Description

Granuloma annulare (GA) is a benign skin condition characterized by groups of skin-colored to erythematous papules that are usually in an annular (ring-like) pattern and typically located on the dorsal aspects of the hands and feet. There are five types of GA: localized, generalized, subcutaneous, patch, and perforating.

Epidemiology

Incidence

• GA is a relatively common, noninfectious granulomatous disease. Incidence is reported to be 0.04% per year within the United States (1).
• Although most lesions resolve spontaneously within 2 years, some persist for ≥10 years.
• Predominant sex: female > male (3:1) (1)
• Onset of symptoms occurs at <30 years old in 2/3 of all patients. Typical ages for onset of each subtype are as follows:
  • Localized: <30 years old
  • Generalized: bimodal: <10 years old, 30 to 60 years old
  • Subcutaneous: 2 to 14 years old
  • Patch: >30 years old
  • Perforating: children and young adults
• Distribution of subtypes:
  • Localized: 75%
  • Generalized: 10–15%
  • Subcutaneous: <5%
  • Patch type: <5%
  • Perforating: <5%

Prevalence
Prevalence is reported to be highest in the 5th decade of life (1).

Etiology and Pathophysiology

The etiology of GA remains unknown; however, recent studies have helped to further elucidate its underlying cause. It is hypothesized to be related to upregulation of T-helper (Th) 1 and Th2 pathways in GA lesions. Increased cytokine expression was subsequently noted to include tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-4, interferon (IFN)-γ, IL-12/IL-23p40, and IL-31. Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways were also found to be activated in GA. Response by “M1” and “M2” macrophages was described, which can be related to histopathologic findings of collagen degradation followed by tissue remodeling and mucin deposition, respectively.

Genetics
There is some evidence for a genetic predisposition. Two studies reported an increased frequency of HLA-Bw35 in patients with generalized GA. Of note, HLA-Bw35 has also been associated with thyroid disease.

Risk Factors

No definite risk factors have been identified. There are reported associations between GA and diabetes mellitus (DM), autoimmune thyroid disease, dyslipidemia, HIV, Epstein-Barr virus, herpes simplex virus, systemic lupus erythematosus, tuberculosis, and hepatitis B and C, among others. There have also been associations with interferon-α therapy, trauma, sun exposure, insect bites, borreliosis, and malignancies (most commonly lymphoma).

General Prevention

There are no known preventive measures for GA.

Commonly Associated Conditions

• DM: The association between GA and DM remains controversial, but there is increasing evidence of an association. Early studies from the 1980s showed a possible link, and a recent large, retrospective cohort study (51,169 patients with GA) showed that 21% of patients had both GA and DM, whereas 13.3% of matched controls had DM (1).
• Autoimmune thyroid disease: Multiple case reports have linked thyroid disease with both generalized and localized GA. In one case-control study, 24 women with localized GA were compared to 100 age-matched women with non-GA dermatologic disease. A statistically significant increase in the incidence of autoimmune thyroid disease among those with localized GA as compared with those with other non-GA cutaneous disease was identified (12% vs. 1%, p = .022) (2),(3).
• Malignancy: There is no definitive relationship between GA and malignancy. A review of the literature found in 14 case reports and two correlation studies in which patients who had one or more malignancies also had GA. In a majority of these cases, the malignancies were hematologic, primarily lymphoma (2),(3).
• Dyslipidemia: Dyslipidemia may be associated with GA. A single case-control study (n = 140) demonstrated a statistically significant increase in hyperlipidemia among patients with GA compared to controls (79.3% vs. 51.9%, p < .001). Further studies, including the large, retrospective cohort study noted above, have demonstrated significant associations with GA and hyperlipidemia.
• Infectious: Among patients with GA, those who also have HIV appear more likely to have the generalized subtype. In one study of 34 patients with GA and HIV, 20 (59%) had generalized GA (2). Additional viral triggers have been suggested to include SARS-CoV-2, Epstein-Barr virus, and varicella zoster virus. There has been recent data showing evidence of potential bacterial triggers, including Chlamydiales spp. and Borrelia spp. (1).
• Iatrogenically-induced: Several drugs have been implicated in triggering GA: acetazolamide, anti-TNFα agents, amlodipine, allopurinol, botulinum toxin, desensitization injections, immune checkpoint inhibitors, immunizations, levetiracetam, paroxetine, topiramate, and phototherapy (1).
• Note: Conclusions regarding associations between GA and various diseases, including those mentioned earlier, are limited by both design and power. Consequently, in the absence of new research, definitive associations between GA and other diseases cannot be made.