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Commentary

The Golden Card of Interleukin-1 Blockers in Systemic Inflammasomopathies of Childhood

1
Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
2
Periodic Fever and Rare Diseases Research Centre, Università Cattolica Sacro Cuore, 00168 Rome, Italy
Int. J. Mol. Sci. 2025, 26(5), 1872; https://doi.org/10.3390/ijms26051872
Submission received: 1 February 2025 / Revised: 19 February 2025 / Accepted: 20 February 2025 / Published: 21 February 2025

Abstract

:
A growing number of systemic hereditary inflammatory diseases characterized by periodic fevers and elevated acute-phase proteins during flares has been linked to deregulated inflammasome function and excessive bioactivity of interleukin (IL)-1. All these conditions respond, at varying degrees, to the specific blockade of IL-1. The remarkable progress with IL-1 antagonists in treating hereditary inflammasome-based disorders has offered new hope for several patients with further non-hereditary autoinflammatory conditions from multifactorial backgrounds. The effectiveness of the IL-1 blockade has transformed our understanding and management of many complex diseases and highlighted the role of aberrant IL-1 signaling in enigmatic conditions, characterized by recurrent or continuous inflammation and a lack of a role for autoreactive T-cells or autoantibody production. To date, the long-term blockade of IL-1 has been found to restore the clinical equilibrium in systemic inflammasomopathies of childhood, and IL-1 inhibitors have become cardinal weapons in managing both monogenic innate immunity defects and a plethora of polygenic diseases occurring in children, including Still’s disease, Kawasaki disease, recurrent pericarditis, chronic non-bacterial osteomyelitis, and Behçet’s disease. Very few side effects have been reported with the long-term use of anakinra, rilonacept, or canakinumab, and their safety profile has been largely documented even in childhood. Further investigations into the role of inflammasomes in the pathogenesis of autoimmune conditions as well as brain degenerative or cardiovascular disorders can be expected, paving the way for precision medicine with benefits beyond inhibiting signaling by individual IL-1-family cytokines.

