Project description: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.
Project description:BackgroundGranuloma annulare has been linked to diabetes, dyslipidemia, thyroid disease, collagen vascular disease, malignancies, infectious hepatitis, and systemic infections. However, these associations have not been systematically investigated when categorized by its clinical variants.ObjectiveTo evaluate disease associations of localized and generalized granuloma annulare.MethodsIn total, 407 granuloma annulare patients from 1989 to 2019 were retrospectively reviewed, categorized by clinical variant (localized or generalized), age (pediatric or adult), and diagnostic method (clinical or histologic). Descriptive statistical analyses and multivariate logistic regression analysis were performed. Fisher's exact tests were conducted to produce unbiased probability values.ResultsOverall, 75.2% of the study sample was female, 47.2% had dyslipidemia, 24.8% were diabetic, and 24.6% had thyroid disease. Dyslipidemia (OR 2.15, CI 1.95-2.35, P < .001), diabetes (OR 1.16, CI 1.01-1.31, P = .041), and histologic diagnosis (OR 2.08, CI 1.21-3.52, P = .007) were associated with increased risk of GGA compared to LGA. When stratified by adult versus pediatric cases, dyslipidemia and diagnostic method remained significant, but diabetes did not.ConclusionsEvaluating granuloma annulare by its clinical variants may help to determine disease associations with each variant.
Project description:PurposeGranuloma annulare (GA) is a rare clinical entity that does not classically arise from the peri-orbital area in adults. The purpose of this case report is to present a 69-year-old female with GA of the orbit. As well, the pathological and immunohistochemical features of these tumors will be discussed.ObservationsOne case of GA of the orbit was identified from a tertiary ophthalmology referral centre. Clinical and histopathological features of the case were reviewed. Other cases of GA were also retrieved from the literature and addressed in this report.Conclusion and importanceGranuloma annulare is a rare orbital lesion in adults. It is known to typically arise on the hands and feet of children. This lesion must be distinguished from necrobiotic xanthogranuloma (NXG), which is a progressive peri-orbital dermatosis seen in middle age men and women. GA is thought to be a benign, often self-resolving condition, whereas NXG tends to be linked to other systemic conditions and may have a poorer prognosis.Differentiating this rare orbital tumor from necrobitotic xanthogranuloma (NXG) is essential, as both a systemic work-up and follow-up must be appropriately arranged. A comprehensive description of pathognomonic microscopic features of GA and NXG is reviewed to achieve the correct diagnosis.
Project description:BackgroundSarcoidosis and granuloma annulare (GA) are cutaneous granulomatous disorders that can be difficult to treat. There is evidence of underlying Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway activation in sarcoidosis, suggesting that JAK inhibition might be effective.ObjectiveTo evaluate treatment with tofacitinib, a JAK inhibitor, in patients with recalcitrant sarcoidosis and GA.MethodsA prospective evaluation of tofacitinib in 4 consecutive patients with recalcitrant cutaneous sarcoidosis (n = 3) and generalized GA (n = 1) was conducted. Immunohistochemical analysis of skin biopsy specimens from other patients with sarcoidosis (n = 21) and GA (n = 17) was performed to characterize patterns of JAK-STAT pathway activation.ResultsTofacitinib resulted in a mean improvement in the baseline Cutaneous Sarcoidosis Activity and Morphology Instrument and Granuloma Annulare Scoring Index scores of 96% (standard deviation, 2%). Histologic resolution of disease was documented in all patients (3 out of 3) who had skin biopsies while receiving therapy. Constitutive STAT1 and STAT3 activation was observed in both sarcoidosis and GA, albeit in different patterns. Signal regulatory protein ? may explain the differences in JAK-STAT signaling between sarcoidosis and GA.LimitationsThe study is limited by the small number of participants.ConclusionsTofacitinib resulted in dramatic improvement in 4 patients with cutaneous sarcoidosis and GA. Larger studies are underway to better understand this effect.
