RARE DISEASE
Muckle-Wells syndrome
Muckle-Wells syndrome
Muckle-Wells syndrome
Synonyms: Neutrophilic urticaria
Synonyms: Neutrophilic urticaria
Synonyms: Neutrophilic urticaria
Drug discovery
2
drugs
With orphan designations
Overview
Muckle-Wells syndrome (MWS) is a rare autosomal dominant autoinflammatory disorder caused by NLRP3 gene mutations, leading to dysregulated interleukin-1β (IL-1β) production. It presents with recurrent fever, urticarial rash, arthralgia, and progressive sensorineural hearing loss. Chronic inflammation predisposes patients to systemic AA amyloidosis, primarily affecting the kidneys. Diagnosis relies on clinical features, genetic testing, and elevated inflammatory markers [1][2].
Categories: rare genetic diseases, rare immunological diseases, rare renal diseases, rare skin diseases, rare systemic and rheumatological diseases, rare systemic or rheumatologic diseases of childhood, rare transplant-related disorders
Research Papers
371 drug discovery papers about Muckle-Wells syndrome, with 1 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
371 drug discovery papers about Muckle-Wells syndrome, with 1 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-16 | PAD4-generated citrullinated histones are triggers for autoinflammation in cryopyrin-associated periodic syndrome.
Cryopyrin-associated periodic syndromes (CAPS) are autoinflammatory disorders caused by gain-of-function NLRP3 variants. Although NLRP3 inflammasomes mediate IL-1β secretion through Gasdermin D (GSDMD), we show that GSDMD deletion did not prevent autoinflammation in mice ubiquitously expressing the Nlrp3A350V variant. Inflamed skin of Nlrp3A350V-expressing GSDMD-deficient mice displayed citrullinated histone 3-containing neutrophil extracellular traps (CitH3-NETs). CitH3-NETs induced IL-1β secretion from murine Nlrp3A350V-expressing GSDMD-deficient macrophages as well as from human CAPS patient monocytes and macrophages. Blocking protein arginine deiminase-4 (PAD4) prevented CitH3 release and disabled the IL-1β-inducing NET effects, identifying CitH3 as crucial trigger. Mechanistically, CitH3-NETs activated GSDME in GSDMD-deficient Nlrp3A350V macrophages, and GSDME deletion prevented pathology in Nlrp3A350V-expressing GSDMD-deficient mice. In addition to this GSDME-dependent autoinflammation axis, PAD4 deletion also prevented autoinflammation in mice with neutrophil-specific Nlrp3A350V expression that develop CAPS in a GSDMD-dependent manner. These observations support a CAPS model in which PAD4-mediated CitH3-NET release can trigger both GSDMD-dependent and GSDME-dependent autoinflammation.
2026-03-19 | Cofilin-1 is a redox-sensitive guard of the NLRP3 inflammasome.
Mutations in NLRP3 can cause a spectrum of the autoinflammatory cryopyrin-associated periodic syndromes (CAPS). Reactive oxygen species (ROS) have a central role in NLRP3 inflammasome activation. Here we show that cofilin-1, an actin-severing protein, is a negative regulator of the NLRP3 inflammasome. In resting cells, cofilin-1 directly bound NLRP3, but after stimulation with NLRP3 inflammasome activators, it was oxidized by ROS and dissociated from NLRP3. CAPS-associated mutant NLRP3 exhibited reduced binding to cofilin-1. Residues 101-104 of cofilin-1 were critical for NLRP3 interaction. Oxidation-independent peptides containing this NLRP3 binding motif suppressed inflammasome activation induced by endogenous CAPS-associated mutations and ex vivo NLRP3 activators such as ATP and nigericin. Bioinformatic structural analyses corroborate a model in which cofilin-1 has a pivotal function in NLRP3 activation by ROS and support the potential use of cofilin-1-derived peptides in individuals who are unresponsive to or intolerant of other forms of NLRP3 blockade.
2026-02-22 | CNS-targeted NLRP3 Inhibition by NT-0527 confers therapeutic advantage in a CAPS mouse model.
BACKGROUND: The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is a key mediator of innate immune responses which functions to facilitate production of inflammatory cytokines Interleukin (IL)-1β and IL-18 and pyroptotic cell death; dysregulated NLRP3 activation contributes to a wide range of inflammatory diseases. Gain-of-function (GoF) mutations in the NLRP3 gene underlie cryopyrin-associated periodic syndromes (CAPS), a spectrum of rare autoinflammatory disorders characterized by both systemic and central nervous system (CNS) involvement. The hD305N mutant CAPS mouse model recapitulates these human disease features, including spontaneous peripheral and CNS manifestations, making it a powerful tool for evaluating the effectiveness of NLRP3 inhibitors. Here, we use this model to compare blood-brain barrier-penetrant NT-0527 and non-penetrant CP-456,773 inhibitors for their ability to provide therapeutic benefit within peripheral and central compartments and to address the question of whether CNS anti-inflammatory outcomes are enhanced by access of an NLRP3 inhibitor to the local tissue environment. RESULTS: The two inhibitors possess similar in vitro pharmacological profiles and effectively inhibited NLRP3 function in vivo following acute LPS challenge of hD305N mice. Moreover, when administered therapeutically, the individual inhibitors reduced peripheral inflammatory biomarkers attendant to IL-1β output resulting from hyperactivity of the hD305N GoF NLRP3 mutein. Peripheral pharmacological impact included direct evidence of NLRP3 target engagement assessed as a reduction in levels of mature IL-1β recovered in tissue homogenates. In sharp contrast, NT-0527 but not CP-456,773 mitigated CNS inflammation as evidenced by normalized expression of a panel of inflammatory genes and reduced accumulation of myeloid cells in brains of hD305N CAPS mice. In line with this differential impact, NT-0527 treatment reduced levels of mature IL-1β recovered in hD305N brain homogenates demonstrating CNS-centric target engagement while CP-456,773 treatment did not. Notably, CP-456,773 reduced inflammatory cell accumulation in the adjacent dura mater, which lies outside the blood–brain and blood–CSF barriers. CONCLUSIONS: These findings highlight the importance of locally generated IL-1β in driving CNS disease manifestations in a mouse CAPS model, and demonstrate a clear therapeutic advantage for a BBB-penetrant NLRP3 inhibitor in mitigating inflammatory outcomes within the central compartment.
2025-12-22 | From “Congenital Urticaria” to CAPS: An Atypical Presentation Within the NLRP3-AID Spectrum
Introduction Cryopyrin-associated periodic syndromes (CAPS) are rare, monogenic autoinflammatory diseases caused by gain-of-function variants in NLRP3. Traditionally classified into three phenotypes—familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and chronic infantile neurologic cutaneous and articular syndrome (CINCA/NOMID)—recent evidence supports a continuum of disease within the NLRP3-associated autoinflammatory disease (NLRP3-AID) spectrum. Case Presentation A 10-year-old girl presented with a lifelong history of daily urticarial rash since the first month of life. Lesions were spontaneous, painless, and non-pruritic. Symptoms worsened with cold exposure, temperature changes, and emotional stress, but also occurred spontaneously. She reported intermittent episodes (every 2–3 months) of self-limited low-grade fever, headache, abdominal pain, arthralgias, and non-purulent conjunctivitis lasting 2–3 days. At age 1, she was diagnosed with “congenital urticaria” based on skin biopsy (interstitial urticarial dermatitis without mast cell proliferation) and treated with H1-antihistamines, without improvement, severely impacting her quality of life. Repeated labs during asymptomatic periods showed persistent anemia, neutrophilic leukocytosis, elevated C-reactive protein/erythrocyte sedimentation rate, and increased IgG/IgD levels. No history of recurrent infections, autoimmunity, consanguinity, or similar family symptoms was reported. Examination revealed widespread urticarial lesions but no other abnormalities. A next-generation sequencing panel for inborn errors of immunity identified a heterozygous pathogenic NLRP3 variant (c.913G>A, p.Asp305Asn). A diagnosis of autosomal dominant NLRP3-AID was made. No neurologic, auditory, or joint damage was found. Colchicine was started while awaiting canakinumab approval. Interestingly, the Auto-Inflammatory Disease Activity Index (AIDAI) score improved from 51 to 39 points on colchicine. Discussion Despite cold sensitivity and a relatively mild course, this patient’s persistent rash and systemic inflammation differ from classic FCAS, highlighting the relevance of adopting the broader NLRP3-AID term. In resource-limited settings, colchicine may offer temporary benefits while awaiting access to IL-1 inhibition targeted therapy.
