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.

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.

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.

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.

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.

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.

Comorbidity and Therapeutic Approaches in Patients with Necrobiosis Lipoidica.

BACKGROUND: Necrobiosis lipoidica (NL) is a rare granulomatous disorder of unknown aetiology. Randomized controlled studies are not available due to it being an orphan disease. OBJECTIVES: We evaluated patients in 2 dermatological centres to cluster data about epidemiology, the therapeutic approaches for NL, and their efficacy. MATERIALS AND METHODS: Comorbidity and the efficacy of the applied treatment was assessed for 98 patients. RESULTS: We identified 54% of patients with concomitant diabetes and 19% with thyroidal disorders. Topical steroids (85.7%) were predominantly used followed by calcineurin inhibitors (31%) and phototherapy (41.8%). Systemically, fumaric acid esters were more frequently applied (26.8%) than steroids (24.4%) and dapsone (24.4%). Steroids, compression therapy, calcineurin inhibitors, phototherapy, fumaric acid esters, and dapsone showed remarkable efficacy. CONCLUSION: Therapeutic options were chosen individually in accordance with the severity of NL and presence of ulceration. Topical calcineurin inhibitors, systemic application of fumaric acid esters, and dapsone represent effective alternatives to the use of steroids.

First Report of Pantoea ananatis Causing Crown Necrobiosis on Strawberry in China.

Strawberry (Fragaria × ananassa) is an economically important crop in Zhejiang, China. In the autumn of 2021, crown necrobiosis and angular leaf spot was observed in commercial strawberry fields (cultivar 'fenyu') in Cixi, Ningbo, Zhejiang, China (N30°9'55″, E121°21'13″). The disease incidence ranged from 5 to 8 % in the field, but could reach 50 to 60 % in some heavily affected plastic tunnels. In the affected field, this disease could reduce strawberry production by 50%. Early symptoms were water-soaked lesions around the vein of the abaxial leaves; subsequently, reddish-brown irregular spots and coalesced lesions developed. In humid conditions, a sticky bacterial ooze exuding from lesions was observed. Finally, the crown of the diseased plant was necrotized, and several pockets were observed inside the crown after dissection. To isolate the causal agent, the infected leaves and crown tissues from six different plants were surface-sterilized with 75% ethanol for 1 min, rinsed twice with sterile distilled water, cut into small pieces, and soaked in 5 ml of sterile distilled water for 20 min. The supernatant from the cut-up pieces was serially diluted and spread on nutrient agar medium. After 2 to 3 days at 28℃, several yellow colonies were grown on the medium. The colonies from five infected plants were gram-negative, anaerobic rods, yellow, viscous, and gloss, which are typical characteristics of Erwinia anana (Wells et al. 1986). To confirm the identity of the causal bacteria, PCR was conducted for six randomly selected colonies to amplify 16S rRNA (Monciardini et al. 2002), fusA, and gyrB (Stice et al. 2002). The amplicons were sequenced and blasted, and the results showed that the six colonies were identical. The 16S rRNA, fusA, gyrB sequences of the isolate CM3 were deposited in GenBank with accession number ON754076.1, OP587277, and OP587278; BLAST search showed 99.93% (1445 bp out of 1446 bp), 100% (746 bp out of 746 bp), 99.64% (1371 bp out of 1376 bp) similarity with strains of Pantoea ananatis (KT741001.1, MH015093.1 and CP066803.1 accessions, respectively). The resulting concatenated data set of 16S rRNA-fusA-gyrB was used to build a multilocus phylogenetic analysis (MLSA) by maximum likelihood criteria. The MLSA tree indicated that the isolate CM3 belonged to Pantoea ananatis. The isolate's identity was further confirmed by P. ananatis-specific primers pagyrB-F/R (Xiao et al. 2022). Thus, this isolate was designated as P. ananatis CM3. To fulfill Koch's postulates, two old leaves were broken off each of the ten 2-month-old strawberry (cultivar 'fenyu') plants to create wounds, each plants was sprayed with a cell suspension of P. ananatis (107CFU/ml, 0.5 ml) on the stem base. Ten plants were sprayed with water to serve as a control. All plants were kept at 28/25°C (day/night) under a 12-h/12-h photoperiod. All plants were covered with transparent plastic bags to maintain humidity. After 48 h, the bags were removed. After 2 weeks, water-soaked lesions on some leaves were observed similar to those in the field . Three to five weeks after inoculation, the crown of the inoculated plants was necrotized, which was similar to the symptoms in the field. No symptoms were observed in the control plants. The experiment was repeated three times. The bacteria were successfully reisolated from the inoculated crown tissues and leaves and confirmed as CM3 according to the same methodologies used for the initial identification. Bacterial leaf blight in strawberry caused by Pantoea ananatis has been reported in Nova Scotia, Canada, and Egypt (Bajpai et al. 2019; Abdel-Gaied et al. 2022). To our knowledge, this is the first report of Pantoea ananatis causing crown necrobiosis on strawberry in China. This report provides a basis for further research on this disease and its management and control.

