MAPK activated kinase 2 inhibition shifts the chemokine signature in arthritis synovial fluid mononuclear cells from CXCR3 to CXCR2.

BACKGROUND: The development of novel treatment strategies of immune-mediated inflammatory arthritis (IMIA) is still a clinical unmet need. The mitogen-activated protein kinase (MAPK) pathway is activated by environmental stressors, growth factors and inflammatory cytokines. However, the inhibition of central MAPK proteins has so far had undesirable side effects. The MAPK-activated protein kinase 2 (MK2) is a downstream mediator in the MAPK signaling pathway. OBJECTIVES: The objective of this study was to explore the effects of a small molecule inhibiting MK2 on synovial fluid mononuclear cells from patients with IMIA. METHODS: Synovial fluid mononuclear cells (SFMCs) were obtained from a study population consisting of patients with active rheumatoid arthritis (RA), peripheral spondyloarthritis (SpA) or psoriatic arthritis (PsA) with at least one swollen joint (for obtaining synovial fluid) (n = 11). SFMCs were cultured for 48 h with and without the MK2 inhibitor CC0786512 at 1000 nM, 333 nM and 111 nMand cell free supernatants were harvested and frozen before they were analyzed by the Olink proseek multiplex interferon panel. RESULTS: In SFMCs cultured for 48 h, the MK2 inhibitor decreased the production of chemokine (C-X-C motif) ligand 9 (CXCL9) (P < 0.001), CXCL10 (P < 0.01), hepatocyte growth factor (HGF) (P < 0.01), CXCL11 (P < 0.01), tumor necrosisfactor-like weak inducer of apoptosis (TWEAK) (P < 0.05), and interleukin 12B (IL-12B) (P < 0.05) and increased the production of CXCL5 (P < 0.0001), CXCL1 (P < 0.0001), CXCL6 (P < 0.001), transforming growthfactoralpha (TGFα) (P = 0.01), monocyte-chemotactic protein 3 (MCP-3) (P < 0.01), latency-associated peptide (LAP) TGFß (P < 0.05) dose-dependently. CONCLUSIONS: This study reveals the downstream effects of MK2 inhibition on the secretory profile of SFMCs. Specifically, C-X-C motif chemokine receptors 3 (CXCR3) chemokines were decreased and CXCR2 chemokines were increased. This shift in the chemokine milieu may be one of the mechanisms behind the anti-inflammatory effects of MK2 inhibitors.

Vasculitis therapy refines vasculitis mechanistic classification.

The primary vasculitides constitute a heterogeneous group of immune mediated diseases of incompletely understood pathogenesis currently classified by the size of blood vessels affected (Chapel Hill classification). In recent years, several drugs with well-characterized immunological targets have been tested in clinical trials in large vessel vasculitis and small vessel vasculitis. Such trials provide "reverse translational" or bedside to bench information about underlying pathogenic mechanisms. Therefore, the aim of this systematic literature review was to examine the evidence base for a more refined mechanistic immunological classification of vasculitis. A total of 40 studies (20 randomized controlled trials (RCTs), 16 prospective studies, 1 retrospective cohort study and 3 case series) were included for full qualitative assessment. RCTs concerning biologic therapy for large vessel vasculitis mainly supports interleukin 6 receptor inhibition (tocilizumab). RCTs concerning biologic therapy for granulomatosis with polyangiitis and microscopic polyangiitis mainly support anti-CD20 treatment (rituximab) and complement inhibition with a small molecule C5a receptor antagonist (avacopan) is an emerging treatment option. The biologic treatment of eosinophilic granulomatosis with polyangiitis is centered around interleukin 5 inhibition (mepolizumab). Studies on tumor necrosis factor alpha inhibition (adalimumab, infliximab, and etanercept) showed negative results in giant cell arteritis but some effect in Takayasu arteritis. Taken together, clinical studies with cytokine and cell specific drugs are dissecting the heterogeneous immunopathogenic mechanisms of vasculitis and support a mechanistic immunological classification. Especially, cytokine antagonism is pointing towards immunological distinctions between eosinophilic granulomatosis with polyangiitis and granulomatosis with polyangiitis/microscopic polyangiitis and differences between giant cell arteritis and Takayasu arteritis.

Spondylitis-psoriasis-enthesitis-enterocolitis-dactylitis-uveitis-peripheral synovitis (SPEED-UP) treatment.

Axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), psoriasis, inflammatory bowel disease (IBD), and noninfectious uveitis form a distinct group among the immune mediated inflammatory diseases. Thus, many patients suffer from more than one of these disease manifestations. Here, we will use the term spondylitis-psoriasis-enthesitis-enterocolitis-dactylitis-uveitis-peripheral synovitis (SPEED-UP) spectrum disease. The aim is to review the new targeted pharmacological treatment options for all these diseases. All biological or targeted synthetic drugs with U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMA) approval for any of the diagnoses axSpA, PsA, psoriasis, IBD, or non-infectious uveitis were included. Some of the drugs have documented efficacy in more than one of the diseases, e.g. tumor necrosis factor (TNF) inhibitors. However, other drugs are particularly effective for a specific inflamed tissue and approved in only one or two of the disease entities, e.g. abatacept for peripheral arthritis and vedolizumab for inflammatory bowel disease. This contributes with bedside to bench understanding of the immunology underlying this disease spectrum and provides clinicians with an overview that can assist stratified treatment decisions. We hope that this review will help guide clinicians to speed up treatment of patients with this disease spectrum.