RARE DISEASE
NLRP3-associated autoinflammatory disease
NLRP3-associated autoinflammatory disease
NLRP3-associated autoinflammatory disease
Synonyms: CAPS, Cryopyrin associated periodic syndrome, Cryopyrinopathy, NLRP3-associated AID, NLRP3-associated autoinflammatory syndrome
Synonyms: CAPS, Cryopyrin associated periodic syndrome, Cryopyrinopathy, NLRP3-associated AID, NLRP3-associated autoinflammatory syndrome
Synonyms: CAPS, Cryopyrin associated periodic syndrome, Cryopyrinopathy, NLRP3-associated AID, NLRP3-associated autoinflammatory syndrome
Drug discovery
5
drugs
With orphan designations
Overview
NLRP3-associated autoinflammatory disease (NLRP3-AID) is a rare, monogenic disorder caused by gain-of-function mutations in the NLRP3 gene, leading to IL-1β-driven systemic inflammation via inflammasome hyperactivation. It encompasses a severity spectrum from familial cold autoinflammatory syndrome (FCAS) to chronic infantile neurological cutaneous articular syndrome (CINCA), with symptoms including recurrent fever, urticaria-like rash, arthropathy, and sensorineural hearing loss [1][5][6].
Burden
Diagnostic delay: Median 5+ years, leading to irreversible organ damage (e.g., deafness, amyloidosis) [6][9]
Morbidity: Chronic inflammation causes growth retardation, neurological deficits, and reduced quality of life [6][16]
Healthcare costs: High due to lifelong biologics, multidisciplinary care, and complications management [4][6][14]
Therapies
Categories: rare genetic diseases, rare immunological diseases, rare skin diseases, rare systemic and rheumatological diseases, rare systemic or rheumatologic diseases of childhood
Research Papers
458 drug discovery papers about NLRP3-associated autoinflammatory disease, with 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
458 drug discovery papers about NLRP3-associated autoinflammatory disease, with 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-09-24 | Teclistamab for the treatment of autoantibody-mediated coagulation disorders.
Teclistamab is a bispecific monoclonal antibody that targets B cell maturation antigen (BCMA) on plasma cells and other B lineage cells and CD3 on T cells, thereby redirecting cytotoxic T cells to eliminate BCMA-expressing antibody-producing cells. Autoantibody-mediated coagulation disorders are often driven by long-lived antibody-producing cells that may persist despite conventional immunosuppression or B cell depletion. To investigate whether teclistamab represents a treatment option for patients with refractory or rapidly progressive autoantibody-mediated coagulation disorders. We retrospectively analyzed seven patients with autoantibody-mediated coagulation disorders treated with teclistamab. Diagnoses included acquired von Willebrand disease (n=2), acquired factor XI deficiency (n=2), and catastrophic antiphospholipid syndrome (CAPS; n=3). Five patients had an underlying paraprotein, whereas two CAPS patients had no detectable paraprotein. All seven patients achieved complete remissions (median time to remission: 24 weeks [range: 2-35]) following teclistamab. In the four patients with acquired von Willebrand disease or factor XI deficiency, improvement in the disease-defining coagulation parameter and cessation of bleeding were observed following initiation of teclistamab. In the three patients with CAPS disappearance of antiphospholipid antibodies or normalization of the aPTT-LA was observed and accompanied by clinical stabilization without further thromboembolic events. Treatment was generally well tolerated. Three patients developed grade 1 cytokine release syndrome. One patient developed transient colitis while another patient experienced reversible seronegative inflammatory joint symptoms. All patients received immunoglobulin replacement. Teclistamab treatment was associated with complete remissions in patients with autoantibody-mediated coagulation disorders. These observations warrant further evaluation of teclistamab in selected patients.
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.
2026-04-12 | Genotype-phenotype correlations in pediatric CAPS with predominantly low-penetrance NLRP3 variants among Turkish patients in Germany and Turkey: beyond borders.
The phenotypic heterogeneity and variable disease course of CAPS cannot be explained solely by NLRP3 mutations, suggesting additional environmental or modifying factors. This study aimed to characterize the phenotypic and genotypic features of Turkish-origin pediatric CAPS patients residing in Turkey (Turkish cohort) and Germany (German cohort). This multicenter, retrospective study included Turkish-origin pediatric patients meeting CAPS criteria from centers in Germany and Turkey. Demographic, genetic, clinical, and treatment data were collected, and disease activity was assessed using PGA and PPGA. The study included 51 Turkish-origin pediatric CAPS patients (living in Turkey: 23; Germany: 28) with a median age of disease onset at 1 year and diagnosis at 4 years. The Turkish cohort had more pathogenic mutations and more severe phenotypes, while the German cohort predominantly carried VUS/Q703K variants with a mild phenotype. Diagnostic delay and attack duration were longer in the Turkish cohort; urticarial rash, fatigue, thoracic pain, fever, and aphthous ulcers were more frequent, whereas diarrhea, lymphadenopathy, and infection-triggered attacks predominated in the German cohort. Baseline disease activity was higher in the Turkish cohort, and most patients achieved remission at last visit under therapy—mainly above-standard doses of Canakinumab—whereas over half of the German cohort reached remission without treatment. VUS and Q703K subgroup: Among patients with similar genotypes (VUS/Q703K), the Turkish cohort presented with older age at diagnosis, longer diagnostic delay, more moderate phenotypes, and higher baseline disease activity, whereas the German cohort exhibited milder phenotypes, infection-triggered attacks, and gastrointestinal involvement. The Turkish cohort received Canakinumab or Anakinra more frequently, often with dose adjustments and above-standard doses, achieving complete remission frequently under therapy at last visit, while the German cohort more often reached remission without treatment. Non-remission and partial remission were observed exclusively in the Turkish cohort. These findings suggest that Turkish-origin pediatric CAPS patients living in Turkey, including those with similar VUS/Q703K genotypes, may experience higher disease activity and greater treatment dependence than their German counterparts. However, as most patients in our cohort carried low-penetrance VUS variants, these observations are not directly generalizable to individuals with clearly pathogenic NLRP3 genotypes. Overall, this supports the notion that factors beyond genetics, potentially including environmental or modifying influences, contribute to CAPS severity and warrant further investigation. The online version contains supplementary material available at 10.1186/s12969-026-01214-7.
2026-03-18 | A case of cryopyrin-associated periodic syndrome presenting with abdominal symptoms due to a novel mutation NLRP3 p.Ile257Met.
