Chronic Urticaria

NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is a cytosolic pattern recognition receptor (PRR) that recognizes multiple pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Once activated, NLRP3 initiates the inflammasome assembly together with the adaptor ASC and the effector caspase-1, leading to caspase-1 activation and subsequent cleavage of IL-1β and IL-18. Aberrant NLRP3 inflammasome activation is linked with the pathogenesis of multiple inflammatory diseases, such as cryopyrin-associated periodic syndromes, type 2 diabetes, non-alcoholic steatohepatitis, gout, and neurodegenerative diseases. Thus, NLRP3 is an important therapeutic target, and researchers are putting a lot of effort into developing its inhibitors. The review summarizes the latest advances in the mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors.

BackgroundThe cytokine interleukin (IL)-1 plays a pivotal role in immune-mediated disorders, particularly in autoinflammatory diseases. Targeting this cytokine proved to be efficacious in treating numerous IL-1-mediated pathologies. Currently, three IL-1 blockers are approved, namely anakinra, canakinumab and rilonacept, and two additional ones are expected to receive approval, namely gevokizumab and bermekimab. However, there is no systematic review on the safety and efficacy of these biologics in treating immune-mediated diseases.ObjectiveTo evaluate safety and efficacy of anakinra, canakinumab, rilonacept, gevokizumab, and bermekimab for the treatment of immune-mediated disorders compared to placebo, standard-of-care treatment or other biologics.MethodsThe PRISMA checklist guided the reporting of the data. We searched the PubMed database between 1 January 1984 and 31 December 2020 focusing on immune-mediated disorders. Our PubMed literature search identified 7363 articles. After screening titles and abstracts for the inclusion and exclusion criteria and assessing full texts, 75 articles were included in a narrative synthesis.ResultsAnakinra was both efficacious and safe in treating cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), gout, macrophage activation syndrome, recurrent pericarditis, rheumatoid arthritis (RA), and systemic juvenile idiopathic arthritis (sJIA). Conversely, anakinra failed to show efficacy in graft-versus-host disease, Sjögren's syndrome, and type 1 diabetes mellitus (T1DM). Canakinumab showed efficacy in treating CAPS, FMF, gout, hyper-IgD syndrome, RA, Schnitzler's syndrome, sJIA, and TNF receptor-associated periodic syndrome. However, use of canakinumab in the treatment of adult-onset Still's disease and T1DM revealed negative results. Rilonacept was efficacious and safe for the treatment of CAPS, FMF, recurrent pericarditis, and sJIA. Contrarily, Rilonacept did not reach superiority compared to placebo in the treatment of T1DM. Gevokizumab showed mixed results in treating Behçet's disease-associated uveitis and no benefit when assessed in T1DM. Bermekimab achieved promising results in the treatment of hidradenitis suppurativa.ConclusionsThis systematic review of IL-1-targeting biologics summarizes the current state of research, safety, and clinical efficacy of anakinra, bermekimab, canakinumab, gevokizumab, and rilonacept in treating immune-mediated disorders.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021228547.

The NLRP3 inflammasome is a multiprotein complex that mediates caspase-1 activation and the release of proinflammatory cytokines, including interleukin (IL)-1β and IL-18. Gain-of-function variants in the gene encoding NLRP3 (also called cryopyrin) lead to constitutive inflammasome activation and excessive IL-1β production in cryopyrin-associated periodic syndromes (CAPS). Here we present functional screening and automated analysis of 534 NLRP3 variants from the international INFEVERS registry and the ClinVar database. This resource captures the effect of NLRP3 variants on ASC speck formation spontaneously, at low temperature, after inflammasome stimulation and with the specific NLRP3 inhibitor MCC950. Most notably, our analysis facilitated the updated classification of NLRP3 variants in INFEVERS. Structural analysis suggested multiple mechanisms by which CAPS variants activate NLRP3, including enhanced ATP binding, stabilizing the active NLRP3 conformation, destabilizing the inactive NLRP3 complex and promoting oligomerization of the pyrin domain. Furthermore, we identified pathogenic variants that can hypersensitize the activation of NLRP3 in response to nigericin and cold temperature exposure. We also found that most CAPS-related NLRP3 variants can be inhibited by MCC950; however, NLRP3 variants with changes to proline affecting helices near the inhibitor binding site are resistant to MCC950, as are variants in the pyrin domain, which likely trigger activation directly with the pyrin domain of ASC. Our findings could help stratify the CAPS population for NLRP3 inhibitor clinical trials and our automated methodologies can be implemented for molecules with a different mechanism of activation and in laboratories worldwide that are interested in adding new functionally validated NLRP3 variants to the resource. Overall, our study provides improved diagnosis for patients with CAPS, mechanistic insight into the activation of NLRP3 and stratification of patients for the future application of targeted therapeutics.

BackgroundMany patients with chronic spontaneous urticaria (CSU) remain symptomatic despite receiving second-generation H1-antihistamines (sgH1-AH). This data analysis from the Chronic Urticaria Registry (CURE) aimed to describe treatment patterns and identify unmet needs in real-world practice.MethodsCURE is an international, prospective registry of patients with chronic urticaria. Treatment responses were categorized as Urticaria Control Test (UCT) changes from baseline (BL) to 6-month follow-up (FU). Complete response was defined as UCT = 16 with a ≥ 3-point increase.ResultsData were available from 3995 adult patients with CSU at BL and 1288 at FU with evaluable UCT. After treatment escalation from BL to FU, 5.3% (no treatment to licensed-dose sgH1-AH), 6.0% (licensed-dose sgH1-AH to up-dosed sgH1-AH), and 28.4% (any dose sgH1-AH to omalizumab) achieved complete response. Factors associated with a lower probability of treatment escalation at FU were UCT ≥ 12 and omalizumab treatment at BL (both p 1-AH (p = 0.031).ConclusionAppropriate treatment escalation improves CSU control, although only about a quarter of patients achieve a complete response, indicating the need for novel treatments. Many patients with poorly controlled CSU do not receive guideline-recommended treatment escalation and remain symptomatic on their current treatments, which deserves further attention.