A Systematic Analysis of Treatment and Outcomes of NOD2-Associated Autoinflammatory Disease

Objectives: Yao syndrome, formerly named NOD2-associated autoinflammatory disease, is a periodic disease characterized by fever, dermatitis, polyarthritis/leg swelling, and gastrointestinal and sicca-like symptoms associated with specific NOD2 sequence variants. Our aim was to evaluate the treatment and outcomes of the disease.

Methods: A total of 52 adult patients with autoinflammatory disease phenotype were diagnosed with Yao syndrome and enrolled at the Cleveland Clinic between November 2009 and May 2015. All patients were genotyped for the NOD2 variants, and systematically studied for treatment outcomes.

Results: Among the 52 Yao syndrome patients, all were white, and 72% were women. The mean age at diagnosis was 38.0 ± 12.0 years, and the disease duration was 8.8 ± 5.8 years. In the multi-organ disease, more common and typical manifestations were recurrent dermatitis and inflammatory arthritis with or without distal leg swelling besides recurrent fever. It was genotypically associated with the NOD2 IVS8⁺¹⁵⁸ or R702W. Therapeutically, glucocorticoids markedly decreased the disease severity and duration of flares in 19 patients (36.6%), sulfasalazine treatment achieved a significant symptomatic improvement in 22 (42%) patients, and 3 patients received canakinumab or tocilizumab with benefits. Prognostically, 13% of the 52 patients had somewhat physical impairment, and there was no mortality during the follow-up. Associated comorbidities were fibromyalgia, asthma, renal stones, and ventricular hypertrophy.

Conclusions: As a systemic disease, Yao syndrome uncommonly affects the solid internal organs, but it can be complicated with chronic pain syndrome and even disability. Glucocorticoids or sulfasalazine may be considered as the first-line treatment option, and interleukin (IL)-1/IL-6 inhibitors may be tried for refractory cases. The potential associations between certain comorbidities and Yao syndrome deserve further study.