Granuloma Annulare

Overview

Granuloma annulare (GA) is a common inflammatory skin disorder characterized clinically by annular, smooth, discolored papules and plaques, and histologically by necrobiotic granulomas. The right term for Granuloma annulare is necrobiotic papulosis.

Granuloma annulare may be a delayed hypersensitivity reaction to a dermal component or a reaction pattern to many stimuli. Many skin diseases and infestations, as well as various forms of skin damage, have been reported as triggering events. 

Granuloma annulare is often identified clinically due to its distinctive appearance. However, there are situations when the diagnosis is not evident, and other illnesses must be explored. A skin biopsy frequently reveals necrobiotic dermal collagen degradation surrounded by an inflammatory response.

Granuloma annulare does not usually require treatment because the patches vanish on their own after a few months, leaving no trace. They can, however, last for years. Individual lesions may benefit from treatment, but it is not curative.

Granuloma Annulare definition

Granuloma annulare (GA) is a cutaneous condition with an unclear cause that is the most frequent type of non-infectious granulomatous illness. The illness is usually self-limiting and harmless. Granuloma annulare is characterized by erythematous plaques or papules grouped in an annular pattern on the upper extremities.

Other clinical forms of granuloma annulare include widespread, perforating, patch, and subcutaneous granuloma annulare, in addition to the most frequent appearance, known as localized granuloma annulare. Despite being a benign disease, it has been linked to more serious disorders such as HIV and cancer.

The following clinical variants are recognized:

• Localized granuloma annulare: This is the most common variation. Skin-colored to violaceous lesions up to 5 cm in diameter describe localized granuloma annulare. Surface marks on the epidermis are often attenuated. Annular rings may be visible, along with isolated hard papules or nodules. Localized granuloma annulare preferentially affects the feet, ankles, lower limbs, and wrists.
• Generalized granuloma annulare: This variant is more common in adults. The trunk, as well as the neck, limbs, face, scalp, palms, and soles, are frequently affected. Lesions range in size from scattered papules to annular plaques to massive, discolored patches that can be yellow or violaceous in hue.
• Subcutaneous granuloma annulare: This kind is more common in children. Subcutaneous granuloma annulare is distinguished by a firm or hard asymptomatic nodules in the deep dermis or subcutaneous tissues, with individual lesions ranging in diameter from 5 mm to 4 cm. The anterotibial plateau, ankles, dorsal feet, buttocks, hands, scalp, and eyelids are all affected.
• Perforating granuloma annulare: This is an extremely unusual form. Perforating granuloma annulare is typically limited to the dorsal hands and fingers, but it can also affect the trunk and extremities. A number of superficial umbilicated papules form, with or without drainage, and cure with scarring.
• Arcuate dermal erythema: This is a rare type of granuloma annulare that appears as infiltrating erythematous spots that can grow into enormous, hyperpigmented rings with central clearing.

Some experts believe actinic granuloma (AG) to be a subset of granuloma annulare, while others consider actinic annulare to be a distinct but related disease.

Epidemiology

Granuloma annulare is predicted to have a prevalence of 0.1 percent to 0.4 percent and an incidence of 0.1 percent to 0.4 percent. Women are more likely to be affected than males, and the condition can affect people of any age. More than two-thirds of patients are under the age of 30.

Etiology 

Granuloma annulare's etiology and pathophysiology remain mainly unclear. Diabetes, thyroid illness, minor trauma, hyperlipidemia, infections (Ebstein-Barr virus, human immunodeficiency virus, varicella-zoster virus, tuberculosis), vaccinations, cancer, and some medicines have all been linked to the disease.

Despite the conventional link with diabetes, data to demonstrate a true association with diabetes is insufficient. Experts feel that a clinician should screen for cancer in a patient with granuloma annulare if the patient is older, has an unusual or broad appearance, or has a resistant disease. More evidence is needed, however, to demonstrate a true link between granuloma annulare and cancer.

According to research, HIV patients are more likely to develop widespread granuloma annulare. There have also been accounts of exceedingly unusual granuloma annulare appearances in HIV patients. Antiretroviral medications have been shown to both improve and worsen HIV. Patients with new-onset granuloma annulare who have HIV risk factors should be tested for the virus. Patients with widespread or perforating granuloma annulare should also be tested for HIV.

According to several studies, prolonged stress is a cause of granuloma annulare. Granuloma annulare also has a preference for sun-exposed skin and photodamaged skin. Photosensitive granuloma annulare has been linked to HIV infection. Finally, after gold therapy and treatment with allopurinol, diclofenac, quinidine, calcitonin, amlodipine, ACE inhibitors, daclizumab, checkpoint inhibitors, and calcium channel blockers, rare cases of granuloma annulare or granuloma annulare–like reactions have been recorded.