A 24-year-old female patient with a 4-year history of recurrent abdominal pain, diarrhea, periodic fever and elevated C-reactive protein was referred to our institution. Colonoscopy, esophago-gastro-duodenoscopy, capsule endoscopy and contrast-enhanced CT showed no significant findings. Because she and her mother had sensorineural hearing loss, a diagnosis of cryopyrin-associated periodic syndrome was suspected. Genetic testing of the patient and her mother revealed a candidate germline variant of NLRP3. The patient was commenced on subcutaneous 150 mg canakinumab, a fully human monoclonal antibody targeting IL-1β, at a dose of 150 mg every 8 weeks, which resulted in the persistence of sensorineural hearing loss but led to the complete disappearance of her abdominal symptoms and periodic fever.
2026-02-03 | Variability of clinical symptoms of cryopyrin-associated periodic syndrome within the family
Cryopyrin-associated periodic syndrome is a group of autoinflammatory diseases caused by mutations in the NLRP3 gene, which lead to uncontrolled inflammasome activation and, consequently, excessive production of the proinflammatory cytokine interleukin 1β. Diagnosis is challenging, since many patients have a heterogeneous multisystem clinical picture. This publication presents a familial case of the disease with variability of manifestations from “blurred” and asymptomatic to a detailed clinical picture with multisystem involvement (persistent inflammatory activity, fever and urticaria associated with cold exposure, erythema nodosum, poly- and monoarthritis, uveitis, aphthous stomatitis, scrotal ulcers, and headache). Two patients had an atypical presentation of symptoms with predominant involvement of the joints, eyes, and oral mucosa, due to which one of them was initially given an alternative diagnosis of Behcet’s disease (syndrome). Genetic testing made it possible to identify a pathogenic mutation in the NLRP3 gene, verify the diagnosis, and promptly prescribe pathogenetic therapy with an interleukin 1 inhibitor, which is necessary to prevent irreversible organ damage (amyloidosis, sensorineural hearing loss, vision loss, etc.) and reduce the burden of the disease.
proteins
2026-07-28 | TRIM21 Orchestrates Inflammasome Assembly and Drives Autoinflammatory Pathology 2300561
Abstract Introduction Inflammasomes are pivotal cytoplasmic scaffolds that drive the maturation of interleukin (IL)-1β and IL-18 and initiate pyroptotic cell death. Tight regulation of inflammasome activity is critical, as uncontrolled IL-1β release underlies chronic inflammation and autoinflammatory disease. The adaptor protein ASC is essential for inflammasome assembly, and its polymerization and extracellular release amplify inflammatory responses. TRIM21, an E3 ubiquitin ligase and common autoantigen in autoimmune diseases, has been implicated in pyroptosis regulation; however, its role in inflammasome assembly and autoinflammatory disease remains unclear. Mechanistic insights into ASC polymerization and particle release are also incomplete. Methods We investigated TRIM21’s role in inflammasome activation using TRIM21-deficient human monocytes and bone marrow—derived macrophages from conditional Trim21 knockout mice. Systemic autoinflammation was assessed in murine models of cryopyrin-associated periodic syndrome (CAPS) and familial Mediterranean fever (FMF), and findings were validated in plasma from CAPS patients. Results TRIM21 is a conserved and essential mediator of inflammasome assembly. It interacts with, ubiquitinates, and promotes polymerization of ASC, facilitating inflammasome assembly and the release of ASC/TRIM21 particles during pyroptosis in human and mouse macrophages. Notably, systemic ASC/TRIM21 particles and corresponding autoantibodies were detected in both murine and human autoinflammatory disease. Conclusion Our findings establish TRIM21 as a critical regulator of inflammasome assembly and particle release, linking it to the pathogenesis of autoinflammatory disease. These results extend TRIM21’s known role in autoimmunity to a previously unrecognized function in driving inflammasome-mediated inflammation, highlighting it as a potential therapeutic target in autoinflammatory disorders. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)
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.
2026-05-21 | 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.
2025-12-03 | Effectiveness of "tumor necrosis factor inhibitors" in monogenic hereditary recurrent fevers in children and adolescents: a systematic review.
This systematic review aims to evaluate the clinical effectiveness of tumor necrosis factor (TNF) inhibitors in treating monogenic hereditary recurrent fevers (HRFs) in children and adolescents. We conducted a comprehensive literature search across MEDLINE, EMBASE, and Scopus up to May 2024, including case reports, case series, and observational studies involving pediatric patients with HRFs treated with TNF inhibitors. Articles were screened and selected based on PRISMA guidelines. Eleven pediatric cases were identified from ten studies, including patients with FMF (n=2), MKD/MKD (n=5), TRAPS (n=2), and CAPS (n=2). Etanercept was the most frequently used TNF inhibitor (10/11 cases), and infliximab was used in one FMF case. Follow-up duration ranged from 3 months to 4 years. Clinical responses varied: full remission in TRAPS cases; partial improvement in some MKD and CAPS cases; and no significant effect in several FMF and MKD/MKD patients. Etanercept showed the best outcomes in TRAPS, while responses in CAPS and MKD/MKD were inconsistent. TNFi may offer a therapeutic option for selected pediatric HRF cases, particularly colchicine-resistant FMF with articular symptoms or where IL-1 blockers are unavailable. However, their efficacy appears limited and variable across HRF subtypes. Larger studies are needed to better define the role of TNF inhibitors in pediatric HRFs.
small molecules
2026-08-20 | Current Advances in the Treatment of Autoinflammatory Disorders
Autoinflammatory disorders arise from dysregulated innate immunity, most commonly involving inflammasome activation and excessive interleukin-1 (IL-1) signaling. Although rare, these conditions are increasingly recognized across age groups as genetic testing expands and phenotypic classification improves. Therapeutic strategies focus on nonspecific immunosuppression of innate immune pathways. Corticosteroids remain effective for rapid suppression of acute inflammatory activity; however, their use is limited due to long-term toxicity. Colchicine is the first-line treatment for many autoinflammatory diseases, yet colchicine-resistant patients will require biologic therapy. IL-1 blockade represents the major therapeutic breakthrough across autoinflammatory syndromes. Anakinra, canakinumab, and rilonacept rapidly control symptoms and reduce the usage of corticosteroids. These agents are effective in cryopyrin-associated periodic syndromes, tumor necrosis factor receptor–associated periodic syndrome (TRAPS), mevalonate kinase deficiency, colchicine-resistant familial Mediterranean fever, and adult-onset Still’s disease. In selected phenotypes, alternative cytokine targeting is appropriate. Tumor necrosis factor inhibitors may benefit TRAPS, whereas IL-6 blockade is effective in Still’s disease–spectrum disorders. Increasing evidence supports the use of JAK inhibitors in interferon-mediated and complex autoinflammatory conditions that are resistant to other therapeutic agents. A new generation of direct inhibitors of the Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is in clinical development. These small molecules aim to suppress upstream inflammasome activation. Earlier diagnosis, rapid control of inflammation, improved quality of life, and prevention of long-term organ damage remain central goals. Guided therapy, cytokine profiling, and treat-to-target strategies using biomarkers together with long-acting biologics and oral inflammasome inhibitors are likely to be the mainstay of therapy over the coming decade. The treatment landscape for autoinflammatory disorders has significantly advanced, with targeted modulation of innate immune pathways and IL-1 blockade forming the backbone of therapy. Promising inflammasome-directed therapies and precision medicine approaches are expected to enhance long-term patient outcomes.
2026-08-20 | Schnitzler Syndrome at 50: What We’ve Learned So Far
First described by Liliane Schnitzler in 1972, Schnitzler syndrome (SchS) has evolved from a rare association of chronic urticarial rash and IgM monoclonal gammopathy into a well-defined acquired autoinflammatory disorder with systemic features—recurrent fever, arthralgia, bone pain, and elevated acute-phase reactants. A major conceptual shift came in the mid-2000s with recognition of overlap with cryopyrin-associated periodic syndromes (CAPS). The pivotal finding was that IL-1 blockade, particularly with anakinra, produced rapid, often complete symptom resolution—establishing IL-1β–mediated inflammation as central and reclassifying SchS as an innate immune disorder. Phenotypic similarity to CAPS prompted searches for NLRP3 mutations. Although isolated somatic mosaicism was reported, larger studies found no consistent mutations in classical SchS; many positive cases are now reclassified as late-onset CAPS. Current evidence supports NLRP3 inflammasome overactivation and excess IL-1β as downstream mechanisms, though the upstream trigger remains unknown. Attention has more recently turned to the clonal hematopoiesis associated with SchS. Somatic MYD88 L265P mutations, characteristic of Waldenström macroglobulinemia, occur in a subset of patients and might represent a plausible bridge (via NF-κB activation) between gammopathy and innate immune activation. Recently described “Schnitzler-like” syndromes, which lack monoclonal gammopathy but demonstrate other SchS traits, including IL-1 responsiveness, have prompted reconsideration of the SchS diagnostic criteria. Therapeutically, IL-1 inhibitors (e.g., anakinra, canakinumab) are now standard of care, inducing sustained remission and reducing AA amyloidosis risk, though they neither eliminate the paraprotein nor prevent lymphoproliferative progression. Clone-directed strategies—Bruton tyrosine kinase inhibitors and plasma cell–targeted agents—are under investigation. The fundamental relationship between monoclonal gammopathy and inflammasome activation remains unresolved, and clarifying it may enable a shift from cytokine suppression toward disease-modifying or curative approaches.
2026-08-12 | Trained immunity in autoinflammatory diseases: Cellular reprogramming across the monogenic-polygenic spectrum.
Trained immunity, an innate immunological memory induced by epigenetic and metabolic reprogramming, has changed the paradigm of host defense and pathogenesis of chronic inflammatory disease. Unlike adaptive immunological memory, trained immunity is characterized by the ability of innate immune cells and their progenitors to respond more robustly or differently to subsequent stimulations and contributes to chronic inflammatory conditions. Emerging data suggests that this process might be essential in autoinflammatory and immune-mediated inflammatory illnesses by enhancing sterile inflammation, decreasing activation thresholds, and boosting disease chronicity. This narrative review summarizes the existing evidence relating trained immunity to monogenic and polygenic autoinflammatory diseases. The greatest evidence in monogenic disease is for mevalonate kinase deficiency, where dysregulated mevalonate metabolism directly overlaps with conventional trained immunity pathways. Moderate evidence exists for familial Mediterranean fever, cryopyrin-associated periodic syndromes, and tumor necrosis factor receptor-associated periodic syndrome. For other rare hereditary autoinflammatory diseases, data are still inadequate. There is convincing evidence for a role of trained immunity in polygenic disorders like gout, atherosclerosis, obesity-associated "metaflammation", and type 2 diabetes and increasing evidence in Behçet's disease, adult-onset Still's disease, psoriasis, hidradenitis suppurativa, inflammatory bowel disease, and related inflammatory spectrum disorders. A major conceptual finding is that autoinflammatory illnesses may be a dynamic interplay between hereditary susceptibility and dysfunctional innate immune memory, rather than isolated static inflammatory abnormalities. However, information gaps still exist in reprogramming at the progenitor level, disease-specific epigenetic markers, and the reversibility of trained states. Understanding these systems may allow the development of therapeutic techniques to de-train abnormal innate immunological memory and obtain resilience for diseases.
2026-07-30 | Redefining the Landscape: Acquired Mutations Driving Systemic Autoinflammatory Diseases.
Mosaicism is a recognised cause of systemic autoinflammatory diseases (SAIDs). Initially described in Cryopyrin-Associated Periodic Syndromes (CAPS), it has since been reported in several dominantly inherited SAIDs, including Blau syndrome, TNF Receptor-Associated Periodic Syndrome (TRAPS), STING-Associated Vasculopathy with Onset in Infancy (SAVI), NLRC4 inflammasomopathies, and familial Mediterranean fever (FMF). Recently, somatic variants underlying Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome have extended this to late-onset disease. This study aimed to characterize the prevalence, spectrum, and clinical significance of acquired variants in SAIDs. 5530 patients referred to a national SAIDs reference centre between 2017-2025 underwent deep next-generation sequencing autoinflammatory gene panel testing to detect low-level mosaicism. Results underwent multidisciplinary review and correlation with clinical data from electronic medical records. SAIDs diagnosis was made in 403/5530 patients (7.3%, 95% CI 6.6-8.0%). Among these, mosaic variants were identified in 83 patients (20.6%, 95% CI 16.9-24.8%), including VEXAS (69%), CAPS (24%), TRAPS (5%), Blau syndrome (1%), and NLRC4 inflammasomopathies (1%). Twenty-three distinct mosaic variants were identified across different SAIDs genes; in eight, the minor allele frequency was ≤5%. We report the first case of vertical transmission of TRAPS due to gonosomal mosaicism. AA amyloidosis complicated the disease course in 20% of patients diagnosed with late-onset mosaic CAPS. Somatic mosaicism is a frequent mechanism underlying late-onset SAIDs, which are often diagnosed late and carry a high risk of AA amyloidosis. To our knowledge, this represents the largest genetically heterogeneous single-centre cohort of mosaic SAIDs reported to date.
