Granuloma annulare (GA) is a granulomatous dermatitis, with various clinical forms such as localized, generalized (or disseminated), perforating and subcutaneous GA.¹

This disease affects mostly young people,¹ the localized form being the most common (75% of cases).² Generalized GA accounts for 8.5-15% of cases and affects mostly female patients over 30,³ while the subcutaneous form is less frequent and encountered especially in children.⁴

Even though various theories regarding the pathogenesis of GA have been proposed, the exact mechanism responsible for the appearance of this cutaneous disorder has not yet been completely clarified. One theory was based on the idea of a cell-mediated immune reaction, while another one sustained a delayed-type hypersensitivity reaction.² Some triggers such as trauma, drugs, infections, phototherapy may also be responsible for the development of GA.⁴

Case report

We report the case of a 68-year-old female patient, who presented for an asymptomatic skin eruption consisting of annular lesions over the extremities and trunk, evolving for more than 5 years. Clinical examination revealed round annular plaques with slightly elevated and well demarcated violaceous borders, composed of multiple coalescing papules and a pale center, symmetrically distributed on the dorsal aspects of the hands and feet, anterior part of the arms, forearms and shins and upper trunk (Figure 1). Since the appearance of the eruption, the patient underwent topical treatment with high potent corticosteroids, calcineurin inhibitors and intralesional steroids, in different dermatology departments without any benefit and a constant progression of the disease. She denied any personal or family antecedents and she did not have other complaints. Based on the aspect of the lesions, a clinical presumptive diagnosis of disseminated granuloma annulare was noted.

Blood tests revealed hyperglycemia (173 mg/dL, reference range 65-110 mg/dL), elevated glycosylated hemoglobin (8.33%, reference range 0.10-6.00%), as well as an abnormal thyroid function represented by thyroperoxidase antibodies level 10 times greater than normal (170 UI/mL, reference range 10-35 UI/mL), decreased levels of free T3 (3.55 pmol/L, reference range 4-8.3 pmol/L) and free T4 (8.61 pmol/L, reference range 10-20 pmol/L) and elevated levels of thyroid stimulating hormone (18.91 μUI/mL, reference range 0.2-5 μUI/mL). The patient was diagnosed with diabetes mellitus type 2, autoimmune thyroiditis and hypothyroidism and subsequently she was referred to a specialist for further evaluation, where she was prescribed oral antidiabetic medication and thyroid hormone replacing therapy. For the cutaneous lesions, tacrolimus 0.1% ointment for 6 weeks was the chosen therapy. At the 2-months follow-up visit, considering the fact that an adequate glycemic control and normal thyroid function status were obtained, the evolution was favorable with marked improvement of the annular plaques, which were replaced by a postinflammatory hyperpigmentation.

 

The pathogenesis of this disease is unknown. A study revealed that granuloma annulare might be caused by a delayed-type hypersensitivity reaction. This consists of a Th1 reaction involving IFN-gamma stimulating macrophages to release matrix metalloproteinases leading to connective tissue degradation. Another study showed that macrophages found in the lesions were differentiated to effector cells that expressed matrix metalloproteinases and tumor necrosis factor-alfa. Patients with granuloma annulare have impaired neutrophil chemotaxis and, because of this, macrophages take over an inflammatory site which leads to the granulomatous inflammation seen in granuloma annulare as opposed to a suppurative neutrophil type inflammation.⁵

Clinically, localized GA has the aspect of erythematous non-scaly annular plaque, whose margins are composed of tiny papules, distributed especially on the hands, feet and in a lower percentage over the trunk.¹The generalized form presents as erythematous or violaceous papules on the trunk or extremities, which may combine to create multiple plaques with annular pattern.¹ Subcutaneous GA is described as nodules distributed on the extremities, while perforating lesions manifest as umbilicated papules with tendency to ulceration.¹

The localized eruption is supposed to remit spontaneously in half of the cases within the first two years,² while the generalized form tends to have a more prolonged course and a smaller rate of spontaneous remission.⁴In addition, the generalized variant is more difficult to treat, associating a risk of frequent recurrences.⁴

Most of the cases are asymptomatic, even though some patients may complain about pruritus or a burning sensation.³ Atypical variants may present as linear, follicular, patch type and fibroelastolytic giant cell GA.⁴

A causative association between GA and different systemic conditions or autoimmune disorders is controversial, even though various case reports and studies have brought this to attention.