Pathophysiology

This disease's etiology and pathogenesis remain unknown. Some researchers believe that granuloma annulare is produced by a delayed-type hypersensitivity reaction, specifically a Th1 reaction involving IFN-gamma prompting macrophages to release matrix metalloproteinases. This eventually leads to connective tissue degeneration. This notion is supported by several investigations.

Helper T cells, for example, have been discovered in granuloma annulare lesions. Another study discovered that many of the T cells in these lesions were CD3+ and had interferon-gamma receptors. It was also discovered that macrophages in the lesions developed into effector cells that expressed matrix metalloproteinases and tumor necrosis factor-alpha.

Patients with granuloma annulare have been observed to have impaired neutrophil chemotaxis. The authors of this study hypothesized that because of the reduced neutrophil response, macrophages take over an inflammatory site, resulting in the granulomatous inflammation found in granuloma annulare as opposed to suppurative neutrophil type inflammation.

Relationship to systemic diseases

Granuloma annulare has been linked to type I diabetes, however it is very infrequently linked to type II diabetes and thyroid illness, according to an increased number of granuloma annulare patients with these diseases in small case series.

Granuloma annulare has been associated with cancer, AIDS, and herpes zoster lesions in small case series. Although no definitive patterns linking granuloma annulare and systemic disease have been thoroughly established, it has been proposed that an atypical histologic (vasculopathy or extravascular neutrophilia) or clinical presentation (unusual appearance or location) may indicate an associated disease. A 2003 study analyzed classic instances in the literature and found no definite association between granuloma annulare and malignant neoplasms.

Certain cancers are accompanied by a variety of mucocutaneous paraneoplastic diseases. Lesions that resemble or are histologically verified to be granuloma annulare have been observed in connection with the following:

• Non-Hodgkin lymphoma
• Hodgkin lymphoma
• Acute myelogenous leukemia
• Chronic lymphocytic leukemia
• Myelomonocytic leukemia
• Large granular lymphocytic leukemia
• Myelodysplastic syndrome
• T-cell lymphoma
• Follicular lymphoma
• Lennert lymphoma
• Solid tumors - Breast tumors, cervical cancer, colon cancer, lung cancer, prostate cancer, testicular tumors, thyroid cancer

Symptoms of Granuloma annulare

Granuloma annulare is frequently found in a ring-like or circinate configuration on the lateral and dorsal hands and feet. Typically, there is no pruritus or other symptom associated with the lesions. The most prevalent subtype of granuloma annulare is the localized variety, which accounts for around 75% of all reported cases.

Other clinical forms of granuloma annulare, in addition to the localized version, include generalized, perforating, patch, and subcutaneous. Generalized granuloma annulare is characterized by many flesh-colored papules in an annular pattern on the trunk and extremities. These lesions, in contrast to the conventional appearance, are frequently pruritic. The generalized form accounts for up to 15% of granuloma annulare cases. This subtype is rarely self-resolving and has a poor response to therapy.

Large nodules on the extremities characterize subcutaneous granuloma annulare. These nodules are also known as pseudorheumatoid nodules. Subcutaneous granuloma annulare is virtually exclusively observed in children, with the condition emerging between the ages of 1 and 14 years.

Granuloma annulare patch appears with erythematous patches that can cover considerable amounts of skin. There is some overlap between this subtype and reactive granulomatous eruptions; distinguishing between the two can be difficult at times. Perforating granuloma annulare is characterized by umbilicated papules. The lesions can be restricted to the limbs or they can include both the trunk and the extremities. It is expected that around half of patients with the localized form of granuloma annulare would undergo spontaneous remission within two years. A patient may have more than one granuloma annulare subtype.

Diagnosis

Laboratory Studies

Laboratory tests in patients with granuloma annulare are mostly inconclusive (GA). There is no need for further workup with a typical history and unimpressive physical examination results

If a comprehensive history is not available or systemic disease is suspected, relevant laboratory testing should be conducted to rule out other diagnostic options. A CBC count, an erythrocyte sedimentation rate, and a rheumatoid factor study, for example, may help to rule out other possible causes of nodules in subcutaneous granuloma annulare.

Imaging Studies

Imaging investigations are not usually required to diagnose granuloma annulare. Radiographs, CT scans, or MRIs, on the other hand, may be useful in the examination of atypical subcutaneous lesions.

Subcutaneous granuloma annulare radiographs indicate a nonspecific soft tissue tumor with no calcification. Subcutaneous granuloma annulare presents on CT scans as a poorly defined mass with varying attenuation and contrast enhancement. Subcutaneous granuloma annulare presents on MRIs as a tumor with poorly defined boundaries that is restricted to subcutaneous tissue. MRI results may be suggestive with subcutaneous granuloma annulare but are not diagnostic.  

