Reply to “Is anti-TPO IgG and total IgE clinically useful for the detection of autoimmune chronic spontaneous urticaria”?

We thank Jorge Sanchez and his team for commenting1Sanchez J. Lopez J.F. Alvarez L. Is anti-TPO IgG and total IgE clinically useful for the detection of autoimmune chronic spontaneous urticaria?.J Allergy Clin Immunol Pract. 2022; 10: 1392Abstract Full Text Full Text PDF Scopus (1) Google Scholar on our recent article2Kolkhir P. Kovalkova E. Chernov A. Danilycheva I. Krause K. Sauer M. et al.Autoimmune chronic spontaneous urticaria detection with IgG anti-TPO and total IgE.J Allergy Clin Immunol Pract. 2021; 9: 4138-4146.e8Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar and for performing further analyses on elevated immunoglobulin G (IgG)–anti–thyroid peroxidase (TPO; aTPO) and low total IgE (aTPOhigh/IgElow) for predicting type IIb autoimmune chronic spontaneous urticaria (aiCSU). The IgG antibodies against IgE and its receptor on mast cells and basophils are thought to drive aiCSU, although IgM, IgA, and IgE autoantibodies that target these antigens have also been detected in some patients with aiCSU. The diagnosis of aiCSU is based on 3 positive tests—the autologous serum skin test (autoreactivity), a basophil test (functionality), and immunoassays (quantitative identification of IgG autoantibodies against FcεRl and/or anti-IgE).3Schoepke N. Asero R. Ellrich A. Ferrer M. Gimenez-Arnau A. Grattan C.E.H. et al.Biomarkers and clinical characteristics of autoimmune chronic spontaneous urticaria: results of the PURIST study.Allergy. 2019; 74: 2427-2436Crossref PubMed Scopus (66) Google Scholar Importantly, aiCSU comes with high disease activity, high rates of autoimmune comorbidities, poor quality of life, and poor response to treatment with antihistamines and omalizumab.3Schoepke N. Asero R. Ellrich A. Ferrer M. Gimenez-Arnau A. Grattan C.E.H. et al.Biomarkers and clinical characteristics of autoimmune chronic spontaneous urticaria: results of the PURIST study.Allergy. 2019; 74: 2427-2436Crossref PubMed Scopus (66) Google Scholar, 4Marcelino J. Baumann K. Skov P.S. Pereira Santos M.C. Wyroslak I. Scheffel J. et al.What basophil testing tells us about CSU patients—results of the CORSA study.Front Immunol. 2021; 12742470Crossref PubMed Scopus (3) Google Scholar, 5Gericke J. Metz M. Ohanyan T. Weller K. Altrichter S. Skov P.S. et al.Serum autoreactivity predicts time to response to omalizumab therapy in chronic spontaneous urticaria.J. Allergy Clin. Immunol. 2017; 139: 1059-1061Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar It is, therefore, essential to bring biomarkers and predictors of aiCSU to routine clinical practice. It is also important that these predictors need to be easy to measure and available to all physicians who treat patients with chronic spontaneous urticaria (CSU). In addition to aTPOhigh/IgElow, other markers that are widely available have been linked to aiCSU including basopenia and eosinopenia.2Kolkhir P. Kovalkova E. Chernov A. Danilycheva I. Krause K. Sauer M. et al.Autoimmune chronic spontaneous urticaria detection with IgG anti-TPO and total IgE.J Allergy Clin Immunol Pract. 2021; 9: 4138-4146.e8Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar,4Marcelino J. Baumann K. Skov P.S. Pereira Santos M.C. Wyroslak I. Scheffel J. et al.What basophil testing tells us about CSU patients—results of the CORSA study.Front Immunol. 2021; 12742470Crossref PubMed Scopus (3) Google Scholar,6Kolkhir P. Church M.K. Altrichter S. Skov P.S. Hawro T. Frischbutter S. et al.Eosinopenia, in chronic spontaneous urticaria, is associated with high disease activity, autoimmunity, and poor response to treatment.J Allergy Clin Immunol Pract. 2020; 8: 318-325.e5Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar,7Sauer M. Scheffel J. Frischbutter S. Kolkhir P. Xiang Y.-K. Siebenhaar F. et al.Lower IgA levels in chronic spontaneous urticaria are associated with lower IgE levels and autoimmunity.Front Immunol. 