Etiology, Diagnosis, and Therapeutic Management of Granuloma Annulare

An Update

Laura A. Thornsberry; Joseph C. EnglishIII


Am J Clin Dermatol. 2013;14(4):279-290. 

In This Article

5 Treatment

Patients with localized disease can be advised that this form of GA is often self-limited and approximately 50 % of these cases resolve within 2 years; therefore, treatment is not always necessary.[42,65] However, patients are often interested in treatment of localized GA because lesions are symptomatic or for cosmetic reasons. Non-localized forms of GA can be more challenging to treat, with over 30 treatments reported in the literature, but only one reported randomized controlled trial and no well-established and evidence-based treatments. The choice of treatment must be individualized for the patient on the basis of comorbidities, baseline blood evaluations, drug interactions, compliance, adverse effect profiles, prior treatments, proximity to clinic, and reproductive status. Reported treatments successfully used for GA are listed in Table 2.

5.1 Localized GA Treatment

Localized GA is most commonly treated with topical high potency corticosteroids or intralesional corticosteroids, although there have not been any studies to determine the efficacy or optimal dosing regimen for these treatments.[1] In general, these treatments are well tolerated but patients must be counseled on the risk of atrophy, pigmentation alterations, and striae. Triamcinolone is a commonly used intralesional corticosteroid, often at a strength of 5 mg/ml or less to try to minimize the risk of adverse effects. Cryosurgery is another option for localized disease; however, there has only been one prospective study of cryosurgery, in which 25 out of 31 patients had resolution of lesions with only one treatment with either liquid nitrogen or nitrous oxide.[109] The optimal duration, number of cycles, and frequency of cryosurgery have not been defined, and application can be highly variable depending on the provider. Cryosurgery carries the risk of pigmentary alterations, scar formation, and localized pain during treatment. Topical tacrolimus 1 % ointment applied twice a day has been reported with success in localized GA,[67,70] but has also been reported as failed therapy in a case series of three pediatric patients.[66] There has been one case series of three patients successfully treated with intralesional recombinant interferon gamma, but optimal dosing and frequency have not been defined.[73]

Only one oral medication has been reported with success for localized GA, in woman with GA secondary to pseudofolliculitis from a waxing treatment, who failed several treatments and then had improvement with isotretinoin (titrated up from 0.5 to 1 mg/kg/day).[89] Phototherapy with localized cream PUVA therapy is another option, with a series of five patients achieving partial (one patient) or complete (four patients) response after failing topical corticosteroids. These patients had treatments four times a week for 17–40 treatments.[112] Photodynamic therapy (PDT) with 5-aminolevulinic acid (5-ALA) has been reported once with localized GA on the fingers, with almost complete resolution after four treatments and no recurrence after 7 months.[118] Finally, in addition to the CO2 laser that was reported several years ago, three lasers have recently been reported as effective treatments for GA in case reports (Table 3).[65,115–117]

5.2 Generalized GA Treatment

The majority of the literature available for the treatment of generalized GA consists of case reports, small case series, and small retrospective studies. The only double-blind, placebo-controlled study of generalized GA did not show a difference in potassium iodide versus placebo in eight patients with disseminated GA.[119]

For the topical treatment of disseminated GA, there has been one case report each for the use of tacrolimus 1 % ointment[68] and pimecrolimus 1 % cream with twice a day application; however, systemic therapy is usually required to achieve clearance of the generalized forms of GA.[71]

The most commonly reported systemic treatments since the year 2000 include fumaric acid esters (FAE), isotretinoin, biologic agents, and phototherapy (Table 4). Since 2001, the use of FAE was reported as a successful treatment six times as single therapy and once in combination with PUVA; however, FAE are not available in the USA.[82–88] Breuer et al.[82] reported a retrospective study of 13 patients treated with FAE at varying doses, with improvement in eight patients. Two patients had no improvement and three patients had to discontinue treatment because of adverse effects (gastrointestinal and eosinophilia).[82] In a retrospective study by Weber et al.,[87] six out of eight patients improved with varying doses of FAE. Notable adverse effects included gastrointestinal symptoms (nausea, diarrhea, abdominal pain) requiring discontinuation in two patients as well as blood count abnormalities in four patients that did not require treatment cessation.[87] Finally, a retrospective study of eight patients by Eberlein-Konig et al.[85] showed improvement in seven patients but was significant for adverse effects in six patients. The use of FAE is commonly complicated by gastrointestinal adverse effects as well as flushing, and it requires routine monitoring of blood counts during therapy.

