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Localized granuloma annulare and autoimmune thyroiditis: A new case report
Localized granuloma annulare and autoimmune thyroiditis: A new case report Francisco Vázquez-López, MD, Marcos A. González-López, MD, Cristina Raya-Aguado, MD, and Narciso Pérez-Oliva, MD Oviedo, Spain We present further evidence that granuloma annulare and autoimmune thyroiditis may be associated. Only 11 cases have been previously reported with this association as far as we know. It may be advantageous to consider checking the thyroid-stimulating hormone and/or antithyroid antibodies before administering medications that could affect thyroid function in patients with granuloma annulare. (J Am Acad Dermatol 2000;43:943-5.)
G
ranuloma annulare (GA) has been considered as a cutaneous manifestation of thyroid disease but evidence remains limited.1 We describe a new case of GA associated with autoimmune thyroiditis. To our knowledge, only 12 cases have been documented in the literature, including the case reported herein. Both generalized and localized forms of GA have been described with this association. This case represents the seventh reported example of a localized form according to current classifications.
CASE REPORT A 29-year-old woman was referred to our department in 1996 with a 5-year history of an asymptomatic annular skin lesion on her right foot. She had a medical history of autoimmune thyroiditis (Hashimoto’s disease). The diagnosis had been established 1 year earlier, in 1995, by the usual means: clinically increased thyroid size; elevated thyroid-stimulating hormone (TSH): 22.0 mU/L (range 0.25-4); raised antibody directed against thyroid peroxidase (TPO) levels (3600 UI/mL); antinuclear antibodies, anti-DNA, and antithyroid antibodies were negative; thyroid hormones (free T4, 1.1 ng/dL [range 0.73-2] and free T3, 2.8 pg/mL [range 2.24.2]); and thyroid scintigraphy revealed a homogeThis supplement is made possible through an educational grant from Ortho Dermatological to the American Academy of Dermatology. From the Department of Dermatology, Central University Hospital, University of Oviedo. Reprint requests: Francisco Vázquez-López, C/Ezcurdia 192, 3M, 33203 GIJÓN, SPAIN. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/4/103187 doi:10.1067/mjd.2000.103187
Fig 1. Papules in annular configuration on right foot.
neous uptake. The patient was receiving thyroxine treatment. Any effect on the cutaneous lesions was not reported with this therapy. Dermatologic examination in our department revealed indurated, erythematous papules in an annular configuration around an atrophic center of 5 cm in diameter. The lesions were located on the dorsal aspect of the right foot (Fig 1). No other lesions were present on skin or mucosa. A biopsy specimen showed a large necrobiotic focus on the dermis, surrounded by a palisade of histiocytes and lymphocytes (Fig 2). Direct immunofluorescence study was not performed. GA was diagnosed in the patient. After a topical treatment with clobetasol propionate (0.05%), the skin lesions resolved. One year after, in 1997, a new similar skin lesion of GA (2 cm in diameter) was observed on the right elbow. The patient was then receiving thyroxine therapy, and anti-TPO antibodies were present, although in lower titers (1260 UI/mL). Resolution of 943
944 Vázquez-López et al
J AM ACAD DERMATOL NOVEMBER 2000
Table I. Granuloma annulare and autoimmune thyroiditis Reference
Gross and Shelley8 Willemsen et al9 Moran and Lamb10 Espinel et al11 Vélez et al12 Magro et al5 Dabski and Winkelman6 Studer et al7 Present case
Number of patients
Sex
GA type*
Location
1 1 1 1 1 1 1 3 1 1
F F F F F F F NR NR F
GGA LGA LGA LGA LGA LGA LGA GGA NR LGA
Trunk and others Arms, legs Elbows, hands, knees, ears Foot Elbows, thighs Elbows, wrists Ankle Trunk and others NR Elbow, foot
GGA = Generalized granuloma annulare; LGA = localized granuloma annulare; NR = not reported. *According to current classifications.6,14
the lesion was again achieved with clobetasol. Since then the patient has been receiving thyroxine therapy. New recurrences of cutaneous lesions have not been evidenced to date, although a deterioration of the thyroid state has recently been detected (March 1999), because the patient became pregnant.
