A guide to recognise and manage Schnitzler syndrome in clinical practice

Schnitzler syndrome is a rare auto-inflammatory disease characterised by distinct skin manifestations. Although effective therapies are available, the pathogenesis of the condition remains only partially understood.

Dr Heleen de Koning (Erasmus Medical Center, the Netherlands) discussed the diagnosis, clinical presentation, treatment options, and ongoing research into the underlying mechanisms of Schnitzler syndrome [1].

Diagnosis is based on 2 mandatory criteria: the presence of chronic urticarial dermatitis and a monoclonal IgM or IgG component. Additionally, patients frequently experience recurring fever, leucocytosis, increased CRP, objective signs of abnormal bone remodelling, bone pain, and a neutrophilic dermal infiltrate on skin biopsy. “For a definitive diagnosis, both mandatory criteria must be fulfilled, and at least 2 minor criteria in cases with IgM or at least 3 minor criteria in cases with IgG component,” said Dr de Koning. As of now, approximately 350 cases of Schnitzler syndrome have been described. However, Dr de Koning expressed that this underestimates the total number of cases. On average, the first symptoms are present at 51 years of age, and the men:women ratio is 1.5 to 1. Patients with Schnitzler syndrome are usually Caucasian or Asian, and no hereditary component associated with disease development is currently known.

In clinical practice, patients typically present with red, nonpruritic, sometimes burning skin lesions accompanied by systemic symptoms such as fever, malaise, and joint and bone pain. “Addressing the disease course and the family history is crucial,” added Dr de Koning. Physical examination often reveals urticarial plaques on the legs, arms, and sometimes the trunk, as well as an increased body temperature. Additional findings may include lymphadenopathy and hepatosplenomegaly. “Patients with arthralgia rarely have arthritis,” noted Dr de Koning. A skin biopsy will display a neutrophilic dermal infiltrate in the affected skin but no vasculitis. Laboratory investigations should include inflammatory markers, full blood count, protein electrophoresis, and calcium and alkaline phosphatase measurements to detect abnormal bone remodelling. “If a paraprotein is identified, a bone marrow biopsy is indicated to exclude lymphoproliferative diseases,” explained Dr de Koning. In addition, a bone scan can be performed to evaluate osteoclastic changes in the tibia and femur. Since the clinical manifestations are not specific, the differential diagnosis is broad, including autoimmune disorders, haematological diseases, other auto-inflammatory syndromes, infections, chronic spontaneous urticaria, and cryoglobulinaemia.

Dr de Koning explained that Schnitzler syndrome shares disease features with another auto-inflammatory condition known as cryopyrin-associated periodic syndrome (CAPS). Since anakinra and canakinumab are efficacious in CAPS, the IL-1 receptor antagonist anakinra has also been tested in patients with Schnitzler syndrome and has been shown to induce rapid improvements. Similarly, the IL-1β inhibitor canakinumab yielded promising results in patients with Schnitzler syndrome [2]. “After stopping anakinra, patients experienced a serious inflammatory reaction,” said Dr de Koning. “Fortunately, this was not the case with canakinumab. If patients discontinued this agent, inflammation remained suppressed for some time.” Canakinumab is injected monthly, which is a benefit over the daily injected anakinra. However, its high cost limits its widespread use, and most patients with Schnitzler syndrome are treated with anakinra.

“We know now that IL-1β overactivity is an important driver of inflammation in Schnitzler syndrome,” Dr de Koning continued. She then turned to a crucial point of discussion, focusing on the underlying cause behind this IL-1β overactivity. An acquired NLRP3 mutation has been proposed as an underlying mechanism. “In 2 of our patients with Schnitzler syndrome, an NLP3 mutation in the myeloid line was found,” said Dr de Koning. However, no such mutation was observed in 79 other patients with Schnitzler syndrome. Another proposed mechanism contributing to the IL-1β overactivity is a MyD88 mutation. About 16% of the patients with Schnitzer syndrome develop a lymphoproliferative condition after 10 years; two-thirds are Waldenstrom macroglobulinaemia. “Interestingly, 90% of the patients with Schnitzler syndrome who develop Waldenstrom macroglobulinaemia carry a MyD88 mutation,” added Dr de Koning. Nonetheless, many patients with Schnitzler syndrome do not have this mutation, indicating the involvement of multiple or currently unidentified pathogenic pathways.

Thus, although certain clues point toward the underlying mechanisms, the pathogenesis of Schnitzler syndrome has not been completely unravelled. “Perhaps we need even more sensitive techniques to learn the true nature of this disease,” Dr de Koning suggested. “Fortunately, effective symptomatic therapies are available nowadays, enabling patients to lead normal lives.”

1. De Koning H. Schnitzler Syndrome. Dermatologendagen 2025, 10–11 April, Apeldoorn, the Netherlands.
2. An J, et al. J Rheumatol. 2024;51(9):848-861.

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Posted on 5 June 20255 June 2025