2025-10-15 | Discovery of novel and potent NLRP3 inflammasome inhibitors with new lipophilic moieties.
The NLRP3 inflammasome plays a pivotal role in innate immunity by triggering caspase-1 mediated release of the pro-inflammatory cytokines IL-1β and IL-18. These cytokines are implicated in various inflammatory and metabolic disorders, including Cryopyrin-Associated Periodic Syndromes (CAPS), gouty arthritis, obesity and cardiovascular diseases. In this study, we report the discovery and synthesis of a novel non-tricyclic series of NLRP3 inhibitors. Among them, the representative compound 32 bearing 3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-triene motif was identified with improved potency and enhanced drug-like properties compared to MCC950. Key optimization strategies included exploring hydrophobic interactions with new moieties, achieving a balance between potency and lipophilicity, and improving physicochemical properties as well as in vitro and in vivo pharmacokinetics. Compound 32 demonstrated significant in vivo efficacy in acute peritonitis model, highlighting its therapeutic potential for inflammatory diseases.
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2026-06-15 | Late-Onset, Low-Penetrance NLRP3-Associated Autoinflammatory Disease Presenting with Urticaria-Like Lesions: A CAPS Spectrum Case
Cryopyrin-associated periodic syndromes (CAPSs) are rare autoinflammatory disorders caused by gain-of-function mutations in the NLRP3 gene, resulting in dysregulated interleukin-1-mediated inflammation.Although traditionally classified into three clinical subtypes according to disease severity and systemic involvement, increasing evidence supports the concept of CAPS as a continuous phenotypic spectrum.Low-penetrance NLRP3 variants may present with milder and atypical phenotypes, creating diagnostic challenges.A 19-year-old male patient presented with a three-month history of recurrent urticaria-like lesions triggered by cold exposure, accompanied by intense pruritus and burning sensation.The lesions appeared on the trunk and extremities, resolved within 24 hours without residual pigmentation, and were not associated with angioedema.The patient denied systemic symptoms such as fever, arthralgia, myalgia, fatigue, or weight loss.Family history was unremarkable.Initially diagnosed with chronic urticaria, he showed no significant response to high-dose second-generation antihistamines.Laboratory investigations during disease flares demonstrated neutrophilia and elevated C-reactive protein and serum amyloid A levels.Skin biopsy revealed superficial and deep perivascular neutrophilic infiltration without evidence of vasculitis.Genetic analysis identified a disease-associated NLRP3 variant, c.592G > A (p.Val198Met), supporting the diagnosis of CAPS.Following initiation of anakinra (100 mg/ day), complete remission of cutaneous symptoms was achieved within two months.This case highlights an atypical CAPS presentation characterized by late onset and skin-limited inflammation without systemic manifestations.The findings support a spectrum-based understanding of CAPS and emphasize that isolated cutaneous phenotypes associated with low-penetrance NLRP3 variants should be considered in patients with antihistamine-resistant urticarialike eruptions accompanied by neutrophilic inflammation and elevated acute-phase reactants.
2026-05-21 | Early-onset renal amyloidosis associated with psoriasis in a child with cryopyrinopathy: a case report.
Cryopyrin-associated periodic syndromes (CAPS) are rare but treatable autoinflammatory disorders, including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile neurologic cutaneous articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID). These conditions can lead to severe complications such as AA amyloidosis, potentially resulting in renal failure. To date, the youngest reported case of CAPS-associated amyloidosis was 10 years old, and no cases with overlapping FCAS/MWS/CINCA features have been described. The coexistence of CAPS and psoriasis is extremely rare, with only one prior report. We report a 10-year-old boy with features of cryopyrinopathy who developed early-onset AA amyloidosis. Clinical manifestations included bilateral sensorineural hearing loss, severe headaches due to chronic aseptic meningitis, splenomegaly, lymphadenopathy, and progressive renal insufficiency, along with a history of recurrent urticarial-like rashes and arthralgias. Genetic testing revealed a heterozygous pathogenic variant in the NLRP3 gene (NM_001079821.3:c.907G > A; p.Asp303Asn). Variant interpretation, based on ACMG/AMP guidelines, classified this variant as pathogenic (PS1, PS2, PS3, PM1, PM2, PM5, PP1, PP3, PP5). Treatment with the IL-1 receptor antagonist anakinra led to resolution of symptoms, stabilization of renal function, and partial improvement in hearing. During follow-up, the patient developed psoriasis, confirmed by skin biopsy, which was successfully managed with topical therapy. To our knowledge, this represents one of the youngest reported cases of AA amyloidosis secondary to CAPS with an overlapping FCAS/MWS/CINCA phenotype. The subsequent co-occurrence of psoriasis highlights the rarity of this case and suggests potential shared pathogenic mechanisms, including dysregulation of inflammatory pathways such as the NLRP3 inflammasome.
2026-02-01 | Targeting cytokine pathways: the role of biologics in autoinflammatory disorders.
Autoinflammatory diseases are inherited disorders of innate immunity, broadly classified into inflammasomopathies, interferonopathies, and complement-mediated disorders. They are characterized by dysregulated cytokine signaling - particularly IL-1, IL-6, TNF, type I interferon, and the JAK-STAT pathway-and are increasingly managed with molecular targeted therapies. Prototypical entities include familial Mediterranean fever (FMF), TNF receptor - associated periodic syndrome (TRAPS), and cryopyrin-associated periodic syndromes (CAPS). Other conditions - notably mevalonate kinase deficiency (MKD/HIDS), deficiency of adenosine deaminase 2 (DADA2), haploinsufficiency of A20 (HA20), OTULIN-related autoinflammatory syndromes, and proteasome-associated autoinflammatory syndromes (PRAAS) - are now recognized as biologic-responsive diseases. This review summarizes molecular mechanisms and therapeutic strategies, focusing on IL-1 blockade with anakinra, canakinumab, and rilonacept, as well as IL-6 and TNF inhibitors, integrating evidence from clinical trials and real-world studies. IL-1 inhibition has transformed the management of inflammasome-mediated diseases, enabling glucocorticoid-free remission and reducing amyloidosis risk. TNF inhibitors remain standard for vasculopathic disorders such as DADA2, while IL-6 blockade and JAK inhibitors are options in selected refractory cases. The recognition of novel syndromes, including HA20, OTULIN deficiency, and PRAAS, has broadened the therapeutic landscape, and next-generation biologics may further enable personalized treatment.
2025-06-23 | Gastrointestinal Involvement in Muckle-Wells Syndrome: A Systematic Review of Clinical Presentation, Diagnostic Patterns, and Therapeutic Response.
