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Granuloma annulare: Management

Granuloma annulare: Management
Author:
Robert T Brodell, MD
Section Editor:
Erik Stratman, MD
Deputy Editor:
Abena O Ofori, MD
Literature review current through: Jul 2022. | This topic last updated: Sep 28, 2021.

INTRODUCTION — Granuloma annulare (GA) is a cutaneous, granulomatous disorder with a variety of clinical presentations. Localized GA, which is considered the classic presentation, characteristically presents as a nonscaly, annular plaque on the distal extremity (picture 1A-F). Additional variants include generalized, subcutaneous, perforating, and patch GA.

The clinical course of GA varies; many cases spontaneously resolve within a few years. However, the appearance and occasional symptoms associated with GA can be distressing, contributing to a desire for treatment.

Efficacy data for treatments for GA are limited and insufficient to confirm the optimal therapeutic approach. Initial management of localized GA typically consists of topical corticosteroid therapy, whereas generalized presentations are often managed with systemic treatment or phototherapy (algorithm 1).

The management of GA will be reviewed here. The pathogenesis, clinical manifestations, and diagnosis of GA are reviewed separately.

(See "Granuloma annulare: Epidemiology, clinical manifestations, and diagnosis".)

LOCALIZED GRANULOMA ANNULARE

Decision to treat — Localized GA is generally asymptomatic and self-limited; therefore, not all patients elect to proceed with treatment. Often, concern regarding the unpredictable time to resolution or psychologic distress related to the appearance of lesions prompts a desire to proceed with treatment.

Initial therapy — Local corticosteroid therapy (intralesional or topical) is the mainstay of treatment for localized GA. Topical calcineurin inhibitor therapy is an alternative approach that is primarily reserved for lesions in sites at greatest risk for corticosteroid-induced skin atrophy (eg, face, intertriginous areas) and patients who fail or experience adverse effects of corticosteroid treatment. (See 'Local corticosteroids' below and 'Topical calcineurin inhibitors' below.)

Local corticosteroids — Although evidence for efficacy is primarily limited to clinical experience, local corticosteroid therapy is considered the preferred initial intervention because of availability, ease of administration, and relative safety:

Administration – The relative efficacy of intralesional corticosteroid injections and topical corticosteroid therapy is unclear. Intralesional injection is our preferred approach based upon personal clinical experience that suggests a higher likelihood of a satisfactory response with intralesional therapy compared with topical therapy:

Intralesional corticosteroid injections – We typically use triamcinolone acetonide in concentrations of 2.5 to 10 mg/mL. Starting with concentrations on the lower end of this range (eg, 2.5 or 5 mg/mL) may be beneficial when treating cosmetically sensitive areas in patients with highly pigmented skin due to the potential for corticosteroid-induced hypopigmentation. Lower initial concentrations are also favored for patients with a history of corticosteroid injection-induced skin atrophy. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

A 30-gauge needle is used to inject 0.1 mL of the mixture into the border of a lesion. For lesions larger than 1 cm, additional injection sites are separated by approximately 5 to 10 mm. Clinical signs of improvement often occur within a few weeks. Injections are repeated every six to eight weeks until resolution or cessation of progressive improvement.

To minimize risk for systemic adverse effects, the total dose of intralesional triamcinolone acetonide given in one treatment session should not exceed 40 mg. (See "Intralesional corticosteroid injection".)

Topical corticosteroid therapy – The discomfort associated with intralesional injection is a deterrent for some children and adults. For patients who prefer to avoid intralesional treatment, we typically prescribe a superpotent topical corticosteroid, such as clobetasol propionate 0.05% (table 1). The corticosteroid should be applied once daily with an occlusive dressing or twice daily if occlusion is not feasible [1]. Flurandrenolide tape (an occlusive tape impregnated with a superpotent topical corticosteroid) can also be used for treatment.

Once- or twice-daily application of the topical corticosteroid should continue for at least two to four weeks prior to assessing for a response. Once significant improvement is noted, the frequency of application can be tapered, followed by discontinuation when signs of disease activity are absent. If there is no response after four to eight weeks of treatment, the patient should be reassessed and alternative treatments, such as intralesional corticosteroids, should be considered.

Efficacy – Responses to corticosteroid therapy vary. Use of intralesional and topical corticosteroids for localized and generalized GA is based upon case reports and case series that suggest benefit for GA [1-4].

Adverse effects – Potential side effects of topical and intralesional corticosteroids include cutaneous atrophy, telangiectasias, and hypopigmentation. Patients should be followed closely for the development of these adverse effects. (See "Topical corticosteroids: Use and adverse effects", section on 'Cutaneous'.)

Systemic absorption leading to adrenal suppression is a risk when large skin areas are treated, making local corticosteroid therapy less favorable for the management of patients with generalized disease. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects' and "Intralesional corticosteroid injection", section on 'Side effects, complications, and pitfalls'.)

Topical calcineurin inhibitors — Topical tacrolimus and topical pimecrolimus tend to be more expensive than some topical corticosteroids but may be helpful for the long-term treatment of GA in sites at high risk for corticosteroid-induced skin atrophy and patients who fail to improve with topical corticosteroids. Unlike corticosteroids, topical calcineurin inhibitors are not associated with risks of cutaneous atrophy and adrenal suppression:

Administration – Topical tacrolimus 0.1% ointment and topical pimecrolimus 1% cream are generally applied twice daily.

Tacrolimus is also commercially available as a 0.03% ointment, the concentration preferred for the treatment of atopic dermatitis in children under the age of 16 years. However, most case reports documenting improvement in GA with topical tacrolimus document use of the 0.1% formulation in adults or children. Improvement is slow but may be evident within the first one to two months of treatment [5-8]. (See "Treatment of atopic dermatitis (eczema)", section on 'Topical calcineurin inhibitors'.)

