The Role of Interleukin-17 in Juvenile Idiopathic Arthritis: History
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Contributor:
Marino Paroli
,
Luca Spadea
,
Rosalba Caccavale
,
Leopoldo Spadea
,
Maria Pia Paroli
,
Nicola Nante

Interleukin-17 (IL-17) is a cytokine family consisting of six members and five specific receptors. IL-17A was the first member to be identified in 1993. Since then, several studies have elucidated that IL-17 has predominantly pro-inflammatory activity and that its production is involved in both the defense against pathogens and the genesis of autoimmune processes.

  • interleukin-17
  • interleukin-23
  • juvenile idiopathic arthritis

2. Molecular Features and Signaling of IL-17

In 1993, a new interleukin was cloned. This interleukin was initially defined as CTLA-8 and later as interleukin-17A (IL-17A) [1][2]. IL-17A showed a sequence homology with an open reading frame of Herpesvirus saimiri, a virus with a specific tropism for T cells. Quite surprisingly, molecular analysis revealed that IL-17A had no homology with other known cytokines, being characterized by an unusual cysteine-knot fold structure [3][4][5]. Two years later, the receptor for IL-17A (IL-17RA) was discovered [6][7]. Other cytokines structurally similar to interleukin-17A were then identified. All these molecules have been grouped into a family defined as IL-17, which includes six members from IL-17A to IL-17F. IL-17A and IL-17F can form both homodimers and heterodimers (IL-17A/F), whereas IL-17B, IL-17C, IL-17D, and IL-17E exist only as homodimers [8][9][10][11]. Four other receptors for IL-17 were subsequently identified [12][13]. Thus, the IL-17 receptors known so far represent a total of five members (IL-17A to IL17C), all containing the shared cytoplasmic SEFIR motif (SEF/IL-17R). [4]. This protein engages the multifunctional adapter Act1. Act1 in turn binds to E3 ubiquitin, leading downstream to the recruitment and ubiquitination of TNF-receptor-associated factor 6 (TRAF6). This ultimately triggers nuclear factor κB (NF-κB), the nuclear transcription factors CCAAT-enhancer-binding protein β (C/EBPβ), and mitogen-activated protein kinase (MAPK)-dependent activating protein-1 (AP-1) for the transcription of IL-17 target genes [7][14][15][16][17][18][19][20][21]. IL-17 signaling can act synergistically with other ligands, including cytokines or microbial products, leading to the activation of alternative signaling pathways [22][23][24]. Table 1 shows the different members of the IL-17 family, their respective cellular receptors, and known or supposed transcription factors activated after cytokine/receptor binding.
Table 1. The interleukin-17 family members, receptors, and target transcription factors.
Cytokine Receptor Activated Transcription Factor
IL-17 A/A IL-17RA/IL-17RC
IL-17RC/IL-17RC
IL-17RA/IL-17RD		 C/EPBβ, AP-1, NF-κB
(NF-κB)
(NF-κB)
IL-17 F/F IL-17RA/IL-17RC
IL-17RC/IL-17RC		 NF-κB
(NF-κB)
IL-17A/F IL-17RA/IL-17RC
IL-17RC/IL-17RC		 NF-κB
(NF-κB)
IL-17B/B IL-17RA/IL-17RB C/EPBβ, AP-1, NF-κB
IL-17E/E (IL-25) IL-17RA/IL-17RB C/EPBβ, AP-1, NF-κB
IL-17C/C IL-17RA/IL-17RE NF-κBζ
IL-17D CD93 Intra-cellular CD93 domain
C/EPBβ = CCAAT-enhancer-binding protein β; AP-1 = activator protein-1; NF-κB(ζ) = nuclear factor kappa-light-chain-enhancer of activated B cells (ζ). Transcription factors in parentheses have not yet been conclusively demonstrated.

2. The Potential Role of IL-17 in Systemic JIA

Attention has also been paid to systemic JIA (sJIA). This particular form of JIA with possible autoinflammatory pathogenesis is considered the counterpart of adult Still’s disease (AOSD) [25]. In a small study, increased Th17 cells were reported in the peripheral blood of patients with sJIA [26]. In a later study, similar results were reported, showing the increased expression of IL-17A in circulating γδT cells [27]. It has recently been reported that acute sJIA is characterized by the expansion of IL-17-expressing Treg cells showing a prominent genetic signature of Th17 cells. These cells are likely to lose their suppressive function on inflammation. Interestingly, the occurrence of this genetic signature was dependent on interleukin-1 activity. Due to their plasticity, Th-17 cells can be reprogrammed in an appropriate cytokine microenvironment to generate effector-type T cells (Teff) in patients with chronic diseases [28]. These results suggest that there may be a “window of opportunity” during which IL-1 blockade can inhibit inflammation and progression to chronicity in patients with sJIA.

3. The IL-23–IL-17 Axis: The Blockade of IL-23 in the Therapy of JIA

Based on the studies that showed the role of IL-17 in the pathogenesis of JIA and, in particular, the role of the “IL-23–IL-17” axis, clinical studies were initially conducted to evaluate the effect of anti-IL23 biologics in the treatment of this disease. In particular, ustekinumab, a human monoclonal antibody that selectively blocks the common p40 subunit of IL-12 and IL-23, preventing their binding to their membrane receptor [29], has been considered for therapy. Ustekinumab has been shown to be effective in several adult inflammatory diseases, including psoriasis, psoriatic arthritis, and Crohn’s disease [30][31][32]. In a retrospective single-center study analyzing data from patients with the JIA subtype ERA in whom both conventional therapy with DMARDs and two subsequent treatments with anti-TNF-alpha biologics had failed, the global assessment of disease activity by a physician decreased in four of the five patients treated with ustekinumab. A reduction in the number of joints with active inflammation and the improvement of enteritis were observed in three and two patients, respectively. The resolution of sacroiliitis was observed in three patients [33]. Ustekinumab has recently been approved by the FDA for the treatment of children with active psoriatic arthritis.

