Emerging Ideas: Prevention of Posttraumatic Arthritis Through Interleukin-1 and Tumor Necrosis Factor-alpha Inhibition

Abstract

Background

Despite surgical and mechanical stabilization of an acutely injured joint through ligament reconstruction, meniscus repair, or labral repair, the risk of posttraumatic arthritis remains high. Joint injury triggers three phases of pathogenic events: the early (acute) phase involves joint swelling, hemarthrosis, expression of inflammatory cytokines (especially interleukin-1 [IL-1] and tumor necrosis factor-α [TNF-α]), and biomarkers of cartilage catabolism; an intermediate phase is characterized by reduction of joint inflammation, ongoing joint catabolism, but no evidence yet for typical features of radiographic osteoarthritis (OA); and a late phase characterized by radiographic OA.

Hypotheses

We hypothesize that the early phase of acute knee injury represents a window of opportunity for providing biologic treatment to promote healing and to slow or prevent a subsequent cascade of destructive joint processes leading to OA.

Proposed program

We propose a phase II, randomized, placebo-controlled, double-blinded, clinical trial to treat acute knee injuries with intraarticular injection of an IL-1 inhibitor. Patient-centered outcomes will include pain reduction and improvement of knee function. MR imaging and measurement of biochemical markers will be monitored during the subsequent 2 years to determine if the structural response to injury can be reversed.

Significance

If this model is validated, modulation of the molecular pathways responsible for articular cartilage breakdown will augment current reconstructive procedures in the treatment of acute joint injuries and prevent the development of injury-related arthritis.

Hypothesis

We hypothesize that blocking IL-1 will reduce the breakdown of articular cartilage normally seen after traumatic injury.

Background

Traumatic knee injuries increase the risk of arthritis five- to 17-fold [12, 36]. Unfortunately, restoration of mechanical stability with ACL reconstruction or meniscus repair does not prevent future arthritis [6, 10, 23, 27, 38]. Evidence is accumulating that molecular mechanisms regulate inflammation and breakdown of articular cartilage and menisci after injury [9, 18, 19, 29, 30, 34, 35, 37]. IL-1 and TNF-α are proinflammatory cytokines produced in response to injury by chondrocytes, meniscocytes, synoviocytes, and macrophages [15, 16, 31]. Animal models support the dominant role of IL-1 early in the development of arthritis, and overexpression of IL-1 alone can create arthritis [13, 14, 32, 33]. In patients with acute ACL injury, IL-1 and TNF-α levels increase substantially, and native interleukin-1 inhibitor (IL-1Ra) decreases sixfold [2, 8, 9]. With decreased IL-1Ra, the inflammatory response cannot be buffered efficiently [4, 7, 17]. Within 1 month after joint injury in humans, Lohmander et al. documented synovial fluid elevations of proteoglycan fragments and metalloproteinases [22], collagen fragments [21], and persistent elevations of these molecules over decades [20, 24–26, 28]. These data suggest a model (Fig. 1) whereby trauma causes an initial inflammatory response in the joint. This inflammatory response, mediated ultimately through IL-1 and TNF-α, then leads to a state of cartilage breakdown.

Fig. 1A–B.

Proposed models of interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) in the development of posttraumatic arthritis are shown. (A) Before major traumatic injury, high levels of interleukin-1 receptor antagonist (IL-1Ra) buffer the downstream effects of any proinflammatory responses. (B) After injury, increased macrophages in the synovial lining reinforce proinflammatory responses and decreased IL-1Ra is available to buffer this inflammatory response. MMPs = matrix metalloproteinases; GM-CSF = granulocyte-macrophage colony-stimulating factor; PGE₂ = prostaglandin E₂; COX2 = cyclo-oxygenase 2.

We became intrigued with cytokine blockade for prevention of posttraumatic arthritis noting chondral preservation with IL-1Ra administration in a dog ACL transection model [3] and TNF-α inhibition in a rat ACL tear model [9]. IL-1 and TNF-α inhibition also improve rat meniscus healing in vitro [29, 30]. In patients, knee injections of IL-1Ra and a TNF-α inhibitor have been reported for OA and inflammatory arthritis [1, 5, 11]. As acute knee injury is characterized by increased articular levels of IL-1 and TNF-α, which play a central role in joint damage, we suggest this early phase of injury represents a window of opportunity for providing biologic treatment to promote healing and to slow or prevent a cascade of joint destructive processes leading to OA.