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.
oligonucleotides
2026-03-20 | Targeting CD177: A Novel Therapeutic Strategy for NLRP3-Associated Autoinflammatory Diseases
NLRP3-associated autoinflammatory diseases (NLRP3-AIDs) are rare autoinflammatory disorders caused by uncontrolled inflammasome activation. While IL-1β blockade is first-line therapy, many patients respond inadequately, highlighting a need for alternative strategies. Transcriptomic analysis was performed on immune cells from a patient with an NLRP3 L573W mutation. Functional validation of CD177 as a downstream effector of NLRP3 activation was conducted. A novel NLRP3 L573W knock-in mouse model was established. Correlation between CD177 expression, disease severity, neutrophilia, and tissue damage was assessed. Therapeutic efficacy of siRNA-mediated CD177 silencing was evaluated and compared with IL-1β blockade. CD177, a neutrophil-specific protein, was significantly upregulated in NLRP3-mutant cells and confirmed as a direct downstream effector of NLRP3 activation. The NLRP3 L573W knock-in mouse recapitulated human disease heterogeneity, from mild self-limited inflammation to severe multi-organ pathology. CD177 expression correlated with disease severity, neutrophilia, and tissue damage. siRNA-mediated CD177 silencing attenuated systemic inflammation, reduced neutrophil infiltration and cytokine levels (IL-1β, IL-6, TNFα), and ameliorated multi-organ damage, with effects comparable to or exceeding those of IL-1β blockade. CD177 is a non-canonical amplifier of NLRP3-driven inflammation. Targeting CD177 represents a superior therapeutic strategy for NLRP3-AIDs, including IL-1β-refractory cases.
2024-09-17 | Modulating NLRP3 splicing with antisense oligonucleotides to control pathological inflammation.
Inflammation has an essential role in healing. However, over-active inflammation disrupts normal cellular functions and can be life-threatening when not resolved. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome, a component of the innate immune system, is an intracellular multiprotein complex that senses stress-associated signals, and, for this reason is a promising therapeutic target for treating unresolved, pathogenic inflammation. Alternative splicing of NLRP3 RNA has been suggested as a regulatory mechanism for inflammasome activation, as some spliced isoforms encode NLRP3 proteins with compromised function. Here, we take advantage of this natural regulatory mechanism and devise a way to control pathogenic inflammation using splice-switching antisense oligonucleotides (ASOs). To identify and induce NLRP3 isoforms lacking inflammatory activity, we tested a series of ASOs, each targeting a different exon, to determine the most effective strategy for down-regulating NLRP3. We identify several ASOs that modulate NLRP3 splicing, reduce NLRP3 protein, and decrease inflammasome signaling in vitro. The most effective ASO suppresses systemic inflammation in vivo in mouse models of acute inflammation and cryopyrin-associated periodic syndrome (CAPS). Overall, these results demonstrate how ASOs can be used to systematically engineer proteins with modified functions and treat pathological inflammation in mice by reducing functional NLRP3.
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.
2022-09-06 | NLRP3 leucine-rich repeats control induced and spontaneous inflammasome activation in cryopyrin-associated periodic syndrome
The cryopyrin-associated periodic syndromes (CAPS) comprise a group of rare autoinflammatory diseases caused by gain-of-function mutations in the NLRP3 gene. NLRP3 contains a leucine-rich repeats (LRR) domain with a highly conserved exonic organization that is subjected to extensive alternative splicing. Aberrant NLRP3 inflammasome assembly in CAPS causes chronic inflammation; however, the mechanisms regulating inflammasome function remain unclear.We aimed to elucidate the mechanisms regulating NLRP3-mediated autoinflammation in human disease, characterizing the role of LRR in inflammasome activation.We analyzed sequence read archive data to characterize the pattern of NLRP3 splicing in human monocytes and investigated the role of each LRR-coding exon in inflammasome regulation in genetically modified U937 cells representing CAPS and healthy conditions.We detected a range of NLRP3 splice variants in human primary cells and monocytic cell lines, including 2 yet-undescribed splice variants. We observe that lipopolysaccharides affect the abundance of certain splice variants, suggesting that they may regulate NLRP3 activation by affecting alternative splicing. We showed that exons 4, 5, 7, and 9 are essential for inflammasome function, both in the context of wild-type NLRP3 activation by the agonist molecule nigericin and in a model of CAPS-mediated NLRP3 inflammasome assembly. Moreover, the SGT1-NLRP3 interaction is decreased in nonfunctional variants, suggesting that alternative splicing may regulate the recruitment of proteins that facilitate inflammasome assembly.These findings demonstrate the contribution of the LRR domain in inflammasome function and suggest that navigating LRR exon usage within NLRP3 is sufficient to dampen inflammasome assembly in CAPS.
2019-05-01 | MicroRNA Post-transcriptional Regulation of the NLRP3 Inflammasome in Immunopathologies
Inflammation has a crucial role in protection against various pathogens. The inflammasome, is an intracellular multiprotein signaling complex, that is linked to pathogen sensing and initiation of the inflammatory response in physiological and pathological conditions. The most characterized inflammasome is the NLRP3 inflammasome, which is a known sensor of cell stress and is tightly regulated in resting cells. However, altered regulation of the NLRP3 inflammasome is found in several pathological conditions, including autoimmune disease and cancer. NLRP3 expression was shown to be post transcriptionally regulated and multiple miRNA have been implicated in post-transcriptional regulation of the inflammasome. Therefore, in recent years, miRNA based post transcriptional control of NLRP3 has become a focus of much research, especially as a potential therapeutic approach. In this review, we provide a summary of the recent investigations on the role of miRNA in the post transcriptional control of the NLRP3 inflammasome, a key regulator of pro-inflammatory IL-1β and IL-18 cytokine production. Current approaches to targeting the inflammasome product were shown to be an effective treatment for diseases linked to NLRP3 overexpression. Although utilizing NLRP3 targeting miRNAs was shown to be a successful therapeutic approach in several animal models, their therapeutic application in patients remains to be determined.
other
2023-06-03 | Constitutive IL-1RA production by modified immune cells protects against IL-1-mediated inflammatory disorders.
Dysregulation of the interleukin-1 (IL-1) pathway leads to immune diseases that can result in chronic tissue and organ inflammation. Although IL-1 blockade has shown promise in ameliorating these symptoms and improving patients' quality of life, there is an urgent need for more effective, long-lasting treatments. We developed a lentivirus (LV)-mediated gene transfer strategy using transplanted autologous hematopoietic stem/progenitor cells (HSPCs) as a source of IL-1 receptor antagonist (IL-1RA) for systemic delivery to tissues and organs. Transplantation of mouse and human HSPCs transduced with an IL-1RA-encoding LV ensured stable IL-1RA production while maintaining the clonogenic and differentiation capacities of HSPCs in vivo. We examined the efficacy of cell-mediated IL-1RA delivery in three models of IL-1-dependent inflammation, for which treatment hindered neutrophil recruitment in an inducible model of gout, prevented systemic and multi-tissue inflammation in a genetic model of cryopyrin-associated periodic syndromes, and reduced disease severity in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Our findings demonstrate HSPC-mediated IL-1RA delivery as a potential therapeutic modality that can be exploited to suppress tissue and organ inflammation in diverse immune-related diseases involving IL-1-driven inflammation.
antibodies
2026-09-24 | Teclistamab for the treatment of autoantibody-mediated coagulation disorders.
