GA initially presents in form of more or less reddened, grouped papules. In some cases, erythema is striking, in others, hyperemia is barely recognizable. Papules subsequently expand, forming large cutaneous lesions with a prominent, often slightly elevated border. The center of those lesions may clear to a certain degree, but does usually not regain the appearance of healthy skin. Coalescence of multiple lesions may be seen. The vast majority of GA-associated lesions preserve the smooth surface of the skin, they are not covered by scales or crusts, and patients don't claim pruritus. The one exception to that rule is perforating GA. Here, papules may turn into pustules or take on an umbilicated appearance as their center subsides and is covered with scales or crusts. Both pain and pruritus may be reported.

In case of localized GA, ring-like lesions characteristic of the disease are typically observed on hands or feet. Involvement of the trunk is common in patients suffering from generalized GA, but these people may also present cutaneous lesions on arms and legs as well as in the head and neck region. A similar distinction can be made for perforating GA: It may be observed on arms and pelvic region, but may additionally encompass skin lesions of the trunk and legs.

Neither of the aforedescribed dermatological findings is characteristic of subcutaneous GA. This variant of the disease is characterized by either solitary or multiple subcutaneous nodules that are readily palpable and grow fast. Predilection sites are the distal parts of the limbs, buttocks, periorbital area and scalp [1].

• Hodgkin Lymphoma

  […] for patients with early unfavourable or advanced stage Hodgkin lymphoma Read more on Cochrane (Australasian Centre) website Imaging-adapted therapy for individuals with Hodgkin lymphoma | Cochrane Hodgkin lymphoma (HL) is a malignant disease of the lymphatic [healthdirect.gov.au]

  Cases have also been reported in patients with AIDS, sarcoidosis, hepatitis C infection, Hodgkin's and non Hodgkin's lymphoma, metastatic adenocarcinoma and granulomatous mycosis fungoides. [histopathology-india.net]

  Unusual Clinical Scenarios to Consider in Patient Management GA can be seen as a paraneoplastic response to a variety of cancers including Hodgkin’s and Non-Hodgkin’s lymphomas. [psychiatryadvisor.com]

  METHODS: We reviewed the medical records and biopsy material from 13 patients with granuloma annulare and lymphoma. RESULTS: Three patients had Hodgkin's disease and 10 had non-Hodgkin's lymphoma. [thedoctorsdoctor.com]

• Lymphadenopathy

  An 83-year-old man with a three-year history of progressive sporotrichoid annular plaques and nodules on the arm developed ipsilateral retroauricular palpable lymphadenopathy, the latter consistent with B-cell lymphoma. [ncbi.nlm.nih.gov]

• Malaise

  […] for 30–50% of all primary heart tumours.1 Over 70% of cardiac myxomas originate from the left atrium.1 It is often referred to as ‘the great mimicker’ of other diseases as 90% of patients present with systemic symptoms including fever, weight loss, malaise [rcpe.ac.uk]

• Cough

  Respiratory symptoms of sarcoidosis include a chronic cough, dyspnea and chest pain, which should prompt a chest X-ray to look for pulmonary granulomas. [podiatrytoday.com]

• Vomiting

  […] proliferation, especially T cells, and has anti-inflammatory effects that are likely related to its antioxidant activity. 10 Adverse effects most commonly include gastrointestinal tract symptoms including epigastric burning, abdominal discomfort, nausea, and vomiting [doi.org]

• Subcutaneous Nodule

  In 1941, Ziegler first described a case of subcutaneous nodules that appeared concomitantly with classical cutaneous lesions of granuloma annulare, as well as the histological aspect of these nodules similar to that of rheumatoid nodules (RN) (7). [ncbi.nlm.nih.gov]

  The nodules are subcutaneous, their size ranges from 0.3 in to 1.5 in (1 to 4 cm), painless, and usually appear individually. [scielo.conicyt.cl]

  SGA occurs exclusively in children and consists of deep dermal or subcutaneous nodules. [pediatrics.aappublications.org]

  A number of clinical variants exist, most commonly localized annular plaques on the hands or feet, generalized lesions, or subcutaneous nodules in children. [mdedge.com]

• Ulcer

  Our case describes the rare association of GA with ulcerative colitis. Various different dermatological conditions have been described in association with ulcerative colitis. [ispub.com]

  There are seven reported cases in the literature, but only one presenting ulcerated necrobiosis lipoidica. [ncbi.nlm.nih.gov]

