Schnitzler syndrome L53.86

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).

The aetiopathogenesis of Schnitzler syndrome has not yet been fully clarified. According to current understanding, it is an acquired autoinflammatory syndrome characterized by a pronounced activation of the interleukin-1 signaling axis, in particular IL-1β. Several clinical and experimental findings indicate that an overactivation of the innate immune system with increased production of proinflammatory cytokines plays a central role.

Pathophysiologically, activation of the inflammasome, in particular the NLRP3 inflammasome, is discussed. This multiprotein intracellular complex system leads via the activation of caspase-1 to the proteolytic cleavage of pro-IL-1β to active IL-1β, which is subsequently secreted and triggers a systemic inflammatory reaction. The central importance of this signaling axis is supported by the pronounced clinical efficacy of IL-1-targeted therapies, in particular the IL-1 receptor antagonist anakinra, the anti-IL-1β monoclonal antibody canakinumab and the soluble IL-1 fusion protein rilonacept. These therapies often result in rapid and almost complete control of systemic symptoms and cutaneous manifestations.

Another characteristic feature of Schnitzler's syndrome is the almost obligatory monoclonal gammopathy, usually of the IgM-κ type, more rarely IgG. The pathogenetic significance of these B-cell clones has not yet been conclusively clarified. Both a paraneoplastic activation of the innate immune system and a direct involvement of monoclonal immunoglobulins in the activation of inflammatory signaling pathways have been discussed. Clinically relevant is the observation that some patients develop a lymphoproliferative disease, in particular Waldenström's disease or non-Hodgkin's lymphoma, in the long-term course of the disease.

Genetic studies have been able to detect somatic mosaic mutations in the NLRP3 gene in individual cases, which lead to inflammasome activation and establish a pathogenetic link to cryopyrin-associated periodic syndromes(CAPS). However, these mutations are only found in a minority of patients, so they are not considered a universal mechanism of Schnitzler syndrome.

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).

The diagnosis of Schnitzler syndrome is based on the Strasbourg criteria. Both main criteria as well as at least two secondary criteria for IgM gammopathy and three secondary criteria for IgG gammopathy must be fulfilled.

Main criteria

• Chronic recurrent urticarial exanthema
• Monoclonal gammopathy (usually IgM, more rarely IgG)

Secondary criteria

• Recurrent fever (>38 °C)
• Objective bone remodeling (osteosclerosis) or bone pain
• Neutrophilic dermatitis in the skin biopsy without evidence of leukocytoclastic vasculitis
• Signs of inflammation in the laboratory (CRP elevation and/or leukocytosis)

In most cases, the urticarial rash is the first clinical manifestation and often precedes the systemic symptoms. In a large case series, the median age at onset of exanthema was around 51 years, while the median age at onset of fever was 52 years (de Koning 2014).

• 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.

Treatment of Schnitzler's syndrome is primarily aimed at blocking the interleukin-1 signaling axis. The IL-1 receptor antagonist Anakinra (100 mg daily subcutaneously) is the first choice therapy. In numerous case series, Anakinra leads to rapid and usually complete control of systemic symptoms and cutaneous manifestations within a few hours to days. With continuous therapy, long-term disease control can be achieved over several years. After discontinuation, however, there is often a rapid recurrence of symptoms.

Alternatively, other IL-1-targeted therapies can be used, in particular the monoclonal anti-IL-1β antibody canakinumab and the fusion protein rilonacept, which are also highly effective.

Systemic glucocorticoids can lead to a rapid improvement in symptoms, but are not a suitable long-term therapy due to the side effects and often inadequate disease control and are mainly used as a bridging therapy.

Antihistamines generally have no relevant effect, as the pathogenesis is not that of mast cell-mediated urticaria.

The use of rituximab has been described in individual cases, but shows inconsistent efficacy and is currently not a standard therapy.

As Schnitzler syndrome is typically associated with a monoclonal gammopathy and some patients may develop a lymphoproliferative disease in the course of the disease, regular hematologic follow-up is recommended.

• 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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