String of successful trials in SLE: have we cracked the code?

Vollenhoven, Ronald van

doi:10.1136/lupus-2019-000380

Cited by 5 publications

(5 citation statements)

References 12 publications

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“…While the benefit of inhibiting the classical arm of RAS for reno-protection is well-recognized, focus has shifted to the protective arm of RAS. Two potential therapeutic activators of Mas are available; A(1-7) and NorLeu 3 -A (1)(2)(3)(4)(5)(6)(7) [NorLeu] a peptide analog of A (1)(2)(3)(4)(5)(6)(7). Our studies here show that Mas agonists reduce pathologies and mitigate immune changes in MLR-lpr mice to the same levels as ACE-Is/ARBs or better.…”

Section: Introductionmentioning

confidence: 59%

“…Unfortunately, the development of new therapeutics has not kept pace as only one new medication, belimumab, has been approved over that same time frame ( 3 ). As of 2019, several new therapies have shown some success, but are yet to be FDA approved ( 4 ). For now, steroids continue to be a mainstay in the treatment of SLE despite their well-documented organ damaging effects.…”

Section: Introductionmentioning

confidence: 99%

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Targeting the Protective Arm of the Renin-Angiotensin System to Reduce Systemic Lupus Erythematosus Related Pathologies in MRL-lpr Mice

et al. 2020

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Patients with Systemic Lupus Erythematosus (SLE) suffer from a chronic inflammatory autoimmune disease that results from the body's immune system targeting healthy tissues which causes damage to various organ systems. Patients with lupus are still in need of effective therapies to treat this complex, multi-system disease. Because polymorphisms in ACE are associated with the activity of SLE and lupus nephritis and based on well-documented renal-protective effects of Renin Angiotensin System (RAS)-modifying therapies, ACE-I are now widely used in patients with SLE with significant efficacy. Our research explores alternate ways of modifying the RAS as a potential for systemic therapeutic benefit in the MRL -lpr mouse model of SLE. These therapeutics include; angiotensin (1-7) [A(1-7)], Nor-Leu-3 Angiotensin (1-7) (NorLeu), Losartan (ARB), and Lisinopril (ACE-I). Daily systemic treatment with all of these RAS-modifying therapies significantly reduced the onset and intensity in rash formation and swelling of the paw. Further, histology showed a corresponding decrease in hyperkeratosis and acanthosis in skin sections. Important immunological parameters such as decreased circulating anti-dsDNA antibodies, lymph node size, and T cell activation were observed. As expected, the development of glomerular pathologies was also attenuated by RAS-modifying therapy. Improved number and health of mesenchymal stem cells (MSCs), as well as reduction in oxidative stress and inflammation may be contributing to the reduction in SLE pathologies. Several studies have already characterized the protective role of ACE-I and ARBs in mouse models of SLE, here we focus on the protective arm of RAS. A(1-7) in particular demonstrates several protective effects that go beyond those seen with ACE-Is and ARBs; an important finding considering that ACE-Is and ARBs are teratogenic and can cause hypotension in this population. These results offer a foundation for further pharmaceutical development of RAS-modifying therapies, that target the protective arm, as novel SLE therapeutics that do not rely on suppressing the immune system.

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Section: Introductionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Targeting the Protective Arm of the Renin-Angiotensin System to Reduce Systemic Lupus Erythematosus Related Pathologies in MRL-lpr Mice

et al. 2020

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“…The range of different interferon-targeting molecules in clinical development is perhaps due to the unprecedented clinical trial activity in SLE and other autoimmune diseases over the past two decades, in which trials are targeting varied mechanisms with biologics, kinase inhibitors, and other small molecule compounds [ 137 ]. While drug discovery in SLE has historically lagged behind other diseases, predominantly owing to challenges associated with measuring lupus disease activity in a heterogeneous disease, the vast number of new trials and improvements in trial outcome measures has led to a series of successful lupus trials with anifrolumab, voclosporin, and belimumab [ 137 , 138 ]. These recent successes, together with the sheer volume of ongoing clinical trials, increases the chance of additional drugs becoming available to patients within the next decade, illustrated by the recent approvals of belimumab and voclosporin for the treatment of patients with LN [ 137 ].…”

Section: Therapeutic Highlights: Past Present and Futurementioning

confidence: 99%

“…While drug discovery in SLE has historically lagged behind other diseases, predominantly owing to challenges associated with measuring lupus disease activity in a heterogeneous disease, the vast number of new trials and improvements in trial outcome measures has led to a series of successful lupus trials with anifrolumab, voclosporin, and belimumab [ 137 , 138 ]. These recent successes, together with the sheer volume of ongoing clinical trials, increases the chance of additional drugs becoming available to patients within the next decade, illustrated by the recent approvals of belimumab and voclosporin for the treatment of patients with LN [ 137 ].…”

Section: Therapeutic Highlights: Past Present and Futurementioning

confidence: 99%

The Pathogenesis, Molecular Mechanisms, and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases

Ramaswamy

Tummala

Streicher

et al. 2021

IJMS

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Therapeutic success in treating patients with systemic lupus erythematosus (SLE) is limited by the multivariate disease etiology, multi-organ presentation, systemic involvement, and complex immunopathogenesis. Agents targeting B-cell differentiation and survival are not efficacious for all patients, indicating a need to target other inflammatory mediators. One such target is the type I interferon pathway. Type I interferons upregulate interferon gene signatures and mediate critical antiviral responses. Dysregulated type I interferon signaling is detectable in many patients with SLE and other autoimmune diseases, and the extent of this dysregulation is associated with disease severity, making type I interferons therapeutically tangible targets. The recent approval of the type I interferon-blocking antibody, anifrolumab, by the US Food and Drug Administration for the treatment of patients with SLE demonstrates the value of targeting this pathway. Nevertheless, the interferon pathway has pleiotropic biology, with multiple cellular targets and signaling components that are incompletely understood. Deconvoluting the complexity of the type I interferon pathway and its intersection with lupus disease pathology will be valuable for further development of targeted SLE therapeutics. This review summarizes the immune mediators of the interferon pathway, its association with disease pathogenesis, and therapeutic modalities targeting the dysregulated interferon pathway.

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“…Considerable strides in the understanding of lupus pathogenesis have formed the bedrock of translational science for this disease and spearheaded the development and testing of novel treatments ( van Vollenhoven, 2020 ). However, even the few therapies hailed as successful have required clinical trials that recruited many hundreds of participants (not an easy task with this uncommon, bordering on rare, disease) to demonstrate only modest efficacy compared to placebo.…”

Section: Introductionmentioning

confidence: 99%