The relationship between granuloma annulare and diabetes mellitus is still debated. While some investigators consider that there is no significant relationship between these two skin conditions,⁴ others support the theory of an association. Likewise, numerous cases of simultaneous occurrence of diabetes and GA in the same patient have been documented.⁴ Scientists discovered that 20% of those generalized granuloma annulare (GGA) cases were diabetic.² A study found more patients diagnosed with diabetes mellitus in the localized form group than in the generalized one.² Another study highlighted the relationship between insulin-dependent type and localized GA.⁴Diabetic patients have a greater likelihood of relapsing than non-diabetics.⁴

Regarding pediatric patients, GA in a child with type 1 diabetes has been reported,⁶ as well as different types of lesions in the same patient (subcutaneous GA and localized GA).⁴

Concerning the connection between thyroid pathology and GA, thyroid disorders were found in 13% of patients with GGA.⁷ A female patient suffering from this skin condition was subsequently diagnosed with autoimmune thyroiditis, whilst she had a positive familial history for autoimmune polyglandular syndrome type II.⁸ Another association of GA with this rare autoimmune syndrome was documented,⁹ as well as other cases regarding localized GA and autoimmune thyroiditis in the same patient.¹⁰A case of GA affecting a child diagnosed with type 1 diabetes mellitus and autoimmune thyroiditis has also been presented.⁶

Moreover, an association between GA (especially the generalized form) and dyslipidemia has been proposed.⁴ A study showed that 19.6% of patients with generalized GA had elevated cholesterol levels and 23.3% of them had hypertriglyceridemia.⁷ It was found that cytokines were involved in the pathogenesis of other disorders associated with dyslipidemia (psoriasis, lichen planus), as well as in GA.⁴ The mechanism behind the association of GA and dyslipidemia is considered unclear. It is consideredthat chronic inflammation leads to the development of lipid abnormalities and, on the other hand, one of the causes of GA can be attributed to microvascular dysfunction and inflammation.

It was postulated that cytokine secretion induced by tumor cells may trigger the granulomatous inflammation.³ GGA appearing in a patient with hematologic malignancy and chronic hepatitis B virus infection has been reported.³ Other oncologic patients with lymphoma were diagnosed with GA.⁴ It is remarkable that the cases linked with malignancy had an atypical GA presentation;⁴ lymphoma was present in approximately 50 percent of the cases. As a result of this study other adults diagnosed with atypical GA presentation should be reevaluated for any association with undiagnosed malignancies.

GGA has been described in association with chronic infection with hepatitis B or C viruses and a favorable evolution of the skin lesions was observed after treating the underlying chronic infection.² In patients with HIV infection, the clinical aspect of the lesions may be atypical, presenting as generalized papules with central umbilication, macules or perforating annular lesions rather than an annular configuration.²In addition, in these individuals, the generalized form is more frequent than the localized one.⁴ Vaccines and different drugs have been considered responsible for the appearance of the lesions.²

Histopathology (Figure 2) may reveal mucin deposits, deteriorated collagen or elastic fibers and granulomatous inflammation within the dermis, characterized by the presence of histiocytes arranged in different variants: interstitial, palisading and epithelioid nodules pattern.¹

Regarding the treatment, various modalities have been tried mostly in isolated case reports with different response rates: topical and intralesional corticosteroids, topical calcineurin inhibitors, phototherapy (NB-UVB, PUVA), dapsone, cryosurgery, doxycycline, hydroxychloroquine, biological agents, isotretinoin.²

The linkage between GA and other systemic conditions remains controversial. The case of our patient, in which an adequate control of the associated systemic diseases had an important contribution in the remission of the cutaneous lesions, sustains the theory of a possible association between GA and diabetes mellitus/autoimmune thyroiditis.

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6.Spicuzza L, Salafia S, Capizzi A, et al. Granuloma annulare as first clinical manifestation of diabetes mellitus in children: a case report. Diabetes Res Clin Pract 2012;95:e55-7. [Crossref]

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8.Kappeler D, Troendle A, Mueller B. Localized granuloma annulare associated with autoimmune thyroid disease in a patient with a positive family history for autoimmune polyglandular syndrome type II. Eur J Endocrinol 2001;145:101-2. [Crossref]

9.Thomas DJ, Rademaker M, Munro DD, Levison DA, Besser GM. Visceral and skin granuloma annulare, diabetes, and polyendocrine disease. Br Med J (Clin Res Ed)1986;293:977-8. [Crossref]

10. Vázquez-López F, González-López MA, Raya-Aguado C, Pérez-Oliva N. Localized granuloma annulare and autoimmune thyroiditis: a new case report. J Am Acad Dermatol 2000;43:943-5. [Crossref]