In a patient with chronic urticaria lasting more than six weeks, what is the next diagnostic step to evaluate for an autoimmune basis, including performing an autologous serum skin test (ASST) or autologous serum test (AST) and related protocols?

Autologous Serum Skin Test (ASST) and Diagnostic Protocols in Chronic Urticaria

Role and Clinical Utility of ASST

The autologous serum skin test (ASST) is suggested as an additional screening procedure for diagnosing the auto-reactive form of chronic spontaneous urticaria (CSU), though its clinical relevance is limited since omalizumab efficacy is independent of ASST results. 1

When to Perform ASST

• ASST should be considered in patients with CSU who remain unresponsive to H1 antihistamines, as it helps identify the autoimmune phenotype and may guide treatment selection toward immunosuppressive therapies rather than biologics 1

• The test is particularly useful for determining whether patients have antibodies directed against IgE, FcεRI, or anti-FcεRII, which serve as prognostic markers for treatment outcomes with omalizumab or cyclosporine 1

• ASST positivity correlates with more severe disease, including more frequent attacks, longer duration, higher urticaria activity scores, and increased likelihood of angioedema 2, 3

ASST Testing Protocol

Test Procedure

• The ASST involves intradermal injection of 0.05 mL of the patient's own serum into the volar forearm, with normal saline as a negative control and histamine as a positive control 4, 2

• A positive result is defined as a wheal diameter at least 1.5 mm larger than the negative control at 30 minutes 4

• Physical urticarias must be excluded before performing ASST, as these conditions can cause false-positive results 5

Autologous Plasma Skin Test (APST)

• APST can be performed alongside ASST by injecting the patient's plasma instead of serum, which helps differentiate between serum factors and clotting-related histamine-releasing factors 4, 6

• Combined ASST and APST testing improves diagnostic accuracy, with both tests positive indicating a more severe autoimmune phenotype 4, 6

• Patients with both positive ASST and APST have significantly lower remission rates (46.1% over 2 years) compared to those with negative tests (81.1% remission rate) 6

Comprehensive Diagnostic Workup for Autoimmune CSU

Basic Laboratory Tests (The "7 Cs" Framework)

The diagnostic workup follows the 7 Cs approach: Confirm diagnosis, identify Causes, assess Cofactors, check Comorbidities, evaluate Consequences, assess Components affecting quality of life, and monitor Course of disease 1

Essential Initial Tests

• Differential blood count to assess for eosinophilia and other hematologic abnormalities 1

• C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR) to evaluate for inflammatory or autoinflammatory conditions 1

• Total IgE level - patients with autoimmune CSU typically have low or very low total IgE levels 1

• IgG anti-thyroid peroxidase (anti-TPO) antibodies - elevated levels suggest autoimmune CSU 1

• The ratio of IgG-anti-TPO to total IgE is currently the best surrogate marker for autoimmune CSU, with a high ratio strongly indicating the autoimmune phenotype 1, 7

Advanced Testing for Antihistamine-Refractory Cases

• CU index testing should be obtained in patients unresponsive to H1 antihistamines to determine presence of antibodies against IgE, FcεRI, or anti-FcεRII 1

• Anti-FcεRIα autoantibody testing by ELISA can be performed, with combined anti-FcεRIα assay, ASST, and APST achieving 100% sensitivity and 100% specificity for autoimmune urticaria diagnosis 4

• Basophil histamine release assay (HRA) remains the gold standard for confirming autoimmune urticaria, though it is technically demanding and not widely available 4

Clinical Significance and Treatment Implications

ASST-Positive Patients

• ASST-positive patients have more severe disease with higher urticaria activity scores, more frequent attacks, and greater likelihood of requiring high-dose antihistamines (4-fold standard dose) 2, 3, 6

• The mean wheal diameter of ASST correlates positively with Dermatology Life Quality Index (DLQI), indicating that larger reactions predict greater disease impact 6

• Antithyroid antibody titers and peripheral B-cell percentages are significantly higher in ASST-positive patients (p = 0.04 and 0.004, respectively) 3

• Absolute eosinophil counts and serum IgE concentrations are lower in ASST-positive patients, though not always reaching statistical significance 3

Prognostic Value

• ASST and APST results predict long-term remission rates: negative test patients have 81.1% remission at 2 years versus 46.1% in patients with both positive ASST and APST (odds ratio 5.0, p = 0.006) 6

• Patients with both positive ASST and APST require higher doses of antihistamines (4-fold standard dose) more frequently than those with negative tests (p = 0.0009) 6

Treatment Algorithm Based on Autoimmune Phenotype

For Confirmed Autoimmune CSU (High IgG-anti-TPO/Total IgE Ratio, Positive ASST)

• First-line: Up-dose second-generation H1-antihistamines to 4-fold standard dose 7

• Second-line: Trial omalizumab 300 mg every 4 weeks for up to 6 months, though response rates are poor in the autoimmune phenotype 7

• Third-line (preferred for autoimmune CSU): Cyclosporine up to 5 mg/kg body weight, which demonstrates 65-70% efficacy in patients with positive ASST 7

Common Pitfalls to Avoid

• Do not delay ASST testing until after multiple treatment failures - early identification of the autoimmune phenotype allows for more targeted therapy selection 5

• Do not interpret ASST results in isolation - combine with total IgE, IgG-anti-TPO, and clinical severity assessments for accurate phenotyping 1, 7

• Do not assume ASST-negative patients have "idiopathic" urticaria - approximately 50% of CSU patients are ASST-positive, but negative results do not exclude autoimmune mechanisms 2, 5

• Avoid performing ASST without first excluding physical urticarias, as dermographism and other physical triggers can cause false-positive results 5