There is significant unmet need in the treatment of lupus nephritis (LN) patients. In this review, we highlight the role of the TWEAK/Fn14 pathway in mediating key pathologic processes underlying LN involving both glomerular and tubular injury, and thus the potential for renal protection via blockade of this pathway. The specific pathological mechanisms of TWEAK – namely promoting inflammation, renal cell proliferation and apoptosis, vascular activation and fibrosis – are described, with supporting data from animal models and in vitro systems. Furthermore, we detail the translational relevance of these mechanisms to clinical readouts in human LN. We present the opportunity for an anti-TWEAK therapeutic as a renal protective agent to improve efficacy relative to current standard of care treatments hopefully without increased safety risk, and highlight a phase II trial with BIIB023, an anti-TWEAK neutralizing antibody, designed to assess efficacy in LN patients. Taken together, targeting the TWEAK/Fn14 axis represents a potential new therapeutic paradigm for achieving renal protection in LN patients.

Objective: To evaluate insulin resistance and systemic inflammation in older patients with systolic (SHF) or diastolic heart failure (DHF). Patients: 52 non-diabetic patients (. 70 and , 90 years old) with chronic heart failure (CHF) and hospitalised within the previous six months for heart failure were studied, together with a control group of older healthy volunteers (n = 26). On the basis of Doppler echocardiographic criteria patients were classed as having SHF (n = 27) or DHF (n = 25). Main outcome measures: Fasting glucose, insulin, C reactive protein, interleukin 6, and tumour necrosis factor a soluble receptor II (TNF-aSRII) concentrations were determined. Insulin resistance was estimated by the homeostasis model assessment (HOMA). Results: HOMA index (median, interquartile range) was higher in patients with DHF (1.77, 1.06-2.26) than in patients with SHF (0.97, 0.81-1.85) or healthy volunteers (1.04, 0.76-1.44; p = 0.01). After adjustment for body mass index, age, and use of angiotensin converting enzyme inhibitors, both groups of patients with CHF were more insulin resistant than were healthy volunteers (p = 0.02). C reactive protein, interleukin 6, and TNF-aSRII were all significantly (p , 0.001) higher in patients with DHF and SHF than in healthy volunteers. All markers of systemic inflammation were independently associated with the presence of clinical CHF. Conclusion: Insulin resistance and inflammatory activation are present in older patients with SHF and DHF.

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Activated T cells drive a range of immune-mediated inflammatory diseases. LAG-3 is transiently expressed on recently activated CD4 + and CD8 + T cells. We describe the engineering and first-inhuman clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG-3 and antibody-dependent cellular cytotoxicity capabilities), which depletes LAG-3 expressing cells. GSK2831781 was tested in a phase I/Ib, double-blind, placebo-controlled clinical study, which randomized 40 healthy participants (part A) and 27 patients with psoriasis (part B) to single doses of GSK2831781 (up to 0.15 and 5 mg/kg, respectively) or placebo. Adverse events were generally balanced across groups, with no safety or tolerability concern identified. LAG-3 + cell depletion in peripheral blood was observed at doses ≥ 0.15 mg/ kg and was dose-dependent. In biopsies of psoriasis plaques, a reduction in mean group LAG-3 + and CD3 + T-cell counts was observed following treatment. Downregulation of proinflammatory genes (IL-17A, IL-17F, IFNγ, and S100A12) and upregulation of the epithelial barrier integrity gene, CDHR1, was observed with the 5 mg/kg dose of GSK2831781. Psoriasis disease activity improved up to day 43 at all GSK2831781 doses (0.5, 1.5, and 5 mg/kg) compared with placebo. Depletion of LAG-3-expressing activated T cells is a novel approach, and this first clinical study shows that GSK2831781 is pharmacologically active and provides encouraging early evidence of clinical effects in psoriasis, which warrants further investigation in T-cell-mediated inflammatory diseases.

Keywords:Renal function Multi-parametric quantitative MRI (qMRI) Arterial spin labeling (ASL) Blood oxygen level dependent (BOLD) T1rho MRI Lupus nephritis (LN) Purpose: To identify potential biomarkers of the renal impairment in lupus nephritis using a multi-parametric renal quantitative MRI (qMRI) protocol including diffusion weighted imaging (DWI), blood oxygen level dependent (BOLD), arterial spin labeling (ASL) and T1rho MRI between a cohort of healthy volunteers and lupus nephritis (LN) patients. Materials and methods: The renal qMRI protocol was performed twice with repositioning in between on 10 LN patients and 10 matched controls at 1.5 T. Navigator-gated and breath-hold acquisitions followed by non-rigid image registration were used to control respiratory motion. The repeatability of the 4 MRI modalities was evaluated with the intra-class correlation coefficient (ICC) and within-subject coefficient of variation (wsCV). Unpaired t-test and stepwise logistic regression were carried out to evaluate qMRI parameters between the LN and control groups. Results: The reproducibility of the 4 qMRI modalities ranged from moderate to good (ICC = 0.4-0.91, wsCV ≤ 12%) with a few exceptions. T1rho MRI and ASL renal blood flow (RBF) demonstrated significant differences between the LN and control groups. Stepwise logistic regression yielded only one significant parameter (medullar T1rho) in differentiating LN from control groups with 95% accuracy. Conclusion: A reasonable degree of test-retest repeatability and accuracy of a multi-parametric renal qMRI protocol has been demonstrated in healthy volunteers and LN subjects. T1rho and ASL RBF are promising imaging biomarkers of LN.