Muckle-Wells syndrome (MWS), a rare autoinflammatory disorder within the cryopyrin-associated periodic syndrome (CAPS) spectrum, is primarily characterized by recurrent fevers, urticarial rash, sensorineural hearing loss, and risk of amyloidosis. Although systemic manifestations are well-documented, gastrointestinal (GI) symptoms remain underrecognized and poorly described. This systematic review explores the prevalence, diagnostic relevance, and treatment response of GI manifestations in MWS. A structured search strategy was employed using major databases, and studies were included if they involved patients with genetically or clinically confirmed MWS and reported GI symptoms such as abdominal pain or oral ulcers. A total of three studies met the inclusion criteria, including two observational cohorts and one case report. Abdominal pain was noted in up to one-third of patients with childhood-onset disease and recurrently in a confirmed case. While IL-1 blockade with anakinra or canakinumab demonstrated overall systemic improvement, GI outcomes were not consistently reported. These findings suggest that gastrointestinal involvement, though infrequently highlighted, may be clinically significant and should be integrated into diagnostic and therapeutic frameworks for MWS.
2025-06-20 | Use of anakinra in cryopyrin-associated periodic syndromes: case report and review of literature.
Cryopyrin-associated periodic syndrome is a rare autoinflammatory syndrome caused by a dysregulation of cytokine signaling pathways, particularly of the interleukin-1β production. Symptoms typical appear early in life and include recurrent fever, arthralgia, and cutaneous rash, often accompanied by systemic manifestations and progressive end-organ damage resulting from chronic inflammation. Interleukin- targeted therapy constitutes the basis for treatment, and can lead to complete resolution of symptoms. We report a case of a 66-year-old man with cryopyrin-associated periodic syndrome related to V198M mutation, successfully treated with anakinra, an interleukin- 1 inhibitor frequently used in rheumatoid arthritis.
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2024-12-23 | Renal transplantation in patients with cryopyrin-associated periodic syndrome: A case report and literature review.
The cryopyrin-associated periodic syndrome (CAPS) is a rare autosomal dominant hereditary inflammatory disease clinically characterized by three overlapping types and associated with interleukin (IL)-1β.We reported a rare case of CAPS in a patient with accompanying symptoms such as growth retardation and urticaria-like rash. These clinical manifestations were caused by mutations in the NALP3 gene. A 28-year-old male patient, with a height of 1.3 m and a weight of 33.4 kg. He began to experience fever, rash, joint swelling and pain, as well as recurrent cerebral infarction, delayed growth and development, and decreased hearing, among other neuroendocrine manifestations six months after birth. After being examined at Peking Union Medical College Hospital in September 2014, a mutation in the NALP3 gene related to the encoding of Cryopyrin protein was detected,leading to a diagnosis of CAPS with a high probability of CINCA. This is a rare case of CAPS, a disease inherited in an autosomal dominant manner and associated with mutations in the NALP3 gene. Based on its clinical manifestations and severity, it can be divided into three subtypes. The clinical presentation involves autoimmune inflammatory disease, with inflammation affecting multiple organs throughout the body, including the joints, skin, face, and kidneys. Involvement of the kidneys can lead to kidney failure, which is one of its most severe complications.
2023-07-05 | Antisense Oligonucleotide Therapy Decreases IL-1β Expression and Prolongs Survival in Mutant Nlrp3 Mice.
Antisense oligonucleotides (ASOs) are a novel therapeutic strategy that targets a specific gene and suppresses its expression. The cryopyrin-associated periodic syndromes (CAPS) are a spectrum of autoinflammatory diseases characterized by systemic and tissue inflammation that is caused by heterozygous gain-of-function mutations in the nucleotide-binding and oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) gene. The aim of this study was to investigate the efficacy of an Nlrp3-specific ASO treatment in CAPS. An Nlrp3-specific ASO was designed and tested in murine cell lines and bone marrow-derived macrophages (BMDMs) from wild-type and CAPS mouse models. Nlrp3 knock-in mice were treated in vivo with Nlrp3-specific ASO, survival was monitored, and expression of organ-specific Nlrp3 and IL-1β was measured. Nlrp3-specific ASO treatment of murine cell lines and BMDMs showed a significant downregulation of Nlrp3 and mature IL-1β protein expression. Ex vivo treatment of Nlrp3 mutant mouse-derived BMDMs with Nlrp3-specific ASO demonstrated significantly reduced IL-1β release. In vivo, Nlrp3-specific ASO treatment of Nlrp3 mutant mice prolonged survival, reduced systemic inflammation, and decreased tissue-specific expression of Nlrp3 and mature IL-1β protein. The results of this study demonstrate that Nlrp3-specific ASO treatment downregulates Nlrp3 expression and IL-1β release in CAPS models, suggesting ASO therapy as a potential treatment of CAPS and other NLRP3-mediated diseases.
2022-08-03 | Inflammasome activity is controlled by ZBTB16-dependent SUMOylation of ASC
Abstract Inflammasome activity is important for our immune response and is instrumental in numerous clinical conditions. Here we identify a novel control mechanism that modulates the central Caspase-1 and NLR (Nod-like receptor) adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD). We show that activation and subsequent oligomerization of ASC is controlled by SUMO (small ubiquitin-like modifier) modification and identify that the nuclear ZBTB16 (Zinc finger and BTB domain-containing protein 16) regulates this SUMOylation. Accordingly, ablating ZBTB16 reduces ASC SUMOylation and ensuing inflammasome activity. This mechanism is pivotal as we demonstrate that ablating ZBTB16 relieves acute inflammatory pathogenesis in a murine model of Muckle-Wells syndrome caused by a hyperactive inflammasome. Our findings advance our understanding of inflammasome activity and, by recognizing processes that control the central adaptor molecule, identify new and more comprehensive therapeutic strategies to target pathogenic inflammasome activity.
2020-10-01 | Emerging role of non-coding RNAs in allergic disorders
RNA transcripts that not undergo translation into polypeptides recently came into focus of research. Long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) comprise the most important groups of these transcripts. LncRNAs have a length over 200 nucleotides and like mRNAs, have regulated transcription in a tissue specific manner. Biogenesis and function of lncRNAs is related to cell differentiation, response to stimuli and regulation of immune responses. LncRNAs can interact with both miRNAs and mRNAs. MiRNAs are characterized by a length of 22–24 nucleotides. MiRNAs regulate expression of genes at the post-transcriptional level. LncRNAs together with miRNAs are considered as regulators of the immune system. Alterations in their biogenesis is an important mechanism in the development immune related disorders. CircRNAs are products of aberrant maturation of protein-coding transcripts in a process of back-splicing, in which a single strand RNA molecule attains a closed circle shape. Despite a low expression, some circRNA were found to titrate miRNAs and interfere with maturation of legitimate protein-coding transcripts. We summarize the current knowledge on the role of non-coding transcripts in allergic disorders: asthma, atopic dermatitis, allergic rhinitis and urticaria. The reviewed data suggest lncRNA and miRNAs as therapeutic targets and biomarkers of allergic disorders.
2020-04-06 | Inflammasome-Dependent Cytokines at the Crossroads of Health and Autoinflammatory Disease.
As key regulators of both innate and adaptive immunity, it is unsurprising that the activity of interleukin (IL)-1 cytokine family members is tightly controlled by decoy receptors, antagonists, and a variety of other mechanisms. Additionally, inflammasome-mediated proteolytic maturation is a prominent and distinguishing feature of two important members of this cytokine family, IL-1β and IL-18, because their full-length gene products are biologically inert. Although vital in antimicrobial host defense, deregulated inflammasome signaling is linked with a growing number of autoimmune and autoinflammatory diseases. Here, we focus on introducing the diverse inflammasome types and discussing their causal roles in periodic fever syndromes. Therapies targeting IL-1 or IL-18 show great efficacy in some of these autoinflammatory diseases, although further understanding of the molecular mechanisms leading to unregulated production of these key cytokines is required to benefit more patients.
