Andrea Pimentel

SIR, We previously reported an autoinflammatory disease associated with nucleotide-binding oligomerization domain containing protein 2 (NOD2) gene mutations, designated as NOD2-associated autoinflammatory disease (NAID) [1, 2]. To date, none of the studies of NOD2 mutations have demonstrated spontaneous inflammation in NOD2-associated diseases [3]. Herein we report a patient with NAID to illustrate the pathogenic role of NOD2 mutations and explore the pathogenesis of the disease. A 23-year-old white man presented with recurrent fever and rash. On physical examination, his blood pressure was 143/104 mmHg and his temperature was 36.8 C; he appeared well developed and nourished, with a body weight of 85 kg; the remainder of the physical examination was unremarkable except for multiple abdominal surgical scars. The scars resulted from multiple surgical procedures due to a complex disease that began to manifest itself 4 h after a normal vaginal delivery. The patient began vomiting bilious material with massive abdominal distension. He underwent colostomy with stoma for suspected Hirschsprung’s disease. Soiling continued after surgery and re-anastomosis was performed at 10 months of age. The patient was doing reasonably well until age 13 years, when he developed several episodes of abdominal pain. Oesophagogastroduodenal endoscopy and inflammatory bowel disease (IBD) markers were negative. Colonoscopy demonstrated multiple lymphoid nodules with rare aggregates of submucosal eosinophils. An exploratory laparotomy disclosed ascites and oedematous bowel, and a subtotal colectomy was performed. There was a marked expansion of submucosal lymphoid tissue of the ileum with activated T cells admixed with eosinophils, without characteristic features of IBD or vasculitis (Fig. 1A and B). Mesenteric lymph node contained interfolicular hyperplasia (Fig. 1C) and activated T cells. At age 15 years he underwent laparoscopic lysis of adhesions and construction of a continent ileostomy T-pouch. At post-surgical day 3 he developed abdominal pain and sepsis-like symptoms. Subsequent exploratory laparoscopy with small bowel and stomach biopsies was not revealing, but partial colon excision showed diffuse active colitis without ulcers, granulomas or dysplasia. Examination of mesenteric lymph nodes demonstrated reactive lymphoid hyperplasia. Immunohistochemistry stains showed positive IL-17 cells in the colon and lymph node tissues, notably the colon mucosa (Fig. 1D and E). The patient had had nearly 20 episodes of flu-like symptoms, high-grade fever and sunburn-like rash on the axilla, neck, trunk and extremities (Fig. 1F) over the past 10 years. A skin biopsy showed spongiotic dermatitis. After invariable treatment of each flare with prednisone 50 mg/day with tapering over 6 days, on the second day the rash and fever faded and resolved completely within 3 days. There was an episode of conjunctivitis, but without uveitis. There was no arthralgia. Laboratory work showed mild leucocytosis with eosinophilia, elevated IgE at 432.0 (normal <114) kU/l, elevated ESR and negative serology for systemic autoimmune diseases. At early active disease, plasma and intracellular [CD4, CD8, natural killer (NK) and natural killer T (NKT) cell] levels of cytokines, such as TNF-a, IFN-r, IL-4, IL-6 and IL-10, were normal. There were increased proportions Letters to the Editor