Clinical Manifestations and Management of Pediatric Granuloma Annulare: A Systematic Review.

OBJECTIVE: To determine the clinical manifestations, management, and outcomes of pediatric granuloma annulare (GA). STUDY DESIGN: We searched MEDLINE via PubMed, Latin American and Caribbean Health Sciences, and EMBASE from inception to January 2021. We included all original reports of patients <18 years of age with a diagnosis of GA and all original reports describing any intervention, including topical or systemic agents, in these patients. Two authors independently extracted sociodemographics and clinical data of the study patients and treatment(s) used. RESULTS: Of 2440 reports screened, 202 were included (836 patients). The mean age was 5.7 (SD 3.8) years and F:M ratio 1.3:1. Localized GA (n = 384/821, 46.8%) and subcutaneous GA (n = 353/821, 43.0%) were the most prevalent subtypes. The most affected site was lower limbs (n = 272/568, 47.9%). Suspected triggering factors were mainly local trauma. Diabetes was associated in 22 (2.6%) patients. The rate of spontaneous remission was high (n = 140/155, 90.3%), with a median time of 12 months. The most frequent therapies were surgery and topical corticosteroids. Recurrence was observed in 38.3% (n = 168/439) of patients, regardless of treatment. CONCLUSIONS: Pediatric GA frequently resolves spontaneously yet displays a high recurrence rate. Hence, in asymptomatic forms, invasive therapies are not recommended as first-line treatment.

Granuloma Annulare: An Updated Review of Epidemiology, Pathogenesis, and Treatment Options.

Granuloma annulare (GA) is an inflammatory granulomatous skin disease that can be localized (localized GA) or disseminated (generalized GA), with patch, perforating, and subcutaneous subtypes being less common variants of this benign condition. Recently, new research has emerged that further elucidates GA epidemiology and etiopathogenesis; importantly, new therapeutic options for GA have also been described, although there remains a paucity of randomized controlled studies. In this review, we summarize recent updates on GA epidemiology and etiopathogenesis and offer an updated review of the therapeutic options for GA currently reported in the literature. We hope that the current review galvanizes randomized controlled studies that will in turn help lead to the recommendation of evidence-based treatments for GA.

Light- and laser-based treatments for granuloma annulare: A systematic review.

BACKGROUND: Granuloma annulare (GA) is challenging to treat, especially when generalized. A systematic review to support the use of light- and laser-based treatments for GA is lacking. METHODS: We performed a systematic review by searching Cochrane, MEDLINE, and Embase. Title, abstract, full-text screening, and data extraction were done in duplicate. Quality appraisal was performed using the Joanna Briggs Institute critical appraisal tool for case series. RESULTS: Thirty-one case series met the inclusion criteria, representing a total of 336 patients. Overall, psoralen ultraviolet light A (PUVA) showed the greatest frequency of cases with complete response (59%, n = 77/131), followed by photodynamic therapy (PDT) (52%, n = 13/25), ultraviolet light B (UVB)/narrowband UVB (nbUVB)/excimer laser (40%, n = 19/47), UVA1 (31%, n = 27/86), and lasers (29%, n = 8/28). Overall across treatment modalities, higher response rates were seen in localized GA compared to generalized GA. CONCLUSIONS: The body of evidence for light- and laser-based treatment of GA is sparse. Our results suggest that PUVA has a high clearance rate for GA but its use may be limited by concerns of carcinogenesis. Although PDT has the second highest clearance rate, adverse effects, small sample sizes, impractical treatment delivery (especially with generalized disease), and long-term concerns of carcinogenesis may limit its use. Although UVB/nbUVB/excimer laser appeared slightly less effective than other light therapies, we recommend UVB/nbUVB/excimer laser therapy as a first-line treatment for patients with generalized GA given wider availability and a favorable long-term safety profile.

Unusual Case of Granuloma Annulare Associated with Diabetes Mellitus.