Efficacy – Improvement of localized, generalized, or perforating GA with topical calcineurin inhibitors has been documented in case reports, including some patients who previously failed topical or intralesional corticosteroids [5-8].

Adverse effects – Topical calcineurin inhibitors may induce a transient, burning sensation following application. Although the US Food and Drug Administration (FDA) has placed a "black box" warning on topical calcineurin inhibitors due to concern for the potential of these agents to increase the risk for internal malignancy, a causal relationship has not been established. (See "Treatment of atopic dermatitis (eczema)", section on 'Efficacy and minor side effects' and "Treatment of atopic dermatitis (eczema)", section on 'Safety'.)

Refractory lesions — The best approach to patients who fail to achieve resolution with local corticosteroid and topical calcineurin inhibitor therapy is unclear. Additional therapies that may be of benefit for patients who want to pursue additional treatment include other topical or intralesional therapies, cryotherapy, light-based therapies, and systemic therapy. However, evidence for the efficacy of these agents is limited:

Other topical therapies – Other therapies reported to be of benefit in patients with localized GA include topical imiquimod [9,10], dapsone 5% gel [11], compounded tofacitinib 2% ointment [12], and intralesional recombinant human interferon-gamma [13]. Worsening of GA after treatment with imiquimod has also been reported [14].

Cryotherapy – Limited data suggest that application of liquid nitrogen may be of benefit. In an uncontrolled study of 28 patients with GA, nitrous oxide or liquid nitrogen applied with a closed probe was associated with lesion resolution in 81 percent of patients, and relapse was noted in only 1 out of 11 patients who were followed for at least two years [15]. However, atrophic scarring, hypopigmentation, or hyperpigmentation occurred in 21 percent of study participants, and an excellent cosmetic result was reported in only 50 percent.

In clinical practice, liquid nitrogen is often administered via spray canister. In our experience, the response to this technique is variable.

Phototherapy – Various forms of phototherapy may have some benefit in the treatment of localized GA [16-22]. In an uncontrolled study of five patients with GA, topical psoralen plus ultraviolet A (PUVA) photochemotherapy four times per week for a mean of 26 treatments led to clearance of lesions in four patients and significant improvement in one patient [16]. Follow-up was short; re-evaluation after four months did not show recurrence of disease. Relapse has been reported following PUVA therapy in patients with other forms of GA [23,24]. PUVA has also been linked to the onset of GA in a case report [25]. (See 'Photochemotherapy' below and "Psoralen plus ultraviolet A (PUVA) photochemotherapy".)

Improvement with ultraviolet A1 (UVA1) [18], a narrowband ultraviolet B (NBUVB) light source [19], and targeted broadband ultraviolet B (UVB) phototherapy [20] has also been reported. Photodynamic therapy was evaluated in a series of seven patients with localized GA [22]. Two patients each had complete clearance or marked clearance of disease, and three patients did not respond to treatment.

Laser therapy – Laser therapy may be an additional treatment modality. Improvement in localized GA following pulsed dye laser treatment is documented in case reports and a small, retrospective study [26-28]. Responses of generalized GA to fractional photothermolysis and excimer laser therapy have also been reported. (See 'Procedural therapies' below.)

Systemic therapy – Improvement of localized GA with systemic therapies used for generalized GA has been reported in individual patients [29,30]. However, given the limited efficacy data, the risks of systemic therapy must be weighed carefully in patients with limited skin involvement. (See 'Generalized granuloma annulare' below.)

GENERALIZED GRANULOMA ANNULARE

Decision to treat — The unpredictable duration, the appearance of skin lesions, and the intractable pruritus that can be associated with generalized GA lead many patients to seek treatment. However, evidence to confirm the efficacy of treatments is limited. Deferring treatment is a reasonable alternative for asymptomatic patients who are not concerned about the appearance of lesions.

Initial therapy — Although the topical therapies used for localized GA may improve lesions of generalized GA, daily application of topical therapy to widespread skin lesions can be challenging. Thus, systemic therapy is typically prescribed for the initial treatment of generalized GA, with topical therapy reserved for the treatment of the most bothersome or resistant lesions (algorithm 1). Narrowband ultraviolet B (NBUVB) phototherapy is an alternative initial approach for patients who prefer to avoid systemic therapy. (See 'Adjunctive topical therapy' below.)

Multiple systemic drugs may be beneficial for generalized GA. Hydroxychloroquine, isotretinoin, or dapsone are common initial therapies due to the accessibility and relative safety of these medications (algorithm 1). Selection among these agents is based upon consideration of comorbidities and patient tolerance for adverse effects profiles.

Hydroxychloroquine is our preferred first-line systemic agent because the drug is generally well tolerated, provided patients are appropriately monitored for retinal toxicity. Treatment with systemic medications is generally discontinued once a satisfactory response is achieved.

Hydroxychloroquine

Administration – Typical adult dosing for hydroxychloroquine is 3 to 5 mg/kg of real body weight per day. A dose of 400 mg per day is commonly used; however, to minimize risk for treatment-related, ocular toxicity, dosing should not exceed 5 mg/kg per day. Improvement usually becomes evident within one to two months. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Ocular effects'.)

Efficacy – A retrospective study that included 14 patients who received hydroxychloroquine (200 to 400 mg per day) for generalized GA suggests benefit of hydroxychloroquine [29]. Of the 14 patients, 9 (64 percent) improved during therapy. Favorable responses have also been reported in other patients [2,31-33].

Adverse effects – Examples of potential adverse effects include ocular toxicity, gastrointestinal distress, cutaneous drug eruptions, headaches, and cardiotoxicity. A baseline ophthalmologic examination should be performed before or soon after the initiation of therapy. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Adverse effects' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Monitoring for toxicity'.)

Isotretinoin

Administration – Typical adult dosing for isotretinoin is 0.5 mg/kg per day. Isotretinoin is usually given for three to four months. The drug is contraindicated in pregnancy. In the United States, participation in the iPLEDGE Risk Evaluation and Mitigation Strategies (REMS) program is required for prescribing isotretinoin. (See "Oral isotretinoin therapy for acne vulgaris", section on 'iPLEDGE program'.)

