Syndrome of idiopathic chronic urticaria and angioedema with thyroid autoimmunity: A study of 90 patients

Syndrome of idiopathic chronic urticaria angioedema with thyroid autoimmunity: study of 90 patients

and A

A. Leznoff, MD, and G. L. Sussman, MD Toronto, Ontario, Canada From a pool of 624 patients with idiopathic chronic urticaria and angioedema, 90 patients had evidence of associated thyroid autoimmunity (TA). Since the number expected by chance alone is 37, given that <6% of normal subjects have TA, the association is significant (p < 0.01; chi-square test). Age and sex distribution was typical of patients with TA. Clinically, most patients suffered relentless and severe urticaria andlor angioedema. With the exception of thyroid function and thyroid antibody tests, other laboratory tests were not rewarding. In most cases, treatment with 1 thyroxine did not improve urticaria or angioedema, but a few patients demonstrated a dramatic response. Awareness of the association resulted in the ident$cation of previously undiagnosed thyroid disease. The authors hypothesize that a subset of idiopathic chronic urticaria and angioedema may be an autoimmune disease. IJ ALLERGYCLIN IMWNOL 1989;84:66-71.)

Urticaria and/or angioedema resulting from welldefined causes, such as allergy to drugs, foods, or insect stings, or to viral infection, is usually acute or subacute. In chronic urticaria (duration longer than 6 weeks), “. . . the rate of successful diagnosis in most studies is probably not greater than 20 percent.“’ In one study, 86 cases of chronic urticaria and angioedema remained idiopathic despite thorough investigation.’ Although the duration and severity of ICUA are quite variable, the pathology consistently reveals vasodilation, edema, and a sparse perivascular infiltration of the upper dermis with mononuclear cells and variably increased numbers of mast cells and eosinophiles.3 The predominant lymphocytes are activated CD4-positive T cells expressing DR surface markers .4 Various hypotheses have been generated to explain the fact that no allergic or other causes are identified in the vast majority of such cases. Poor diagnostic acumen by physicians is often blamed, leading to extensive investigation protocols that are rarely rewarding. Matthews5 hypothesized that some cases may be

From the Divisions of Allergy and Clinical Immunology, St. Michael’s Hospital and Wellesley Hospital, Toronto, Ontario, Canada. Received for publication Sept. 29, 1988. Revised Jan. 5, 1989. Accepted for publication Jan. 27, 1989. Reprint requests:A. Leznoff, MD, St. Michael’s Hospital Annex, 38 Shuter St., Suite 215, Toronto, Ontario, Canada.

66

Abbreviations used

ICUA: TA: TMA: TGA: TSH:

Idiopathic chronic urticaria and angioedema Thyroid autoimmunity Thyroid microsomal antibodies Thyroglobulin antibodies Thyroid-stimulating hormone

due to autoimmunity, and Leznoff et a1.6reported an association of ICUA and TA. In this article, we summarize the clinical and laboratory features of 90 patients with ICUA associated with TA and propose that ICUA may be an autoimmune disease.

DEFINITIONS AND METHODS Urticaria and angioedemawere defined according to the definition of Kaplan.’ If daily outbreakscontinued for longer than 6 weeks, the diseasewas consideredchronic. The disease was defined as severe if it could not be controlled without the use of prednisone, if angioedema was frequent, disfiguring, or dangerous,or if the diseasesignificantly impaired the patient’s ability to function. When ICUA was present for months or years followed by a long asymptomatic interval (6 months to 5 years), which in turn was followed by a second long recurrence, this was called a “skip pattern.” Histologic criteria were those noted by Natbony et al.’ If individual skin lesions persisted longer than 24 hours and regressed, leaving a palpable purpuric, indurated, or atrophic residue, and if a biopsy specimen revealed necrotizing cellular infiltration within the vessel walls, these findings were diagnosed as leukocytoclastic vasculitis and patients were excluded from the study.

