Granuloma Annulare

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Background

Granuloma annulare (GA) is a benign inflammatory dermatosis. T. Colcott Fox first described granuloma annulare in 1895; however, not until 1902 did Radcliffe-Crocker label it as granuloma annulare.

Granuloma annulare is relatively common disease that occurs in all age groups, but it is rare in infancy. Granuloma annulare is characterized clinically by dermal papules and annular plaques. The precise cause of granuloma annulare is unknown. Histological examination reveals foci of degenerative collagen associated with palisaded granulomatous inflammation.

The following clinical variants are recognized:

Some authorities consider actinic granuloma (AG) to be a subset of granuloma annulare, but others view actinic annulare as a separate, but related, entity.[4]

Pathophysiology

Proposed pathogenic mechanisms for granuloma annulare include cell-mediated immunity (type IV), immune complex vasculitis, and an abnormality of tissue monocytes. Some other possible mechanisms include primary degeneration of connective tissue leading to granulomatous inflammation, lymphocyte-mediated immune reaction with macrophage activation, and cytokine-mediated degradation of connective tissue.

Epidemiology

Frequency

International

The frequency of granuloma annulare is in the general population is unknown. Granuloma annulare does not favor a particular race, ethnic group, or geographical area.

Mortality/Morbidity

Most cases of granuloma annulare resolve without adverse medical sequelae.

Sex

Women are affected by granuloma annulare twice as often as men.

Age

History

Physical

Causes

The etiology of granuloma annulare is usually unknown, and the pathogenetic mechanisms are poorly understood, with a vast majority of granuloma annulare cases occurring in patients who are otherwise healthy. The range of predisposing events and associated diseases is diverse, and granuloma annulare is thought to represent a reaction pattern with many different initiating factors.

Granuloma annulare has been hypothesized to be associated with tuberculosis, insect bites, trauma, sun exposure, thyroiditis, vaccinations, and viral infections, including HIV, Epstein-Barr virus, hepatitis B virus, hepatitis C virus, and herpes zoster virus. However, these suggested etiologic factors remain unproven.

Familial cases of granuloma annulare observed in identical twins and siblings in several generations, along with an association of granuloma annulare with HLA phenotypes, suggest the possibility of a hereditary component in some cases. The HLA-B8 level has been reported to be increased in localized granuloma annulare; HLA-A29 and HLA-BW35 levels are reported to be increased in generalized granuloma annulare.

Some reports associate chronic stress with granuloma annulare as a trigger of the disease. Granuloma annulare also has some predilection for the sun-exposed areas and photodamaged skin. Photosensitive granuloma annulare has been found in association with HIV infection. Finally, some cases of granuloma annulare or granuloma annulare–like reactions have been reported after gold therapy and treatment with allopurinol, diclofenac, quinidine, calcitonin, amlodipine, ACE inhibitors, daclizumab,[5] and calcium channel blockers.

Relationship to systemic diseases

Granuloma annulare has been associated primarily with type I diabetes mellitus, but it is only rarely associated with type II diabetes mellitus and thyroid disease, based on an increased number of granuloma annulare patients with these diseases in small case series.[6]

Small case series have reported granuloma annulare to occur in association with malignancy, AIDS, and herpes zoster lesions. Although no definite patterns relating granuloma annulare and systemic disease have been thoroughly established, it has been suggested that an atypical histologic (vasculopathy or extravascular neutrophilia) or clinical presentation (unusual appearance or location) may indicate an associated disease. In the case of malignancy, a 2003 study by Li et al reviewed classic cases in the literature and could find no definite relationship between granuloma annulare and malignant neoplasms.[7]

Relationship with malignant diseases

Certain malignancies are accompanied by different mucocutaneous paraneoplastic syndromes. Lesions that mimic granuloma annulare or are histologically confirmed as granuloma annulare have occurred in association with:

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Early interstitial or incomplete granuloma annulare lesions show an interstitial pattern characterized by lymphocytes around vessels of the superficial and deep plexuses and by macrophages scattered between reticular dermal collagen bundles that are separated by mucin within which mast cells may be found. Mucin in granuloma annulare is hyaluronic acid and is visible in sections stained with hematoxylin and eosin as faintly basophilic stringy material. Its presence can be confirmed by staining with colloidal iron or Alcian blue at pH 2.5.