Efficacy – Treatment with isotretinoin has been associated with resolution of generalized GA in several case reports [34-39]. Some patients have had remissions lasting for more than six months, while others have relapsed after the discontinuation of treatment.

Adverse effectsIsotretinoin is teratogenic and contraindicated in pregnancy. Other common adverse effects include mucocutaneous changes (eg, cheilitis, xerosis) and hyperlipidemia. Less common adverse effects include visual changes, hepatotoxicity, bone marrow suppression, idiopathic intracranial hypertension, and bone changes. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Adverse effects'.)

Dapsone

Administration – Typical adult dosing for dapsone is 100 mg per day. Treatment durations generally range between a few weeks and four months [40].

Efficacy – Case reports and an uncontrolled study suggest benefit of dapsone therapy. In one series of six patients, all showed complete clearing of disease with dapsone; four remained clear at a follow-up visit between 4 and 20 months after the cessation of therapy [41]. In an uncontrolled study, 7 of 10 patients with generalized GA responded to treatment (four complete responses and three partial responses), but all relapsed within three months [30].

Adverse effects – Potential adverse effects of dapsone include hemolysis, agranulocytosis, methemoglobinemia, dapsone hypersensitivity syndrome, and peripheral neuropathy. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are at increased risk for severe hemolytic anemia. Screening for G6PD deficiency is advised prior to beginning dapsone therapy. Periodic laboratory monitoring is indicated for all patients receiving dapsone therapy. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Acute hemolytic anemia' and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Avoidance of unsafe drugs and chemicals' and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Diagnostic evaluation'.)

Narrowband ultraviolet B phototherapy

Administration – Narrowband ultraviolet B (NBUVB) phototherapy usually consists of exposure to an ultraviolet B (UVB) light-emitting device approximately three times per week. Improvement may be evident within the first two months of treatment [42,43]. Protocols for phototherapy are reviewed separately. (See "UVB therapy (broadband and narrowband)", section on 'Dosimetry and treatment protocols'.)

Efficacy – Small, retrospective studies suggest benefit of NBUVB phototherapy. In a retrospective study of 13 patients who received thrice-weekly NBUVB phototherapy for generalized GA, three patients had complete disappearance of lesions, and four had at least 50 percent improvement [42]. The average number of treatments was 35. Treatment was discontinued if there was no improvement after 20 treatments. In a separate retrospective study, 7 of 10 patients treated with NBUVB achieved clearance or minimal residual disease, with a median of 32 treatments [44].

Case reports documenting improvement in generalized GA during NBUVB phototherapy also suggest benefit of this therapy [43,45]. Almost complete clearance with combination therapy with acitretin and NBUVB has also been reported [46].

Adverse effects – Potential adverse effects include skin erythema, skin dryness, pruritus, blistering, increased reactivation of herpes simplex virus infection, and photoaging. The impact of skin cancer risk remains unclear. (See "UVB therapy (broadband and narrowband)", section on 'Short- and long-term adverse effects'.)

Refractory disease — Biologic tumor necrosis factor (TNF)-alpha inhibitors, cyclosporine, and psoralen plus ultraviolet A (PUVA) photochemotherapy are additional options that are primarily reserved for patients with generalized GA refractory to hydroxychloroquine, isotretinoin, or dapsone (algorithm 1). Cyclosporine has potential, severe adverse effects and is typically limited to patients with severe, refractory GA.

Biologic tumor necrosis factor-alpha inhibitors — Limited data suggest adalimumab and infliximab may be effective for GA. Although improvement in GA with etanercept has been reported [47], etanercept generally appears to be ineffective in GA [48]:

Administration – Typical dosing for adults is as follows:

Adalimumab – 80 mg at week 0 followed by 40 mg every other week beginning at week 1

Infliximab – 5 mg/kg at weeks 0, 2, 6, and every 8 weeks

Marked improvement may be evident within the first one to three months of treatment [49-51].

Efficacy – Randomized trial data to confirm efficacy of TNF-alpha inhibitors are lacking [52]. Adalimumab appeared effective and well tolerated in a retrospective case series of seven adults with generalized or disseminated GA refractory to local corticosteroid therapy, including four who had also failed to respond to phototherapy [49]. All seven patients had clinical improvement, as assessed by GA Investigator Global Assessment scores and body surface area. Patients were treated with an initial dose of 80 mg of adalimumab, followed by 40 mg every other week; however, escalation to weekly dosing was necessary for two patients due to poor initial responses. Two of five patients who discontinued therapy and were followed for at least 2 to 40 months had recurrences after the discontinuation of treatment. Other case reports have demonstrated sustained improvement of recalcitrant GA in patients treated with adalimumab [50,51,53-56].

Infliximab has appeared effective for generalized GA in case reports, with improvement noted within one to two months [57,58].

There are also reports of GA induced by adalimumab, infliximab, and etanercept [59].

Adverse effectsAdalimumab and infliximab are generally well tolerated. Examples of potential adverse effects include injection site reactions, infusion reactions (infliximab), increased risk for infection and nonmelanoma skin cancer, neutropenia, and hepatotoxicity. Based upon potential associations with demyelinating disease (eg, multiple sclerosis) and heart failure, use is typically avoided in patients with these diseases. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

Cyclosporine — Patients with severe, refractory, generalized GA may benefit from oral cyclosporine therapy:

Administration – Typical adult dosing for cyclosporine is 3 to 4 mg/kg per day. Doses of cyclosporine have ranged from 3 to 6 mg/kg per day, and improvement may be evident within one month [60-64].

Efficacy – Case reports suggest benefit of cyclosporine [60-64]. Some patients have relapsed following cyclosporine therapy, while others have had remissions lasting at least one year.

