Scleromyxedema is a rare, chronic cutaneous mucinosis defined histopathologically by a triad of dermal mucin deposition, fibroblast proliferation, and dermal fibrosis. However, additional underrecognized histopathologic patterns or findings may complicate diagnosis and lead to misclassification. A retrospective review of 22 biopsy-confirmed cases of scleromyxedema was performed to characterize both classic and uncommon histopathologic variants of scleromyxedema, with emphasis on patterns that may obscure or mimic other dermatologic entities. All cases were evaluated for mucin, fibrosis, fibroblast proliferation, inflammatory infiltrates, granulomas, eosinophilic infiltration, and eccrine gland hyperplasia using hematoxylin and eosin and special stains, with immunohistochemistry as it was needed. Sixteen cases (72.7%) demonstrated the classic histologic triad. In contrast, 6 cases (27.3%) showed a granulomatous pattern characterized by interstitial collections of CD68+ histiocytes, multinucleated giant cells, sparse lymphocytes, and mucin, but lacked the full classical triad-posing a risk of misdiagnosis as granuloma annulare or other granulomatous dermatoses. Eosinophilic infiltrates were identified in 4 cases (18.2%), and eccrine gland hyperplasia in 2 cases (9.1%). Both findings coexisted with the classical triad and may mimic inflammatory or adnexal conditions. Scleromyxedema presents with broader histopathologic variability than classically recognized. The granulomatous pattern, which may lack the defining triad, can obscure diagnosis without clinical correlation. In contrast, eosinophilic infiltration and eccrine gland hyperplasia, though infrequent, typically coexist with classic features and should be recognized as part of the histologic spectrum. Awareness of these variants is essential to avoid misdiagnosis and ensure accurate clinicopathologic interpretation.

Granuloma Annulare: An Updated Review of Epidemiology, Molecular Pathogenesis, and Management.

Dysregulated type I interferon (IFN-I) signalling is implicated in the pathogenesis of several systemic autoimmune conditions, collectively termed type I interferonopathies. Emerging evidence suggests that aberrant IFN-I pathway activity may similarly contribute to certain autoimmune dermatoses, namely granuloma annulare (GA), lichen planus (LP), cutaneous sarcoidosis (CS) and morphea. We sought to investigate this association using large, real-world cohorts, with type I interferonopathies serving as proxies for IFN-I-driven inflammation. Four retrospective cohort studies were conducted in parallel using the TriNetX Global Collaborative Network. Patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjogren's disease (SjD) and dermatomyositis (DM) were 1:1 propensity score-matched to healthy controls (HCs), and relative risks (RRs) for developing GA, CS, LP and morphea were calculated. Sensitivity analyses compared each interferonopathy cohort to patients with gout and ankylosing spondylitis, rheumatologic conditions not mediated by IFN-I pathways. Increased risk of morphea and LP was observed across all four interferonopathy cohorts relative to HCs. Patients with SLE, SSc and SjD had an increased risk of developing CS. GA risk was significantly increased only among patients with SLE and DM. Sensitivity analyses were broadly corroborative. These findings reveal consistent associations between type I interferonopathies and subsequent development of LP, CS and morphea. The results of these analyses are hypothesis-generating and complement existing evidence of an IFN-I mediated pathogenesis for these dermatoses. Prospective studies employing large, representative cohorts paired with transcriptomic and proteomic technologies for mechanistic confirmation are warranted.

Exploratory evaluation of local hyperthermia (44 ± 2 °C) in granuloma annulare: A pilot randomized controlled study.

Granuloma annulare (GA) and cutaneous sarcoidosis (cSAR) have an overlapping immunopathology, in which the aberrant activation of macrophages by IFN-γ constitutes a central driver. Nevertheless, the molecular understanding in GA and cSAR macrophages remains limited. We reanalyzed single-cell RNA sequencing data of GA and cSAR and performed in vitro experiments with primary human cells showing that oxidative phosphorylation (OXPHOS) is a dominant metabolic pathway in IFN-γ–activated macrophages. Furthermore, we identify an IFN-γ–induced response network in GA and cSAR macrophages, sensitive to electron transport chain (ETC) inhibitors. Guanylate-binding protein 1 (GBP1) was central in controlling IFN-γ–mediated macrophage activation. Meanwhile, inhibition of IFN-γ signaling, ETC complexes, and GBP1 reduced granuloma formation in a human in vitro model. Metformin, a clinically used ETC complex I inhibitor, suppressed IFN-γ activation of macrophages and in vitro granulomas. Together, we suggest that OXPHOS and GBP1 represent druggable targets in granulomatous diseases and that drug repurposing of metformin is a possible strategy.

