Dear Editors, NOD2-associated autoinflammatory disease (NAID), formerly known as Yao syndrome, is a rare systemic autoinflammatory condition associated with variants in the NOD2 gene.1 Reported triggers for disease activity include viral infections, vaccinations, and psychological stress.2, 3 In this report, we describe a case of NAID that exhibited exacerbations during the late stage and postpartum period of the first pregnancy, followed by recurrence during the postpartum period of the second pregnancy after a prolonged symptom-free interval. A 35-year-old woman presented with a history of recurrent fevers, widespread erythematous rashes, and polyarthralgia. Her initial episode began in May 2019 at 34 weeks of pregnancy, manifesting with high-grade fevers (38.3–39.5°C), myalgias, and pruritic erythematous papules and plaques on the trunk and extremities (targetoid lesions on the palms). (Figure 1a, b) She experienced flare-ups every 2–3 weeks through July 2019, each lasting 3–7 days and accompanied by arthralgia and occasional abdominal pain. A tapering prednisone regimen (starting at 60 mg/day over three months) provided symptom control. The episodes decreased in frequency and severity by late 2019 and resolved completely by February 2020. In October 2023, three weeks postpartum following her second pregnancy, she developed recurrent flares approximately every two months through April 2024. Each flare lasted about one week, featuring low-grade fevers (38°C), joint swelling and erythema, and urticarial plaques on the face, axillae, groin folds, abdomen, and limbs (Figure 1c, d). She reported a single episode of non-bloody diarrhea with abdominal discomfort in December 2023. Family history was negative for similar conditions and there was no evidence of drug exposure relevant to disease onset or recurrence. Evaluation during the 2019 flares included broad infectious and autoimmune testing (HIV, hepatitis viruses, EBV, CMV, HSV, Mycoplasma, RPR, ANA, ANCA, complements, SPEP), all of which were unremarkable. Blood counts were unremarkable. CRP ranged from 42.7–78 mg/L. Liver transaminases began rising at disease onset, peaked in June 2019 (AST/ALT up to 500s/1400s), and gradually normalized by August. Liver biopsy showed subacute portal and lobular hepatitis without autoimmune features. Skin biopsy revealed mild spongiotic and interface vacuolar dermatitis (Figure 2a). During the 2024 flares, liver enzymes remained normal. Laboratory testing revealed elevated CRP (172.3 mg/L), normal WBC and ferritin, and negative autoimmune panels. Infectious serologies remained unremarkable. Skin biopsy revealed urticarial dermatitis without vasculitis (Figure 2b). Urticarial vasculitis and systemic lupus erythematosus were ruled out based on histology and negative ANA. Still's disease was excluded due to the absence of leukocytosis, splenomegaly, and hyperferritinemia. Schnitzler syndrome was ruled out by the negative serum protein electrophoresis. Progesterone hypersensitivity was considered unlikely, given her lack of luteal-phase symptoms and tolerance of oral contraceptives. Given the clinical pattern, autoinflammatory syndromes were suspected, including TNF receptor–associated periodic syndrome and cryopyrin-associated periodic syndromes, but the lack of serositis, ocular involvement, and cold-induced flares made them unlikely. An autoinflammatory disorders gene panel identified two NOD2 heterozygous variants: N289S (c.866A > G, p.Asn289Ser) and V955I (c.2863G > A, p.Val955Ile). No pathogenic variants in other autoinflammatory genes were found. The patient met the proposed diagnostic criteria for NOD2-AID: all major criteria, two minor criteria (arthritis and gastrointestinal symptoms), and supporting genetic findings (Table 1).2 Arthralgia (oligo- or polyarthralgia/inflammatory arthritis, or distal extremity swelling)* GI symptoms (abdominal pain or diarrhea) Sicca-like symptoms Pericarditis Pleuritis NAID was originally described by Yao et al. in 2011.1 Although commonly associated with IVS8+158 and R702W mutations, other NOD2 variants of uncertain significance, like those found in our patient, have been reported.3-5 While transaminitis have been reported in a small minority of NAID cases,6 the marked transaminase elevation during her 2019 episode is unusual and remains unexplained, especially without drug-induced liver injury or autoimmune hepatitis. Known triggers for disease activity include vaccinations, viral infections, and psychological stress.2, 3 Our case is noteworthy, as NAID was exacerbated during late pregnancy and the postpartum period. Immunologic changes in pregnancy, such as shifts in cytokine profiles and hormonal modulation, are thought to contribute to both remission and exacerbation of autoinflammatory and autoimmune diseases.7-9 After delivery, the rapid decline in estrogen and progesterone, together with normalization of cortisol and other immunosuppressive hormones, leads to increased production of inflammatory mediators (e. g., IL-12, TNF-α) and a shift toward a pro-inflammatory state,7, 10 which may enhance activation of NOD2-mediated inflammatory pathways. Management of mild NAID typically includes short courses of glucocorticoids or daily sulfasalazine, while colchicine and hydroxychloroquine have generally been less effective.3 In severe or refractory cases, biologics targeting IL-1 and IL-6 have shown effectiveness.4 Our patient initially responded to prednisone but developed bilateral femoral head osteonecrosis, requiring right hip arthroplasty. Hydroxychloroquine was initiated in February 2024 but led to a morbilliform eruption, suspected to be drug-induced. Consequently, anakinra is being considered as a therapeutic option should flare-ups recur. None.
Nguyen et al. (Mon,) studied this question.