Proposed Program

To assess the effect of IL-1 inhibition on cartilage breakdown, a double-blind, placebo-controlled trial will be conducted with intraarticular administration of an IL-1 inhibitor after traumatic knee injury. The functional and metabolic state of the injured joint will be followed with time to assess the effect of blocking IL-1 during the initial proinflammatory state after injury. A homogenous injury population with isolated ACL tears will be studied and functional outcome will be assessed clinically with patient-based outcome scores, pain assessment, ROM, and functional recovery tools. Because the development of cartilage damage substantial enough to cause radiographic evidence of arthritis takes many years, the metabolic status of the articular cartilage will be followed with time with intraarticular and serum-based biomarkers of cartilage breakdown, such as serum hyaluronan (HA). Intraarticular and serum cytokine profiles, including IL-1α, IL-1β, IL-1RA, and TNF-α, also will be followed with time to assess any change in response to administration of the IL-1 inhibitor. Finally, qualitative MRI, for example, dGEMRIC and T2 mapping, will be used to assess for early matrix changes typical of arthritis.

Preliminary data in a small pilot trial showed that intraarticular administration of a short acting IL-1 inhibitor, anakinra (Swedish Orphan Biovitrum Sverige AB, Stockholm, Sweden), substantially decreased pain and improved clinical outcomes compared with saline placebo. Although inflammatory profiles did not change considerably, biomarkers of cartilage breakdown did suggest that IL-1 inhibition could protect against major cartilage breakdown.

Limitations

The presence of prior traumatic knee injuries and the variability in the treated injury pattern are major limitations with the use of human subjects. The timing of administration of the IL-1 inhibitor is also a limitation as the time of presentation and diagnosis are not uniform. Recruitment and followup also sometimes are difficult. However, although these limitations present challenges in the interpretation of the data, they also represent the reality of treatment if IL-1 inhibition is to have widespread clinical use. Resorting to a large animal model would be the most plausible alternative approach.

Biomarkers and qualitative MR imaging to assess cartilage breakdown after injury remain unproven surrogate outcome measures to predict the development of arthritis. Ultimately long-term followup studies will be needed to determine if IL-1 inhibition can truly alter the natural history of traumatic joint injuries.

The pharmacokinetics of intraarticular delivery of the medications may limit their effectiveness, especially when compounded with the variability in patient presentation. Although a longer-acting dimeric IL-1 receptor inhibitor, an IL-1 tartrate-resistant acid phosphatase (TRAP), rilonacept (Arcalyst, Regeneron Pharmaceuticals, Inc, Tarrytown, NY), has been developed and may show improved response because of its longer half-life, it is possible that polymerized, depot, or nanoparticle preparations may be needed to provide sustained intraarticular delivery. Gene therapy strategies also may sustain intraarticular levels of inhibitors and prevent the development of arthritis [39].

Next Steps

To fully translate these findings to clinical practice, investigators will have to address many challenges. First, we will need to determine the ideal timing of IL-1 inhibition. To determine this, a more-detailed assessment of the postinjury inflammatory response and the effect that modulation of that response has on the metabolic state of the articular cartilage will be necessary. These investigations also will help answer the second critical question, namely, the duration of the inhibitory effect required to prevent cartilage breakdown. As indicated above, preparations with different pharmacokinetics, or alternative strategies, such as gene therapy approaches may need to be developed to make this technology a viable clinical tool. Finally, depending on the critical timing issues, the general approach to treatment of traumatic joint injuries may require rethinking. It may be that the initial few hours after the injury are the most critical to prevent long-term arthritis. If this is the case, healthcare-delivery systems will have to think of traumatic joint injuries as emergencies, not unlike how we treat stroke or myocardial infarction.

Implications and Future Directions

Even if current IL-1 or TNF-α inhibitors are not able to prevent the development of arthritis after traumatic joint injuries, the preclinical studies showing the dramatic chondroprotective effects of these agents underscore the primary role that the molecular mechanisms regulating cartilage breakdown play in the development of arthritis after injury. Although mechanical derangement clearly leads to arthritis, it appears to exert this response through alterations in the cellular and molecular mechanisms regulating cartilage metabolism. Understanding the cellular interactions and the molecular pathways at play in this process and developing tools to manipulate them promise to have a dramatic effect on preventing arthritis.