Dermoscopy is a non-invasive technique, which is increasingly used in the diagnosis of many dermatological diseases. Dermoscopy may be a helpful tool in the diagnostic process of the subacute cutaneous lupus erythematosus (SCLE). Dermatoscopy of SCLE has been reported in several cases. Dermatoscopic examination may provide helpful clues in differentiating SCLE from other differential diagnoses including pityriasis rosea, psoriasis, granuloma annulare, and mycosis fungoides.

Patients with granuloma annulare treated with Jak inhibitors show Cutibacterium acnes expansion: A clue to the mechanism underlying acneiform eruptions seen with Jak inhibitors.

Cutaneous and subcutaneous lumps are frequently encountered in the pediatric population and are usually benign. Although some lesions can be diagnosed clinically, ultrasound plays a pivotal role in evaluation by delineating lesion morphology, depth, extent, internal composition, and vascularity. Technological advances in high-frequency transducers and image resolution have significantly improved visualization of superficial soft tissues, enhancing diagnostic confidence. Despite substantial overlap in sonographic appearance among different lesions, specific imaging characteristics can help narrow the differential diagnosis and guide management. This review summarizes both common and uncommon pediatric superficial soft tissue masses, emphasizing their tissue of origin, key ultrasound features, and distinguishing findings that assist in accurate characterization and appropriate clinical decision-making. Conditions covered include epidermal inclusion cysts, sebaceous cysts, hair follicle lesions (hidradenitis suppurativa, pilonidal sinus disease, pilomatricomas, trichilemmal cysts), juvenile xanthogranulomas, dermatofibromas, subcutaneous granuloma annulare, and cutaneous leukemia/lymphoma.

Granuloma annulare (GA) is a chronic inflammatory dermatosis with limited effective treatments and inconsistent response rates across modalities. The Goeckerman protocol, consisting of coal tar, phototherapy, and topical corticosteroids (TCS), has demonstrated robust efficacy in other inflammatory dermatoses but has not been systematically evaluated in GA. This study aimed to characterize treatment outcomes across multiple therapeutic approaches, including the Goeckerman protocol, and to explore clinical factors associated with treatment response. A retrospective cohort study was performed at Sheba Medical Center (2010-2024) including 240 patients with biopsy-confirmed GA. Treatment modalities included TCS, phototherapy, combination therapy, the Goeckerman protocol, and observation. Responses were dermatologist-assessed as complete, partial, or none. Multivariate logistic regression was used to examine factors associated with treatment response. Among 240 patients (mean age 55.4 years; 77.5% female), 184 had follow-up data (median 3.0 months). The overall response rate was 58.2% (107/184). Response differed significantly by modality: Goeckerman protocol 93.5% (29/31), TCS + phototherapy 69.6% (16/23), TCS alone 56.3% (49/87), no active treatment 32.4% (12/37), and phototherapy alone 16.7% (1/6). In multivariate analysis, the Goeckerman protocol was the strongest factor associated with treatment response (odds ratio [OR] 32.52; 95% CI 7.45-233.64; p < 0.001), followed by combination therapy (OR 5.79; p = 0.006) and TCS (OR 2.82; p = 0.015). Hyperlipidemia was associated with response in univariate analysis but did not remain significant in the multivariable model. Treatment modality was the factor most strongly associated with treatment response in this cohort. The Goeckerman protocol demonstrated a notably high response rate compared with other commonly used therapies. Although these findings should be interpreted in the context of a retrospective design and potential selection bias, they suggest that intensive multimodal anti-inflammatory therapy may represent a promising treatment strategy for this challenging condition.

