DURHAM, North Carolina—Local, intraarticular delivery of tumor necrosis factor alpha (TNF-α) inhibitors and/or interleukin-1 (IL-1) blockers may help promote healing following meniscal tears, according to a new study in the September issue of Arthritis & Rheumatism.¹

"These findings support the hypothesis that meniscal repair may be inhibited or delayed in vivo due to local or systemic increase in IL-1 and TNF-α as well as potentially other proinflammatory cytokines," conclude the researchers led by Amy L. McNulty, PhD, a postdoctoral fellow at Duke University Medical Center, in Durham, North Carolina. They note that IL-17 is another potential target.

Meniscal tear repair just the beginning

Using a porcine model, the researchers showed that pathophysiologic concentrations of both IL-1 and TNF-α significantly decreased repair strength, cell migration, and tissue formation at the site of injury. Inhibiting IL-1 and TNF prevented these effects.

The researchers exposed pig knees to various concentrations of IL-1 and TNF. As the cytokine concentrations increased, the meniscus tissue was less able to repair itself. The range of concentrations of IL-1 and TNF used in the experiment match those found in the joint fluid of humans with rheumatoid arthritis (RA) and osteoarthritis (OA).

"We provide evidence that IL-1 receptor antagonist and TNF monoclonal antibody may have beneficial effects on the meniscus, specifically for integrative meniscal repair on an inflammatory microenvironment," the study authors conclude.

The challenge ahead is how to deliver these drugs locally so that they persist long enough to permit better repair of meniscal tears.

"We are working with collaborators to develop ways to deliver these agents locally so that they stick around at the site," study coauthor Farshid Guilak, PhD, told CIAOMed. Dr. Guilak is director of orthopaedic research at Duke. "The clearance rates are high if we inject Enbrel® (etanercept) or Kineret® (anakinra) in joint [as it is]." Drug development is going well so far. "Within a year, you might see something from us."

The next step would be to test the agent in culture and then in animal studies. "If that works," he said, "we are really on our way toward clinical study because these drugs are available and appear relatively safe."

And meniscal tear repair may just be the beginning. Dr. Guilak thinks that similar mechanisms interfere with healing of other joint tissues such as cartilage and ligament. "In combination injuries such as anterior cruciate ligament (ACL)/meniscal tears, there is an upregulation of inflammatory cytokines that is probably transient, but the damage may occur during this initial short period of time," Dr. Guilak explained. "If we get in early and inhibit inflammatory pathways we can have a tremendous impact on a lot of joint injuries."

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