State‐of‐the‐art treatment of systemic lupus erythematosus

Abstract

Int J Rheum Dis. 2020;23:465-471. | 465 wileyonlinelibrary.com/journal/apl | INTRODUC TI ONSystemic lupus erythematosus (SLE) is a typical systemic autoimmune disease, common in women of reproductive age, which causes multiorgan disorder. It affects organs throughout the body, such as the skin, joints, heart, kidneys, serosa, nerves, and blood vessels, and presents with various clinical symptoms. Onset occurs commonly in the third and fourth decades of life, and the male-to-female ratio is between about 1:10. The prognosis of SLE has dramatically improved since the 1960s because of the widespread uptake of glucocorticoid therapy, with survival rates reported to be 90% or higher after 5 years, 70%-90% after 10 years, and 50%-70% after 20 years. Given the age at onset, these survival rates are relatively low. In Japan and overseas, the most common cause of death is infection; thus, the pressing issues are appropriate management of the primary disease and immunosuppressed state by using glucocorticoids, immunosuppressive drugs, and other appropriate drugs, and the development of drugs that cause fewer adverse reactions. The biological belimumab, which is an anti-B cell-activating factor belonging to the tumor necrosis factor family (BAFF) antibody, has been approved for the treatment of SLE, and many molecular targeted drugs are in development. In this article, the progress made in the diagnosis and treatment of SLE has been reviewed. AbstractAs glucocorticoids and immunosuppressive drugs are non-specific therapeutic agents that cause many adverse reactions, the development of biologicals aiming to control specific molecular targets is anticipated for the treatment of systemic lupus erythematosus (SLE). The antibody targeting B cell-activating factor belonging to the tumor necrosis factor family (BAFF) belimumab was the first biological approved for SLE. At present, many biologicals, such as anifrolumab (anti-type I interferon receptor antibody) and ustekinumab (antibody against interleukin 12/23 [p40]), are in clinical trials. Thus, successful treatments with biologicals targeting "bridging cytokines" produced by dendritic cells, which form a bridge between the innate and acquired immune/autoimmune systems, is of particular interest. Moreover, a phase IIb clinical trial of baricitinib, a low-molecular-weight compound targeting Janus kinase 1/2, in patients with SLE revealed that baricitinib was significantly more effective for relieving arthritis and skin manifestations than placebo, and the trial met the primary endpoint. In the future, it is expected that drugs with better efficacy and safety profiles will be used to apply therapeutic strategies, such as precision medicine, in which different molecular target drugs are used for patients classified by their conditions, and to set a therapeutic goal of the discontinuation of glucocorticoids. K E Y W O R D Sbiological, innate immunity, JAK inhibitor, systemic lupus erythematosus, treatment

Anifrolumab, a monoclonal antibody to the type I interferon receptor subunit 1, for the treatment of systemic lupus erythematosus: an overview from clinical trials

“…Despite improvements in survival rates, the management of SLE is not optimal, and complete control of disease activity is not frequently achieved [7,8], owing to the wide spectrum and severity of clinical manifestations observed in patients with SLE, association with flares (periods of heightened disease activity), and toxicity associated with long-term use of oral corticosteroids (OCS) and immunosuppressants [9,10]. Patients experience excessive risk of progressive irreversible organ damage as well as significantly reduced health-related quality of life (HRQoL), the latter of which has not improved despite advances in overall SLE prognosis [9,11].…”

“…Based on the key role of type I IFN signaling in SLE pathogenesis, IFN-a, IFNAR, and related signaling molecules have become therapeutic targets for the treatment of SLE [27]. In clinical studies, rontalizumab, a humanized IgG1 monoclonal anti-IFN-a antibody, rapidly suppressed IFN response genes, but in a phase 2 trial of patients with active SLE, it failed to meet its primary efficacy endpoint (British Isles Lupus Assessment Group [BILAG] response) [8,28]. Sifalimumab, a fully human IgG1OE monoclonal anti-IFN-a antibody, met the primary efficacy endpoint of SLE Responder Index [SRI (4)] response in a phase 2 trial of patients with active SLE but did not proceed into further development [8,28].…”

“…In clinical studies, rontalizumab, a humanized IgG1 monoclonal anti-IFN-a antibody, rapidly suppressed IFN response genes, but in a phase 2 trial of patients with active SLE, it failed to meet its primary efficacy endpoint (British Isles Lupus Assessment Group [BILAG] response) [8,28]. Sifalimumab, a fully human IgG1OE monoclonal anti-IFN-a antibody, met the primary efficacy endpoint of SLE Responder Index [SRI (4)] response in a phase 2 trial of patients with active SLE but did not proceed into further development [8,28]. Consistent with the mixed results seen with anti-IFN-a antibodies, a vaccine preparation shown to induce neutralizing, polyclonal anti-IFN-a antibodies (IFN-Kinoid) normalized the IFNGS and reduced Lupus Low Disease Activity State in a phase 2 trial but did not significantly improve BILAG score compared with placebo [8,29,30].…”

“…Sifalimumab, a fully human IgG1OE monoclonal anti-IFN-a antibody, met the primary efficacy endpoint of SLE Responder Index [SRI (4)] response in a phase 2 trial of patients with active SLE but did not proceed into further development [8,28]. Consistent with the mixed results seen with anti-IFN-a antibodies, a vaccine preparation shown to induce neutralizing, polyclonal anti-IFN-a antibodies (IFN-Kinoid) normalized the IFNGS and reduced Lupus Low Disease Activity State in a phase 2 trial but did not significantly improve BILAG score compared with placebo [8,29,30]. Targeting the IFN receptor as opposed to IFN-a may prove a more effective approach to blocking type I IFN signaling.…”

Cutaneous Manifestations in Biological-Treated Inflammatory Bowel Disease Patients: A Narrative Review

“…Ustekinumab-induced lupus is rare although new onset of lupus and exacerbation of lupus symptoms have been reported [ 57 , 58 ]. Nonetheless, ustekinumab is investigated in clinical trials as a treatment for lupus and can be a good option in IBD patients with coexisting lupus [ 59 ]. The data on vedolizumab- and natalizumab-induced lupus are mostly limited to case reports [ 60 , 61 ].…”