Edit concept Question Editor Create issue ticket

Granuloma Annulare

Granuloma annulare is a chronic skin disease characterized by grouped papules that expand to form circular lesions with a prominent border. Localized granuloma annulare is distinguished from the generalized form of the disease.


Presentation

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].

Sepsis
  • Three months later, the patient was admitted with the diagnosis of sepsis secondary to a gastroenteritis dyeing on the fourth day of presentation.[ncbi.nlm.nih.gov]
Thyroid Nodule
  • Personal medical history was significant for a thyroid nodule, surgically removed at the age of 22. A general physical exam did not reveal pathological changes.[ncbi.nlm.nih.gov]
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]
Anorexia
  • Its adverse effects include somnolence, fatigue, paresthesia, anorexia and weight loss, and other abnormalities. We report a 50-year-old woman in whom topiramate at 50 mg/d was initiated in January 2010.[ncbi.nlm.nih.gov]
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]
Thrombosis
  • 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[symptoma.com]
Subcutaneous Nodule
  • A 29-year-old female patient reported the onset of several small subcutaneous nodules on the dorsal aspect of the second interphalangeal joint of the left medius finger and the left elbow, accompanied by vague joint pain, had occurred 13 years ago.[ncbi.nlm.nih.gov]
  • Keywords: Granuloma annulare, subcutaneous granuloma annulare, subcutaneous nodules Introduction The granuloma annulare (GA) is an inflammatory granulomatous dermatitis, benign and self-limited.[scielo.conicyt.cl]
  • SGA occurs exclusively in children and consists of deep dermal or subcutaneous nodules.[pediatrics.aappublications.org]
Ulcer
  • There are seven reported cases in the literature, but only one presenting ulcerated necrobiosis lipoidica.[ncbi.nlm.nih.gov]
  • 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]
  • 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]
  • Perforating granuloma annulare (5% of cases) is characterised by bumps with central pits, which can become crusty, pustular, ulcerate and cause scarring. The back of hands and fingers are most commonly affected.[dermcoll.edu.au]
  • Ulceration and involvement of mucous membranes are rare. Most of the plaques involute with no residual scarring.[consultant360.com]
Eczema
  • In any case, though, granuloma annulare typically responds well to herbal treatments, much like treatment for eczema.[earthclinic.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]
  • If you would prefer to save the trip to the hospital and treat yourself at home, like eczema granuloma annulare responds very well to a variety of similar natural remedies.[healthyfocus.org]
  • Some skin conditions have become common knowledge, like eczema, warts, acne, and skin cancer. But the more informed you are, the better care you can take of your health.[dermatlanta.com]
  • Credit: ISM/SCIENCE PHOTO LIBRARY In localised granuloma annulare, the top of the skin feels smooth and, unlike in other skin conditions, such as pityriasis versicolor, ringworm or eczema, it isn't rough, dry or scaly.[nhs.uk]
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]
  • annulare centrifigum Discoid Lupus Sarcoidosis IX.[fpnotebook.com]
  • Due to the appearance of cutaneous lesions, GA may easily be confounded with tinea corporis, erythema annulare centrifugum or cutaneous lupus erythematosus.[symptoma.com]
Annular Skin Lesion
  • A man whose granuloma annulare skin lesions mimicked sarcoidosis is described.[ncbi.nlm.nih.gov]
  • Skin lesion, left elbow, excision: - Palisading granulomas with cores of necrobiotic collagen, and scant mucin consistent with granuloma annulare. COMMENT: An alcian-blue stain (pH 2.5) shows scant mucin.[librepathology.org]
  • Differential diagnosis [ 2 ] Many annular skin lesions may be mistaken for granuloma annulare.[patient.info]
Somnolence
  • Its adverse effects include somnolence, fatigue, paresthesia, anorexia and weight loss, and other abnormalities. We report a 50-year-old woman in whom topiramate at 50 mg/d was initiated in January 2010.[ncbi.nlm.nih.gov]
Paresthesia
  • Its adverse effects include somnolence, fatigue, paresthesia, anorexia and weight loss, and other abnormalities. We report a 50-year-old woman in whom topiramate at 50 mg/d was initiated in January 2010.[ncbi.nlm.nih.gov]
Urinary Urgency
  • Medical history was significant for asthma, depression, cesarean sections, and urinary urgency. On physical examination, erythematous annular plaques were on the dorsum of the hand.[doi.org]
Cesarean Section
  • Medical history was significant for asthma, depression, cesarean sections, and urinary urgency. On physical examination, erythematous annular plaques were on the dorsum of the hand.[doi.org]

Workup

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.

