Chapter 173. Granuloma Annulare

A 39-year-old woman presents with raised rings on her right hand only. Not knowing the correct diagnosis, another physician prescribed topical steroids and antifungal medicines with no benefit. The diagnosis of granuloma annulare (GA) was made by the typical clinical appearance and the patient was offered intralesional steroids. Triamcinolone acetonide was injected as seen in Figure 173-1, A. The patient noted improvement over the subsequent weeks, but within a month new lesions began to appear on her other hand (Figure 173-1, B). Additional injections were provided and 1 month later the patient had regression of the treated lesions but had new lesions on the right arm (Figure 173-2, A). At the next visit, the patient had new lesions on her feet as well (Figure 173-2, B). The diagnosis of disseminated GA was made and systemic treatment was started.

GA is a common dermatologic condition that presents as small, light-red, dermal papules coalescing into annular plaques without scale. As in the above vignette, it is often mistaken as nummular eczema or tinea corporis. Distribution, pattern, and lack of scale are important diagnostic clues.

• GA affects twice as many women as men.1
• The four presentations of GA are localized, disseminated/generalized, perforating, and subcutaneous.
• Of the four variations, the localized form is seen most often.1

• Benign cutaneous, inflammatory disorder of unknown origin.1
• Disease may be self-limiting, but may persist for many years.
• Reported associations include diabetes mellitus, viral infections (including HIV), Borrelia and streptococcal infections, insect bites, lymphoma, tuberculosis, and trauma.2,3
• One proposed mechanism for GA is a delayed-type hypersensitivity reaction as a result of T-helper-type cell (Th)-1 lymphocytic differentiation of macrophages. These macrophages become effector cells that express tumor necrosis factor (TNF)-α and matrix metalloproteinases. The activated macrophages are responsible for dermal collagen matrix degradation.4
• An association between high expression of gil-1 oncogene and granulomatous lesions of the skin, including GA, has been established.5

The only identifiable risk factor is being a woman. There are several associations, but nothing has been shown to be causative.

Clinical Features

Annular lesions have raised borders that are skin-colored to erythematous (Figures 173-1 and 173-2). The rings may become hyperpigmented or violaceous (Figure 173-2, B). There is often a central depression within the ring. These lesions range from 2 mm to 5 cm. Although the classical appearance of GA is annular, the lesions may be arcuate instead of forming a complete ring (Figure 173-3). Most importantly, there should be no scaling as seen in tinea corporis (ringworm).

Typical Distribution

Each of the four types of GA has a different distribution. Localized and disseminated GA differ only in that disseminated lesions can spread to the trunk and neck and may be more pronounced in sun-exposed areas.6

• Localized—This is the most common form of GA affecting 75% of GA patients.1 It typically presents as solitary lesions on the dorsal surfaces of extremities, especially of hands and feet (Figure 173-4).
• Disseminated or generalized—Adults are most affected by this form, which begins in the extremities and can spread to the trunk and neck (Figure 173-5).
• Perforating—Children and young adults present with 1 to hundreds of 1- to 4-mm annular papules that may coalesce to form a typical annular plaque. Although this form can appear anywhere on the body, it has an affinity for extremities, especially the hands and fingers.7 The papules may exude a thick and creamy or clear and viscous fluid.
• Subcutaneous—These lesions present as rapidly growing, nonpainful, subcutaneous or dermal nodules on the extremities, scalp, and forehead. Subcutaneous GA mainly affects children, with a mean age of 3.9 years (Figure 173-6).6 These lesions are often ill defined and less discrete.

Laboratory Studies

Often a diagnosis of GA is made on clinical presentation alone, without the need for biopsy. Subcutaneous GA may be an exception, as the unusual appearance may be mistaken for a rheumatoid nodule. Histologic examination reveals an increase of mucin, which is a hallmark of GA. There is also a dense infiltrate of histiocytes in the mid-dermis and sparse perivascular lymphocytic infiltrate. The histiocytes are either organized as palisading cells lining a collection of mucin or as a diffuse interstitial pattern. There are no signs of epidermal change.3

• Tinea corporis has a raised, scaling border and can present on any body surface. KOH preparation reveals hyphae with multiple branches (see Chapter 138, Tinea Corporis).
• Erythema annulare centrifugum has an affinity for thighs and legs. The diameter of these lesions can expand at a rate of 2 to 5 mm/day and may present with a trailing scale inside the advancing border.2 Biopsy is helpful to differentiate this condition from GA (see Chapter 206, Erythema Annulare Centrifugum).
• Nummular eczema presents commonly on extremities, but is almost always associated with scaling plaques and intense itching (see Chapter 148, Nummular Eczema).
• Pityriasis rosea often has oval lesions with a trailing collarette of scale. The lesions are minimally raised and have scale that is absent in GA (see Chapter 153, Pityriasis Rosea).
• Rheumatoid nodules may mimic appearance of subcutaneous GA. These nodules are often seen over the elbows, fingers, and other joints in a patient with joint pains and other clinical signs of arthritis (see Chapter 97, Rheumatoid Arthritis). Rheumatoid nodules have fibrin deposition on histologic examination, in contrast to mucin in GA.

