Spatial transcriptomics reveals organized and distinct immune activation in cutaneous granulomatous disorders.

BACKGROUND: Noninfectious (inflammatory) cutaneous granulomatous disorders include cutaneous sarcoidosis (CS), granuloma annulare (GA), necrobiosis lipoidica (NL), and necrobiotic xanthogranuloma (NXG). These disorders share macrophage-predominant inflammation histologically, but the inflammatory architecture and the pattern of extracellular matrix alteration varies. The underlying molecular explanations for these differences remain unclear. OBJECTIVE: We sought to understand spatial gene expression characteristics in these disorders. METHODS: We performed spatial transcriptomics in cases of CS, GA, NL, and NXG to compare patterns of immune activation and other molecular features in a spatially resolved fashion. RESULTS: CS is characterized by a polarized, spatially organized type 1-predominant response with classical macrophage activation. GA is characterized by a mixed but spatially organized pattern of type 1 and type 2 polarization with both classical and alternative macrophage activation. NL showed concomitant activation of type 1, type 2, and type 3 immunity with a mixed pattern of macrophage activation. Activation of type 1 immunity was shared among, CS, GA, and NL and included upregulation of IL-32. NXG showed upregulation of CXCR4-CXCL12/14 chemokine signaling and exaggerated alternative macrophage polarization. Histologic alteration of extracellular matrix correlated with hypoxia and glycolysis programs and type 2 immune activation. CONCLUSIONS: Inflammatory cutaneous granulomatous disorders show distinct and spatially organized immune activation that correlate with hallmark histologic changes.

Shedding Light on Photodynamic Therapy in the Treatment of Necrobiosis Lipoidica: A Multicenter Real-Life Experience.

Necrobiosis Lipoidica (NL) is a dermatological condition characterized by the development of granulomatous inflammation leading to the degeneration of collagen and subsequent formation of yellowish-brown telangiectatic plaques usually localized on the pretibial skin of middle-aged females. Due to its rarity and unclear etiopathogenesis, therapeutic options for NL are not well-standardized. Among them, photodynamic therapy (PDT) is an emerging tool, although its efficacy has primarily been evaluated in single case reports or small case series. This study reports the real-life experience of a cohort of NL patients treated with PDT at the Section of Dermatology of the University Hospital of Messina and Reggio-Emilia. From 2013 to 2023, 17 patients were enrolled -5 males (29%) and 12 females (71%) aged between 16 and 56 years (mean age: 42 ± 13 years), with a median duration of NL of 8 years. The overall complete clearance (>75% lesion reduction) was 29%, while the partial clearance (25-75% lesion reduction) was 59%, with 12% being non-responders. This study adds to the little amount of evidence present in the literature regarding the effectiveness of PDT in the treatment of NL. Variability in treatment responses among patients underscores the need for personalized protocols, optimizing photosensitizers, light sources, and dosimetry. The standardization of treatment protocols and consensus guidelines are essential to ensure reproducibility and comparability across studies.

A Breakthrough in the Treatment of Necrobiosis Lipoidica? Update on Treatment, Etiopathogenesis, Diagnosis, and Clinical Presentation.

Necrobiosis lipoidica (NL) is a rare granulomatous disease of a not fully understood etiopathogenesis. Classically, NL is associated with insulin-dependent diabetes mellitus. The disease often fails to respond to conventional treatments and adversely affects patients' quality of life. First-line medications are usually topical corticosteroids, but patients respond to them with varying degrees of success. Other options include tacrolimus, phototherapy, cyclosporine, fumaric acid esters, and biologics (adalimumab, etanercept, and infliximab). Our review aims to present new therapeutic approaches potentially effective in patients with refractory lesions, describe the presumed etiopathogenesis, and provide diagnostic guidance for clinicians. The review concludes that Janus kinase inhibitors and biologics such as ustekinumab and secukinumab can be used effectively in patients with recalcitrant NL. Another promising treatment option is tapinarof (an aryl hydrocarbon receptor agonist). However, studies on larger groups of patients are still needed to evaluate the effectiveness of different therapeutic options and to define consistent treatment regimens for NL. It is advisable to improve the awareness of physicians of various specialties regarding necrobiosis lipoidica as lesions diagnosed earlier usually have a better response to treatment.