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TABLE I. Summary

of patients

TABLE II. Clinical characteristics

with ICUA

624 31* 90+ 7/l n-72 46 6

100% 6‘%* 14%/cf

*Expected number from total pool of 624 patients with ICUA assuming 6% of normal subjectshave TA. ? Associanon of IC1’4 with TA, significant: p < 0.01.

Ninety patients with ICUA and TA were identified in-dependently in the consultation practices of the authors and two hospital clinics. Patients who were first observed with “physical allergies” only were not excluded from the total pool of patients with urticaria studied, but no patients with physical urticaria (except dermographism and delayedpressure urticaria occurring in patients with ICUA) were demonstrated to have TA. Criteria for the diagnosis of TA were a titer of TMA 2 1: 1600, a titer of TGA ~1: 160, a biopsy specimen or needle aspirate of the thyroid gland demonstrating lymphocytic infiltration compatible with autoimmune thyroiditis, or a combination of idiopathic hypothyroidism longer than 5 years duration with a TMA titer 2 1:400. The elevated titers must have been confirmed on at least two tests 3 months apart. Hypothyroidism was diagnosed by clinical criteria and laboratory evidence of 1 thyroxine <50 nmoli L, triiodothyronine radioactive uptake 7 p,U/L; hyperthyroidism was diagnosed by clinical criteria and evidence of 1 thyroxine >142 nmol/L. TMA and TGA were measured by a standardized microtitration hemagglutination test. Antinuclear antibodies were tested by indirect immunofluorescence on frozen sections of mouse kidney. IgG, IgA, and IgM, and complement factors C3 and C4 were measured by radial immunodiffusion, and circulating immune complexes, by the Clq binding method.7 Rheumatoid factor was measured by the latex fixation method on standardized latex particles by the tubedilution method. Hepatitis B surface antigen was measured by radioimmunoassay. Statistical analysis of the frequency of association of ICUA with TA was not performed on patients of A. L. since this was believed to be a biased sample because of previously reported interest in these cases,b but analysis was performed on the cases of author G. L. S. with the chisquare test.

RESULTS From a total of 624 patients with ICUA, there were 90 patients who had evidence of TA. Seventy-eight were female patients with a female: male ratio of 7: 1. Patients ranged in age from 8 to 72 years when the concurrent processes were first identified (Table

Disease

pattern

Urticaria and angioedema Urticaria alone Angioedema alone Skip pattern

67

of patient

with ICUA and TA

and TA Total patients with ICUA Expected number with TA* Actual number with TA F/M ratio Age distribution Treated with 1 thyroxine Remission of ICUA with 1 thyroxine

autoimmunity

__-___

Total patients

Severe ICUA

77

64

10 3 31

3 2 24

Duration of ICUA (yr) -__-___ f

1-2

2

3

l{,

35

-1 0 14

3 I 11

i 3 6

I). Eightly percent were between the ages of 20 and 60 years with almost equal numbers in each decade. Forty-seven patients with ICUA and TA were identified from a total of 336 patients with ICUA of author G. L. S., representing 14% of the total. The prevalence of TA in unselected patients visiting our familypractice clinic was 5.6%,6 whereas Tunbridge et al.” demonstrated 5.3% of normal subjects had elevated titers of TMA. Assuming 6% to be the expected prevalence, the reported association is significant (p < 0.01) with the chi-square test. The clinical characteristics of ICUA in these patients are noted in Table II. Seventy-seven patients had urticaria and angioedema, 10 had urticaria alone, and three patients had angioedema alone. The most characteristic features of the group were the relentless course of the disease with daily urticaria and/or angioedema from 3 months to 19 years, the severity of the urticaria, and the frequent concurrence of angioedema that was often disfiguring but rarely life threatening. Thirty-one patients experienced two or three persistent outbreaks of ICUA lasting months to years. separated by long symptom-free intervals lasting months to years (skip pattern). Response to antihistamines (H, blockers or H, and H, blockers combined), as well as to other therapeutic agents (theophylline, a-agonists, ketotifen, and doxepin), was generally poor despite adequate cutaneous histamine blockade documented by intradermal skin test with histamine. Sixty patients required prednisone at some stage of their disease. Urticaria and/or angioedema was occasionally aggravated by physical factors or acetylsalicylic acid, but all these patients continued to have ICUA in the absence of these stimuli. In 76 patients, strict avoidance of nonsteroidal antiinflammatory agents, dyes, preservatives, natural salicylates, and rigid oligoantigenic diets” for 2 or 3 weeks was not helpful. Forty-six patients were treated with I thyroxine to suppress TA or as replacement therapy. (Selection criteria for treatment with 1 thy-