Project description:Here we report the data generated by short-read sequencing of mRNA (polyA) isolated from granuloma annulare and leprosy skin lesions. Our main aim was to identify putative mRNA biomarkers for distinguishing leprosy from other differential diagnoses. Additionally, we also explored the distinction between MB and PB by using differential expression analysis as well as training a penalized logistic regression to select important features. Our results showed that few genes are enough to differentiate leprosy lesions, including paucibacillary cases, from other morphological and histopathological similar skin diseases. Some of these genes have been replicated in a larger and more heterogeneous sample with RT-qPCR, validating their classification potential. We also suggest important novel gene candidates to improve our understanding of molecular differences between MB and PB lesions, which could either pinpoint new pathways and targets for host-based specialized adjuvant treatment for leprosy. Finally, this dataset has been used to explore the relationship between cornification and keratinocyte-related genes and TGFB-mediated epithelial-mesenchymal transition (EMT), which could indicate that in skin, M. leprae could be de-differentiating, directly or indirectly, other cell types into a progenitor/stem-like phenotype, facilitating mycobacterial survival and migration within the host. Alternatively, this could highlight which pathways are activated during granuloma formation and/or skin barrier assembly/disassembly.
Project description:Granuloma annulare (GA) is an idiopathic condition characterized by granulomatous inflammation in the skin. Prior studies have suggested that GA develops from various triggers, leading to a complex interplay involving innate and adaptive immunity, tissue remodeling, and fibrosis. Macrophages are the major immune cells comprising GA granulomas, however, the molecular drivers and inflammatory signaling cascade behind macrophage activation is poorly understood. Histologically, GA exhibits both palisaded and interstitial patterns on histology, however the molecular composition of GA at the spatial level remains unexplored. GA is a condition without FDA-approved therapies despite the significant impact of GA on quality of life. Spatial transcriptomics is a valuable tool for profiling localized, genome-wide gene expression changes across tissue with emerging applications in clinical medicine. To improve our understanding of the spatially localized gene expression patterns underlying GA, we profiled the spatial gene expression landscape from six patients with GA. Our findings revealed mixed Th1 and Th2 signals comprising the GA microenvironment and spatially distinct M1 and M2 macrophage polarization characteristics. IFN- and TNF signals emerged as important regulators of GA granulomatous inflammation and interleukin-32 emerged as a key driver of granulomatous inflammation. Overall, our spatial transcriptomics data indicate that GA exhibits mixed immune and macrophage polarization.
Project description:Granuloma annulare (GA) is a common inflammatory cutaneous disorder characterized by macrophage accumulation and activation in the skin. Its pathogenesis is poorly understood and there are no reliably effective treatments. Its potential health implications, if any, are unknown. Using single cell RNA sequencing (scRNAseq) we show that in GA, CD4+ T cells over-produce interferon (IFN)-g resulting in inflammatory polarization of macrophages and in altered extracellular matrix (ECM) production induced by the activity of oncostatin M, an interleukin (IL)-6 family cytokine, on fibroblasts. This mechanism identifies Janus kinase (JAK) inhibition as a potential therapeutic strategy, as both IFN-g and OSM signal via the JAK-STAT pathway. Indeed, treatment of five patients with severe, longstanding GA with tofacitinib (a JAK1/3 inhibitor) resulted in clinical and histologic disease remission in three patients and marked improvement in the other two. Treatment was associated with suppression of pathogenic cytokine activity in the skin and dissolution of macrophages. We also found that severe GA was associated with hypercytokinemia in plasma of patients, and JAK inhibition normalized this hypercytokiemia. Together, our results highlight the constitutive activity of the JAK-STAT pathway in GA as a result of IFN-g and OSM and identify JAK inhibitors as a potential molecularly targeted treatment for this disorder.
Project description:Granuloma annulare (GA) is a common inflammatory cutaneous disorder characterized by macrophage accumulation and activation in the skin. Its pathogenesis is poorly understood and there are no reliably effective treatments. Its potential health implications, if any, are unknown. Using single cell RNA sequencing (scRNAseq) we show that in GA, CD4+ T cells over-produce interferon (IFN)-g resulting in inflammatory polarization of macrophages and in altered extracellular matrix (ECM) production induced by the activity of oncostatin M, an interleukin (IL)-6 family cytokine, on fibroblasts. This mechanism identifies Janus kinase (JAK) inhibition as a potential therapeutic strategy, as both IFN-g and OSM signal via the JAK-STAT pathway. Indeed, treatment of five patients with severe, longstanding GA with tofacitinib (a JAK1/3 inhibitor) resulted in clinical and histologic disease remission in three patients and marked improvement in the other two. Treatment was associated with suppression of pathogenic cytokine activity in the skin and dissolution of macrophages. We also found that severe GA was associated with hypercytokinemia in plasma of patients, and JAK inhibition normalized this hypercytokiemia. Together, our results highlight the constitutive activity of the JAK-STAT pathway in GA as a result of IFN-g and OSM and identify JAK inhibitors as a potential molecularly targeted treatment for this disorder.