What syndromes are associated with Chronic Spontaneous Urticaria (CSU)?

Syndromes Associated with Chronic Spontaneous Urticaria

CSU is associated with both hereditary and acquired autoinflammatory syndromes, as well as autoimmune thyroid disease, which represents the most common comorbid autoimmune condition.

Autoinflammatory Syndromes

Hereditary Autoinflammatory Syndromes

The following hereditary conditions can present with urticaria-like manifestations 1:

• Cryopyrin-associated periodic syndromes (CAPS) - including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID) 1
• Hyper-IgD syndrome (HIDS) 1
• TNF-α-associated periodic syndrome (TRAPS) 1

These hereditary patterns typically present in early childhood with spontaneous wheals, pyrexia, malaise, and other defining features such as renal amyloidosis and sensorineural deafness in Muckle-Wells syndrome 1.

Acquired Autoinflammatory Syndromes

• Schnitzler syndrome - characterized by chronic urticaria with monoclonal gammopathy 1
• Systemic-onset juvenile idiopathic arthritis (sJIA) 1
• Adult-onset Still disease 1

When autoinflammatory syndromes are suspected, test for elevated inflammation markers (C-reactive protein and erythrocyte sedimentation rate), paraproteinemia in adults, look for neutrophil-rich infiltrates on skin biopsy, and perform gene mutation analysis for hereditary periodic fever syndromes 1.

Autoimmune Thyroid Disease

Prevalence and Association

• Thyroid autoimmunity occurs in 14% of CSU patients compared to 6% in population controls 1
• Elevated anti-thyroid peroxidase (anti-TPO) antibodies are found in 51.2% of CSU patients versus only 6% in controls 2
• Anti-thyroglobulin (anti-TG) antibodies are elevated in 41.9% of CSU patients compared to 4% in controls 2
• Hypothyroidism is present in 27.9% of CSU patients versus 4% in controls 2

Clinical Significance

• Anti-TPO positivity predicts longer disease duration, with 100% of anti-TPO-positive patients suffering from CSU for more than 12 months compared to 82.6% of anti-TPO-negative patients 3
• The high ratio of IgG-anti-TPO to total IgE is the best surrogate marker for Type IIb autoimmune CSU 4, 5
• Hashimoto's thyroiditis and hypothyroidism are more common than Graves' disease and hyperthyroidism in CSU patients 6

Ultrasound Findings

• Heterogeneous thyroid structure is observed in 72.1% of CSU patients compared to 14% in controls 2
• Nodular thyroid changes are present in 34.88% of CSU patients versus 6% in controls 2

Other Associated Conditions

Urticarial Vasculitis

• Urticarial vasculitis presents clinically as urticaria but shows small vessel vasculitis on histology 1
• Wheals in urticarial vasculitis typically persist for days rather than the 2-24 hours seen in ordinary CSU 1
• Skin biopsy showing damage to small vessels in the papillary and reticular dermis with fibrinoid deposits distinguishes this from CSU 1

Celiac Disease

• A significantly higher prevalence of celiac disease has been reported in children and adolescents with severe chronic urticaria compared to case-matched controls 1

Diagnostic Pitfalls

• Essential basic testing for all CSU patients should include differential blood count, C-reactive protein/ESR, total IgE, and IgG-anti-TPO levels 4
• The autologous serum skin test has limited clinical relevance for treatment decisions, as omalizumab efficacy is independent of test results, but remains useful for confirming Type IIb autoimmune CSU when combined with other markers 4
• Patients with positive autologous plasma skin test (APST) are more difficult to treat, with 61.2% requiring advanced therapy versus 37.8% of APST-negative patients 3