Granuloma annulare

 

 

 

 

Salient features

 

·       Small grouped papules assuming an annular configuration, often in a symmetrical and acral distribution

 

·       Seen primarily in children and young adults

 

·       Clinical variants include localized, generalized, and subcutaneous forms

 

·       Possible associations with systemic diseases, including diabetes mellitus, hyperlipidemia, thyroid disease, and rarely HIV infection, remain controversial

 

·       Histopathologically, there is an infiltrative or palisading granulomatous dermatitis with focal degeneration of collagen and elastin and deposition of mucin

 

Introduction

 

Granuloma annulare (GA) is benign inflammatory, self-limiting granulomatous dermatosis that is seen in both adults and children. It is a relatively common idiopathic disorder, in which, in typical cases, the dermis and subcutaneous tissue is involved in a process characterized by foci of alteration of collagen (necrobiosis) surrounded by histiocytes and lymphocytes. The typical presentation is granulomatous annular plaques, nodules or papules on the extremities, which slowly enlarge before eventually flattening and fading over months or years.

 

 

Epidemiology

 

Age

 

Granuloma annulare is most common in children and young adults but can occur at any age. Two-thirds of affected individuals are under 30 years of age. Generalized GA occurs more commonly in adults with a mean around 50 years. Subcutaneous GA is seen predominantly in children. Perforating GA has been reported in both adults and children.

 

Sex

 

The female-to-male ratio is approximately 2: 1 in this common disease.

 

 

Pathogenesis

 

Although the etiology and pathogenesis of granuloma annulare are unknown, it appears likely that it represents a reaction pattern to a variety of triggering factors such as trauma, insect bite reactions, tuberculin skin testing, sun exposure, PUVA therapy, and viral infections. Based on the T-cell subpopulations identified in GA lesions, a delayed-type hypersensitivity reaction to an unknown antigen has been postulated as the precipitating event.

Morphologic similarities to other granulomatous processes suggest that GA is caused by a Th1 inflammatory reaction, with elevations in IL-2R-positive lymphocytes, IFN-γ-producing lymphocytes, and TNF production by macrophages. These lymphocytes release cytokines, including macrophage inhibitory factor, that cause monocytes to accumulate within the dermis and release lysosomal enzymes that can degrade connective tissue. One ultrastructural study found that the main alteration in GA is elastic fiber degeneration and suggested that this disease is primarily a disorder of elastic tissue injury.

 

 

Familial cases of GA have been reported, including cases in identical twins, and one small study suggested that an association may exist between generalized GA and HLA-Bw35. Vessel-based mixed inflammatory cell infiltrates with endothelial swelling are sometimes detected in routine histopathologic specimens, and direct immunofluorescence studies of GA may show vessel-based deposits of immunoreactants, but a role for these findings in the pathogenesis of this disease has not been established.

 

 

 

 

Associated diseases

 

Both localized and generalized GA has been reported in association with autoimmune thyroiditis in women. Generalized GA has also been reported in a patient with a toxic adenoma of the thyroid (Plummer disease). The incidence of hyperlipidaemia has recently been reported to be four times higher amongst people with generalized GA.

 

Histopathology

 

GA is a granulomatous dermatitis characterized by focal degeneration of collagen and elastic fibers, mucin deposition, and a perivascular and interstitial lymphohistiocytic infiltrate in the upper and mid dermis. The key to the histopathologic diagnosis of GA is the identification of histiocytes in one of three patterns. In general, more than one histopathologic pattern may coexist in the same patient.

 

The most common (accounting for ~70% of cases) is the interstitial pattern in which histiocytes and lymphocytes are present around blood vessels and between fragmented collagen bundles, and collagen fibers are separated by mucin. Degeneration of collagen fibers is minimal, but granular, basophilic mucin deposition between collagen bundles can be highlighted with Alcian blue and colloidal iron stains.

 

The second pattern (25% of cases) is more obvious and is easier to diagnose. It consists of one to several palisading granulomas with central connective tissue degeneration (foci of necrobiosis) surrounded by histiocytes and lymphocytes, with the histiocytes commonly forming a palisaded pattern. There are varying numbers of multinucleate giant cells in this peripheral zone. T cells in the lymphocytic infiltrate are of the helper/inducer phenotype (CD4+).  Mucin demonstrated by Alcian blue or colloidal iron stains, is abundant within the central foci of the necrobiosis. The granulomas are most typically located in the upper and mid reticular dermis. At the periphery of lesions a leukocytoclastic vasculitis may rarely be found. IgM and C3 in the blood vessels walls of the skin lesions are found in about half of patients.

 

The sarcoidal or tuberculoid pattern is uncommon, and consists of epithelioid histiocytic nodules that can resemble cutaneous sarcoidosis. The presence of mucin and eosinophils can help to distinguish granuloma annulare from sarcoidosis.

