Background/Purpose

NOD2-associated autoinflammatory disease (NAID) is an emerging systemic inflammatory disease. The aim is to report our extended study of the phenotypic and genotypic features of the disease.

Methods

A total of 143 adult patients with autoinflammatory phenotypes at presentation were suspected of having NAID over the past 4 years. All patients were genotyped for the NOD2 mutations. They were then clinically followed and prospectively studied. All patients were divided into two groups predicated on the presence or absence of the NOD2mutations. NAID was diagnosed according to our previously reported criteria. The data of the 2 groups were compared and analyzed.

Results

Of 143 patients, we identified 46.9% of patients carrying NOD2 mutations. The genotype frequencies were significantly higher than historical healthy controls, with IVS8+158 being 35.7%, R702W 11.2% and rare mutations 14.0%(Table 1). The frequency of IVS8+158 was significantly higher than non-Jewish white Crohn’s patients. Fifty seven of the 67 NOD2 positive patients were diagnosed with NAID. The remaining included 5 cases of Crohn’s disease, 2 ulcerative colitis, 2 Blau syndrome, and 1 autoimmune disease. The frequency of NAID was estimated to be 3%-7% of our outpatients.

All 57 NAID patients were white with 68.4% of women. The mean age at onset was (33.2 ± 14.0) years, and the mean disease duration at diagnosis was (10.6 ± 8.3) years. NAID was sporadic in 93% of cases. The phenotypic features of this disease included periodic fever (63.2%), dermatitis (91.2%) and inflammatory arthritis/arthralgia (87.7%)(Table 2). Compared with NOD2 negative patients, the skin disease was overrepresented by dermatitis manifested as erythematous patches or plaques on trunk(Figure 1). Oligo-polyarthritis were common mainly involving the lower extremities. Distal lower extremity swelling was more common(Figure 1).  There were gastrointestinal symptoms in 73.7% but without inflammatory bowel disease and sicca-like symptoms in 56.1%. Pericarditis and pleuritis were occasionally seen. Acute phase reactants were elevated in 40.4%, and autoantibodies are largely absent, with only 8.8% of patients having low titters of ANA.  Associated NOD2 gene mutations were IVS8+158 (80.7%) and/or R702W (26.3%), and rare mutations (24.1%)(Table 2).

Of the 76 NOD2 mutation negative subjects, 28 patients turned out to have autoimmune diseases and 4 cases of autoinflammatory disease. The remaining were still non-diagnostic. The medications used to treat the disease entailed nonsteroidal anti-inflammatory agents (34.5%), glucorcorticoids (36.4%), sulfasalazine (32.1%) and biologics (7.1%). Prednisone and sulfasalazine were found effective and 2 cases were treated with infliximab and tocilizumab.

Conclusion The largest cohort study has demonstrated that the NOD2 genotype frequencies are significantly higher in our study patients and associated with NAID. NAID represents a genetically complex autoinflammatory disorder, and is distinct from Crohn’s disease. This disease is more prevalent than initially thought, with an estimated frequency of about 5% in our rheumatology outpatients. This report will further increase awareness of this entity in the medical community.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/nod2-associated-autoinflammatory-disease-the-largest-cohort-study/