  Key diagnostic factors asymptomatic grouped annular pink or flesh-coloured dermal papules More key diagnostic factors Other diagnostic factors flesh-coloured, pink, or brown macules or small papules soft-tissue nodules perforating papules, crusting or ulcerated [bestpractice.bmj.com]

  The lesions never ulcerate and may disappear without a trace. 73% may clear within two years. 25% may persist for many years. The generalized form of granuloma annulare is less common. [randyjacobsmd.com]

• Eczema

  Eczema is a common skin condition, and atopic dermatitis (also called atopic eczema) is one of the most common forms of eczema. Eczema can affect adults or children. The condition isn’t contagious. View a slideshow to get an overview on eczema. [webmd.com]

  In any case, though, granuloma annulare typically responds well to herbal treatments, much like treatment for eczema. [earthclinic.com]

  Types & treatments Childhood eczema Adult eczema Insider secrets Types of hair loss Treatment for hair loss Causes of hair loss Hair care matters Insider secrets What is psoriasis Diagnosis & treatment Skin, hair & nail care Triggers Insider secrets What [aad.org]

  Smithee is experienced in treating both adult and pediatric patients, from eczema to skin cancer to more complex dermatologic conditions. [westlakedermatology.com]

  It looked like eczema, and so I started moisturizing it with creams, but it stayed put – darker some days, lighter on other days – no matter what I did. [ramshackleglam.com]

• Skin Rash

  Granuloma Annulare is a rare skin disease, which is long-standing (chronic) where you find skin rash in the form of red bumps arranged in the form of a circle or a ring. [askdrshah.com]

  Granuloma annulare is a harmless type of skin rash. The rash is most often discolored and raised, and roughly in the shape of a ring. The rash may be on just one part of the body. [massgeneral.org]

  We use the Psoriaid herbal tablets and the Skin Detox formula to treat granuloma annulare. * These herbs will help to decrease inflammation in the skin, and expel toxins that may be causing the skin rash. [merryclinic.com]

• Erythema Annulare

  Interstitial granulomatous dermatitis Palisaded neutrophilic granulomatous dermatitis Panniculitis Perforating collagenosis Elastosis perforans serpiginosa Sarcoidosis Erythema annulare centrifugum Lichen planus (especially the annular variant) – Usually [visualdx.com]

  […] present Erythema Migrans ( Lyme Disease ) Tertiary Syphilis Nummular Eczema Psoriasis Erythema annulare centrifigum Discoid Lupus Sarcoidosis IX. [fpnotebook.com]

  Less common annular skin conditions (e.g., subacute cutaneous lupus erythematosus, erythema annulare centrifugum) have associated scaling and can be ruled out. [aafp.org]

  Differential Diagnosis Actinic granuloma annulare Dermoid cyst Erythema nodosum Erythema annulare centrifugum Elastosis perforans serpiginosa Foreign body granuloma Insect bite Lichen planus Necrobiosis lipoidica diabeticorum Perforating granuloma annulare [ncbi.nlm.nih.gov]

• Irritability

  Moulded orthoses can have defects after manufacturing that can lead to localised skin irritation, inflammation and subsequent rash formation. [ncbi.nlm.nih.gov]

  Granulomas can be part of the immune system’s response to: infection inflammation irritants foreign objects When the cells clump together, they protect the body from potential threats in two ways. [medicalnewstoday.com]

  The bumps are caused by cells of the immune system that have gathered under the skin in response to an irritant, such as insect bites, infections, TB skin tests, vaccinations, or sun exposure. [merryclinic.com]

  Although it commonly resolves on its own within a few months to few years, most people seek treatment at an earlier stage for cosmetic reasons or because of skin irritation associated with the condition. [dermcoll.edu.au]

• Burning Sensation

  Most patients complain of itching and, less frequently, burning sensation, dyspareunia, dysuria, and painful defecation [5]. [hindawi.com]

Diagnosis of GA and exclusion of differential diagnoses is based on the histopathological analysis of biopsy specimens. Indeed, the name of the disease has been derived from its characteristic microscopic appearance: that of a granulomatous inflammation.