Teclistamab is a bispecific monoclonal antibody that targets B cell maturation antigen (BCMA) on plasma cells and other B lineage cells and CD3 on T cells, thereby redirecting cytotoxic T cells to eliminate BCMA-expressing antibody-producing cells. Autoantibody-mediated coagulation disorders are often driven by long-lived antibody-producing cells that may persist despite conventional immunosuppression or B cell depletion. To investigate whether teclistamab represents a treatment option for patients with refractory or rapidly progressive autoantibody-mediated coagulation disorders. We retrospectively analyzed seven patients with autoantibody-mediated coagulation disorders treated with teclistamab. Diagnoses included acquired von Willebrand disease (n=2), acquired factor XI deficiency (n=2), and catastrophic antiphospholipid syndrome (CAPS; n=3). Five patients had an underlying paraprotein, whereas two CAPS patients had no detectable paraprotein. All seven patients achieved complete remissions (median time to remission: 24 weeks [range: 2-35]) following teclistamab. In the four patients with acquired von Willebrand disease or factor XI deficiency, improvement in the disease-defining coagulation parameter and cessation of bleeding were observed following initiation of teclistamab. In the three patients with CAPS disappearance of antiphospholipid antibodies or normalization of the aPTT-LA was observed and accompanied by clinical stabilization without further thromboembolic events. Treatment was generally well tolerated. Three patients developed grade 1 cytokine release syndrome. One patient developed transient colitis while another patient experienced reversible seronegative inflammatory joint symptoms. All patients received immunoglobulin replacement. Teclistamab treatment was associated with complete remissions in patients with autoantibody-mediated coagulation disorders. These observations warrant further evaluation of teclistamab in selected patients.
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.
2026-04-12 | Genotype-phenotype correlations in pediatric CAPS with predominantly low-penetrance NLRP3 variants among Turkish patients in Germany and Turkey: beyond borders.
The phenotypic heterogeneity and variable disease course of CAPS cannot be explained solely by NLRP3 mutations, suggesting additional environmental or modifying factors. This study aimed to characterize the phenotypic and genotypic features of Turkish-origin pediatric CAPS patients residing in Turkey (Turkish cohort) and Germany (German cohort). This multicenter, retrospective study included Turkish-origin pediatric patients meeting CAPS criteria from centers in Germany and Turkey. Demographic, genetic, clinical, and treatment data were collected, and disease activity was assessed using PGA and PPGA. The study included 51 Turkish-origin pediatric CAPS patients (living in Turkey: 23; Germany: 28) with a median age of disease onset at 1 year and diagnosis at 4 years. The Turkish cohort had more pathogenic mutations and more severe phenotypes, while the German cohort predominantly carried VUS/Q703K variants with a mild phenotype. Diagnostic delay and attack duration were longer in the Turkish cohort; urticarial rash, fatigue, thoracic pain, fever, and aphthous ulcers were more frequent, whereas diarrhea, lymphadenopathy, and infection-triggered attacks predominated in the German cohort. Baseline disease activity was higher in the Turkish cohort, and most patients achieved remission at last visit under therapy—mainly above-standard doses of Canakinumab—whereas over half of the German cohort reached remission without treatment. VUS and Q703K subgroup: Among patients with similar genotypes (VUS/Q703K), the Turkish cohort presented with older age at diagnosis, longer diagnostic delay, more moderate phenotypes, and higher baseline disease activity, whereas the German cohort exhibited milder phenotypes, infection-triggered attacks, and gastrointestinal involvement. The Turkish cohort received Canakinumab or Anakinra more frequently, often with dose adjustments and above-standard doses, achieving complete remission frequently under therapy at last visit, while the German cohort more often reached remission without treatment. Non-remission and partial remission were observed exclusively in the Turkish cohort. These findings suggest that Turkish-origin pediatric CAPS patients living in Turkey, including those with similar VUS/Q703K genotypes, may experience higher disease activity and greater treatment dependence than their German counterparts. However, as most patients in our cohort carried low-penetrance VUS variants, these observations are not directly generalizable to individuals with clearly pathogenic NLRP3 genotypes. Overall, this supports the notion that factors beyond genetics, potentially including environmental or modifying influences, contribute to CAPS severity and warrant further investigation. The online version contains supplementary material available at 10.1186/s12969-026-01214-7.
2026-03-18 | A case of cryopyrin-associated periodic syndrome presenting with abdominal symptoms due to a novel mutation NLRP3 p.Ile257Met.
A 24-year-old female patient with a 4-year history of recurrent abdominal pain, diarrhea, periodic fever and elevated C-reactive protein was referred to our institution. Colonoscopy, esophago-gastro-duodenoscopy, capsule endoscopy and contrast-enhanced CT showed no significant findings. Because she and her mother had sensorineural hearing loss, a diagnosis of cryopyrin-associated periodic syndrome was suspected. Genetic testing of the patient and her mother revealed a candidate germline variant of NLRP3. The patient was commenced on subcutaneous 150 mg canakinumab, a fully human monoclonal antibody targeting IL-1β, at a dose of 150 mg every 8 weeks, which resulted in the persistence of sensorineural hearing loss but led to the complete disappearance of her abdominal symptoms and periodic fever.
2026-02-03 | Variability of clinical symptoms of cryopyrin-associated periodic syndrome within the family
Cryopyrin-associated periodic syndrome is a group of autoinflammatory diseases caused by mutations in the NLRP3 gene, which lead to uncontrolled inflammasome activation and, consequently, excessive production of the proinflammatory cytokine interleukin 1β. Diagnosis is challenging, since many patients have a heterogeneous multisystem clinical picture. This publication presents a familial case of the disease with variability of manifestations from “blurred” and asymptomatic to a detailed clinical picture with multisystem involvement (persistent inflammatory activity, fever and urticaria associated with cold exposure, erythema nodosum, poly- and monoarthritis, uveitis, aphthous stomatitis, scrotal ulcers, and headache). Two patients had an atypical presentation of symptoms with predominant involvement of the joints, eyes, and oral mucosa, due to which one of them was initially given an alternative diagnosis of Behcet’s disease (syndrome). Genetic testing made it possible to identify a pathogenic mutation in the NLRP3 gene, verify the diagnosis, and promptly prescribe pathogenetic therapy with an interleukin 1 inhibitor, which is necessary to prevent irreversible organ damage (amyloidosis, sensorineural hearing loss, vision loss, etc.) and reduce the burden of the disease.