Palisaded and interstitial granulomatous dermatoses are a spectrum of presumed reactive cutaneous disorders sometimes associated with underlying diseases, notably malignant haemopathies. Specific associations between some of these dermatoses and particular haematological neoplasms may exist. To describe the spectrum of haematologic neoplasms associated with palisaded and interstitial granulomatous dermatoses and to establish whether specific associations exist. We conducted a retrospective monocentric study of all cases of palisaded and interstitial granulomatous dermatoses associated with haematologic neoplasms seen in our department, completed with a systematic literature review. Clinical and pathological data were extracted from patient files and articles. A hundred and forty-six cases were identified (31 from our institution, 115 from the literature review). Granuloma annulare (n=76) and elastolytic giant cell granulomas (n=9) were mainly associated with B- and T-cell lymphoid neoplasms (69.4% of cases). Four cases of necrobiosis lipoidica were identified, of which 2 were associated with plasma cell dyscrasias. Interstitial granulomatous dermatitis (n=22) were associated in half of cases with myeloid neoplasms. This association was even stronger (64.7%) for palisaded neutrophilic granulomatous dermatitis (n=17), especially with chronic myelomonocytic leukaemia (47.1%). We also identified 18 cases of unclassified granulomatous dermatoses which were most often associated with lymphoid neoplasm (55.6%). Anamnestic arguments suggestive of a non-coincidental link were identified in 40 cases in total (27.4%). This work shows that there is a preferential link between some palisaded or interstitial granulomatous dermatoses and types of haematological neoplasms, the pathophysiological nature of which remains to be elucidated.

The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Granuloma annulare (GA) is a benign, non-infectious granulomatous skin disorder of unknown etiology, typically presenting as annular or papular lesions. This review analyzes 15 English-language case reports published between 2014 and 2024, retrieved from PubMed, to summarize clinical features, histopathology, associated conditions, treatment responses, and outcomes. The series included 13 females and 2 males, aged 5–69 years (median 48.5 years), with 11 generalized, 3 localized, and 1 subcutaneous case. Lesions appeared as erythematous to skin-colored papules, plaques, or nodules; generalized forms showed widespread distribution, while localized cases were more confined. Histopathology consistently demonstrated palisading or interstitial granulomas, collagen degeneration, and mucin deposition in the dermis. Potential triggers included vaccinations (pneumococcal, SARS-CoV-2), infections, and trauma; comorbidities such as diabetes, dyslipidemia, hypertension, breast cancer, and autoimmune diseases were noted in several patients. Localized GA often resolved spontaneously or with topical/intralesional steroids within months and carried a better prognosis, whereas generalized cases frequently required phototherapy or systemic agents (e.g., dapsone, hydroxychloroquine, adalimumab) with variable success. Most patients improved or cleared, either spontaneously or with treatment.

Identifying metabolites and metabolic reactions specific to a cellular state, such as inflammatory state in immune cells, is of great interest, as it can provide important biomarkers and point to compounds and reactions of specific biological functions. However, many cell state-specific metabolites remain in the unannotated part of metabolome. Here we identified a series of sulfur-containing metabolites that are actively produced in macrophages upon classical activation, but not in resting state or alternative activation state. Isotopic tracing, in vitro assays and genetic perturbations further revealed that they are formed from reactions between free cysteine and several important intermediates in glycolysis and TCA cycle. Upon classical activation, macrophages specifically upregulate the import of cystine viaSlc7a11, supporting the production of these adducts. Their production dynamically responds to changes in central metabolism, environmental nutrient levels, and is regulated by nitric oxide. Finally, we confirmed these newly identified compounds also present in human samples, and most of them are significantly elevated in inflammatory granuloma annulare lesions. This work elucidated a previously uncharted part of metabolic network that is associated with inflammation and metabolic stress condition, which has important implications and set foundation for many future discoveries.

ABSTRACT We report typical cases of biopsy confirmed granuloma annulare occurring on irradiated skin in the context of breast cancer in three women in their seventies. The lesions appeared immediately after start of irradiation in one patient, 4 and 15 months after the end of radiation treatment in the other two. The lesions eventually spread elsewhere on the body in two patients. Similar to morphea, which is a well‐known side effect of irradiation, we believe that radiotherapy can induce tissue damage, leading to dermal inflammation ultimately responsible for the emergence of granuloma annulare.

Understanding Pediatric Granuloma Annulare: Findings from 126 Cases

Distinct outcomes in localized versus generalized granuloma annulare: A retrospective cohort study highlighting subtype-specific management implications.

Treatment of Generalized Granuloma Annulare With Biologics and Oral JAK Inhibitors: A Case Series.