68

Leznoff

and Sussman

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TABLE III. Other autoimmune “polyendocrine” disease in 90 patients ICUA and TA Disease

CLIN. IMMUNOL. JULY 1989

with

No. of patients

Vitiligo Adrenalitis” Parathyroiditis t Pernicious anemiat t, Diagnosed by histology. *Diagnosed by presence of adrenal antibodies. TMegaloblastic anemia; vitamin B,, levels < 110 pmol/L.

FIG. 1. Numbers of patients with ICUA and with indicated titers of thyroid antibodies. TMA and TGA titers are expressed as reciprocals of actual titers x 100.

roxine were presence of hypothyroidism, the presence of elevated TSH levels, or extremely severe ICUA.) Remission of ICUA occurred within 4 weeks in eight cases. In two cases, ICUA subsequently reappeared despite continued 1 thyroxine, but four of these patients with high thyroid antibody titers demonstrated repeated remissions of ICUA when they were treated with 1 thyroxine, and with recurrence when the hormone was stopped on three separate trials. Three of these four patients had TGA levels >1280. Results of skin biopsy specimens in seven patients were consistent with urticaria. All patients had criteria for TA, as described in Definitions and Methods. The range of antibody titers is noted in Fig. 1. High TMA is much more frequent than high TGA. In addition to serologic evidence of TA, 44 patients had clinical evidence of thryoid disease, as manifested by goiter and/or dysfunction (Fig. 2). Six patients who were euthyroid when they were first studied became hypothyroid during the follow-up period. Biopsy or needle aspiration was attempted in nine patients with thyromegaly, eight of whom demonstrated features compatible with autoimmune thyroiditis.” In 20 of 44 patients with clinical thyroid disease and in 44 of 46 patients with TA, but no clinical disease, the identification of the thyroid (actual or potential) problem derived from the ICUA investigation (Fig. 2). Twelve patients had other diseases in the polyendocrine autoimmune spectrum (Table III). No other chronic or recurring diseases occurring in this group were present with unusual frequency. Several patients complained of arthralgia during severe outbreaks of ICUA, but this was caused

by periarticular swelling, and none had other stigmata of rheumatoid arthritis or raised titers of rheumatoid factor. Hepatitis B surface antigen was not identified in the serum of any of 83 patients. Erythrocyte sedimentation rate was elevated between 20 and 30 mm/hr in 18 patients and was >30 mm/hr in four patients (all of whom had TMA > 1: 25,600). Only two patients demonstrated eosinophilia >500 eosinophils per cubic millimeter. Immunologic and other laboratory testing was unrewarding (Table IV). Complement C3 and C4 were normal in all patients with ICUA, and total hemolytic complement was normal in all 30 patients tested. Clq binding was elevated temporarily in one of 40 patients tested. Cryoglobulins were temporarily elevated in one case, and six patients had a persistent titer of antinuclear antibody between 1: 100 and 1:400 with no other evidence of connective tissue disease. Immunoglobulin analysis was normal except for one patient with IgA deficiency. DISCUSSION Whenever two common medical conditions occur independently, both will be present in a predictable number of patients. Since TA (as defined earlier) occurs in 3% to 6% of normal subject@ *, ” and since ICUA is a common problem, the association of these two diseases in some patients is not surprising. However, in a previous study in which unselected ICUA cases were studied,6 we found 12.1% of patients with ICUA had evidence of TA. In the unselected patients of G. L. S. in this study, TA was present in 14% of cases. This is significant with the chi-square test, p value
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Disease

autoimmunity

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Total Patients m Diagnosed re: ICUAD Previously Diagnosed m

10

Autoimmunity Only

Thyroid Disease

Goiter

Hypothyroid

Hyperthyroid

FIG. 2. Number of patients with ICUA and with TA but no clinical disease any clinical thyroid disease. The three bar graphs on the right indicate indicated thyroid disease. Total numbers of patients in each category are a comparison of the number diagnosed as a consequence of the ICUA number previously diagnosed.

