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Anti-IL-1 molecules: New comers and new indications
Joint Bone Spine 77 (2010) 102–107
Review
Anti-IL-1 molecules: New comers and new indications Anna Moltó , Alejandro Olivé ∗ Rheumatology Section, Hospital Universitari Germans Trias i Pujol, Ctra del Canyet s/n, 08916 Badalona, Spain
a r t i c l e
i n f o
Article history: Accepted 29 October 2009 Available online 31 December 2009 Keywords: Interleukin 1 Anakinra Rheumatoid arthritis Autoinflammatory syndromes Spondyloarthropathy
a b s t r a c t The interleukin 1 family is composed by the interleukin 1 (IL-1) and its natural occurring inhibitor, the interleukin 1 receptor antagonist (IL-1Ra). The role of both molecules in rheumatoid arthritis has been widely established, and in this sense new molecules blocking IL-1 actions are under investigation. Anakinra is the recombinant form of IL-1Ra, and has proven to be well tolerated and indicated in the treatment of rheumatoid arthritis. Nevertheless, other molecules such as mAb anti-IL-1 and IL-1 Trap are being developed. Moreover, the recent relation of IL-1 in the inflammasome and pathways of innate immunity has lead to new indications of anti-IL-1 molecules, especially in the autoinflammatory syndromes as well as in other inflammatory diseases. Herein we have performed a review of the literature, limited to English language journals (PUBMED search: combination of descriptors IL-1 and anakinra, systemic juvenile idiopathic arthritis, adult’s onset Still’s disease, autoinflammatory syndromes, gout, pseudogout, ankylosing spondylitis, and systemic lupus erythematosus from January 1985–December 2008) emphasizing the possible new indications. Although sufficient data is not yet available to fully assess the efficacy and safety of anti-IL-1 molecules in patients with inflammatory disorders other than rheumatoid arthritis, new data is promising. © 2009 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction
2.1. IL-1˛
Interleukin 1 (IL-1) is a proinflammatory cytokine and its role in the inflammatory response has been well established. It has been implicated in the pathogenesis of several chronic diseases, including rheumatoid arthritis (RA), and until today anti-IL-1 molecules are a valid therapy for refractory RA. Nevertheless, the recent implication of IL-1 in the inflammasome and the NALP receptors opens a new lead of investigation. NALP3 mutations are thought to be responsible for a group of diseases called autoinflammatory syndromes through an abnormal activation of the inflammasome leading to an excessive IL-1 production. More recently, IL-1 has also been implicated in the inflammatory cascade of the acute gout and pseudogout attack via the NALP3-inflammasome. Those recent findings have lead to explore new therapeutical roles for anti-IL-1 molecules.
Most IL-1␣ remain intracellular in its precursor form and it is believed to function as an autocrine messenger. Nevertheless, there is evidence that a small part of this precursor is transported to the cell surface and associated with the cell membrane. It has been postulated that it might act as a paracrine messenger to adjacent cells [1].
2. Interleukin 1 family IL-1 is a major inflammatory mediator and exists in two forms: IL-1␣ and IL-1. Each form is the product of two separate genes, but is related to each other structurally at a three-dimension level. Mononuclear cells, primarily monocytic phagocytes synthesize both IL-1 [1].
∗ Corresponding author. Tel.: +0034 93 465 12 00 (3288); Cell: 670844037. E-mail address: [email protected] (A. Olivé).
2.2. IL-1ˇ In contrast, near all IL-1 is released from the cell into the extracellular space and circulation. The IL-1 precursor must be cleaved for optimal biologic activity by several common enzymes. An intracellular protease, the IL-1-converting enzyme (ICE), also known as caspase-1, seems to be highly specific for cleaving the IL-1 [1] (Fig. 1). IL-1 is a systemic, hormone-like mediator intended to be released from cells, whereas IL-1␣ is primarily a regulator of intracellular events and mediator of local inflammation. 2.3. IL-1 receptor antagonist IL-1 receptor antagonist (IL-1Ra) is the third member of the IL-1 family. Produced and secreted by almost all cells expressing IL-1, IL-1Ra functions as a competitive receptor antagonist, binding to IL-1 receptors (IL-1R), but not activating target cells.
1297-319X/$ – see front matter © 2009 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2009.10.011
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Fig. 1. Production of IL-1
2.4. IL-1 receptors There are 2 different IL-1R, namely IL-1RI and IL-1RII. Binding of IL-1␣ or IL-1 to IL-1RI produces activation, subsequent intracellular transduction and cellular responses, whereas binding to IL-1RII does not transduce signal. IL-1RII seems to be a decoy receptor, acting as a buffer to compensate excessive concentrations of IL-1 [2]. Although all three members of IL-1 family have different aminoacid sequence, each can bind with high affinity to the IL-1R: IL-1␣ and IL-1 as agonists of IL-1RI, and IL-1Ra blocking the IL-1␣ and IL-1 binding [3] (Fig. 2). 3. Biological actions of IL-1 The biological effects of IL-1␣ and IL-1 [2] have been reviewed in detail, particularly in the areas of IL-1 effects on the hypothalamic-pituitary-adrenal axis [4] bone metabolism [5], in the pathogenesis of RA and loss of lean body mass [6]. Systemic injection of recombinant IL-1 elicits fever, anorexia, hypotension, leucopenia and thrombocytopenia. IL-1 stimulates production of acute phase proteins by the liver, including IL-6, fibrinogen, complement components, and various clotting factors. IL-1 also stimulates the hypothalamic-pituitary-adrenal axis leading to production of adenocorticotrophic hormone, growth hormone, vasopressin and somatostatin [4]. In the haematopoietic system, IL-1 increases production of colony stimulating factors
Fig. 2. IL-1 and IL-1 Ra interaction with IL-1 RI and IL-1RII.
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and stem cell factors and acts synergistically with these factors to augment production of granulocytes and platelets [7]. The basis for the varied biologic properties of IL-1 is the effects of this cytokine on the expression of various genes and surface receptors. In general, IL-1 either initiates transcription or stabilizes mRNA for a variety of genes, including the ability of both IL-1 to increase the expression of the IL-1 family of genes itself. In a similar way, other inflammatory cytokines, lymphocyte growth factors, colony-stimulating factors, and mesenchymal growth factor genes are up-regulated by IL-1. It has been proven that IL-1 acts synergistically with bradykinin, other cytokines, and growth factors and it is remarkable that synergism between IL-1 and TNF␣ is highly consistent. It is a frequently reported phenomenon, also observed in vivo, whereas the synergism between IL-1 and the various growth factors is mostly on prostanoid synthesis and is primarily an in vitro finding. The mechanism for synergism may also involve receptor modulation; however, in the case of IL-1 and TNF␣ synergism, TNF␣-receptors are down-regulated by IL-1, and thus blocking one cytokine may only reduce disease severity by 50% [8]. Furthermore, IL-1 promotes Th17 differentiation in humans. Th17 is a type of effector T-cell (along with Th1 and Th2) and its pathway is prominently involved in inflammation and autoimmunity. Th17 cells are pivotal in RA. The current hypothesis is that RA is caused by a Th1/Th17 imbalance (with predominance of Th17) [9]. In joints, IL-1 stimulates chondrocytes to release collagenase and other proteolytic enzymes involved in the cartilage degradation. IL-1 also stimulates the differentiation of the osteoclast’s progenitor and contributes to the activation of the mature osteoclasts leading to bone resorption.