• In GA, areas of dermal necrobiosis comprising foci of degenerated collagen and mucin deposits are surrounded by palisading histiocytes and lymphocytes [7]. Necrobiotic areas are anuclear regions; mucin confers a pale, light-blue color to the extracellular matrix if samples are stained with hematoxylin and eosin. It may be necessary to examine multiple samples in order to detect characteristic, necrobiotic areas. Epidermal alterations are usually not observed.
• However, in perforating GA, necrobiotic material is eliminated through the epidermis, thus giving rise to pustule-like lesions [8].
• In contrast, dermal participation is atypical for subcutaneous GA and inflammatory processes mainly take place in subcutaneous tissues [14]. Accordingly, this form of the disease is characterized by subcutaneous necrobiosis and palisading immune cells. In about 25% of subcutaneous GA, dermal lesions consistent with the more common forms of GA coincide with granulomatous panniculitis.

Further diagnostic measures are generally not required to confirm GA. If an underlying primary disease is suspected, e.g., any pathological condition associated with immunodeficiency, a target-oriented workup to this end is recommended. It may include laboratory analyses of blood samples, screenings for viral infectious diseases and a glucose tolerance test to rule out latent diabetes mellitus.

GA is a self-limiting disease. Patients suffering from localized GA are expected to experience spontaneous remission within two years, but generalized GA may persist for longer periods of time. Accordingly, treatment is often demanded for cosmetic reasons. Unfortunately, there is no reliable data regarding the effectivity of distinct treatment options, and dermatologists often base their decisions on personal experience. In detail, the following drugs have been used to treat GA:

• Corticosteroids (antiinflammatory effects)
• Pimecrolimus, tacrolimus (inhibition of IL-2 and IFN-γ)
• Vitamin E (modulation of T helper cell-mediated immune response)
• Etretinate, isotretinoin (inhibition of delayed hypersensitivity)
• Fumaric acid esters (modulation of T helper cell-mediated immune response)
• Dapsone (antiinflammatory effects)
• Psoralen plus ultraviolet A, ultraviolet A1 (antiinflammatory effects)

As well as:

• Hydroxychloroquine, chloroquine (antiinflammatory effects)
• Cyclosporine (inhibition of extracellular matrix breakdown)
• Pentoxifylline (reduction of blood viscosity)
• Etanercept, infliximab (TNF-α inhibitors)
• and many more

Favorable responses have been reported for the majority of these compounds, but there are several studies documenting less beneficial outcomes. Excellent reviews on this topic are available elsewhere [1] [15]. In most described cases, topical application of immunosuppressive agents has been combined with systemic treatment. Retrospective analysis of a large number of studies has lead to the recommendation of topical corticosteroids or topical pimecrolimus/tacrolimus and/or oral vitamin E as first-line treatment. If insufficient, phototherapy should be offered. Patients who respond to neither therapy may receive systemic medication: Retinoids, fumaric acid esters, dapsone or pimecrolimus/tacrolimus may be administered.

Of note, subcutaneous GA may also be expected to resolve spontaneously. If surgical excision is performed, recurrence is likely. Malignant transformation has not been reported.

GA is a self-limiting disease, but spontaneous remission may not occur until several years after symptom onset. This particularly applies to generalized GA, which may persist for decades [8]. In contrast, about half of localized GA cases resolves within two years. Recurrence is common and may be associated with periods of stress-induced immunodeficiency. In general, morbidity mainly consists in psychological burdens, but the response to treatment is often poor. Patients may thus benefit from psychological counseling.

The etiology of GA is only poorly understood. The disease has been related to viral infectious diseases, insect bites, malignancies, and trauma. However, patients may not report exposure to either of those triggers and other causes are likely to be involved in the development of skin lesions related to GA. In this context, it has been hypothesized that immunocompromised patients may be more prone to the disease than the general population. Immunodeficiency may be drug-induced [2], caused by infection with the human immunodeficiency virus [3], or by common pathologies like diabetes mellitus. In fact, diabetics have been reported to be more susceptible to chronic recurrent GA than nondiabetic patients [4], but it cannot be ruled out that this observation is merely the result of a diminished capacity of tissue repair. Moreover, malignancies related to GA most commonly corresponded to myeloproliferative disorders that interfered with the patient's immune system [5].

There have been no large-scale studies regarding incidence and prevalence of GA. The only available data to this end date from 1980 and include an estimation of 0.1 to 0.4% of patients presenting to dermatologists being affected by GA [6].

