ObjectiveInterleukin (IL)-17A has emerged as pivotal in driving tissue pathology in immune-mediated inflammatory diseases. The role of IL-17F, sharing 50% sequence homology and overlapping biological function, remains less clear. We hypothesised that IL-17F, together with IL-17A, contributes to chronic tissue inflammation, and that dual neutralisation may lead to more profound suppression of inflammation than inhibition of IL-17A alone.MethodsPreclinical experiments assessed the role of IL-17A and IL-17F in tissue inflammation using disease-relevant human cells. A placebo-controlled proof-of-concept (PoC) clinical trial randomised patients with psoriatic arthritis (PsA) to bimekizumab (n=39) or placebo (n=14). Safety, pharmacokinetics and clinical efficacy of multiple doses (weeks 0, 3, 6 (240 mg/160 mg/160 mg; 80 mg/40 mg/40 mg; 160 mg/80 mg/80 mg and 560 mg/320 mg/320 mg)) of bimekizumab, a humanised monoclonal IgG1 antibody neutralising both IL-17A and IL-17F, were investigated.ResultsIL-17F induced qualitatively similar inflammatory responses to IL-17A in skin and joint cells. Neutralisation of IL-17A and IL-17F with bimekizumab more effectively suppressed in vitro cytokine responses and neutrophil chemotaxis than inhibition of IL-17A or IL-17F alone. The PoC trial met both prespecified efficacy success criteria and showed rapid, profound responses in both joint and skin (pooled top three doses vs placebo at week 8: American College of Rheumatology 20% response criteria 80.0% vs 16.7% (posterior probability >99%); Psoriasis Area and Severity Index 100% response criteria 86.7% vs 0%), sustained to week 20, without unexpected safety signals.ConclusionsThese data support IL-17F as a key driver of human chronic tissue inflammation and the rationale for dual neutralisation of IL-17A and IL-17F in PsA and related conditions.Trial registration numberNCT02141763; Results.

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Alzheimer’s disease is associated with cerebral accumulation of amyloid-β peptide and hyperphosphorylated tau. In the past 28 years, huge efforts have been made in attempting to treat the disease by reducing brain accumulation of amyloid-β in patients with Alzheimer’s disease, with no success. While anti-amyloid-β therapies continue to be tested in prodromal patients with Alzheimer’s disease and in subjects at risk of developing Alzheimer’s disease, there is an urgent need to provide therapeutic support to patients with established Alzheimer’s disease for whom current symptomatic treatment (acetylcholinesterase inhibitors and N-methyl d-aspartate antagonist) provide limited help. The possibility of an infectious aetiology for Alzheimer’s disease has been repeatedly postulated over the past three decades. Infiltration of the brain by pathogens may act as a trigger or co-factor for Alzheimer’s disease, with Herpes simplex virus type 1, Chlamydia pneumoniae, and Porphyromonas gingivalis being most frequently implicated. These pathogens may directly cross a weakened blood–brain barrier, reach the CNS and cause neurological damage by eliciting neuroinflammation. Alternatively, pathogens may cross a weakened intestinal barrier, reach vascular circulation and then cross blood–brain barrier or cause low grade chronic inflammation and subsequent neuroinflammation from the periphery. The gut microbiota comprises a complex community of microorganisms. Increased permeability of the gut and blood–brain barrier induced by microbiota dysbiosis may impact Alzheimer’s disease pathogenesis. Inflammatory microorganisms in gut microbiota are associated with peripheral inflammation and brain amyloid-β deposition in subjects with cognitive impairment. Oral microbiota may also influence Alzheimer’s disease risk through circulatory or neural access to the brain. At least two possibilities can be envisaged to explain the association of suspected pathogens and Alzheimer’s disease. One is that patients with Alzheimer’s disease are particularly prone to microbial infections. The other is that microbial infection is a contributing cause of Alzheimer’s disease. Therapeutic trials with antivirals and/or antibacterials could resolve this dilemma. Indeed, antiviral agents are being tested in patients with Alzheimer’s disease in double-blind placebo-controlled studies. Although combined antibiotic therapy was found to be effective in animal models of Alzheimer’s disease, antibacterial drugs are not being widely investigated in patients with Alzheimer’s disease. This is because it is not clear which bacterial populations in the gut of patients with Alzheimer’s disease are overexpressed and if safe, selective antibacterials are available for them. On the other hand, a bacterial protease inhibitor targeting P. gingivalis toxins is now being tested in patients with Alzheimer’s disease. Clinical studies are needed to test if countering bacterial infection may be beneficial in patients with established Alzheimer’s disease.

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