DISCUSSION The cause of GA remains obscure. A pathogenetic role has been suggested for the following2-4: (a) humoral and delayed-type hypersensitivity, (b) vascular damage, (c) metabolic disorder or (d) primary collagen and/or elastin alteration mediated through an immunologic mechanism. The association of GA with thyroid disease has been described in the literature but remains to be clarified.1 Several studies found 6% to 13% of patients with GA and thyroid disease but failed to find a definitive correlation.5-7 The association of GA with autoimmune thyroiditis (AT) has been documented in these works and also in case reports.8-12 We present further evidence of this rarely described association. As far as we know, only 11 cases have been previously recorded, both in the generalized form (GGA) and in the localized form (LGA) of GA (Table I). Comparing our case with those reported in the literature (Table I), we would like to emphasize that: (a) all cases detailing the sex of the patients involved were female, as in our case; in this way, it may be worth noting that thyroid autoimmunity associated with chronic urticaria is also much more frequent in females13; (b) according to current classifications,6,14 5 cases presented GGA (defined by more than 10 lesions distributed either on the trunk alone or on the trunk and limbs). Seven cases, including this patient, presented LGA (defined by a single lesion or by the presence of 2 or more lesions localized in 1 or more regions but absent on the
trunk). Several patients, as in our case, had lesions on the elbows, where GA with underlying disorders has been described to be more frequent5; (c) it may also be noteworthy that, including the case presented herein, 3 patients with this association have been described in Spain.11,12 In this way, it has been proposed that the wide variety of results on correlations between GA and metabolic disorders such as diabetes may be due to genetic and social differences in the populations studied.15 The association of GA with diabetes has been extensively researched but still remains controversial at the present time.16 Thus, it is not surprising that further studies are necessary to clarify the significance of the less investigated association of GA with thyroiditis. The association of GA with autoimmune disorders such as autoimmune thyroiditis supports the hypothesis that GA may be secondary to an immune attack. It remains to be established whether the link between these 2 disorders may be based on a common immunogenetic predisposition or whether they could share a common pathogenic pathway. There is no evidence of any cross-reaction of antithyroid antibodies with dermal antigens, and these antibodies are only 1 of several factors required for the development of AT.17 Thus, it seems unlikely that they may represent the main factor causing GA on the skin, and other mechanisms are probably involved. Advances in molecular and immunologic studies may increase our understanding of this. In this way, immune-mediated apoptosis has been implicated in the pathogenesis not only of AT17 but also of other GA-associated autoimmune diseases such as morphea18,19 or diabetes.20 Whether GA may share this or other pathologic changes with these disorders remains to be clarified. The association of GA and AT also has important therapeutic implications. In our opinion, it may be
J AM ACAD DERMATOL VOLUME 43, NUMBER 5
Vázquez-López et al 945
advantageous when treating patients with GA to consider checking a TSH and/or antimicrosomal or antithyroglobulin antibodies before administering medications, such as potassium iodide or interferon, that could affect thyroid function.21,22 REFERENCES 1. Heymann WR. Cutaneous manifestations of thyroid disease. J Am Acad Dermatol 1992;26:885-902. 2. Romero LS, Kantor GR. Eosinophils are not a clue to the pathogenesis of granuloma annulare. Am J Dermatopathol 1998;20: 29-34. 3. Smith MD, Downie JB, DiCostanzo D. Granuloma annulare. Int J Dermatol 1997;36:326-33. 4. Hanna WM, Moreno-Merlo F, Andrighetti L. Granuloma annulare: an elastic tissue disease? Case report and literature review. Ultrastruct Pathol 1999;23:33-8. 5. Magro CM, Crowson AN, Rergauer S. Granuloma annulare and necrobiosis lipoidica tissue reactions as a manifestation of systemic disease. Hum Pathol 1996;27:50-6. 