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2026-08-01 | Cryptic NLRP3 Mosaicism Uncovered by Deep Sequencing in Muckle-Wells Syndrome: A Case Report
Background Muckle-Wells syndrome is part of the cryopyrin-associated periodic syndrome (CAPS) family, a group of rare autoinflammatory conditions caused by gain-of-function variants in the NLRP3 gene, leading to uncontrolled activation of the inflammasome and excessive IL-1β release. Although most patients have a detectable genetic change, a small number present with a typical CAPS phenotype but do not carry a known pathogenic variant in NLRP3 on conventional sequencing. In-depth genetic analyses have recently shown that some of these cases are explained by hidden, low-level NLRP3 mosaicism. Case Report A 21-year-old male first presented in 2012 at the age of 6 with recurrent episodes of transient, non-pruritic urticarial rash, low-grade fever, fatigue, episodic arthritis of the knees and ankles, and enthesitis predominantly involving the Achilles tendon and dorsal foot insertions. During flares, inflammatory markers were elevated (CRP 12-18 mg/L, ESR 31-38 mm/h, serum amyloid A >160,000 ng/mL), with mild normocytic anemia. Autoimmune serologies and complement levels were normal. In 2013, mild unilateral sensorineural hearing loss was identified and remained stable; MRI of the brain and internal auditory canals was normal. Initial genetic testing with a recurrent fever syndrome panel in 2014 and whole-exome sequencing in 2018 were both reported as negative. Anakinra, initiated in 2014, provided partial improvement but was discontinued due to injection-site reactions. In 2018, with worsening symptoms and elevated inflammation (CRP 47 mg/L, ESR 31 mm/h, SAA 55,264 ng/mL), canakinumab was started, leading to rapid and sustained normalization of inflammatory markers and resolution of clinical symptoms. The patient remained in long-term disease quiescence for approximately 4 years (2018-2022), after which the patient discontinued treatment and was lost to follow-up. In 2025, stored DNA was re-analyzed with high-depth sequencing for a panel of 101 known autoinflammatory genes and identified a NLRP3 variant (p. Arg260Pro, Clinvar classification pathogenic) in approximately 5% of reads. Retrospective analysis of existing whole-exome data did not identify this low-level variant. Conclusion Consistent with previous reports of NLRP3 mosaicism as a cause of CAPS, this case demonstrates that negative genetic testing does not exclude cryopyrin-associated periodic syndromes and that somatic mosaicism should be considered when the clinical phenotype is compelling. As sequencing technologies evolve, periodic re-analysis offers a critical second opportunity for diagnosis and targeted treatment.
2026-06-10 | IL-1-targeted therapy in dermatologic conditions.
Interleukin-1 (IL-1) plays a key role in inflammasome activation, keratinocyte signaling and neutrophil recruitment, and is a driving force behind many neutrophil-rich and suppurative dermatoses. There is robust evidence supporting the use of IL-1 blockade as a disease-modifying therapy in cryopyrin-associated periodic syndromes and other monogenic periodic fever syndromes, as well as in the treatment of Schnitzler syndrome, where it can rapidly control urticarial and neutrophilic eruptions. Cohort- and series-level data demonstrate high efficacy in IL-1 receptor antagonist deficiency and steroid-refractory pyoderma gangrenosum, whereas benefits appear more heterogeneous in hidradenitis suppurativa, pustular psoriasis and proline-serine-threonine phosphatase-interacting protein 1-associated autoinflammatory diseases. In contrast, conditions such as IL-36 receptor antagonist deficiency, synovitis acne pustulosis hyperostosis osteitis syndrome, Sweet syndrome and vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome are supported only by scattered case reports or theoretical rationale, with highly variable or uncertain responses to IL-1 blockade, highlighting the importance of careful clinical and, where possible, genetic phenotyping. We summarize practical considerations for selecting agents, pediatric and adult dosing and safety. IL-1 antagonists are indispensable for a subset of IL-1-driven disorders and represent a rational rescue option for selected neutrophilic dermatoses.
2026-06-01 | The effect of omalizumab treatment on inflammatory parameters in urticarial diseases: a retrospective study.
Chronic spontaneous urticaria (CSU) and urticarial vasculitis (UV) are chronic inflammatory skin disorders. Monoclonal anti-IgE therapy is widely approved for CSU and is increasingly investigated for its broader immunomodulatory effects. This study aimed to evaluate the impact of anti-IgE therapy on systemic inflammatory markers, including complete blood count (CBC)-derived ratios and C-reactive protein (CRP), in patients with CSU and UV. In this retrospective study, 80 patients (67 with CSU, 13 with UV) who received anti-IgE therapy for at least 12 weeks were analysed. Pre- and post-treatment values of hematologic parameters (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], neutrophil-to-monocyte ratio [NMR], lymphocyte-to-monocyte ratio [LMR], mean platelet volume [MPV], red cell distribution width [RDW]) and CRP were compared. Correlation analyses were also performed. In the CSU group, significant reductions were observed in neutrophil count, CRP, NLR, PLR, and NMR, whereas lymphocyte count increased (p < 0.05). In UV patients, NLR decreased significantly, while other parameters, including CRP, showed no statistically significant changes. A positive correlation between CRP and NLR was detected in the CSU group. No significant differences were found in MPV, RDW, LMR, eosinophils, or basophils. Anti-IgE therapy demonstrated measurable anti-inflammatory effects in CSU, reflected by reductions in CRP and CBC-derived markers, which may serve as accessible biomarkers for monitoring treatment response. The effect was less evident in UV, possibly due to distinct disease mechanisms. Larger prospective studies in UV populations are warranted.
2025-10-01 | 3618 Atypical neurological presentation of cryopyrin-associated periodic syndrome: a diagnostic challenge for neurologists
Cryopyrin-associated periodic syndrome (CAPS) is a rare autoinflammatory disorder resulting from mutations in the NLRP3 gene, leading to excessive interleukin-1b production and persistent systemic inflammation.Although classically characterised by recurrent fevers, urticarial rash, and progressive sensorineural hearing loss, the clinical heterogeneity of CAPS often results in diagnostic delays.We report the case of a Somali woman in her 20s who presented with bilateral optic disc swelling, progressive sensorineural hearing loss, and recurrent headaches, initially raising suspicion for intracranial hypertension.Despite the absence of typical febrile episodes and overt systemic inflammation, her persistent symptoms warranted further investigation.Genetic testing revealed a heterozygous pathogenic NLRP3 mutation (c.2576A>G, p.(Tyr859Cys)), confirming a diagnosis of CAPS within the Muckle-Wells spectrum.This case highlights the importance of recognising CAPS as a differential diagnosis in patients presenting with unexplained intracranial hypertension and progressive hearing loss.A delayed diagnosis carries significant morbidity, including the risk of amyloidosis, irreversible hearing loss, and vision impairment.Given the broad phenotypic spectrum of CAPS, neurologists should maintain a high index of suspicion and incorporate genetic testing into the evaluation of patients with refractory systemic inflammatory symptoms.Early initiation of IL-1 inhibition can substantially modify disease trajectory, preventing long-term complications and improving patient outcomes.
2025-09-27 | Role of Mast Cells in Human Health and Disease: Controversies and Novel Therapies.
Mast cells have been implicated in allergic diseases such as asthma, rhinitis, conjunctivitis, atopic dermatitis, urticaria, and anaphylaxis. However, it is now well established that they also fulfill critical roles in tissue homeostasis, repair, and defense. Despite considerable progress, their ontogeny, proliferation, and differentiation remain subjects of debate, as does their involvement in a wide spectrum of diseases, including cancer and cardiovascular disorders. What remains indisputable is their essential contribution to both innate and adaptive immune responses. Importantly, the activity of their effector molecules can elicit either protective or deleterious outcomes. A complete absence of mast cells (MCs) in humans would undoubtedly provide valuable insight into their fundamental role in immunity, much as neutropenia and agranulocytosis have historically clarified the functions of neutrophils. In this review, we provide a comprehensive overview of mast cell (MC) biology, emphasizing their functional diversity and pathogenic potential. Furthermore, we highlight emerging therapeutic strategies, particularly the use of inhibitors and monoclonal antibodies, which are reshaping current approaches to conditions such as allergy, mastocytosis, and related disorders.
