Phase II randomised trial of type I interferon inhibitor anifrolumab in patients with active lupus nephritis

Jayne, David; Rovin, Brad H.; Mysler, Eduardo; Furie, Richard; Houssiau, Frédéric; Trasieva, Teodora; Knagenhjelm, Jacob; Schwetje, Erik; Chia, Yen Lin; Tummala, Raj; Lindholm, Catharina

doi:10.1136/annrheumdis-2021-221478

Cited by 107 publications

(99 citation statements)

References 39 publications

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“…Anifrolumab, a monoclonal antibody to type I interferon receptor, recently became the first FDA-approved medication targeting the interferon pathway in SLE [ 35 ]. A phase 2 trial (NCT02547922) evaluating anifrolumab in LN failed to meet the primary endpoint, but showed numerical improvement, and anifrolumab is now being evaluated in a phase 3 study in LN (NCT05138133) [ 36 ]. IFN-γ is the only member of type II IFN, and plays important roles in innate and adaptive immunity via the activation of chemotactic cytokines (chemokines) [ 34 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Serum and Urine Interferon Gamma-Induced Protein 10 (IP-10) Levels in Lupus Nephritis

Brady

Chava

Tandon

et al. 2022

JCM

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Background: Lupus nephritis (LN) is a prevalent and severe complication of systemic lupus erythematosus (SLE). Non-invasive diagnostics are limited, and current therapies have inadequate response rates. Expression of the chemokine Interferon-γ-induced protein 10 (IP-10) is regulated by Interferon-γ signaling and NF-κB, and its molecular activity and enhanced urine concentrations are implicated in LN, but its utility as a diagnostic marker and association with demographic, clinical, or pathologic features is not defined. Methods: 38 LN patients and 11 patients with non-LN glomerular diseases (GD) with active disease were included. Eighteen of the LN patients had achieved remission at one follow-up during the study time. Serum and urine were obtained from these samples, and the IP-10 levels were measured. Results: Serum and urine IP-10 levels are significantly enhanced in LN patients with active disease as compared with normal individuals (serum average 179.7 pg/mL vs. 7.2 pg/mL, p < 0.0001; urine average 28.7 pg/mg vs. 1.6 pg/mg, p = 0.0019) and patients with other forms of glomerular disease (serum average 179.7 pg/mL vs. 84.9 pg/mL, p = 0.0176; urine average 28.7 pg/mg vs. 0.18 pg/mg, p = 0.0011). Urine IP-10 levels are significantly higher in patients with proliferative LN (PLN) than those with membranous LN (MLN) (average 32.8 pg/mg vs. 7.6 pg/mg, p = 0.0155). Urine IP-10 levels are also higher in MLN versus primary membranous nephropathy (MN) (average 7.6 pg/mg vs. 0.2 pg/mg, p = 0.0193). Importantly, serum IP-10 levels remain elevated during active LN and LN remission, but urine IP-10 levels are decreased from active LN to remission in 72% of our patients. Lastly, serum, but not urine IP-10 levels are significantly higher in African American than White American LN patients in active LN (average 227.8 pg/mL vs. 103.4 pg/mL, p = 0.0309) and during LN remission (average 254.6 pg/mL vs. 89.2 pg/mL, p = 0.0399). Conclusions: Our findings suggest that serum and urine IP-10 measurements provide promising tests for monitoring LN activity, differentiation between classifications of LN, and differentiation between LN and other forms of glomerular disease. We also conclude that further assessment of elevated IP-10 levels in the serum and urine of high-risk populations (i.e., African American) could be beneficial in determining why many of these patients have worse outcomes and are non-responsive to standard therapeutics.

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Section: Discussionmentioning

confidence: 99%

Serum and Urine Interferon Gamma-Induced Protein 10 (IP-10) Levels in Lupus Nephritis

Brady

Chava

Tandon

et al. 2022

JCM

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“…Anifrolumab, recently approved by the US Food and Drug Administration for the treatment of SLE, is a fully human, IgG1κ monoclonal antibody to the type I interferon receptor subunit 1, and inhibits signaling by all type I interferons (71,72). Anifrolumab is currently being evaluated for LN, and results from a phase II trial will be available later this year (73). While there are no current data regarding the use of anifrolumab in refractory LN, a transcriptomic analysis of protocol kidney biopsies after induction therapy showed that interferon pathway transcripts remained up‐regulated in the kidneys of patients who did not respond to therapy, but declined in patients who had a complete clinical response after induction (74).…”

