Granuloma Annulare

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Background

Granuloma annulare (GA) is a benign inflammatory dermatosis. It is a relatively common disease that occurs in all age groups, though it is rare in infancy.[1, 2] Clinically, GA is characterized by dermal papules and annular plaques (see the image below). The precise cause is unknown. Histologic examination reveals foci of degenerative collagen associated with palisaded granulomatous inflammation.



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Granuloma annulare. Image from Mierlo at English Wikipedia via Wikimedia Commons. Public domain.

The following clinical variants are recognized:

Some authorities have considered actinic granuloma (AG) to be a subset of GA, but it is now commonly viewed as a separate but related entity.[5]

Pathophysiology

Proposed pathogenic mechanisms for GA have included cell-mediated immunity (type IV), immune complex vasculitis, and an abnormality of tissue monocytes. Other possible mechanisms have included primary degeneration of connective tissue leading to granulomatous inflammation, lymphocyte-mediated immune reaction with macrophage activation, and cytokine-mediated degradation of connective tissue.[1]

Etiology

The etiology of GA has not been defined, and the pathogenetic mechanisms are poorly understood, with the vast majority of cases occurring in patients who are otherwise healthy. The range of predisposing events and associated diseases is diverse, and GA is thought to represent a reaction pattern with many different initiating factors.[1]

GA has been hypothesized to be associated with tuberculosis, insect bites, trauma, sun exposure, thyroiditis, vaccinations, and viral infections (eg, HIV, Epstein-Barr virus [EBV], hepatitis B virus [HBV], hepatitis C virus [HCV], and herpes zoster virus [HZV]). However, these suggested etiologic factors remain unproven as causes.

Familial cases of GA observed in identical twins and siblings in several generations, along with an association of GA with human leukocyte antigen (HLA) phenotypes, have suggested the possibility of a hereditary component in some cases. The HLA-B8 level has been reported to be increased in localized GA; HLA-A29 and HLA-BW35 levels have been reported to be increased in generalized GA.

Some reports have suggested that chronic stress may be a trigger of GA. GA also has some predilection for sun-exposed areas and photodamaged skin. Photosensitive GA has been found in association with HIV infection. Finally, some cases of GA or GA-like reactions have been reported after gold therapy and treatment with allopurinol, diclofenac, quinidine, calcitonin, amlodipine, angiotensin-converting enzyme (ACE) inhibitors, daclizumab,[6] checkpoint inhibitors,[7, 8, 9] and calcium-channel blockers.

Associations with systemic diseases

GA has been associated primarily with type I diabetes mellitus (DM); it is only rarely associated with type II DM and thyroid disease, on the basis of an increased number of GA patients with these diseases in small case series.[10]

Small case series have reported GA to occur in association with malignancy, AIDS, and herpes zoster lesions. Although no definite patterns relating GA and systemic disease have been thoroughly established, it has been suggested that an atypical histologic finding (vasculopathy or extravascular neutrophilia) or clinical presentation (unusual appearance or location) may indicate an associated disease. In the case of malignancy, a 2003 review of classic cases in the literature was unable to confirm a definite relationship between GA and malignant neoplasms.[11]

Associations with specific malignancies

Certain malignancies are accompanied by different mucocutaneous paraneoplastic syndromes. Lesions that mimic GA or have been histologically confirmed as GA have occurred in association with the following:

Epidemiology

The frequency of GA is in the general population is unknown. Of the various subtypes, localized GA is the most common. The generalized subtype occurs in 9-15% of all patients with GA. Perforating GA has a reported prevalence of 5% among GA subtypes; reports suggest that this subtype may be more common in the Hawaiian Islands.

Localized GA is most commonly found in children and in adults younger than 30 years. Generalized GA demonstrates a bimodal age distribution, occurring in patients younger than 10 years and in patients aged 30-60 years. Although subcutaneous GA can occur in adults, it is predominantly a disease of otherwise healthy children (typical age range, 2-10 y). Similarly, perforating GA most often affects children.

Women are affected by GA twice as frequently as men are.

GA has no known predilection for any particular race, ethnic group, or geographical area.

Prognosis

Spontaneous resolution of localized GA has occurred within 2 years in 50% of cases, though lesions may last weeks to decades. Recurrence, often at the same site, is noted in 40% of cases.