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2026-07-16 | PAD4-generated citrullinated histones are triggers for autoinflammation in cryopyrin-associated periodic syndrome.
Cryopyrin-associated periodic syndromes (CAPS) are autoinflammatory disorders caused by gain-of-function NLRP3 variants. Although NLRP3 inflammasomes mediate IL-1β secretion through Gasdermin D (GSDMD), we show that GSDMD deletion did not prevent autoinflammation in mice ubiquitously expressing the Nlrp3A350V variant. Inflamed skin of Nlrp3A350V-expressing GSDMD-deficient mice displayed citrullinated histone 3-containing neutrophil extracellular traps (CitH3-NETs). CitH3-NETs induced IL-1β secretion from murine Nlrp3A350V-expressing GSDMD-deficient macrophages as well as from human CAPS patient monocytes and macrophages. Blocking protein arginine deiminase-4 (PAD4) prevented CitH3 release and disabled the IL-1β-inducing NET effects, identifying CitH3 as crucial trigger. Mechanistically, CitH3-NETs activated GSDME in GSDMD-deficient Nlrp3A350V macrophages, and GSDME deletion prevented pathology in Nlrp3A350V-expressing GSDMD-deficient mice. In addition to this GSDME-dependent autoinflammation axis, PAD4 deletion also prevented autoinflammation in mice with neutrophil-specific Nlrp3A350V expression that develop CAPS in a GSDMD-dependent manner. These observations support a CAPS model in which PAD4-mediated CitH3-NET release can trigger both GSDMD-dependent and GSDME-dependent autoinflammation.
2026-03-19 | Cofilin-1 is a redox-sensitive guard of the NLRP3 inflammasome.
Mutations in NLRP3 can cause a spectrum of the autoinflammatory cryopyrin-associated periodic syndromes (CAPS). Reactive oxygen species (ROS) have a central role in NLRP3 inflammasome activation. Here we show that cofilin-1, an actin-severing protein, is a negative regulator of the NLRP3 inflammasome. In resting cells, cofilin-1 directly bound NLRP3, but after stimulation with NLRP3 inflammasome activators, it was oxidized by ROS and dissociated from NLRP3. CAPS-associated mutant NLRP3 exhibited reduced binding to cofilin-1. Residues 101-104 of cofilin-1 were critical for NLRP3 interaction. Oxidation-independent peptides containing this NLRP3 binding motif suppressed inflammasome activation induced by endogenous CAPS-associated mutations and ex vivo NLRP3 activators such as ATP and nigericin. Bioinformatic structural analyses corroborate a model in which cofilin-1 has a pivotal function in NLRP3 activation by ROS and support the potential use of cofilin-1-derived peptides in individuals who are unresponsive to or intolerant of other forms of NLRP3 blockade.
2026-02-22 | CNS-targeted NLRP3 Inhibition by NT-0527 confers therapeutic advantage in a CAPS mouse model.
BACKGROUND: The NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is a key mediator of innate immune responses which functions to facilitate production of inflammatory cytokines Interleukin (IL)-1β and IL-18 and pyroptotic cell death; dysregulated NLRP3 activation contributes to a wide range of inflammatory diseases. Gain-of-function (GoF) mutations in the NLRP3 gene underlie cryopyrin-associated periodic syndromes (CAPS), a spectrum of rare autoinflammatory disorders characterized by both systemic and central nervous system (CNS) involvement. The hD305N mutant CAPS mouse model recapitulates these human disease features, including spontaneous peripheral and CNS manifestations, making it a powerful tool for evaluating the effectiveness of NLRP3 inhibitors. Here, we use this model to compare blood-brain barrier-penetrant NT-0527 and non-penetrant CP-456,773 inhibitors for their ability to provide therapeutic benefit within peripheral and central compartments and to address the question of whether CNS anti-inflammatory outcomes are enhanced by access of an NLRP3 inhibitor to the local tissue environment. RESULTS: The two inhibitors possess similar in vitro pharmacological profiles and effectively inhibited NLRP3 function in vivo following acute LPS challenge of hD305N mice. Moreover, when administered therapeutically, the individual inhibitors reduced peripheral inflammatory biomarkers attendant to IL-1β output resulting from hyperactivity of the hD305N GoF NLRP3 mutein. Peripheral pharmacological impact included direct evidence of NLRP3 target engagement assessed as a reduction in levels of mature IL-1β recovered in tissue homogenates. In sharp contrast, NT-0527 but not CP-456,773 mitigated CNS inflammation as evidenced by normalized expression of a panel of inflammatory genes and reduced accumulation of myeloid cells in brains of hD305N CAPS mice. In line with this differential impact, NT-0527 treatment reduced levels of mature IL-1β recovered in hD305N brain homogenates demonstrating CNS-centric target engagement while CP-456,773 treatment did not. Notably, CP-456,773 reduced inflammatory cell accumulation in the adjacent dura mater, which lies outside the blood–brain and blood–CSF barriers. CONCLUSIONS: These findings highlight the importance of locally generated IL-1β in driving CNS disease manifestations in a mouse CAPS model, and demonstrate a clear therapeutic advantage for a BBB-penetrant NLRP3 inhibitor in mitigating inflammatory outcomes within the central compartment.
2025-12-22 | From “Congenital Urticaria” to CAPS: An Atypical Presentation Within the NLRP3-AID Spectrum
Introduction Cryopyrin-associated periodic syndromes (CAPS) are rare, monogenic autoinflammatory diseases caused by gain-of-function variants in NLRP3. Traditionally classified into three phenotypes—familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and chronic infantile neurologic cutaneous and articular syndrome (CINCA/NOMID)—recent evidence supports a continuum of disease within the NLRP3-associated autoinflammatory disease (NLRP3-AID) spectrum. Case Presentation A 10-year-old girl presented with a lifelong history of daily urticarial rash since the first month of life. Lesions were spontaneous, painless, and non-pruritic. Symptoms worsened with cold exposure, temperature changes, and emotional stress, but also occurred spontaneously. She reported intermittent episodes (every 2–3 months) of self-limited low-grade fever, headache, abdominal pain, arthralgias, and non-purulent conjunctivitis lasting 2–3 days. At age 1, she was diagnosed with “congenital urticaria” based on skin biopsy (interstitial urticarial dermatitis without mast cell proliferation) and treated with H1-antihistamines, without improvement, severely impacting her quality of life. Repeated labs during asymptomatic periods showed persistent anemia, neutrophilic leukocytosis, elevated C-reactive protein/erythrocyte sedimentation rate, and increased IgG/IgD levels. No history of recurrent infections, autoimmunity, consanguinity, or similar family symptoms was reported. Examination revealed widespread urticarial lesions but no other abnormalities. A next-generation sequencing panel for inborn errors of immunity identified a heterozygous pathogenic NLRP3 variant (c.913G>A, p.Asp305Asn). A diagnosis of autosomal dominant NLRP3-AID was made. No neurologic, auditory, or joint damage was found. Colchicine was started while awaiting canakinumab approval. Interestingly, the Auto-Inflammatory Disease Activity Index (AIDAI) score improved from 51 to 39 points on colchicine. Discussion Despite cold sensitivity and a relatively mild course, this patient’s persistent rash and systemic inflammation differ from classic FCAS, highlighting the relevance of adopting the broader NLRP3-AID term. In resource-limited settings, colchicine may offer temporary benefits while awaiting access to IL-1 inhibition targeted therapy.
2025-10-15 | Discovery of novel and potent NLRP3 inflammasome inhibitors with new lipophilic moieties.