6. Dabsky K, Winkelman RK. Generalized granuloma annulare: clinical and laboratory findings in 100 patients. J Am Acad Dermatol 1989;20:39-47. 7. Studer EM, Calza AM, Saurat JH. Precipitating factors and associated diseases in 84 patients with granuloma annulare: a retrospective study. Dermatology 1996;193:364-8. 8. Gross PR, Shelley WB.The association of generalized granuloma annulare with antithyroid antibodies. Acta Derm Venereol 1971;51:59-62. 9. Willensem MJ, deConinck AL, Jonckheer MH, Roseeuw DI. Autoimmune thyroiditis and generalized granuloma annulare: remission of the skin lesions after thyroxine therapy. Dermatologica 1987;175:239-43. 10. Moran J, Lamb J. Localized granuloma annulare and autoimmune thyroid disease, are they associated? Can Fam Physician 1995;41:2143-4. 11. Espinel Vázquez ML, Esteban Chicharro A. Granuloma anular generalizado y tiroiditis autoinmune. Actas Dermo-Sif 1993;84: 105-6. 12. Vélez García-Nieto A, de la Mata García M, Valverde Blanco F, Fernández Roldán JC, Bancés García-Rovés R. Granuloma anular generalizado en una paciente con enfermedad hepática autoinmune y tiroiditis de Hashimoto. Actas Dermo-Sif 1994; 85:267-9. 13. Heymann WR. Chronic urticaria and angioedema associated with thyroid autoimmunity: review and therapeutic implications. J Am Acad Dermatol 1999;40:229-32. 14. Patrizi A, Meri I, Guerrini V, Marini R, Fiorillo L. Granuloma annulare: clinical and laboratory findings in a pediatric group of patients. Acta Derm Venereol 1996;76:326-8. 15. Veraldi S, Bencini PL, Drudi E, Caputo R. Laboratory abnormalities in granuloma annulare: a case-control study. Br J Dermatol 1997;136:633-4. 16. Gannon TF, Lynch PJ. Absence of carbohydrate intolerance in granuloma annulare. J Am Acad Dermatol 1994;30:662-3.
Fig 2. Histologic appearance of lesion. Large necrobiotic focus on dermis surrounded by palisade of histiocytes and lymphocytes.
17. Arscott PL, Baker JR. Apoptosis and thyroiditis. Clin Immunol Immunopathol 1998;87:207-17. 18. Sgonc R, Gruschwitz MS, Dietrich H, Recheis H, Gershwin ME, Wick G. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest 1996;98:785-92. 19. Ben-Amitai D, Hodak E, Ladipoth M, David M. Coexisting morphoea and granuloma annulare—are the conditions related? Clin Exp Dermatol 1999;24:86-9. 20. Benoist C, Mathis D. Cell death mediators in autoimmune diabetes—no shortage of suspects. Cell 1997;89:1-3. 21. Weiss JM, Muchenberger S, Schopf E, Simon JC. Treatment of granuloma annulare by local injections with low-dose recombinant human interferon gamma. J Am Acad Dermatol 1998; 39:117-9. 22. Caserio RJ, Eaglstein WH, Allen CM. Treatment of granuloma annulare with potassium iodide. J Am Acad Dermatol 1984;10: 294-5.
G
ranuloma annulare (GA) has been considered as a cutaneous manifestation of thyroid disease but evidence remains limited.1 We describe a new case of GA associated with autoimmune thyroiditis. To our knowledge, only 12 cases have been documented in the literature, including the case reported herein. Both generalized and localized forms of GA have been described with this association. This case represents the seventh reported example of a localized form according to current classifications.
CASE REPORT A 29-year-old woman was referred to our department in 1996 with a 5-year history of an asymptomatic annular skin lesion on her right foot. She had a medical history of autoimmune thyroiditis (Hashimoto’s disease). The diagnosis had been established 1 year earlier, in 1995, by the usual means: clinically increased thyroid size; elevated thyroid-stimulating hormone (TSH): 22.0 mU/L (range 0.25-4); raised antibody directed against thyroid peroxidase (TPO) levels (3600 UI/mL); antinuclear antibodies, anti-DNA, and antithyroid antibodies were negative; thyroid hormones (free T4, 1.1 ng/dL [range 0.73-2] and free T3, 2.8 pg/mL [range 2.24.2]); and thyroid scintigraphy revealed a homogeThis supplement is made possible through an educational grant from Ortho Dermatological to the American Academy of Dermatology. From the Department of Dermatology, Central University Hospital, University of Oviedo. Reprint requests: Francisco Vázquez-López, C/Ezcurdia 192, 3M, 33203 GIJÓN, SPAIN. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/4/103187 doi:10.1067/mjd.2000.103187
Fig 1. Papules in annular configuration on right foot.