proteins
2026-07-28 | TRIM21 Orchestrates Inflammasome Assembly and Drives Autoinflammatory Pathology 2300561
Abstract Introduction Inflammasomes are pivotal cytoplasmic scaffolds that drive the maturation of interleukin (IL)-1β and IL-18 and initiate pyroptotic cell death. Tight regulation of inflammasome activity is critical, as uncontrolled IL-1β release underlies chronic inflammation and autoinflammatory disease. The adaptor protein ASC is essential for inflammasome assembly, and its polymerization and extracellular release amplify inflammatory responses. TRIM21, an E3 ubiquitin ligase and common autoantigen in autoimmune diseases, has been implicated in pyroptosis regulation; however, its role in inflammasome assembly and autoinflammatory disease remains unclear. Mechanistic insights into ASC polymerization and particle release are also incomplete. Methods We investigated TRIM21’s role in inflammasome activation using TRIM21-deficient human monocytes and bone marrow—derived macrophages from conditional Trim21 knockout mice. Systemic autoinflammation was assessed in murine models of cryopyrin-associated periodic syndrome (CAPS) and familial Mediterranean fever (FMF), and findings were validated in plasma from CAPS patients. Results TRIM21 is a conserved and essential mediator of inflammasome assembly. It interacts with, ubiquitinates, and promotes polymerization of ASC, facilitating inflammasome assembly and the release of ASC/TRIM21 particles during pyroptosis in human and mouse macrophages. Notably, systemic ASC/TRIM21 particles and corresponding autoantibodies were detected in both murine and human autoinflammatory disease. Conclusion Our findings establish TRIM21 as a critical regulator of inflammasome assembly and particle release, linking it to the pathogenesis of autoinflammatory disease. These results extend TRIM21’s known role in autoimmunity to a previously unrecognized function in driving inflammasome-mediated inflammation, highlighting it as a potential therapeutic target in autoinflammatory disorders. Funding Source n/a Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)
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.
2026-05-21 | 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.
2025-12-03 | Effectiveness of "tumor necrosis factor inhibitors" in monogenic hereditary recurrent fevers in children and adolescents: a systematic review.
This systematic review aims to evaluate the clinical effectiveness of tumor necrosis factor (TNF) inhibitors in treating monogenic hereditary recurrent fevers (HRFs) in children and adolescents. We conducted a comprehensive literature search across MEDLINE, EMBASE, and Scopus up to May 2024, including case reports, case series, and observational studies involving pediatric patients with HRFs treated with TNF inhibitors. Articles were screened and selected based on PRISMA guidelines. Eleven pediatric cases were identified from ten studies, including patients with FMF (n=2), MKD/MKD (n=5), TRAPS (n=2), and CAPS (n=2). Etanercept was the most frequently used TNF inhibitor (10/11 cases), and infliximab was used in one FMF case. Follow-up duration ranged from 3 months to 4 years. Clinical responses varied: full remission in TRAPS cases; partial improvement in some MKD and CAPS cases; and no significant effect in several FMF and MKD/MKD patients. Etanercept showed the best outcomes in TRAPS, while responses in CAPS and MKD/MKD were inconsistent. TNFi may offer a therapeutic option for selected pediatric HRF cases, particularly colchicine-resistant FMF with articular symptoms or where IL-1 blockers are unavailable. However, their efficacy appears limited and variable across HRF subtypes. Larger studies are needed to better define the role of TNF inhibitors in pediatric HRFs.
small molecules
2026-08-20 | Current Advances in the Treatment of Autoinflammatory Disorders
Autoinflammatory disorders arise from dysregulated innate immunity, most commonly involving inflammasome activation and excessive interleukin-1 (IL-1) signaling. Although rare, these conditions are increasingly recognized across age groups as genetic testing expands and phenotypic classification improves. Therapeutic strategies focus on nonspecific immunosuppression of innate immune pathways. Corticosteroids remain effective for rapid suppression of acute inflammatory activity; however, their use is limited due to long-term toxicity. Colchicine is the first-line treatment for many autoinflammatory diseases, yet colchicine-resistant patients will require biologic therapy. IL-1 blockade represents the major therapeutic breakthrough across autoinflammatory syndromes. Anakinra, canakinumab, and rilonacept rapidly control symptoms and reduce the usage of corticosteroids. These agents are effective in cryopyrin-associated periodic syndromes, tumor necrosis factor receptor–associated periodic syndrome (TRAPS), mevalonate kinase deficiency, colchicine-resistant familial Mediterranean fever, and adult-onset Still’s disease. In selected phenotypes, alternative cytokine targeting is appropriate. Tumor necrosis factor inhibitors may benefit TRAPS, whereas IL-6 blockade is effective in Still’s disease–spectrum disorders. Increasing evidence supports the use of JAK inhibitors in interferon-mediated and complex autoinflammatory conditions that are resistant to other therapeutic agents. A new generation of direct inhibitors of the Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is in clinical development. These small molecules aim to suppress upstream inflammasome activation. Earlier diagnosis, rapid control of inflammation, improved quality of life, and prevention of long-term organ damage remain central goals. Guided therapy, cytokine profiling, and treat-to-target strategies using biomarkers together with long-acting biologics and oral inflammasome inhibitors are likely to be the mainstay of therapy over the coming decade. The treatment landscape for autoinflammatory disorders has significantly advanced, with targeted modulation of innate immune pathways and IL-1 blockade forming the backbone of therapy. Promising inflammasome-directed therapies and precision medicine approaches are expected to enhance long-term patient outcomes.