The NLRP3 inflammasome plays a pivotal role in innate immunity by triggering caspase-1 mediated release of the pro-inflammatory cytokines IL-1β and IL-18. These cytokines are implicated in various inflammatory and metabolic disorders, including Cryopyrin-Associated Periodic Syndromes (CAPS), gouty arthritis, obesity and cardiovascular diseases. In this study, we report the discovery and synthesis of a novel non-tricyclic series of NLRP3 inhibitors. Among them, the representative compound 32 bearing 3-(1-cyclopropylethyl)bicyclo[4.2.0]octa-1(6),2,4-triene motif was identified with improved potency and enhanced drug-like properties compared to MCC950. Key optimization strategies included exploring hydrophobic interactions with new moieties, achieving a balance between potency and lipophilicity, and improving physicochemical properties as well as in vitro and in vivo pharmacokinetics. Compound 32 demonstrated significant in vivo efficacy in acute peritonitis model, highlighting its therapeutic potential for inflammatory diseases.
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2026-06-15 | Late-Onset, Low-Penetrance NLRP3-Associated Autoinflammatory Disease Presenting with Urticaria-Like Lesions: A CAPS Spectrum Case
Cryopyrin-associated periodic syndromes (CAPSs) are rare autoinflammatory disorders caused by gain-of-function mutations in the NLRP3 gene, resulting in dysregulated interleukin-1-mediated inflammation.Although traditionally classified into three clinical subtypes according to disease severity and systemic involvement, increasing evidence supports the concept of CAPS as a continuous phenotypic spectrum.Low-penetrance NLRP3 variants may present with milder and atypical phenotypes, creating diagnostic challenges.A 19-year-old male patient presented with a three-month history of recurrent urticaria-like lesions triggered by cold exposure, accompanied by intense pruritus and burning sensation.The lesions appeared on the trunk and extremities, resolved within 24 hours without residual pigmentation, and were not associated with angioedema.The patient denied systemic symptoms such as fever, arthralgia, myalgia, fatigue, or weight loss.Family history was unremarkable.Initially diagnosed with chronic urticaria, he showed no significant response to high-dose second-generation antihistamines.Laboratory investigations during disease flares demonstrated neutrophilia and elevated C-reactive protein and serum amyloid A levels.Skin biopsy revealed superficial and deep perivascular neutrophilic infiltration without evidence of vasculitis.Genetic analysis identified a disease-associated NLRP3 variant, c.592G > A (p.Val198Met), supporting the diagnosis of CAPS.Following initiation of anakinra (100 mg/ day), complete remission of cutaneous symptoms was achieved within two months.This case highlights an atypical CAPS presentation characterized by late onset and skin-limited inflammation without systemic manifestations.The findings support a spectrum-based understanding of CAPS and emphasize that isolated cutaneous phenotypes associated with low-penetrance NLRP3 variants should be considered in patients with antihistamine-resistant urticarialike eruptions accompanied by neutrophilic inflammation and elevated acute-phase reactants.
2026-05-21 | Early-onset renal amyloidosis associated with psoriasis in a child with cryopyrinopathy: a case report.
Cryopyrin-associated periodic syndromes (CAPS) are rare but treatable autoinflammatory disorders, including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile neurologic cutaneous articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID). These conditions can lead to severe complications such as AA amyloidosis, potentially resulting in renal failure. To date, the youngest reported case of CAPS-associated amyloidosis was 10 years old, and no cases with overlapping FCAS/MWS/CINCA features have been described. The coexistence of CAPS and psoriasis is extremely rare, with only one prior report. We report a 10-year-old boy with features of cryopyrinopathy who developed early-onset AA amyloidosis. Clinical manifestations included bilateral sensorineural hearing loss, severe headaches due to chronic aseptic meningitis, splenomegaly, lymphadenopathy, and progressive renal insufficiency, along with a history of recurrent urticarial-like rashes and arthralgias. Genetic testing revealed a heterozygous pathogenic variant in the NLRP3 gene (NM_001079821.3:c.907G > A; p.Asp303Asn). Variant interpretation, based on ACMG/AMP guidelines, classified this variant as pathogenic (PS1, PS2, PS3, PM1, PM2, PM5, PP1, PP3, PP5). Treatment with the IL-1 receptor antagonist anakinra led to resolution of symptoms, stabilization of renal function, and partial improvement in hearing. During follow-up, the patient developed psoriasis, confirmed by skin biopsy, which was successfully managed with topical therapy. To our knowledge, this represents one of the youngest reported cases of AA amyloidosis secondary to CAPS with an overlapping FCAS/MWS/CINCA phenotype. The subsequent co-occurrence of psoriasis highlights the rarity of this case and suggests potential shared pathogenic mechanisms, including dysregulation of inflammatory pathways such as the NLRP3 inflammasome.
2026-02-01 | Targeting cytokine pathways: the role of biologics in autoinflammatory disorders.
Autoinflammatory diseases are inherited disorders of innate immunity, broadly classified into inflammasomopathies, interferonopathies, and complement-mediated disorders. They are characterized by dysregulated cytokine signaling - particularly IL-1, IL-6, TNF, type I interferon, and the JAK-STAT pathway-and are increasingly managed with molecular targeted therapies. Prototypical entities include familial Mediterranean fever (FMF), TNF receptor - associated periodic syndrome (TRAPS), and cryopyrin-associated periodic syndromes (CAPS). Other conditions - notably mevalonate kinase deficiency (MKD/HIDS), deficiency of adenosine deaminase 2 (DADA2), haploinsufficiency of A20 (HA20), OTULIN-related autoinflammatory syndromes, and proteasome-associated autoinflammatory syndromes (PRAAS) - are now recognized as biologic-responsive diseases. This review summarizes molecular mechanisms and therapeutic strategies, focusing on IL-1 blockade with anakinra, canakinumab, and rilonacept, as well as IL-6 and TNF inhibitors, integrating evidence from clinical trials and real-world studies. IL-1 inhibition has transformed the management of inflammasome-mediated diseases, enabling glucocorticoid-free remission and reducing amyloidosis risk. TNF inhibitors remain standard for vasculopathic disorders such as DADA2, while IL-6 blockade and JAK inhibitors are options in selected refractory cases. The recognition of novel syndromes, including HA20, OTULIN deficiency, and PRAAS, has broadened the therapeutic landscape, and next-generation biologics may further enable personalized treatment.
2025-06-23 | Gastrointestinal Involvement in Muckle-Wells Syndrome: A Systematic Review of Clinical Presentation, Diagnostic Patterns, and Therapeutic Response.
Muckle-Wells syndrome (MWS), a rare autoinflammatory disorder within the cryopyrin-associated periodic syndrome (CAPS) spectrum, is primarily characterized by recurrent fevers, urticarial rash, sensorineural hearing loss, and risk of amyloidosis. Although systemic manifestations are well-documented, gastrointestinal (GI) symptoms remain underrecognized and poorly described. This systematic review explores the prevalence, diagnostic relevance, and treatment response of GI manifestations in MWS. A structured search strategy was employed using major databases, and studies were included if they involved patients with genetically or clinically confirmed MWS and reported GI symptoms such as abdominal pain or oral ulcers. A total of three studies met the inclusion criteria, including two observational cohorts and one case report. Abdominal pain was noted in up to one-third of patients with childhood-onset disease and recurrently in a confirmed case. While IL-1 blockade with anakinra or canakinumab demonstrated overall systemic improvement, GI outcomes were not consistently reported. These findings suggest that gastrointestinal involvement, though infrequently highlighted, may be clinically significant and should be integrated into diagnostic and therapeutic frameworks for MWS.
2025-06-20 | Use of anakinra in cryopyrin-associated periodic syndromes: case report and review of literature.