Generalized GA has a more chronic course, with rare spontaneous resolution, poor response to treatment, and frequent relapses.

Subcutaneous GA lesions often regress spontaneously. Local or distant recurrences have been reported in 20-75% of cases in different studies.

Patient Education

Patients and families should be reassured about the typically benign nature and course of granuloma annulare.

History

Both localized and generalized granuloma annulare (GA) lesions usually manifest as asymptomatic cutaneous lesions. Lesions may improve in winter and worsen in summer.

Subcutaneous GA most often manifests as a large, asymptomatic soft-tissue mass. Although nodules are usually stable for months, they may rapidly enlarge over the course of weeks.

Physical Examination

Patients with localized GA commonly present with groups of 1- to 2-mm papules that range in color from flesh-toned to erythematous, often in an annular arrangement over distal extremities. Grouped lesions may expand into arciform or annular plaques measuring 1-5 cm in diameter. Centers of lesions may be slightly hyperpigmented and depressed in relation to their borders, which may be solid or composed of numerous dermal papules. Lesions most commonly manifest on the dorsal surfaces of the feet, hands, and fingers and on the extensor aspects of the arms and legs. Rarely, they appear on the face, scalp, or penis.

Patients with generalized GA characteristically present with a few to thousands of 1- to 2-mm papules or nodules that range in color from flesh-toned to erythematous and involve multiple body regions. Lesions may coalesce into annular plaques, which measure 3-6 cm in diameter and which may enlarge centrifugally over weeks to months. Although any part of the cutaneous surface may be involved, lesions tend to be symmetrically disposed over acral areas and the trunk. Rarely, the head, palms, soles, and mucous membranes are involved.

Patients with subcutaneous GA present with a firm, nontender flesh-colored or pinkish nodule without overlying epidermal alteration. Lesions are typically solitary but may occur in clusters. The most commonly reported site of involvement is a lower extremity (65% of cases), often on the pretibial surface. Other typical sites include the fingers and palms and the dorsa of the feet. The buttocks, forehead, and scalp are less commonly affected. Deep dermal or subcutaneous nodules on the extremities are attached to fascia and thus are often mobile, whereas lesions on the scalp are attached to underlying periosteum and thus are fixed or only slightly mobile.

Patients with perforating GA present with one to hundreds of grouped 1- to 4-mm papules that range in color from flesh-toned to erythematous. Papules often coalesce to form annular plaques. In some patients, the erythematous papules may evolve into yellowish pustular lesions that subsequently exude a thick and creamy or clear and viscous fluid, forming umbilicating, crusting, or scaling papular lesions that heal, leaving atrophic hypopigmented or hyperpigmented scars. Larger and more ulcerated plaques are common in middle-aged and elderly patients. Lesions affect all areas of the body but have a predilection for the extensor surfaces of extremities and the dorsa of hands and fingers.

Arcuate dermal erythema is an uncommon form of GA that manifests as infiltrated erythematous patches that may form large hyperpigmented rings with central clearing. Papules are a less prominent feature in this variant. Patches typically appear on the trunk and may spread centrifugally over weeks to months.

Patients with actinic granuloma (AG) present with one to 10 plaques, which tend to be annular or serpiginous areas with raised erythematous borders. Lesions may be hypopigmented centrally; the epidermis is otherwise spared. Plaques are typically distributed over sun-exposed areas, such as the arms, neck, face, and dorsa of the hands. Other than by their location on heat- or sun-damaged skin, AG lesions are difficult to distinguish clinically from eruptions of GA.

Laboratory Studies

Laboratory studies are largely noncontributory in patients with granuloma annulare (GA). With a classic history and unremarkable physical examination findings (other than the presenting lesion or lesions), no additional workup is necessary.

If, however, a thorough history is not available or systemic disease is considered likely, appropriate laboratory evaluations should be performed to exclude other diagnostic possibilities. For example, in subcutaneous GA, a complete blood count (CBC) count, an erythrocyte sedimentation rate (ESR), and a rheumatoid factor (RF) study may assist in excluding other possible causes for nodules.

Imaging Studies

Imaging studies are not generally necessary in diagnosing GA. However, radiography, computed tomography (CT), or magnetic resonance imaging (MRI) may be helpful in the evaluation of atypical subcutaneous lesions.