4. The Role of Anti-IL-17A Blocking Antibodies in JPsA and ERA Subtypes of JIA

Regarding the use of anti-IL-17 biologics, the investigations have focused on secukinumab, a human anti-IL-17A antibody that directly blocks the binding of this cytokine to its receptor [34]. Secukinumab is effective in several inflammatory rheumatic diseases in adults. In particular, the use of secukinumab has been approved for the treatment of psoriatic arthritis and ankylosing spondylitis, including non-radiographic axial spondylitis [35][36][37]. Psoriatic arthritis is a form of juvenile idiopathic arthritis (JIA) and is characterized by chronic joint inflammation and swelling, as well as an increased risk of the asymptomatic inflammation of the eyes [38]. The enthesitis-related arthritis (ERA) category of JIA describes a heterogeneous group of children, including those with enthesitis, arthritis, and inflammatory bowel disease (IBD)-associated arthropathy. ERA accounts for about 15–20% of JIA cases and has a peak age of onset of 12 years [39]. PsA and adult non-radiographic axial spondylitis are considered the respective counterparts of the JIA subtypes juvenile psoriatic arthritis (JPsA) and enthesitis-related arthritis (ERA) [40][41]. Given the pathogenic role of interleukin-17 and, in particular, member IL-17A in these forms of JIA (as demonstrated in the studies described above), as well as the limited effectiveness of currently available therapies (including JPsA [42] and ERA [43][44][45][46][47]), it was hypothesized that secukinumab could be successfully used in the treatment of these two forms of JIA. In a retrospective study that analyzed patients who had already been treated using biologics with other mechanisms of action, it was found that patients with JIA showed significant improvements in signs and symptoms in different disease domains [48]. In a recent phase-three study [49], the administration of this biologic was shown to reduce the frequency of disease flare-ups in children with JIA compared with control subjects. In more detail, the 2-year, randomized-withdrawal, double-blind, placebo-controlled JUNIPERA trial included 86 patients and consisted of three treatment periods. In treatment period 1 (TP1), all eligible subjects entered the trial to receive 12 weeks of open-label secukinumab at a dose predicted to achieve secukinumab serum levels equivalent to those in adults administered with a 150 mg dose regimen. Secukinumab was administered subcutaneously weekly for the first 4 weeks and every 4 weeks thereafter. Clinical response (JIA ACR 30) was assessed at Week 12. Responders advanced to TP2 and non-responders exited the trial and entered into the post-treatment follow-up period. In TP2, subjects who were responders (defined as achieving JIA ACR 30 at Week 12) entered the double-blind withdrawal period and were randomly assigned 1:1 to either secukinumab or placebo on that visit and then every 4 weeks, until they either experienced a disease flare-up or completed TP2. TP2 was event-driven and was planned to be closed when 33 subjects experienced a disease flare-up, as per the JIA definition. Alternatively, the study could be closed when all subjects reached the total study duration of 104 weeks, and therefore the subjects who did not experience a disease flare-up remained in TP2 for the duration of the study and completed the study without entering into TP3. Subjects experiencing a disease flare-up in TP2 immediately entered TP3 to receive open-label secukinumab every 4 weeks until the total study duration of 104 weeks for that subject was achieved. A post-treatment follow-up period lasting 12 weeks from the final study drug administration was required for all subjects, unless they qualified and entered the secukinumab extension trial. Patients were initially included if they presented with acute-phase JPsA or ERA, had not been treated previously with biologics, and showed inadequate response to standard therapy. The dosage used ranged from 75 to 150 mg monthly after an induction period with the weekly administration of secukinumab for 4 weeks. The study results showed the rapid improvement of several clinical domains such as arthritis, dactylitis, and enthesitis in treated children compared with the control group. Importantly, the risk of flare-ups was found to be decreased by 72%. In addition, the goal of achieving inactive disease was achieved in 40% of subjects throughout the study. These studies support the conclusion that blocking IL-17A activity by secukinumab is a safe and effective treatment in patients with the JPsA and ERA subtypes of JIA. Based on the results of the JUNIPER study, secukinumab was recently approved by both the FDA and EMA for the treatment of JPsA and ERA in children aged ≥6 years. In Table 2, the currently available biologics that selectively block the IL-23–IL-17 axis are shown.
Table 2. Approved anti-IL23 and anti-IL-17 biologics for adult indications.
Biologic Mechanism of Action Approved Indication
Ustekinumab Binding to IL-23/IL-12 PsO, PsA, CD, UC
Guselkumab Binding to IL-23 PsO, PsA
Tildrakizumab Binding to IL-23 PsO
Risankizumab Binding to IL-23 PsO, PsA, CD
Secukinumab Binding to IL-17A PsO, PsA, AS, nr-axSpA
Ixekizumab Binding to IL-17A PsO, PsA
Brodalumab Binding to IL-17RA PsO
PsO = psoriasis; PsA = psoriatic arthritis; CD = Crohn’s disease; UC = ulcerative colitis; AS = ankylosing spondylitis; nr-axSpA = non-radiographic axial spondiloarthritis.

This entry is adapted from the peer-reviewed paper 10.3390/medicina58111552

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