SARS-CoV-2 Infection Induces Psoriatic Arthritis Flares and Enthesis Resident Plasmacytoid Dendritic Cell Type-1 Interferon Inhibition by JAK Antagonism Offer Novel Spondyloarthritis Pathogenesis Insights

Abstract

ObjectiveBacterial and viral infectious triggers are linked to spondyloarthritis (SpA) including psoriatic arthritis (PsA) development, likely via dendritic cell activation. We investigated spinal entheseal plasmacytoid dendritic cells (pDCs) toll-like receptor (TLR)-7 and 9 activation and therapeutic modulation, including JAK inhibition. We also investigated if COVID-19 infection, a potent TLR-7 stimulator triggered PsA flares.MethodsNormal entheseal pDCs were characterized and stimulated with imiquimod and CpG oligodeoxynucleotides (ODN) to evaluate TNF and IFNα production. NanoString gene expression assay of total pDCs RNA was performed pre- and post- ODN stimulation. Pharmacological inhibition of induced IFNα protein was performed with Tofacitinib and PDE4 inhibition. The impact of SARS-CoV2 viral infection on PsA flares was evaluated.ResultsCD45+HLA-DR+CD123+CD303+CD11c- entheseal pDCs were more numerous than blood pDCs (1.9 ± 0.8% vs 0.2 ± 0.07% of CD45+ cells, p=0.008) and showed inducible IFNα and TNF protein following ODN/imiquimod stimulation and were the sole entheseal IFNα producers. NanoString data identified 11 significantly upregulated differentially expressed genes (DEGs) including TNF in stimulated pDCs. Canonical pathway analysis revealed activation of dendritic cell maturation, NF-κB signaling, toll-like receptor signaling and JAK/STAT signaling pathways following ODN stimulation. Both tofacitinib and PDE4i strongly attenuated ODN induced IFNα. DAPSA scores elevations occurred in 18 PsA cases with SARS-CoV2 infection (9.7 ± 4 pre-infection and 35.3 ± 7.5 during infection).ConclusionEntheseal pDCs link microbes to TNF/IFNα production. SARS-CoV-2 infection is associated with PsA Flares and JAK inhibition suppressed activated entheseal plasmacytoid dendritic Type-1 interferon responses as pointers towards a novel mechanism of PsA and SpA-related arthropathy.

Post-COVID-19 Arthritis and Sacroiliitis: Natural History with Longitudinal Magnetic Resonance Imaging Study in Two Cases and Review of the Literature

“…Moreover, as described in many studies, SARS-CoV-2 is able to activate in different ways the immune system; in particular, it can induce interleukin-6 (IL-6)-dependent pathways leading to cytokine storm and macrophage activation syndromes; in addition, it might alter interferon signalling in some cases [ 19 , 54 , 55 , 56 , 57 , 58 ].…”

Successful Use of Certolizumab Pegol for Refractory Psoriatic Arthritis Triggered by COVID-19 Infection

“…The mechanism underlying the onset of PsA after COVID-19 in the present case was unclear, but one study reported that oligodeoxynucleotide (ODN)/imiquimod stimulation induced entheseal plasmacytoid dendritic cells (pDCs) related interferon (IFN)-α production via NF-κB signaling, Toll-like receptor signaling, and JAK/STAT signaling pathways ( 21 ). In addition, the Disease Activity Index score for PsA increases following COVID-19 due to the stimulation of Toll-like receptor 7 pathways in patients with PsA ( 21 ).…”

Clinical Dermatology and COVID-19 Pandemic

“…[ 41 ] Infections have also been associated with flares of psoriatic arthritis and enthesis. [ 42 ] Such findings have also been extrapolated in pediatric patients suffering from psoriasis who experienced disease flares during a mandatory lockdown and had their medication stopped for COVID-related reasons. [ 43 ] Despite these associations, as well as the excellent safety profile of biological agents in psoriasis patients infected with COVID-19,[ 44 45 46 47 48 49 50 51 ] the rate of biological initiation for psoriasis has decreased during the pandemic.…”