> Table of Contents > Granuloma Annulare
Granuloma Annulare
Mary Iaculli, DO
Joanne Wilkinson, MD, MSc
image BASICS
DESCRIPTION
A benign skin condition characterized by grouped, flesh-colored, or erythematous papules, which typically occur in an annular (ring-like) pattern. Five variants have been described; the most common of which is localized granuloma annulare (GA). The other types are generalized, patch type, subcutaneous (SC) (deep dermal), and perforating.
EPIDEMIOLOGY
Incidence
  • GA is not common, although exact prevalence in the general population is unknown.
  • Predominant sex: female > male (2.5:1)
  • Most lesions resolve in 2 to 24 months but may last up to 5 to 10 years. 2/3 of patients are <30 years, and the age distribution varies by type, as follows:
    • Localized: children and adults <30 years
    • Generalized: bimodal: children <10 years and adults 30 to 60 years
    • Patch type: adults >30 years
    • SC: children 2 to 10 years
    • Perforating: typically children but also young adults
Prevalence
Among cases of GA, the approximate distribution is as follows:
  • Localized: 75%
  • Generalized: 10-15%
  • Patch type: <5%
  • Subcutaneous: <5%
  • Perforating: <5% (perhaps higher in Hawaii)
ETIOLOGY AND PATHOPHYSIOLOGY
The cause of GA remains unknown, although it is hypothesized to be a delayed-type hypersensitivity to an unknown antigen. Lymphohistiocytic infiltrates, degeneration of collagen, and mucin deposition are characteristic histopathologic features of GA.
Genetics
There is some evidence for a possible hereditary component. Increased frequency of HLA-B35 in patients with generalized GA were reported in two studies (1,2).
RISK FACTORS
No definite risk factors have been identified. There is some evidence for possible associations with diabetes mellitus; TB; HIV, EBV, and other viral infections (including HSV); interferon-&agr; therapy; trauma; insect bites; borreliosis; and malignancies (most commonly lymphoma).
GENERAL PREVENTION
There are no established strategies for preventing GA.
COMMONLY ASSOCIATED CONDITIONS
  • Diabetes mellitus: There are conflicting reports about the association of GA with diabetes mellitus, and methodological design for these studies is weak. One retrospective study of 557 aged-matched patients found a higher incidence in localized GA with insulin-dependent diabetes mellitus (3). Another retrospective study reported higher incidence of diabetes mellitus in generalized GA versus localized GA (4). In contrast, two small studies, one is a case control and one is a prospective study, did not reveal an association between these disorders (5,6).
  • Malignancy: There is a possible association with GA and malignancy; however, data is severely lacking. Cases linked with malignancy most commonly had an atypical presentation of GA with lymphoma (7).
  • Dyslipidemia: Dyslipidemia may be associated with GA. A case-control study of 140 adults showed a statistically significant increase in elevated lipids in patients with GA, most commonly generalized GA (8).
  • HIV: There are many case reports suggesting an association between GA and HIV. Generalized GA is most common pattern with HIV.
  • For all associations, weak evidence exists through poorly designed, underpowered studies. More investigations are necessary.
image DIAGNOSIS
PHYSICAL EXAM
  • Localized: asymptomatic, flesh-colored, or erythematous annular or arciform plaque with a moderately firm, rope-like border and central clearing, ranging from 5-mm to 5-cm in diameter. Small 1- to 2-mm papules may be noted in periphery, often not in continuous border. The most common locations are the dorsal aspects of the distal extremities. Involvement of palms is rare. 50% will have multiple lesions.
  • Generalized: similar to localized but a higher number of lesions (>10), which are more diffuse distribution, often larger, and typically persist longer
  • Patch type: erythematous macules and patches distributed symmetrically on the extremities and trunk. The typical annular configuration may or may not be present; often involves proximal extremities.
  • SC: firm, nontender, SC nodule, which tends to grow rapidly; usually solitary but may occur in groups. Most common location is scalp or lower extremities, especially pretibial; other sites include upper extremities and buttocks.