The human immune system is equipped with a multi-layered gendarmerie to sense and counteract infectious agents, endogenous metabolites, or non-self and hidden dangers with the aim of ensuring the body’s safety and its integrity [1]. Immunity cells impact the response gating through pattern recognition receptors which coordinate cell migration, phagocytosis, cytolytic activity, and the release of cytokines to patrol and manage cell turnover and death in jeopardized tissues [2]. Interleukin (IL)-1 is an ancestral pyrogen with varying functions through a squad of adjutants, governing an intertwined network of molecules which incipiunt many innate immunity responses after a stressful event [3]. The components of the ‘enlarged’ IL-1 family include ligands endowed with agonist, antagonist, pro-inflammatory, or anti-inflammatory activities, and receptor chains that contribute to the shaping and steering of inflammation, as well as polarizing myeloid cells towards either innate or adaptive pathways: IL-1α,/1β, IL-18, IL-33, IL-36α/β/γ act as extracellular soluble factors, while IL-1/IL-36 receptor antagonists, IL-37, IL-38, with uneven powers and localization, have counterbalancing effects [4]. IL-1α and IL-1β share the same receptor complex, and both are synthesized as outrider proteins: the first by mesenchymal cells without the need for enzymatic cleavage, and the second by different mononuclear cells after caspase-related cleavage [5]. IL-18 is another IL-1 family-striker which induces interferon release and promotes cytotoxic and natural killer cells, magnifying the loop of IL-1 activities, and finally enhancing antimicrobial activity and long-term immunologic memory [6]. Both IL-1β and IL-18 are generated by the ‘inflammasome’, an intracellular multi-protein complex that transmutes the sensing of danger signals to caspase-1 cleaving activity upon pro-IL-1β and pro-IL-18 [7]. According to the dominant driver of inflammation—specifically IL-1, nuclear factor-κB [combined with tumor necrosis factor (TNF)], or interferon—the related “autoinflammatory diseases” can be outlined into inflammasomopathies, relopathies, or interferonopathies, respectively, justifying coherently targeted therapies (Table 1).
Inflammasome activation triggers two major responses: the induction of gasdermin D pore-mediated inflammatory cell death, known as pyroptosis, and the caspase-1-promoted secretion of pro-inflammatory cytokines. The subverted production of IL-1 bonds many conditions driven by disrupted inflammasome activity [8], either monogenic or multifactorial, that may involve countless tissues and organs, even the seemingly most inert ones like serosal membranes and skin [9,10]. Inflammasomes take their name from the sensor component; of these, the NLRP3 inflammasome is the most studied: the discovery that gain-of-function NLRP3 mutations caused the cryopyrin-associated periodic syndrome (CAPS) was a breakthrough at the doorway of the post-genomic medicine era [11]. Non-anti-IL-1 agents, which were the first biologics introduced in pediatric rheumatology, are poorly effective in controlling the CAPS disease spectrum, varying from familial cold-induced urticaria to CINCA syndrome [12], while IL-1 inhibition was the only solution for the most severe CAPS symptoms: initially anakinra, the recombinant form of the natural IL-1 antagonist that inhibits both IL-1α and IL-1β, followed by rilonacept, a dimeric fusion protein consisting of the soluble receptor that traps both IL-1α and IL-1β, and canakinumab, the human-specific anti-IL-1β monoclonal antibody [13,14].
A peculiar pyrin inflammasome is otherwise involved in children with familial Mediterranean fever (FMF), the most common autoinflammatory disorder, which is caused by mutations in the MEFV gene. Mutated pyrins specifically have a decreased activation threshold, leading to pyrin hypophosphorylation and blooming release of IL-1β and IL-18 [15,16]. The link to IL-1 production may be less direct for other conditions, such as TNF receptor-associated periodic fever syndrome, caused by mutations in the TNFRSF1A gene encoding the 55-kD TNF receptor: neutrophils of these patients are less prone to apoptosis and oversecrete many transcription factors [17], but the intracellular accumulation of misfolded TNF receptors triggers inflammasome activation and enhances IL-1β release [18]. Lastly, the increased production of IL-1β due to reduced protein geranylgeranylation underlies the inflammatory flares in children with mevalonate kinase deficiency, a metabolic disease arising from variants within the MVK gene, which block isoprenoid biosynthesis and bring about a vast array of autoinflammatory manifestations [19].
For these reasons, the IL-1 pathway is the logical therapeutic target for patients affected by inflammasomopathies, as supported by different case series demonstrating the efficacy of IL-1 inhibitors, confirmed by improvements in inflammatory markers and improvements in diary scores, as well as physician and patient global pain assessment tools. Despite their motley clinical signs, heritability pattern, and penetrance, all inflammasomopathies have been shown to share a favorable response to the IL-1 blockade, which has become their seminal branding. A diagnosis of inflammasome-related diseases may even be corroborated by the results following the administration of IL-1 inhibitors [20]. The once-daily injection of anakinra, the once-weekly injection of rilonacept, and the once-monthly injection of canakinumab may result in a different compliance to therapies. However, there are very few randomized controlled studies assessing interventions for children with inflammasomopathies comparing active interventions (including IL-1 antagonists) with placebo or no treatment or comparing active drugs to each other.
In addition to notable success in treating patients with such rare autoinflammatory diseases, targeting IL-1 activity has shown considerable promise in more common diseases considered to have inflammatory IL-1 activity as a key pathogenic mechanism. For instance, this strategy has been extended beyond pediatric patients to include brain degenerative or cardiovascular disorders and autoinflammatory-based pericardial diseases, while the significance of IL-1 in tumor development is currently under investigation [21]. Despite the clinical advantage of IL-1 blockers over other standards of care, they unfortunately remain largely out of reach for patients living in low- or middle-income countries, reflecting access to care as an arduous social issue that is prevalent worldwide [22]. In addition, even if IL-1 blockers have presented excellent long-term effectiveness in terms of drug retention rate, there are no strict rules to support the choice of a specific drug, and no recommendations are available for dose escalations.
The overexpression of inflammatory cytokines, such as IL-1, has led to the consideration of other complex polygenic conditions in childhood marked by an oversensitive innate immune system with loss of a physiological regulation. Indeed, recipients of the IL-1 blockade have expanded to include many other children affected by protean diseases in which monocytes, macrophages, and neutrophils are the main dysfunctional cells [23]. For instance, Still’s disease is an infrequent hyper-cytokinemic syndrome characterized by fever, skin rash, generalized lymphoid hyperplasia, thrombocytosis, and huge levels of ferritin; it also exhibits life-threatening complications such as macrophage activation syndrome and chronic lung disease, for which IL-1 inhibition has shown the highest therapeutic efficacy [24]. Despite the small number of randomized controlled trials with IL-1 inhibitors, they are strongly recommended in the treatment of Still’s disease due to the overwhelming body of evidence from real-world experience supporting their efficacy in controlling all aspects of the disease and to limit patients’ exposure to corticosteroids. Increasing evidence has also revealed the central role of IL-1 signaling in cases of coronary arteritis in children with Kawasaki disease, a bizarre disease occurring worldwide, but predominantly in East Asian children, for which IL-1 dysregulation parallels the severity of systemic inflammation and treatment responsiveness [25,26]. IL-1 antagonists have also been essential for the full management of a recently reported hyper-cytokinemic condition, i.e., coronavirus-related multisystem inflammatory syndrome [27]. Interestingly, the investigation into such phenotypes has further disclosed the coexistence of innate and adaptive immune abnormalities, blurring the thin line between autoinflammation and autoimmunity [28].
As the biological pipeline advances, the discovery of additional novel pathways that are probably involved in the pathogenesis of autoinflammatory disorders might provide more personalized and tailored solutions. For now, both observational studies and clinical trials have certified the amazing efficacy of the IL-1 blockade via anakinra, rilonacept, and canakinumab in cases of inflammasomopathy, also confirming their excellent safety profile in children [29]. A sustained abatement in the severity of inflammasomopathies might depend on the decision to start IL-1 inhibitors as soon as possible. Future work should focus on understanding the role of anti-inflammatory re-balancing factors of the IL-1 family, both for untangling the mechanisms in play behind these diseases, and in devising more specific approaches to such difficult patients.