 

Ultrastructurally, degeneration of collagen and elastic fibers is seen. Collagen degeneration, most commonly fragmentation of collagen bundles, is more common in localized GA than in generalized GA. Elastic tissue is reduced or absent within the histiocytic aggregates in approximately 20% of generalized GA and 35% of localized GA cases. Metalloproteinases are probably involved in the damage to collagen and elastic fibers.

Vascular changes in GA are variable, but include fibrin, C3 and IgM deposition in vessel walls (detected by direct immunofluorescence) and occlusion of vascular lumina. One study found that the presence of leukocytoclastic or granulomatous vasculitis or a thrombotic vasculopathy within the lesions of GA was predictive of associated systemic disease, and the possibility of palisading neutrophilic and granulomatous dermatitis as a reflection of disorders such as rheumatoid arthritis needs to be considered.

In perforating GA there is a superficial area of necrobiosis surrounded by palisading histiocytes, situated beneath a perforation in the epidermis. The necrobiotic material is extruded via the perforation. At the margins of the perforation there are varying degrees of epidermal hyperplasia.

In subcutaneous granuloma annulare the foci of necrobiosis are larger and are usually of the palisaded granulomatous type and extend into the deep dermis and subcutaneous fat. They may be distinguished from rheumatoid nodules by the presence of mucin in the necrobiotic zone.

 

Clinical features

History

 

Patients with subcutaneous GA may complain of tenderness and generalized GA may be itchy, but most patients are asymptomatic. Commonly, the annular lesions will have been treated with antifungal agents before the correct diagnosis is reached.

 

Presentation and clinical variants

 

Clinical variants include localized, generalized, perforating and subcutaneous, which typically appear independently, although some patients may exhibit more than one variant.

 

Localized GA

 

This accounts for about three‐quarters of cases and classically presents as arciform to annular plaques. The annular margin is firm to palpation and may be continuous or consist of discrete or coalescent small, smooth, shiny, beaded, skin colored or erythematous papules in a complete or partial circle. Stretching the skin enables the papules to be seen more readily. The surface of the skin over the papules is intact and there is usually no scaling. Within the annular ring, the skin may have a violaceous or pigmented appearance. Annular lesions tend to enlarge centrifugally before eventually clearing. They may be solitary or multiple, and may occur anywhere on the skin, although acral distribution, commonly arising on the lateral or dorsal surfaces of the fingers, dorsa of the hands and feet, and knuckles. Some, typically acral, lesions enlarge as nodules rather than as annular plaques.

 

Generalized (disseminated) GA

 

Generalized or disseminated GA makes up 10–15% of cases, is seen predominantly in women in the fifth and sixth decades. Pruritus may be the presenting feature. Interestingly, it is the commonest form seen in HIV patients. Generalized GA has a later age of onset, poorer response to therapy, and an increased prevalence of the HLA-Bw35 allele. It occurs in a minority of patients, is characterized by myriad, small, skin-colored to erythematous papules in a symmetric distribution on the trunk and limbs. Some of these papules may coalesce to form small annular plaques surrounding a faint violaceus central area. The sparing of vaccination sites in a case of generalized GA is an interesting phenomenon.

 

Perforating GA

 

Perforating GA presents clinically as small papules and develops a yellowish central core and discharges a clear, viscous fluid that dries to form a crust, which eventually separates, and may leave a hypo- or hyper pigmented scar. This core represents transepidermal elimination of the degenerated collagen in the center of GA lesions. It may be localized, usually to the dorsal hands and fingers, or generalized over the trunk and extremities. This variant occurs up to 5% of patients with GA. Papular umbilicated granuloma annulare on the hands of children and a generalized follicular pustular type of granuloma annulare may be clinical variants.

 

Subcutaneous GA

 

The subcutaneous form of granuloma annulare occurs predominantly in children <6 years of age. It is characterized by firm to hard, large, skin-colored nodules located in the deep dermis and subcutaneous tissues which may be mistaken for rheumatoid nodules, leading to the term pseudo rheumatoid nodule. It occurs predominantly on the scalp and legs, particularly in the pretibial region, but unusual locations include periorbital area, palm and penis. The lesions may extend to underlying muscle, and nodules on the scalp and orbit are often adherent to the underlying periosteum. Multiple lesions are usually present. There is often a history of trauma to the affected area preceding the appearance of a lesion. Magnetic resonance imaging features are diagnostically helpful. As many as 50% of individuals with subcutaneous GA lesions also have associated classic lesions.

 

Granuloma annulare in human immunodeficiency (HIV) disease and malignancy

 

GA may occur in persons with HIV infection at all stages of disease. Lesions are typically papular and generalized GA is more common (60%) than localized GA (40%). Photo distributed and perforating lesions may also occur. The histology is identical to GA in the normal host. The natural history of GA in HIV is unknown.

