Granuloma annulare

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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 usually a benign and self limiting skin disease of unknown etiology. There are a number of variants: localized, generalized or disseminated, subcutaneous, papulo-pustular and perforating. It is characterized histologically by palisading granulomata with a central core of necrobiotic or degenerative collagen surrounded by a lympho-histiocytic infiltrate. The disease often resolves spontaneously, with no long term sequelae.

Management strategy

The localized variant of GA is often diagnosed clinically, but a skin biopsy may be required to confirm the diagnosis of the more unusual varieties such as generalized, papulo-pustular, perforating, and subcutaneous forms. Once the diagnosis is established, it is prudent to check the urine for glucose to exclude diabetes mellitus. In disseminated and generalized variants HIV, hepatitis C, and lymphomas are rare associations.

Because the majority of cases of GA are asymptomatic and self limiting, the need for active treatment should be considered carefully; in many cases, reassurance that the disease is benign and will resolve spontaneously is sufficient. Painful or unsightly lesions may justify more active treatment, though the evidence to support the efficacy of many of the treatments is poor.

Localized GA may be treated effectively with topical or intralesional steroids. Clobetasol propionate (Dermovate) lotion under occlusion with a hydrocolloid dressing, changed weekly, can be used for up to 6 weeks. Alternatively, intralesional injections of triamcinolone may be used, at intervals of 6 to 8 weeks. Cryotherapy using liquid nitrogen can be repeated at 3 or 4 weeks if required. Treatment of refractory lesions includes photodynamic therapy, UVA1, intralesional interferon; large, tumid lesions may require excision.

Generalized GA may be persistent and its unsightly appearance causes patients to seek active treatment, though the results are often disappointing. Both UVA and PUVA may be used, but relapses can occur. Isotretinoin and dapsone have been associated with improvement or clearance of generalized GA. Topical tacrolimus and pimecrolimus have been used, with greater success in generalized disease than in the localized variety. Other reported treatments for this condition include laser, fumaric acid esters, hydroxychloroquine, chlorambucil, cyclosporine, hydroxyurea, doxycycline, systemic steroids, adalimumab, infliximab, anthralin, vitamin E, allopurinol, nicotinamide, pentoxifylline, and defibrotide.

Specific investigations

Check urine for glucose

Unlike necrobiosis lipoidica, in which there is a strong association with diabetes mellitus, the relationship between GA and diabetes is unclear. Nevertheless, it would seem sensible to use the diagnosis of GA as a cue to exclude undiagnosed diabetes, and at least check the urine for glucose.

Carbohydrate tolerance in patients with granuloma annulare. Study of fifty two cases.

Haim S, Friedman-Birnbaum R, Haimn Shafrir A, Ravina A. Br J Dermatol 1973; 88: 447–51.

In a study of 39 patients with localized GA the incidence of abnormal carbohydrate tolerance was 23% and similar to that of a control population, compared to an incidence of 77% in 13 patients with generalized disease.

Absence of carbohydrate intolerance in patients with granuloma annulare.

Gannon TF, Lynch PJ. J Am Acad Dermatol 1994; 30: 662–3.

In a study of 23 patients with GA, 13 patients had localized lesions and 10 patients had generalized form of the disease; glycosylated haemoglobin levels were found to be normal.

Localised granuloma annulare is associated with insulin-dependent diabetes mellitus.

Muhlemann MF, Williams DR. Br J Dermatol 1984; 111: 325–9.

This retrospective study looked at 557 insulin-dependent diabetics and found that 16 patients had GA, significantly more than the 0.9 cases that might have been expected.

Localized granuloma annulare

First-line therapies

Intralesional steroids	B
Cryotherapy	B
Topical steroids	E

Granuloma annulare and necrobiosis lipoidica treated by jet injector.

Sparrow G, Abell E. Br J Dermatol 1975; 93: 85–9.

In this study of 45 patients with GA, intralesional triamcinolone produced a complete response in 68% of patients after three treatments carried out at 6- and 8-week intervals. About half of the patients suffered recurrences, which responded to re-treatment.

Successful outcome of cryosurgery in patients with granuloma annulare.

Blume-Peytavi U, Zouboulis CH, Jacobi H, Scholz A, Bisson S, Orfanos CE. 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 lesions were cleared. Four cases had persistent atrophic scars, where large lesions had been treated with liquid nitrogen.

It should be possible to prevent cryo-atrophy by avoiding freeze-thaw cycles of more than 10 seconds, and taking care not to overlap treatment areas.

Successful treatment of chronic skin diseases with clobetasol propionate and a hydrocolloid occlusive dressing.

Volden G. Acta Derm Venereol 1992; 72: 69–71.

One of three cases of GA showed a complete response after 4 weeks of treatment with clobetasol propionate under occlusion.

This treatment has the advantage of being painless, but evidence for its efficacy is not strong.

Second-line therapies

Laser	C
Photodynamic therapy	D
Imiquimod	E
UVA1	E
Interferon	E
Scarification	E
Surgery	E
Rifampin, ofloxacin, minocycline combination	D

Treatment of granuloma annulare with the 595 nm pulsed dye laser (PDL), a multicentre retrospective study with long-term follow-up.

Passeron T, Fusade T, Vabres P, Bousquet-Rouaud R, Collet-Vilette A-M, et al. J Eur Acadol 2011 [E-pub].

In this study, five patients with localized and eight with generalized GA were treated with three sessions of pulsed-dye laser. A significant response was only seen in the localized forms.