Hypercholesterolemia
  • […] primarily on neck, trunk and extensor surfaces of extremities. [4] Generalized granuloma annulare is characterized by a later onset, poorer response to therapy and an increased prevalence of the HLA-Bw35 allele. [4] Alterations in the lipid profile (hypercholesterolemia[ijdvl.com]
  • Clinical laboratory tests showed mild glucose intolerance (HbA1c 6.2%), mild liver dysfunction (AST: 86 IU/L, ALT: 76 IU/l), slight hypercholesterolemia (total cholesterol: 235 mg/dl), and severe hyperlipidemia (triglyceride: 962 mg/ml).[raysahelian.com]

Treatment

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:

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.

Prognosis

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.

Etiology

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].

Epidemiology

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.

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

No specific measures can be recommended to prevent GA.

Summary

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.

Patient Information

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.

References

Article

  1. Cyr PR. Diagnosis and management of granuloma annulare. Am Fam Physician. 2006; 74(10):1729-1734.
  2. Paul M, Cribier B, Heid E, Grosshans E, Lipsker D. [Generalized granuloma annulare and drug-induced immunodeficiency]. Ann Dermatol Venereol. 2004; 131(12):1051-1054.
  3. Toro JR, Chu P, Yen TS, LeBoit PE. Granuloma annulare and human immunodeficiency virus infection. Arch Dermatol. 1999; 135(11):1341-1346.
  4. Studer EM, Calza AM, Saurat JH. Precipitating factors and associated diseases in 84 patients with granuloma annulare: a retrospective study. Dermatology. 1996; 193(4):364-368.
  5. Bassi A, Scarfi F, Galeone M, Arunachalam M, Difonzo E. Generalized granuloma annulare and non-Hodgkin's lymphoma. Acta Derm Venereol. 2013; 93(4):484-485.
  6. Muhlbauer JE. Granuloma annulare. J Am Acad Dermatol. 1980; 3(3):217-230.
  7. Kassardjian M, Patel M, Shitabata P, Horowitz D. Management of Periocular Granuloma Annulare Using Topical Dapsone. J Clin Aesthet Dermatol. 2015; 8(7):48-51.
  8. Gamo Villegas R, Sopena Barona J, Guerra Tapia A, Vergara Sanchez A, Rodriguez Peralto JL, Iglesias DL. Pustular generalized perforating granuloma annulare. Br J Dermatol. 2003; 149(4):866-868.
  9. Penas PF, Jones-Caballero M, Fraga J, Sanchez-Perez J, Garcia-Diez A. Perforating granuloma annulare. Int J Dermatol. 1997; 36(5):340-348.
  10. Suite M, Jankey N. Familial granuloma annulare. Int J Dermatol. 1992; 31(11):818.
  11. Dahl MV, Ullman S, Goltz RW. Vasculitis in granuloma annulare: histopathology and direct immunofluorescence. Arch Dermatol. 1977; 113(4):463-467.
  12. Umbert P, Belcher RW, Winkelmann RK. Lymphokines (MIF) in the serum of patients with sarcoidosis and cutaneous granuloma annulare. Br J Dermatol. 1976; 95(5):481-485.
  13. Piette EW, Rosenbach M. Granuloma annulare: Pathogenesis, disease associations and triggers, and therapeutic options. J Am Acad Dermatol. 2016; 75(3):467-479.
  14. Requena L, Fernandez-Figueras MT. Subcutaneous granuloma annulare. Semin Cutan Med Surg. 2007; 26(2):96-99.
  15. Lukács J, Schliemann S, Elsner P. Treatment of generalized granuloma annulare - a systematic review. J Eur Acad Dermatol Venereol. 2015; 29(8):1467-1480.

Ask Question

5000 Characters left Format the text using: # Heading, **bold**, _italic_. HTML code is not allowed.
By publishing this question you agree to the TOS and Privacy policy.
• Use a precise title for your question.
• Ask a specific question and provide age, sex, symptoms, type and duration of treatment.
• Respect your own and other people's privacy, never post full names or contact information.
• Inappropriate questions will be deleted.
• In urgent cases contact a physician, visit a hospital or call an emergency service!
Last updated: 2019-07-11 21:29