neous uptake. The patient was receiving thyroxine treatment. Any effect on the cutaneous lesions was not reported with this therapy. Dermatologic examination in our department revealed indurated, erythematous papules in an annular configuration around an atrophic center of 5 cm in diameter. The lesions were located on the dorsal aspect of the right foot (Fig 1). No other lesions were present on skin or mucosa. A biopsy specimen showed a large necrobiotic focus on the dermis, surrounded by a palisade of histiocytes and lymphocytes (Fig 2). Direct immunofluorescence study was not performed. GA was diagnosed in the patient. After a topical treatment with clobetasol propionate (0.05%), the skin lesions resolved. One year after, in 1997, a new similar skin lesion of GA (2 cm in diameter) was observed on the right elbow. The patient was then receiving thyroxine therapy, and anti-TPO antibodies were present, although in lower titers (1260 UI/mL). Resolution of 943
944 Vázquez-López et al
J AM ACAD DERMATOL NOVEMBER 2000
Table I. Granuloma annulare and autoimmune thyroiditis Reference
Gross and Shelley8 Willemsen et al9 Moran and Lamb10 Espinel et al11 Vélez et al12 Magro et al5 Dabski and Winkelman6 Studer et al7 Present case
Number of patients
Sex
GA type*
Location
1 1 1 1 1 1 1 3 1 1
F F F F F F F NR NR F
GGA LGA LGA LGA LGA LGA LGA GGA NR LGA
Trunk and others Arms, legs Elbows, hands, knees, ears Foot Elbows, thighs Elbows, wrists Ankle Trunk and others NR Elbow, foot
GGA = Generalized granuloma annulare; LGA = localized granuloma annulare; NR = not reported. *According to current classifications.6,14
the lesion was again achieved with clobetasol. Since then the patient has been receiving thyroxine therapy. New recurrences of cutaneous lesions have not been evidenced to date, although a deterioration of the thyroid state has recently been detected (March 1999), because the patient became pregnant.
DISCUSSION The cause of GA remains obscure. A pathogenetic role has been suggested for the following2-4: (a) humoral and delayed-type hypersensitivity, (b) vascular damage, (c) metabolic disorder or (d) primary collagen and/or elastin alteration mediated through an immunologic mechanism. The association of GA with thyroid disease has been described in the literature but remains to be clarified.1 Several studies found 6% to 13% of patients with GA and thyroid disease but failed to find a definitive correlation.5-7 The association of GA with autoimmune thyroiditis (AT) has been documented in these works and also in case reports.8-12 We present further evidence of this rarely described association. As far as we know, only 11 cases have been previously recorded, both in the generalized form (GGA) and in the localized form (LGA) of GA (Table I). Comparing our case with those reported in the literature (Table I), we would like to emphasize that: (a) all cases detailing the sex of the patients involved were female, as in our case; in this way, it may be worth noting that thyroid autoimmunity associated with chronic urticaria is also much more frequent in females13; (b) according to current classifications,6,14 5 cases presented GGA (defined by more than 10 lesions distributed either on the trunk alone or on the trunk and limbs). Seven cases, including this patient, presented LGA (defined by a single lesion or by the presence of 2 or more lesions localized in 1 or more regions but absent on the
trunk). Several patients, as in our case, had lesions on the elbows, where GA with underlying disorders has been described to be more frequent5; (c) it may also be noteworthy that, including the case presented herein, 3 patients with this association have been described in Spain.11,12 In this way, it has been proposed that the wide variety of results on correlations between GA and metabolic disorders such as diabetes may be due to genetic and social differences in the populations studied.15 The association of GA with diabetes has been extensively researched but still remains controversial at the present time.16 Thus, it is not surprising that further studies are necessary to clarify the significance of the less investigated association of GA with thyroiditis. The association of GA with autoimmune disorders such as autoimmune thyroiditis supports the hypothesis that GA may be secondary to an immune attack. It remains to be established whether the link between these 2 disorders may be based on a common immunogenetic predisposition or whether they