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    Drugs & Diseases>Dermatology

    Granuloma Annulare

    Updated: Feb 07, 2025
    • Author: Ruby Ghadially, MBChB, FRCP(C)Derm; Chief Editor: William D James, MD  more...
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    Overview

    Background

    Granuloma annulare (GA) is a benign inflammatory dermatosis. It is a relatively common disease that occurs in all age groups, though it is rare in infancy. [1, 2] Clinically, GA is characterized by dermal papules and annular plaques (see the image below). The precise cause is unknown. Histologic examination reveals foci of degenerative collagen associated with palisaded granulomatous inflammation.

    Granuloma annulare. Image from Mierlo at English WGranuloma annulare. Image from Mierlo at English Wikipedia via Wikimedia Commons. Public domain.

    The following clinical variants are recognized:

    • Localized GA (the most common form) - This form has a predilection for the feet, ankles, lower limbs, and wrists; it is characterized by skin-colored to violaceous lesions up to 5 cm in diameter; usually, the epidermis has attenuated surface markings; annular rings with solitary firm papules or nodules may be present
    • Generalized GA (predominantly occurring in adults) - This form usually involves the trunk, as well as the neck, extremities, face, scalp, palms, and soles; lesions range from widespread papules to annular plaques to large discolored patches exhibiting a range of coloration from yellow to violaceous
    • Subcutaneous GA [3]  (predominantly occurring in children) - This form is characterized by firm or hard asymptomatic nodules in the deep dermis or subcutaneous tissues, with individual lesions measuring from 5 mm to 4 cm in diameter; lesions are prevalent on the anterotibial plateau, ankles, dorsal feet, buttocks, hands, scalp, and eyelids
    • Perforating GA [4]  (very rare) - This form is usually localized to the dorsal hands and fingers but may sometimes be generalized on the trunk and extremities; various superficial umbilicated papules develop, with or without a discharge, that heal with scarring
    • Arcuate dermal erythema (uncommon) - This form manifests as infiltrated erythematous patches that may form large hyperpigmented rings with central clearing

    Some authorities have considered actinic granuloma (AG) to be a subset of GA, but it is now commonly viewed as a separate but related entity. [5]

    Next: Pathophysiology

    Pathophysiology

    Proposed pathogenic mechanisms for GA have included cell-mediated immunity (type IV), immune complex vasculitis, and an abnormality of tissue monocytes. Other possible mechanisms have included primary degeneration of connective tissue leading to granulomatous inflammation, lymphocyte-mediated immune reaction with macrophage activation, and cytokine-mediated degradation of connective tissue. [1]

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    Etiology

    The etiology of GA has not been defined, and the pathogenetic mechanisms are poorly understood, with the vast majority of cases occurring in patients who are otherwise healthy. The range of predisposing events and associated diseases is diverse, and GA is thought to represent a reaction pattern with many different initiating factors. [1]

    GA has been hypothesized to be associated with tuberculosis, insect bites, trauma, sun exposure, thyroiditis, vaccinations, and viral infections (eg, HIV, Epstein-Barr virus [EBV], hepatitis B virus [HBV], hepatitis C virus [HCV], and herpes zoster virus [HZV]). However, these suggested etiologic factors remain unproven as causes.

    Familial cases of GA observed in identical twins and siblings in several generations, along with an association of GA with human leukocyte antigen (HLA) phenotypes, have suggested the possibility of a hereditary component in some cases. The HLA-B8 level has been reported to be increased in localized GA; HLA-A29 and HLA-BW35 levels have been reported to be increased in generalized GA.

    Some reports have suggested that chronic stress may be a trigger of GA. GA also has some predilection for sun-exposed areas and photodamaged skin. Photosensitive GA has been found in association with HIV infection. Finally, some cases of GA or GA-like reactions have been reported after gold therapy and treatment with allopurinol, diclofenac, quinidine, calcitonin, amlodipine, angiotensin-converting enzyme (ACE) inhibitors, daclizumab, [6] checkpoint inhibitors, [7, 8, 9] and calcium-channel blockers.

    Associations with systemic diseases

    GA has been associated primarily with type I diabetes mellitus (DM); it is only rarely associated with type II DM and thyroid disease, on the basis of an increased number of GA patients with these diseases in small case series. [10]

    Small case series have reported GA to occur in association with malignancy, AIDS, and herpes zoster lesions. Although no definite patterns relating GA and systemic disease have been thoroughly established, it has been suggested that an atypical histologic finding (vasculopathy or extravascular neutrophilia) or clinical presentation (unusual appearance or location) may indicate an associated disease. In the case of malignancy, a 2003 review of classic cases in the literature was unable to confirm a definite relationship between GA and malignant neoplasms. [11]

    Associations with specific malignancies

    Certain malignancies are accompanied by different mucocutaneous paraneoplastic syndromes. Lesions that mimic GA or have been histologically confirmed as GA have occurred in association with the following:

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    Epidemiology

    The frequency of GA is in the general population is unknown. Of the various subtypes, localized GA is the most common. The generalized subtype occurs in 9-15% of all patients with GA. Perforating GA has a reported prevalence of 5% among GA subtypes; reports suggest that this subtype may be more common in the Hawaiian Islands.

    Localized GA is most commonly found in children and in adults younger than 30 years. Generalized GA demonstrates a bimodal age distribution, occurring in patients younger than 10 years and in patients aged 30-60 years. Although subcutaneous GA can occur in adults, it is predominantly a disease of otherwise healthy children (typical age range, 2-10 y). Similarly, perforating GA most often affects children.

    Women are affected by GA twice as frequently as men are.

    GA has no known predilection for any particular race, ethnic group, or geographical area.

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    Prognosis

    Spontaneous resolution of localized GA has occurred within 2 years in 50% of cases, though lesions may last weeks to decades. Recurrence, often at the same site, is noted in 40% of cases.

    Generalized GA has a more chronic course, with rare spontaneous resolution, poor response to treatment, and frequent relapses.

    Subcutaneous GA lesions often regress spontaneously. Local or distant recurrences have been reported in 20-75% of cases in different studies.

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    Patient Education

    Patients and families should be reassured about the typically benign nature and course of granuloma annulare.

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