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SynopsisSchnitzler syndrome is a rare autoinflammatory disorder associated with immunoglobulin M (IgM) or, less frequently, IgG monoclonal gammopathy. Schnitzler syndrome typically manifests with an urticarial eruption, intermittent fever, arthralgias, myalgias, and bone pain in around 40% of patients. Other manifestations include angioedema, lymphadenopathy, and hepatosplenomegaly. There is slight male predominance, and onset occurs on average early in the sixth decade. Due to the rarity of this condition (approximately 300 cases reported worldwide), the diagnosis is often delayed for years.
The pathogenesis of Schnitzler syndrome remains unclear, although it is thought to be an acquired autoinflammatory disorder in which increased interleukin (IL)-1b and IL-6 leads to loss of anti-inflammatory Th17 cell properties. The role of the paraprotein is unknown, although increased IL-1 stimulation could contribute to IgM paraproteinemia.
Schnitzler syndrome may progress to Waldenström macroglobulinemia or other lymphoproliferative disorders. Waldenström disease is the most common complication, occurring in 15% of cases after 10-20 years of symptom onset. As with several other autoinflammatory conditions, ongoing inflammation leads to production of hepatic acute phase reactants, including serum amyloid A protein, which can lead to AA amyloidosis. Overall prognosis depends on whether this progression to hematologic dyscrasia or secondary amyloidosis occurs.
D47.2 – Monoclonal gammopathy
402415001 – Schnitzler syndrome
Differential Diagnosis & Pitfalls
- Adult-onset Still disease (AOSD) – Both Schnitzler syndrome and AOSD are characterized by urticarial rash, fever, joint pain, and leukocytosis. Distinguishing features of AOSD include elevated ferritin levels, increased transaminases, and pharyngitis.
- Rheumatoid arthritis – Positive anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor; elevated inflammatory markers erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP); synovitis on examination with pain, swelling, and warmth of small joints of the fingers, wrists, and ankles; morning stiffness lasting more than 1 hour that improves with activity.
- Cryopyrin-associated periodic syndrome – A spectrum of rare autoinflammatory genetic diseases involving the cryopyrin protein.
- Urticarial vasculitis – Presents similarly to Schnitzler syndrome with rash, fever, and joint pain. Decreased levels of complement as a result of increased consumption and anti-C1q antibodies are present in urticarial vasculitis but not in Schnitzler syndrome. Unlike true vasculitides, skin biopsy in Schnitzler syndrome will not show fibrinoid necrosis.
- Cryoglobulinemic vasculitis – Low complement values and presence of cryoglobulins causing systemic effects such as skin and renal disease; associated with hepatitis C, malignancy, or autoimmune condition.
- Systemic lupus erythematosus – SOAP BRAIN MD mnemonic (serositis, oral ulcers, arthritis, photosensitivity, blood disorders, renal involvement, antinuclear antibodies, immunologic phenomena, neurologic disorder, malar rash, discoid rash); must fulfill 4 of 11 of criteria according to the American College of Rheumatology.
- Chronic idiopathic urticaria
- Monoclonal gammopathy of undetermined significance (MGUS) – Clinically does not cause signs or symptoms; usually affects elderly patients with peak age older than 85 years.