Is chronic urticaria an autoimmune disease?

Is Chronic Urticaria an Autoimmune Disease?

Chronic spontaneous urticaria (CSU) has an autoimmune mechanism in approximately 50% or more of cases, primarily driven by autoantibodies against the high-affinity IgE receptor (FcεRI), making it an autoimmune disease in a substantial subset of patients rather than a uniformly autoimmune condition. 1, 2

Understanding the Autoimmune Subset

The evidence strongly supports that CSU exists along a spectrum:

• Over half of chronic idiopathic urticaria cases occur through autoimmune mechanisms, specifically through autoantibodies targeting the FcεRI receptor on mast cells and basophils 1, 2
• The remaining cases involve non-autoimmune mechanisms including nonimmunological mast cell degranulation, physical triggers, or truly idiopathic pathways 3
• Thyroid autoimmunity occurs in 14% of CSU patients versus only 6% in population controls, demonstrating a clear autoimmune association 3

Strong Population-Level Evidence for Autoimmune Links

Large-scale epidemiological data confirms the autoimmune connection:

• A study of 12,778 CSU patients showed significantly increased odds ratios for multiple autoimmune diseases including hypothyroidism, hyperthyroidism, and antithyroid antibodies 4
• Female CSU patients have significantly higher incidence of rheumatoid arthritis, Sjögren syndrome, celiac disease, type 1 diabetes, and systemic lupus erythematosus, with most diagnosed within 10 years after CSU diagnosis 4
• Autoantibodies (rheumatoid factor, antinuclear antibodies) and inflammatory markers (high mean platelet volume) are significantly more prevalent in CSU patients, supporting a chronic autoimmune inflammatory process 4

Clinical Implications for Identifying Autoimmune CSU

The most practical approach to identifying autoimmune CSU involves measuring the IgG-anti-TPO to total IgE ratio, which serves as the best surrogate marker for Type IIb autoimmune CSU 5, 6:

• High IgG-anti-TPO to total IgE ratio indicates autoimmune (non-histaminergic) CSU 5, 6
• Elevated IgG-anti-TPO levels alone suggest autoimmune pathogenesis 6
• Failure to respond to standard or updosed H1-antihistamines strongly suggests non-histaminergic autoimmune CSU 6

Treatment Implications Based on Autoimmune Status

For Type IIb autoimmune CSU (high IgG-anti-TPO to total IgE ratio), advance earlier to cyclosporine rather than prolonged omalizumab trials, as this population responds poorly to antihistamines and omalizumab but responds well to cyclosporine 5

• Histaminergic (non-autoimmune) responders should progress through antihistamine updosing and potentially omalizumab 6
• Non-histaminergic (autoimmune) responders require earlier advancement to cyclosporine or omalizumab, with cyclosporine being particularly effective 6

Critical Distinctions from Other Syndromes

Be aware that CSU must be distinguished from:

• Autoinflammatory syndromes (CAPS, Schnitzler syndrome) which require IL-1 inhibitors, not antihistamines or omalizumab, as the mechanism involves interleukin-1 rather than histamine 5
• Urticarial vasculitis where wheals persist >24 hours (versus 2-24 hours in ordinary urticaria) and skin biopsy shows small vessel vasculitis 3, 5

Common Pitfalls to Avoid

• Do not assume all CSU is autoimmune—approximately 50% have autoimmune mechanisms while the remainder have other etiologies 1, 2
• Do not overlook screening for associated autoimmune diseases, particularly thyroid disease, which has major implications for morbidity and quality of life 3, 4
• Do not continue prolonged antihistamine trials in patients with high IgG-anti-TPO to total IgE ratios—these patients need immunosuppressive therapy 5