This study reveals a typical clinical profile of patients with ICUA and TA. This profile is not exclusive to this group and is shared by some other patients with ICUA who do not have TA. However, for reasons discussed below, they may share a common pathogenesis. Not surprisingly, the age and sex distribution is what would be expected in TA.‘” The ICUA was usually severe and relentless for months to years. although some patients experienced long disease-free intervals. In contradistinction, a pattern of repeated short sporadic outbreaks of urticaria and angioedema was conspicuous by its absence. Otherwise, the patients did not feel sick. The response to antihistamines was poor, and prednisone was often required. The patients in whom improvement in ICUA appeared to relate to 1 thyroxine treatment were too few to be significant. With the exception of dermographism and delayed-pressure urticaria” occurring in patients with ICUA, none of our patients with physical allergies (cold, heat, cholinergic, or exercise-induced urticaria) had evidence of TA. Except for tests for thyroid antibodies and function, laboratory investigation revealed no consistent abnormality and was not useful in identifying a cause for the ICUA. This study suggests that in patients with ICUA, who fit this profile, routine extensive investigative protocols are not indicated unless they are suggested by specific clinical findings. Thyroid antibody tests and thyroid function tests should be done in all patients (especially female patients) with ICUA. This will result in the diagnosis of existing or potential thyroid diseaseI in some patients.

TABLE IV. Abnormal laboratory

tests

and of patients with numbers with each indicated, as well as investigation versus

results

in other

in 90 patients

with

ICUA

and TA

Test

Antinuclear antibody Rheumatoid factor Cryoglobulins CA C: Clq binding HBs AC ESR Eosinophil

Abnormal range

No. tested

No. abnormal

r1 : 100

16

6

j. I : 60

76

0

> 1: 2

65 76

I 0


16

0

>21% Positive >20 mmihr 1500 x IO”lL

40 83 90 90

I 0 12 2

CO.18 giL

count

H5s Ag, hepatitisB surfaceantigen;ESR, erythrocytesedimentation rate.

We hypothesize that a subgroup of ICUA may be an autoimmune disease of skin and mucous membranes that is associated with TA in the same way as diseases in the polyendocrine autoimmune disease spectrum are associated with TA.“. ” The fact that ICUA is statistically associated with TA is but one evidence in favor of this hypothesis. Additional support is the pathology of ICUA in which the presence of activated CD4-positive T cells“ is consistent with their presence in other organ-specific autoimmune dis-

70 Leznoff and Sussman

ease.16The continued failure by many skilled physicians to identify an allergic or other causein >80% of suchcasesis also suggestiveof the pattern observed in the history of other autoimmune disease.We have not identified the effector antibody, lymphocyte, or the target cell receptor. Possibletargetsaretissuemast cells or the H, receptor on cutaneous blood vessels. TA is the most common of the organ-specific autoimmune processeswith 3% to 6% of the population demonstratingsignificantly raised titers of thyroid antibodies, as defined in Definitions and Methods. (If low titers are considered, a larger number of normal subjectsare positive, but these low titers are not believed to be indicative of TA.) In other autoimmune diseases,thyroid antibodiesare often present,but even if thesethyroid antibodiesarecross-reactivewith other organ-specific antibodies, they do not cause the disease.” Thus, approximately 50% of patients with pernicious anemiaI or 30% of patients with vitiligo19 have TA. If there were no specific immunologic tests for pernicious anemia or vitiligo in patients who are suspectfor these diseases,the presenceof TA would constitute a crude marker for each of these autoimmune illnesses, although it would only identify a fraction of the cases.Similarly, in the absenceof a specific immunologic test to identify the postulated subsetof ICUA, which may be autoimmune, the presenceof TA probably identified only a fraction of the total autoimmune subset. Consequently,it is reasonableto hypothesize that the subset of ICUA, which is (possibly) autoimmune, is >14% identified by the association with TA. There are other possible explanations for the association of TA with ICUA. Since ICUA involves the largest organ of the body and is characterizedby the presenceof activated CD4 T cells in the perivascular tissue, it is possible that these patients continuously produce excess quantities of lymphokines. Therapeutic administration of interferon-y has been demonstrated to induce TA.20 Interleukin-2 plus lymphokine-activated killer cells can induce hypothyroidism.*’ Interleukin-3 plus interleukin-4 promotes mastcell growth,” and histamine-releasingfactor can stimulate basophil histamine release.23Thus, TA and ICUA may be related by nonspecific inflammatory mechanisms.Against this hypothesis is the fact that many patients exhibited TA many years before ICUA developed, whereasother patients with ICUA and TA have a sustainedremission in ICUA with continuation of the thyroid disease.By similar reasoning, ICUA is unlikely to be causedby the TA. Somepatients in our series had undergone subtotal thyroidectomy demonstrating autoimmunethyroiditis on histology but developedICUA many yearslater. Thus, we hypothesize