Cryopyrin-associated periodic syndrome is a rare autoinflammatory syndrome caused by a dysregulation of cytokine signaling pathways, particularly of the interleukin-1β production. Symptoms typical appear early in life and include recurrent fever, arthralgia, and cutaneous rash, often accompanied by systemic manifestations and progressive end-organ damage resulting from chronic inflammation. Interleukin- targeted therapy constitutes the basis for treatment, and can lead to complete resolution of symptoms. We report a case of a 66-year-old man with cryopyrin-associated periodic syndrome related to V198M mutation, successfully treated with anakinra, an interleukin- 1 inhibitor frequently used in rheumatoid arthritis.
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2024-12-23 | Renal transplantation in patients with cryopyrin-associated periodic syndrome: A case report and literature review.
The cryopyrin-associated periodic syndrome (CAPS) is a rare autosomal dominant hereditary inflammatory disease clinically characterized by three overlapping types and associated with interleukin (IL)-1β.We reported a rare case of CAPS in a patient with accompanying symptoms such as growth retardation and urticaria-like rash. These clinical manifestations were caused by mutations in the NALP3 gene. A 28-year-old male patient, with a height of 1.3 m and a weight of 33.4 kg. He began to experience fever, rash, joint swelling and pain, as well as recurrent cerebral infarction, delayed growth and development, and decreased hearing, among other neuroendocrine manifestations six months after birth. After being examined at Peking Union Medical College Hospital in September 2014, a mutation in the NALP3 gene related to the encoding of Cryopyrin protein was detected,leading to a diagnosis of CAPS with a high probability of CINCA. This is a rare case of CAPS, a disease inherited in an autosomal dominant manner and associated with mutations in the NALP3 gene. Based on its clinical manifestations and severity, it can be divided into three subtypes. The clinical presentation involves autoimmune inflammatory disease, with inflammation affecting multiple organs throughout the body, including the joints, skin, face, and kidneys. Involvement of the kidneys can lead to kidney failure, which is one of its most severe complications.
2023-07-05 | Antisense Oligonucleotide Therapy Decreases IL-1β Expression and Prolongs Survival in Mutant Nlrp3 Mice.
Antisense oligonucleotides (ASOs) are a novel therapeutic strategy that targets a specific gene and suppresses its expression. The cryopyrin-associated periodic syndromes (CAPS) are a spectrum of autoinflammatory diseases characterized by systemic and tissue inflammation that is caused by heterozygous gain-of-function mutations in the nucleotide-binding and oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) gene. The aim of this study was to investigate the efficacy of an Nlrp3-specific ASO treatment in CAPS. An Nlrp3-specific ASO was designed and tested in murine cell lines and bone marrow-derived macrophages (BMDMs) from wild-type and CAPS mouse models. Nlrp3 knock-in mice were treated in vivo with Nlrp3-specific ASO, survival was monitored, and expression of organ-specific Nlrp3 and IL-1β was measured. Nlrp3-specific ASO treatment of murine cell lines and BMDMs showed a significant downregulation of Nlrp3 and mature IL-1β protein expression. Ex vivo treatment of Nlrp3 mutant mouse-derived BMDMs with Nlrp3-specific ASO demonstrated significantly reduced IL-1β release. In vivo, Nlrp3-specific ASO treatment of Nlrp3 mutant mice prolonged survival, reduced systemic inflammation, and decreased tissue-specific expression of Nlrp3 and mature IL-1β protein. The results of this study demonstrate that Nlrp3-specific ASO treatment downregulates Nlrp3 expression and IL-1β release in CAPS models, suggesting ASO therapy as a potential treatment of CAPS and other NLRP3-mediated diseases.
2022-08-03 | Inflammasome activity is controlled by ZBTB16-dependent SUMOylation of ASC
Abstract Inflammasome activity is important for our immune response and is instrumental in numerous clinical conditions. Here we identify a novel control mechanism that modulates the central Caspase-1 and NLR (Nod-like receptor) adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD). We show that activation and subsequent oligomerization of ASC is controlled by SUMO (small ubiquitin-like modifier) modification and identify that the nuclear ZBTB16 (Zinc finger and BTB domain-containing protein 16) regulates this SUMOylation. Accordingly, ablating ZBTB16 reduces ASC SUMOylation and ensuing inflammasome activity. This mechanism is pivotal as we demonstrate that ablating ZBTB16 relieves acute inflammatory pathogenesis in a murine model of Muckle-Wells syndrome caused by a hyperactive inflammasome. Our findings advance our understanding of inflammasome activity and, by recognizing processes that control the central adaptor molecule, identify new and more comprehensive therapeutic strategies to target pathogenic inflammasome activity.
2020-10-01 | Emerging role of non-coding RNAs in allergic disorders
RNA transcripts that not undergo translation into polypeptides recently came into focus of research. Long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) comprise the most important groups of these transcripts. LncRNAs have a length over 200 nucleotides and like mRNAs, have regulated transcription in a tissue specific manner. Biogenesis and function of lncRNAs is related to cell differentiation, response to stimuli and regulation of immune responses. LncRNAs can interact with both miRNAs and mRNAs. MiRNAs are characterized by a length of 22–24 nucleotides. MiRNAs regulate expression of genes at the post-transcriptional level. LncRNAs together with miRNAs are considered as regulators of the immune system. Alterations in their biogenesis is an important mechanism in the development immune related disorders. CircRNAs are products of aberrant maturation of protein-coding transcripts in a process of back-splicing, in which a single strand RNA molecule attains a closed circle shape. Despite a low expression, some circRNA were found to titrate miRNAs and interfere with maturation of legitimate protein-coding transcripts. We summarize the current knowledge on the role of non-coding transcripts in allergic disorders: asthma, atopic dermatitis, allergic rhinitis and urticaria. The reviewed data suggest lncRNA and miRNAs as therapeutic targets and biomarkers of allergic disorders.
2020-04-06 | Inflammasome-Dependent Cytokines at the Crossroads of Health and Autoinflammatory Disease.
As key regulators of both innate and adaptive immunity, it is unsurprising that the activity of interleukin (IL)-1 cytokine family members is tightly controlled by decoy receptors, antagonists, and a variety of other mechanisms. Additionally, inflammasome-mediated proteolytic maturation is a prominent and distinguishing feature of two important members of this cytokine family, IL-1β and IL-18, because their full-length gene products are biologically inert. Although vital in antimicrobial host defense, deregulated inflammasome signaling is linked with a growing number of autoimmune and autoinflammatory diseases. Here, we focus on introducing the diverse inflammasome types and discussing their causal roles in periodic fever syndromes. Therapies targeting IL-1 or IL-18 show great efficacy in some of these autoinflammatory diseases, although further understanding of the molecular mechanisms leading to unregulated production of these key cytokines is required to benefit more patients.
