Schnitzler syndrome L53.86

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 19.01.2024

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Schnitzler`s syndromes; urticarial vasculitis; Urticaria vasculitis

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Carver, 1972

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Schnitzler syndrome (SchS) is a rare, late-onset, non-hereditary (familial) autoinflammatory disease (AID), of which < 350 cases have been reported in the medical literature to date (de Koning HD 2014). According to the Strasbourg diagnostic criteria established in 2012 (see below), Schnitzler syndrome shows a chronic urticarial rash and a monoclonal gammopathy of the IgM and rarely IgG type (85%/15% of cases; mandatory main criteria/de Koning HD 2014). Minor Strasbourg criteria of the disease include recurrent fever, abnormal bone remodeling with or without bone pain, a neutrophilic infiltrate in the skin biopsy, and leukocytosis or elevated CRP.

The frequency of skin findings varies widely, with some patients having constant skin symptoms, while others have outbreaks only a few times a year. Individual skin lesions persist for 12-48 hours (de Koning 2014). Rashes and fever often occur simultaneously and can be triggered by stress, cold, heat, alcohol, spicy food and physical activity (de Koning et al.2014; Lipsker D 2010). In addition to the Strasbourg criteria, patients may present with arthralgia, myalgia, lymphadenopathy, weight loss, hepatosplenomegaly and angioedema (de Koning, 2014). The risk of developing a lymphoproliferative disorder, usually Waldenström's macroglobulinemia, within 10 years is around 13% (de Koning, 2014).

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Unexplained. Autoimmune etiology has not been conclusively clarified. It appears that IL-1 and the dysfunctional interleukin-1 receptor play a central role in the pathogenesis of the disease. Autoantibodies against IL-1 have been detected. It is possible that these AK prolong the biological half-life and thus the effect of this cytokine. This could explain the therapeutic effect of the interleukin-1 receptor antagonist anakinra.

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The mean age of the disease is 52 years. Men and women are affected similarly frequently (m:w = 1.6:1).

Clinical features
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Significant feeling of illness with recurrent fever attacks (in about 90% of patients with temperatures < 40 °C), recurrent, itchy or painful, urticarial exanthema (neutrophilic urticarial dermatosis /NUD) (exanthema attacks accompany the periodic fever), fatigue and tiredness, arthralgias, arthritides and bone pain (esp.especially tibia and pelvic bones). Lymph node swelling and hepatosplenomegaly may also occur.

Neutrophilic urticarial dermatosis (NUD) is the characteristic skin finding of SchS and often precedes other signs and symptoms of the disease (de Koning, 2014). However, NUD is not specific to SchS, as it can also occur in other autoinflammatory syndromes such as CAPS and AOSD (adult-onset Still's syndrome), which must be excluded as differential diagnoses (Chen p. 2022). NUD is characterized by sometimes confluent, erythematous, annular or maculopapular lesions between 0.5 and 3 cm in diameter. Compared to chronic spontaneous urticaria, SchS lesions are less edematous. The rash is symmetrically distributed and affects the trunk and extremities, while the head and neck are rarely affected. The palms of the hands and soles of the feet are never affected. The frequency of exanthema varies considerably, ranging from daily to a few times per year, while individual skin lesions usually last 12-48 hours and heal without scarring (de Koning, 2014). Cutaneous involvement can be triggered by various factors such as stress, alcohol, hot spices, food, physical labor and exposure to hot or cold temperatures (Lipsker, 2010). However, a local cold test (ice cube test is negative Krause et al. 2012b). Only 21% of patients with SchS develop itchy skin lesions over time, with patients often reporting a burning sensation instead. Angioedema occurs in only 8% of patients with SchS (de Koning HD 2014).

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High CRP, high BSG, anemia, leukocytosis and thrombocytosis; detection of IgM (G) gamma-gammopathy, Bence-Jones proteinuria (in about 30% of cases).

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The picture of leukocytoclastic vasculitis is possible. Even purely urticarial patterns are detectable.

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At least 2 major criteria and 2 minor criteria (for IgM gammopathy) or three minor criteria (for IgG gammopathy) must be fulfilled for the diagnosis. In general, the urticarial rash is the first sign of the disease and precedes other signs and symptoms (median age at onset of rash = 51 years, median age at onset of fever = 52 years) (de Koning, 2014).

