Email updates

Keep up to date with the latest news and content from Arthritis Research & Therapy and BioMed Central.


Desperately looking for the right target in osteoarthritis: the anti-IL-1 strategy

Xavier Chevalier1*, Thierry Conrozier2 and Pascal Richette3

Author Affiliations

1 Department of Rheumatology, University of Paris XII, Henri Mondor Hospital, Bd de Lattre de Tassigny, Creteil 94010, France

2 Department of Rheumatology, University of Lyon SUD, Hospital Pierre Bénite, Lyon, Chemin du grand revoyet, 69495 Pierre Benite, France

3 Department of Rheumatology, University of Paris VII, Hospital Lariboisière, 10 rue Ambroise paré, Paris 75010, France

For all author emails, please log on.

Arthritis Research & Therapy 2011, 13:124  doi:10.1186/ar3436

See related research by Cohen et al.,

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

Published:26 August 2011

© 2011 BioMed Central Ltd


Blocking IL-1 in patients with knee osteoarthritis is an attractive strategy. Cohen and colleagues report a randomised, placebo-controlled, multiple-dose trial using a monoclonal antibody blocking IL-1 type 1 receptor. They failed to show any positive results in terms of evolution of pain for up to 12 weeks, in line with the former trials using intraarticular injections of IL-1 receptor antagonist. A trend was observed, however, in a subgroup of patients with high level of pain at baseline. Although these data may suggest cessation of IL-1 therapy in osteoarthritis, other methods such as limited intraarticular anti-IL-1 delivery should still be considered.


One of the most exciting challenges in rheumatology for the future is to find a therapeutic target for osteoarthritis (OA) [1]. Indeed, clinicians and our patients are still waiting for a new drug that exhibits an analgesic effect and structure-modulating properties.

OA is characterised by an imbalance between catabolic and anabolic responses of stimulated chondrocytes, driven locally by a soup of cytokines where IL-1β is regarded as the chief orchestrator. On the one hand, IL-1 can induce the production of enzymes, prostanoids, nitric oxide and free radicals; on the other hand, IL-1 can block the production of collagen type 2 and proteoglycans [2,3]. IL-1 is also involved in the transmission of pain [4]. Considering all these factors, targeting IL-1 in OA seems a logical approach to slow down the disease progression.

In different animal models, Martel-Pelletier and colleagues were the first to use IL-1 receptor antagonist (IL-1ra) injected intraarticularly - either directly or through gene therapy - with encouraging results in terms of cartilage preservation [5]. Moreover, in patients with rheumatoid arthritis, anakinra (IL-1ra) injected subcutaneously daily demonstrates a disease-modifying antirheumatic effect [6].

In this context, we performed two trials with one single intraarticular injection of IL-1ra in knee OA [7,8]. The main result of the randomised, placebo-controlled trial using two doses of IL-1ra (50 mg and 150 mg) was negative regarding the evolution of pain after a follow-up of 3 months [8]. However, different hypotheses could possibly explain this negative result: the short half-life of IL-1ra, the single intraarticular injection, or the excess of IL-1ra already present in the synovial fluid.

The contribution of Cohen and colleagues, published in the present issue of Arthritis Research & Therapy, is therefore a major contribution to enlighten the anti-IL-1 strategy in OA [1]. The authors use systemic administration of a monoclonal antibody (AMG 108) directed against the functional type 1 receptor of IL-1. This is a two-part randomised, double-blind, placebo-controlled, multiple-dose study in patients with OA. The most interesting part of the study is the second, in which patients received 300 mg AMG 108 subcutaneously once every 4 or 12 weeks compared with placebo. There are two major conclusions that could be drawn from this study: one on efficacy, and one on safety. The main end-point was the level of pain at 6 weeks and no statistical difference with placebo was observed. Furthermore, AMG 108 induced a decrease in neutrophil count and, while the incidence of serious infections was similar in the AMG 108 and placebo groups, a death in this trial might be indirectly related to neutropaenia in an 80-year-old man and may lead to suspension of the programme.

Regarding this negative trial, should we definitively put nails in the coffin of an anti-IL-1 option in OA?

Looking at the benefit/risk ratio in the study by Cohen and colleagues, it is tempting to answer yes. However, we should probably bring some reservations to this opinion.

