Granuloma Annulare


Key Points

  • Granuloma annulare is a reactive inflammatory skin condition, which commonly presents as annular pink, erythematous thin plaques on the distal extremities.
  • Granuloma annulare usually presents as localized disease, generalized plaques or papules, or subcutaneous nodules.
  • Granuloma annulare may be associated with internal disease such as diabetes, hyperlipidemia, thyroid disease, or HIV, albeit in limited studies. Malignancy associated and medication-induced forms have been reported as well.

Introduction

Granuloma annulare (GA) is a relatively common inflammatory skin condition, which can manifest with cutaneous eruptions in a handful of patterns. GA tends to occur in the third to fifth decades of life, with a roughly equal female: male ratio with perhaps a slight female predominance.

GA most typically presents as localized granuloma annulare (LGA), single or few annular (ring-like, circular), pink-erythematous, thin plaques over the dorsal hands or feet. Generalized granuloma annulare (GGA) is the next most common presentation, which can either include widespread annular plaques, patches, or disseminated, small, erythematous, firm papules, distributed widely over the trunk and extremities. Subcutaneous GA (SGA) is rare in adults, but is the most common type in children, and presents with firm painless subcutaneous nodules (which may have more typical GA overlying the skin above the nodule), usually on the lower limbs. A number of rare presentations of GA have been described. The differential diagnosis of GA typically includes tinea infection (which often presents with annular lesions on the dorsal hands as well, although tinea tends to have scale, whereas GA usually does not), sarcoidosis, other cutaneous granulomatous eruptions, and urticarial eruptions.

A diagnosis of GA may be made clinically, but confirmation with biopsy is sometimes necessary; the histopathology of GA is often distinctive, with two histologic variants, interstitial GA or palisading GA.

The etiopathogenesis of GA remains unknown. There are limited data regarding a genetic/inheritable risk for GA, although single case reports and small case series have identified siblings and first-degree relatives with GA in some patients. One report identified identical twins who developed GA with the HLA-AH8.1 mutation, and HLA-Bw35 has been reported as potentially conferring risk for GGA, however, these studies are quite small and limited in scope. The triggering event that generates the cutaneous granulomatous inflammatory response has yet to be elucidated. Some have hypothesized that blood vessel damage—potentially via immune complex deposition—may trigger a reactive inflammatory response; this hypothesis has been suggested for similar reactive granulomatous processes in the skin (such as palisaded neutrophilic and granulomatous dermatitis or interstitial granulomatous dermatitis). Others have suggested that GA represents a delayed hypersensitivity response to an unidentified host antigen, perhaps abnormal collagen bundles or elastic fibers. Another theory proposed that abnormal neutrophil function and migration may lead to increased macrophage response and granuloma formation. Many have sought an infectious etiology, as there have been reports of GA in the setting of HIV, viral hepatitis, and following some vaccines. GA may occur in response to cutaneous injury as an isotopic response, including following lightning strike, tattoo placement, bug bites, and after vaccination. Medication-induced GA is not as widely reported as other forms of medication-induced reactive granulomatous processes, however, drug-induced forms do exist in isolated case reports, including following treatment with TNF-α inhibitors, gold therapy, and interferon.

Granuloma annulare is frequently asymptomatic, but patients often request treatment as the lesions are frequently found on exposed sites (such as the dorsal hands), and GGA may be symptomatically bothersome in some cases. Notably, many patients with GA will spontaneously improve within a few years of disease onset. However, recurrences (whether following spontaneous remission or treatment response) are common, occurring in up to 40% of cases. It is essential to appropriately counsel patients that the disease is often recalcitrant to therapy, may self-resolve, and can unpredictably return.

Regardless of the clinical type, when diagnosing GA, physicians should be aware of potential disease associations. Most of the data surrounding GA and potential associated diseases comes from small, retrospective studies, with large-scale epidemiologic studies lacking. With that caveat, there is a growing literature suggesting a potential association between GA and diabetes. Other potential disease associations include dyslipidemia and thyroid disease. Again, while the data is based on small studies, screening for these conditions is relatively low cost and low risk, and is worth offering to patients with a new diagnosis of GA. Rare reports exist linking GA with malignancies, particularly lymphoproliferative/hematopoietic malignancies, and beyond age-appropriate malignancy screening, patients with GA likely warrant at least a CBC, and, if atypical features are present, potentially further testing. GA has been reported in patients with HIV, both with typical and atypical presentations of the eruption; perforating GA, GGA (particularly with papules), and other atypical forms of GA should prompt extra consideration for potential underlying HIV. Given the CDC recommendations of more broad HIV testing and the benefits of early diagnosis, it is likely prudent to consider and/or offer HIV testing to all patients with GA, particularly if patients have risk factors for HIV.