2026-08-20 | Schnitzler Syndrome at 50: What We’ve Learned So Far
First described by Liliane Schnitzler in 1972, Schnitzler syndrome (SchS) has evolved from a rare association of chronic urticarial rash and IgM monoclonal gammopathy into a well-defined acquired autoinflammatory disorder with systemic features—recurrent fever, arthralgia, bone pain, and elevated acute-phase reactants. A major conceptual shift came in the mid-2000s with recognition of overlap with cryopyrin-associated periodic syndromes (CAPS). The pivotal finding was that IL-1 blockade, particularly with anakinra, produced rapid, often complete symptom resolution—establishing IL-1β–mediated inflammation as central and reclassifying SchS as an innate immune disorder. Phenotypic similarity to CAPS prompted searches for NLRP3 mutations. Although isolated somatic mosaicism was reported, larger studies found no consistent mutations in classical SchS; many positive cases are now reclassified as late-onset CAPS. Current evidence supports NLRP3 inflammasome overactivation and excess IL-1β as downstream mechanisms, though the upstream trigger remains unknown. Attention has more recently turned to the clonal hematopoiesis associated with SchS. Somatic MYD88 L265P mutations, characteristic of Waldenström macroglobulinemia, occur in a subset of patients and might represent a plausible bridge (via NF-κB activation) between gammopathy and innate immune activation. Recently described “Schnitzler-like” syndromes, which lack monoclonal gammopathy but demonstrate other SchS traits, including IL-1 responsiveness, have prompted reconsideration of the SchS diagnostic criteria. Therapeutically, IL-1 inhibitors (e.g., anakinra, canakinumab) are now standard of care, inducing sustained remission and reducing AA amyloidosis risk, though they neither eliminate the paraprotein nor prevent lymphoproliferative progression. Clone-directed strategies—Bruton tyrosine kinase inhibitors and plasma cell–targeted agents—are under investigation. The fundamental relationship between monoclonal gammopathy and inflammasome activation remains unresolved, and clarifying it may enable a shift from cytokine suppression toward disease-modifying or curative approaches.
2026-08-12 | Trained immunity in autoinflammatory diseases: Cellular reprogramming across the monogenic-polygenic spectrum.
Trained immunity, an innate immunological memory induced by epigenetic and metabolic reprogramming, has changed the paradigm of host defense and pathogenesis of chronic inflammatory disease. Unlike adaptive immunological memory, trained immunity is characterized by the ability of innate immune cells and their progenitors to respond more robustly or differently to subsequent stimulations and contributes to chronic inflammatory conditions. Emerging data suggests that this process might be essential in autoinflammatory and immune-mediated inflammatory illnesses by enhancing sterile inflammation, decreasing activation thresholds, and boosting disease chronicity. This narrative review summarizes the existing evidence relating trained immunity to monogenic and polygenic autoinflammatory diseases. The greatest evidence in monogenic disease is for mevalonate kinase deficiency, where dysregulated mevalonate metabolism directly overlaps with conventional trained immunity pathways. Moderate evidence exists for familial Mediterranean fever, cryopyrin-associated periodic syndromes, and tumor necrosis factor receptor-associated periodic syndrome. For other rare hereditary autoinflammatory diseases, data are still inadequate. There is convincing evidence for a role of trained immunity in polygenic disorders like gout, atherosclerosis, obesity-associated "metaflammation", and type 2 diabetes and increasing evidence in Behçet's disease, adult-onset Still's disease, psoriasis, hidradenitis suppurativa, inflammatory bowel disease, and related inflammatory spectrum disorders. A major conceptual finding is that autoinflammatory illnesses may be a dynamic interplay between hereditary susceptibility and dysfunctional innate immune memory, rather than isolated static inflammatory abnormalities. However, information gaps still exist in reprogramming at the progenitor level, disease-specific epigenetic markers, and the reversibility of trained states. Understanding these systems may allow the development of therapeutic techniques to de-train abnormal innate immunological memory and obtain resilience for diseases.
2026-07-30 | Redefining the Landscape: Acquired Mutations Driving Systemic Autoinflammatory Diseases.
Mosaicism is a recognised cause of systemic autoinflammatory diseases (SAIDs). Initially described in Cryopyrin-Associated Periodic Syndromes (CAPS), it has since been reported in several dominantly inherited SAIDs, including Blau syndrome, TNF Receptor-Associated Periodic Syndrome (TRAPS), STING-Associated Vasculopathy with Onset in Infancy (SAVI), NLRC4 inflammasomopathies, and familial Mediterranean fever (FMF). Recently, somatic variants underlying Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome have extended this to late-onset disease. This study aimed to characterize the prevalence, spectrum, and clinical significance of acquired variants in SAIDs. 5530 patients referred to a national SAIDs reference centre between 2017-2025 underwent deep next-generation sequencing autoinflammatory gene panel testing to detect low-level mosaicism. Results underwent multidisciplinary review and correlation with clinical data from electronic medical records. SAIDs diagnosis was made in 403/5530 patients (7.3%, 95% CI 6.6-8.0%). Among these, mosaic variants were identified in 83 patients (20.6%, 95% CI 16.9-24.8%), including VEXAS (69%), CAPS (24%), TRAPS (5%), Blau syndrome (1%), and NLRC4 inflammasomopathies (1%). Twenty-three distinct mosaic variants were identified across different SAIDs genes; in eight, the minor allele frequency was ≤5%. We report the first case of vertical transmission of TRAPS due to gonosomal mosaicism. AA amyloidosis complicated the disease course in 20% of patients diagnosed with late-onset mosaic CAPS. Somatic mosaicism is a frequent mechanism underlying late-onset SAIDs, which are often diagnosed late and carry a high risk of AA amyloidosis. To our knowledge, this represents the largest genetically heterogeneous single-centre cohort of mosaic SAIDs reported to date.
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.
oligonucleotides
2026-03-20 | Targeting CD177: A Novel Therapeutic Strategy for NLRP3-Associated Autoinflammatory Diseases
NLRP3-associated autoinflammatory diseases (NLRP3-AIDs) are rare autoinflammatory disorders caused by uncontrolled inflammasome activation. While IL-1β blockade is first-line therapy, many patients respond inadequately, highlighting a need for alternative strategies. Transcriptomic analysis was performed on immune cells from a patient with an NLRP3 L573W mutation. Functional validation of CD177 as a downstream effector of NLRP3 activation was conducted. A novel NLRP3 L573W knock-in mouse model was established. Correlation between CD177 expression, disease severity, neutrophilia, and tissue damage was assessed. Therapeutic efficacy of siRNA-mediated CD177 silencing was evaluated and compared with IL-1β blockade. CD177, a neutrophil-specific protein, was significantly upregulated in NLRP3-mutant cells and confirmed as a direct downstream effector of NLRP3 activation. The NLRP3 L573W knock-in mouse recapitulated human disease heterogeneity, from mild self-limited inflammation to severe multi-organ pathology. CD177 expression correlated with disease severity, neutrophilia, and tissue damage. siRNA-mediated CD177 silencing attenuated systemic inflammation, reduced neutrophil infiltration and cytokine levels (IL-1β, IL-6, TNFα), and ameliorated multi-organ damage, with effects comparable to or exceeding those of IL-1β blockade. CD177 is a non-canonical amplifier of NLRP3-driven inflammation. Targeting CD177 represents a superior therapeutic strategy for NLRP3-AIDs, including IL-1β-refractory cases.
2024-09-17 | Modulating NLRP3 splicing with antisense oligonucleotides to control pathological inflammation.
