Etiology, Diagnosis, and Therapeutic Management of Granuloma Annulare

An Update

Laura A. Thornsberry; Joseph C. EnglishIII


Am J Clin Dermatol. 2013;14(4):279-290. 

In This Article

3 Etiology and Disease Associations

The etiology of GA remains unknown. On the basis of the histological features, a delayed-type hypersensitivity reaction is favored.[15] In 2000, Fayyazi et al.[15] investigated the roles of cytokines and matrix metalloproteinases (MMPs) in GA, concluding that the expression of tumor necrosis factor alpha, MMP2, and MMP9 by activated macrophages leads to matrix degeneration. Mempel et al.[16] studied GA biopsies and reported increased production of interleukin-2, favoring a T-helper 1 cell-mediated process. Hanna et al.[17] demonstrated elastic fiber degeneration with electron microscopy to suggest that the elastic tissue may be targeted in GA. In 1978, generalized GA was associated with the HLA-Bw35 allele;[18] however, more recent genetic associations have not been reported other than a report of GA presenting in a set of identical twins.[19]

Several systemic associations have been reported with generalized GA (including generalized annular, disseminated papular, and atypical GA), including DM, malignancy, thyroid disease, lipid abnormalities, human immunodeficiency virus (HIV), hepatitis B, hepatitis C, and rheumatoid arthritis.[20–22] GA has been reported twice following administration of the bacille Calmette–Guérin (BCG) vaccination.[23,24] Other potential triggering factors include insect bites or other trauma[3] and herpes zoster.[25]

There have been conflicting reports about the association between GA and DM. In 2002, a case–control study of 126 patients failed to find an association between the two.[26] Additionally, a 2001 study of pediatric patients with subcutaneous GA did not show an increased incidence of DM.[27] Contrarily, there has been a case report in the pediatric literature of GA as a presenting sign of type 1 DM,[28] and in a 2009 retrospective Korean study, the prevalence of DM was higher (4 out of 54 patients) than in the general population of Korea.[5]

Granuloma annulare has been reported in the setting of malignancy numerous times, including lung adenocarcinoma,[29] cervical cancer,[30] prostate cancer,[31] breast cancer,[32] mycosis fungoides,[33] Hodgkin lymphoma,[34–37] non-Hodgkin lymphoma,[38–40] and chronic myelomonocytic leukemia.[41] In 2003, Li et al.[29] reviewed 16 cases of malignancy and GA and concluded that screening for underlying malignancy can be considered in older patients or patients with atypical GA, although their review did not find a relationship between malignancy and GA. An evidence-based review of GA and malignancy in 2010 by Hawryluk et al.[42] did not support a causal relationship on the basis of a review of 14 case reports, two correlation studies, and one retrospective study. In patients with generalized, disseminated, atypical, or recalcitrant GA, a thorough review of systems and a physical examination including lymph node palpation can be used to help differentiate patients that may require further laboratory or imaging examinations.

There have been three case reports[43–45] and one case–control study[46] of patients with localized GA and autoimmune thyroiditis. The case–control study showed three out of 24 women with localized GA and autoimmune thyroiditis versus one woman out of 100 patients in the control group.[46] In a retrospective review of 32 patients with long-term follow-up (mean follow-up time of 35 years), five patients had developed thyroid disorders, but more detailed information is not available.[47] Given the increased incidence of thyroid disease in localized GA, screening for underlying thyroid disease with thyroid function tests can be considered, and thyroid palpation can be performed to evaluate for structural abnormalities.

Recently, a case–control study suggested an association between dyslipidemia and generalized GA, with 79.3 % of GA patients and 51.9 % of control patients having dyslipidemia.[48] These two groups had statistically significant differences in total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels.[48] The clinical significance of this remains unclear, but a lipid panel can be considered in patients with generalized GA, especially if they have other risk factors for dyslipidemia.

The role of infection, such as Borrelia,[49] hepatitis B,[50] hepatitis C,[51] or HIV,[52,53] in the pathogenesis of GA has been considered, and although GA can represent a reaction to a systemic infection, GA remains a non-infectious process. Recently, the biopsies of ten patients were closely examined using molecular studies, cultures, in addition to patient serologies, and all of the samples were negative for any evidence of infection.[54]

Finally, drug-induced GA has also been reported, most commonly with biologic therapies, some of which have also been reported as effective treatments for GA.[55] A study of 199 patients on biologic agents for rheumatoid arthritis reported nine patients that developed GA (two patients on infliximab, six on adalimumab, and one on etanercept).[56] In a patient with rheumatoid arthritis on adalimumab, GA developed and then cleared when the medication was stopped, then redeveloped when started on etanercept.[57] Finally, drug-induced GA has been reported with the use of intranasal calcitonin, amlodipine, allopurinol, diclofenac, and intramuscular gold.[58,59] If a drug-related dermatitis is suspected, careful examination of the timing of the start of the medication and onset of skin lesions should be analyzed.