Isotretinoin has been reported several times as a successful treatment at dosages of 0.5–1 mg/kg/day for generalized GA,[72,90–93] but has also been noted to fail at least twice.[121] Localized application of pimecrolimus 1 % cream was successfully used in combination with isotretinoin therapy in one patient to target the often treatment-resistant areas on the hands and feet.[72] Etretinate, another systemic retinoid, has also been effective in one case report but it is not available in the USA.[94] The use of systemic retinoids is limited by the adverse effect profile and the requirement for frequent monitoring of blood counts, hepatic function, and lipid levels. Patients must be counseled on the risks of potential adverse effects and teratogenicity.

There have been two case reports of intravenous use of infliximab for generalized GA, with improvement seen as early as 4 weeks after initiating treatment.[101,102] Adalimumab has also shown a quick response in several case reports, often within 2–6 weeks with an initial subcutaneous dose of 80 mg followed by 40 mg every 2 weeks.[103–105] Etanercept has shown mixed results, with an initial report of one patient improving over a 12-week treatment;[107] however, a later series of four patients treated showed no improvement in two patients and worsening disease in the other two patients.[122] Efalizumab has been reported once in a patient who received it though a phase III psoriasis clinical trial (patient also had psoriasis) and had improvement of GA lesions after 12 weeks of treatment.[108]

A retrospective study of 33 patients treated with PUVA (oral psoralen) showed improvement in 66 % of the patients; however, most of these patients relapsed within 2 years.[112] Older studies of PUVA for generalized GA have shown clearance in one patient after 53 treatments,[123] in four patients after an average of 26 treatments,[110] and in four patients treated with high-dose PUVA five times a week for 3 weeks.[124] PUVA has also been reported once as an effective treatment for generalized GA in an 11-year-old child.[111] PUVA is limited by the necessity of frequent office visits and increased risk of skin cancer. A study of NB-UVB for inflammatory diseases reported two patients that only had minimal to mild improvement of GA with this treatment.[113] Alternatively, a patient treated with once weekly NB-UVB achieved near clearance after 24 treatments.[125] PDT with methyl aminolevulinate (MAL) was effective in three patients after three to five treatments performed every 2 weeks.[126] In a retrospective study of 13 patients treated with MAL-PDT, nine patients showed moderate (50–75 %) to marked (greater than 75 %) improvement after an average of 2.8 treatments.[120] A prospective study of seven patients treated with 5-ALA PDT showed marked to complete improvement in four patients after two to three sessions, but no response in three patients.[114]

The numerous single case reports and case series of treatments reported for generalized GA since the year 2000 are best summarized in table form (Table 5). Interestingly, methotrexate is the most commonly used immunosuppressant by dermatologists other than prednisone,[127] but it has only been reported once as treatment for generalized GA.[4] Oral dapsone for generalized GA was reported three times in the 1980s[128–130] at dosages of 100–200 mg daily, but not again until 2008, in one patient treated with 100 mg daily with clearance after 15 months.[75] Cyclosporine has shown promising results in a small case series of four patients.[81] Triple therapy with rifampin, ofloxacin, and minocycline was effective in a case series of six patients within 3–5 months of treatment[77] and doxycycline alone has also been effective for GA.[76] Effective combination therapy has been reported three times: PUVA plus prednisone 10 mg every other day;[14] isotretinoin plus topical pimecrolimus 1 % cream;[72] and photochemotherapy plus FAE.[88]