4. Biological actions of IL-1Ra Secreted IL-1Ra is an inducible gene in most cells, but intracellular IL-1Ra is expressed constitutively in keratinocytes and intestinal epithelial cells. IL-1Ra represents the first naturally occurring cytokine or hormone-like molecule acting as a specific receptor antagonist. Many experiments have tried to elucidate the biological properties of IL-1Ra over the past years, and no unequivocal agonists effects have been reported so far. Natural sIL-1Ra is a 22-kD glycosylated protein, but the recombinant (non-glycosylated) 17-kD form of IL-1Ra (anakinra) retains a comparable ability to inhibit IL1 binding in vitro. As we mentioned before, if IL-1Ra binds to IL-1RI with high affinity, how does it not yet trigger a response? The currently hypothesis is that as IL-1RI presents three binding domains, and IL-1Ra occupies only one site of the receptor, by lacking the second binding site, IL-1Ra would not trigger a signal, and after IL-1Ra binding to IL-1RI-bearing cells, there would not be phosphorylation of the epidermal growth factor receptor, and no signal transduction. One of the main unanswered questions about IL-1 is its role in normal physiology, and the availability of recombinant IL-1Ra allows these questions to be examinated, first in animal models and over the last years in human diseases. In normal homeostasis, the actions of IL-1 are balanced by IL-1Ra, as much as by other IL-1 natural inhibitors (IL-1RII and circulating IL-1 RI), and a pool of antiinflammatory cytokines. However, an increased production of IL-1 has been observed in a wide range of diseases, including infection, solid tumours, and autoimmune diseases. In RA, for example, systemic and synovial fluid concentrations of IL-1 are raised, and they correlate with disease severity and histological features [10,11]. IL1Ra levels are also increased in many patients with RA, but they may not be sufficient for keeping IL-1 activity in balance [12].
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5. IL-1 Inhibition: new comers
5.3. IL-1 Trap
The role of IL-1 in various disease animal models has been inferred by the protective effects of recombinant IL-1Ra, soluble IL1 receptors and neutralizing antibodies to IL-1-␣ and IL-1. There are several strategies for reducing IL-1 activities (Table 1).
The IL-1 Trap comprises high affinity blockers of cytokine action that may offer a more potent way of inhibition than other strategies proposed previously. Rilonacept is the currently commercialised IL-1 Trap. It is a combination of both the IL-1 receptor accessory protein and the IL-1R, arranged inline and fused to the Fc portion of human IgG1. As this drug binds both IL-1␣ and IL-1, it has the potential to inhibit a wider range of IL-1 effects in vivo than other IL-1 targeted therapies [17]. It was the first therapy approved by the FDA for the treatment of CAPS, and it received the orphan drug approval from the FDA for familial cold auto-inflammatory syndrome (FCAS) and the MuckleWells syndrome (MWS) in adults and children aged 12 years or older [18]. The administration is subcutaneous weekly. The FDA based its approval on the results of two consecutive randomised double blind, placebo-controlled phase III clinical studies, testing safety and efficacy of rilonacept in adults with CAPS [19,20].
5.1. IL-1Ra gene therapy IL-1Ra gene therapy appears promising for both inflammatory arthritis and osteoarthritis. The onset of murine collage-induced arthritis was abrogated by transfection of knee synovial fibroblasts with the IL-1Ra gene. Based on this animal model data, studies evaluating gene therapy using retroviral constructs encoding human IL-1Ra are underway in patients with RA [13]. IL-1Ra gene therapy involves removal of synovium from the joint of a patient awaiting total joint arthroplasty, transfecting it with the IL-1Ra gene, and reimplantation of the synovium at the time of joint replacement. Evans et al. presented nine patients with osteoarthritis awaiting metacarpophalangeal arthroplasty: the procedure was well tolerated and expression of the transgene was documented [14].
5.2. Monoclonal anti-IL-1ˇ antibody Canakinumab (ACZ885) is a fully human monoclonal antibody against IL-1. Its administration is intravenous or subcutaneous, and has been established every two weeks. Its effectiveness has been proven in animal models of disease, such as collagen-induced arthritis [15], and its clinical use is currently being evaluated in phase III trials. The drug has received the EU and US Orphan drug status for systemic-onset juvenile idiopathic arthritis (SoJIA) and cryopyrin-associated periodic syndromes (CAPS). Canakinumab has promising clinical safety and pharmacokinetics properties, and besides its potential use in the mentioned diseases, it may also play a role in other complex inflammatory diseases, such as RA [16].
Table 1 Potential therapeutical uses of IL-1 blockade. IL-1 blockers
Potential theurapeutical uses
Anakinra (metHuIL-1Ra)
Rheumatoid arthritis (randomised controlled trials) Autoinflammatory syndromes: CAPS (caser reports) FMF (case reports) Schnitzler’s syndrome (case report) SoJIA and AoSD (prospective studies) Gout (open-labelled study) Pseudogout (case report) Ankylosing Spondylitis (open label study) Systemic lupus erythematosus (case series) Antisynthetase syndrome (case report) Relapsing polychondritis (case report)
Rilonacept (IL-1 trap)
CAPS (phase III trials) SoJIA
Canakinumab (ACZ885)
FCAS (randomised double-blind phase III trial) MWS (randomised double-blind phase III trial)
IL-1Ra gene therapy
Has not been established yet
CAPS: cryopyrin-associated periodic syndromes; FMF: familiar mediterranean fever; SoJIA: systemic-onset juvenile idiopathic arthritis; AoSD: adult’s onset Stills disease; FCAS: familial cold autoinflammatory syndrome; MWS: Muckle-Wells syndrome. FDA approved indications.