In general, GA may affect patients of any age. However, age peaks differ with regards to the distinct forms of the disease. Subcutaneous GA is mainly diagnosed in pediatric patients aged less than five years. As for the more common forms of the disease, there is a trend to an increased incidence in patients aged less than 30 years, but there are frequent reports about GA in elder individuals [2] [7] [8]. Perforating GA is as common in children and young adults as in patients beyond their third decade of life [8] [9].

Women are affected more than twice as often as men, implying a genetic component in the disease' etiology. In fact, there have been occasional reports about familial accumulation of GA [10], but they are insufficient to support a general hypothesis to this end.

No racial predilection has been reported to date.

The hypothesis of GA being the result of immune-mediated pathophysiological events dates back to the 1970s [11]. Dahl and colleagues observed vascular lesions in biopsy samples obtained from GA samples and reasoned that endothelial damage, thrombosis and thickening of vascular walls may indicate an immune complex vasculitis, i.e., a type III hypersensitivity reaction. At about the same time, it has been suggested that cell-mediated (type IV) hypersensitivity gives rise to GA [12]. Macrophages and lymphocytes may be recruited to the dermis and trigger inflammatory processes and vascular damage. Forty years later, evidence supporting either theory is still scarce. The latter is gaining certain acceptance because single studies have documented immune cell subpopulations and cytokines released by cells encountered at the site of lesion to agree with the idea of a delayed hypersensitivity [13]. In detail, T helper cells may stimulate the maturation of histiocytes, which subsequently release pro-inflammatory cytokin tumor necrosis factor-α and matrix metalloproteinases that catalyze the breakdown of extracellular matrix components.

No specific measures can be recommended to prevent GA.

Granuloma annulare (GA) is a benign skin disease of largely unknown etiology. In general, initial manifestations are grouped papules which subsequently expand to ring-like lesions that may measure several centimeters in diameter. Patients usually present multiple lesions, but they are often restricted to the distal parts of upper and lower limbs. This form of the disease is known as localized GA and accounts for about 80% of all cases. Less frequently, GA may affect large parts of the skin, develop on the trunk, more distal parts of the limbs and the face and neck region. Accordingly, these patients are diagnosed with generalized GA.

Due to the appearance of cutaneous lesions, GA may easily be confounded with tinea corporis, erythema annulare centrifugum or cutaneous lupus erythematosus. However, scales are important indicators of those conditions and are absent in most forms of GA. Nevertheless, it is not uncommon for GA patients to present with a medical history of unsuccessful antimycotic or immunosuppressive therapy. Indeed, corticosteroids are sometimes used to treat generalized GA, but evidence regarding the effectivity of this therapeutic approach is scarce. Localized GA is self-limiting and does not require special therapy.

Of note, there are two clinical variants of the disease, namely subcutaneous and perforating GA [1]. Both are rare entities. Patients presenting with subcutaneous GA don't show anomalies of the skin surface, but report groups of protruding, palpable nodules in distinct parts of their body. In perforating GA, cell debris and degenerated components of the extracellular matrix that accumulate in the dermis are drained through the epidermis. This process gives rise to pustules and crusts, while the skin surface is usually intact in other forms of the disease.

Granuloma annulare (GA) is a benign dermatological condition whose designation is derived from its microscopic and macroscopic appearance: Affected individuals usually note the appearance of group papules on their hands and feet, on more proximal parts of their limbs, on the trunk, and in the face and neck region. These papules are more or less reddened but are neither itchy nor covered by scales or crusts. Subsequently, they expand to ring-like lesions that may measure several centimeters in diameter. Such lesions often have a prominent border while their center starts to clear; multiple lesions may coalesce into large plaques. In most cases, patients present with few lesions restricted to hands or feet, and they are diagnosed with localized GA. About one in five people affected by GA suffers from a generalized variant of the disease, which involves multiple lesions that may cover considerable parts of the skin. GA is a self-limiting disease, i.e., patients may expect spontaneous remission. However, several years may pass until lesions resolve, particularly in case of generalized GA. Unfortunately, treatment options are limited and response to therapy is often poor. Thus, the treating physician will have to outweigh possible side effects of a prolonged drug therapy against the potential benefits of such treatment.

Of note, there are additional, less frequent variants of the disease, e.g., subcutaneous GA - characterized by the formation of palpable nodules under the skin - and perforating GA. The latter is caused by pathophysiological events similar to those occurring in the more common forms of the disease, but cell debris and degenerated components of cutaneous tissue is eliminated through the outer layer of the skin. Thus, lesions are covered by scales or crusts in these cases.

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