Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of IL-1β. We studied a family with dominantly inherited autoinflammatory disease characterised by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. Disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The clinical distinction from FMF, also caused by MEFV mutation, was due to loss of a 14-3-3 binding motif at phosphorylated S242. This interaction represents a guard regulating pyrin activation, which is downstream of bacterial effectors that trigger the pyrin inflammasome. S242R mutation recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1β production. Successful therapy targeting IL-1β has been initiated in one patient, resolving Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND). This unique disease provides evidence that a guard mechanism, originally identified in plant innate immunity, also exists in humans.3 Main textAutoinflammatory diseases are characterized by recurrent episodes of fever with systemic and organ-specific inflammation, as well as uncontrolled activation of the innate immune response in the apparent absence of an infectious trigger(1). Familial Mediterranean fever (FMF, OMIM ID: 249100) is the most common of these monogenic diseases, characterized by short (24-72 h) episodes of fever associated with serositis, progressing to amyloidosis if untreated(2). FMF is an autosomal recessive disease caused by mutations in both alleles of the MEFV (MEditerranean FeVer) locus, which encodes the protein pyrin(3). Normally, pyrin functions as a link between intracellular pathogen sensing and activation of the inflammasome, allowing the production of inflammatory mediators during infection. As a potent checkpoint for the initiation of inflammation, the mechanisms of pyrin regulation are critical, and yet still poorly understood.We studied a three-generation Belgian family of 22 individuals, of whom 12 developed autoinflammatory disease (Figure 1a). The disease was characterized by neutrophilic dermatosis, childhood-onset recurrent episodes of fever lasting several weeks, increased levels of acute-phase reactants, arthralgia and myalgia/myositis (Figure 1b). The neutrophilic dermatosis comprised a spectrum of clinical manifestations including severe acne, sterile skin abscesses, pyoderma gangrenosum and neutrophilic small vessel vasculitis (Figure 1c,d).Pathological examination of affected skin showed a dense, predominantly neutrophilic, vascular, perivascular and interstitial infiltrate (Figure 1d). Serum cytokine analysis revealed elevated inflammatory mediators such as IL-1β, IL-6 and TNFα, and cytokines induced by inflammation such as IL-1Ra (Figure 1e, Figure S1a unlike some of the more typical FMF variants, that naturally occur in other species(7). Despite the association of MEFV mutations w...
Coronavirus disease 2019 (COVID‐19) is a continued leading cause of hospitalization and death. Safe, efficacious COVID‐19 antivirals are needed urgently. Nirmatrelvir (PF‐07321332), the first orally bioavailable, severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) M pro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile. We report safety, tolerability, and pharmacokinetic data of nirmatrelvir with and without ritonavir as a pharmacokinetic enhancer, from an accelerated randomized, double‐blind, placebo‐controlled, phase I study. Two interleaving single‐ascending dose (SAD) cohorts were evaluated in a three‐period crossover. Multiple‐ascending dose (MAD) with nirmatrelvir/ritonavir twice daily (b.i.d.) dosing was evaluated over 10 days in five parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase II/III clinical trials were supported by integrating modeling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP). In SAD, MAD, and supratherapeutic exposure cohorts, nirmatrelvir/ritonavir was safe and well‐tolerated. Nirmatrelvir exposure and half‐life were considerably increased by ritonavir, enabling selection of nirmatrelvir/ritonavir dose and regimen for phase II/III trials (300/100 mg b.i.d.), to achieve concentrations continuously above those required for 90% inhibition of viral replication in vitro . The QSP model suggested that a 5‐day regimen would significantly decrease viral load in SARS‐CoV‐2‐infected patients which may prevent development of severe disease, hospitalization, and death. In conclusion, an innovative and seamless trial design expedited establishment of phase I safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase II/III dose selection and accelerated pivotal trials’ initiation (NCT04756531).
Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling.
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