5.4. Anakinra The recombinant form of the naturally occurring IL-1Ra is called anakinra (rmetHuIL-1Ra), and differs from the native human protein in that it is not glycosilated and has an additional N-terminal methionine. Early studies with anakinra focused on endotoxaemia, septic shock and steroid resistant graft vs. host disease. Nowadays anakinra is approved for treating the signs and symptoms as well as the joint destructive components of RA. However, the challenge for anakinra for occupying the large number of IL-1R is formidable, as these receptors are expressed on all cells excepts red blood cells: moreover, anakinra is rapidly excreted by the kidney, and blood levels are low after 24 hours. IL-1R are also readily generated each day, so a daily injection of anakinra is necessary [21]. The feasibility of delivering anakinra by subcutaneous injection in patients with RA was demonstrated in a three-week dose ranging and dose frequency study. Once-daily administration was well tolerated and showed better clinical activity than every three or seven days dosage. Although no head-to-head study comparing efficacy between anakinra and classical TNF␣ inhibitors has been performed so far, a recent meta-analysis revealed that treatment with anakinra was superior to placebo, but less efficacious than TNF␣ inhibitors. Prescription of anakinra is scarce compared with TNF␣ inhibitors [22–24]. 6. IL-1 and IL-1Ra in disease 6.1. Rheumatoid arthritis Several publications have reported that inflammatory autoimmune diseases developed spontaneously in IL-1Ra knockout mice. Horai et al. reported the development of an inflammatory erosive arthritis in IL-1Ra deficient mice. The arthropathy was marked by pannus invasion of the joint surface and histological evidence of marked synovial and periarticular inflammation, resembling to the changes typically seen in RA. No such disease developed in control mice, which had normal amounts of IL-1Ra. Levels of IL-1mRNA in the joint of these mice were 10 times as high as the level in control mice [25,26]. In a same fashion, animal models have revealed that injection of high concentration of IL-1 in rabbit knee joint produced clinical and histological features of RA [27]. Experimental models of arthritis in IL-1Ra deficient mice showed clearly enhanced levels of Th17 cells, and the anti-IL-1 treatment significantly reduced the percentage of IL-17+Th17 cells, suggesting that IL-1 might be the driving force behind the Th17 imbalance in RA [28].
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Fig. 4. NALP3 inflammasome
7.2. Inflammatory disorders A growing number of systemic inflammatory disorders characterized by fever anaemia and an elevation of acute phase proteins have been linked to excessive production and bioactivity of IL1. All these conditions respond, to varying degrees, to specific blockade of the IL-1R. Furthermore, several of these diseases are associated with abnormalities in NRL signalling pathways, as in the cryopyrinopathies, also termed as the cold-induced autoinflammatory syndrome 1 (CIAS1)-associated periodic syndromes.
Fig. 3. NALP3 structure
7. IL-1 and the inflammasome: new indications 7.1. The inflammasome The recent identification of cytosol-expressed Nod-like receptors (NLR) has changed the concept of innate immunity as non-specific. NALP belonging to the NLR family have a N-terminal of pyrin domain (PYD). The PYD ensures interaction with the apoptosis-associated speck-like protein containing a caspaserecruitment-domain (ASC) adapter, which ensures the recruitment of an inflammatory caspase. NALP3 (Fig. 3) is probably the best understood of all, and is involved in the recognition of numerous exogenous and host ligands. Inflammasomes are multiprotein cytoplasmic complexes that mediate the activation of caspases, and are composed by the NALP and its ASC adapter. The components of the NALP3 inflammasome include the NALP3 itself, the ASC and caspase-1 (also known as ICE-1). IL-1 needs cleavage by the ICE-1, but recent publications describe that a second stimulus to induce the formation of this inflammasome to enhance the proteolytic maturation and secretion of IL-1 would be necessary [29]. The mechanisms of activation of the NALP3 remain still not clear, but it seems to recognize a range of compounds, including bacterial RNA, ATP, monosodium urate crystals and some antiviral compounds [30]. Sensing of these stimuli causes NALP3 to oligomerize, to recruit ACS and ICE-1 and form the inflammasome NALP3 complex (Fig. 4).
7.2.1. Autoinflammatory syndromes 7.2.1.1. Autoinflammatory syndromes related to CIAS1 gene mutation. These syndromes, also CAPS, constitute a subfamily of hereditary periodic fever syndromes. Clinical presentation includes unexplained fever and severe localized inflammation. This entire family of autoinflammatory syndromes (AIS) is characterized by unexplained systemic inflammation in the absence of high titres of autoantibodies or specific T-cells. Although these syndromes are all related to the same gene, their features and severity vary. They include the FCAS, the MWS and the chronic infantile neurological cutaneous and articular/neonatal-onset multisystemic inflammatory disease (CINCA/NOMID) [31]. FCAS is the less severe disease of the spectrum and usually presents with urticaria and conjunctivitis triggered by exposure to cold. CINCA/NOIMD is the most severe and presents with aseptic meningitis and mental retardation. These disorders are caused by mutations in the CIAS1, and are herited as autosomal-dominant traits, but de novo mutations must occur also. The mutations are thought to result in a gain-of-function effect, probably in the loss of a regulatory step associated with the NALP3 inflammasome activation that causes excessive production of IL-1. Treatment of these patients is not easy. While corticosteroids are useful in acute attacks, long-term therapy is responsible for many adverse effects, gradual loss of efficacy and dependence. Therapy with anakinra at doses of 1 mg/Kg per day has been established as an efficient and safe treatment in CAPS, in the acute attack, with resolution of the symptoms within 24 hours [32] and as a longterm therapy decreasing the frequency of attacks [33,34]. However, the drug failed to stop the progression of the ocular, auditory and neurological involvement [35]. 7.2.1.2. Familiar mediterranean fever. Familiar Mediterranean Fever (FMF) in another autoinflammatory disease, characterized by periodic fever and serosal inflammation, often complicated by systemic amyloidosis. Maintenance treatment of FMF with colchicine can reduce disease activity and prevent amyloidosis. Some patients, however, fail colchicine therapy [36]. The reports published concerning the effective use of anakinra in other AIS
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have prompted clinicians to essay Anakinra in FMF. Until date, only four cases have been reported, with acute attack clinical improvement and no relapsing during the follow-up (six months) [37].
dogout successfully treated with anakinra has also been reported [45,46].
7.2.1.3. Schnitzler’s syndrome. Schnitzler’s syndrome is another autoinflammatory disease of unknown aetiology, characterized by urticarial rash and monoclonal component. Some case reports successfully treated with anakinra 100 mg/d have also been reported [38].
7.3.1. Ankylosing spondylitis Ankylosing spondylitis (AS) is the prototype of the spondyloarthritides, and the currently established treatment consists of non-steroidal anti-inflammatory drugs (NSAID) and physical therapy. Except for sulfasalazine [47], which seems to be effective in peripheral joint involvement, no established DMARD treatment is available. TNF␣ inhibitors infliximab [48] and etanercept [49] as well as adalimumab have recently proved to be highly effective in active AS resistant to NSAIDs. Genetic factors that predispose individuals to AS are not fully understood, but are unlikely to be restricted to HLA-B27 [50]. On the other hand, IL-1 has been found to be up-regulated in AS and other spondyloarthritides. Anakinra has shown clinical efficacy in AS patients. Tan et al. performed an open label study with nine patients with NSAID-resistant AS, treated with anakinra 100 mg/24 h during three months: 67% of patients achieved a significant response (assessed by MRI) [50]. Anakinra might have a role in patients with AS who cannot tolerate anti-TNF treatment or for whom it has failed. Further randomised controlled trials are needed to formally demonstrate efficacy.