Adverse effects – Potential, serious adverse effects (renal failure, malignancy, hepatotoxicity, hypertension, and infections) limit use of cyclosporine. (See "Pharmacology of cyclosporine and tacrolimus", section on 'Side effects'.)

Photochemotherapy

Administration – Psoralen plus ultraviolet A (PUVA) therapy consists of administration of a photosensitizing agent prior to exposure to ultraviolet A (UVA) light. Treatment is administered approximately two times per week. Protocols for PUVA are reviewed in detail separately. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Treatment protocols'.)

Efficacy – PUVA has shown efficacy for generalized GA in published reports of small numbers of patients [65-67]. A study of five patients, including one patient with perforating lesions, showed flattening as early as one month after the start of therapy [23]. All patients were clear of disease within three to four months. Although relapse recurred after the discontinuation of treatment, patients responded to retreatment. Another study showed clearing of three patients in 6 to 12 months, but only one patient had a durable remission [24].

Adverse effects – Risks of PUVA include nausea, phototoxicity, pruritus, premature skin aging, and increased risk for cutaneous malignancies and cataracts. The risk for cutaneous malignancies and cataracts appears to be most prominent in patients who receive long-term therapy. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Adverse effects'.)

Adjunctive topical therapy — Clinical experience suggests benefit of topical corticosteroids, intralesional corticosteroids, and topical calcineurin inhibitors for lesions of generalized GA. However, daily application to large body surfaces can be challenging, and extensive use of topical or intralesional corticosteroids may increase risk for systemic adverse effects. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

In our experience, topical therapy is most beneficial for treating select lesions in patients with generalized GA, such as lesions in cosmetically sensitive areas or resistant lesions. Treatment regimens for lesions of generalized GA and localized GA are similar. (See 'Local corticosteroids' above and 'Topical calcineurin inhibitors' above.)

Other therapies — Additional therapies that have been used for generalized GA include UVA1 phototherapy, various systemic therapies, and light-based procedural therapies.

Ultraviolet A1 phototherapy — The availability of ultraviolet A1 (UVA1) phototherapy is primarily limited to academic centers. Although UVA1 appears to have some efficacy for generalized GA, further studies are necessary to identify the optimal treatment regimen. (See "UVA1 phototherapy".)

The initial report of UVA1 for generalized GA documented marked improvement in four patients treated with this modality (cumulative dose of UVA1 = 1840 J/cm2) [68]. However, responses to treatment have been less consistent in subsequent studies in which patients received lower cumulative doses of UVA1. In an uncontrolled, prospective study of patients with long-standing, disseminated GA, 16 patients were treated with high-dose UVA1 (median treatment dose 110 J/cm2, median total dose 1770 J/cm2), and 4 patients were treated with medium-dose UVA1 (median treatment dose 50 J/cm2, median total dose 890 J/cm2) [69]. Nine patients (56 percent) in the high-dose group and one patient (25 percent) in the medium-dose group achieved substantial improvement or near complete clearance of disease. However, seven out of nine patients for whom follow-up data were available relapsed after the cessation of therapy (median time to relapse = 3 months).

A subsequent, retrospective study of UVA1 phototherapy for a variety of skin diseases reported modest benefit of UVA1 in generalized GA. Out of 20 patients treated with UVA1 (mean treatment dose 75 J/cm2, mean total dose 1352 J/cm2), 7 patients had mild improvement, 3 had moderate improvement, and 3 had marked improvement [70]. No patients achieved complete remission.

Acute adverse effects of UVA1 include erythema, pruritus, and reactivation of herpes simplex virus infection. The long-term risk for skin cancer with UVA1 remains uncertain; however, this modality is generally considered to be less carcinogenic than PUVA [71]. (See "UVA1 phototherapy", section on 'Adverse effects'.)

Systemic therapies — Apremilast [72-74], oral tofacitinib [75], nicotinamide [76], pentoxifylline [77], hydroxyurea [78], and fumaric acid esters [79-81] have led to improvement in generalized GA in case reports. Clinical benefit has also been documented in patients treated with doxycycline [82] or a combination of rifampin, ofloxacin, and minocycline [83,84]. Oral or subcutaneous methotrexate appeared to improve generalized GA in 7 of 11 patients in a case series [85]. A retrospective study found a nonstatistically significant trend towards a greater likelihood of resolution of generalized GA among 20 patients treated with daily oral vitamin E than among 16 untreated patients (40 versus 31 percent) [86].

Procedural therapies — Improvement of generalized GA lesions following photodynamic therapy has been reported [87]. In addition, responses to laser interventions, including pulsed dye laser [28], fractional photothermolysis [88,89], and excimer laser treatment [90], have been documented in case reports and small series. Randomized trials are needed to confirm efficacy of these treatments [91].

SUBCUTANEOUS, PATCH, AND PERFORATING GRANULOMA ANNULARE

Subcutaneous granuloma annulare – Treatment is not usually necessary for subcutaneous GA [92]. Most patients can be managed with reassurance and periodic clinical follow-up.

Although excisional biopsy of one lesion is useful for diagnosis, surgery for treatment of this benign condition is not usually indicated [92-95]. Recurrence is common following surgical excision. Examples of other therapies reported to be of benefit in individual patients include topical or intralesional corticosteroids [96], bath psoralen plus ultraviolet A (PUVA) [97], and local hyperthermia [98].

Patch or perforating granuloma annulare – The best approach to the treatment of patch or perforating GA is unclear. Treatments similar to those used in the more common localized and generalized manifestations of GA can be attempted in patients with patch or perforating GA [8,99,100]. Of note, resolution in patch GA following biopsy was reported in one patient [101]. The response of perforating GA to treatment is often disappointing [102].

CHILDREN — Subcutaneous GA and localized GA are the variants of GA typically seen in children [103]. Treatment of these and other GA variants is often not necessary, given the expectation for eventual spontaneous resolution. (See 'Prognosis' below and 'Subcutaneous, patch, and perforating granuloma annulare' above.)