The Intersection of Dermatological Dilemmas and Endocrinological Complexities: Understanding Necrobiosis Lipoidica-A Comprehensive Review.

BACKGROUND: Necrobiosis lipoidica (NL) is a rare granulomatous skin disorder with a predilection for females, often associated with diabetes mellitus (DM). This paper aims to comprehensively review the literature on NL, focusing on its association with DM, thyroid disorders, and the metabolic syndrome. METHODS: A systematic search was conducted in English-language literature from inception to October 2023, utilizing PubMed. We identified 530 studies and selected 19 based on clinical significance, statistical support, and relevance to the paper's goals. RESULTS: The coexistence of NL and DM is prevalent, with rates ranging from 11% to 65.71%. NL may precede DM diagnosis and a correlation between NL and increased daily insulin requirements has been observed in such patients. NL is suggested as a potential prognostic marker for DM complications; however, recent studies question this association, highlighting the need for further research. Studies in the context of NL and Thyroid Disease indicate a correlation, especially with autoimmune thyroiditis. Regarding NL and Metabolic Syndrome, the prevalence of metabolic syndrome among NL patients is notably higher than in the general population. Additionally, DM patients with ulcerated NL commonly exhibit hypertension or obesity, raising questions about the potential influence of hypertension and obesity on NL ulcerations. CONCLUSION: Additional research is required to untangle the complex connections between NL and various comorbidities.

Disseminated perforating necrobiosis lipoidica: A case report and literature review.

Key Clinical Message: Necrobiosis lipoidica is a rare cutaneous granulomatous disease that mainly affects diabetic patients. The perforating type of the disease is an uncommon variant that is resistant to therapy and can be easily identified using dermoscopy. Abstract: Perforating necrobiosis lipoidica (NL) is a rare NL variant that primarily affects patients with diabetes mellitus (DM). Dermoscopy helps to differentiate this type of disease. The disseminated form of perforating NL mainly occurs in the setting of DM. Here we present a case of disseminated perforating NL in a 24-year-old woman with type 1 DM.

Successful treatment of necrobiosis lipoidica and associated retinal vasculitis with tumor necrosis factor (TNF)-alpha inhibitor.

Purpose: To report the clinical and histopathologic features of necrobiosis lipoidica and associated retinal vasculitis and describe successful treatment of both skin and eye manifestations with adalimumab, a tumor necrosis factor (TNF)-alpha inhibitor. Observations: A 35-year-old patient with bipolar disorder and ocular hypertension was referred for evaluation of bilateral retinal vasculitis. Fluorescein angiography revealed bilateral occlusive retinal vasculitis. Physical exam was notable for multiple annular and round erythematous hyperpigmented and atrophic patches and plaques on both lower extremities. Skin biopsy revealed a diagnosis of necrobiosis lipoidica, a rare granulomatous skin disease. Both the patient's retinal vasculitis and skin patches responded favorably to treatment with adalimumab, a TNF-alpha inhibitor. Conclusions and importance: This case highlights the importance of obtaining a complete history and physical exam in patients who present with ocular inflammation, as extraocular manifestations of disease may be present. It also demonstrates the effectiveness of a multidisciplinary approach to evaluation and management of these patients, as both skin and eye involvement were successfully treated with adalimumab, a TNF-alpha inhibitor.

Nonulcerated Necrobiosis Lipoidica Successfully Treated with Tapinarof: A Case Report.

Necrobiosis lipoidica (NL) is a chronic granulomatous disorder of the skin which usually presents with red papules and plaques on the lower extremities. Diabetes mellitus has been found to be associated with NL, but the pathophysiology of the disease is unknown. Based on a Doppler flowmetry study showing increased blood flow at NL lesions and the macrophage upregulation of granulomatous disorders, it is reasonable to conclude that there is an inflammatory component to it. NL is extremely challenging to manage. The initial treatment of choice is usually topical or intralesional corticosteroids, and if this fails to work, many dermatologists depend on the small number of case reports for more treatment options. We present a pre-diabetic patient with nonulcerative NL who was successfully treated with the first-in-class therapeutic aryl hydrocarbon receptor (AHR)-modulating agent tapinarof cream (VTAMA, Dermavant). Following the case presentation is a discussion of this topical novel agent and its unique anti-inflammatory mechanism of action. Tapinarof specifically binds to and activates AHR leading to downregulation of TNF-α/IL-23/IL-17 and inhibition of IL-4/IL-13 mediated STAT6 activation. Anti-TNF-α agents and JAK-inhibitors have also been found to be beneficial in treating NL; tapinarof seems to target both these pathways without the risk of their serious adverse reactions.

