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New Adult Clinical Syndromes
of Autoinflammatory Disease Case: Case Report

Qingping Yao, MD, PhD


A 45-year-old white female presentedwith a 1-year history of recurrent erythematous rash. The rash would usually last 3 to 7 days then disappear for 1 or 2 days. The rash predominately appeared on her forehead, face, neck, and upper chest.


The patient also had recurrent morning joint pain, swelling, and weakness in the handfingers, and feet, rarely in the forearms and knees. She complained of blurred vision and had several episodes of abdominal pain lasting for a few hours in the morning. She did not report any fevers.

The review of systems revealedweight loss, night sweats, and dry mouth. Her family history was negative for periodic disease. She was born in Wales and is currently married with two healthy children.

On physical examination, there were erythematous patches and plaques on her face and forehead. Otherwise, it was unremarkable.

Various laboratory tests were ordered (see Table 1). These included routine blood tests,urinalysis, acute phase reactants, and tests for systemic autoimmune diseases. In addition, diagnostic endoscopic procedures were performed to evaluate the abdominal pain and gastrointestinal (GI) symptoms. An ophthalmic exam also was performed. No abnormal results for any of these tests were observed except for mild dry eyes.

Table 1.Laboratory tests and results.

Test Result


all within normal limits

ESR, serology, CK, aldolase

all within normal limits

EGD and colonoscopy


Ophthalmic exam


Biopsy of minor salivary glands of the lip


NOD2 gene mutations

heterozygous IVS8+158, R702W
TNFRSF1A for TRAPS negative

Abbreviations: CBC=complete blood test; CK=creatinine kinase; CMP=complete metabolic profile; EGD=esophagogastroduodenoscopy; ESR=erythrocyte sedimentation rate; TRAPS= Tumor necrosis factor receptor-associated periodic fever syndrome; UA=urinalysis

1. What is this patient’s most likely diagnosis?

  1. Familial Mediterranean fever (FMF)
  2. Tumor necrosis factor receptor associated periodic fever syndrome (TRAPS)
  3. Blau’s syndrome
  4. NOD2-associated autoinflammatory disease

Discussion.Patients with FMF typically experience episodic fever lasting fewer than 3 days, serositis, erysipeloid rash on the lower extremities, and mono-oligoarthritis usually in the lower extremities. MEFV gene mutations are present in about 80% of cases. TRAPS isautosomal dominant disease, characterized by periodic fever of several days or more, various forms of rash with underlying myalgia, and mild mono-oligoarthritis. Genetic testing forTNFRSF1A  is clinically employed for diagnostic purpose. Blau’s syndrome is anautosomal dominant disease, characterized by granulomatous dermatitis, uveitis, and inflammatory arthritis with 4th and 5th finger flexion deformities (camptodactyly). It is associated with NOD2 gene mutations mostly on exon 4. In addition, GI symptoms are lacking.

NOD2-associated autoinflammatory disease (NAID)

This patient’s presentations are distinct andsupportive of a newly defined autoinflammatory disease termed NOD2-associated autoinflammatory disease (NAID).Phenotypically, patients have periodic episodes of fever, dermatitis, mostly spongiotic dermatitis, polyarthritis, and/or pedal swelling, and absence of autoantibodies. Its genotypeusually shows the NOD2 gene mutationsIVS8+158and/or R702W. It occurs predominantly in Caucasian adults.

A report of 22 cases has defined the characteristic and laboratory findings of NAID (see Table 2). It indicates a mostly system disease, affecting both sexes equally with slight female predominance. The mean age at diagnosis is about 40 years. All patients were white. Only three people had a family history of autoinflammatory disease. The disease is mostly sporadic. Apart from theclinical picture of periodic feverand polyarthritis and/or polyarthralgia, most patients present with recurrence of erythematous plaques, patches, and macules. Approximately 50% to 60% of patients had some GI symptoms but without evidence of inflammatory bowel disease. About 40% of patients present with sicca-like symptoms but without evidence of primary Sjogren’s syndrome. Acute phase reactants can be elevated in 50% of patients.

Table 2. Characteristics of NAID reported in 22 cases.

Variable Occurrence
Gender (female:male) 13:9
Mean age at diagnosis 40.1 years (range 17-72)
Mean disease duration 4.7 years (range 1-13)
Ethnicity (white) 22/22 (100%)
Familial 3/22 (13.6%)
Weight loss 13/22 (59.1%)
Fever 13/22 (59.1%)
Skin disease 19/22 (86.4%)
Arthritis/arthralgia 20/22 (90.9%)
Gastrointestinal 13/22 (59.1%)
Serositis/chest pain  5/22 (22.7%)
Sicca-like  9/22 (40.9%)
Pulmonary  3/22 (13.6%)
Uveitis  0/22 (0%)
Raised ESR/CRP  9/20 (45.0%)
Adapted from Yao Q, Su LC, Tomecki KY, et al. Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations. J Am Acad Dermatol. 2013;68(4):624-31.

The NOD2 gene has been mapped tochromosome 16. Approximately 120 NOD2 gene mutations or variantshave been identified, some of which are associated with Crohn’s disease, Blau’s syndrome, and NAID. TheNOD2 protein is composed of 1,014 amino acidsand it contains two N-terminal CARDs, a central NOD-like receptor(NACHT) or NBD, and six C-terminal leucine-rich repeats (LRRs).

The pathogenesis of NAID is unclear. Presumably, the interaction between NOD2 gene mutations and environmental factors (eg, GI stress, trauma) could play a role.Our preliminary study suggests that Th1/Th2 cells and their cytokines might not contribute to the disease. Rather, interleukin 17 and latency-associated peptide-positive T cells may play a role.

Treatment for patients with NAID depends on their clinical phenotypes. Cutaneous lesions can be treated with small doses of oral prednisone or topical steroids. Polyarthritis is more difficult to treat and, typically, does not respond well to nonsteroidal anti-inflammatory drugs. Among medications used for rheumatic diseases, sulfasalazine has been observed to improve the arthritic symptoms in many of the cases. Colchicine, hydroxychloroquine, and methotrexate have been found ineffective. The therapeutic role of tumor necrosis factor inhibitorsor other biologics awaits further evaluation.

In terms of prognosis, the disease appears to run a benign and intermittent course in most patients. However, some patients have nearly persistent polyarthritis, fatigue, rash, and fever that may cause substantial morbidity. Further research for improving the care and outcomes with these patients is imperative.

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