Funding

This editorial received no external funding.

Acknowledgments

The author acknowledges the Periodic Fever and Rare Diseases Research Centre, especially R. Manna, and gives a shout-out to A. Gasbarrini and F. Locatelli for the priceless support received in these years.

Conflicts of Interest

The author declares no conflicts of interest.

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Table 1. Simplified scheme listing the most studied autoinflammatory disorders involving interleukin-1, nuclear factor-κB/tumor necrosis factor, or interferon as their dominant active cytokine.
Table 1. Simplified scheme listing the most studied autoinflammatory disorders involving interleukin-1, nuclear factor-κB/tumor necrosis factor, or interferon as their dominant active cytokine.
Inflammasomopathies and disorders of interleukin (IL)-1 production
Disease AcronymGene (Locus)Basic Disease MechanismClinical Signs during FlaresMain Treatment Studied
CAPSNLRP3 (1q44)NLRP3-inflammasome activationFevers, fatigue, cold-
induced urticaria-like
rash, arthralgia, knee
deformity, chronic
meningitis,
sensorineural deafness
Anakinra, rilonacept,
canakinumab
FMFMEFV (16p13.3)Pyrin inflammasome activationFevers, polyserositis,
arthritides, erysipelas-
like rash, orchitis,
association with
vasculitides
Colchicine,
canakinumab,
anakinra
TRAPSTNFRSF1A (12p13.31)Multiple mechanisms; accumulation of misfolded TNF receptors (or defective shedding of TNF receptors) leading to inflammasome activationFevers, migratory
centrifugal cellulitis-like rash, monocytic
fasciitis. arthritides,
abdominal pain,
polyserositis,
conjunctivitis
Corticosteroids,
canakinumab,
etanercept
MKDMVK (12q24.11)Altered biosynthesis of nonsterol isoprenoids with increased RhoA activity and pyrin inflammasome activationFevers, heterogeneous
rash, abdominal pain,
arthralgia, lymph node
enalergement
On-demand anakinra,
canakinumab
PAPAsPSTPIP1 (15q24.3)Abnormal interaction with the pyrin inflammasome Pyogenic arthritis,
pyoderma gangrenosum,
cystic acne
Corticosteroids,
TNF-inhibitors,
anakinra, canakinumab
MSLPIN2 (18p11.31)Abnormal NLRP3 inflammasome activationChronic multifocal osteomyelitis,
dyserythropoietic
anemia, neutrophilic
dermatosis
Anakinra,
corticosteroids,
bisphosphonates,
TNF-inhibitors
AIECNLRC4 (2p22.3)NLRC4-inflammasome activationEarly-onset enterocolitis,
arthralgia, pancytopenia,
rash
Anakinra
DIRAIL1RN (2q14.1)Unbalanced IL-1 signaling Neonatal-onset severe
rash, multifocal
osteomyelitis
Anakinra
Disorders of nuclear factor (NF)-κB and/or aberrant activity of tumor necrosis factor (TNF)
Disease acronymGene (locus)Basic disease mechanismClinical signsMain treatment studied
BS/EOSNOD2/CARD15 (16q12.1)NF-κB activation Symmetric
granulomatous
arthritides, joint
contractures,
granulomatous
panuveitis,
granulomatous rash
Corticosteroids,
methotrexate, TNF-
inhibitors (infliximab,
adalimumab),
canakinumab
EOIBDIL10RA (11q23.3), IL10RB (21q22.11),
IL37 (2q14.1)
Multiple mechanisms in play; aberrant IL-10 activityInfantile ulcerative
colitis
Corticosteroids,
TNF-inhibitors
(adalimumab), IL-18
inhibitors
DADA2CECR1 (22q11.1)Dysregulation of TNFEarly-onset vasculitis,
stroke-like disease,
livedo reticularis
TNF-inhibitors (etanercept),
tocilizumab
ORASOTULIN (5p15.2)TNF-driven inflammationNeonatal-onset fever,
neutrophilic rash,
panniculitis
TNF-inhibitors
A20hTNFAIP3 (6q23.3)Dysregulation of NF-κB signalingOral and genital ulcers
(familial Behçet-like
disease), rash,
gastrointestinal signs
TNF-inhibitors
RELAhRELA (11q13.1)Dysregulation of NF-κB signaling with IFN overproductionMucocutaneous ulcers, cytopenia, inflammatory bowel diseaseTNF-inhibitors
