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F1000 Biol Rep. 2009; 1: 70.
Published online 2009 September 8. doi:  10.3410/B1-70
PMCID: PMC2948254

Targeting cytokines in inflammatory diseases: focus on interleukin-1-mediated autoinflammation


In this commentary, we summarize the most recent advances in the cytokine-targeting therapies. We focus on new aspects of interleukin-1 (IL-1)-mediated autoinflammation and novel strategies to target IL-1.

Introduction and context

The treatment of the broad and heterogeneous group of inflammatory diseases has been revolutionized with the introduction of therapies that target cytokines [1]. Since 1998, the year that tumor necrosis factor-alpha (TNF-α) blockade was first approved for rheumatoid arthritis (RA), our cytokine-targeting armamentarium has been enriched [1]. Table 1 summarizes all of the anti-cytokine regimens approved by the US Food and Drug Administration (FDA), and Table 2 lists the cytokine-targeting therapies that are still under investigation [2]. Recent evidence suggests that interleukin-6 (IL-6) blockade using tocilizumab is effective in RA [3] and that the p40 neutralizing antibody ustekinumab (targeting both IL-12 and IL-23) is beneficial for psoriasis [4].

Table 1.
Cytokine-targeting therapies approved by the US Food and Drug Administration for the treatment of inflammatory diseases
Table 2.
Cytokine-targeting therapies that are under investigation in clinical trials

ASp, ankylosing spondylitis; CAPS, cryopyrin-associated periodic syndrome; CD, Crohn's disease; Fab, fragment antigen-binding; FDA, US Food and Drug Administration; IgG, immunoglobulin G; IL-1, interleukin-1; IL-1AcP, interleukin-1 accessory protein; IL-1Ra, interleukin-1 receptor antagonist; JIA, juvenile idiopathic arthritis; Mab, monoclonal antibody; PEG, polyethylene glycol; PsA, psoriatic arthritis; RA, rheumatoid arthritis; TNF-α, tumor necrosis factor-alpha; TNFR, tumor necrosis factor receptor; UC, ulcerative colitis.

For further information, see [2]. AOSD, adult-onset Still’s disease; APRIL, a proliferation-inducing ligand; ASp, ankylosing spondylitis; BAFF, B-cell activating factor of tumor necrosis factor family; BLyS, B lymphocyte stimulator; CAPS, cryopyrin-associated periodic syndrome; CD, Crohn's disease; COPD, chronic obstructive pulmonary disease; CSS, Churg-Strauss syndrome; DM II, diabetes mellitus type II; FMF, familial Mediterranean fever; HES, hyper-eosinophilic syndromes; hIgG1, human immunoglobulin G1; IFN-α, interferon-alpha; IL, interleukin; IPF, idiopathic pulmonary fibrosis; LIGHT, lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells; LT, lymphotoxin; Mab, monoclonal antibody; MS, multiple sclerosis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; RANKL, receptor activator of nuclear factor-kappa B ligand; SLE, systemic lupus erythematosus; SoJIA, systemic onset juvenile idiopathic arthritis; SSc, systemic scleroderma; TACI, transmembrane activator and CAML (calcium modulator and cyclophilin ligand) interactor; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha.

Despite all of these breakthroughs in targeting cytokines, the treatment of inflammatory diseases is still imperfect and challenging. The high cost and the treatment-related adverse events (mainly infections and the reported, but controversial, increased risk for malignancies) are major drawbacks of cytokine targeting [5-7]. In addition, the available cytokine blockade is not always effective, as exemplified by the failure of the anti-p40 monoclonal antibody to show a significant benefit in patients with multiple sclerosis [8]. Furthermore, approximately 30% of RA patients do not respond adequately to anti-TNF-α treatments [9] and the IL-1 inhibitor anakinra appears to be only moderately effective in its FDA-approved indication for RA in clinical practice [5].