If treatment of localized GA is desired, topical corticosteroids and topical calcineurin inhibitors are the mainstays of therapy. (See 'Localized granuloma annulare' above.)

Efficacy data on phototherapy and systemic therapies for GA in children are limited [103].

PROGNOSIS — It is estimated that approximately 50 percent of cases of localized GA resolve within two years [104]. As resolution occurs, the papules at the periphery recede. Blanchable, macular erythema remains for months until the lesions completely disappear without scarring. Recurrences are not uncommon and tend to appear in the same areas as the original lesions. The majority of recurrent lesions may resolve within two years [104].

Generalized GA may persist or clear spontaneously. In a retrospective review of 100 patients with generalized GA, at least 25 percent had disease courses of greater than five years, and at least 10 percent had persistent disease after 10 years [2].

Spontaneous remission is also possible in other variants. A systematic review that identified 58 reported cases of perforating GA found documentation of remission in approximately 60 percent of patients overall, regardless of therapeutic approach, and spontaneous remission in 10 of 13 patients who received no treatment [102,105]. In a series of 68 patients with subcutaneous GA, lesions disappeared within 1 week to 19 months in 24 of 43 untreated patients and improved in 16 untreated patients [96].

SUMMARY AND RECOMMENDATIONS

Overview – Granuloma annulare (GA) is a cutaneous, granulomatous disorder with multiple clinical presentations, including localized (picture 1A-F), generalized, subcutaneous, patch, and perforating GA. GA is often asymptomatic but may be pruritic. Spontaneous resolution may occur within a few years; however, the time to resolution is unpredictable. (See 'Introduction' above and 'Prognosis' above.)

Decision to treat – GA is a benign condition. Therefore, deferring treatment is a reasonable alternative for asymptomatic patients who are not bothered by the appearance of lesions. Given the unpredictable time course to resolution and the occasional association with pruritus, some patients desire treatment. The clinical presentation influences the approach to treatment. (See 'Decision to treat' above and 'Decision to treat' above.)

Treatment of localized granuloma annulare – Local therapy with intralesional corticosteroid injections, a high-potency topical corticosteroid, or a topical calcineurin inhibitor is the mainstay of therapy (see 'Localized granuloma annulare' above):

For the initial treatment of localized GA on the extremities or trunk, we suggest intralesional corticosteroid therapy rather than topical corticosteroid therapy or topical calcineurin inhibitor therapy (Grade 2C). Treatment with a high-potency topical corticosteroid is an alternative for patients who cannot tolerate or prefer to avoid intralesional injections.

We typically reserve topical calcineurin inhibitors for treatment of sites at greatest risk for corticosteroid-induced skin atrophy (eg, face, intertriginous skin) or patients who fail topical corticosteroid therapy. (See 'Topical calcineurin inhibitors' above.)

Treatment of generalized granuloma annulare – A therapeutic approach for generalized GA is reviewed in an algorithm (algorithm 1):

For patients with generalized GA, we suggest hydroxychloroquine rather than local therapy alone or other systemic treatments for initial therapy (Grade 2C). Although lesions of generalized GA may respond to topical therapies, treatment of widespread disease can be challenging. Other options for initial systemic treatment include isotretinoin and dapsone. Local therapy may be helpful as an adjunct to systemic therapy. (See 'Generalized granuloma annulare' above.)

For patients who prefer to avoid systemic therapy, narrowband ultraviolet B (NBUVB) phototherapy is an acceptable alternative. (See 'Narrowband ultraviolet B phototherapy' above.)

Patients who fail to respond to initial therapies may benefit from adalimumab, infliximab, cyclosporine, or psoralen plus ultraviolet A (PUVA) photochemotherapy. (See 'Refractory disease' above.)

Other variants – For patients with asymptomatic subcutaneous GA, we suggest observation rather than surgical excision (Grade 2C). Recurrence of subcutaneous GA is common following surgical excision.

The best approach to patch or perforating GA is unclear. Therapies for localized and generalized GA can be attempted for patients with these variants. (See 'Subcutaneous, patch, and perforating granuloma annulare' above.)

Prognosis – The natural course of GA is eventual spontaneous resolution; however, some presentations persist for more than two years. (See 'Prognosis' above.)