Dear Editor, Granuloma annulare (GA) is an asymptomatic, chronic, and relatively common granulomatous skin condition which presents with annular papules usually slowly progressing into plaques on the extremities and the trunk. It usually presents with non-scaly, erythematous, annular plaques on the distal extremity (1,2). The pathogenesis of GA is still unknown, although a variety of possible factors contributing the disease have been reported, including drugs (3), insect bites, sun exposure, trauma, vaccinations, and viral infections (e.g. hepatitis B, hepatitis C, HIV, Epstein-Barr virus) (1). Several cases in which GA developed on residual skin changes from herpes zoster have also been reported (4). A 47-year-old woman presented with erythematous-livid plaques on the dorsa of her hands and linear and circular lesions on her neck, gradually spreading for the last 4 months prior to admission at our Department (Figure 1a and Figure 1b). She reported excessive thirst and sweating in the last 30 days, but did not consider it significant since it was summer. The patient was otherwise healthy and was not taking any medications. Mycological swabs taken from the dorsal parts of both hands and the neck were negative. Biopsy of the skin changes was consistent with GA, showing palisading granulomatous inflammation which surrounded degenerated collagen within the dermis. A routine laboratory check revealed increased levels of glucose (23 mmol/L) and HgbA1C, while lipid and thyroid hormone levels were normal. Fasting blood sugar lever was 17 mmol/L. Therapy with topical corticosteroid (betamethasone cream) for skin lesions was initiated and applied two times daily for 2 weeks. The patient was immediately referred to an endocrinologist and insulin therapy was initiated due to diabetes mellitus. Complete remission of the skin changes was observed on the follow-up visit after 3 months. There are many clinical variants of GA such as localized, generalized, disseminated, subcutaneous, arcuate dermal erythema, and perforating GA (1). The localized form of GA is most common with annular plaques on the distal extremities. In addition to the typical lesions on the dorsal side of both hands, our patient also presented with atypical, circular lesions around her neck. The relationship between GA and systemic diseases such as diabetes mellitus, thyroid disorders, dyslipidemia, and malignancies remains unclear (5). It is also uncertain whether genetic factors influence susceptibility to GA. Familial cases have been documented, but studies investigating the association between the disease and human leukocyte antigen (HLA) genes have yielded inconsistent results (6). Increased frequency of HLA-B35 in patients with the generalized form has been reported in a few studies (7). GA mostly affects children and young adults, mostly women. Many cases of GA resolve spontaneously within 2 years, but relapses occur in many patients. Treatment is divided into localized skin therapies and systemic therapies (1). High potency topical corticosteroids along with intralesional corticosteroids are the most common localized treatments (8). Systemic therapy includes corticosteroids, chloroquine, dapsone, and isotretinoin (1,9). Cryotherapy and UV-therapy can also be used, although with limited efficacy (10). GA is a common idiopathic disorder of the dermis and subcutaneous tissue that can be associated with a variety of underlying conditions such as diabetes mellitus. The relationship between GA and diabetes mellitus is still unknown. Since skin lesions preceded the diagnosis of DM in our patient and complete remission of skin changes occurred with induction of insulin therapy, it is important to perform routine laboratory test in every patient.

A Monocentric, Retrospective Analysis of 61 Patients with Generalized Granuloma Annulare.