Radiographs of subcutaneous GA show a nonspecific soft-tissue mass without calcification. On CT, subcutaneous GA appears as a poorly defined mass with variable attenuation and variable contrast enhancement. On MRI, subcutaneous GA appears as a mass with poorly defined margins that is limited to subcutaneous tissue. MRI findings may be suggestive, but not diagnostic, of subcutaneous GA.[13, 14]

Procedures

Biopsy is recommended for a subcutaneous lesion and for a presentation that is atypical with respect to the history (ie, rapid enlargement, pain) or location of the lesion.

Histologic Findings

Early interstitial or incomplete GA 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 GA 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 GA lesions and deep subcutaneous GA nodules demonstrate palisaded granulomatous dermatitis and a septal and lobular panniculitis, respectively. Macrophages surround acellular necrobiotic areas in which collagen bundles are thinned, or they may have a pale, homogeneous light-blue appearance, due to the presence of mucin.

In many cases of subcutaneous GA 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. The presence of fibrinogen can be demonstrated by means of direct immunofluorescence (DIF) 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 GA have also been described.

Actinic granuloma (AG; also known as annular elastolytic giant cell granuloma) may lack the classic palisaded arrangement observed in GA. Although elastosis is abundant in the middermis 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 GA.

Thus, AG can be distinguished histologically from GA 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, though the level of evidence supporting these methods has been 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 was shown in a prospective uncontrolled trial to be an effective treatment for localized GA. Secondary dyschromia may be a complication of cryotherapy.[15]

Hyperthermic 20 MHz high-intensity focused ultrasound (HIFU) has been suggested as a potentially promising means of treating GA that may cause less skin necrosis than cryotherapy.[16]

Laser therapy using multiple different modalities, including pulsed dye and excimer, has been successfully used for both localized and generalized GA.[17, 18, 19, 20, 21, 22]

Anecdotal reports of therapeutic efficacy in both localized and generalized GA have been published for tacrolimus and pimecrolimus,[23, 24, 25, 26, 27, 28] as well as for imiquimod cream.[29, 30]

Generalized granuloma annulare

Generalized GA tends to be more persistent and unsightly; consequently, patients with this condition may be more likely to accept more aggressive treatment. Unfortunately, treatment of generalized GA is fraught with a lack of consistently effective options.[31]

Over the past two decades, success with the use of ultraviolet (UV)-B (mostly narrowband UV-B) therapy, a relatively harmless treatment compared with the alternatives, has made this a first-line option for generalized GA. Multiple groups have described single or small groups of cases,[32, 33, 34, 35, 36, 37] and a 2015 retrospective analysis described 13 cases of generalized GA treated with narrowband UVB.[38]

There is evidence to support the use of phototherapy with oral psoralen and UV-A (PUVA) as first-line options for generalized GA.[39, 40, 41, 42] However, the risks of malignancy when treating an essentially benign condition must be discussed.

On the basis of a number of case reports, isotretinoin may be a first-line option.[43, 41, 42, 44, 45, 46, 47, 48, 49]  A US Food and Drug Administration (FDA)-mandated registry is in place for all individuals prescribing, dispensing, or taking isotretinoin.[50]

Antimalarials may also be quite effective, as suggested by a large case series[51] and individual reports.[52, 53] Grewal et al found chloroquine to give the highest response, though hydroxychloroquine was also useful.[51]

Piaserico et al reported success with using methyl aminolevulinate photodynamic therapy to treat long-standing generalized GA.[54] Weisenseel et al reported moderate success with photodynamic therapy using 20% 5-aminolevulinic acid (ALA) gel.[55] Cazavara-Pinton et al reported responses in nine of 13 patients.[56]

In a report involving six patients with GA that was refractory to standard treatment, Marcus et al described the use of combination therapy with rifampin 600 mg, ofloxacin 400 mg, and minocycline hydrochloride 100 mg once monthly for 3 months.[57] By 3-5 months after the initiation of treatment, the plaques had cleared completely. Postinflammatory hyperpigmentation was reported by some patients. Although the treatment was successful, the authors suggested that further studies may be needed to confirm this combination therapy as a successful option for recalcitrant GA.