Dear Editor, Granuloma annulare is a chronic inflammatory skin disorder characterized by annular dermal papules and plaques. While localized forms often resolve spontaneously, generalized granuloma annulare tends to persist and frequently proves resistant to conventional therapies. The pathogenesis of the disease remains unclear, but increasing evidence suggests a dysregulated immune response involving T cells, macrophages, and cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and interferon-gamma (IFN-γ). [...].

In their recent manuscript published in the International Journal of Dermatology, Poddine et al. describe the response to upadacitinib treatment in a patient with annular elastophagocytic giant cell granuloma (AEGCG) [1]. They discuss the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway as a potential therapeutic target in this disease. The case report is relevant given that the current treatment options for these patients are often insufficient and clinical studies are lacking. Here, we would like to offer a dermatopathological perspective on the topic and highlight some key discussion points. As the authors outline, AEGCG is characterized by dermal aggregates of multinucleated giant cells displaying signs of elastophagocytosis within the annular border of the lesions. These mark an abrupt transition to the central area with complete loss of elastic fibers. The histopathological characteristics partially overlap with those of granuloma annulare. The presence of mucin deposits and palisading histiocytes in the dermis surrounding necrobiosis have been discussed as being typical for granuloma annulare and absent in AEGCG. However, there has been some discussion as to whether these variable findings are sufficient to establish AEGCG as an independent diagnosis. The term AEGCG was first mentioned in 1979 by Hanke et al. who reported five cases and reviewed previously published cases of “actinic granuloma,” “Miescher's granuloma of the face,” and “necrobiosis lipoidica presenting on the face and scalp,” summarizing all these entities under the diagnostic category of AEGCG [2]. In the same year, Ackerman reviewed 30 cases with granulomatous inflammation, observing elastophagocytosis in granulomatous skin diseases in sun-exposed skin. These included foreign body reactions, mycosis fungoides, granulomatous syphilis, and most frequently, granuloma annulare. In 20 cases reported by Limas et al. features of necrobiosis and mucin deposits were seen in conjunction with “typical” lesions of AEGCG, calling into question the independence of this condition [3, 4]. We would therefore like to emphasize that, to our knowledge there are no clear-cut clinicopathological criteria to differentiate between actinic granuloma, actinic elastolytic granuloma, and granuloma annulare. It appears probable that they all belong to the same spectrum of diseases where elastophagocytosis, loss of elastic fibers, necrobiosis, palisading histiocytes, and mucin deposits are variable findings. We recommend to be careful not to split up entities with overlapping histological and clinical criteria. Historical and somewhat artificial classifications, derived from small sample sizes and without consideration of molecular characteristics, need to be critically re-evaluated. JAK inhibitors have been successful in the treatment of single patients and case series with disseminated granuloma annulare and actinic granuloma [5]. In the interest of the affected patients, adopting a broad disease definition based on molecular pathogenetic mechanisms may therefore be beneficial and facilitate the initiation of much-needed clinical trials in this indication. Open Access funding enabled and organized by Projekt DEAL. The authors declare no conflicts of interest. The authors have nothing to report.

Granuloma annulare (GA) is a benign inflammatory dermatosis characterized by dermal granuloma formation. While its etiology is unclear, GA has been linked to systemic comorbidities. Localized GA typically responds to corticosteroids, but generalized GA often follows a more refractory course. Pentoxifylline has emerged as a potential steroid-sparing agent, though data are limited. A retrospective chart review was conducted on 102 patients diagnosed with GA at a single academic dermatology clinic in rural Appalachia. Demographic data, disease subtype, treatment history, and comorbidities were recorded. Comorbidity prevalence was compared with state and national averages. Statistical analysis assessed associations between disease extent, treatment response, and comorbidity burden. The cohort was 79% female with a mean age of 46 years; 19% of cases were pediatric. Generalized GA accounted for 46% of cases and showed elevated rates of type 2 diabetes (36%), hypothyroidism (26%), and autoimmune disease (15%). Patients with &ge;3 comorbidities were more likely to have prolonged disease (&gt;2 years). Generalized GA required more treatment attempts (P&lt;0.001) and had higher failure rates than localized disease. Pentoxifylline achieved a 64% response rate in generalized GA, outperforming hydroxychloroquine and topical corticosteroids. Generalized GA is more treatment-resistant and associated with a greater comorbidity burden. Pentoxifylline demonstrated favorable efficacy and may serve as a first-line systemic agent in refractory cases. Further multi-center studies are needed to validate these findings and guide evidence-based management of GA. &nbsp.