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2026-08-01 | Cryptic NLRP3 Mosaicism Uncovered by Deep Sequencing in Muckle-Wells Syndrome: A Case Report
Background Muckle-Wells syndrome is part of the cryopyrin-associated periodic syndrome (CAPS) family, a group of rare autoinflammatory conditions caused by gain-of-function variants in the NLRP3 gene, leading to uncontrolled activation of the inflammasome and excessive IL-1β release. Although most patients have a detectable genetic change, a small number present with a typical CAPS phenotype but do not carry a known pathogenic variant in NLRP3 on conventional sequencing. In-depth genetic analyses have recently shown that some of these cases are explained by hidden, low-level NLRP3 mosaicism. Case Report A 21-year-old male first presented in 2012 at the age of 6 with recurrent episodes of transient, non-pruritic urticarial rash, low-grade fever, fatigue, episodic arthritis of the knees and ankles, and enthesitis predominantly involving the Achilles tendon and dorsal foot insertions. During flares, inflammatory markers were elevated (CRP 12-18 mg/L, ESR 31-38 mm/h, serum amyloid A >160,000 ng/mL), with mild normocytic anemia. Autoimmune serologies and complement levels were normal. In 2013, mild unilateral sensorineural hearing loss was identified and remained stable; MRI of the brain and internal auditory canals was normal. Initial genetic testing with a recurrent fever syndrome panel in 2014 and whole-exome sequencing in 2018 were both reported as negative. Anakinra, initiated in 2014, provided partial improvement but was discontinued due to injection-site reactions. In 2018, with worsening symptoms and elevated inflammation (CRP 47 mg/L, ESR 31 mm/h, SAA 55,264 ng/mL), canakinumab was started, leading to rapid and sustained normalization of inflammatory markers and resolution of clinical symptoms. The patient remained in long-term disease quiescence for approximately 4 years (2018-2022), after which the patient discontinued treatment and was lost to follow-up. In 2025, stored DNA was re-analyzed with high-depth sequencing for a panel of 101 known autoinflammatory genes and identified a NLRP3 variant (p. Arg260Pro, Clinvar classification pathogenic) in approximately 5% of reads. Retrospective analysis of existing whole-exome data did not identify this low-level variant. Conclusion Consistent with previous reports of NLRP3 mosaicism as a cause of CAPS, this case demonstrates that negative genetic testing does not exclude cryopyrin-associated periodic syndromes and that somatic mosaicism should be considered when the clinical phenotype is compelling. As sequencing technologies evolve, periodic re-analysis offers a critical second opportunity for diagnosis and targeted treatment.
2026-06-10 | IL-1-targeted therapy in dermatologic conditions.
Interleukin-1 (IL-1) plays a key role in inflammasome activation, keratinocyte signaling and neutrophil recruitment, and is a driving force behind many neutrophil-rich and suppurative dermatoses. There is robust evidence supporting the use of IL-1 blockade as a disease-modifying therapy in cryopyrin-associated periodic syndromes and other monogenic periodic fever syndromes, as well as in the treatment of Schnitzler syndrome, where it can rapidly control urticarial and neutrophilic eruptions. Cohort- and series-level data demonstrate high efficacy in IL-1 receptor antagonist deficiency and steroid-refractory pyoderma gangrenosum, whereas benefits appear more heterogeneous in hidradenitis suppurativa, pustular psoriasis and proline-serine-threonine phosphatase-interacting protein 1-associated autoinflammatory diseases. In contrast, conditions such as IL-36 receptor antagonist deficiency, synovitis acne pustulosis hyperostosis osteitis syndrome, Sweet syndrome and vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome are supported only by scattered case reports or theoretical rationale, with highly variable or uncertain responses to IL-1 blockade, highlighting the importance of careful clinical and, where possible, genetic phenotyping. We summarize practical considerations for selecting agents, pediatric and adult dosing and safety. IL-1 antagonists are indispensable for a subset of IL-1-driven disorders and represent a rational rescue option for selected neutrophilic dermatoses.
2026-06-01 | The effect of omalizumab treatment on inflammatory parameters in urticarial diseases: a retrospective study.
Chronic spontaneous urticaria (CSU) and urticarial vasculitis (UV) are chronic inflammatory skin disorders. Monoclonal anti-IgE therapy is widely approved for CSU and is increasingly investigated for its broader immunomodulatory effects. This study aimed to evaluate the impact of anti-IgE therapy on systemic inflammatory markers, including complete blood count (CBC)-derived ratios and C-reactive protein (CRP), in patients with CSU and UV. In this retrospective study, 80 patients (67 with CSU, 13 with UV) who received anti-IgE therapy for at least 12 weeks were analysed. Pre- and post-treatment values of hematologic parameters (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], neutrophil-to-monocyte ratio [NMR], lymphocyte-to-monocyte ratio [LMR], mean platelet volume [MPV], red cell distribution width [RDW]) and CRP were compared. Correlation analyses were also performed. In the CSU group, significant reductions were observed in neutrophil count, CRP, NLR, PLR, and NMR, whereas lymphocyte count increased (p < 0.05). In UV patients, NLR decreased significantly, while other parameters, including CRP, showed no statistically significant changes. A positive correlation between CRP and NLR was detected in the CSU group. No significant differences were found in MPV, RDW, LMR, eosinophils, or basophils. Anti-IgE therapy demonstrated measurable anti-inflammatory effects in CSU, reflected by reductions in CRP and CBC-derived markers, which may serve as accessible biomarkers for monitoring treatment response. The effect was less evident in UV, possibly due to distinct disease mechanisms. Larger prospective studies in UV populations are warranted.
2025-10-01 | 3618 Atypical neurological presentation of cryopyrin-associated periodic syndrome: a diagnostic challenge for neurologists
Cryopyrin-associated periodic syndrome (CAPS) is a rare autoinflammatory disorder resulting from mutations in the NLRP3 gene, leading to excessive interleukin-1b production and persistent systemic inflammation.Although classically characterised by recurrent fevers, urticarial rash, and progressive sensorineural hearing loss, the clinical heterogeneity of CAPS often results in diagnostic delays.We report the case of a Somali woman in her 20s who presented with bilateral optic disc swelling, progressive sensorineural hearing loss, and recurrent headaches, initially raising suspicion for intracranial hypertension.Despite the absence of typical febrile episodes and overt systemic inflammation, her persistent symptoms warranted further investigation.Genetic testing revealed a heterozygous pathogenic NLRP3 mutation (c.2576A>G, p.(Tyr859Cys)), confirming a diagnosis of CAPS within the Muckle-Wells spectrum.This case highlights the importance of recognising CAPS as a differential diagnosis in patients presenting with unexplained intracranial hypertension and progressive hearing loss.A delayed diagnosis carries significant morbidity, including the risk of amyloidosis, irreversible hearing loss, and vision impairment.Given the broad phenotypic spectrum of CAPS, neurologists should maintain a high index of suspicion and incorporate genetic testing into the evaluation of patients with refractory systemic inflammatory symptoms.Early initiation of IL-1 inhibition can substantially modify disease trajectory, preventing long-term complications and improving patient outcomes.
2025-09-27 | Role of Mast Cells in Human Health and Disease: Controversies and Novel Therapies.
Mast cells have been implicated in allergic diseases such as asthma, rhinitis, conjunctivitis, atopic dermatitis, urticaria, and anaphylaxis. However, it is now well established that they also fulfill critical roles in tissue homeostasis, repair, and defense. Despite considerable progress, their ontogeny, proliferation, and differentiation remain subjects of debate, as does their involvement in a wide spectrum of diseases, including cancer and cardiovascular disorders. What remains indisputable is their essential contribution to both innate and adaptive immune responses. Importantly, the activity of their effector molecules can elicit either protective or deleterious outcomes. A complete absence of mast cells (MCs) in humans would undoubtedly provide valuable insight into their fundamental role in immunity, much as neutropenia and agranulocytosis have historically clarified the functions of neutrophils. In this review, we provide a comprehensive overview of mast cell (MC) biology, emphasizing their functional diversity and pathogenic potential. Furthermore, we highlight emerging therapeutic strategies, particularly the use of inhibitors and monoclonal antibodies, which are reshaping current approaches to conditions such as allergy, mastocytosis, and related disorders.
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Drug Discovery Landscape
2 orphan drug designations for Muckle-Wells syndrome, including 2 approved therapies.
2 orphan drug designations for Muckle-Wells syndrome, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
anakinra [Kineret] | proteins | FDA | 2010-08-19 | 2012-12-21 | Swedish Orphan Biovitrum AB (publ) |
canakinumab [Ilaris] | antibodies | FDA | 2007-12-18 | 2009-06-17 | Novartis Pharmaceuticals Corporation |
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