Garg and Baveja also reported successful treatment of five cases of generalized GA with the same three antibiotics.[58]

Other anecdotal reports and small series have described successful systemic treatment with dapsone,[59, 60, 61, 62] steroids, pentoxifylline,[63, 64] cyclosporine, fumaric esters,[65] interferon gamma, potassium iodide, nicotinamide, etanercept,[66, 67, 68, 69] infliximab,[70, 71, 72] adalimumab,[73, 74, 75, 76, 77, 78] Janus kinase (JAK) inhibitors,[79, 80, 81, 82, 83]  apremilast,[84, 85]  and tapinarof cream.[86]

Complications

A case report by Gass et al described a 70-year-old man with disseminated GA in a photosensitive distribution, who, after successful systemic and topical treatment, developed milia and scarring.[87] This was believed to be the first report of scarring and milia formation after successful treatment of GA.

Clobetasol (Clobex, Clobex Spray, Cormax)

Clinical Context: 

Triamcinolone topical (Kenalog Orabase, Kenalog topical, Pediaderm TA)

Clinical Context: 

Prednisone (Deltasone, Prednisone Intensol, Rayos)

Clinical Context: 

Isotretinoin (Absorica, Absorica LD, Amnesteem)

Clinical Context: 

Methoxsalen (8MOP, Oxsoralen, Oxsoralen Ultra)

Clinical Context: 

What is granuloma annulare?What are the types of granuloma annulare?What is the pathogenesis of granuloma annulare?What is the etiology of granuloma annulare?What etiologic factors have been proposed for granuloma annulare?What is the evidence of a familial etiology for granuloma annulare?What are risk factors for granuloma annulare?What conditions are associated with granuloma annulare?Which malignancies have been associated with granuloma annulare?What is the frequency of granuloma annulare in the general population?What is the most common subtype of granuloma annulare?How does the prevalence of granuloma annulare vary by sex?How does the prevalence of granuloma annulare vary by age?What is the prognosis of granuloma annulare?What information about granuloma annulare should be given to patients?What are the signs and symptoms of granuloma annulare?Which physical findings are characteristic of localized granuloma annulare?Which physical findings are characteristic of generalized granuloma annulare?Which physical findings are characteristic of subcutaneous granuloma annulare?Which physical findings are characteristic of perforating granuloma annulare?Which physical findings are characteristic of the arcuate dermal erythema type of granuloma annulare?Which physical findings are characteristic of actinic annulare?Which conditions should be included in the differential diagnosis of granuloma annulare?What are the differential diagnoses for Granuloma Annulare?What is the role of lab studies in the workup of granuloma annulare?What is the role of imaging studies in the workup of granuloma annulare?What is the role of biopsy in the workup of granuloma annulare?Which histologic findings are characteristic of incomplete granuloma annulare lesions?Which histologic findings are characteristic of fully evolved granuloma annulare lesions?Which histologic findings are characteristic of subcutaneous granuloma annulare lesions?Which histologic findings are characteristic of actinic annulare?What are the treatment options for localized granuloma annulare?What are the treatment options for generalized granuloma annulare?What are the possible complications of granuloma annulare?What therapies may be considered as initial approaches for localized granuloma annulare?What are the initial treatment approaches for generalized granuloma annulare?Which medications in the drug class Retinoid-like Agents are used in the treatment of Granuloma Annulare?Which medications in the drug class Corticosteroids are used in the treatment of Granuloma Annulare?Which medications in the drug class Corticosteroids, Topical are used in the treatment of Granuloma Annulare?

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.

Specialty Editors

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

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

Disclosure: Received honoraria from Amgen for consulting; Received honoraria from Abbvie for consulting; Received honoraria from Galderma for speaking and teaching; Received consulting fee from Lilly for consulting; Received ownership interest from www.DrScore.com for management position; Received ownership interest from Causa Reseasrch for management position; Received grant/research funds from Janssen for consulting; Received honoraria from Pfizer for speaking and teaching; Received consulting fee from No.

Chief Editor

William D James, MD, Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Additional Contributors

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

Disclosure: Nothing to disclose.

Acknowledgements

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

Amit Garg, MD is a member of the following medical societies: American Academy of Dermatology and American Medical Student Association/Foundation

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

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Granuloma annulare. Image from Mierlo at English Wikipedia via Wikimedia Commons. Public domain.

Granuloma annulare. Image from Mierlo at English Wikipedia via Wikimedia Commons. Public domain.