Neutrophilic epitheliotropism, proposed as an auto‐inflammatory condition of neutrophilic urticarial dermatosis including Schnitzler syndrome, is also observed in Japanese cases

Schnitzler syndrome (SchS) is a rare autoinflammatory disease characterized by bone pain, recurrent fever, leukocytosis, and elevated C‐reactive protein, along with an urticaria‐like rash and monoclonal immunoglobulin (Ig)M or IgG gammopathy. Notably, the condition is distinguished by a relatively persistent recurrent urticarial‐like rash. Histopathological features observed in the skin comprise diffuse neutrophil infiltration into the dermis, absence of dermal edema, and vascular wall degeneration, all of which classify SchS as a neutrophilic urticarial dermatosis (NUD). Accumulated histological data from skin biopsies of patients with NUD have revealed a sensitive histopathological marker for NUD, acknowledged as neutrophilic epitheliotropism, which has been proposed as reflecting an autoinflammatory condition. In this report, we present three SchS patients: two men (ages 55 and 68) and a woman (age 75), all displaying neutrophilic epitheliotropism in their skin biopsy specimens. Additionally, a review of eight previously reported SchS cases in Japan identified neutrophilic epithliotropism in five cases. These findings suggest that the inclination of neutrophils toward the epithelial tissue could aid in confirming diagnoses of NUD in most cases that need to be differentiated from conventional urticaria. Consequently, we emphasize that acknowledging neutrophilic epithelial predilection as a hallmark of NUD is critical for expediting early diagnosis and appropriate treatment for SchS.

Schnitzler syndrome (SchS) is considered to be an acquired form of an autoinflammatory syndrome due to its late onset, typically around 50 years of age, 1 and its resemblance to clinical phenotypes of cryopyrin-associated periodic syndrome (CAPS). 2 The diagnosis of SchS is based on the Strasbourg criteria established by Lipsker et al., 3 which includes chronic urticarial rash and monoclonal immunoglobulin (Ig)M or IgG as two obligate criteria.Minor criteria include a neutrophilic dermal infiltrate on skin biopsy, recurrent fever, objective findings of abnormal bone remodeling with or without bone pain, and leukocytosis or elevated C-reactive protein (CRP).As mentioned in the minor criteria, SchS may present a different pathological picture from ordinary urticaria.Kieffer et al. 4 claim that some autoinflammatory diseases, including SchS, present a pathological picture known as neutrophilic urticarial dermatosis (NUD).Clinically, patients with NUD have a recurrent or chronic cutaneous eruption consisting of macules, papules, or plaques, with individual lesions resolving within 48 h and may or may not be pruritic.Pathologically, a skin biopsy specimen shows a diffuse neutrophilic infiltrate in the dermis with interstitial involvement, but without vessel wall alteration (especially parietal necrosis) and dermal edema.Broekaert et al. 5 further examined NUD pathology by analyzing patients with SchS, CAPS, Still disease, systemic lupus erythematosus (LE), Sjögren syndrome, and other conditions.Comparison of these samples with skin biopsies of neutrophilic urticaria, neutrophilexpressing LE, and eruptive drug reactions that did not meet NUD criteria showed neutrophilic infiltration also in the epidermis, hair follicles, sebaceous glands, sweat glands, and ductal epithelium in NUD.They termed this feature "neutrophilic epitheliotropism", proposed as an indicator of an underlying autoinflammatory condition.
In this report, we reviewed skin biopsies from three experienced SchS cases and found neutrophilic epitheliotropism in all biopsies.
Additionally, a review of eight previously reported SchS cases in Japan identified neutrophilic epitheliotropism in five cases.These findings suggest neutrophilic epitheliotropism is a useful feature of NUD and a valuable finding in diagnosing SchS.