Fully evolved granuloma annulare lesions and deep subcutaneous granuloma annulare nodules demonstrate palisaded granulomatous dermatitis or a septal and lobular panniculitis, respectively. Macrophages surround acellular necrobiotic areas in which collagen bundles are thinned, or they sometimes have a pale, homogeneous, light-blue appearance, the latter of which is due to the presence of mucin.

In many cases of subcutaneous granuloma annulare, and in some dermal infiltrates, the centers of granulomas contain degenerated, homogeneous-appearing collagen and are deeply eosinophilic. In some sections, necrotic small vessels in the centers of palisaded foci are surrounded by nuclear dust. Presence of fibrinogen can be shown by direct immunofluorescence in the centers of palisaded granulomas. In perforating lesions, necrobiotic material is extruded through focal perforations. Epidermal hyperplasia at the edge of the perforation forms a pseudochannel communicating with an underlying necrobiotic granuloma.

Rare cases of nonnecrobiotic, sarcoidal, or tuberculoid granuloma annulare are also described.

Actinic annulare, also known as annular elastolytic giant cell granuloma, may lack the classic palisaded arrangement observed in granuloma annulare. Although elastosis is abundant in the mid dermis outside the granuloma, elastic tissue is absent from the center of the annulus. Giant cells frequently abut elastotic tissue, and phagocytosed elastotic fibers are noted in histiocytic cells at the advancing edge. Collagen has a normal appearance outside the lesion but a finely fibrillar pattern within the annulus. Mucin deposition is not increased as it is in granuloma annulare. Thus, actinic annulare can be distinguished histologically from granuloma annulare by a preponderance of giant cells in relation to elastotic tissue, by absence of mucin, and, occasionally, by absence of palisading histiocytes around granulomas.

Medical Care

Localized granuloma annulare

Localized granuloma annulare (GA) is not often symptomatic and it has a tendency towards spontaneous resolution. Reassurance is often all that is necessary. Painful or disfiguring lesions have been treated by various methods, although the level of evidence supporting these methods is low.

Localized lesions have been treated with potent topical corticosteroids with or without occlusion for 4-6 weeks, as well as with intralesional corticosteroids with varying total doses of steroid.

Cryotherapy using liquid nitrogen or nitrous oxide as refrigerants has been shown in a prospective, uncontrolled trial to be an effective treatment for localized granuloma annulare. Secondary dyschromia may be a complication of cryotherapy.[11]

Other anecdotes of therapeutic efficacy in both localized and generalized granuloma annulare involve tacrolimus and pimecrolimus[12, 13, 14] and imiquimod cream.[15, 16]

Generalized granuloma annulare

Generalized granuloma annulare tends to be more persistent and unsightly. Treatment of the generalized disease is unfortunately fraught with a lack of consistently effective options. While the treatment of choice remains to be defined, the available literature supports the use of isotretinoin or phototherapy with oral psoralen and UV-A (PUVA) as first-line options for generalized granuloma annulare.[17, 18, 19]

Piaserico et al report successful therapy for long-standing generalized granuloma annulare using methyl aminolevulinate photodynamic therapy.[20] Weisenseel et al reported moderate success with photodynamic therapy using 20% 5-aminolevulinic acid (ALA) gel.[21]

Marcus et al report on 6 patients with granuloma annulare that was refractory to standard treatment. The patients were treated with monthly combination therapy including rifampin at 600 mg, ofloxacin at 400 mg, and minocycline hydrochloride at 100 mg monthly for 3 months. Three to 5 months after the initiation of treatment, the plaques were cleared completely. Postinflammatory hyperpigmentation was reported by some patients. Although the treatment was successful, the authors suggested further studies may be needed to confirm this combination therapy as a successful option for recalcitrant granuloma annulare.[22]

Other anecdotal reports and small series describe successful treatment with dapsone, narrow-band UVB, systemic steroids, pentoxifylline, hydroxychloroquine, cyclosporine, fumaric esters, interferon-gamma, potassium iodide, nicotinamide, etanercept, infliximab, adalimumab, and efalizumab.[23, 24, 25]

Consultations

A clinical guideline, the 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections, may be helpful.[26]

Medication Summary

Therapies that may be considered as initial approaches for patients seeking therapy for localized granuloma annulare include intralesional corticosteroids, potent topical corticosteroids alone or under occlusion, and cryotherapy.