Laser and light therapies for the treatment of necrobiosis lipoidica.

Necrobiosis lipoidica (NL) is a rare, inflammatory granulomatous skin disorder involving collagen degeneration. In recent years, several light and laser therapies have been proposed and used in the treatment of NL with variable outcomes. The aim of the study was to investigate the efficacy and safety of lasers and light therapies for the treatment of NL. A review of PubMed was conducted to search for studies using laser and light therapies for the treatment of NL. Articles that employed a combination of treatment modalities were excluded. Twenty-four studies were reviewed. Light and laser therapies used in these studies included CO2 laser, pulsed dye laser, methyl aminolevulinate (MAL)-photodynamic therapy (PDT), aminolevulinic acid (ALA)-PDT, ultraviolet A1 (UVA1) phototherapy, and psoralen plus ultraviolet-A (PUVA). PUVA was identified as the modality with the most available evidence (7 studies), followed by MAL-PDT and ALA-PDT (5 studies each), pulsed dye laser and UVA1 (3 studies each), and lastly CO2 laser (2 studies). Most modalities demonstrated variable efficacies and side effects with the exception of PDL, which consistently showed successful outcomes. Multiple dermatologic light and laser therapies have been investigated for the treatment of NL, including PUVA, ALA-PDT, MAL-PDT, pulsed dye laser, UVA1, and CO2 laser. However, a clear consensus on the preferred treatment is yet to be addressed. Each treatment option demonstrates both advantages and disadvantages that should be discussed with patients when selecting the treatment modality.

Necrobiosis lipoidica with rapid response to doxycycline.

Necrobiosis lipoidica (NL) is a rare granulomatous disease of unknown etiology. Multiple therapies may be used with varying efficacy. We report a pediatric patient with a history of type I diabetes mellitus and NL with minimal response to an ultrapotent topical steroid, topical calcineurin inhibitor, and intralesional triamcinolone, complicated by steroid atrophy, who rapidly responded after addition of doxycycline.

Necrobiosis Lipoidica in a Patient with ß-Thalassemia Major: A Case Report and Review of the Literature.

Necrobiosis lipoidica (NL) is a rare granulomatous disease that predominantly affects middle-aged women and is often associated with diabetes mellitus (DM), rheumatoid arthritis (RA) and other metabolic disorders. Thalassemias are the most common hereditary hemoglobin (Hb) disorders worldwide. A few studies investigated dermatologic problems that coexist with ß-thalassemia major (ß-TM). The most common skin disorders in patients with ß-TM are xerosis, urticaria, pseudoxanthoma, hyperpigmentation, leg ulcers and small-vessel vasculitis. Necrobiosis lipoidica has only been occasionally reported in patients with ß-TM. Herein, we present a female with ß-TM and NL. Furthermore, a brief review of the literature was performed.

[Wound treatment in diabetes patients and diabetic foot ulcers]. / Wundbehandlung bei Diabetes und diabetischem Fußulkus.

Diabetes mellitus (DM) is a paramount and rising medical challenge in both industrial and emerging nations. For Germany, 6.9 million out of 64.9 million insured persons in 2010 were reported to suffer from DM and approximately 5.8 million suffered from type 2 DM. The prevalence of diabetic foot ulcer (DFU) or diabetic foot syndrome (DFS) is 2-10% and the incidence is 2-6%. In addition, patients with DM present associated skin disorders with chronic wound healing, e.g., pyoderma gangrenosum or lecrobiosis lipoidica. Knowledge of the pathogenesis and skills for treatment of chronic wounds in diabetic patients are important for dermatologists. Patients with diabetes and wound healing disorders and accompanied unspecific skin disorders like eczema, cellulitis or contact dermatitis are often primarily or secondarily treated by dermatologists. In this article, practical hints for the treatment of DFS and other chronic wound in patients with DM are presented.

The Promise of JAK Inhibitors for Treatment of Sarcoidosis and Other Inflammatory Disorders with Macrophage Activation: A Review of the Literature.

Certain inflammatory disorders are characterized by macrophage activation and accumulation in tissue; sometimes leading to the formation of granulomas, as in sarcoidosis. These disorders are often difficult to treat and more effective, molecularly targeted therapies are needed. Recent work has shown that overproduction of inflammatory cytokines, such as interferon gamma (IFN-γ) leading to constitutive activation of the JAK-STAT pathway may be a conserved feature of these disorders. Use of JAK inhibitors, which can block these signals, has resulted in dramatic improvement in several patients with sarcoidosis. JAK inhibitors also appear to have activity in other inflammatory disorders with macrophage activation including hemophagocytic lymphohistiocystosis, Crohn's disease, granuloma annulare, and necrobiosis lipoidica. Here, we review the role of JAK dependent cytokines in macrophage activation and granuloma formation and the clinical evidence supporting the use of JAK inhibition in these disorders. Ongoing efforts to evaluate role of JAK inhibitors in these disorders is also discussed.