J. ALLERGY

CLIN. IMMUNOL. JULY 1989

that these are two independent diseasesthat are associated with each other in a manner similar to the association of diseasesin the polyendocrine autoimmune diseasespectrum. Nevertheless,we cannot rule out the possibility that chronic immunologic inflammation in one organ may increase the potential for autoimmunity in anotherorgan or tissue in appropriate genetic setting. Managementof urticaria and angioedemain these patientsis no different than managementin other cases of ICUA except that we recommend, in euthyroid patients, a trial of 1 thyroxine, 0.15 to 0.20 mg/day, for 4 to 8 weeks. Managementof the thyroid disease dependson thyroid function or presenceof symptomatic thyroiditis. In euthyroid patients with TA, tests of thyroid function and TSH should be done annually becausemost patients will ultimately become hypothyroid.13 In all patients with TA, other special endocrine and immunologic tests should be done only if there is clinical evidence of other endocrine or autoimmune disease. SUMMARY Ninety patients with ICUA and TA are described. These patients represent 14% of the pool of patients with ICUA. The associationis significant (p < 0.01). The patients demonstrateda recognizableclinical profile characterizedby severeand relentless disease.In suchpatients, laboratory testsfor TA and thyroid dysfunction may lead to the identification of (potential or actual) thyroid disease,but other investigations should be guided by eachpatient’s clinical findings. Because of the association of ICUA with TA and previously described histologic features, we hypothesize that somesubsetsof ICUA may be an autoimmunedisease. REFERENCES 1. Kaplan AP. Urticaria and angioedema. In: Middleton E Jr, Reed CE, Ellis EF, eds. Allergy: principles and practice, vol 2. 3rd ed. St. Louis: CV Mosby, 1988:1391. 2. QuarantaJ, Rohr AS, Rachelefsky GS, Seigel SC, Katz RM, Spector SL. The etiology and natural history of chronic urticariaiangioedema(U/A) [Abstract]. J ALLERGY CLINIMMIJNOL 1987;79:182. 3. Nabotny SF, Philips ME, Elias JM, Godfrey HP, Kaplan AP. Histologic studies of chronic idiopathic urticaria. J ALLERGY CLINIMMUNOL1983;71:177-83. 4. Mekori YA, Giomo RC, Anderson P, Kohler PF. Lymphocyte subpopulationsin the skin of patients with chronic m&aria. J ALLERGYCLIN IMMUNOL1983;72:681-4. 5. Matthews KP. Exploiting the cold urtica.ria model. N Engl J Med 1981;305:1090-1. 6. Leznoff A, JosseRG, Denburg J, Dolovich J. Association of chronic urticaria and angioedemawith thyroid autoimmunity. Arch Dermatol 1983;119:636-40. 7. Zubler RH, Lambert PH. The ‘=I Clq binding test for detection of soluble circulating immune complexes. In: Bloom BR,

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