2021; 12657211Crossref Scopus (5) Google Scholar We fully agree with the notion that the clinical utility of proposed predictors such as the combined use of aTPO and IgE needs to be further evaluated and that the accuracy of this and other biomarkers for CSU including predictors of aiCSU requires confirmation. Indeed, we ended our recent article2Kolkhir P. Kovalkova E. Chernov A. Danilycheva I. Krause K. Sauer M. et al.Autoimmune chronic spontaneous urticaria detection with IgG anti-TPO and total IgE.J Allergy Clin Immunol Pract. 2021; 9: 4138-4146.e8Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar by calling for studies that “better define the strength of the association between aTPOhigh/IgElow and aiCSU-defining tests, and the predictive values, sensitivity, and specificity of the former to predict the latter.” Furthermore, other factors that may increase the diagnostic accuracy of aTPOhigh/IgElow, for example, different cut-off values and/or combination with additional autoimmunity-related markers (eg, basopenia) have to be investigated in further studies (Table I). For example, the component-resolved screening for autoimmune chronic spontaneous urticaria study4Marcelino J. Baumann K. Skov P.S. Pereira Santos M.C. Wyroslak I. Scheffel J. et al.What basophil testing tells us about CSU patients—results of the CORSA study.Front Immunol. 2021; 12742470Crossref PubMed Scopus (3) Google Scholar recently investigated a different cut-off value for total IgE (<30 U/mL). Finally, we measured IgE and aTPO levels only at 1 time point, although they can change over time, and this should also be taken into account in upcoming studies.Table IEmerging features and markers of autoimmune chronic spontaneous urticaria diagnosed based on basophil testing (BAT and/or BHRA)∗Basophil testing is the best stand-alone approach for diagnosing autoimmune CSU. It should be performed where available.Features/markersaiCSUReferencesAngioedemaOften2,4Nocturnal symptomsOften4Symptoms for > 5 d/wkOften4Disease activity (UAS7)High2-4Quality of life (DLQI)Low4Disease control (UCT)Low4Response to omalizumabSlow and/or poor5Total IgELow3,4,7IgG-anti-TPOHigh3,4Total IgALow7Blood basophil countsLow3,6Blood eosinophil countsLow6BAT, basophil activation test; BHRA, basophil histamine release assay; DLQI, dermatology life quality index; UAS7, urticaria activity score for 7 consecutive days; UCT, urticaria control test.∗ Basophil testing is the best stand-alone approach for diagnosing autoimmune CSU. It should be performed where available. Open table in a new tab BAT, basophil activation test; BHRA, basophil histamine release assay; DLQI, dermatology life quality index; UAS7, urticaria activity score for 7 consecutive days; UCT, urticaria control test. Here, we double down on our call for further studies. We invite Jorge Sanchez and his team as well as all Urticaria Centers of Reference and Excellence (UCAREs) to help with this effort. The validation of biomarkers is a global task and requires large numbers of samples derived from a diverse population of patients. The UCARE network can help to achieve this goal. To this end, we set up, on the UCARE Website (www.ga2len-ucare.com), a call for all UCAREs to participate in the CU-TIGER project (the characterization of urticaria markers including anti-TPO and IgE in serum). We encourage participation in this UCARE project. Our combined efforts to establish predictors of aiCSU will improve the management of this difficult to treat CSU subtype in clinical practice. Is anti-TPO IgG and total IgE clinically useful for the detection of autoimmune chronic spontaneous urticaria?The Journal of Allergy and Clinical Immunology: In PracticeVol. 10Issue 5PreviewRecently, Kolkhir et al1 published an interesting study regarding how high anti– thyroid peroxidase (aTPO) immunoglobulin G (IgG) and low total IgE combined (aTPOhigh/IgElow) are linked to features of type IIb autoimmune chronic spontaneous urticaria (aiCSU). In the study's conclusion, they highlight that aTPOhigh/IgElow is a useful diagnostic marker for identifying patients with aiCSU in clinical practice. These results are in line with the current recommendation given by the European Urticaria guidelines. Full-Text PDF