Potassium Iodide for Cutaneous Inflammatory Disorders: A Monocentric, Retrospective Study.

OBJECTIVES: Potassium iodide (KI) is a medication that has been used for decades in dermatology and it is mentioned as a treatment option in all major dermatology textbooks. Yet, there is little recent information on its efficacy. In our study, we wanted to retrospectively evaluate the therapy response to KI in our patients. METHODS: The hospital information system was searched for patients treated with KI at the Department of Dermatology (University Hospital Zurich) in the last 20 years (January 1, 1998 to December 31, 2017). A total of 52 patients were found and, subsequently, 35 patients were included in our study. RESULTS: KI was prescribed for the following skin conditions: erythema nodosum, disseminated granuloma anulare, necrobiosis lipoidica, nodular vasculitis, cutaneous sarcoidosis, and granulomatous perioral dermatitis/ rosacea. The median duration of KI intake was 5 ± 7.7 weeks (range 1-26). The global assessment of efficacy by the treating physician showed an improvement of disease in about a third of all patients. No response was seen in 14 patients and 9 even had a progression of disease. An adverse event was documented in 16 cases. CONCLUSIONS: Our findings show that an improvement was reached in only about a third of all cases. High response rates with only mild side effects (in 16 out of 35 patients) were observed.

Diagnostic ambiguity of aseptic necrobiosis of a uterine fibroid in a term pregnancy: a case report.

BACKGROUND: Uterine fibroids are the most common uterine tumours in females of reproductive age. During pregnancy, uterine fibroids may be complicated by aseptic necrobiosis. We herein report an ambiguous clinical presentation of uterine fibroids in pregnancy and discuss the diagnostic challenges encountered in our resource-constraint setting. CASE PRESENTATION: A term pregnant Cameroonian woman was admitted to our maternity unit with clinical findings suggestive of a strangulated umbilical hernia. She underwent an emergency caesarean section which fortuitously revealed aseptic necrobiosis of a uterine fibroid, managed within the same surgical intervention by myomectomy. Her post-operative course was uneventful. CONCLUSION: The authors highlight the need for a high index of suspicion by healthcare providers, as well as the need for a multidisciplinary approach for a favourable maternal and foetal outcome.

The long-term effect of pulsed dye laser on Necrobiosis Lipoidica: A case study.

A 57-year-old female was presented with an irrepressible case of Necrobiosis Lipoidica considering the possibility of a surgical skin graft. Instead, a pulsed dye laser treatment was used as an alternate treatment. Previous case studies have been found in the literature on the effect of pulsed dye laser on Necrobiosis Lipoidica. The use of a pulsed dye laser in this case resulted in rendering the lesions asymptomatic for pain and a reduction in volume. Prolonged control was exhibited. From this case, we conclude that pulsed dye laser therapy is effective when increasing the number of treatments of laser therapy, and can be used as a treatment for Necrobiosis Lipoidica.

Atypical presentation of necrobiosis lipoidica in a pediatric patient.

Necrobiosis lipoidica (NL) is a rare chronic granulomatous inflammatory skin disease characterized by brownish-red papules and yellowish plaques with atrophic centers, which usually affect the legs, bilaterally. The average age of onset is 30-40 years, and there are very few reported cases of necrobiosis lipoidica in children. A nondiabetic girl aged 14 years presented to our clinic with a history of an asymptomatic, 7 × 5-cm single red plaque over her back in the interscapular area, which had started 5 years ago. Her laboratory tests were normal. A histopathologic evaluation confirmed the diagnosis of NL, and local treatment with clobetasol propionate twice daily was administrated. The patient will be followed up to monitor plasma glucose levels and evaluation of the lesion. Herein, we report a pediatric patient without diabetes mellitus who had NL in an atypical location and review the literature in view of the clinical features, complications, and treatment regimens for NL in children.

Necrobiosis lipoidica in a Nigerian woman - Report of a case.

Necrobiosis lipoidica (NL), one of a group of "necrobiotic" granulomatous cutaneous disorders, is characterized histologically by layers of poorly defined, horizontally oriented, altered "necrobiotic" collagen surrounded by, and alternating with, layers of chronic inflammatory cells, histiocytes, and giant cells throughout the full thickness of the dermis. It is a rare disease associated mostly with diabetes mellitus in whom it may affect 0.3%-1.2% although it has also been associated with other cutaneous and systemic disorders and may occur in otherwise normal people. NL has been reported from all over the world, but there appears to be very few reports of NL in Black Africans. We report the case of a 55-year-old diabetic Nigerian woman who presented with typical NL lesions on the lower legs and who responded very well to topical betamethasone dipropionate 0.05% cream. We also briefly review the probable underlying mechanisms leading to the condition and the various treatments that have been found useful.