Mimicking urticaria: a Schnitzler syndrome case

Dear Editor,

Schnitzler Syndrome (SchS) is a rare disorder, with ∼350 cases reported in the literature, characterized by a neutrophilic urticarial dermatosis and monoclonal gammopathy (IgM in more than 90% of the cases), associated with clinical and biological signs of inflammation.¹-³ In 2013, Lipsker, Schnitzler, and other experts met and proposed the Strasbourg diagnostic criteria, which are widely used today to diagnose SchS (Table 1).¹,⁴ We report a case of a man with a clinical and laboratory diagnosis of SchS in Brazil.

Table 1
Strasbourg diagnostic criteria of Schnitzler syndrome.

Obligate criteria

- Chronic urticarial rash and

- Monoclonal IgM or IgG

Minor Criteria

- Recurrent fevera

- Objective findings of abnormal bone remodeling with or without bone painb

- A neutrophilic dermal infiltrate on skin biopsyc

- Leukocytosis and/or elevated CRPd

Definite diagnosis if

- Two obligate criteria AND at least two minor criteria if IgM and three minor criteria if IgG

Probable diagnosis if

- Two obligate criteria AND at least one minor criteria if IgM and two minor criteria if IgG

• ^a
  Must be >38 °C and otherwise unexplained. Occurs usually ‒ but not obligatory ‒ together with the skin rash.
• ^b
  As assessed by bone scintigraphy, MRI, or elevation of bone alkaline phosphatase.
• ^c
  Corresponds usually to the entity described as “neutrophilic urticarial dermatosis”; absence of fibrinoid necrosis and significant dermal edema.
• ^d
  Neutrophils >10,000 mm³ and/or CRP > 3 mg/dL.

A 67-year-old man presented to our department with recurrent pruritic, not painful, urticaria-like lesions on the extremities and the trunk (Fig. 1). The lesions resolved within 24 hours without leaving behind dusky hyperpigmentation. He had intermittent fever of up to 39 °C, generalized arthralgia, and fatigue. The inflammatory episodes lasted for 2-5 days with severe general impairment. The patient suffered outbreaks with variable intensity on almost a monthly basis over the past fifteen years. Histopathology of lesional skin showed a perivascular and interstitial polymorphonuclear infiltrate, described as consistent with the diagnosis of urticarial lesions and compatible with SchS (Fig. 2).

Fig. 1
Urticarial lesions on the trunk and left arm.

Fig. 2
Inflammatory cells around superficial dermal vessels with neutrophils (A, Hematoxylin & eosin, ×100) also observed in the interstitial space among collagen fibers (B, Hematoxylin & eosin, ×400).

Laboratory investigations revealed leucocytosis (up to 21.000 mm³, ref 4000-11600 mm³), an elevated ESR (120 mm/hr; 0∼20 mm/hr), and increased IgM levels (2550 mg/dL; 46∼260 mg/dL) in serum protein electrophoresis (Fig. 3). In the bone scan, there is a slight asymmetry of uptake in the tibias, slightly greater on the left. Bone marrow biopsy was performed with a negative cytogenetic study for lymphoproliferative diseases. Based on these clinical and laboratory findings, he was diagnosed with Schnitzler Syndrome.

Fig. 3
Increased IgM levels in serum protein electrophoresis test.

He was started on a high-dose corticosteroid, NSAIDs, and antihistamines with partial remission of his symptoms.

There are a few cases reported in Latin America and in general, it is underdiagnosed despite the well-established diagnostic criteria, but the pathogenesis is unknown.⁵

The major complication is hematological malignancy, with lymphoproliferative disorder occurring in about 10%‒20% of patients.⁵,⁶ In addition to chronic spontaneous urticaria, other differential diagnoses should be considered (Table 2).⁷

Table 2
Differential diagnoses of Schnitzler syndrome.