Section: The Clinical Challengementioning

confidence: 99%

“…Anifrolumab is currently being evaluated for LN, and results from a phase II trial will be available later this year (73). While there are no current data regarding the use of anifrolumab in refractory LN, a transcriptomic analysis of protocol kidney biopsies after induction therapy showed that interferon pathway transcripts remained upregulated in the kidneys of patients who did not respond to therapy, but declined in patients who had a complete clinical response after induction (74).…”

Section: Evidencementioning

confidence: 99%

Expert Perspective: An Approach to Refractory Lupus Nephritis

Arora

Rovin

2022

Arthritis & Rheumatology

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Systemic lupus erythematosus affects the kidneys in ~50% of all patients, and lupus nephritis (LN) is the most common manifestation of kidney involvement. Despite prompt diagnosis and treatment with aggressive immunosuppression, a significant proportion of LN patients do not respond to treatment and are considered to have refractory LN. Several factors other than drug resistance, such as nonadherence to treatment, undertreatment with conventional drugs, the effects of accumulated chronic damage, and genetic factors, may contribute to a poor response to treatment and should be considered. We define refractory LN as no change in (or worsening of) proteinuria and/or estimated glomerular filtration rate in response to 2 different standard-of-care induction regimens after 4-6 months in patients who are adherent to treatment. For patients who have LN that is truly refractory to standard of care, B cell-targeted therapy, specifically rituximab (RTX), is the most common next step. There is limited evidence available on alternative rescue therapies that may be used when there is no response to RTX. These include anti-CD38, leflunomide, intravenous immunoglobulin, plasma exchange, autologous stem cell transplantation, chimeric antigen receptor T cell therapy, anticomplement therapy, and interleukin-2 therapy.

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“…TULIP-LN was a phase II, double-blind RCT investigating the efficacy and safety of an intravenous regimen of two different doses of anifrolumab versus the placebo in a group of 145 subjects with active, biopsy-proven, Class III or IV LN [ 75 ]. As the original TULIP-1 and TULIP-2 trials excluded patients with severe, active LN, TULIP-LN was an RCT that was designed to specifically evaluate the efficacy of anifrolumab in active LN.…”

Section: Biologics Targeting Type I Interferons In Slementioning

confidence: 99%

Type I Interferons in Systemic Lupus Erythematosus: A Journey from Bench to Bedside

Sim

Ong

Mak

et al. 2022

IJMS

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Dysregulation of type I interferons (IFNs) has been implicated in the pathogenesis of systemic lupus erythematosus (SLE) since the late 1970s. The majority of SLE patients demonstrate evidence of type I IFN pathway activation; however, studies attempting to address the relationship between type I IFN signature and SLE disease activity have yielded conflicting results. In addition to type I IFNs, type II and III IFNs may overlap and also contribute to the IFN signature. Different genetic backgrounds lead to overproduction of type I IFNs in SLE and contribute to the breakdown of peripheral tolerance by activation of antigen-presenting myeloid dendritic cells, thus triggering the expansion and differentiation of autoreactive lymphocytes. The consequence of the continuous stimulation of the immune system is manifested in different organ systems typical of SLE (e.g., mucocutaneous and cardiovascular involvement). After the discovery of the type I IFN signature, a number of different strategies have been developed to downregulate the IFN system in SLE patients, finally leading to the successful trial of anifrolumab, the second biologic to be approved for the treatment of SLE in 10 years. In this review, we will discuss the bench to bedside translation of the type I IFN pathway and put forward some issues that remain unresolved when selecting SLE patients for treatment with biologics targeting type I IFNs.

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Phase II randomised trial of type I interferon inhibitor anifrolumab in patients with active lupus nephritis

Cited by 107 publications

References 39 publications

Serum and Urine Interferon Gamma-Induced Protein 10 (IP-10) Levels in Lupus Nephritis

Serum and Urine Interferon Gamma-Induced Protein 10 (IP-10) Levels in Lupus Nephritis

Expert Perspective: An Approach to Refractory Lupus Nephritis

Type I Interferons in Systemic Lupus Erythematosus: A Journey from Bench to Bedside

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