Researchers may have uncovered genetic mechanisms underlying psoriatic arthritis mutilans, according to a study published by Wang et al in EMBO Molecular Medicine. Researchers used the PAM Nordic cohort to conduct massive parallel sequencing in 61 patients with psoriatic arthritis mutilans. They discovered three rare variants in the NOX4 gene—two of which affected the same codon in the nicotinamide adenine dinucleotide phosphate–binding domain, and one of which affected the flavin adenine dinucleotide–binding domain—in four of the patients involved in the study. The variants were shown to be potentially damaging through in silico predictions and located in significant domains for the function of NOX4 enzymes. The researchers noted that NOX enzymes are the only enzymes responsible for producing reactive oxygen species (ROS) such as hydrogen peroxide, and that the enzymes play a critical role in osteoclast differentiation. After follow-up studies using cell cultures, zebrafish embryos, and patient-derived osteoclasts, the researchers revealed that NOX4 variants increased ROS levels in vitro and in vivo, representing NOX4’s potential status as a susceptibility gene for psoriatic arthritis mutilans. The researchers hope their novel findings can help advance the understanding of how NOX4 enzymes and ROS pathways may cause joint destruction as well as lead to new therapeutic interventions to treat the disease.