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BASICS

Description

  • Benign granulomatous skin disease with skin-colored to erythematous papules in annular (ring-like) pattern.
  • Commonly on dorsal hands and feet.
  • Five subtypes: localized, generalized, subcutaneous, patch, perforating.

Epidemiology

  • Incidence: ~0.04% per year in the U.S.
  • Female predominance (3:1).
  • Onset <30 years in most localized cases; bimodal in generalized.
  • Localized most common (75%), generalized 10-15%, others <5%.

Etiology and Pathophysiology

  • Unknown cause.
  • Involves upregulation of Th1/Th2 pathways; increased cytokines: TNF-α, IL-1β, IL-4, IFN-γ, IL-12/IL-23p40, IL-31.
  • Activation of JAK/STAT pathways.
  • M1 macrophages: collagen degradation; M2 macrophages: tissue remodeling and mucin deposition.
  • Genetic predisposition: HLA-Bw35 association (linked also to thyroid disease).

Risk Factors

  • No definite risk factors.
  • Associations reported with:
  • Diabetes mellitus
  • Autoimmune thyroid disease
  • Dyslipidemia
  • HIV infection
  • Viral infections: EBV, herpes simplex, SARS-CoV-2, varicella-zoster
  • Systemic lupus erythematosus
  • Tuberculosis
  • Hepatitis B and C
  • Trauma, sun exposure, insect bites
  • Malignancies (especially lymphoma)
  • Certain medications (acetazolamide, anti-TNFα, amlodipine, allopurinol, botulinum toxin, immune checkpoint inhibitors, phototherapy, and others)

Prevention

  • No known preventive measures.

DIAGNOSIS

History

  • Lesions usually asymptomatic.
  • May persist months to years; can spontaneously resolve or recur.

Physical Exam

  • Localized: Flesh-colored or erythematous annular plaques, firm, 5 mm to 5 cm, on dorsal distal extremities.
  • Generalized: Larger, more numerous (>10), more widespread.
  • Subcutaneous: Firm, nontender nodules on scalp, legs, upper extremities.
  • Patch: Symmetric erythematous macules/patches, annular or not.
  • Perforating: Papules with central umbilication, crusting, widespread, may scar.

Differential Diagnosis

  • Localized: tinea corporis, annular lichen planus, necrobiosis lipoidica, pityriasis rosea, erythema migrans, leprosy.
  • Generalized: sarcoidosis, lichen planus, cutaneous metastases, mycosis fungoides.
  • Patch: erythema migrans.
  • Subcutaneous: rheumatoid nodules.
  • Perforating: molluscum contagiosum, sarcoidosis, insect bites.

Diagnostic Tests

  • Usually clinical.
  • KOH prep to exclude fungal infection.
  • Labs as indicated for comorbidities (lipids, glucose, thyroid, HIV, hepatitis, malignancy).
  • Punch biopsy with histology if needed:
  • Palisading granulomas around degenerated collagen with mucin deposition.
  • Variants: interstitial, classic, epithelioid granulomas.
  • Immunohistochemistry: CD68/KP-1 marker for histiocytes.
  • Ultrasound may assist diagnosis of subcutaneous GA.

TREATMENT

General Measures

  • Condition is often self-limited; many cases require only reassurance.
  • Educate patients on benign nature and variable course.

Medication

  • Trauma from biopsy can induce lesion involution.
  • Assess risk-benefit of treatment.
  • First Line:
  • High-potency topical corticosteroids (class I or II) with or without occlusion.
  • Intralesional triamcinolone (2.5–5 mg/mL).
  • Second Line:
  • Doxycycline 100 mg/day for 8–10 weeks.
  • Pimecrolimus 1% cream BID.
  • Tacrolimus 0.1% ointment BID.
  • Chloroquine or hydroxychloroquine.
  • Isotretinoin 0.5–0.75 mg/kg/day.
  • Rifampin + ofloxacin + minocycline combination.
  • Dapsone 100 mg/day.
  • Cyclosporine 3–4 mg/kg/day.
  • Methotrexate 10 mg IM weekly.
  • Niacinamide 500 mg TID.
  • Fumaric acid esters.
  • Interferon gamma 1b intralesional injections.
  • TNF-α inhibitors (infliximab, adalimumab, etanercept).
  • Photodynamic therapy.
  • Pentoxifylline 400 mg TID.

Additional Therapies

  • Cryotherapy.
  • Fractional thermolysis (YAG laser).
  • Pulsed dye laser (585–595 nm).
  • NBUVB and PUVA phototherapy.
  • Surgical excision for subcutaneous GA.
  • Apremilast (PDE4 inhibitor).
  • Tofacitinib (JAK inhibitor).
  • Control comorbidities such as diabetes and hyperlipidemia.

ONGOING CARE

Follow-Up

  • Routine follow-up unnecessary if untreated.
  • Monitor for adverse effects if on treatment.
  • Refer dermatology for generalized, refractory, or cosmetically concerning disease.

Patient Education

  • GA is benign, self-limited, noninfectious, and not contagious.
  • Lesions may persist or recur.
  • Screening for associated conditions may be beneficial in generalized/atypical cases.

Prognosis

  • 50% resolve spontaneously within 2 months to 2 years.

  • Recurrence common (>40%), usually at same sites.
  • Younger patients (<39 years) tend to have shorter disease duration.

Complications

  • Treatment-related adverse effects more common than complications of GA itself.

Clinical Pearls

  • Consider GA in annular lesions negative for fungal infection.
  • Assess metabolic and autoimmune comorbidities in generalized cases.
  • Use potent topical or intralesional corticosteroids initially.
  • Consider phototherapy or systemic agents for extensive disease.

References

  1. Joshi TP, Duvic M. Granuloma annulare: an updated review of epidemiology, pathogenesis, and treatment options. Am J Clin Dermatol. 2022;23(1):37-50.
  2. Piette EW, Rosenbach M. Granuloma annulare: pathogenesis, disease associations and triggers, and therapeutic options. J Am Acad Dermatol. 2016;75(3):467-479.
  3. Keimig EL. Granuloma annulare. Dermatol Clin. 2015;33(3):315-329.