What is the role of immunoglobulins (IgE and IgG) in the pathogenesis and management of urticaria?

Role of Immunoglobulins in Urticaria

Immunoglobulins play dual pathogenic roles in chronic spontaneous urticaria (CSU): IgE autoantibodies drive autoallergic mechanisms while IgG autoantibodies (particularly IgG1 and IgG3) mediate autoimmune mast cell activation, and measuring total IgE and IgG-anti-TPO levels is now recommended in the diagnostic workup to distinguish these endotypes and predict treatment responses.

Pathogenic Mechanisms

IgE-Mediated Autoallergic CSU (Type I Autoimmune)

• IgE autoantibodies target self-antigens including the high-affinity IgE receptor (FcεRI) itself, making it function as an autoallergen in CSU pathogenesis 1.
• More than 50% of CSU patients demonstrate IgE autoantibodies to FcεRI, with significantly higher levels compared to healthy controls 2, 3.
• IgE autoantibodies can also target thyroid antigens (thyroglobulin), tissue factor, and other autoantigens, triggering mast cell degranulation 2, 4.

IgG-Mediated Autoimmune CSU (Type IIb)

• IgG autoantibodies (35-40% of CSU patients) target the α-subunit of FcεRI, with an additional 5-10% having IgG antibodies against IgE itself 5.
• The pathogenic IgG subclasses are IgG1, IgG3, and to a lesser degree IgG4, but not IgG2 1, 6.
• These autoantibodies activate complement (particularly C5a release), which augments histamine secretion from mast cells and basophils 5, 6.

Co-Occurrence of Both Mechanisms

• More than 50% of CSU patients have simultaneous IgE and IgG autoantibodies to the same autoantigens, particularly in patients who respond slowly to treatment 2.
• The co-existence of anti-FcεRI IgG and IgE autoantibodies occurs predominantly in late-responders and non-responders to omalizumab, never in early responders 3.

Diagnostic Utility

Recommended Basic Testing

The 2022 international urticaria guidelines now recommend measuring total IgE and IgG-anti-TPO levels as part of the basic diagnostic workup for all CSU patients 1.

Total IgE as a Biomarker

• Low or very low total IgE levels (≤43.8 IU/mL) suggest Type IIb autoimmune CSU and predict poor response to omalizumab but better response to cyclosporine 7, 8.
• High total IgE levels indicate higher disease activity, longer disease duration, and better response to omalizumab 7.
• The ratio of IgG-anti-TPO to total IgE is currently the best surrogate marker for autoimmune CSU, with high ratios indicating autoimmune mechanisms 1.

Additional Testing for Refractory Cases

• In patients not responsive to H1-antihistamines, obtain a CU index to detect antibodies against IgE, FcεRI, or FcεRII 1.
• These biomarkers predict treatment outcomes with omalizumab or immunosuppressants like cyclosporine 1.
• The autologous serum test can identify auto-reactive disease, though its clinical relevance is limited since omalizumab efficacy is independent of this test result 1.

Treatment Implications

Omalizumab (Anti-IgE Therapy)

• Start with 300 mg every 4 weeks as second-line treatment after inadequate response to antihistamines 1.
• Patients with high total IgE respond quickly to omalizumab, while those with low IgE and high IgG-anti-TPO respond poorly or slowly 7, 8.
• For insufficient response, updose to a maximum of 600 mg every 2 weeks, allowing up to 6 months for response 1.
• The mechanism involves reducing free IgE, downregulating FcεRI expression on mast cells and basophils, and neutralizing IgE autoantibodies 4, 9.

Cyclosporine for Autoimmune CSU

• Consider cyclosporine as third-line therapy for patients who fail high-dose omalizumab, particularly those with low total IgE and elevated IgG-anti-TPO suggesting Type IIb autoimmune CSU 1.
• Dose up to 5 mg/kg body weight, with monitoring of blood pressure and renal function (BUN, creatinine) every 6 weeks 1.

Clinical Pitfalls

• Do not rely on binding assays alone (ELISA, immunoblot) to identify pathogenic autoantibodies, as nonfunctional antibodies can bind without causing histamine release 6.
• Patients with autoimmune disease and CSU typically present as middle-aged women with basopenia, eosinopenia, elevated ESR, positive antinuclear antibodies, and positive autologous serum skin test 8.
• The co-occurrence of IgE and IgG autoantibodies to the same antigen explains slower treatment responses and should prompt consideration of combination or alternative therapies 2, 3.