disease is still considerable, and work disability is common.5 Additionally, the use of glucocorticoids can result in a wide spectrum of short-term and long-term toxicities. The simultaneous effects of the disease and the treatment had considerably increased mortality due to cardiovascular disease and other comorbidities as well.5
In addition, health-related quality of life in patients with SLE is often markedly reduced compared with matched healthy controls or patients with other chronic diseases, even in countries where broad access to high-quality health care exists. A significant unmet need remains for having safe and effective therapies to treat this complex autoimmune disorder.5
Targeted therapies in SLE
The development of improved therapies for SLE has been very difficult and hampered by uncertainty in the most suitable molecular or cellular targets for intervention. Although some trials were shown successful and led to the approval of anti-B cell therapy, several other trials of interventions targeting B cells have been ineffective.6 Further, targeting the interferon (IFN) type I system has also shown positive results, but only patients with increased expression of type I IFN-regulated genes (IFN-I signature) at baseline responded significantly better than placebo in a clinical trial targeting the type I IFN receptor.6
Consequently, additional pathways are likely to be the important drivers of SLE activity. In the pathogenesis of SLE, the cytokines interleukin (IL)-12 and IL-23 are recognized as important mediators of immunity. IL-12 is essential for the development of T helper 1 (Th1) and T follicular helper cells, and the activation and function of cytotoxic T cells. IL-23 drives the expansion and survival of pathogenic Th17 and other IL-17-producing cells, which promote the inflammation in tissues.6 Cytokine dysregulation, including increase of IL-12, IL-6 and IL-23 concentrations, has been reported in patients with SLE, suggesting that the inflammatory environment in SLE is prone to induce Th1 or Th17 cells. Nevertheless, genetic risk for developing SLE has been associated with IL-12, and the IL-12 receptor pathway also suggests that these cytokines are key elements to targeted therapies of SLE.6
Durable reduction of frequent SLE induced flares
Ustekinumab is a fully human monoclonal antibody, which targets the p40 subunit shared by the cytokines IL-12 and IL-23. It has been approved worldwide for the treatment of psoriatic arthritis and Crohn’s disease in adults.7 On the basis of research implicating IL-12 and IL-23 in SLE and the established safety profile of ustekinumab in other indications, a phase 2 clinical trial was designed to assess the efficacy and safety of ustekinumab for the treatment of SLE in patients with moderate to severe disease activity despite conventional treatment.7
The results of phase 2 study were presented at EULAR 2019 by the lead investigator Ronald van Vollenhoven MD PhD, Professor and Chief of Rheumatology at the Amsterdam University Medical Center. It is a global randomized, placebo-controlled trial of 102 adults with seropositive SLE, following the Systemic Lupus International Collaborating Clinics (SLICC) criteria.1 Patients had active disease despite ongoing standard of care therapy including steroid, antimalarial and/or immunosuppressive therapies.1 Patients were randomized (3:2) to receive intravenous ustekinumab or placebo, both were in addition to standard of care therapy for 24 weeks. At week 24, patients in the placebo arm crossed over to receive the active study agent.1
Results published previously at week 24 showed considerable efficacy of ustekinumab vs. placebo.1 The new long-term results over 48 weeks confirmed the sustained clinical efficacy of ustekinumab, which reduced the occurrence of severe flares associated with SLE.2 Results also showed a 4-fold decrease in the rate of severe flares with ustekinumab vs. placebo in weeks 0–24 (Figure 1).2 The flare rate in the ustekinumab arm was also lower in week 24-48 compared to placebo (Figure 1).2 In addition, a consistent safety profile was observed with ustekinumab through one year.2
In light of the positive outcome of ustekinumab, Prof. van Vollenhoven commented, “SLE flares are very unpredictable and have a major impact on patients’ quality of life. As such, these results present an impactful and clinically relevant finding, and suggest that ustekinumab could offer patients a valuable new treatment option in the future.”8