HOIL-1d RBCK1 (20p13)Abnormal NF-κB activationBacterial infections, lymphangectasia, colitis, muscular amylopectinosisLUBAC inhibitors
TBK1dTBK1 (12q14.2)TNF-driven inflammation Arthritides, vasculitidesTNF-inhibitors
CRIAsRIPK1 (6p25.2)IL-6 and TNF-driven inflammationFevers, gastrointestinal signs, arthralgia, oral ulcers, lymph node enlargementTocilizumab
Interferon (IFN)-opathies
Disease acronymGene (locus)Basic disease mechanismClinical signsMain treatment studied
AGSTREX1 (3p21.31), RNASEH2B (13q14.3), RNASEH2C (11q13.1), RNASEH2A (19p13.13), SAMHD1 (20q11.23), ADAR (1q21.3),
IFIH1 (2q24.2)
Abnormal nucleic acid processing and degradationSubacute
encephalopathy,
cerebral calcifications,
brain atrophy
None effective
SAVITMEM137 (5q31.2)Activation of the IFN I pathwayInterstitial lung
disease, severe skin
signs, distal ulcerative
lesions with gangrene
Janus kinase inhibitors
COPasCOPA (1q23.2)Activation of the IFN I pathwayEarly-onset lung disease, arthritides, glomerulonephritisJanus kinase inhibitors
PRAASPSMA3 (14q23.1), PSMB4 (1q21.3), PSMB8 (6p21.32),
PSMB10 (16q22.1), POMP (13q12.3), PSMG2 (18p11.21)
Subverted proteasome processingEarly-onset skin signs,
neutrophilic
dermatosis, joint
contractures,
lipodystrophy,
panniculitis, myositis
Corticosteroids,
anakinra,
tocilizumab,
TNF-inhibitors,
Janus kinase inhibitors
NOCARHCDC42 (1p36.12)Activation of the IFN I pathway, upregulation of pyrin-inflammasome, actin polymerization abnormalityNeonatal-onset
lymphohistiocytosis, urticaria-like rash
Anakinra, Janus kinase inhibitors
Acronyms: AGS = Aicardi–Goutières syndrome; AIEC = autoinflammation with infantile enterocolitis; BS = Blau syndrome; CAPS = cryopyrin-associated periodic syndrome; COPas = COPA (coatomer protein a) syndrome; CRIAs = cleavage-resistant RIPK1-induced autoinflammation syndrome; DADA2 = deficiency of adenosine deaminase 2; DIRA = deficiency of interleukin-1 receptor antagonist; EOIBD = early-onset inflammatory bowel disease; EOS = early-onset sarcoidosis; FMF = familial Mediterranean fever; A20h = haploinsufficiency of A20; HOIL-1d = HOIL-1 deficiency; MKD = mevalonate kinase deficiency; MS = Majeed syndrome; NOCARH = neonatal-onset cytopenia, autoinflammation, rash and hemophagocytic lymphohistiocytosis; ORAS = OTULIN-related autoinflammatory syndrome; PAPAs = pyogenic arthritis pyoderma gangrenosum and acne syndrome; PRAAS = proteasome-associated autoinflammatory syndrome; RELAh = haploinsufficiency of RELA; SAVI = STING-associated vasculopathy with onset in infancy; TBK1d = TBK1 deficiency; TRAPS = tumor necrosis factor receptor-associated periodic syndrome.
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Rigante, D. The Golden Card of Interleukin-1 Blockers in Systemic Inflammasomopathies of Childhood. Int. J. Mol. Sci. 2025, 26, 1872. https://doi.org/10.3390/ijms26051872

AMA Style

Rigante D. The Golden Card of Interleukin-1 Blockers in Systemic Inflammasomopathies of Childhood. International Journal of Molecular Sciences. 2025; 26(5):1872. https://doi.org/10.3390/ijms26051872

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Rigante, Donato. 2025. "The Golden Card of Interleukin-1 Blockers in Systemic Inflammasomopathies of Childhood" International Journal of Molecular Sciences 26, no. 5: 1872. https://doi.org/10.3390/ijms26051872

APA Style

Rigante, D. (2025). The Golden Card of Interleukin-1 Blockers in Systemic Inflammasomopathies of Childhood. International Journal of Molecular Sciences, 26(5), 1872. https://doi.org/10.3390/ijms26051872

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