Schnitzler syndrome is an extremely rare acquired autoinflammatory systemic syndrome. It is characterized by the presence of a chronic urticarial-like rash and immunoglobulin-M (IgM) monoclonal gammopathy (or, less commonly, IgG), along with recurrent fever, arthralgia, fatigue, lymphadenopathy, bone morphological changes, leukocytosis, and elevated inflammatory markers [1]. The exact prevalence of this syndrome remains undefined, and diagnosis is frequently delayed. The diagnosis is based on the Strasbourg Criteria, which require two obligate criteria—chronic urticarial rash and monoclonal IgM or IgG gammopathy—and at least two minor criteria. Minor criteria include recurrent fever, abnormal bone remodeling, a neutrophilic dermal infiltrate on skin biopsy, leukocytosis, and/or elevated C-reactive protein (CRP). Complications may include lymphoproliferative disorders and, in untreated cases, rare secondary amyloidosis [2]. The pathophysiology of Schnitzler syndrome is not fully understood, but research suggests it involves an abnormal autoinflammatory response driven by the activation of inflammatory cytokines, particularly interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-α). Accordingly, IL-1 blockade with anakinra is considered the treatment of choice. Tocilizumab, corticosteroids, colchicine, and dapsone represent second-line options [3]. This is, to our knowledge, the first case of anakinra-related recall urticaria (RU) in a patient with Schnitzler syndrome.

The timeline is shown in Figure 1.

We present the case of a 75-year-old Caucasian woman, referred to our clinic seven years after symptom onset. The patient had previously been treated, based on the diagnostic hypothesis of chronic spontaneous urticaria, with high-dose antihistamines (four administrations/day), and subsequently with subcutaneous omalizumab 300 mg every 4 weeks for over a year, without significant improvement. Histopathological examination of lesional skin revealed acanthosis, spongiosis, papillary dermal edema, and an interstitial and perivascular inflammatory infiltrate composed of eosinophils and rare neutrophils—findings consistent with urticaria. The diagnosis of Schnitzler syndrome was subsequently established, fulfilling both obligate criteria (urticarial rash and monoclonal IgM gammopathy) and three minor criteria (recurrent fever, leukocytosis, elevated inflammatory markers). Laboratory findings at the time of diagnosis are described in Table 1. Subcutaneous anakinra (100 mg daily) was initiated, leading to rapid improvement of cutaneous and systemic symptoms. However, by the fourteenth administration of anakinra, the patient developed a delayed-onset giant wheal at the injection site and previous injection areas, arising more than 12 hours post-administration (Figure 2). Laboratory tests during the episode revealed leucocytosis, neutrophilia, elevated CRP, and an elevated erythrocyte sedimentation rate (Table 2). Anakinra was discontinued, and the patient was started on a tapering course of oral steroids and antihistamines, resulting in the resolution of pruritus but persistence of hyperpigmented macules for two weeks. The clinical pattern suggested a dual mechanism: an immediate hypersensitivity reaction (pruritic wheals) and a delayed response (persistent lesions). At the patient’s request, no further investigations were conducted. Colchicine (1.5 mg/day) was initiated, leading to sustained control of systemic manifestations.

At the time of diagnosis, a comprehensive laboratory assessment was performed, and the main findings consistent with Schnitzler syndrome are summarized in Table 1. Laboratory parameters obtained during the acute reaction are presented in Table 2, highlighting the changes observed compared with baseline values.

“I was relieved to finally receive a clear diagnosis after years of uncertainty and unsuccessful treatments. When the reaction to anakinra occurred, I was frightened and chose not to undergo further allergy testing, but I felt reassured by my doctors’ care and am now satisfied with the improvement achieved with the new therapy.”

Although local reactions at the injection site occur in up to 70% of patients treated with anakinra [4], the presentation in this case was consistent with RU—a rare phenomenon characterized by the reappearance of wheals at previous injection sites after re-exposure to the same drug. RU has been described with subcutaneous allergen immunotherapy, heparin, nonsteroidal anti-inflammatory drugs [5], and other biological agents. The underlying mechanisms of RU remain debated, with hypotheses including IgE-mediated pathways, T-cell involvement, and cyclooxygenase type I inhibition [4]. In our case, the latency and persistence of lesions point toward a type IV hypersensitivity reaction mediated by intraepidermal CD8+ T cells.

To our knowledge, this is the first documented case of RU triggered by anakinra in a patient with Schnitzler syndrome. This finding broadens the spectrum of anakinra-associated adverse events and highlights the importance of awareness and further research into the immunopathogenesis of RU.