Title: Antithyroid antibodies in chronic urticaria and angioedema
Abstract: Chronic urticaria (CU) was a cutaneous disease of unknown origin until the past decade, during which a subpopulation comprising approximately 35% to 45% of patients was found to show evidence of an autoimmune disorder. At least 35% of patients with CU have an IgG antibody directed to the α subunit of the IgE receptor,1Hide M Francis DM Grattan CEH Hakimi J Kochan JP Greaves MW Autoantibodies against the high affinity IgE receptor as a cause of histamine release in chronic urticaria.N Engl J Med. 1993; 328: 1599-1604Crossref PubMed Scopus (799) Google Scholar, 2Fiebiger E Maurer D Holub H Reininger B Hartmann G Woisetschlager M et al.Serum IgG autoantibodies directed against the α chain of FcϵRI: a selective marker and pathogenic factor for a distinct subset of chronic urticaria patients.J Clin Invest. 1995; 96: 2606-2612Crossref PubMed Scopus (289) Google Scholar whereas an additional 5% to 10% of patients have anti-IgE that is functional.3Gruber BL Baeza M Marchese M Agnella V Kaplan AP Prevalence and functional role of anti-IgE autoantibodies in urticaria syndromes.J Invest Dermatol. 1988; 90: 213-217Abstract Full Text PDF PubMed Google Scholar These antibodies cross-link the IgE receptor to cause mast cell degranulation. Fixation of complement and liberation of C5a augments leads to further mast cell activation and histamine release4Ferrer M Nakazawa K Kaplan AP Complement dependence of histamine release in chronic urticaria.J Allergy Clin Immunol. 1999; 104: 169-172Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 5Kikuchi Y Kaplan AP Mechanisms of autoimmune activation of basophils in chronic urticaria.J Allergy Clin Immunol. 2001; 107: 1056-1062Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar by interaction with the C5a receptor.6Kikuchi Y Kaplan AP A role for C5a in augmenting IgG-dependent histamine release from basophils in chronic urticaria.J Allergy Clin Immunol. 2002; 109: 114-118Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar A cellular infiltrate with characteristics of a combined TH1 or TH2 (or THO) response results, with a perivascular distribution. The first indications that CU might have an autoimmune origin were noted by Leznoff et al,7Leznoff A Josse RG Denberg J Dolovich J Association of chronic urticaria and angioedema with thyroid autoimmunity.Arch Dermatol. 1983; 119: 636-640Crossref PubMed Scopus (241) Google Scholar, 8Leznoff A Sussman FL Syndrome of idiopathic chronic urticaria and angioedema with thyroid autoimmunity: a study of 90 patients.J Allergy Clin Immunol. 1989; 84: 66-71Abstract Full Text PDF PubMed Scopus (326) Google Scholar who suggested that there is an increased incidence of antithyroid antibodies (antimicrosomal and antithyroglobulin) in such patients, the estimate being 12% to 15%. It is not clear, however, whether antithyroid antibodies segregate with antibodies to the IgE receptor or whether patients who remain "idiopathic" rather than autoimmune also have antithyroid antibodies. In this brief report, we have prospectively assessed 282 patients with CU for antibody to the IgE receptor, as assessed by histamine release from human basophils10Bjoro T Holmen J Kruger O Midthjell K Hunstad K Schreiner T et al.Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase antibodies in a large, unselected population. The Health Study of Nord-Trondelag (HUNT).Eur J Endocrinol. 2000; 143: 639-647Crossref PubMed Scopus (364) Google Scholar and antithyroid antibodies by commercial assay. The percent positive for anti-thyroglobulin antibody was 8.5% (24 patients), and the percent positive for antimicrosomal antibody was 16.6% (47 patients); 5.7% (16 patients) had both antibodies. The percentage positive for histamine release from basophils (positive >15% release) was 51%. We next divided patients into those who were positive or negative for anti-IgE receptor and determined the percentages positive or negative for antithyroid antibodies (Table I). Table IRelationship of antithyroid antibodies to anti–IgE receptor antibodyAntithyroid (+)Antithyroid (–)TotalHistamine release (+)40 (27.7%)104 (72.3%)144Histamine release (−)15 (10.9%)123 (89.1%)138Totals55227282P < .001 (χ2). Open table in a new tab For this assessment, a patient was considered positive if either antibody was present or if both were present; there were 55 such patients. P < .001 (χ2). The results indicate that antithyroid antibodies clearly segregate with the presence of antibodies to the IgE receptor (or to IgE). However, there is not an absolute concordance between them. At least 80% of patients lack antithyroid antibodies, regardless of whether they are considered autoimmune. On the other hand, the incidence of antithyroid antibodies in the population at large is reported to be between 5% and 10%,9Ajjan RA Weetman AP Autoimmune thyroid disease, Addison disease, and autoimmune polyglandular syndromes.in: Samter's immunologic diseases. Vol. II. Lippincott, Williams and Wilkins, Philadelphia2001: 605-626Google Scholar which is not too dissimilar from the 10.9% (15 patients) who lacked evidence of autoimmune CU. In another prospective study, the incidence of antiperoxidase antibodies was 13.9% in female patients and 2.8% in male patients.10Bjoro T Holmen J Kruger O Midthjell K Hunstad K Schreiner T et al.Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase antibodies in a large, unselected population. The Health Study of Nord-Trondelag (HUNT).Eur J Endocrinol. 2000; 143: 639-647Crossref PubMed Scopus (364) Google Scholar Our patients have a female-to-male ratio of 2 to 1. Hashimoto's thyroiditis has an increased incidence in other autoimmune diseases, including autoimmune polyendocrinopathy and systemic lupus erythematosus. Although there remains controversy regarding any efficacy of thyroid hormone in the treatment of CU, there is no evidence that thyroid hormone affects any of the aforementioned autoimmune disorders, and it seems more likely that antithyroid antibodies and antibody to the IgE receptor are associated immune abnormalities than that one causes the other. Our data reinforce the association of antithyroid antibodies with antibodies to the IgE receptor. Furthermore, we have considered the possibility that those patients who are currently termed "idiopathic" have some different autoimmune mechanism. However, thus far there has been no serologic evidence to support this possibility, inasmuch as such patients do not have an increased incidence of antithyroid antibodies and, by definition, lack anti-IgE receptor or functional anti-IgE.