  1. Volden G. Successful treatment of chronic skin diseases with clobetasol propionate and a hydrocolloid occlusive dressing. Acta Derm Venereol 1992; 72:69.
  2. Dabski K, Winkelmann RK. Generalized granuloma annulare: clinical and laboratory findings in 100 patients. J Am Acad Dermatol 1989; 20:39.
  3. Rallis E, Stavropoulou E, Korfitis C. Granuloma annulare of childhood successfully treated with potent topical corticosteroids previously unresponsive to tacrolimus ointment 0.1%: report of three cases. Clin Exp Dermatol 2009; 34:e475.
  4. Sparrow G, Abell E. Granuloma annulare and necrobiosis lipoidica treated by jet injector. Br J Dermatol 1975; 93:85.
  5. Grieco T, Cantisani C, Faina P, et al. Tacrolimus 0.1% and granuloma annulare: description of three cases. J Eur Acad Dermatol Venereol 2009; 23:1445.
  6. Jain S, Stephens CJ. Successful treatment of disseminated granuloma annulare with topical tacrolimus. Br J Dermatol 2004; 150:1042.
  7. Rigopoulos D, Prantsidis A, Christofidou E, et al. Pimecrolimus 1% cream in the treatment of disseminated granuloma annulare. Br J Dermatol 2005; 152:1364.
  8. Lopez-Navarro N, Castillo R, Gallardo MA, et al. Successful treatment of perforating granuloma annulare with 0.1% tacrolimus ointment. J Dermatolog Treat 2008; 19:376.
  9. Badavanis G, Monastirli A, Pasmatzi E, Tsambaos D. Successful treatment of granuloma annulare with imiquimod cream 5%: a report of four cases. Acta Derm Venereol 2005; 85:547.
  10. Kuwahara RT, Naylor MF, Skinner RB. Treatment of granuloma annulare with topical 5% imiquimod cream. Pediatr Dermatol 2003; 20:90.
  11. Kassardjian M, Patel M, Shitabata P, Horowitz D. Management of Periocular Granuloma Annulare Using Topical Dapsone. J Clin Aesthet Dermatol 2015; 8:48.
  12. Damsky W, King BA. Treatment of granuloma annulare with tofacitinib 2% ointment. JAAD Case Rep 2020; 6:69.
  13. Weiss JM, Muchenberger S, Schöpf E, Simon JC. Treatment of granuloma annulare by local injections with low-dose recombinant human interferon gamma. J Am Acad Dermatol 1998; 39:117.
  14. Stephenson S, Nedorost S. Granuloma annulare: dramatically altered appearance after application of 5% imiquimod cream. Pediatr Dermatol 2008; 25:138.
  15. Blume-Peytavi U, Zouboulis CC, Jacobi H, et al. Successful outcome of cryosurgery in patients with granuloma annulare. Br J Dermatol 1994; 130:494.
  16. Grundmann-Kollmann M, Ochsendorf FR, Zollner TM, et al. Cream psoralen plus ultraviolet A therapy for granuloma annulare. Br J Dermatol 2001; 144:996.
  17. Salomon N, Walchner M, Messer G, et al. [Bath-PUVA therapy of granuloma annulare]. Hautarzt 1999; 50:275.
  18. Frigerio E, Franchi C, Garutti C, et al. Multiple localized granuloma annulare: ultraviolet A1 phototherapy. Clin Exp Dermatol 2007; 32:762.
  19. Nisticò SP, Saraceno R, Schipani C, et al. Different applications of monochromatic excimer light in skin diseases. Photomed Laser Surg 2009; 27:647.
  20. Do TT, Bailey EC, Wang F, et al. Targeted broadband ultraviolet B phototherapy improves disorders characterized by increased dermal matrix. Br J Dermatol 2009; 161:1405.
  21. Kim YJ, Kang HY, Lee ES, Kim YC. Successful treatment of granuloma annulare with topical 5-aminolaevulinic acid photodynamic therapy. J Dermatol 2006; 33:642.
  22. Weisenseel P, Kuznetsov AV, Molin S, et al. Photodynamic therapy for granuloma annulare: more than a shot in the dark. Dermatology 2008; 217:329.
  23. Kerker BJ, Huang CP, Morison WL. Photochemotherapy of generalized granuloma annulare. Arch Dermatol 1990; 126:359.
  24. Hindson TC, Spiro JG, Cochrane H. PUVA therapy of diffuse granuloma annulare. Clin Exp Dermatol 1988; 13:26.
  25. Dorval JC, Leroy JP, Massé R. [Disseminated granuloma annulare following puvatherapy]. Ann Dermatol Venereol 1979; 106:79.
  26. Sniezek PJ, DeBloom JR 2nd, Arpey CJ. Treatment of granuloma annulare with the 585 nm pulsed dye laser. Dermatol Surg 2005; 31:1370.
  27. Sliger BN, Burk CJ, Alvarez-Connelly E. Treatment of granuloma annulare with the 595 nm pulsed dye laser in a pediatric patient. Pediatr Dermatol 2008; 25:196.
  28. Passeron T, Fusade T, Vabres P, et al. Treatment of granuloma annulare with the 595-nm pulsed dye laser, a multicentre retrospective study with long-term follow-up. J Eur Acad Dermatol Venereol 2013; 27:785.
  29. Grewal SK, Rubin C, Rosenbach M. Antimalarial therapy for granuloma annulare: Results of a retrospective analysis. J Am Acad Dermatol 2017; 76:765.
  30. Steiner A, Pehamberger H, Wolff K. Sulfone treatment of granuloma annulare. J Am Acad Dermatol 1985; 13:1004.
  31. Simon M Jr, von den Driesch P. Antimalarials for control of disseminated granuloma annulare in children. J Am Acad Dermatol 1994; 31:1064.
  32. Carlin MC, Ratz JL. A case of generalized granuloma annulare responding to hydroxychloroquine. Cleve Clin J Med 1987; 54:229.
  33. Cannistraci C, Lesnoni La Parola I, Falchi M, Picardo M. Treatment of generalized granuloma annulare with hydroxychloroquine. Dermatology 2005; 211:167.
  34. Looney M, Smith KM. Isotretinoin in the treatment of granuloma annulare. Ann Pharmacother 2004; 38:494.
  35. Pasmatzi E, Georgiou S, Monastirli A, Tsambaos D. Temporary remission of disseminated granuloma annulare under oral isotretinoin therapy. Int J Dermatol 2005; 44:169.