| Case 1
A 55-year-old man presented to a dermatology clinic with fever, fatigue, and a non-itching skin rash.The patient had a prolonged fever of 38°C, lasting for a few days, accompanied by nonpruritic urticaria-like eruptions.Colchicine (1.5 mg/day) was started for suspected SchS, which led to an improvement in his symptoms.However, 7 years after the onset of symptoms, the fever and rash worsened, prompting the patient to seek further examination and treatment at our department.An urticarial skin rash was observed on his chest, abdomen, lower back, and arms (Figure 1).Laboratory examination revealed monoclonal IgM gammopathy (742 mg/dL), neutrophilic leukocytosis (white blood cells [WBC]), 10 580/μL; neutrophils, 70.1%), and slightly elevated CRP (0.74 mg/dL).This case corresponds to Case 27 in our previous report of clinically diagnosed cases in Japan. 1 A biopsy was performed from the right lower abdomen.Histopathology showed diffuse neutrophilic infiltration within the dermis, as well as neutrophilic infiltration into the epidermis, which could be indicative of NUD (Figure 2a,b).

| Case 2
A 68-year-old man is reported as Case 2 in a previous study on the efficacy of molecularly targeted drugs for SchS, 6 and Case 22 in our case summary. 1 He was undergoing treated with oral prednisolone The skin lesion biopsied in Case 1.
(5 mg/day) and tocilizumab, experiencing occasional fatigue and fever over 38°C about 1-2 times a week.Laboratory findings showed monoclonal IgM gammopathy (328 mg/dL), neutrophilic leukocytosis (WBC, 13 820/μL; neutrophils, 88.5%), but normal CRP due to tocilizumab.During his first visit to our department, a skin biopsy was performed on his left hypochondrium.Histopathology revealed neutrophilic infiltration into the epidermis and epithelia of eccrine glands, in addition to the dermis (Figure 2c-e).

| Case 3
A 75-year-old woman is reported as Case 1 in our previous publication 6 and Case 23 in the case summary. 1 Additionally, we have reported elsewhere that the skin biopsy tissue of this case showed characteristic inducible skin-associated lymphoid tissue. 7Approximately 3 years after initial diagnosis, tocilizumab was switched to anakinra, an interleukin (IL)-1 inhibitor, and the skin rash and clinical symptoms improved dramatically, except for monoclonal IgM gammopathy (1848 mg/dL).A skin biopsy was performed before anakinra administration.Laboratory findings were as follows: monoclonal IgM gammopathy (1656 mg/dL), neutrophilic leukocytosis (WBC, 9790/μL; neutrophils, 77.5%), but normal CRP.Histopathology demonstrated, in addition to the dermis, neutrophilic infiltration within the secretory epithelia of eccrine glands (Figure 2f,g).

| Other domestic cases
We contacted attending physicians to reevaluate tissue from previously reported domestic SchS cases. 1 Out of 12 cases, we could not review tissue in four instances due to either their unavailability from prior biopsies or the extended time since the biopsies were conducted.In the eight cases we were able to assess, we identified neutrophilic epitheliotropism in five cases, while the remaining three cases did not confirm these findings (Table 1).

F I G U R E 2
Histopathological findings of the skin lesion.(a) Hematoxylin and eosin (HE) staining of the biopsy from Case 1 (scale bar = 200 μm);white circle indicates neutrophilic epitheliotropism.(b) Higher resolution of the circled area shows a neutrophil in the epidermis observed in Case 1 (scale bar = 50 μm).(c) HE staining of the biopsy from Case 2 (scale bar = 200 μm).(d) The white arrowhead demonstrates a neutrophil within the ductal epithelia of the eccrine gland noted in Case 2 (scale bar = 50 μm).(e) The white circle indicates a neutrophil within the epidermis in Case 2 (scale bar = 50 μm).(f) HE staining and (g) immunohistochemical staining for myeloperoxidase of the biopsy from Case 3. Arrowheads demonstrate neutrophils within the secretory epithelia of eccrine glands and harbored neutrophils around the eccrine glands (scale bar = 50 μm).