  • Main criteria:
    • Chronic recurrent urticarial exanthema
    • monoclonal IgM gammopathy (more rarely IgG gammopathy) of unclear significance ( MGUS).
  • Secondary criteria:
    • Intermittent fever
    • Arthralgia or arthritis of the large joints
    • Bone pain
    • Lymphadenopathy
    • Hepato- or splenomegaly
    • BSG/CRP elevations or leukocytosis
    • Bone densification.

Differential diagnosis
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  • Chronic urticaria (most important differential diagnosis): No fever attacks; also the broad symptoms of the Schnitzler syndrome are missing. No evidence of MGUS.
  • Urticaria, autoreactive. Picture of chronic (not febrile), therapy-resistant urticaria. Frequently angioedema; usually increased anti-TPO-AAK and increased CRP.
  • Adult breastfeeding syndrome: Similar clinical symptoms with recurrent febrile attacks, arthralgia and muscle pain. A gammopathy is absent. Skin lesions are of similar nature. Furthermore: Leukocytosis (> 10.000/μl) with > 80% neutrophilia, serositis, rheumatoid factor negative, ANA negative.
  • CAPS = Cryopyrin-associated periodic syndrome: Very rare disease; clinical picture of cold-induced urticaria with mutant arthralgias. Long-term consequences due to the constantly elevated inflammatory parameters are systemic amyloidosis in some patients.
  • Systemic lupus erythematosus (SLE): Urticarial or urticarial-papular febrile exanthema may also occur; however, laboratory and immunological symptoms (ANA, ENA; immunofluorescence) are conclusive.
  • Lymphoproliferative diseases with paraproteinemia (see below paraproteinemia, skin changes).
  • Fever syndromes, hereditary, periodic (very rare; corresponding family history; no gammopathies). S.a. Muckle-Wells syndrome; CINCA syndrome (chronic infantile neurological cutaneous and articular syndrome) and cryopyrin-associated periodic syndrome.
  • POEMS syndrome (very rare): polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy (myeloma detection!). Skin changes are described as hyperpigmentation, hypertrichosis, edema of the extremities and thickening of the skin; the picture is quite different.

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The Il-1 antagonist anakinra (100 mg/day s.c.) led in several cases (follow-up period of > 3 years) to complete remission (therapy of the 1st choice). Medium high-dose glucocorticoids (e.g. prednisolone 75-100mg/day) act promptly (long-term therapy!). With regard to the need for treatment of MGUS, a haematological consultation appears to be useful. Otherwise symptomatic therapy depending on the clinic. Antihistamines have no effect on the clinical symptoms. Therapeutic success under rituximab must be evaluated rather critically.

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Mortality is comparable to that of the non-diseased population, with a 15-year survival rate of 94%. In about 15% of the cases a lymphoproliferative disease develops which then defines the prognosis.

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Antihistamines are ineffective for this clinical picture!

Case report(s)
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  • The 52-year-old patient had been observing recurrent urticarial skin changes on the entire integument for 10 years. The relapses, which persisted for about 4-6 weeks, initially occurred at intervals of several months. Over the years they have become more frequent. In the last year, however, she observed daily skin symptoms. She felt regularly "ill" like a flu with indisposition, exhaustion, indefinable myalgia and variable, quite painful joint complaints. The general practitioner had noticed a clearly increased BSG and a leucocytosis of 12.000-15.000 /µl. The previous therapy was carried out with intermittent glucocorticoids (which in medium doses helped promptly), temporarily in combination with azathioprine (100 mg/day p.o.).
  • Findings: Considerable feeling of illness with temperatures between 39.5 and 40 °C. Dense trunk urticarial exanthema. Fatigue and tiredness, arthralgia, arthritis and bone pain. Sonographically proven splenomegaly and moderate lymphadenopathy. CRP is significantly elevated, high BSG, variable high leukocytosis (12-15,000 ul) with neutrophilia, thrombocytosis; detection of IgM-gammopathy (6.5 mg/l), no Bence-Jones proteinuria.
  • Histology (non-specific): moderately dense vascular perivascular round cell infiltrate. Immunohistology: unspecific.
  • Dg. Schnitzler syndrome.
  • Therapy: Anakinra (100 mg/day s.c.). Including prompt improvement of clinical symptoms. However, discontinuation of the preparation led to a prompt recurrence. Under the now continued therapy with Anakinra the patient is free of symptoms for 10 months.

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Last updated on: 19.01.2024