Although anakinra did not fulfill all of the expectations for managing RA, this therapeutic showed remarkable effectiveness in a heterogeneous group of heritable and sporadic disorders now considered IL-1-mediated autoinflammatory diseases [10]. The prototype of these diseases is the cryopyrin-associated periodic syndrome (CAPS) [11]. CAPS is now considered a continuum of one disorder with varying severity and includes the mild phenotype known as familial cold autoinflammatory syndrome (FCAS), the intermediate Muckle-Wells syndrome (MWS), and the severe form of neonatal-onset multisystem inflammatory disorder (also called chronic infantile neurologic cutaneous and articular syndrome) [11].

The immune system discriminates self from nonself and distinguishes pathogens from commensal organisms and specifically eliminates pathogens. Regulation of immune responses restrains concurrent tissue damage and orchestrates tissue repair. This balance between defense and protection of tissue integrity results from a tight regulation of the innate and adaptive branches of the immune system. Failure of these regulatory mechanisms causes an aberrant immune response ranging from inadequate defense to uncontrolled/unprovoked inflammation. Generation of pathogenic autoantibodies or autoreactive T-cell clones or both, due to deregulated adaptive immunity, leads to ‘autoimmunity’ [12]. Systemic lupus erythematosus exemplifies systemic autoimmunity, whereas autoimmune thyroiditis and diabetes mellitus type I reflect some facets of tissue-specific autoimmunity [12].

Now it is well established that genetic defects in molecules regulating the function of the innate immune system are the cause of several diseases characterized by systemic or localized inflammation in the absence of infection, autoreactive lymphocytes, and high titers of autoantibodies [11,13,14]. To distinguish this group of diseases from autoimmune diseases, emphasizing the primary role of innate immunity in driving their pathogenesis, the term ‘autoinflammatory diseases’ has been proposed [11,13,14]. The new aspects in the concept of IL-1-mediated autoinflammation and the recent advances in targeting IL-1 will be the focus of this commentary.

Major recent advances

Understanding Horror autoinflammaticus

More than 60 mutations in the CIAS1 gene are responsible for a hyperactive NALP3 (cryopyrin) leading to CAPS [11]. NALP3 functions as a sensor of pathogens and danger signals and is expressed mainly in immune cells, chondrocytes, and epithelial cells [15]. Upon activation, NALP3 recruits ASC (apoptosis-associated speck-like protein containing caspase-recruitment domain), Cardinal, and pro-caspase-1, assembling a multimeric complex called the inflammasome. NALP3 inflammasomes activate the downstream caspase-1, the protease that cleaves pro-IL-1, releasing the potent pyrogen IL-1β [15,16]. The understanding of the direct role of NALP3 in IL-1β processing led to the concept that CAPS (a result of hyperactive inflammasome due to mutated NALP3) is an IL-1-mediated autoinflammatory disease, justifying the use of IL-1 blockade to control disease activity [11].

Targeting IL-1β to treat autoinflammation

The recombinant human IL-1 receptor antagonist anakinra was the first IL-1-targeting intervention used in patients with CAPS with impressive effectiveness [17-19]. The short half-life of anakinra necessitates daily injections for efficient responses, and injection site reactions are commonly observed [5,17-19]. To overcome these limitations, sophisticated investigation resulted in new efficient strategies to target IL-1 with improved pharmacokinetics and thus better compliance and tolerance [20,21].

Rilonacept is a new IL-1 blocker that functions as an IL-1 trap, binding IL-1 with an affinity at least 100-fold higher than that of the native IL-1 cell surface receptor complex [22]. Normally, IL-1β binds first to IL-1RI on the surface of target cells and subsequently IL-1 accessory protein (IL-1AcP) is recruited, thus forming a trimolecular signaling complex [16]. Rilonacept is an artificial molecule that contains the ligand-binding portions of both IL-1RI and IL-1AcP fused to a dimeric molecule containing the Fc segment of hIgG1 (human immunoglobulin G1) [22]. In contrast to the daily injected anakinra, rilonacept has a half-life of approximately 7 days and thus is administered once weekly [20].

