Schnitzler syndrome (SchS) is a rare and often underreported chronic multisystem disorder, diagnosed on the basis of the presence of two major criteria: chronic/recurrent urticarial and monoclonal IgM or, less likely, IgG gammopathy, accompanied by laboratory evidence and symptoms of inflammation.^1,2,3,4 At least two minor criteria (recurrent unexplained fever [>38°C]; abnormal bone remodeling with or without bone pain; neutrophilic dermal infiltrate in the skin biopsy and presence of elevated neutrophils >10,000/mm³ and/or C-reactive protein >30 mg/L) are required for a diagnosis of SchS in patients with IgM gammopathy and at least three criteria must be present for patients with IgG gammopathy.^1,2,3,4

The male-to-female ratio is 1.76 with a median 3 and mean age of onset of approximately 51 years.⁴ The exact pathogenesis of SchS is unknown. Interleukin-1β (IL-1β) plays a pivotal role in mediating the inflammatory cascade in SchS, as highlighted by a dramatic response to treatment with anti-IL-1 antibody (anakinra). Circulating mononuclear cells release increased amounts of IL-1β, even in the absence of elevated levels of IL-1.⁵ IL-6 and IL-18 may participate in regulating IL-1 activity.^6,7 Mutation of leucin-rich family (NLR), pyrin containing 3 gene (NLRP3) V198M variant in some SchS patients suggests a relation to cryopyrin-associated periodic syndrome (CAPS).^8,9

SchS is characterized by a course of recurrences and spontaneous remissions. Fever is a cardinal feature, and may reach 40 ^°C, but is well tolerated. An urticaria-like rash is the most specific and constant symptom in patient with SchS.⁴ Lesions are faintly erythematous patches, plaques, or papules, located predominantly on the trunk and extremities, sparing head and neck. Although the rash resembles urticaria in duration (<24 hours) and appearance, itch is not common. The rash is characteristically recalcitrant to treatment with antihistamines. Nonpruritic dermographism, angioedema, and mucosal swelling may occasionally occur.¹⁰

Biopsies typically reveal neutrophilic urticarial dermatosis. There is a predominantly neutrophilic perivascular and interstitial infiltrate, demonstrating leukocytoclasia without vasculitis, with variable foci of basophilic necrobiotic collagen alteration.⁴ The infiltrate may concentrate around eccrine glands and in the subcutis (Fig. 65-1A). Eosinophils are often present , differentiating this from Sweet syndrome. (Fig. 65-1B). Dermal edema is not typical (Fig. 65-1C). Direct immunofluorescence may reveal IgM and C3 in the vessels or basement membrane zone IgM.^10,11