Photodynamic therapy for granuloma annulare: more than a shot in the dark.

Weisenseel P Kuznetsov AV, Molin S, Ruzicka T, Berking C, Prinz JC. Dermatology 2008; 217: 329–32.

Seven patients with GA were treated with three sessions of ALA-PDT with an interval of 2 to 4 weeks between each session. In two patients, GA cleared completely, in two the skin lesions improved markedly, and in three no response was observed.

Successful treatment of granuloma annulare with imiquimod cream 5%: a report of four cases.

Badavanis G, Monastirli A, Pasmatzi E, Tsambaos D. Acta Derm Venereol 2005; 85: 547–8.

Four patients with multiple lesions of GA treated with imiquimod cream once daily. The majority of lesions cleared within 12 weeks of treatment with no recurrence at 18 months follow-up.

Granuloma annulare: dramatically altered appearance after application of 5% imiquimod cream.

Stephenson S, Nedorost S. Pediatr Dermatol 2008; 25: 138–9.

GA worsened in a child after accidental application of imiquimod used to treat adjacent plane warts.

Multiple localized granuloma annulare: ultraviolet A1 phototherapy.

Frigerio E, Franchi C, Garutti C, Spadino S, Altomare GF. Clin Exp Dermatol 2007; 32: 762–4.

Four patients responded to high-dose UVA1, starting with 60 J/cm² on day 1 followed by fixed daily doses of 100 J/cm² five times weekly for 3 weeks.

Treatment of granuloma annulare by local injections with low dose recombinant human interferon gamma.

Weiss JM, Muchenberger S, Schöpf E, Simon JC. J Am Acad Dermatol 1998; 39: 117–19.

Three patients achieved clearance of localized GA treated with intralesional interferon-γ 2.5 × 10⁵ IU on 7 consecutive days and continued three times weekly for a further 2 weeks.

Scarification treatment of granuloma annulare.

Wilkin JK, DuComb D, Castrow FF. Arch Dermatol 1982; 118: 68–9.

Two patients successfully treated by scarification once weekly for 8 weeks, and every 3 weeks thereafter, using the point of a 19G injection needle drawn across the lesions to produce capillary bleeding.

Surgical pearl: surgical treatment of tumour sized granuloma annulare of the fingers.

Shelley WB, Shelley ED. J Am Acad Dermatol 1997; 37: 473–4.

A case report of nodular GA treated with shave excision, allowing the wound to heal by secondary intention.

Granuloma annulare treated with rifampin, ofloxacin, and minocycline combination therapy.

Marcus DV, Mahmoud BH, Hamzavi IH. Arch Dermatol 2009; 145: 787–9.

Six patients with localized GA achieved complete clearance after 5 months combination therapy with rifampin 600 mg, ofloxacin 400 mg, and minocycline 100 mg.

Generalized granuloma annulare

First-line therapies

UVA1	B
Isotretinoin	C
Dapsone	C
Tacrolimus	E
Photodynamic therapy	E

UVA1 phototherapy for disseminated granuloma annulare.

Schnopp C, Tzaneva S, Mempel M, Schulmeister K, Abeck D, Tanew A. Photodermatol, Photoimmunol Photomed 2005; 21: 68–71.

Twenty patients with disseminated GA underwent phototherapy with UVA1 340–400 nm, which provided good or excellent results in half of them and satisfactory responses in the majority. Discontinuation of treatment was followed by early recurrence.

Resolution of disseminated granuloma annulare with isotretinoin.

Schleicher SM, Milstein HJ, Lim SJ, Stanton CD. Int J Dermatol 1992; 31: 371–2.

Six women treated with isotretinoin 0.5 mg/kg/day showed complete or almost complete resolution.

There is a report in which etretinate was used successfully in this condition.

The response of generalised granuloma annulare to dapsone.

Czarnecki DB, Gin D. Acta Derm Venereol 1986; 66: 82–4.

Six patients with generalized GA treated with dapsone 100 mg daily showed a complete response, five clearing within 8 weeks, with four remaining clear for 20 months after stopping treatment.

Successful treatment of disseminated granuloma annulare with topical tacrolimus.

Jain S, Stephens CJ. Br J Dermatol 2004; 150: 1042–3.

Four patients were treated with topical tacrolimus 0.1% ointment for 6 weeks: two showed complete clearance and maintained it for at least 6 weeks, and two had marked improvement.

Successful treatment of perforating granuloma annulare with 0.1% tacrolimus ointment.

Lopez-Navarro N, Castillo R, Gallardo MA, Alcaide A, Matilla A, Herrera E. J Dermatolog Treat 2008; 19: 376–7.

A case responded to topical tacrolimus 0.1% ointment.

Generalized granuloma annulare treated with methylaminolevulinate photodynamic therapy.

Piaserico S, Zattra E, Linder D, Peserico A. Dermatology 2009; 218: 282–4.

Three patients with persistent generalized GA responded to MAL-PDT.

Second-line therapies

PUVA	B
Fumaric acid esters	D
Hydroxychloroquine	D
Topical steroids	E
Systemic steroids	E
Chlorambucil	D
Cyclosporine	E
Hydroxyurea	E
Doxycycline	E
Laser (Nd : YAG)	E
Pimecrolimus	E
Adalimumab	E
Infliximab	E
Allopurinol	E
Nicotinamide	E
Pentoxifylline	E
Defibrotide	E
Vitamin E topically	E
Anthralin	E