In February 2008, rilonacept (Arcalyst™; Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA) was approved by the FDA for the treatment of CAPS. IL-1 trap was proven very effective and safe in a small open-label pilot study [23] and in a larger two-part phase III clinical trial [24] which included patients with FCAS and MWS. Rilonacept not only rapidly improved patients’ symptoms, but also reduced serum levels of serum amyloid A (SAA) [20,24]. The latter is of great importance given that high serum levels of SAA are directly related to the risk of developing secondary amyloidosis [25], the main cause of renal insufficiency in these patients. Injection site reactions and upper respiratory tract infections were the two most commonly observed adverse events in patients treated with rilonacept [20].

A third IL-1 blocker, the monoclonal human anti-IL-1β canakinumab (ACZ885), was used in patients with CAPS in one small study [26] and a second recently reported randomized placebo-control clinical trial [27]. Canakinumab was administered subcutaneously once every 8 weeks and induced a remarkable clinical response with normalization of SAA and C-reactive protein levels [27]. During the treatment period, only two serious adverse events were observed: one case of urosepsis and an episode of vertigo [27].

Future directions

Recently, it was shown that MSU (monosodium urate monohydrate) and CPPD (calcium pyrophosphate dihydrate) crystals activate NALP3 inflammasome and that IL-1 plays a central role in driving acute inflammation during gout and pseudo-gout attacks [28]. In a small uncontrolled study and in case reports, anakinra has been proven to be very effective in controlling disease flares in patients with gout and pseudo-gout [29-31]. Rilonacept and canakinumab are under investigation in crystal-induced arthritides, and the preliminary results have been promising (Table 2 and [2]). In this context, targeting IL-1 could be a therapeutic alternative, at least for the cases of crystal-induced arthritis with refractoriness or intolerance to the standard treatment with nonsteroidal anti-inflammatory drugs, steroids, and colchicine.

The group of IL-1-mediated autoinflammatory diseases has been broadened with the addition of TNF receptor-associated periodic syndrome, familial Mediterranean fever, hyper-IgD syndrome, PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome, Schnitzler syndrome, systemic onset juvenile idiopathic arthritis, and adult-onset Still’s disease [11,16]. In the above inflammatory disorders, anakinra was remarkably effective [10] and, in the near future, it is expected that the novel IL-1-targeting therapeutics rilonacept and canakinumab will be useful treatment choices for these diseases.


This work was supported by a grant from the National Institutes of Health (NIH) to LBI.


apoptosis-associated speck-like protein containing caspase-recruitment domain
cryopyrin-associated periodic syndrome
calcium pyrophosphate dehydrate
familial cold autoinflammatory syndrome
US Food and Drug Administration
human immunoglobulin G1
interleukin-1 accessory protein
monosodium urate monohydrate
Muckle-Wells syndrome
pyogenic arthritis, pyoderma gangrenosum, and acne
rheumatoid arthritis
serum amyloid A
tumor necrosis factor


The electronic version of this article is the complete one and can be found at:


Competing interests

The authors declare that they have no competing interests.