The evidence for various treatments is at best small series of cases that are not randomized controlled trials. This disease is asymptomatic, and treatments only improve cosmetic appearance. Many patients may want intervention as diffuse lesions can cause psychological distress. Although GA will eventually resolve, some treatments may cause pigment change or atrophy that might be permanent. Several of the treatments below have shown promise, but these treatments may appear to work when in fact the resolution was natural.

Localized GA:

• In a retrospective study of children with localized GA (mean age: 8.6 years), 39 of 42 presented with complete clearance within 2 years. The average duration was 1 year. Researchers of this study consider most treatments unnecessary because of the self-limiting nature of this variation.7 One treatment option is watchful waiting.8 SOR B
• Intralesional corticosteroids can be injected into GA lesions with resolution of the area injected (Figure 173-1). Inject directly into the ring itself with 3 to 5 mg/mL triamcinolone acetonide (Kenalog) using a 27-gauge needle. SOR C A large completed ring may take 4 injections to reach 360 degrees of the circle. The major complications include hypopigmentation (Figure 173-2, A) and skin atrophy at the injected sites.
• Cryotherapy was studied using nitrous oxide for 9 patients and liquid nitrogen for 22 patients. The results showed 80% clearing after a single freeze; however, 4 of 19 patients treated with liquid nitrogen developed atrophic scars when lesions were larger than 4 cm. All patients developed blisters.9 Cryoatrophy may possibly be prevented by avoiding freeze thaw cycles greater than 10 seconds and not overlapping treatment areas.10 SOR C
• A 53-year-old Hispanic woman with GA on the dorsal surface of both hands agreed to treatment with cryotherapy on the right hand and intralesional steroids on the left hand (Figure 173-7). Cryotherapy was performed using a 9- to 10-second freeze time and a single freeze. The intralesional injections were performed with a 30-gauge needle and 5 mg/mL triamcinolone (10 mg/mL diluted 1:1 with 1% lidocaine). During the treatment the patient rated the pain from cryotherapy as 9 out of 10 and intralesional steroid 2 out of 10. Figure 173-7 shows the initial lesions and final results after 1 month. The patient was happy with the results of intralesional steroid and disappointed with the results of the cryotherapy. The lesion treated with cryotherapy did not resolve and spotted areas of hyperpigmentation and hypopigmentation occurred. Upon questioning, the patient states that the lesion treated with cryotherapy was painful for many days whereas she had no residual pain from the lesion treated with intralesional steroid. The patient then asked for the two remaining lesions on her right hand to be injected with steroid. Although this is a single case example, we could find no published studies of a head-to-head comparison between these commonly used methods for local treatment of GA.

Generalized/disseminated GA:

• This variant is more difficult to treat, and often has a longer duration than localized GA. Many treatments have been claimed to be effective, but the studies touting these treatments have small sample sizes and were not randomized.
• In 2009, Marcus et al. reported the successful treatment of 6 patients with a combination of rifampin 600 mg, ofloxacin 400 mg, and minocycline 100 mg. All patients had complete clearance after 3 to 5 months of treatment.11
• Successful treatment of 6 patients with GA was achieved with 100 mg of dapsone, once a day. Complete clearance in all patients took between 4 weeks and 3 months.12 SOR C
• UVA1 phototherapy provided good or excellent results in 10 of 20 patients with disseminated GA. In patients with only a satisfactory treatment response, the disease reappeared soon after phototherapy was discontinued.13 SOR C
• In a study of 4 patients, topical 5% imiquimod cream was effective when used once daily for an average of 2 months. After discontinuing treatment, 3 patients went an average of 12 months without recurrence; the fourth patient had remission 10 days after treatment stopped, but after an additional 6 weeks of applying cream once daily, he was lesion-free for 18 months.14 SOR C
• Four patients were treated with twice-daily topical application of 0.1% tacrolimus ointment for 6 weeks; all reported improvement after 10 to 21 days. At treatment conclusion, two patients had complete clearance and the other two had marked improvement.15 SOR C
• Treatment with 0.5 to 1 mg/kg of isotretinoin daily has produced some positive results across multiple small studies; however, because of the potential for adverse effects, this option should be reserved for the most severe, nonresponsive cases in patients who are at low risk for the adverse effects of isotretinoin.16 SOR C
• Three patients were treated with vitamin E 400 IU daily and zileuton 2400 mg daily. All responded within 3 months with complete clinical clearing.17 SOR C

Perforating, subcutaneous:

• Although we could find no specific data to inform the treatment of these less-common types of GA, treatments for both localized and disseminated GA could be applied based on clinical judgment along with patient's severity and preferences.

In 50% of cases there is spontaneous resolution within 2 years; however, recurrence rate is as high as 40%.18 Patients with skin of color may have postinflammatory hyperpigmentation once the papules and plaques resolve.

Follow-up visits should be offered to patients who want active treatment.

It is important to reassure patients that this disease is self-limiting. Despite a displeasing appearance, the best treatment may be to let lesions resolve naturally. Numerous individual case studies and treatments have been attempted without consistent success. Treatments may produce side effects that are equally as unwanted, but more permanent, than the GA.

Patient Resources

• Skinsight. Granuloma Annulare: Information for Adults—http://www.skinsight.com/adult/granulomaAnnulare.htm.

Provider Resources

• Medscape.Granuloma Annulare—http://emedicine.medscape.com/article/1123031.