Background/Purpose:

NOD2-associated autoinflammatory disease, now redesignated as Yao Syndrome(YS) is a newly described and increasingly recognized entity. It is characterized by periodic fever, dermatitis, polyarthritis, sicca-like and gastrointestinal symptoms, and genotypically associated with NOD2 mutations. Our aim was to evaluate the treatment and outcomes of the disease.

Methods:

A cohort of 52 adult patients with autoinflammatory phenotypes diagnosed with YS were enrolled at the Cleveland Clinic between November 2009 and March 2015. All patients were genotyped for the NOD2mutations. These patients were prospectively studied for treatment outcomes.

Results: All 52 patients were whites, with female accounting for 72%. The mean age at diagnosis was 38.0±12.0 years and the disease duration was 8.8±5.8 years. The clinical phenotypes included periodic occurrence, weight loss (42%), fever (67%), dermatitis (90%), inflammatory arthritis (79%), leg swelling (30%), gastrointestinal symptoms (65%), sicca-like (58%), oral ulcers (27%), and pericarditis/pleuritis (8%). All 52 patients carry NOD2 gene mutations, including IVS8+158(98%) and/or R702W (19%). The majority (90%) of patients tried nonsteroidal anti-rheumatic drugs without obvious benefits. Nineteen (36%) received prednisone for flares, including a short course (30-40 mg/day x1-3 days) in 9 patients, with a marked reduction in disease severity and interval. Twenty-two (42%) received sulfasalazine (2g/day), with significant symptomatic improvement. Methotrexate and hydroxychloroquine were tried without noticeable benefits. For frequent flares, particularly high fever and inflammatory arthritis, three patients received infliximab with only partial clinical response in one. Two patients received anakinra with partial response in one. Two patients received canakinumab and both had partial response. One patient received tocilizumab with good response. During nearly 9 years of the disease course,  most patients had intermittent disease flares. Only one patient had mild joint deformity. No inflammatory bowel disease or primary Sjögren’s syndrome was found. Five patients had mild anemia,  and no patients developed nephritis, liver, lung parenchymal or central nervous system disease. Seven patients had low levels of immunologobulins, four of whom had recurrent infections, and one received intravenous immunoglobulin infusions. One patient had monoclonal gammopathy of undetermined significance. Associated comorbidities with YS included fibromyalgia in 11 patients, asthma in seven, renal stones in three, and ventricular hypertrophy in two. Seven of the 52 patients had impaired physical functionality.  No mortality was found.

Conclusion: Our study demonstrates that YS is a systemic autoinflammatory disease without major solid organ involvement, though it may lead to chronic pain and potential functional impairment. Glucocorticoids and sulfasalazine are effective, and IL-1 and IL-6 antagonists may be beneficial. Further study of the disease mechanisms and a search for more effective drugs are warranted.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/nod2-associated-autoinflammatory-disease-therapy-and-outcomes/