could share a common pathogenic pathway. There is no evidence of any cross-reaction of antithyroid antibodies with dermal antigens, and these antibodies are only 1 of several factors required for the development of AT.17 Thus, it seems unlikely that they may represent the main factor causing GA on the skin, and other mechanisms are probably involved. Advances in molecular and immunologic studies may increase our understanding of this. In this way, immune-mediated apoptosis has been implicated in the pathogenesis not only of AT17 but also of other GA-associated autoimmune diseases such as morphea18,19 or diabetes.20 Whether GA may share this or other pathologic changes with these disorders remains to be clarified. The association of GA and AT also has important therapeutic implications. In our opinion, it may be
J AM ACAD DERMATOL VOLUME 43, NUMBER 5
Vázquez-López et al 945
advantageous when treating patients with GA to consider checking a TSH and/or antimicrosomal or antithyroglobulin antibodies before administering medications, such as potassium iodide or interferon, that could affect thyroid function.21,22 REFERENCES 1. Heymann WR. Cutaneous manifestations of thyroid disease. J Am Acad Dermatol 1992;26:885-902. 2. Romero LS, Kantor GR. Eosinophils are not a clue to the pathogenesis of granuloma annulare. Am J Dermatopathol 1998;20: 29-34. 3. Smith MD, Downie JB, DiCostanzo D. Granuloma annulare. Int J Dermatol 1997;36:326-33. 4. Hanna WM, Moreno-Merlo F, Andrighetti L. Granuloma annulare: an elastic tissue disease? Case report and literature review. Ultrastruct Pathol 1999;23:33-8. 5. Magro CM, Crowson AN, Rergauer S. Granuloma annulare and necrobiosis lipoidica tissue reactions as a manifestation of systemic disease. Hum Pathol 1996;27:50-6. 6. Dabsky K, Winkelman RK. Generalized granuloma annulare: clinical and laboratory findings in 100 patients. J Am Acad Dermatol 1989;20:39-47. 7. Studer EM, Calza AM, Saurat JH. Precipitating factors and associated diseases in 84 patients with granuloma annulare: a retrospective study. Dermatology 1996;193:364-8. 8. Gross PR, Shelley WB.The association of generalized granuloma annulare with antithyroid antibodies. Acta Derm Venereol 1971;51:59-62. 9. Willensem MJ, deConinck AL, Jonckheer MH, Roseeuw DI. Autoimmune thyroiditis and generalized granuloma annulare: remission of the skin lesions after thyroxine therapy. Dermatologica 1987;175:239-43. 10. Moran J, Lamb J. Localized granuloma annulare and autoimmune thyroid disease, are they associated? Can Fam Physician 1995;41:2143-4. 11. Espinel Vázquez ML, Esteban Chicharro A. Granuloma anular generalizado y tiroiditis autoinmune. Actas Dermo-Sif 1993;84: 105-6. 12. Vélez García-Nieto A, de la Mata García M, Valverde Blanco F, Fernández Roldán JC, Bancés García-Rovés R. Granuloma anular generalizado en una paciente con enfermedad hepática autoinmune y tiroiditis de Hashimoto. Actas Dermo-Sif 1994; 85:267-9. 13. Heymann WR. Chronic urticaria and angioedema associated with thyroid autoimmunity: review and therapeutic implications. J Am Acad Dermatol 1999;40:229-32. 14. Patrizi A, Meri I, Guerrini V, Marini R, Fiorillo L. Granuloma annulare: clinical and laboratory findings in a pediatric group of patients. Acta Derm Venereol 1996;76:326-8. 15. Veraldi S, Bencini PL, Drudi E, Caputo R. Laboratory abnormalities in granuloma annulare: a case-control study. Br J Dermatol 1997;136:633-4. 16. Gannon TF, Lynch PJ. Absence of carbohydrate intolerance in granuloma annulare. J Am Acad Dermatol 1994;30:662-3.
Fig 2. Histologic appearance of lesion. Large necrobiotic focus on dermis surrounded by palisade of histiocytes and lymphocytes.
17. Arscott PL, Baker JR. Apoptosis and thyroiditis. Clin Immunol Immunopathol 1998;87:207-17. 18. Sgonc R, Gruschwitz MS, Dietrich H, Recheis H, Gershwin ME, Wick G. Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest 1996;98:785-92. 19. Ben-Amitai D, Hodak E, Ladipoth M, David M. Coexisting morphoea and granuloma annulare—are the conditions related? Clin Exp Dermatol 1999;24:86-9. 20. Benoist C, Mathis D. Cell death mediators in autoimmune diabetes—no shortage of suspects. Cell 1997;89:1-3. 21. Weiss JM, Muchenberger S, Schopf E, Simon JC. Treatment of granuloma annulare by local injections with low-dose recombinant human interferon gamma. J Am Acad Dermatol 1998; 39:117-9. 22. Caserio RJ, Eaglstein WH, Allen CM. Treatment of granuloma annulare with potassium iodide. J Am Acad Dermatol 1984;10: 294-5.