Autoimmune diseases

Adult Onset Still Disease (AOSD)

Systemic Lupus erythematosus

Acquired C1-esterase inhibitor deficiency

Hematologic diseases

Monoclonal gammopathy of undetermined significance (MGUS)

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, mono-clonal gammopathy and skin changes)

Waldenström macroglobulinemia

Lymphomas

Multiple myeloma

Hereditary autoinflammatory syndromes

Cryopyrin-associated syndromes (CAPS):

Familial cold urticaria

Muckle-Wells syndrome

Chronic infantile neurologic cutaneous and articular syndrome (CINCA)

Infectious diseases

Hepatitis B and C

Chronic meningococcemia

Other

Chronic Spontaneous Urticaria

Hypocomplementemic urticarial vasculitis

Delayed pressure urticaria

Cryoglobulinemia

Behçet syndrome

Mastocytosis

At present, for patients with CRP < 3 mg/dL, treatment options include, colchicine, Nonsteroidal Anti-inflammatory Drugs (NSAIDs), and hydroxychloroquine.¹,² Corticosteroids has a moderate effect and antihistamine therapy has no effect.⁸ According to Simon et al., the efficacy of colchicine is only 25%, but based on the benefit/risk ratio, colchicine is recommended as the first choice of treatment.⁹ Experts recommend the use of anakinra (IL-1 block) in more symptomatic patients, such as Erythrocyte Sedimentation Rate (ESR) and CRP above the upper limit of normal (CRP > 3 mg/dL).¹

Treatment with corticosteroids, NSAIDs, and antihistamines is symptomatic and unsatisfactory.⁹ Anakinra (IL-1-neutralizing) is the choice drug. The effect of inhibition of IL-1 has led to new expectations, but there is currently unavailable in Brazil. An alternative drug could be canakinumab, a human anti-IL-1β monoclonal antibody aiming at the neutralization of 1β signaling.¹⁰

In patients presenting with chronic urticaria associated with signs of systemic inflammation, this rare and debilitating syndrome should be considered. Early treatment can improve patient's quality of life and disease prognosis.

• Financial support
  None declared.

References

• ¹ Matsuda T, Takimoto-Ito R, Lipsker D, Kambe N. Similarities and differences in autoinflammatory diseases with urticarial rash, cryopyrin-associated periodic syndrome and Schnitzler syndrome. Allergol Int. 2023;72:385-93.
• ² Bonnekoh H, Krause K, Kolkhir P. Chronic recurrent wheals - if not chronic spontaneous urticaria, what else? Allergol Select. 2023;7:8-16.
• ³ Sá DC, Festa C Neto. Inflammasomes and dermatology. An Bras Dermatol. 2016;91:566-78.
• ⁴ Gusdorf L, Lipsker D. Schnitzler syndrome: a review. Curr Rheumatol Rep. 2017;19:46.
• ⁵ Aceituno Caño AM, Vogt Sánchez EA, León Ruiz L. Schnitzler's syndrome: a case report. Med Clin (Barc). 2021;157:301-2.
• ⁶ Tinoco G, Kanji R, Moola D. Schnitzler's syndrome: a case report. Case Rep Med. 2013;2013:956464.
• ⁷ Eiling E., Schröder JO, Gross WL, Kreiselmaier I, Mrowietz U, Schwarz T. The Schnitzler syndrome: chronic urticaria and monoclonal gammopathy - an autoinflammatory syndrome? J Dtsch Dermatol Ges. 2008;626-31.
• ⁸ Chu CQ. Schnitzler syndrome and Schnitzler-like syndromes. Chin Med J (Engl). 2022;135:1190-202.
• ⁹ Simon A, Asli B, Braun-Falco M, De Koning H, Fermand JP, Grattan C, et al. Schnitzler's syndrome: diagnosis, treatment, and follow-up. Allergy. 2013;68:562-8.
• ¹⁰ Fujita Y, Asano T, Sakai A, Norikawa N, Yamamoto T, Matsumoto H, et al. A case of Schnitzler's syndrome without monoclonal gammopathy successfully treated with canakinumab. BMC Musculoskelet Disord. 2021;22:257.

Publication Dates

• Publication in this collection
  10 Jan 2025
• Date of issue
  Sep-Oct 2024

History

• Received
  21 Sept 2023
• Accepted
  11 Oct 2023
• Published
  26 Aug 2024