  36. Tang WY, Chong LY, Lo KK. Resolution of generalized granuloma annulare with isotretinoin therapy. Int J Dermatol 1996; 35:455.
  37. Schleicher SM, Milstein HJ, Lim SJ, Stanton CD. Resolution of disseminated granuloma annulare with isotretinoin. Int J Dermatol 1992; 31:371.
  38. Baskan EB, Turan A, Tunali S. A case of generalized granuloma annulare with myelodysplastic syndrome: successful treatment with systemic isotretinoin and topical pimecrolimus 1% cream combination. J Eur Acad Dermatol Venereol 2007; 21:693.
  39. Schleicher SM, Milstein HJ. Resolution of disseminated granuloma annulare following isotretinoin therapy. Cutis 1985; 36:147.
  40. Martín-Sáez E, Fernández-Guarino M, Carrillo-Gijón R, et al. [Efficacy of dapsone in disseminated granuloma annulare: a case report and review of the literature\]. Actas Dermosifiliogr 2008; 99:64.
  41. Czarnecki DB, Gin D. The response of generalized granuloma annulare to dapsone. Acta Derm Venereol 1986; 66:82.
  42. Pavlovsky M, Samuelov L, Sprecher E, Matz H. NB-UVB phototherapy for generalized granuloma annulare. Dermatol Ther 2016; 29:152.
  43. Yong A, Chong WS, Pan JY. Disseminated granuloma annulare responding to narrowband UVB phototherapy. Photodermatol Photoimmunol Photomed 2016; 32:107.
  44. Cunningham L, Kirby B, Lally A, Collins P. The efficacy of PUVA and narrowband UVB phototherapy in the management of generalised granuloma annulare. J Dermatolog Treat 2016; 27:136.
  45. Muylaert BPB, Almada R, Vasconcelos RCF. Granuloma annulare treated with narrowband UVB phototherapy. An Bras Dermatol 2017; 92:82.
  46. Bala HR, Khan S, Chong AH. Two cases of generalised granuloma annulare successfully treated with acitretin and NB UVB therapy. Australas J Dermatol 2016; 57:327.
  47. Shupack J, Siu K. Resolving granuloma annulare with etanercept. Arch Dermatol 2006; 142:394.
  48. Kreuter A, Altmeyer P, Gambichler T. Failure of etanercept therapy in disseminated granuloma annulare. Arch Dermatol 2006; 142:1236.
  49. Min MS, Lebwohl M. Treatment of recalcitrant granuloma annulare (GA) with adalimumab: A single-center, observational study. J Am Acad Dermatol 2016; 74:127.
  50. Rosmarin D, LaRaia A, Schlauder S, Gottlieb AB. Successful treatment of disseminated granuloma annulare with adalimumab. J Drugs Dermatol 2009; 8:169.
  51. Mahmood T, Mansouri B, Menter A. Successful treatment of generalized granuloma annulare with adalimumab. Clin Exp Dermatol 2015; 40:537.
  52. Chen A, Truong AK, Worswick S. The role of biologics in the treatment of chronic granuloma annulare. Int J Dermatol 2019; 58:622.
  53. Werchau S, Enk A, Hartmann M. Generalized interstitial granuloma annulare--response to adalimumab. Int J Dermatol 2010; 49:457.
  54. Knoell KA. Efficacy of adalimumab in the treatment of generalized granuloma annulare in monozygotic twins carrying the 8.1 ancestral haplotype. Arch Dermatol 2009; 145:610.
  55. Torres T, Pinto Almeida T, Alves R, et al. Treatment of recalcitrant generalized granuloma annulare with adalimumab. J Drugs Dermatol 2011; 10:1466.
  56. Kozic H, Webster GF. Treatment of widespread granuloma annulare with adalimumab: a case report. J Clin Aesthet Dermatol 2011; 4:42.
  57. Hertl MS, Haendle I, Schuler G, Hertl M. Rapid improvement of recalcitrant disseminated granuloma annulare upon treatment with the tumour necrosis factor-alpha inhibitor, infliximab. Br J Dermatol 2005; 152:552.
  58. Murdaca G, Colombo BM, Barabino G, et al. Anti-tumor necrosis factor-α treatment with infliximab for disseminated granuloma annulare. Am J Clin Dermatol 2010; 11:437.
  59. Lytvyn Y, Mufti A, Sachdeva M, et al. Development of granuloma annulare in patients on biologic therapies: A systematic review. J Am Acad Dermatol 2021; 85:1594.
  60. Filotico R, Vena GA, Coviello C, Angelini G. Cyclosporine in the treatment of generalized granuloma annulare. J Am Acad Dermatol 1994; 30:487.
  61. Ho VC. Cyclosporine in the treatment of generalized granuloma annulare. J Am Acad Dermatol 1995; 32:298.
  62. Fiallo P. Cyclosporin for the treatment of granuloma annulare. Br J Dermatol 1998; 138:369.
  63. Spadino S, Altomare A, Cainelli C, et al. Disseminated granuloma annulare: efficacy of cyclosporine therapy. Int J Immunopathol Pharmacol 2006; 19:433.
  64. Granjo E, Lima M, Lopes JM, et al. Response to cyclosporine in a patient with disseminated granuloma annulare associated with CD4+/CD8+(dim)/CD56+ large granular lymphocytic leukemia. Arch Dermatol 2002; 138:274.
  65. Batchelor R, Clark S. Clearance of generalized papular umbilicated granuloma annulare in a child with bath PUVA therapy. Pediatr Dermatol 2006; 23:72.
  66. Schmutz JL. PUVA therapy of granuloma annulare. Clin Exp Dermatol 2000; 25:451.
  67. Setterfield J, Huilgol SC, Black MM. Generalised granuloma annulare successfully treated with PUVA. Clin Exp Dermatol 1999; 24:458.
  68. Muchenberger S, Schöpf E, Simon JC. Phototherapy with UV-A-I for generalized granuloma annulare. Arch Dermatol 1997; 133:1605.
  69. Schnopp C, Tzaneva S, Mempel M, et al. UVA1 phototherapy for disseminated granuloma annulare. Photodermatol Photoimmunol Photomed 2005; 21:68.
  70. Rombold S, Lobisch K, Katzer K, et al. Efficacy of UVA1 phototherapy in 230 patients with various skin diseases. Photodermatol Photoimmunol Photomed 2008; 24:19.