The flare rate was calculated as proportion of patient-days – number of days during which each patient had flares to the total number of days patients had been followed up. The ustekinumab group had a severe flare rate of 2.1/10,000 patient-days in weeks 0–24, compared to 8.4/10,000 patient-days in the placebo group. In weeks 24-48, the rate of severe flares for patients in the ustekinumab group was 1.1/10,000 patient-days.2 Patients in the placebo group who crossed over to ustekinumab at week 24 had severe flare rate of 4.6/10,000 patient-days.2
Ustekinumab associated with reduced IFN-γ production via IL-12 pathway
The second study regarding biomarker data of the same phase 2 clinical trial was presented by Dr. George Tsokos, the study steering committee lead and Chief of the Division of Rheumatology and Clinical Immunology, Beth Israel Deaconess Medical Center, Boston. It was an additional analysis of the ustekinumab phase 2 study that could help explain the mechanism through which ustekinumab might be effective in SLE. Biomarker data was collected over 24 weeks from ustekinumab responders, non-responders and patients on placebo. The analysis specifically showed an association of clinical response with novel biomarker responses that were independent of IFN-I.3 The analysis measured the cytokines interferon gamma (IFN-γ), IL-17 and IL-22, which are downstream mediators of the IL-12/IL-23 pathways, as well as type I interferons (IFN-I), which is believed to be a major contributor to SLE pathogenesis.3
The results demonstrated that people who responded to ustekinumab had durable reductions in IFN-γ protein levels relative to baseline – a finding which was not observed in patients who did not respond to ustekinumab or who received placebo.3 Other biomarkers measured including IFN-I, IL-17 and IL-22 remained largely unchanged. These findings therefore demonstrated the involvement of IL-12 pathway linked to IFN-γ production.
IL-12 pathway is important in T helper 1 and T follicular helper cell differentiation in autoimmune diseases, production of IFN-γ, and activation and function of cytotoxic cells. Dr. George Tsokos, further explained the results, “This is an important finding because SLE drivers have, until recently, been considered to be led by IFN-I. These results suggested that the classical model suspected to be functioning in SLE may be supported by an alternative mechanism of disease via IL-12/-23-dependent T helper 1 cell differentiation and IFN-γ. It might be this pathway helping improve the clinical disease activity and reduce severe flares, which are currently challenging to manage with lupus.”8
SLE is a complex autoimmune disease with several life-threatening complications that could be fatal. Ustekinumab has demonstrated a significantly positive impact among SLE patients. Additionally, a large meta-analysis that aimed to identify novel targets and potential drugs for SLE has highlighted ustekinumab as the top scoring candidate for treatment repositioning in SLE.9
1. van Vollenhoven R, Hahn BH, Tsokos GC, et al. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet. 2018 Oct 13;392(10155):1330-1339.
2. Van Vollenhoven R. Tsokos G, Gordon R, et al. Op0041 Poster. Maintenance of efficacy and safety and reduction of bilag flares with ustekinumab, an interleukin-12/23 inhibitor, in patients with active systemic lupus erythematosus (SLE): 1-year results of a phase 2, randomized placebo-controlled, crossover study. EULAR 2019.
3. Cesaroni M. Seridi L, Jordan J, et al. Op0278 Poster. Biomarker profiling reveals novel mechanistic insights into ustekinumab therapeutic responses in systemic lupus erythematosus. EULAR 2019.
4. Choi MY, Flood K, Bernatsky S, et al. A review on SLE and malignancy. Best Pract Res Clin Rheumatol. 2017 Jun;31(3):373-396.
5. Bakshi J, Ismajli M, Rahman A. A. New therapeutic avenues in SLE. Best Pract Res Clin Rheumatol. 2015 Dec;29(6):794-809.
6. Ugarte-Gil MF, González LA, Alarcón GS. Lupus: the new epidemic. Lupus. 2019 Jul 12 (Epub ahead of print).
7. STELARA-US Prescribing Information-2015.
8. Ustekinumab Reduces Severe Flares in Active SLE, Trial Shows. Lupus News Today (2019).
9. Grammer AC, Ryals MM, Heuer SE, et al. Drug repositioning in SLE: crowd-sourcing, literature-mining and Big Data analysis. Lupus. 2016 Sep;25(10):1150-70.