Inflammation has an essential role in healing. However, over-active inflammation disrupts normal cellular functions and can be life-threatening when not resolved. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome, a component of the innate immune system, is an intracellular multiprotein complex that senses stress-associated signals, and, for this reason is a promising therapeutic target for treating unresolved, pathogenic inflammation. Alternative splicing of NLRP3 RNA has been suggested as a regulatory mechanism for inflammasome activation, as some spliced isoforms encode NLRP3 proteins with compromised function. Here, we take advantage of this natural regulatory mechanism and devise a way to control pathogenic inflammation using splice-switching antisense oligonucleotides (ASOs). To identify and induce NLRP3 isoforms lacking inflammatory activity, we tested a series of ASOs, each targeting a different exon, to determine the most effective strategy for down-regulating NLRP3. We identify several ASOs that modulate NLRP3 splicing, reduce NLRP3 protein, and decrease inflammasome signaling in vitro. The most effective ASO suppresses systemic inflammation in vivo in mouse models of acute inflammation and cryopyrin-associated periodic syndrome (CAPS). Overall, these results demonstrate how ASOs can be used to systematically engineer proteins with modified functions and treat pathological inflammation in mice by reducing functional NLRP3.
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.
2022-09-06 | NLRP3 leucine-rich repeats control induced and spontaneous inflammasome activation in cryopyrin-associated periodic syndrome
The cryopyrin-associated periodic syndromes (CAPS) comprise a group of rare autoinflammatory diseases caused by gain-of-function mutations in the NLRP3 gene. NLRP3 contains a leucine-rich repeats (LRR) domain with a highly conserved exonic organization that is subjected to extensive alternative splicing. Aberrant NLRP3 inflammasome assembly in CAPS causes chronic inflammation; however, the mechanisms regulating inflammasome function remain unclear.We aimed to elucidate the mechanisms regulating NLRP3-mediated autoinflammation in human disease, characterizing the role of LRR in inflammasome activation.We analyzed sequence read archive data to characterize the pattern of NLRP3 splicing in human monocytes and investigated the role of each LRR-coding exon in inflammasome regulation in genetically modified U937 cells representing CAPS and healthy conditions.We detected a range of NLRP3 splice variants in human primary cells and monocytic cell lines, including 2 yet-undescribed splice variants. We observe that lipopolysaccharides affect the abundance of certain splice variants, suggesting that they may regulate NLRP3 activation by affecting alternative splicing. We showed that exons 4, 5, 7, and 9 are essential for inflammasome function, both in the context of wild-type NLRP3 activation by the agonist molecule nigericin and in a model of CAPS-mediated NLRP3 inflammasome assembly. Moreover, the SGT1-NLRP3 interaction is decreased in nonfunctional variants, suggesting that alternative splicing may regulate the recruitment of proteins that facilitate inflammasome assembly.These findings demonstrate the contribution of the LRR domain in inflammasome function and suggest that navigating LRR exon usage within NLRP3 is sufficient to dampen inflammasome assembly in CAPS.
2019-05-01 | MicroRNA Post-transcriptional Regulation of the NLRP3 Inflammasome in Immunopathologies
Inflammation has a crucial role in protection against various pathogens. The inflammasome, is an intracellular multiprotein signaling complex, that is linked to pathogen sensing and initiation of the inflammatory response in physiological and pathological conditions. The most characterized inflammasome is the NLRP3 inflammasome, which is a known sensor of cell stress and is tightly regulated in resting cells. However, altered regulation of the NLRP3 inflammasome is found in several pathological conditions, including autoimmune disease and cancer. NLRP3 expression was shown to be post transcriptionally regulated and multiple miRNA have been implicated in post-transcriptional regulation of the inflammasome. Therefore, in recent years, miRNA based post transcriptional control of NLRP3 has become a focus of much research, especially as a potential therapeutic approach. In this review, we provide a summary of the recent investigations on the role of miRNA in the post transcriptional control of the NLRP3 inflammasome, a key regulator of pro-inflammatory IL-1β and IL-18 cytokine production. Current approaches to targeting the inflammasome product were shown to be an effective treatment for diseases linked to NLRP3 overexpression. Although utilizing NLRP3 targeting miRNAs was shown to be a successful therapeutic approach in several animal models, their therapeutic application in patients remains to be determined.
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2023-06-03 | Constitutive IL-1RA production by modified immune cells protects against IL-1-mediated inflammatory disorders.
Dysregulation of the interleukin-1 (IL-1) pathway leads to immune diseases that can result in chronic tissue and organ inflammation. Although IL-1 blockade has shown promise in ameliorating these symptoms and improving patients' quality of life, there is an urgent need for more effective, long-lasting treatments. We developed a lentivirus (LV)-mediated gene transfer strategy using transplanted autologous hematopoietic stem/progenitor cells (HSPCs) as a source of IL-1 receptor antagonist (IL-1RA) for systemic delivery to tissues and organs. Transplantation of mouse and human HSPCs transduced with an IL-1RA-encoding LV ensured stable IL-1RA production while maintaining the clonogenic and differentiation capacities of HSPCs in vivo. We examined the efficacy of cell-mediated IL-1RA delivery in three models of IL-1-dependent inflammation, for which treatment hindered neutrophil recruitment in an inducible model of gout, prevented systemic and multi-tissue inflammation in a genetic model of cryopyrin-associated periodic syndromes, and reduced disease severity in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Our findings demonstrate HSPC-mediated IL-1RA delivery as a potential therapeutic modality that can be exploited to suppress tissue and organ inflammation in diverse immune-related diseases involving IL-1-driven inflammation.
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Drug Discovery Landscape
5 orphan drug designations for NLRP3-associated autoinflammatory disease, including 1 approved therapy.
5 orphan drug designations for NLRP3-associated autoinflammatory disease, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Ethenesulfonamide, 2-[(2R)-1,2-dimethyl-2- pyrrolidinyl]-N-[[(1,2,3,5,6,7-hexahydro-s-indacen-4- yl)amino]carbonyl]-, (1E)- | small molecules | FDA | Zydus Therapeutics Inc. | |
ATI-450, an orally available small molecule inhibitor of the p38alpha mitogen activated protein kinase (MAPK)/MAPK-activated protein kinase 2 (MK2) inflammatory signaling pathway | small molecules | FDA | Aclaris Theapeutics Inc. | |
N-[[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl) amino]carbonyl]-1-(1-methylethyl)-1H-Pyrazole-3-sulfonamide | small molecules | FDA | Genentech, Inc., a Member of the Roche Group | |
Rilonacept [Rilonacept] | proteins | EMA | [INACTIVE] Regeneron UK Limited | |
Rilonacept [Arcalyst] | proteins | FDA | Approved | Regeneron Pharmaceuticals, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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