Topical Ruxolitinib in the Treatment of Necrobiosis Lipoidica: A Prospective, Open-Label Study.

Necrobiosis lipoidica (NL) is a rare granulomatous disease. There are few effective treatments for NL. We sought to investigate the efficacy and safety of the Jak1/2 inhibitor, ruxolitnib, in the treatment of NL and identify the biomarkers associated with the disease and treatment response. We conducted an open-label, phase 2 study of ruxolitinib in 12 patients with NL. We performed transcriptomic analysis of tissue samples before and after treatment. At week 12, the mean NL lesion score decreased by 58.2% (SD = 28.7%, P = .003). Transcriptomic analysis demonstrated enrichment of type I and type II IFN pathways in baseline disease. Weighted gene coexpression network analysis demonstrated post-treatment changes in IFN pathways with key hub genes IFNG and signal transducer and activator of transcription 1 gene STAT1. Limitations include small sample size and a study group limited to patients with <10% body surface area. In conclusion, ruxolitinib is an effective treatment for NL and targets the key pathogenic mediators of the disease.

Familial necrobiosis lipoidica not associated with diabetes.

A 42-year-old woman presented with a 12-year history of extensive yellow and erythematous plaques, round and oblong with irregular configuration and glossy atrophic central areas on the pretibial aspects of both legs. Her 45-year-old sister presented with a 7-year history of a single plaque with erythematous margins, abundant telangiectases, and an atrophic center in the lower portion of the left leg. There was no family history of type-1 or type-2 diabetes mellitus. Both patients had normal fasting glucose concentration, oral glucose tolerance test, and glucose overload test. Different treatment options including topical corticosteroids were unsuccessful. Treatment with oral fumaric acid esters was attempted but the medication was discontinued because of intolerable side effects (flushing and gastrointestinal discomfort). At present, after a follow-up of 2 years, the plaques remain unchanged. These two cases should be added to the few cases of familial nondiabetic necrobiosis lipoidica previously reported.

gli-1 Oncogene is highly expressed in granulomatous skin disorders, including sarcoidosis, granuloma annulare, and necrobiosis lipoidica diabeticorum.

BACKGROUND: Sarcoidosis, which occurs most commonly in African American women, is a granulomatous multisystem disorder affecting the skin, lungs, and central nervous system. In a previous immunohistochemistry study of keloids, a scar granuloma stained highly positive for glioma-associated oncogene homologue (gli)-1. OBSERVATION: This observation led us to study whether gli-1, one of the vertebrate zinc finger transcription factor genes of the gli superfamily, is expressed in granulomatous skin disorders such as cutaneous sarcoidosis, granuloma annulare (GA), and necrobiosis lipoidica diabeticorum (NLD). Immunohistochemistry studies for gli-1 were performed on biopsy specimens from patients with cutaneous sarcoidosis, GA, and NLD. All sarcoid lesions were highly positive for gli-1 expression, and 75% of the cells demonstrated positivity with a stain intensity of 3 on a scale of 1 to 3. The gli-1 expression was confined to cutaneous granulomas. CD68 staining was highly positive in the sarcoid lesions as well. Similarly, GA and NLD lesions were uniformly positive for gli-1 expression. CONCLUSIONS: We found that gli-1 is inappropriately expressed in granulomatous lesions of the skin such as cutaneous sarcoidosis, GA, and NLD. These findings provide a rationale for clinical trials of inhibitors of gli-1 signaling, including tacrolimus and sizolimus, for the treatment of cutaneous sarcoidosis and other granulomatous disorders of the skin.

Necrobiosis lipoidica: only a minority of patients have diabetes mellitus.

Although it is commonly accepted that necrobiosis lipoidica (NL) is associated with diabetes mellitus (DM), there is some controversy regarding the degree of this association. In a retrospective review of 65 patients with NL attending our dermatology out-patient clinics we found that just seven (11%) were known to have DM at the time of presentation. Seven further patients (11%) were diagnosed as having impaired glucose tolerance/DM at presentation and over a 15-year follow-up period. Thus, only a minority of our patients with NL had DM.

Familial non-diabetic necrobiosis lipoidica.

Necrobiosis lipoidica (NL) is a cutaneous disorder with distinctive clinical and morphologic characteristics. It is associated with diabetes mellitus in two thirds of cases. The aetiology and pathogenesis of NL are unknown but familial cases of NL seem to be extremely rare. We report the occurrence of NL in two sisters with normal glucose tolerance.

Unique mosaicism in Prader-Labhart-Willi syndrome--a contiguous gene or aneuploidy syndrome?

A 16-year-old boy with Prader-Labhart-Willi syndrome (PLWS) had hypotonia, feeding difficulties, failure to thrive, strabismus and bilateral inguinal hernias with cryptorchidism during infancy followed by hyperphagia, marked early-onset obesity with insulin-dependent diabetes mellitus and necrobiosis lipoidica diabeticorum, short stature, hypogonadotropic hypogonadism and some of the facial characteristics of the individuals with the PLWS. IQ is estimated around 90. Cytogenetic studies showed mosaicism: 45,X, t(Y;15) with partial deletion 15 (15pter----15q12); 46,X, t(Y;15), dic (15)(15pter----15q12::15q12----15pter) and 47, X, t(Y;15), dic(15), dic(15). The dic(15) was bisatellited, NOR-positive on both arms and represented inv dup(15). Thus, the 2 lines with the dic(15) showed partial trisomy 15 (15pter----15q12) and partial pentasomy 15 (15pter----15q12), respectively. The cell line ratios were different in lymphocyte and fibroblast cultures. The unique cytogenetic findings in this patient, the reports of a variety of chromosome 15 aberrations in PLWS, as well as aberrations of other chromosomes, suggest that the condition is a contiguous gene syndrome rather than an aneuploidy syndrome.

Non-diabetic necrobiosis lipoidica. Hitherto unrecognized papulonecrotic, nodulo-ulcerative and familial forms of the disease.

Necrobiosis lipoidica of the legs, in which deep ulcers resembling erythema induratum, gummas or a variety of other chronic progressive ulcerating skin diseases occur, is described. In 2 cases the lesions were precipitated by a crush injury elsewhere in the same leg, but not at the site of the ultimate lesions. In 2 further pairs of siblings the same problem arose as a familial complaint without trauma. These cases were distinguished by severe necrosis in the absence of diabetes.