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

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.

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 diff erent animal models, Martel-Pelletier and colleagues were the fi rst 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 eff ect [6].
In this context, we performed two trials with one single intraarticular injection of IL-1ra in knee OA [7,8]. Th e 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, diff erent 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 fl uid.
Th e contribution of Cohen and colleagues, published in the present issue of Arthritis Research & Th erapy, is there fore a major contribution to enlighten the anti-IL-1 strategy in OA [1]. Th e authors use systemic administration of a monoclonal antibody (AMG 108) directed against the functional type 1 receptor of IL-1. Th is is a two-part randomised, double-blind, placebo-controlled, multiple-dose study in patients with OA. Th e 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. Th ere are two major conclusions that could be drawn from this study: one on effi cacy, and one on safety. Th e main endpoint was the level of pain at 6 weeks and no statistical diff erence 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-yearold man and may lead to suspension of the programme.
Regarding this negative trial, should we defi nitively put nails in the coffi n of an anti-IL-1 option in OA?
Looking at the benefi t/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 effi cacy favouring AMG 108 compared with placebo, especially in patients with a high level of pain at baseline (Western Ontario and

Abstract
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. MacMaster Universities index >325). Lack of diff erence 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, signifi cant effi cacy 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 benefi t [8]. Interestingly, ultra sensitive 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 infl ammation, and is a good prognostic marker of disease progression [9,10]. Th e question of chondro protection by anti-IL-1 therapy is still so far unanswered, although some preliminary results with magnetic resonance imaging indicate improvement of synovial membrane infl ammation [8]. Th e nonlinear nature of the pharmacokinetics may also contribute to variations in the local concentration of AMG 108 in the synovial fl uid (calculated to be around 50 nM) [1]. Th e remain ing question is whether this concentration is able to block IL-1 activity not only in the synovial fl uid but also in the superfi cial cartilage layers.
Th e other conclusion concerns safety. What we can learn from this current study is that long-term bio therapy, which may expose patients to serious side eff ects, 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 intra articular injections to increase the local concen tration of the drug into the joint, especially during fl are-up of the disease. In doing so, we can also hope to diminish the risk of serious side eff ects.
For sure, the story is not fi nished.