IL-1 Inhibitors in the Treatment of Monogenic Periodic Fever Syndromes: From the Past to the Future Perspectives

Abstract

Autoinflammatory diseases (AIDs) represent a rare and heterogeneous group of disorders characterized by recurrent episodes of inflammation and a broad range of clinical manifestations. The most common symptoms involve recurrent fevers, musculoskeletal symptoms, and serositis; however, AIDs can also lead to life-threatening complications, such as macrophage activation syndrome (MAS) and systemic AA amyloidosis. Typical monogenic periodic fever syndromes include cryopyrin-associated periodic fever syndrome (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyper IgD syndrome (MKD/HIDS), and familial Mediterranean fever (FMF). However, a number of other clinical entities, such as systemic juvenile idiopathic arthritis (sJIA), adult-onset Still's disease (AOSD), Kawasaki disease (KD) and idiopathic recurrent pericarditis (IRP), display similar phenotypical and immunological features to AIDs. All these diseases are pathophysiologicaly characterized by dysregulation of the innate immune system and the central pathogenic role is attributed to the IL-1 cytokine family (IL-1α, IL-1β, IL-1Ra, IL-18, IL-36Ra, IL-36α, IL-37, IL-36β, IL-36g, IL-38, and IL-33). Therefore, reasonable therapeutic approaches aim to inhibit these cytokines and their pathways. To date, several anti-IL-1 therapies have evolved. Each drug differs in structure, mechanism of action, efficacy for the treatment of selected diseases, and side effects. Most of the available data regarding the efficacy and safety of IL-1 inhibitors are related to anakinra, canakinumab, and rilonacept. Other promising therapeutics, such as gevokizumab, tadekinig alfa, and tranilast are currently undergoing clinical trials. In this review, we provide sophisticated and up-to-date insight into the therapeutic uses of different IL-1 inhibitors in monogenic periodic fever syndromes.

Keywords: CAPS; FMF; IL-1; TRAPS; anakinra; canakinumab; rilonacept.

Figure 1

Scheme of caspase - 1/3/7 activation mediated by inflammasome and/or apoptosome. (a-1) initiation of NLRP3 oligomerization (by DAMPs; PAMPs; ROS; UA; potassium eflux; calcium influx); (a-2) APAF-1 oligomerization (upon intrinsic apoptotic way of activation by DNA damage; hypoxia; ER stress); (b-1) cleavage of pro-caspase 1 N-terminal region (inactive form) by the inlfammasome molecular complex; (b2) cleavage of pro-caspase-9 N-terminal region (inactive form) by the apoptosome molecular complex; (C) caspase-8/10 activaton by extrinsic apoptotic way of activation (by TNF; TRIAL; FAS molecules); (D) effector caspase-3/7 activation; (e-1) IL-1β and IL-18 activation from pro- IL1β and pro-IL18 inactive form by caspase-1; (e-2) IL33 mature form activation by caspase-3/7 (NLRP3, Nucleotide-binding oligomerization domain; leucine rich repeat and pyrin domain containing; DAMPs, Damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; ROS, Reactive oxygen species; UA, Uric acid; APAF-1, Apoptotic protease activating factor-1; ER, Endoplasmic reticulum; TNF, Tumor necrosis factor; TRIAL, TNF-related apoptosis-inducing ligand).

Figure 2

Scheme of IL1 receptor family signaling. (a) Cytokine binding on primary receptor initiates TIR domain containing accessory receptor recruitment necessary for signal transmission; (b) IRAK activation via MyD88 adaptor protein; (c) activation of TRAF6 ubiquitin ligase; (d) ubiquitin mediated activation of TAK1; (e-1) NFkB activation via IKK and (e-2) NFkB transition into nucleus; (e-3) AP1 activation via MAP kinases (MKK 4/7) and JNK (TIR- Toll/interleukin-1 receptor domain; MyD88, Myeloid differentiation primary response 88; IRAK, Interleukin-1 receptor associated kinase; (TRAF9, TNF Receptor Associated Factor 6; TAK1, Transforming growth factor beta-activated kinase 1; IKK, IkB kinase; IkB, NFkB inhibitor; NFkB, Nuclear factor kappa B; MAP, Mitogen activated protein kinase; JNK, c-Jun N-terminal kinase; AP1, Activator protein 1).

Figure 3

Scheme of IL1 receptor family structures and mechanisms of regulation. (a) cell membrane receptors structure of binary complexes—primary (IL-1R1, IL-18Rα, ST2, IL-1Rrp2) and accessory receptors (IL1-RAcP, IL-18Rβ), (b) signal transmission via TIR domains, (c) regulatory role of TIR-less receptors (IL1-R2) binding cytokines without signal transmission (inhibition 🚫), (d) regulatory role of soluble receptors (IL1-R1, IL1-R2, ST2) and (e) binding proteins (IL18-BP) binding cytokines without signal transmission, (f) inhibitory role of receptor antagonists (IL-1Ra, IL-36Ra, IL-38) (TIR, Toll/interleukin-1 receptor).

Figure 4

Flowchart diagram of the selection process. Anakinra, rilonacept and canakinumab in CAPS, TRAPS, FMF and MKD/HIDS were used as the key words in the search strategy, open-label and randomized clinical trials and registry-based studies were reviewed.