  • Perforating: Damaged collagen from dermis is extruded onto skin surface. Papules may be up to 4 mm and display yellowish umbilication, crusting, or scale. Lesions are often generalized and may occur anywhere. Lesions often heal with scar.
DIFFERENTIAL DIAGNOSIS
  • Localized: tinea corporis, annular lichen planus, necrobiosis lipoidica, pityriasis rosea, erythema migrans of Lyme disease, leprosy
  • Generalized: sarcoidosis, lichen planus, cutaneous metastases, mycosis fungoides
  • Patch type: erythema migrans
  • SC: rheumatoid nodule
  • Perforating: molluscum contagiosum, sarcoidosis, insect bites
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Diagnosis is typically established by history and physical, so lab investigations are rarely needed. Skin scraping/KOH test may be useful for excluding a fungal process.
  • May consider work up for dyslipidemia, DM, HIV, and malignancy if clinically indicated
Diagnostic Procedures/Other
Skin punch biopsy is useful to confirm the diagnosis and designate subtype. Immunohistochemical streptavidin-biotin-horseradish peroxidase (HRP) analysis for CD68/KP-1, which is a marker for histiocytic differentiation, may aid in the diagnosis.
Test Interpretation
Dermal granulomatous infiltrate demonstrating foci of degenerative collagen associated with palisading around an anuclear dermis with mucin deposition. Histologic variants include interstitial (histiocytic infiltrate between collagen fibers), classic (palisading dermal granulomas), and epithelioid (tuberculoid and sarcoidal granulomas).
image TREATMENT
GENERAL MEASURES
GA is a self-limited, asymptomatic condition that is likely to regress spontaneously. The clinician's primary role after diagnosis is to educate the patient regarding the anticipated natural history and to provide reassurance.
P.425

MEDICATION
  • No strong evidence supports therapeutic intervention for GA. Reassurance with observation may be an adequate treatment for localized, asymptomatic disease.
  • The trauma induced by biopsy alone can cause involution of the lesions through an unknown mechanism.
  • The following therapies have been tried with variable success, and the possible benefit of treatment must be weighed against the significant toxicities of these treatments.
First Line
Corticosteroids (9)
  • High-potency topical, with or without occlusion
  • Intralesional triamcinolone: 2.5 to 5 mg/mL
Second Line
  • Methotrexate: 15 mg IM weekly (10)
  • Rifampin: 600 mg, ofloxacin 400 mg, with minocycline 100 mg once daily (11)
  • Pimecrolimus 1% cream BID
  • Isotretinoin: 0.5 to 0.75 mg/kg/day
  • Dapsone: 100 mg/day
  • Chloroquine: 3 mg/kg/day
  • Hydroxychloroquine: 3 to 6 mg/kg/day
  • Cyclosporine: 3 to 4 mg/kg/day
  • Niacinamide: 500 mg TID
  • TNF-&agr; inhibitors, such as infliximab 5 mg/kg IV weeks 0, 2, and 6 and monthly thereafter for 10 months or adalimumab 80 mg SC × 1 for the 1st week then 40 SC × 1 for weeks 2 to 4
ADDITIONAL THERAPIES
  • Fractional thermolysis (Er:YAG fractionated laser)
  • Psoralen ultraviolet A (PUVA)
  • Cryotherapy
  • Surgical excision for SC GA
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Routine follow-up is not required unless treatment is initiated. Then follow-up may be important to monitor for possible adverse effects associated with treatment. Referral to a dermatologist is prudent in cases of generalized GA and in those cases that persist despite conservative therapy.
PATIENT EDUCATION
The patient should be educated that GA is a benign, self-limited condition that may persist a long time, resolve, and/or recur.
PROGNOSIS
>50% of cases resolve spontaneously within 2 months to 2 years; although recurrence, typically at the original site, is common (>40%). Patients <39 years have been shown to have a shorter duration of illness.