BACKGROUND: Granuloma annulare is a chronic noninfectious granulomatous skin condition with variable clinical presentations. Generalized granuloma annulare, defined as widespread disease with >10 skin lesions, accounts for 15% of all cases. Numerous associated diseases have been controversially discussed, most importantly diabetes mellitus, dyslipidemia, thyroid disease, malignancy and systemic infections. OBJECTIVES: The objective of our study is to describe disease characteristics, treatment outcome and associated diseases in patients treated at the Department of Dermatology of the University Hospital Zurich during the last 20 years. METHODS: The hospital database was searched for patients with generalized granuloma annulare in the last 20 years (January 1, 1998, to December 31, 2017). Overall, 61 patients, 14 males and 47 females, were included in our study. The mean age was 58 years at first consultation. The diagnosis was verified clinically and histologically. RESULTS: Generalized granuloma annulare occurred at a mean age of 55 years, more commonly in females. Pruritus was absent in 51% of all patients. Metabolic diseases including diabetes mellitus, hypercholesterinemia and hypertriglyceridemia were present in 10.5, 8.2 and 4.9%, respectively. Thyroid disease was present in 9.8% and malignant disease in 23%, including colorectal cancer, lymphoproliferative disease, squamous cell carcinoma of the esophagus, basal cell carcinoma and gynecological malignancy. Therapy was initiated in 92%, while second- and third-line therapy was performed in 70 and 39%, respectively. Benefit during therapy (e.g., full and partial remission) was achieved in 39.3% during first-line, in 39.4% during second-line and in 33.8% during third-line treatment. Topical corticosteroids were the most commonly prescribed treatment, mostly leading to stable disease (46.6%). Combined full and partial remission occurred in a large proportion of patients receiving UVA1 (45%), PUVA (63.6%) and intralesional triamcinolone acetonide (100%). CONCLUSIONS: Generalized granuloma annulare is a mostly asymptomatic and benign disease with a strong tendency for treatment resistance. We suggest to screen all patients for dyslipidemia, thyroid disease and malignant disease. While randomized trials are needed, we suggest topical corticosteroids as the first-line treatment, intralesional triamcinolone acetonide for persistent solitary lesions and, if further treatment is needed, UVA1 or PUVA.

Patch-type granuloma annulare: An institution-based study of 23 cases.

BACKGROUND: Granuloma annulare (GA) is a skin disorder of uncertain etiology. Patch (type) GA is an uncommon variant of GA with a paucity of data characterizing it. We describe the features of 23 cases of patch GA. METHODS: The archives of dermatopathology were searched for cases of patch GA. The clinical history and morphology for each patient were reviewed. Only cases with patch clinical morphology were included. The clinical and histopathologic features were assessed including the pattern of granulomatous inflammation and presence of other inflammatory cell types. RESULTS: Most patients were female (19/23) with erythematous patches on the trunk and proximal extremities. The most common clinical differential diagnosis included mycosis fungoides (MF), morphea and contact dermatitis. Dyslipidemia was the most common comorbidity (30%), followed by diabetes (15%) and hypertension (15%). Histopathologic features included interstitial lymphocytes and histiocytes with dermal mucin. Two cases showed focal palisaded granulomas. Eosinophils and plasma cells were present in 1/3 of cases. CONCLUSION: Patch GA is an uncommon GA variant with an interstitial granulomatous histopathologic pattern that predominantly affects women over 50. It can mimic interstitial MF and early morphea both clinically and histopathologically. Awareness of this GA variant can help prevent misdiagnosis and inappropriate treatment for these patients.

[Generalized granuloma annulare: A clinicopathological study]. / Granulome annulaire généralisé : étude anatomoclinique.

BACKGROUND: Granuloma annulare (GA) is a benign granulomatous skin disorder that is generalized (GGA) in 15 % of cases. Although many case reports describe a relationship between GGA and systemic diseases, few large series have been published, and their association is debated. We present herein a series of GGA in order to describe their clinical and histological features. PATIENTS AND METHODS: We included all biopsy-proven cases of GA presenting at the dermatopathology laboratory of Strasbourg where generalized (i.e. over 10 lesions). Clinical features were obtained from patients' medical files. RESULTS: We included 35 GGA, with a sex ratio of 0.5. The mean age was 54 years. Lesions were annular or non-annular in equal measure and were symptomatic in 25 % of cases. Most patients (77 %) had an associated disease, already known in 60 % of cases, including dyslipidemia (27 %), diabetes mellitus (20 %), immunosuppressive drugs (17 %), atopy (17 %), auto-immune disease (17 %), hematological disease (14 %), and cancer (9 %). Histological analysis revealed the predominant pattern to be interstitial (54 %) rather than palisading (20 %), having no correlation with clinical type. Eosinophils were frequent (46 %) in GA but were not correlated with systemic disease or drug taking. Among the 40 % of patients treated, 50 % had a successful outcome on topical corticosteroids, doxycycline, antimalarial drugs or phototherapy. DISCUSSION: GGA differs from localized GA, which is mostly associated with an already known systemic disease, whether metabolic, infectious or neoplastic, uncorrelated with clinical or histological features, and screening is necessary.