First, there is a real trend of efficacy favouring AMG 108 compared with placebo, especially in patients with a high level of pain at baseline (Western Ontario and MacMaster Universities index >325). Lack of difference may be linked to the small number of patients in this subgroup (n = 22 AMG 108-treated patients and n = 25 placebo-treated patients), which may subsequently contribute to the overall negative result. Similarly, significant efficacy was observed in the randomised, placebo-controlled trial with one single intraarticular injection of IL-1ra (150 mg) compared with placebo at day 4, suggesting some real but unstained clinical benefit [8]. Interestingly, ultrasensitive C-reactive protein levels decreased with anti-IL-1 therapy [1]. C-reactive protein is a relevant marker in OA related to tibial cartilage volume and local inflammation, and is a good prognostic marker of disease progression [9,10]. The question of chondroprotection by anti-IL-1 therapy is still so far unanswered, although some preliminary results with magnetic resonance imaging indicate improvement of synovial membrane inflammation [8]. The nonlinear nature of the pharmacokinetics may also contribute to variations in the local concentration of AMG 108 in the synovial fluid (calculated to be around 50 nM) [1]. The remaining question is whether this concentration is able to block IL-1 activity not only in the synovial fluid but also in the superficial cartilage layers.

The other conclusion concerns safety. What we can learn from this current study is that long- term biotherapy, which may expose patients to serious side effects, is not acceptable in a benign disease such as OA.

We should therefore rethink an IL-1 strategy in OA. One of the most appealing approaches could be the intraarticular route of administration with repeated intraarticular injections to increase the local concentration of the drug into the joint, especially during flare-up of the disease. In doing so, we can also hope to diminish the risk of serious side effects.

For sure, the story is not finished.


IL: interleukin; IL-1ra: IL-1 receptor antagonist; OA: osteoarthritis.

Competing interests

The authors declare that they have no competing interests.


  1. Cohen SB, Proudman S, Kivitz AJ, Burch FX, Donohue JP, Burstein D, Sun Y-N, Banfield C, Vincent MS, Ni L, Zack DJ: A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL 1R1) in patients with osteoarthritis of the knee.

    Arthritis Res Ther 2011, 13:R125. PubMed Abstract | BioMed Central Full Text OpenURL

  2. Pelletier JP, Martel-Pelletier J, Abramson SE: Review: osteoarthritis, an inflammatory disease: potential implication for the selection of new therapeutic targets.

    Arthritis Rheum 2001, 44:1237-1247. PubMed Abstract | Publisher Full Text OpenURL

  3. Chevalier X: Up-regulation of enzymatic activity by interleukin-1 in osteoarthritis.

    Biomed Pharmacother 1997, 51:58-62. PubMed Abstract | Publisher Full Text OpenURL

  4. Sachs D, Cunha FQ, Poole S, Ferreira SH: Tumour necrosis factor-α, interleukin-1β and interleukin-8 induce persistent mechanical nociceptor hypersensitivity.

    Pain 2002, 96:89-97. PubMed Abstract | Publisher Full Text OpenURL

  5. Caron JP, Fernandes JC, Martel-Pelletier J, Tardif G, Mineau F, Geng C, Pelletier JP: Chondroprotective effect of intra-articular injections of interleukin-1 receptor antagonist in experimental osteoarthritis. Suppression of collagenase-1 expression.

    Arthritis Rheum 1996, 39:1535-1544. PubMed Abstract | Publisher Full Text OpenURL

  6. Bresnihan B: Anakinra as a new therapeutic option in rheumatoid arthritis: clinical results and perspectives.

    Clin Exp Rheumatol 2002, 20(5 Suppl 27):S32-S34. PubMed Abstract OpenURL

  7. Chevalier X, Giraudeau B, Conrozier T, Marliere J, Kiefer P, Goupille P: Safety study of intraarticular injection of interleukin 1 receptor antagonist in patients with painful knee osteoarthritis: a multicenter study.

    J Rheumatol 2005, 32:1317-1323. PubMed Abstract | Publisher Full Text OpenURL

  8. Chevalier X, Goupille P, Beaulieu AD, Burch FX, Bensen WG, Conrozier T, Loeuille D, Kivitz AJ, Silver D, Appleton BE: Intra-articular injection of anakinra (r-met-huIL-1ra) in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study.

    Arthritis Rheum 2009, 61:344-352. PubMed Abstract | Publisher Full Text OpenURL

  9. Hanna FS, Bell RJ, Cicuttini FM, Davison SL, Wluka AE, Davis SR: High sensitivity C-reactive protein is associated with lower tibial cartilage volume but not lower patella cartilage volume in healthy women at mid-life.

    Arthritis Res Ther 2008, 10:R27. PubMed Abstract | BioMed Central Full Text | PubMed Central Full Text OpenURL

  10. Sharif M, Shepstone L, Elson CJ, Dieppe PA, Kirwan JR: Increased serum C reactive protein may reflect events that precede radiographic progression in osteoarthritis of the knee.

    Ann Rheum Dis 2000, 59:71-74. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL