The interleukin-1 (IL-1) family of cytokines comprises 11 proteins (IL-1F1 to IL-1F11) encoded by 11 distinct genes in humans and mice. IL-1-type cytokines are major mediators of innate immune reactions, and blockade of the founding members IL-1alpha or IL-1beta by the interleukin-1 receptor antagonist (IL-1RA) has demonstrated a central role of IL-1 in a number of human autoinflammatory diseases. IL-1alpha or IL-1beta rapidly increase messenger RNA expression of hundreds of genes in multiple different cell types. The potent proinflammatory activities of IL-1alpha and IL-1beta are restricted at three major levels: (i) synthesis and release, (ii) membrane receptors, and (iii) intracellular signal transduction. This pathway summarizes extracellular and intracellular signaling of IL-1alpha or IL-1beta, including positive- and negative-feedback mechanisms that amplify or terminate the IL-1 response. In response to ligand binding of the receptor, a complex sequence of combinatorial phosphorylation and ubiquitination events results in activation of nuclear factor kappaB signaling and the JNK and p38 mitogen-activated protein kinase pathways, which, cooperatively, induce the expression of canonical IL-1 target genes (such as IL-6, IL-8, MCP-1, COX-2, IkappaBalpha, IL-1alpha, IL-1beta, MKP-1) by transcriptional and posttranscriptional mechanisms. Of note, most intracellular components that participate in the cellular response to IL-1 also mediate responses to other cytokines (IL-18 and IL-33), Toll-like-receptors (TLRs), and many forms of cytotoxic stresses.

The innate immune system senses molecular patterns from invading microorganisms. Once activated, it orchestrates the inflammatory response by secreting proinflammatory cytokines, such as interleukin-1 (IL-1)-type cytokines, in particular IL-1beta. IL-1 mediates the expression of a vast array of genes involved in secondary inflammation. IL-1-responsive genes coordinate all aspects of local inflammation and also attract and activate cells of the adaptive immune system at sites of infection. Moreover, the innate immune system can also sense a wide range of nonmicrobial molecular patterns that represent danger or damage signals. These signals activate the NALP3-inflammasome pathway, which plays a central role in acute and chronic sterile inflammation. Here, we describe the essential components of the NALP3-inflammasome that control processing and release of IL-1beta.

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BackgroundCAPS (Cryopyrin-associated periodic fever syndromes) are monogenic autoinflammatory diseases causing great burden to patients due to severe systemic and organ inflammation caused by increased production of interleukin-1β (IL-1β). In clinical trials as well as in real-life, the monoclonal antibody canakinumab (CAN) effectively inhibits IL-1β and results in rapid suppression of CAPS symptoms.ObjectivesThe RELIANCE registry explores long-term safety and effectiveness of CAN under routine clinical practice conditions in pediatric (≥2 years) and adult patients with CAPS, including Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal onset multisystem inflammatory disease (NOMID)/chronic infantile neurological cutaneous and articular syndrome (CINCA).MethodsThis prospective, non-interventional, observational study enrolls patients with clinically confirmed diagnoses of CAPS routinely receiving CAN. Clinical data, physician assessments and patient-reported outcomes are evaluated in 6-monthly intervals.Results107 CAPS patients (53% female; 16% NOMID/CINCA subtypes) were enrolled by December 2022. At baseline, median age was 23 years and median duration of prior CAN treatment was 6 years. 92% of patients received greater than standard dose CAN.75% of the patients were in disease remission at month 48 by physician assessment. Patients report stable low level disease activity (median 2.0 at baseline and 1.5 at month 48) and fatigue (median 3.0 at baseline and 1.0 at month 48). No relevant differences regarding subtype severity were observed (Table 1). At baseline vs. month 48, 46% vs. 50% of patients experienced impairment of social life and 32% vs. 25% reported days off from school or work due to the disease.Severe adverse events (SAE) suspected to be drug-related were reported for N=9 (8.4%) CAPS patients. The incidence rate (IR) per 100 patient-years kept stable over time.ConclusionThe 48-month interim analysis of the RELIANCE registry demonstrates that long-term CAN treatment is safe and effective in patients with CAPS, independent of subtype severity.Table 1.Assessment of clinical CAPS disease activity and laboratory markers over time.Baseline24 months48 monthsNOMID/CINCAMWS, FCASNOMID/ CINCAMWS, FCASNOMID/ CINCAMWS, FCASNumber* of patients, N17801054313Number (%**) of patients with days absent from work/school during last 6 months6 (35)25 (32)2 (20)20 (37)0 (0)4 (31)Number (%**) of patients in disease remission (physician assessment)13 (77)53 (68)8 (80)33 (61)2 (67)10 (77)Patient’s assessment of current disease activity; 0–10, median (min; max)1.0 (0; 7)2.0 (0; 7)2.0 (0; 4)1.0 (0; 8)0.0 (0; 0)2.0 (0; 5)Patient’s assessment of current fatigue; 0–10, median (min; max)3.0 (0; 9)3.0 (0; 9)2.0 (0; 7)2.0 (0; 9)0.0 (0; 0)1.0 (0; 7)Number (%**) of patientswithoutimpairment of social life by the disease5 (56)29 (57)3 (50)25 (63)0 (0)2 (67)Current influence of the disease on mood; % of patients** with negative | positive | no influence30 | 10 | 6023 | 19 | 5917 | 33 | 5024 | 37 | 400 | 0 | 025 | 25 | 50CRP, median (mg/dl)0.20.10.30.20.90.1SAA, median (mg/dl)0.40.40.90.40.60.2ESR, median (mm/h)6.05.08.05.05.02.5SAENumber of eventsIR‡per 100 patient-yearsAll types of SAE6522.85SADR28#9.84NOMID/CINCA00MWS/FACS2611.55#Abdominal pain, Alport’s syndrome, appendicitis, arthralgia, blister, cardiovascular disorder, chest pain, circulatory collapse, dehydration, diplopia, dyspnoea, erythema, febrile convulsion, gastroenteritis, glomerulonephritis, haemophilus test positive, myalgia, oedema, pneumonia, premature delivery, skin discolouration, tonsillectomy, tonsillitis bacterial, tonsillitis streptococcal, vision blurred (all N=1 event), pyrexia (N=3 events)*subtype not reported for all patients.**not reported for all patients.‡IR = number of events * 36525/ sum of observation days (=103905)CRP, c-reactive protein; ESR, erythrocyte sedimentation rate; SAA, serum amyloid A; SADR, serious adverse drug reactionREFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsJ. B. Kuemmerle-Deschner Consultant of: Novartis, AbbVie, Sobi, Grant/research support from: Novartis, AbbVie, Sobi, Birgit Kortus-Goetze Consultant of: Novartis, Catharina Schuetz Grant/research support from: Novartis, Prasad Oommen Grant/research support from: Novartis, Ales Janda: None declared, Jürgen Rech Speakers bureau: AbbVie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD; Mylan, Novartis, Roche, Sanofi, Sobi, UCB, Consultant of: AbbVie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD, Mylan, Novartis, Roche, Sanofi, Sobi, UCB, Grant/research support from: Novartis, Sobi, Frank Weller-Heinemann: None declared, Tilmann Kallinich Speakers bureau: Roche, Anne Pankow: None declared, Gerd Horneff Speakers bureau: AbbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Grant/research support from: AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Ivan Foeldvari Consultant of: Novartis, Peter Wasiliew Grant/research support from: Novartis, Michael Borte Grant/research support from: Pfizer, Shire, Michael Fiene: None declared, Florian Meier Speakers bureau: Novartis, Tobias Krickau Speakers bureau: Novartis, Consultant of: Novartis, Grant/research support from: Novartis, Ioana Andreica Speakers bureau: Abbvie, Chugai, Novartis, UCB, MSD, Lilly, Sobi, Astrazeneca, Amgen, Pfizer, Gilead, Paid instructor for: Astrazeneca, UCB; Consultant Abbvie, Chugai, Novartis, UCB, Galapagos, Takeda, Astrazeneca, Lilly, Boehringer Ingelheim, Amgen, Sobi, Julia Weber-Arden Employee of: Novartis, Norbert Blank Consultant of: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, Grant/research support from: Novartis, Sobi.

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