REFERENCES
1. Friedman-Birnbaum R, Haim S, Gideone O, et al. Histocompatibility antigens in granuloma annulare. Comparative study of the generalized and localized types. Br J Dermatol. 1978;98(4):425-428.
2. Friedman-Birnbaum R, Gideoni O, Bergman R, et al. A study of HLA antigen associated in localized and generalized granuloma annulare. Br J Dermatol. 1986:115(3):329-333.
3. Muhlemann MF, Williams DR. Localized granuloma annulare is associated with insulin-dependent diabetes mellitus. Br J Dermatol. 1984;111(3):325-329.
4. Dabski K, Winkelmann RK. Generalized granuloma annulare: clinical and laboratory findings in 100 patients. J Am Acad Dermatol. 1989;20(1): 39-47.
5. Nebesio CL, Lewis C, Chuang TY. Lack of an association between granuloma annulare and type 2 diabetes mellitus. Br J Dermatol. 2002;146(1): 122-124.
6. Gannon TF, Lynch PJ. Absence of carbohydrate intolerance in granuloma annulare. J Am Acad Dermatol. 1994;30(4):662-663.
7. Li A, Hogan DJ, Sanusi ID, et al. Granuloma annulare and malignant neoplasms. Am J Dermatopathol. 2003;25(2):113-116.
8. Wu W, Robinson-Bostom L, Kokkotou E, et al. Dyslipidemia in granuloma annulare: a case-control study. Arch Dermatol. 2012;148(10):1131-1136.
9. Cyr PR. Diagnosis and management of granuloma annulare. Am Fam Physician. 2006;74(10): 1729-1734.
10. Plotner AN, Mutasim DF. Successful treatment of disseminated granuloma annulare with methotrexate. Br J Dermatol. 2010;163(5):1123-1124.
11. Marcus DV, Mahmoud BH, Hamzavi IH. Granuloma annulare treated with rifampin, ofloxacin, and minocycline combination therapy. Arch Dermatol. 2009;145(7):787-789.
Additional Reading
&NA;
  • Browne F, Turner D, Goulden V. Psoralen and ultraviolet A in the treatment of granuloma annulare. Photodermatol Photoimmunol Photomed. 2011;27(2):81-84.
  • Duarte AF, Mota A, Pereira MA, et al. Generalized granuloma annulare—response to doxycycline. J Eur Acad Dermatol Venereol. 2009;23(1):84-85.
  • Liu A, Hexsel CL, Moy RL, et al. Granuloma annulare successfully treated using fractional photothermolysis with a 1,550-nm erbium-doped yttrium aluminum garnet fractionated laser. Dermatol Surg. 2011;37(5):712-715.
  • Mazzatenta C, Ghilardi A, Grazzini M. Treatment of disseminated granuloma annulare with allopurinol: case report. Dermatol Therapy. 2010;(23 Suppl 1):S24-S27.
  • Misago N, Narisawa Y. Subcutaneous granuloma annulare with overlying localized granuloma annulare. J Dermatol. 2010;37(8):755-757.
  • Plotner AN, Mutasim DF. Successful treatment of disseminated granuloma annulare with methotrexate. Br J Dermatol. 2010;163(5):1123-1124.
  • Shanmuga SC, Rai R, Laila A, et al. Generalized granuloma annulare with tuberculoid granulomas: a rare histopathologic variant. Indian J Dermatol Venereol Leprol. 2010;76(1):73-75.
  • Werchau S, Enk A, Hartmann M. Generalized interstitial granuloma annulare—response to adalimumab. Int J Dermatol. 2010;49(4):457-460.
  • Wu W, Robinson-Bostom L, Kokkotou E, et al. Dyslipidemia in granuloma annulare: a case-control study. Arch Dermatol. 2012;148(10):1131-1136.
Codes
&NA;
ICD10
L92.0 Granuloma annulare
Clinical Pearls
&NA;
  • This condition is benign and often self resolves. Consider risk-benefit with patient when discussing treatment.
  • In cases of suspected tinea that lack scaling, consider GA.
  • Consider lipid testing, especially in those with generalized subtype.