7.2.2. Systemic juvenile idiopathic arthritis and adult’s onset Still disease SoJIA and adult-onset Still disease (AoSD) are rare systemic inflammatory disorders of unknown aetiology. SoJIA shares many clinical, haematological and biochemical manifestations with the AIS, and this has led to speculations over whether SoJIA should be reclassified as an AIS rather than an autoimmune disease [17]. Dysregulation of IL-1 production has been proposed to be a remarkable factor in the pathogenesis of the SoJIA. It has been demonstrated that serum from SoJIA patients induces transcription of innate immunity genes, inlcuding IL-1 genes in healthy peripheral mononuclear blood cells, increasing IL-1 levels. Pascual et al. observed a good response to anakinra in seven out of nine patients with SoJIA, remaining in clinical remission [38]. Recently, Lequerré et al. published a prospective study to assess the efficacy and safety of anakinra in SoJIA and AoSD in 35 patients during 24 months [39]. A significant proportion of SoJIA and most of the AoSD patients presented a quick and sustained response to anakinra, confirming previous published data and providing more evidence that IL-1 is a key cytokine in both diseases [40]. No mutations involving the IL-1 regulation has been identified so far in SoJIA patients neither AoSD. Nevertheless, speculation remains that susceptibility to SoJIA might also involve mutations in components of the inflammasome. The use of anakinra in AoSD patients refractory to other therapies has shown favourable results: many publications have documented its efficacy and safety, and in some cases complete remission has been reported [41]. 7.2.3. Gout and pseudogout Gout is a metabolic joint disease, associated with chronic hyperuricemia. Attacks of acute arthritis with severe pain and fever are the hallmark of the disease, and are related to deposition and precipitation of monosodium urate (MSU) crystals in joints and periarticular tissues. This precipitation of MSU within joints induces a strong local inflammatory response. Crystals are phagocyted by monocytes, which produce mediators of inflammation such as IL-1 and TNF-␣, causing a major flow of inflammatory cells. In a same way, pseudogout arises from deposition of calcium pyrophosphate dihydrate crystals (CPPD), owing to unknown causes [42]. Martinon et al. have recently established that MSU and CCPD engaged the ICE-1 activating NALP3-inflammasome, resulting in the production of active IL-1 and IL-18. Macrophages from mice deficient in various components of the inflammasome such as ICE-1, ASC and NALP3 were defective in crystal-induced IL-1 activation. Moreover, an impaired neutrophil influx was found in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1R [43]. Based on these findings, an open-labelled study was performed: 10 patients with gout resistant or intolerant to standard antiinflammatory therapies received 100 mg anakinra daily for three days. All 10 patients with acute gout responded rapidly to anakinra. No adverse effects were observed [44]. A case of refractory pseu-
7.3. Miscellaneous indications
7.3.2. Connective tissue diseases An IL-1Ra gene polymorphism in systemic lupus erythematosus (SLE) has been described and related to disease severity rather than disease susceptibility [51,52]. Concentrations of circulating IL-1Ra vary considerably with the disease course in SLE and with different types of SLE manifestations. Levels of IL-1Ra are commonly increased in active extra-renal SLE, and low concentrations of IL-1Ra have been assessed in patients with renal disease [53]. Interestingly enough four patients with refractory lupus arthritis improved [54]. Very high IL-1Ra concentrations have been found in patients with active polymyositis and dermatomyositis [55] but no clinical use of anakinra in these diseases has been reported so far. A case report of antisynthetase syndrome with refractory polyarthritis and fever was successfully treated with anakinra with no relapses after 20 months of follow-up [56]. 7.3.3. Relapsing polychondritis Relapsing polychondritis is a chronic inflammatory autoimmune disease, whose cause is unknown. The usual therapy is corticosteroids, but standard treatment has not been established in refractory patients. Some small case-series and case reports of successful treatment with biologic agents have been published. A case report of relapsing polychondritis refractory to classical immunosuppressive drugs, and six months therapy with anti-TNF␣, showed clinical improvement and no relapses for over 14 months under anakinra treatment [57]. 8. Conclusion Anakinra (rIL-1Ra) is the anti-IL-1 molecule with wider efficacy and safety data, and is nowadays approved for therapeutical use, for RA and the AIS treatment. Other IL-1 inhibition strategies have been reported to be effective in vitro in RA, and are now on trials to establish their role on a clinical setting. A new broad of therapeutical uses are now under investigation, namely the identification of IL-1 as a product of the inflammasome and NALP3 pathways, and its key-role in the so-called AIS with both anakinra and the other anti-IL-1 molecules. Furthermore, promising results have been reported in the treatment
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Joint Bone Spine 2007;74:544–50. [32] Ramos E, Arostegui JI, Campuzano S, et al. Positive clinical and biochemical responses to anakinra in a 3-year-old patient with cryopyrin-associated periodic syndrome (CAPS). Rheumatology (Oxford) 2005;44:1072–3. [33] Hoffman HM, Rosengren S, Boyle DL, et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 2004;364:1779–85. [34] Gerard S, le Goff B, Maugars Y, et al. Lasting remission of a Muckle-Wells syndrome with CIAS-1 mutation using half-dose anakinra. Joint Bone Spine 2007;74:659. [35] Kuijk LM, Govers AM, Frenkel J, et al. Effective treatment of a colchicineresistant familial Mediterranean fever patient with anakinra. Ann Rheum Dis 2007;66:1545–6. [36] Roldan R, Ruiz AM, Miranda MD, et al. Anakinra: new therapeutic approach in children with Familial Mediterranean Fever resistant to colchicine. Joint Bone Spine 2008;75:504–5. [37] Klemmer N, Lenain P, Balguerie X, et al. Effectiveness of anti-IL-1 in Schnitzler’s syndrome. Joint Bone Spine 2007;74:509–10. [38] Pascual V, Allantaz F, Arce E, et al. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med 2005;201:1479–86. [39] Lequerré T, Quartier P, Rosellini D, et al. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 2008;67:302–8. [40] Fitzgerald AA, Leclercq SA, Yan A, et al. Rapid responses to anakinra in patients with refractory adult-onset Still’s disease. Arthritis Rheum 2005;52:1794–803. [41] Pétrilli V, Martinon F. The inflammasome, autoinflammatory diseases, and gout. Joint Bone Spine 2007;74:571–6. [42] Martinon F, Glimcher LH. Gout: new insights into an old disease. J Clin Invest 2006;116:2073–5. [43] So A, De Smedt T, Revaz S, et al. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 2007;9:28. [44] McGonagle D, Tan AL, Madden J, et al. Successful treatment of resistant pseudogout with anakinra. Arthritis Rheum 2008;58:631–3. [45] Church LD, Cook GP, McDermott MF. Primer: inflammasomes and interleukin 1beta in inflammatory disorders. Nat Clin Pract Rheumatol 2008;4:34–42. [46] Dougados M, van der Linden S, Leirisalo-Repo M, et al. Sulfasalazine in the treatment of spondyloarthritides. Arthritis Rheum 1995;38:618–27. [47] Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab – a double-blind placebo controlled multicenter trial. Lancet 2002;359:1187–93. [48] Davis JC, Van Der Heijde D, Braun J, et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheum 2003;48:3230–6. [49] McGarry F, Neilly J, Anderson N, et al. A polymorphism within the interleukin 1 receptor antagonist (IL-1Ra) gene is associated with ankylosing spondylitis. Rheumatology (Oxford) 2001;40:1359–64. [50] Tan AL, Marzo-Ortega H, O’Connor P, et al. Efficacy of anakinra in active ankylosing spondylitis: a clinical and magnetic resonance imaging study. Ann Rheum Dis 2004;63:1041–5. [51] Blakemore AI, Tarlow JK, Cork MJ, et al. Interleukin-1 receptor antagonist gene polymorphism as a disease severity factor in systemic lupus erythematosus. Arthritis Rheum 1994;37:1380–5. [52] Suzuki H, Takemura H, Kashiwagi H. Interleukin-1 receptor antagonist in patients with active systemic lupus erythematosus: enhanced production by monocytes and correlation with disease activity. Arthritis Rheum 1995;38:1055–9. [53] Moosig F, Zeuner R, Renk C, et al. IL-1RA in refractory systemic lupus erythematosus. Lupus 2004;13:605–6. [54] Ostendorf B, Iking-Konert C, Kurz K, et al. Preliminary results of safety and efficacy of the interleukin 1 receptor antagonist anakinra in patients with severe lupus arthritis. Ann Rheum Dis 2005;64:630–3. [55] Son K, Tomita Y, Shimizu T, et al. Abnormal IL-1 receptor antagonist production in patients with polymyositis and dermatomyositis. Intern Med 2000;39:128–35. [56] Furlan A, Botsios C, Ruffatti A, et al. Antisynthetase syndrome with refractory polyarthritis and fever successfully treated with the IL-1 receptor antagonist, anakinra: a case report. Joint Bone Spine 2008;75:366–7. [57] Wendling D, Govindaraju S, Prati C, et al. Efficacy of anakinra in a patient with refractory relapsing polychondritis. Joint Bone Spine 2008;75:622–4.
Review
Anti-IL-1 molecules: New comers and new indications Anna Moltó , Alejandro Olivé ∗ Rheumatology Section, Hospital Universitari Germans Trias i Pujol, Ctra del Canyet s/n, 08916 Badalona, Spain
a r t i c l e
i n f o
Article history: Accepted 29 October 2009 Available online 31 December 2009 Keywords: Interleukin 1 Anakinra Rheumatoid arthritis Autoinflammatory syndromes Spondyloarthropathy
a b s t r a c t The interleukin 1 family is composed by the interleukin 1 (IL-1) and its natural occurring inhibitor, the interleukin 1 receptor antagonist (IL-1Ra). The role of both molecules in rheumatoid arthritis has been widely established, and in this sense new molecules blocking IL-1 actions are under investigation. Anakinra is the recombinant form of IL-1Ra, and has proven to be well tolerated and indicated in the treatment of rheumatoid arthritis. Nevertheless, other molecules such as mAb anti-IL-1 and IL-1 Trap are being developed. Moreover, the recent relation of IL-1 in the inflammasome and pathways of innate immunity has lead to new indications of anti-IL-1 molecules, especially in the autoinflammatory syndromes as well as in other inflammatory diseases. Herein we have performed a review of the literature, limited to English language journals (PUBMED search: combination of descriptors IL-1 and anakinra, systemic juvenile idiopathic arthritis, adult’s onset Still’s disease, autoinflammatory syndromes, gout, pseudogout, ankylosing spondylitis, and systemic lupus erythematosus from January 1985–December 2008) emphasizing the possible new indications. Although sufficient data is not yet available to fully assess the efficacy and safety of anti-IL-1 molecules in patients with inflammatory disorders other than rheumatoid arthritis, new data is promising. © 2009 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction
2.1. IL-1˛
Interleukin 1 (IL-1) is a proinflammatory cytokine and its role in the inflammatory response has been well established. It has been implicated in the pathogenesis of several chronic diseases, including rheumatoid arthritis (RA), and until today anti-IL-1 molecules are a valid therapy for refractory RA. Nevertheless, the recent implication of IL-1 in the inflammasome and the NALP receptors opens a new lead of investigation. NALP3 mutations are thought to be responsible for a group of diseases called autoinflammatory syndromes through an abnormal activation of the inflammasome leading to an excessive IL-1 production. More recently, IL-1 has also been implicated in the inflammatory cascade of the acute gout and pseudogout attack via the NALP3-inflammasome. Those recent findings have lead to explore new therapeutical roles for anti-IL-1 molecules.
Most IL-1␣ remain intracellular in its precursor form and it is believed to function as an autocrine messenger. Nevertheless, there is evidence that a small part of this precursor is transported to the cell surface and associated with the cell membrane. It has been postulated that it might act as a paracrine messenger to adjacent cells [1].
2. Interleukin 1 family IL-1 is a major inflammatory mediator and exists in two forms: IL-1␣ and IL-1. Each form is the product of two separate genes, but is related to each other structurally at a three-dimension level. Mononuclear cells, primarily monocytic phagocytes synthesize both IL-1 [1].
∗ Corresponding author. Tel.: +0034 93 465 12 00 (3288); Cell: 670844037. E-mail address: [email protected] (A. Olivé).
2.2. IL-1ˇ In contrast, near all IL-1 is released from the cell into the extracellular space and circulation. The IL-1 precursor must be cleaved for optimal biologic activity by several common enzymes. An intracellular protease, the IL-1-converting enzyme (ICE), also known as caspase-1, seems to be highly specific for cleaving the IL-1 [1] (Fig. 1). IL-1 is a systemic, hormone-like mediator intended to be released from cells, whereas IL-1␣ is primarily a regulator of intracellular events and mediator of local inflammation. 2.3. IL-1 receptor antagonist IL-1 receptor antagonist (IL-1Ra) is the third member of the IL-1 family. Produced and secreted by almost all cells expressing IL-1, IL-1Ra functions as a competitive receptor antagonist, binding to IL-1 receptors (IL-1R), but not activating target cells.