Treatment of GA is challenging. Once again, treatment recommendations are somewhat limited by the lack of robust evidence or large trials. Compounding this, many patients with GA will spontaneously improve after a few years, making study interpretation challenging. Patients with limited disease (usually localized GA) will often respond to intralesional corticosteroid injections. Patients with more widespread disease may respond to either antimalarial therapy or phototherapy, particularly PUVA or UVA-1. Evidence for other therapeutic options is limited to a very small number of cases. Alternative therapies include dapsone, saturated solution of potassium iodide, selected lasers (PDL, excimer), cryotherapy, TNF-α inhibitors, fumaric acid esters, anti-inflammatory antibiotics (tetracycline class agents), rifampin-ofloxacin-minocycline combination therapy, allopurinol, cyclosporine, methotrexate, systemic retinoids, and more. Experienced physicians counsel patients that any given therapy has about a 1 in 3 chance of improving GA, and that even with treatment response it is important to remember that a significant number of patients will experience relapse and recurrence of skin lesions.

Initial Evaluation

Differential Diagnosis

Urticaria

Tinea/Dermatophytosis

Psoriasis

Lupus (subacute cutaneous lupus erythematosus)

Treatment

First-line therapy: For limited disease, topical corticosteroids may help, but intralesional injections of corticosteroids are often required. More widespread disease should be treated with either antimalarial drugs or phototherapy (generally PUVA).

First steps

  • Topical corticosteroids (short course of clobetasol 0.05% to individual lesions on extremities).
  • Intralesional triamcinolone injections (strength varying by anatomic site, size and depth of lesion, generally 10-20 mg/mL).

Subsequent steps

  • More widespread disease often requires antimalarial therapy (hydroxychloroquine 200 mg twice daily / up to 6.5 mg/kg/day dosing) or phototherapy (PUVA three times weekly).
  • Non-responders may warrant alternative treatment options, of which there is a wide range, with varying mechanisms, risks, benefits, and generally limited data supporting most alternative treatments.
  • Alternative options include: systemic retinoids, combination antibiotic therapy (including rifampin/oxacillin/minocycline), dapsone, potassium iodide solution, systemic corticosteroids, alternate immunosuppressive agents, combination therapy, and TNF-α inhibitors.
  • Patients with the most severe disease should be referred to dermatology.

Pitfalls

  • Patients with other cutaneous granulomatous eruptions may be misdiagnosed as having GA, particularly the rare reactive entities palisaded neutrophilic and granulomatous dermatitis (PNGD) and interstitial granulomatous dermatitis (IGD). PNGD and IGD are often seen as cutaneous phenomena in the setting of a systemic inflammatory process (such as inflammatory arthritis or connective tissue disease).
  • Annular lesions on the hand are often initially diagnosed as tinea/dermatophyte infection before being recognized as GA. However, if treating an annular lesion on the hand as GA with corticosteroids leads to worsening or the development of pustules, consider reevaluating for dermatophytosis as use of steroids on the skin can worsen tinea infestations.
  • Atypical forms of GA may occur in the setting of malignancy, particularly hematologic malignancies or HIV; testing should be considered in the appropriate clinical context.

Clinical Case

Case 1

  • 38-year-old man
  • No significant past medical history
  • Review of systems reveals no complaints, including no joint pain, fevers, arthritis, eye symptoms, or recent illness
  • Social history is unremarkable
  • Presents for evaluation of asymptomatic, fine, flesh-colored-to-pink papules grouped into a circle on the dorsal hands. He was treated with over-the-counter antifungals without response

Initial evaluation

  • Healthy appearing male
  • Numerous minute, pinpoint, erythematous papules grouped into an annular ring on the dorsal hands, bilaterally
  • There is no lymphadenopathy or hepatosplenomegaly on exam

Diagnosis: Granuloma annulare

  • Attempt a KOH scraping to evaluate for presence of dermatophyte infestation (ruling out tinea)
  • Biopsy a representative skin lesion for confirmation
  • Perform routine blood work, including complete blood count and comprehensive metabolic profile
  • Thorough review of social history, exposures, and behaviors to evaluate for any high-risk sexual behaviors and consider HIV testing
  • Initiate treatment with high-potency topical corticosteroids

Follow-up evaluation

  • The biopsy is interpreted as consistent with granuloma annulare
  • The patient reports no improvement with topical corticosteroids
  • Initiate therapy with intralesional corticosteroid injections; over subsequent visits the patient notes good response

References

Avitan-Hersh E, Sprecher H, Ramon M, Bergman R (2013). Does infection play a role in the pathogenesis of granuloma annulare? J Am Acad Dermatol, 68(2):342-343.

Dabski K, Winkelmann RK (1989). Generalized granuloma annulare: histopathology and immunopathology. Systemic review of 100 cases and comparison with localized granuloma annulare. J Am Acad Dermatol, 20(1):28-39.

Piette EW, Rosenbach M. Granuloma annulare: a comprehensive review and update for the dermatologist. J Am Acad Dermatol, (manuscript submitted for publication).

Requena L, Fernandez-Figueras MT (2007). Subcutaneous granuloma annulare. Semin Cutan Med Surg, 26(2):96-99.

Thornsberry LA, English JC 3rd (2013). Etiology, diagnosis, and therapeutic management of granuloma annulare: an update. Am J Clin Dermatol, 14(4):279-290.