 

GA has been described as a paraneoplastic granulomatous reaction to solid organ tumors, Hodgkin disease, non-Hodgkin lymphoma and granulomatous mycosis fungoides. In these patients, the clinical pattern is frequently atypical, with painful lesions in unusual locations, including the palms and soles.

 

 

Disease course and prognosis

 

In about 50% of patients the lesions resolved within 2 years. However, about 40% of those whose lesions cleared had a recurrence, in the majority of cases at the same sites as the original lesions, but clear more rapidly (80% within 2 years). While most cases spontaneously resolve, leaving entirely normal skin, loss of elastic tissue may occur, leaving atrophic lesions resembling mid dermal elastolysis or anetoderma. GA lesions will sometimes spontaneously resolve when biopsied.

 

 

Investigations

 

Biopsy may be necessary in nodular, subcutaneous, perforating, generalized and atypical forms. Investigation for diabetes, thyroid disease, malignancy and/or hyperlipidemia is probably necessary only in exceptional cases.

 

 

Differential diagnosis

 

GA is diagnosed based on its clinical and histopathologic features – there are no laboratory tests which aid in confirming the diagnosis. When the typical annular arrangement of papules is present, the diagnosis is usually straightforward. When the diagnosis of subcutaneous GA versus rheumatoid nodule is in question, a rheumatoid factor level identifies patients at risk for the latter.

 

Treatment

 

Given the self-limited and benign nature of GA, reassurance and clinical observation may be the treatment of choice for localized, asymptomatic disease, particularly in children.

 

In persistent localized GA, high-potency topical corticosteroids even under occlusion have little effect. Localized lesions have responded to imiquimod cream, tacrolimus and pimecrolimus.

Cryotherapy and intralesional steroid injection of triamcinolone acetonide (2.5 to 5 mg/ml) may be appropriate for symptomatic localized lesions. Nitrous oxide has been reported to give a better cosmetic result.

Generalized GA has been reported to respond to oral niacinamide (nicotinamide; 500 mg three times daily), isotretinoin (0.5–0.75 mg/kg/day), antimalarial (chloroquine 3 mg/kg/day or hydroxychloroquine 6 mg/kg/day), dapsone (100 mg/day), niacinamide (1.5 gm/day), methotrexate, narrow-band ultraviolet B therapy, and PUVA. In one series of six patients, a combination of three antibiotics (rifampin, ofloxacin and minocycline) administered monthly for 3 months led to improvement. Four patients with disseminated GA were treated with a cycle of cyclosporine therapy for 6 weeks. Cyclosporine was started at a dose of 4 mg/kg/day for 4 weeks, and subsequently reduced by 0.5 mg/kg/day every 2 weeks. The lesions resolved within 3 weeks and there were no relapses.

 

Lesions of subcutaneous granuloma annulare should be left to resolve spontaneously once the diagnosis has been confirmed.

 

Localized GA

First-line

u High-potency corticosteroids topical +/- intralesional

·       Clobetasol 0.05% cream BID x 2-4 w

·       Triamcinolone acetonide 2.5-10 mg/cc q 6-8 w

u Others (limited evidence)

·       Cryotherapy

·       Topical calcineurin inhibitors – tacrolimus, pimecrolimus

·       Phototherapy – PUVA, UVA1, NB-UVB, PDT

·       Topical dapsone

·       Intralesional IFN-γ 

 uImiquimod

 

 

Generalized GA

First-line

u High potency topical/intralesional corticosteroids

u Topical calcineurin inhibitors

·       Tacrolimus 0.1% ointment BID x 6 w

·       Pimecrolimus 1% cream

u Phototherapy

·       UVA1 – high cumulative doses most effective = 1770 – 1840 J/cm2

·       PUVA – oral or bath PUVA with cumulative dose 60.4 J/cm2

·       Narrow-band UVB – cumulative dose 47.7 J/cm2 à 54% complete/partial response

·       Photodynamic therapy

 

Systemic treatment

 

uAntimalarials – first line

·       Hydroxychloroquine – 3 – 6 mg/kg/d

·       Chloroquine – 3 mg/kg/d

u TNF-⍺ inhibitors

·       Adalimumab – 80 mg at week 0 à 40 mg every other week SQ

·       Infliximab – 5 mg/kg at weeks 0, 2, 6 à every month IV

uIsotretinoin – 0.5-1 mg/kg/d

uDapsone – 100 mg/d

uPentoxifylline – 400 mg TID

uNicotinamide – 500 mg TID

u Cyclosporine – 3-4 mg/kg/d

u ROM (rifampin, ofloxacin, minocycline)

u Vitamin E oral – 400-600 IU daily 

u Other case reports: doxycycline, clofazimine, allopurinol, methotrexate, hydroxyurea, alkylating agents (chlorambucil), oral calcitriol, defibrotide, etretinate