1297-319X/$ – see front matter © 2009 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2009.10.011
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Fig. 1. Production of IL-1
2.4. IL-1 receptors There are 2 different IL-1R, namely IL-1RI and IL-1RII. Binding of IL-1␣ or IL-1 to IL-1RI produces activation, subsequent intracellular transduction and cellular responses, whereas binding to IL-1RII does not transduce signal. IL-1RII seems to be a decoy receptor, acting as a buffer to compensate excessive concentrations of IL-1 [2]. Although all three members of IL-1 family have different aminoacid sequence, each can bind with high affinity to the IL-1R: IL-1␣ and IL-1 as agonists of IL-1RI, and IL-1Ra blocking the IL-1␣ and IL-1 binding [3] (Fig. 2). 3. Biological actions of IL-1 The biological effects of IL-1␣ and IL-1 [2] have been reviewed in detail, particularly in the areas of IL-1 effects on the hypothalamic-pituitary-adrenal axis [4] bone metabolism [5], in the pathogenesis of RA and loss of lean body mass [6]. Systemic injection of recombinant IL-1 elicits fever, anorexia, hypotension, leucopenia and thrombocytopenia. IL-1 stimulates production of acute phase proteins by the liver, including IL-6, fibrinogen, complement components, and various clotting factors. IL-1 also stimulates the hypothalamic-pituitary-adrenal axis leading to production of adenocorticotrophic hormone, growth hormone, vasopressin and somatostatin [4]. In the haematopoietic system, IL-1 increases production of colony stimulating factors
Fig. 2. IL-1 and IL-1 Ra interaction with IL-1 RI and IL-1RII.
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and stem cell factors and acts synergistically with these factors to augment production of granulocytes and platelets [7]. The basis for the varied biologic properties of IL-1 is the effects of this cytokine on the expression of various genes and surface receptors. In general, IL-1 either initiates transcription or stabilizes mRNA for a variety of genes, including the ability of both IL-1 to increase the expression of the IL-1 family of genes itself. In a similar way, other inflammatory cytokines, lymphocyte growth factors, colony-stimulating factors, and mesenchymal growth factor genes are up-regulated by IL-1. It has been proven that IL-1 acts synergistically with bradykinin, other cytokines, and growth factors and it is remarkable that synergism between IL-1 and TNF␣ is highly consistent. It is a frequently reported phenomenon, also observed in vivo, whereas the synergism between IL-1 and the various growth factors is mostly on prostanoid synthesis and is primarily an in vitro finding. The mechanism for synergism may also involve receptor modulation; however, in the case of IL-1 and TNF␣ synergism, TNF␣-receptors are down-regulated by IL-1, and thus blocking one cytokine may only reduce disease severity by 50% [8]. Furthermore, IL-1 promotes Th17 differentiation in humans. Th17 is a type of effector T-cell (along with Th1 and Th2) and its pathway is prominently involved in inflammation and autoimmunity. Th17 cells are pivotal in RA. The current hypothesis is that RA is caused by a Th1/Th17 imbalance (with predominance of Th17) [9]. In joints, IL-1 stimulates chondrocytes to release collagenase and other proteolytic enzymes involved in the cartilage degradation. IL-1 also stimulates the differentiation of the osteoclast’s progenitor and contributes to the activation of the mature osteoclasts leading to bone resorption.
4. Biological actions of IL-1Ra Secreted IL-1Ra is an inducible gene in most cells, but intracellular IL-1Ra is expressed constitutively in keratinocytes and intestinal epithelial cells. IL-1Ra represents the first naturally occurring cytokine or hormone-like molecule acting as a specific receptor antagonist. Many experiments have tried to elucidate the biological properties of IL-1Ra over the past years, and no unequivocal agonists effects have been reported so far. Natural sIL-1Ra is a 22-kD glycosylated protein, but the recombinant (non-glycosylated) 17-kD form of IL-1Ra (anakinra) retains a comparable ability to inhibit IL1 binding in vitro. As we mentioned before, if IL-1Ra binds to IL-1RI with high affinity, how does it not yet trigger a response? The currently hypothesis is that as IL-1RI presents three binding domains, and IL-1Ra occupies only one site of the receptor, by lacking the second binding site, IL-1Ra would not trigger a signal, and after IL-1Ra binding to IL-1RI-bearing cells, there would not be phosphorylation of the epidermal growth factor receptor, and no signal transduction. One of the main unanswered questions about IL-1 is its role in normal physiology, and the availability of recombinant IL-1Ra allows these questions to be examinated, first in animal models and over the last years in human diseases. In normal homeostasis, the actions of IL-1 are balanced by IL-1Ra, as much as by other IL-1 natural inhibitors (IL-1RII and circulating IL-1 RI), and a pool of antiinflammatory cytokines. However, an increased production of IL-1 has been observed in a wide range of diseases, including infection, solid tumours, and autoimmune diseases. In RA, for example, systemic and synovial fluid concentrations of IL-1 are raised, and they correlate with disease severity and histological features [10,11]. IL1Ra levels are also increased in many patients with RA, but they may not be sufficient for keeping IL-1 activity in balance [12].
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5. IL-1 Inhibition: new comers
5.3. IL-1 Trap
The role of IL-1 in various disease animal models has been inferred by the protective effects of recombinant IL-1Ra, soluble IL1 receptors and neutralizing antibodies to IL-1-␣ and IL-1. There are several strategies for reducing IL-1 activities (Table 1).
The IL-1 Trap comprises high affinity blockers of cytokine action that may offer a more potent way of inhibition than other strategies proposed previously. Rilonacept is the currently commercialised IL-1 Trap. It is a combination of both the IL-1 receptor accessory protein and the IL-1R, arranged inline and fused to the Fc portion of human IgG1. As this drug binds both IL-1␣ and IL-1, it has the potential to inhibit a wider range of IL-1 effects in vivo than other IL-1 targeted therapies [17]. It was the first therapy approved by the FDA for the treatment of CAPS, and it received the orphan drug approval from the FDA for familial cold auto-inflammatory syndrome (FCAS) and the MuckleWells syndrome (MWS) in adults and children aged 12 years or older [18]. The administration is subcutaneous weekly. The FDA based its approval on the results of two consecutive randomised double blind, placebo-controlled phase III clinical studies, testing safety and efficacy of rilonacept in adults with CAPS [19,20].
5.1. IL-1Ra gene therapy IL-1Ra gene therapy appears promising for both inflammatory arthritis and osteoarthritis. The onset of murine collage-induced arthritis was abrogated by transfection of knee synovial fibroblasts with the IL-1Ra gene. Based on this animal model data, studies evaluating gene therapy using retroviral constructs encoding human IL-1Ra are underway in patients with RA [13]. IL-1Ra gene therapy involves removal of synovium from the joint of a patient awaiting total joint arthroplasty, transfecting it with the IL-1Ra gene, and reimplantation of the synovium at the time of joint replacement. Evans et al. presented nine patients with osteoarthritis awaiting metacarpophalangeal arthroplasty: the procedure was well tolerated and expression of the transgene was documented [14].