Procedures

A biopsy is advised for a subcutaneous lesion as well as an unusual appearance in terms of history (e.g., rapid expansion, discomfort) or location of the lesion.

Management

Although granuloma annulare lesions normally disappear, they can return. Treatment is occasionally advised for this reason, as well as for cosmetic reasons. Many therapy are tried by doctors, but there is insufficient research to back them up. Furthermore, researchers found no significant difference in the duration of lesions between untreated and treated individuals in one study of 67 granuloma annulare patients.

Despite a lack of evidence, experts believe that intralesional steroid injection is the first-line treatment for granuloma annulare lesions. Certain sorts of trauma to the lesions, such as biopsy, pricking, incision, and cryotherapy, have been reported to improve the condition. In several research, phototherapy has yielded encouraging benefits. Both the excimer laser and the pulsed dye laser have been reported to be effective.

Hydroxychloroquine has been demonstrated to be effective in a few modest studies and reports. Despite the fact that additional evidence is needed to confirm efficacy, some researchers believe that hydroxychloroquine should be used as first-line therapy for widespread granuloma annulare. Tumor necrosis factor-alpha inhibitors have been demonstrated to be effective in the treatment of both widespread and persistent granuloma annulare.

However, as previously said, there have been instances of TNF-alpha inhibitors causing or intensifying the disease, thus additional research is required to assess the risks and advantages of utilizing TNF-alpha inhibitors to treat this disease. Surgical excision has also been attempted; however, lesions tend to return.

Vitamin E, isotretinoin, tetracyclines, intralesional interferons, topical imiquimod, niacinamide, oral calcitriol, dapsone, hydroxyurea, topical tacrolimus, clofazimine, and rifampin have all been tried and shown to be useful in small studies.

Generalized granuloma annulare

Granuloma annulare generalized is more chronic and ugly. Unfortunately, there aren't many methods for treating the broad disease that is consistently effective. Over the last 10-15 years, success with the use of ultraviolet (UV) B, primarily narrowband UVB, a reasonably innocuous treatment when compared to alternatives, has elevated it to a first-line option for widespread granuloma annulare. A retrospective study of 13 cases of generalized granuloma annulare treated with narrowband UVB was published in 2015.

The evidence supports the use of phototherapy with oral psoralen and UVA (PUVA) as a first-line treatment option for widespread granuloma annulare. However, while treating an essentially benign illness, the chances of malignancy must be evaluated.

Based on numerous case reports, isotretinoin may be the first-line treatment. As evidenced by a wide case series and individual reports, antimalarials may also be extremely effective. The most effective treatment was chloroquine, however, hydroxychloroquine was also effective.

Six patients had granuloma annulare that was resistant to normal treatment. For three months, the patients were given a monthly combination of rifampin 600 mg, ofloxacin 400 mg, and minocycline hydrochloride 100 mg. The plaques were entirely eliminated three to five months after treatment began.

Some patients complained of postinflammatory hyperpigmentation. Although the treatment was effective, the authors advised that more research is needed to prove this combination therapy as a viable treatment option for recalcitrant granuloma annulare.

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
• Perforating collagenosis
• Rheumatoid nodule
• Subcutaneous granuloma annulare
• Sarcoidosis

Prognosis

Granuloma annulare is a harmless, self-limiting disorder. Lesions can spontaneously dissolve without leaving any residual effects, usually within a few months to years. There is no effective treatment for GA, but because the lesions are usually asymptomatic, watchful waiting is frequently sufficient.

For the majority of people, the disease resolves after a few years. When it spreads to various places (generalized form), it tends to be more persistent than when it is isolated in one location (localized form).

Complications

Granuloma annulare is a benign, often self-limiting condition.

Conclusion 

Granuloma annulare (GA) is a noninfectious granulomatous skin disorder with a wide range of cutaneous morphologies. Collagen degradation, mucin deposition, and palisaded or interstitial histiocytes define it. Although the mechanism underlying the development of GA is unknown, research suggests that it is caused by a cell-mediated hypersensitivity reaction 

Atypical GA has systemic correlations with diabetes, thyroid problems, lipid abnormalities, cancer, and infection. Localized skin-directed therapies are distinguished from systemic immunomodulatory or immunosuppressive medications.

Patients suffering from granuloma annulare should see their primary care physician, internist, or dermatologist. The most important thing to understand is that this skin lesion is benign and can spontaneously regress. The majority of instances do not necessitate treatment. Patients do, however, seek treatment for cosmesis. Unfortunately, despite the availability of dozens of treatments, none of them perform consistently or reliably; recurrences are common with all treatments.