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Granuloma annulare
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Granuloma annulare (GA) is an inflammatory cutaneous disease thought to be driven by immune mechanisms. Previous studies have suggested that some variants of GA represent delayed-type (type IV) hypersensitivity reactions to an unknown variety of antigenic triggers. GA may occur as an isolated, idiopathic entity but has also been described in association with multiple systemic processes. Diabetes, dyslipidemia, and thyroid disease are the most commonly reported associated conditions (though contrary studies exist as well); however, GA has also been reported in association with infections and, rarely, some malignancies. This relationship may be coincidental rather than correlative. GA-associated infections include human immunodeficiency virus (HIV), infectious hepatitis, and Borrelia burgdorferi most commonly; however, conflicting evidence surrounding the strength of these associations exists. GA developing in the setting of hepatitis C infection, and improving with interferon-α therapy, has been reported and screening for hepatitis C is recommended. GA has developed after bacillus Calmette–Guérin, hepatitis B, tetanus and diphtheria toxoid, and anti-tetanus vaccination. The health benefits of vaccinations greatly outweigh the exceedingly rare and potential risks of GA development in all cases. GA has developed as an isotopic response at prior sites of herpes zoster infection. While a temporal relationship between GA and malignancy has occasionally been reported, recent studies suggested there is no consistent causative link. Expert consensus remains that age appropriate screening is indicated, but extended malignancy screening should be considered in older patients with extensive GA, or those with widespread, atypical (such as palmar plaques), or recalcitrant disease.
GA encompasses a spectrum of disease and may be localized GA (LGA) or generalized GA (GGA). Children may present with subcutaneous GA, which often self-resolves in adolescence. LGA is the most common variant and is characterized by pink to red, arciform and annular, non-scaly papules and plaques on the extremities. Other variants include perforating, patch, and palmoplantar forms of GA. Histology shows palisading (about one-third of cases) or interstitial (about two-thirds of cases) granulomatous inflammation with a central core of necrobiotic collagen surrounded by a lymphohistiocytic infiltrate, typically with mucin.
Management Strategy
LGA is often diagnosed clinically, but a skin biopsy may be required to exclude other entities or confirm the diagnosis of less common variants. Patients with GA may benefit from screening for diabetes, hyperlipidemia, thyroid disease, and hepatitis C.
Approximately half of LGA cases are self-limiting within 2 years. As most patients are asymptomatic, reassurance that the disease is benign and may resolve spontaneously is sufficient. For patients with symptomatic or cosmetically sensitive lesions, treatment may be desired. There have been numerous reported treatment options for GA; unfortunately, a review of GA publications shows the median number of patients per study was one over a 25-year period.
LGA may be treated with topical or intralesional steroids. Superpotent topical steroids under occlusion with a hydrocolloid dressing, changed weekly, can be used for up to 6 weeks. Alternatively, intralesional triamcinolone injections may be used at intervals of 6–8 weeks. Liquid nitrogen cryotherapy can be repeated every 3–4 weeks as required. Treatment of refractory lesions includes photodynamic therapy, ultraviolet A1 (UVA1) phototherapy, intralesional interferon, and laser therapy; large, tumid lesions may rarely require excision. Recalcitrant lesions can also be treated with some of the treatments described below for generalized disease.
Generalized GA may be persistent, and its unsightly appearance causes patients to seek active treatment. Antimalarial therapy is often effective in GGA; initial reports were with chloroquine , though hydroxychloroquine is also effective and confers a more favorable side-effect profile. Phototherapy can be an effective treatment. While both psoralen and ultraviolet A ( PUVA) and UVA1 phototherapy have been reported, narrowband phototherapy is also effective and may be used, but relapses can occur. Intertriginous, patch-type GA may be particularly responsive to phototherapy. Isotretinoin and dapsone have been associated with improvement or clearance of generalized GA. Topical tacrolimus and pimecrolimus have been used, with some reports describing greater success in generalized disease than in the localized variety. Other reported treatments for this condition include laser, fumaric acid esters, methotrexate, chlorambucil, ciclosporin, hydroxyurea, doxycycline, pulsed triple-antibiotic therapy, systemic corticosteroids, adalimumab, infliximab, anthralin, vitamin E, allopurinol, nicotinamide, pentoxifylline, apremilast, and defibrotide . Biopsy alone has reportedly improved patch GA and GGA. New, emerging reports describe response to oral and topical tofacitinib , with JAK-inhibitors showing promise for multiple granulomatous diseases.
Specific Investigations
The relationship between GA and diabetes remains unclear; however, screening HbA1c in patients with risk factors or symptoms of glucose intolerance should be considered. Hyperlipidemia and thyroid disease are both seen at increased rates in patients with granulomatous diseases, including GA, and are easy to screen for with low risk, cost effective tests.
Generalized granuloma annulare: clinical and laboratory findings in 100 patients
Dabski K, Winkelmann RK. J Am Acad Dermatol 1989; 20: 39–47.
Retrospective review identifying GGA in 20% of 100 biopsy-proven cases of GA at a tertiary referral institution.
Localized granuloma annulare is associated with insulin-dependent diabetes mellitus
Muhlemann MF, Williams DR. Br J Dermatol 1984; 111: 325–9.
Retrospective study of 557 insulin-dependent diabetics. Sixteen patients had GA, significantly more than the 0.9 cases that might have been expected.
Laboratory abnormalities in granuloma annulare: a case-control study
Veraldi S, Bencini PL, Drudi E, et al. Br J Dermatol 1997; 136: 652–3.