5.2. Monoclonal anti-IL-1ˇ antibody Canakinumab (ACZ885) is a fully human monoclonal antibody against IL-1. Its administration is intravenous or subcutaneous, and has been established every two weeks. Its effectiveness has been proven in animal models of disease, such as collagen-induced arthritis [15], and its clinical use is currently being evaluated in phase III trials. The drug has received the EU and US Orphan drug status for systemic-onset juvenile idiopathic arthritis (SoJIA) and cryopyrin-associated periodic syndromes (CAPS). Canakinumab has promising clinical safety and pharmacokinetics properties, and besides its potential use in the mentioned diseases, it may also play a role in other complex inflammatory diseases, such as RA [16].
Table 1 Potential therapeutical uses of IL-1 blockade. IL-1 blockers
Potential theurapeutical uses
Anakinra (metHuIL-1Ra)
Rheumatoid arthritis (randomised controlled trials) Autoinflammatory syndromes: CAPS (caser reports) FMF (case reports) Schnitzler’s syndrome (case report) SoJIA and AoSD (prospective studies) Gout (open-labelled study) Pseudogout (case report) Ankylosing Spondylitis (open label study) Systemic lupus erythematosus (case series) Antisynthetase syndrome (case report) Relapsing polychondritis (case report)
Rilonacept (IL-1 trap)
CAPS (phase III trials) SoJIA
Canakinumab (ACZ885)
FCAS (randomised double-blind phase III trial) MWS (randomised double-blind phase III trial)
IL-1Ra gene therapy
Has not been established yet
CAPS: cryopyrin-associated periodic syndromes; FMF: familiar mediterranean fever; SoJIA: systemic-onset juvenile idiopathic arthritis; AoSD: adult’s onset Stills disease; FCAS: familial cold autoinflammatory syndrome; MWS: Muckle-Wells syndrome. FDA approved indications.
5.4. Anakinra The recombinant form of the naturally occurring IL-1Ra is called anakinra (rmetHuIL-1Ra), and differs from the native human protein in that it is not glycosilated and has an additional N-terminal methionine. Early studies with anakinra focused on endotoxaemia, septic shock and steroid resistant graft vs. host disease. Nowadays anakinra is approved for treating the signs and symptoms as well as the joint destructive components of RA. However, the challenge for anakinra for occupying the large number of IL-1R is formidable, as these receptors are expressed on all cells excepts red blood cells: moreover, anakinra is rapidly excreted by the kidney, and blood levels are low after 24 hours. IL-1R are also readily generated each day, so a daily injection of anakinra is necessary [21]. The feasibility of delivering anakinra by subcutaneous injection in patients with RA was demonstrated in a three-week dose ranging and dose frequency study. Once-daily administration was well tolerated and showed better clinical activity than every three or seven days dosage. Although no head-to-head study comparing efficacy between anakinra and classical TNF␣ inhibitors has been performed so far, a recent meta-analysis revealed that treatment with anakinra was superior to placebo, but less efficacious than TNF␣ inhibitors. Prescription of anakinra is scarce compared with TNF␣ inhibitors [22–24]. 6. IL-1 and IL-1Ra in disease 6.1. Rheumatoid arthritis Several publications have reported that inflammatory autoimmune diseases developed spontaneously in IL-1Ra knockout mice. Horai et al. reported the development of an inflammatory erosive arthritis in IL-1Ra deficient mice. The arthropathy was marked by pannus invasion of the joint surface and histological evidence of marked synovial and periarticular inflammation, resembling to the changes typically seen in RA. No such disease developed in control mice, which had normal amounts of IL-1Ra. Levels of IL-1mRNA in the joint of these mice were 10 times as high as the level in control mice [25,26]. In a same fashion, animal models have revealed that injection of high concentration of IL-1 in rabbit knee joint produced clinical and histological features of RA [27]. Experimental models of arthritis in IL-1Ra deficient mice showed clearly enhanced levels of Th17 cells, and the anti-IL-1 treatment significantly reduced the percentage of IL-17+Th17 cells, suggesting that IL-1 might be the driving force behind the Th17 imbalance in RA [28].
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Fig. 4. NALP3 inflammasome
7.2. Inflammatory disorders A growing number of systemic inflammatory disorders characterized by fever anaemia and an elevation of acute phase proteins have been linked to excessive production and bioactivity of IL1. All these conditions respond, to varying degrees, to specific blockade of the IL-1R. Furthermore, several of these diseases are associated with abnormalities in NRL signalling pathways, as in the cryopyrinopathies, also termed as the cold-induced autoinflammatory syndrome 1 (CIAS1)-associated periodic syndromes.
Fig. 3. NALP3 structure
7. IL-1 and the inflammasome: new indications 7.1. The inflammasome The recent identification of cytosol-expressed Nod-like receptors (NLR) has changed the concept of innate immunity as non-specific. NALP belonging to the NLR family have a N-terminal of pyrin domain (PYD). The PYD ensures interaction with the apoptosis-associated speck-like protein containing a caspaserecruitment-domain (ASC) adapter, which ensures the recruitment of an inflammatory caspase. NALP3 (Fig. 3) is probably the best understood of all, and is involved in the recognition of numerous exogenous and host ligands. Inflammasomes are multiprotein cytoplasmic complexes that mediate the activation of caspases, and are composed by the NALP and its ASC adapter. The components of the NALP3 inflammasome include the NALP3 itself, the ASC and caspase-1 (also known as ICE-1). IL-1 needs cleavage by the ICE-1, but recent publications describe that a second stimulus to induce the formation of this inflammasome to enhance the proteolytic maturation and secretion of IL-1 would be necessary [29]. The mechanisms of activation of the NALP3 remain still not clear, but it seems to recognize a range of compounds, including bacterial RNA, ATP, monosodium urate crystals and some antiviral compounds [30]. Sensing of these stimuli causes NALP3 to oligomerize, to recruit ACS and ICE-1 and form the inflammasome NALP3 complex (Fig. 4).
7.2.1. Autoinflammatory syndromes 7.2.1.1. Autoinflammatory syndromes related to CIAS1 gene mutation. These syndromes, also CAPS, constitute a subfamily of hereditary periodic fever syndromes. Clinical presentation includes unexplained fever and severe localized inflammation. This entire family of autoinflammatory syndromes (AIS) is characterized by unexplained systemic inflammation in the absence of high titres of autoantibodies or specific T-cells. Although these syndromes are all related to the same gene, their features and severity vary. They include the FCAS, the MWS and the chronic infantile neurological cutaneous and articular/neonatal-onset multisystemic inflammatory disease (CINCA/NOMID) [31]. FCAS is the less severe disease of the spectrum and usually presents with urticaria and conjunctivitis triggered by exposure to cold. CINCA/NOIMD is the most severe and presents with aseptic meningitis and mental retardation. These disorders are caused by mutations in the CIAS1, and are herited as autosomal-dominant traits, but de novo mutations must occur also. The mutations are thought to result in a gain-of-function effect, probably in the loss of a regulatory step associated with the NALP3 inflammasome activation that causes excessive production of IL-1. Treatment of these patients is not easy. While corticosteroids are useful in acute attacks, long-term therapy is responsible for many adverse effects, gradual loss of efficacy and dependence. Therapy with anakinra at doses of 1 mg/Kg per day has been established as an efficient and safe treatment in CAPS, in the acute attack, with resolution of the symptoms within 24 hours [32] and as a longterm therapy decreasing the frequency of attacks [33,34]. However, the drug failed to stop the progression of the ocular, auditory and neurological involvement [35]. 7.2.1.2. Familiar mediterranean fever. Familiar Mediterranean Fever (FMF) in another autoinflammatory disease, characterized by periodic fever and serosal inflammation, often complicated by systemic amyloidosis. Maintenance treatment of FMF with colchicine can reduce disease activity and prevent amyloidosis. Some patients, however, fail colchicine therapy [36]. The reports published concerning the effective use of anakinra in other AIS
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have prompted clinicians to essay Anakinra in FMF. Until date, only four cases have been reported, with acute attack clinical improvement and no relapsing during the follow-up (six months) [37].
dogout successfully treated with anakinra has also been reported [45,46].