1. Feldmann M. Many cytokines are very useful therapeutic targets in disease. J Clin Invest. 2008;118:3533–6. doi: 10.1172/JCI37346. [PMC free article] [PubMed] [Cross Ref]
2. homepage. [ ]
3. Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T, Alten R, OPTION Investigators Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371:987–97. doi: 10.1016/S0140-6736(08)60453-5. [PubMed] [Cross Ref] F1000 Factor 3.0 Recommended
Evaluated by Johanne Martel-Pelletier 21 May 2008
4. Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, Li S, Dooley LT, Gordon KB, PHOENIX 1 study investigators Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1) Lancet. 2008;371:1665–74. doi: 10.1016/S0140-6736(08)60725-4. [PubMed] [Cross Ref]
5. Clark W, Jobanputra P, Barton P, Burls A. The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis. Health Technol Assess. 2004;8:1–105. [PubMed]
6. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295:2275–85. doi: 10.1001/jama.295.19.2275. [PubMed] [Cross Ref] F1000 Factor 6.5 Must Read
Evaluated by Michael Ward 30 May 2006, Peter Taylor 15 Jun 2006, Joel Gelfand 12 Jul 2006
7. Askling J, Baecklund E, Granath F, Geborek P, Fored M, Backlin C, Bertilsson L, Cöster L, Jacobsson LT, Lindblad S, Lysholm J, Rantapää-Dahlqvist S, Saxne T, van Vollenhoven R, Klareskog L, Feltelius N. Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas: relative risks and time trends in the Swedish Biologics Register. Ann Rheum Dis. 2009;68:648–53. doi: 10.1136/ard.2007.085852. [PubMed] [Cross Ref] F1000 Factor 3.0 Recommended
Evaluated by Zoltán Szekanecz 22 May 2009
8. Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 2008;7:796–804. doi: 10.1016/S1474-4422(08)70173-X. [PubMed] [Cross Ref] F1000 Factor 6.0 Must Read
Evaluated by Roland Martin 14 Nov 2008
9. Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN, Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343:1594–602. doi: 10.1056/NEJM200011303432202. [PubMed] [Cross Ref]
10. Kalliolias GD, Liossis SN. The future of the IL-1 receptor antagonist anakinra: from rheumatoid arthritis to adult-onset Still’s disease and systemic-onset juvenile idiopathic arthritis. Expert Opin Investig Drugs. 2008;17:349–59. doi: 10.1517/13543784.17.3.349. [PubMed] [Cross Ref]
11. Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*) Annu Rev Immunol. 2009;27:621–68. doi: 10.1146/annurev.immunol.25.022106.141627. [PMC free article] [PubMed] [Cross Ref]
12. Davidson A, Diamond B. Autoimmune diseases. N Engl J Med. 2001;345:340–50. doi: 10.1056/NEJM200108023450506. [PubMed] [Cross Ref]
13. McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, Mansfield E, Gadina M, Karenko L, Pettersson T, McCarthy J, Frucht DM, Aringer M, Torosyan Y, Teppo AM, Wilson M, Karaarslan HM, Wan Y, Todd I, Wood G, Schlimgen R, Kumarajeewa TR, Cooper SM, Vella JP, Amos CI, Mulley J, Quane KA, Molloy MG, Ranki A, Powell RJ, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97:133–44. doi: 10.1016/S0092-8674(00)80721-7. [PubMed] [Cross Ref]
14. McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLoS Med. 2006;3:e297. doi: 10.1371/journal.pmed.0030297. [PMC free article] [PubMed] [Cross Ref]
15. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol. 2009;27:229–65. doi: 10.1146/annurev.immunol.021908.132715. [PubMed] [Cross Ref]
16. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–50. doi: 10.1146/annurev.immunol.021908.132612. [PubMed] [Cross Ref]
17. Hawkins PN, Lachmann HJ, McDermott MF. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome. N Engl J Med. 2003;348:2583–4. doi: 10.1056/NEJM200306193482523. [PubMed] [Cross Ref]