Patients with generalized granuloma annulare may accept more aggressive treatment because of the chronicity or pronounced cosmetic disfigurement associated with the disease. Generalized granuloma annulare may be treated initially with isotretinoin or PUVA, if not otherwise contraindicated.

Clobetasol (ointment, cream, lotion) 0.05% (Temovate, Olux)

Clinical Context:  For inflammatory dermatoses responsive to steroids. Decreases inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability. Affects production of lymphokines and has inhibitory effect on Langerhans cells.

Triamcinolone acetonide (Aristocort, Kenalog)

Clinical Context:  For inflammatory dermatoses responsive to steroids. Decreases inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability. Affects production of lymphokines and has inhibitory effect on Langerhans cells.

Prednisone (Deltasone, Orasone)

Clinical Context:  Synthetic corticosteroid, strong immunosuppressant, and anti-inflammatory drug with proven effects in cutaneous inflammatory disorders.

Class Summary

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Isotretinoin (Accutane)

Clinical Context:  Oral agent that treats serious dermatologic conditions. Synthetic 13-cis isomer of the naturally occurring tretinoin (trans -retinoic acid). Both agents are structurally related to vitamin A. Should be prescribed only by physicians experienced and/or trained in its use.

A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

Class Summary

Vitamin A derivatives have many roles. They encourage cellular differentiation, are antiproliferative, and serve as immunomodulators.

Methoxsalen plus UVA (8-MOP, Oxsoralen)

Clinical Context:  Inhibits mitosis by binding covalently to pyrimidine bases in DNA when photoactivated by UV-A. May have a direct cytotoxic effect on activated histiocytes, fibroblasts, and lymphocytes in dermal infiltrate of lesions. May control lymphokine production through modulation of activated lymphocytes.

Class Summary

These agents inhibit cell proliferation.

Complications

Prognosis

Author

Ruby Ghadially, MBChB, FRCP(C)Derm, Professor, Department of Dermatology, University of California, San Francisco, School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Akos Z Szabo, MD, Resident Physician, Department of Obstetrics and Gynecology, University of Heidelberg Medical Center, Germany

Disclosure: Nothing to disclose.

Amit Garg, MD, Director of Clinical Elective in Dermatology, Assistant Professor, Department of Internal Medicine, Division of Dermatology, University of Massachusetts Medical School

Disclosure: Abbott Immunology Honoraria Speaking and teaching; Centocor Grant/research funds Other; RegenRx Grant/research funds Other

Specialty Editors

Arash Taheri, MD, Research Fellow, Center for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Steven R Feldman, MD, PhD, Professor, Departments of Dermatology, Pathology and Public Health Sciences, Wake Forest University Health Sciences; Director, Center for Dermatology Research, Director, Psoriasis Treatment Center, Director of Industry Relations, Department of Dermatology, Wake Forest University School of Medicine

Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Galderma Honoraria Speaking and teaching; Taro Consulting fee Consulting; www.DrScore.com Ownership interest Management position; Causa Reseasrch Ownership interest Management position; Janssen Consulting; Pfizer Honoraria Speaking and teaching; Novartis Consulting fee Consulting; Celgene Consulting fee Consulting

Catherine M Quirk, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Nothing to disclose.

References

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  2. Felner EI, Steinberg JB, Weinberg AG. Subcutaneous granuloma annulare: a review of 47 cases. Pediatrics. Dec 1997;100(6):965-7. [View Abstract]
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