JIA Patients with CAT Gene Mutation Less Likely to Respond to Anti-TNF-α Therapy

JIA Patients with CAT Gene Mutation Less Likely to Respond to Anti-TNF-α Therapy

Patients with juvenile idiopathic arthritis (JIA) who carry a mutation in the CAT gene are less likely to respond to anti-TNF-alpha therapy, a new study suggests. Having this mutation increases the risk of developing the disease.

The study, “The association of CAT-262C/T polymorphism with catalase activity and treatment response in juvenile idiopathic arthritis,” was published in Rheumatology International.

JIA is the most common chronic inflammatory disease of childhood. Oxidative stress is thought to play an important role in the development of JIA. Oxidative stress is when molecules known as reactive oxygen species (ROS) start to accumulate at high levels in the body. ROS are toxic at high levels and cause damage to cellular structures.

To prevent ROS-related damage, cells contain antioxidant enzymes that help neutralize ROS.

While numerous studies have demonstrated that JIA patients have increased production of ROS that leads to erosive destruction of joints, studies that have evaluated the role of antioxidant enzymes in JIA have produced contradictory results.

One of these enzymes is called catalase. It is one of the most active and widespread enzymes that helps counteract ROS. The gene that provides instructions to produce catalase is called CAT.

Genetic mutations in the CAT gene, particularly one known as CAT-262C/T, result in decreased levels of catalase, and have been associated with the development of other diseases, including diabetes mellitus, inflammatory bowel disease and cancer. However, the significance of the CAT-262C/T mutation had not yet been evaluated in JIA.

TNF-alpha is one of the major inflammatory molecules that contributes to the development of oxidative stress. TNF-alpha inhibitors, such as Amgen’s Enbrel (etanercept), have been shown to be effective in the treatment of JIA. However, anti-TNF-alpha treatment comes with a risk of adverse effects and considerable cost. Thus, there is a need to identify how patients will respond to therapy before beginning treatment.

Therefore, researchers investigated the association of CAT-262C/T polymorphism with JIA, as well as the influence of this genetic mutation on catalase activity and on the outcome in JIA patients treated with Enbrel.

The study enrolled 60 JIA patients with active disease (receiving Enbrel therapy) and 94 healthy volunteers, who were screened for the CAT-262C/T mutation. The activity of the catalase enzyme was assessed prior to and 12 months after initiation of treatment.

Patients’ clinical outcome was assessed according to the JIA ACR (American College of Rheumatology) response criteria.

Results revealed that the frequency of the CAT-262C/T gene mutation was significantly higher in JIA patients compared with healthy volunteers. Those with this genetic mutation had 4.36 times the likelihood of having JIA compared to those with the normal gene.

In regard to response to treatment, after 12 months, JIA patients without this mutation had significantly higher enzymatic activity and achieved a greater response rate to therapy than patients with the mutation.

JIA patients with the normal enzyme (no mutation) had 7.41 times the likelihood of achieving high response to treatment (ACR70) compared to those who had the mutant enzyme.

In light of the results, the authors believe that having a normal catalase enzyme has a “potential protective effect” and that patients without the specific CAT-262C/T polymorphism, or mutation, are more likely to respond to anti-TNF-alpha therapy.

“However, future research in a larger cohort should focus on testing this polymorphism as a genetic biomarker for the prediction of the treatment outcome,” researchers concluded.

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