18. Hoffman HM, Rosengren S, Boyle DL, Cho JY, Nayar J, Mueller JL, Anderson JP, Wanderer AA, Firestein GS. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet. 2004;364:1779–85. doi: 10.1016/S0140-6736(04)17401-1. [PubMed] [Cross Ref]
19. Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, Kim HJ, Brewer C, Zalewski C, Wiggs E, Hill S, Turner ML, Karp BI, Aksentijevich I, Pucino F, Penzak SR, Haverkamp MH, Stein L, Adams BS, Moore TL, Fuhlbrigge RC, Shaham B, Jarvis JN, O’Neil K, Vehe RK, Beitz LO, Gardner G, Hannan WP, Warren RW, Horn W, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006;355:581–92. doi: 10.1056/NEJMoa055137. [PubMed] [Cross Ref]
20. Hoffman HM. Rilonacept for the treatment of cryopyrin-associated periodic syndromes (CAPS) Expert Opin Biol Ther. 2009;9:519–31. doi: 10.1517/14712590902875518. [PubMed] [Cross Ref]
21. Church LD, McDermott MF. Canakinumab, a fully-human mAb against IL-1beta for the potential treatment of inflammatory disorders. Curr Opin Mol Ther. 2009;11:81–9. [PubMed]
22. Economides AN, Carpenter LR, Rudge JS, Wong V, Koehler-Stec EM, Hartnett C, Pyles EA, Xu X, Daly TJ, Young MR, Fandl JP, Lee F, Carver S, McNay J, Bailey K, Ramakanth S, Hutabarat R, Huang TT, Radziejewski C, Yancopoulos GD, Stahl N. Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat Med. 2003;9:47–52. doi: 10.1038/nm811. [PubMed] [Cross Ref]
23. Goldbach-Mansky R, Shroff SD, Wilson M, Snyder C, Plehn S, Barham B, Pham TH, Pucino F, Wesley RA, Papadopoulos JH, Weinstein SP, Mellis SJ, Kastner DL. A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheum. 2008;58:2432–42. doi: 10.1002/art.23620. [PMC free article] [PubMed] [Cross Ref]
24. Hoffman HM, Throne ML, Amar NJ, Sebai M, Kivitz AJ, Kavanaugh A, Weinstein SP, Belomestnov P, Yancopoulos GD, Stahl N, Mellis SJ. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 2008;58:2443–52. doi: 10.1002/art.23687. [PubMed] [Cross Ref]
25. Lachmann HJ, Goodman HJ, Gilbertson JA, Gallimore JR, Sabin CA, Gillmore JD, Hawkins PN. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007;356:2361–71. doi: 10.1056/NEJMoa070265. [PubMed] [Cross Ref]Changes Clinical Practice
F1000 Factor 6.0 Must Read
Evaluated by Jurg Schifferli 22 Jun 2007
26. Lachmann HJ, Lowe P, Felix SD, Rordorf C, Leslie K, Madhoo S, Wittkowski H, Bek S, Hartmann N, Bosset S, Hawkins PN, Jung T. In vivo regulation of interleukin 1beta in patients with cryopyrin-associated periodic syndromes. J Exp Med. 2009;206:1029–36. doi: 10.1084/jem.20082481. [PMC free article] [PubMed] [Cross Ref]
27. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, Gitton X, Widmer A, Patel N, Hawkins PN, Canakinumab in CAPS Study Group Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009;360:2416–25. doi: 10.1056/NEJMoa0810787. [PubMed] [Cross Ref]
28. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–41. doi: 10.1038/nature04516. [PubMed] [Cross Ref] F1000 Factor 9.7 Exceptional
Evaluated by Marina Botto 30 Jan 2006, Richard Pope 17 Mar 2006, Robert Terkeltaub 28 Mar 2006
29. So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther. 2007;9:R28. doi: 10.1186/ar2143. [PMC free article] [PubMed] [Cross Ref]
30. McGonagle D, Tan AL, Madden J, Emery P, McDermott MF. Successful treatment of resistant pseudogout with anakinra. Arthritis Rheum. 2008;58:631–3. doi: 10.1002/art.23119. [PubMed] [Cross Ref]
31. Announ N, Palmer G, Guerne PA, Gabay C. Anakinra is a possible alternative in the treatment and prevention of acute attacks of pseudogout in end-stage renal failure. Joint Bone Spine. 2009;76:424–6. doi: 10.1016/j.jbspin.2009.01.001. [PubMed] [Cross Ref]

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