Post-traumatic ulcerated and chronic necrobiosis lipoidica of the elbow: A new entity?

BACKGROUND: Necrobiosis lipoidica (NL) is a chronic granulomatous dermatosis usually affecting the lower limbs, although less common sites have been described. Herein we report a series of cases of NL located on the elbow, with an unusual presentation and occurring after trauma or surgery. OBSERVATIONS: Our series includes three men and one woman, with a mean age of 64 years. Three had undergone surgery for elbow bursitis and one had had trauma after a fall from a horse, with exposure of subcutaneous tissue prior to healing. Within 5 years, they had all developed an atrophic erythematous annular plaque with papular and telangiectatic edges, with recurrent episodes of ulceration and scarring. Repeated tests for infectious agents were negative. Histological examinations showed granulomas and necrobiosis with palisading or early-stage palisading. Partial healing was achieved in two patients after 6 months of doxycycline. Treatment with adalimumab resulted in disappearance of the ulcers at 6 months in one patient. DISCUSSION: Unusual sites of NL impose consideration of other types of palisading granuloma or mycobacterial infections, which we were able to rule out. Two other cases of NL of the elbow similar to ours are reported in the literature. These cases, involving multiple ulcerations over a very long period of time, probably constitute a distinct entity because of the very distinct character of these 6 cases. Tetracyclines are partially active and tumour necrosis factor alpha (TNF)-alpha inhibitors may offer an option.

Lower leg reconstruction after resection of a squamous cell carcinoma on necrobiosis lipoidica with a pedicled fibula and an extended anterolateral thigh flap-a case report.

BACKGROUND: Extensive loss of soft tissue and bone due to neoplasia, trauma, or infection in extremities often leads to amputation. CASE PRESENTATION: We present the case of a 72-year-old female patient presenting with an extended cutaneous squamous cell carcinoma of the lower leg, developed on top of necrobiosis lipoidica. After achieving the R0 resection, a 26 × 20-cm soft tissue and 15-cm tibial bone defect resulted. The contralateral leg had been lost due to the same disease 18 years before. We achieved a successful reconstruction of the leg using a pedicled fibula transplantation, an extended anterolateral thigh perforator flap, and an internal fixation with plate and screws. Two years after the original surgery, the patient is relapse-free and mobile, with adequate function of the reconstructed foot. CONCLUSIONS: Our case presented a unique combination of pedicled fibula transplantation and free extended ALT perforator flap to reconstruct an extensive defect after resection of a rare cSCC on top of NL. In selected cases, the boundaries of limb salvage can be pushed far beyond the current standards of treatment.

Necrobiosis lipoidica of the breast associated with Crohn's disease: a case report.

BACKGROUND: Necrobiosis lipoidica located to the breast; without evidence of glucose intolerance, is extremely rare, and its association to Crohn's disease is not usual. CASE PRESENTATION: We report an interesting case of an association of necrobiosis lipoidica of the breast and Crohn's disease in a 54-year-old Moroccan woman. Skin necrobiotic changes are a characteristic feature in necrobiosis lipoidica, but they are exceptional in metastatic Crohn's disease, since there are only three published cases of necrobiotic skin lesions on the lower leg resembling erythema nodosum in metastatic Crohn's disease. CONCLUSIONS: On the basis of this rare observation, necrobiosis lipoidica without evidence of glucose intolerance should be recognized as a possible cutaneous manifestation or association of Crohn's disease.

Atypical Ulcerative Necrobiosis Lipoidica Diabeticorum: A Case Study.

