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:
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.
2026-07-16 | 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.
2026-06-15 | 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.
2026-06-10 | 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.
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.
2026-07-16 | 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.
2026-06-15 | 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.
2026-06-10 | 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.
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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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