Retrospective case-control study of 61 patients showing significantly increased risk of insulin-dependent diabetes in patients with GA. Higher prevalence of diabetes mellitus (DM) identified in patients with LGA versus GGA.
Lack of an association between granuloma annulare and type 2 diabetes mellitus
Nebesio CL, Lewis C, Chuang TY. Br J Dermatol 2002; 146: 122–4.
Study of 126 patients with GA in which no association was found between GA and DM in comparison to controls with psoriasis. Notably, potential associations between DM and psoriasis have recently been identified.
Localized Granuloma Annulare
Granuloma annulare and necrobiosis lipoidica treated by jet injector
Sparrow G, Abell E. Br J Dermatol 1975; 93: 85–9.
Comparison of 45 patients with LGA treated with intralesional injection of triamcinolone 5 mg/mL or sterile saline over 6- and 8-week intervals. Of those treated with steroid injection, 68% experienced complete clearance versus 44% in the sterile saline group. Partial clearance was higher in the saline group (33%) versus in the steroid group (24%), and less than 50% of patients in both groups had recurrence of GA.
Successful outcome of cryosurgery in patients with granuloma annulare
Blume-Peytavi U, Zouboulis CH, Jacobi H, et al. Br J Dermatol 1994; 130: 494–7.
In a study of 31 patients with GA, 22 patients were treated with liquid nitrogen and nine with nitrous oxide. After a single freeze–thaw cycle, 81% of GA lesions treated with liquid nitrogen cleared. Four cases had persistent atrophic scars at sites of treatment.
Granuloma annulare of childhood successfully treated with potent topical corticosteroids previously unresponsive to tacrolimus ointment 0.1%: report of three cases
Rallis E, Stavropoulou E, Korfitis C. Clin Exp Dermatol 2009; 34: e475–6.
Twice-daily application of clobetasol propionate 0.05% or mometasone furoate 0.1% without occlusion for 2–3 weeks led to complete remission of LGA in three children.
Successful treatment of chronic skin diseases with clobetasol propionate and a hydrocolloid occlusive dressing
Volden G. Acta Derm Venereol 1992; 72: 69–71.
One in three cases of GA showed a complete response after 4 weeks of treatment with clobetasol propionate under occlusion.
Second-Line Therapies
Treatment of granuloma annulare with the 595 nm pulsed dye laser (PDL), a multicenter retrospective study with long-term follow-up
Passeron T, Fusade T, Vabres P, et al. J Eur Acad Dermatol Venereol 2013; 27: 785–8.
Five patients with LGA and eight patients with GGA were treated with three sessions of PDL. A significant response was seen only in the localized forms while GGA showed weak improvement, with a high recurrence rate.
Granuloma annulare treated with excimer laser
Bronfenbrener R, Ragi J, Milgraum S. J Clin Aesthet Dermatol 2012; 5: 43–5.
A 73-year-old woman with an over 40-year history of GGA underwent treatment with excimer laser on the dorsal hands. The regimen comprised fluence of 300 mJ/cm 2 with five doses per treatment session. After 15 treatments there was complete resolution with no recurrence at treated sites at 6-month follow-up.
Photodynamic therapy for granuloma annulare: more than a shot in the dark
Weisenseel P, Kuznetsov AV, Molin S, et al. Dermatology 2008; 217: 329–32.
Seven patients with GA were treated with three sessions of photodynamic therapy with topical aminolevulinic acid (ALA-PDT) and an interval of 2–4 weeks between each session. In two patients, GA cleared completely; in two patients, the skin lesions improved markedly; and in three patients, no response was observed.
A retrospective analysis of real-life practice of off-label photodynamic therapy using methyl aminolevulinate (MAL-PDT) in 20 Italian dermatology departments. Part 1: inflammatory and esthetic indications
Calzavara-Pinton PG, Rossi MT, Aronson E, et al. J Photochem Photobiol Sci 2013; 12: 148–57.
Retrospective observational study of patients treated with MAL-PDT in Italian hospital centers. Nine out of 13 patients with GA showed improvement.
Successful treatment of granuloma annulare with imiquimod cream 5%: a report of four cases
Badavanis G, Monastirli A, Pasmatzi E, et al. Acta Derm Venereol 2005; 85: 547–8.
Four patients with multiple lesions of LGA treated with imiquimod 5% cream once daily. The majority of lesions cleared within 12 weeks of treatment with no recurrence observed at 18 months follow-up. There is also a report of GA worsening after treatment of adjacent warts with imiquimod.
Management of periocular granuloma annulare using topical dapsone
Kassardjian M, Patel M, Shitabata P, et al. J Clin Aesthet Dermatol 2015; 8: 48–51.
A 41-year-old male with arciform LGA of the right upper eyelid and lateral canthus was treated with dapsone 5% gel applied twice daily, with significant improvement at 3 weeks.
Periorbital granuloma annulare successfully treated with tacrolimus 0.1% ointment
Gomez-Moyano E, Vera-Casaño A, Martinez S, et al. Int J Dermatol 2014; 53: e156–7.
A 6-year-old child with LGA of the upper eyelid was successfully treated with topical tacrolimus 0.1% ointment twice daily. Significant improvement was noticed at 6 weeks with sustained response.
Multiple localized granuloma annulare: ultraviolet A1 phototherapy
Frigerio E, Franchi C, Garutti C, et al. Clin Exp Dermatol 2007; 32: 762–4.
Four patients responded to high-dose UVA1, starting with 60 J/cm 2 on day 1, followed by fixed daily doses of 100 J/cm 2 five times weekly for 3 weeks.
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