Granuloma anular perforante: patologia inusual / Perforating Granuloma Annulare: unusual pathology

Resumen El Granuloma Anular (GA) es una dermatosis inflamatoria crónica, benigna, auto limitada, de etiología desconocida. Existen numerosas variantes clínicas dentro de las cuales se encuentra la perforante, de presentación inusual. La histopatología más característica de GA, cuenta con la presencia de histiocitos epitelioides en empalizada alrededor de áreas de degeneración focal de fibras de colágeno con depósitos de mucina. La variedad perforante evidencia eliminación transepidérmica de fibras de colágeno. Se presenta un paciente de 72 años de edad, diabético, dislipémico, con lesiones pruriginosas en dorso de ambas manos, con el diagnóstico de granuloma anular perforante. Realizó tratamiento con clobetasol tópico, más antihistamínicos por vía oral, quedando una cicatriz atrófica.

Abstract Granuloma annulare is a chronic, benign, self-limiting, inflammatory dermatosis of unknown etiology. There are numerous clinical variants within which is the perforating, unusual presentation. The most histopathology characteristic of GA is the presence of palisading epithelioid histiocytes around areas of focal degeneration of collagen with mucin deposits. The perforating variety evidences transepidermal elimination of collagen tissue. A 72 years-old, diabetes, dyslipidemic patient is presented with pruritic lessions on the dorsum of both hands, with the diagnosis of perforating granuloma annulare. I perform medical treatment with topical clobetasol, leaving an atrophic scar.

[Experience with fractional photothermolysis in the therapy of gra-nuloma annulare]. / Opyt primeneniia fraktsionnogo fototermoliza v terapii kol'tsevidnoi granulemy.

BACKGROUND: Granuloma annulare is a benign inflammatory dermatosis of unknown etiology, which is characterized by the development of flesh-colored or red papules often arranged in rings on the skin. Currently there are no effective treatments for granuloma annulare. Topical and intradermal applications of glucocorticosteroids produce a short-term and insufficient therapeutic effect. The method cannot be used in extensive rashes. Fractional photothermolysis is a physical method for ablative exposure of tissues to an erbium laser via their local heating with light energy in certain areas. AIM: To investigate the efficiency of fractional photothermolysis in the therapy of patients with granuloma annulare. MATERIAL AND METHODS: Twenty-eight patients diagnosed with granuloma annulare were followed up. All the patients were treated with fractional Fotona Fidelis XS erbium laser at a wavelength of 2940 nm using a FS01 maniple. The treatment cycle consisted of 5 sessions. RESULT: After the treatment, the GASI index was decreased by 50, 75, and 100% in 5 (17.9%), 15 (53.6%), and 8 (28.6%) patients, respectively. The median GASI index was decreased by a total of 2.8 times (p<0.05). CONCLUSION: The study showed the high efficiency of fractional photothermolysis in the treatment of patients with granuloma annulare. This method can be recommended for the treatment of common forms of granuloma annulare.

Localized Perforating Granuloma Annulare.

Perforating granuloma annulare (PGA) is a rare type of granulomatous skin disease. The etiology and pathogenesis of PGA are still unknown. Diagnosis and treatment of PGA is complex and challenging. We present the case of a 31-year-old male patient with a localized form of PGA successfully treated with topical steroids.

Granuloma annulare: a retrospective series of 133 patients.

Although granuloma annulare (GA) is a relatively common dermatologic condition, little is known about its epidemiology and pathogenesis. Additionally, there is conflicting evidence regarding its association with other diseases. In our retrospective study, we attempted to determine the number of cases of GA seen annually at a large academic center and clarify disease associations with GA. We utilized PennSeek, a tool developed by the Penn Medicine Data Analytics Center to search electronic medical records (EMRs), to identify all cases of GA seen at the University of Pennsylvania (Philadelphia, Pennsylvania) from 2008 to 2014. All biopsy-proven cases of GA from 2010 to 2014 were reviewed for medical comorbidities, medications, treatments, and outcomes. On average, the percentage of patients given a diagnosis of GA annually was 0.22%. There were 133 cases of biopsy-proven GA that were reviewed. The findings solidify our understanding of the epidemiology of GA and diseases that can be associated with GA.