Necrobiosis lipoidica is a granulomatous skin condition commonly associated with diabetes. When associated with diabetes mellitus, the name expands to necrobiosis lipoidica diabeticorum (NLD). In these patients, this rare condition has an incidence rate of 0.3% to 1.6%. The cause of NLD remains unknown even though many speculations exist in the medical literature. The treatment of this condition has most researchers agreeing on the use of topical steroids for the anti-inflammatory effect on NLD; however, the role of glucose control in the treatment of this disorder has been debatable. The following case presents a patient who, despite better glucose control, did not improve until the introduction of doxycycline.

Photodynamic therapy in pediatric age: Current applications and future trends.

Photodynamic therapy (PDT) is a photochemotherapy based on local application of a photosensitive compound and subsequent exposure to a light source of adequate wavelength. It is a non-invasive therapeutic procedure widely used in oncodermatology for treatment of numerous skin cancers, but in the last years its use has been gradually extended to an increasing list of skin diseases of both infectious and inflammatory nature. Although PDT is proven as a safe and effective therapeutic option in adults, its use is not well standardized in the pediatric population. In this review, we will focus on clinical applications, mechanisms of action, protocols, and adverse events in children and adolescents. Most of pediatric experiences concerned treatment of skin cancers in Gorlin syndrome and xeroderma pigmentosum, acne vulgaris, and viral warts, but other applications emerged, such as cutaneous lymphoma and pseudo-lymphomas, necrobiosis lipoidica, hidradenitis suppurativa, dissecting cellulitis, leishmaniasis, angiofibromas, verrucous epidermal nevus, and linear porokeratosis. In these pediatric diseases, PDT appeared as an effective therapeutic alternative. The results on vitiligo were limited and not fully encouraging. Although highly versatile, PDT is not a therapy for all skin diseases, and a deeper knowledge of its mechanisms of action is required to better define its spectrum of action and safety in pediatric patients.

Histopathologic features of necrobiosis lipoidica.

BACKGROUND: Necrobiosis lipoidica (NL) is an uncommon granulomatous dermatosis that can occur in patients with or without associated diabetes mellitus (DM). Prior studies have attempted to determine distinctive histopathologic features of NL in patients with and without DM. METHODS: A retrospective review of 97 patients with NL was performed to determine the similar and distinctive histopathologic features in patients with DM and without DM. RESULTS: Of the 97 patients, 32% (n = 31) had DM. Epidermal acanthosis was seen more commonly in diabetics than nondiabetics (32.3% vs. 12.1%; p = 0.017). Naked (sarcoidal/tuberculoid) granulomas were more frequently observed in nondiabetics than diabetics (22.7% vs. 3.2%; p = 0.016). Eosinophils were more common in nondiabetics than diabetics (38.5% vs. 9.7%; p = 0.004), while neutrophilic infiltration was more common in diabetics than nondiabetics (45.2% vs. 17.5%; p = 0.004). CONCLUSIONS: This study corroborates well-documented histopathologic features of NL and shows distinctive histopathologic features of NL among patients with DM-I, DM-II, and without DM. These results support the hypothesis that there are different underlying drivers of NL between diabetics and nondiabetics.

Skin Involvement in Paediatric Patients with Type 1 Diabetes.

Skin involvement is an overlooked aspect in the management of paediatric patients with type 1 diabetes. A comprehensive search of published literature using the PubMed database was carried out using the following key terms: "children," "pediatric/paediatric patients," "skin," "skin disorders," "type 1 diabetes." Dermatological side effects are frequently observed among diabetic children and adolescents. Insulin-induced lipodystrophies and allergic contact dermatitis caused by insulin pumps or glycaemic sensors are the most common skin reactions in these patients. Furthermore, several diabetes-associated skin diseases such as necrobiosis lipoidica, granuloma annulare, vitiligo, and bullosis diabeticorum may already be present in paediatric patients. Paediatric diabetes specialists should pay attention to their patients' skin to recognize these disorders, identify the potential causes, and choose the most suitable treatment. Finally, the evaluation of skin concentrations of advanced glycation end-products using non-invasive diagnostic techniques may be used to assess the risk of chronic complications of diabetes as early as adolescence.