7.2.1.3. Schnitzler’s syndrome. Schnitzler’s syndrome is another autoinflammatory disease of unknown aetiology, characterized by urticarial rash and monoclonal component. Some case reports successfully treated with anakinra 100 mg/d have also been reported [38].
7.3.1. Ankylosing spondylitis Ankylosing spondylitis (AS) is the prototype of the spondyloarthritides, and the currently established treatment consists of non-steroidal anti-inflammatory drugs (NSAID) and physical therapy. Except for sulfasalazine [47], which seems to be effective in peripheral joint involvement, no established DMARD treatment is available. TNF␣ inhibitors infliximab [48] and etanercept [49] as well as adalimumab have recently proved to be highly effective in active AS resistant to NSAIDs. Genetic factors that predispose individuals to AS are not fully understood, but are unlikely to be restricted to HLA-B27 [50]. On the other hand, IL-1 has been found to be up-regulated in AS and other spondyloarthritides. Anakinra has shown clinical efficacy in AS patients. Tan et al. performed an open label study with nine patients with NSAID-resistant AS, treated with anakinra 100 mg/24 h during three months: 67% of patients achieved a significant response (assessed by MRI) [50]. Anakinra might have a role in patients with AS who cannot tolerate anti-TNF treatment or for whom it has failed. Further randomised controlled trials are needed to formally demonstrate efficacy.
7.2.2. Systemic juvenile idiopathic arthritis and adult’s onset Still disease SoJIA and adult-onset Still disease (AoSD) are rare systemic inflammatory disorders of unknown aetiology. SoJIA shares many clinical, haematological and biochemical manifestations with the AIS, and this has led to speculations over whether SoJIA should be reclassified as an AIS rather than an autoimmune disease [17]. Dysregulation of IL-1 production has been proposed to be a remarkable factor in the pathogenesis of the SoJIA. It has been demonstrated that serum from SoJIA patients induces transcription of innate immunity genes, inlcuding IL-1 genes in healthy peripheral mononuclear blood cells, increasing IL-1 levels. Pascual et al. observed a good response to anakinra in seven out of nine patients with SoJIA, remaining in clinical remission [38]. Recently, Lequerré et al. published a prospective study to assess the efficacy and safety of anakinra in SoJIA and AoSD in 35 patients during 24 months [39]. A significant proportion of SoJIA and most of the AoSD patients presented a quick and sustained response to anakinra, confirming previous published data and providing more evidence that IL-1 is a key cytokine in both diseases [40]. No mutations involving the IL-1 regulation has been identified so far in SoJIA patients neither AoSD. Nevertheless, speculation remains that susceptibility to SoJIA might also involve mutations in components of the inflammasome. The use of anakinra in AoSD patients refractory to other therapies has shown favourable results: many publications have documented its efficacy and safety, and in some cases complete remission has been reported [41]. 7.2.3. Gout and pseudogout Gout is a metabolic joint disease, associated with chronic hyperuricemia. Attacks of acute arthritis with severe pain and fever are the hallmark of the disease, and are related to deposition and precipitation of monosodium urate (MSU) crystals in joints and periarticular tissues. This precipitation of MSU within joints induces a strong local inflammatory response. Crystals are phagocyted by monocytes, which produce mediators of inflammation such as IL-1 and TNF-␣, causing a major flow of inflammatory cells. In a same way, pseudogout arises from deposition of calcium pyrophosphate dihydrate crystals (CPPD), owing to unknown causes [42]. Martinon et al. have recently established that MSU and CCPD engaged the ICE-1 activating NALP3-inflammasome, resulting in the production of active IL-1 and IL-18. Macrophages from mice deficient in various components of the inflammasome such as ICE-1, ASC and NALP3 were defective in crystal-induced IL-1 activation. Moreover, an impaired neutrophil influx was found in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL-1R [43]. Based on these findings, an open-labelled study was performed: 10 patients with gout resistant or intolerant to standard antiinflammatory therapies received 100 mg anakinra daily for three days. All 10 patients with acute gout responded rapidly to anakinra. No adverse effects were observed [44]. A case of refractory pseu-
7.3. Miscellaneous indications
7.3.2. Connective tissue diseases An IL-1Ra gene polymorphism in systemic lupus erythematosus (SLE) has been described and related to disease severity rather than disease susceptibility [51,52]. Concentrations of circulating IL-1Ra vary considerably with the disease course in SLE and with different types of SLE manifestations. Levels of IL-1Ra are commonly increased in active extra-renal SLE, and low concentrations of IL-1Ra have been assessed in patients with renal disease [53]. Interestingly enough four patients with refractory lupus arthritis improved [54]. Very high IL-1Ra concentrations have been found in patients with active polymyositis and dermatomyositis [55] but no clinical use of anakinra in these diseases has been reported so far. A case report of antisynthetase syndrome with refractory polyarthritis and fever was successfully treated with anakinra with no relapses after 20 months of follow-up [56]. 7.3.3. Relapsing polychondritis Relapsing polychondritis is a chronic inflammatory autoimmune disease, whose cause is unknown. The usual therapy is corticosteroids, but standard treatment has not been established in refractory patients. Some small case-series and case reports of successful treatment with biologic agents have been published. A case report of relapsing polychondritis refractory to classical immunosuppressive drugs, and six months therapy with anti-TNF␣, showed clinical improvement and no relapses for over 14 months under anakinra treatment [57]. 8. Conclusion Anakinra (rIL-1Ra) is the anti-IL-1 molecule with wider efficacy and safety data, and is nowadays approved for therapeutical use, for RA and the AIS treatment. Other IL-1 inhibition strategies have been reported to be effective in vitro in RA, and are now on trials to establish their role on a clinical setting. A new broad of therapeutical uses are now under investigation, namely the identification of IL-1 as a product of the inflammasome and NALP3 pathways, and its key-role in the so-called AIS with both anakinra and the other anti-IL-1 molecules. Furthermore, promising results have been reported in the treatment
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