  71. Kroft EB, Berkhof NJ, van de Kerkhof PC, et al. Ultraviolet A phototherapy for sclerotic skin diseases: a systematic review. J Am Acad Dermatol 2008; 59:1017.
  72. Bishnoi A, Raj D, Vinay K, Dogra S. Refractory Generalized Granuloma Annulare Treated With Oral Apremilast. JAMA Dermatol 2019; 155:1318.
  73. Blum S, Altman D. Treatment of generalized granuloma annulare with apremilast: A report of 2 cases. JAAD Case Rep 2019; 5:976.
  74. Hansel K, Biondi F, Bianchi L, et al. Generalized granuloma annulare successfully treated with apremilast: report of two cases and literature review. Clin Exp Dermatol 2021; 46:1603.
  75. Damsky W, Thakral D, McGeary MK, et al. Janus kinase inhibition induces disease remission in cutaneous sarcoidosis and granuloma annulare. J Am Acad Dermatol 2020; 82:612.
  76. Ma A, Medenica M. Response of generalized granuloma annulare to high-dose niacinamide. Arch Dermatol 1983; 119:836.
  77. Rubel DM, Wood G, Rosen R, Jopp-McKay A. Generalised granuloma annulare successfully treated with pentoxifylline. Australas J Dermatol 1993; 34:103.
  78. Hall CS, Zone JJ, Hull CM. Treatment of recalcitrant disseminated granuloma annulare with hydroxyurea. J Am Acad Dermatol 2008; 58:525.
  79. Acharya U. Successful treatment of disseminated granuloma annulare with oral fumaric acid esters. Int J Dermatol 2013; 52:633.
  80. Weber HO, Borelli C, Röcken M, Schaller M. Treatment of disseminated granuloma annulare with low-dose fumaric acid. Acta Derm Venereol 2009; 89:295.
  81. Wollina U. Granuloma annulare disseminatum responding to fumaric acid esters. Dermatol Online J 2008; 14:12.
  82. Duarte AF, Mota A, Pereira MA, et al. Generalized granuloma annulare--response to doxycycline. J Eur Acad Dermatol Venereol 2009; 23:84.
  83. Garg S, Baveja S. Generalized granuloma annulare treated with monthly rifampicin, ofloxacin, and minocycline combination therapy. Indian J Dermatol 2013; 58:197.
  84. Marcus DV, Mahmoud BH, Hamzavi IH. Granuloma annulare treated with rifampin, ofloxacin, and minocycline combination therapy. Arch Dermatol 2009; 145:787.
  85. Naka F, Strober BE. Methotrexate treatment of generalized granuloma annulare: a retrospective case series. J Dermatolog Treat 2018; 29:720.
  86. Poppe H, Poppe LM, Goebeler M, Trautmann A. Treatment of disseminated granuloma annulare with oral vitamin E: 'primum nil nocere'. Dermatology 2013; 227:83.
  87. Piaserico S, Zattra E, Linder D, Peserico A. Generalized granuloma annulare treated with methylaminolevulinate photodynamic therapy. Dermatology 2009; 218:282.
  88. Karsai S, Hammes S, Rütten A, Raulin C. Fractional photothermolysis for the treatment of granuloma annulare: a case report. Lasers Surg Med 2008; 40:319.
  89. Liu A, Hexsel CL, Moy RL, Ozog DM. Granuloma annulare successfully treated using fractional photothermolysis with a 1,550-nm erbium-doped yttrium aluminum garnet fractionated laser. Dermatol Surg 2011; 37:712.
  90. Bronfenbrener R, Ragi J, Milgraum S. Granuloma annulare treated with excimer laser. J Clin Aesthet Dermatol 2012; 5:43.
  91. Verne SH, Kennedy J, Falto-Aizpurua LA, et al. Laser treatment of granuloma annulare: a review. Int J Dermatol 2016; 55:376.
  92. Sabuncuoğlu H, Oge K, Söylemezoğlu F, Sağlam A. Subcutaneous granuloma annulare of the scalp in childhood: a case report and review of the literature. Turk Neurosurg 2007; 17:19.
  93. Felner EI, Steinberg JB, Weinberg AG. Subcutaneous granuloma annulare: a review of 47 cases. Pediatrics 1997; 100:965.
  94. Jankowski PP, Krishna PH, Rutledge JC, et al. Surgical management and outcome of scalp subcutaneous granuloma annulare in children: case report. Neurosurgery 2008; 63:E1002; discussion E1002.
  95. McNeal S, Daw JL Jr. Subcutaneous granuloma annulare: an unusual presentation in the eyelids and scalp. Ann Plast Surg 2005; 55:684.
  96. Endo Y, Sekiguchi A, Motegi SI, Ishikawa O. Subcutaneous granuloma annulare on the heel: A case report and review of the Japanese published work. J Dermatol 2020; 47:677.
  97. Tsubouchi K, Kato H, Nishida E, et al. Successful treatment of subcutaneous granuloma annulare with bath-psoralen plus ultraviolet A therapy. J Dermatol 2015; 42:1114.
  98. Yang Y, Zheng S, Li XD, et al. Case of successful treatment of subcutaneous granuloma annulare with local hyperthermia. J Dermatol 2017; 44:e246.
  99. Mutasim DF, Bridges AG. Patch granuloma annulare: clinicopathologic study of 6 patients. J Am Acad Dermatol 2000; 42:417.
  100. Aichelburg MC, Pinkowicz A, Schuster C, et al. Patch granuloma annulare: clinicopathological characteristics and response to phototherapy. Br J Dermatol 2019; 181:198.
  101. Levin NA, Patterson JW, Yao LL, Wilson BB. Resolution of patch-type granuloma annulare lesions after biopsy. J Am Acad Dermatol 2002; 46:426.
  102. Penas PF, Jones-Caballero M, Fraga J, et al. Perforating granuloma annulare. Int J Dermatol 1997; 36:340.
  103. Patrizi A, Gurioli C, Neri I. Childhood granuloma annulare: a review. G Ital Dermatol Venereol 2014; 149:663.
  104. Wells RS, Smith MA. The Natural History of Granuloma Annulare. Br J Dermatol 1963; 75:199.
  105. Zhong W, Shao Y, Ye T, et al. Perforating granuloma annulare: a case report and literature review. J Eur Acad Dermatol Venereol 2016; 30:1246.
Topic 132093 Version 1.0

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