Granuloma anular generalizado y fenómeno isotópico de Wolf / Generalized annular granuloma and Wolf''s isotopic response

El granuloma anular (GA) es una dermatosis inflamatoria granulomatosa, generalmente asintomática, con distintas formas de presentación clínica, que puede distribuirse de forma localizada o generalizada. su etiología es incierta pero se la ha vinculado a factores desencadenantes como traumatismos, fármacos, diabetes mellitus, tiroideopatías, neoplasias, infecciones virales (herpes simple y varicela zóster) y excepcionalmente puede aparecer en la misma localización donde previamente aconteció otra enfermedad con la cual no guarda relación alguna (fenómeno isotópico de Wolf). En su patogenia intervendrían mecanismos de hipersensibilidad retardada y de estrés oxidativo celular. Existen múltiples terapias con respuesta variable y se ha observado autorresolución en casi el 75% de los casos. Presentamos el caso de una mujer de 64 años de edad, hipotiroidea de larga data, con un granuloma anular generalizado que apareció sobre cicatrices residuales de un herpes zóster (fenómeno isotópico de Wolf) y su respuesta al tratamiento con Vitamina E por vía oral

Granuloma annulare (GA) is a granulomatous inflammatory dermatosis, usually asymptomatic, with different forms of clinical presentation, which can be localized or generalized. Its etiology is uncertain but has been linked to triggers such as trauma, drugs, diabetes mellitus, thyroid disease, neoplasms and viral infections (herpes simplex, varicella-zoster). Exceptionally, it may appear in the same location where another disease has previously occurred but with no relationship to it (Wolf isotopic response). In their pathogenesis, delayed hypersensitivity mechanisms and cellular oxidative stress would intervene. There are multiple therapies with variable response, and autorresolution has been observed in almost 75% of the cases. We present the case of a 64-year-old woman with a long history of hypothyroidism, with diagnosis of generalized granuloma annulare on residual scars of Herpes Zoster (Wolf 's isotopic response) and its response to oral Vitamin E.

Advances in Inflammatory Granulomatous Skin Diseases.

Inflammatory granulomatous dermatitides include cutaneous sarcoidosis, necrobiosis lipoidica, granuloma annulare, and reactive granulomatous dermatitis. The etiopathogenesis of these disorders is not well understood; but the T helper 1 response mediated by interferon-gamma, tumor necrosis factor-alpha, and interleukin (IL) 1, 2, and 6 and the T helper 17 response mediated by IL-17 play a role. These inflammatory granulomatous disorders often have cutaneous manifestations in addition to extracutaneous manifestations or associations with systemic diseases. The authors review these disorders, propose diagnostic and evaluative approaches to these diseases, and explore recent literature with regard to the etiopathogenesis and treatment of these entities.

Granuloma Annulare: A Focused Review of Therapeutic Options.

Granuloma annulare (GA) is a benign inflammatory disease associated with many conditions such as malignancy, trauma, thyroid disease, diabetes mellitus, and HIV infection. Common clinical subtypes include localized GA, generalized GA, subcutaneous GA, perforating GA, and patch GA. There exists an abundance of literature on GA, yet we know relatively little about its exact etiology and even less about its treatment. The paucity of conclusive data on effective treatment options is largely because the majority of published studies are limited to small case reports, case series, and retrospective studies. As such, there does not yet exist a gold standard of care to guide clinical management. Depending on the clinical subtype, the clinical prognosis for GA can vary. The localized variant generally self-resolves within 2 years without treatment, whereas the generalized form is more chronic and less responsive to treatment. This focused up-to-date review serves to summarize the latest therapeutic options available for GA.