Clinical Features and Comorbidities of Patients With Necrobiosis Lipoidica With or Without Diabetes.

Importance: Necrobiosis lipoidica (NL) is a rare granulomatous condition. Current knowledge of its key features is based on a limited number of studies and case reports, leading to wide variability in the characterization of its defining features, with limited comparison of patients with or without diabetes. Objective: To evaluate the epidemiologic characteristics, clinical features, and disease associations of NL in patients with or without type 1 or 2 diabetes. Design, Setting, and Participants: This multicenter retrospective review included 236 patients aged 15 to 84 years who were evaluated and received a diagnosis of NL at the University of Pennsylvania Health System between January 1, 2008, and July 15, 2018; University of Iowa Hospitals and Clinics between January 1, 2000, and June 15, 2018; and Brigham and Women's Hospital and Massachusetts General Hospital between January 1, 2000, and February 15, 2018. Main Outcomes and Measures: Patient demographics, clinical features, medical comorbidities, and biopsy status. Results: Of the 236 patients with NL, 200 were women and 36 were men, and 182 were white, with a median age at presentation of 50.0 years (interquartile range, 33.0-59.0 years). The diagnosis was biopsy proven in 156 patients (66.1%). Of the 230 patients with location specified, 225 (97.8%) had NL on the lower legs. A total of 138 patients with NL (58.5%; 95% CI, 52.7%-65.3%) had diabetes. The median hemoglobin A1c for patients with diabetes was 8.00% (interquartile range, 6.68%-9.50%) (to convert hemoglobin A1c to proportion of total hemoglobin, multiply by 0.01). Patients with diabetes were significantly younger than patients without diabetes (median age, 45.0 vs 52.0 years; P = .005), and slightly less likely to be female (112 of 138 [81.2%] vs 87 of 96 [90.6%]; P = .046), but lesion characteristics were otherwise comparable. Other notable comorbidities included obesity in 95 of 184 patients (51.6%; 95% CI, 44.4%-58.9%), hypertension in 104 of 230 patients (45.2%), dyslipidemia in 98 of 225 patients (43.6%), and thyroid disease in 56 of 229 patients (24.5%). Conclusions and Relevance: This study of NL supports its associations with diabetes as well as obesity, hypertension, dyslipidemia, and thyroid disease. Younger age and female sex were observed more frequently in patients with diabetes. Otherwise, NL lesions in patients with or without diabetes shared many clinical features, suggesting that risk factors outside of elevated blood glucose may play an important role in the disease. Future studies should evaluate these associations with the goal of further elucidating NL's underlying pathophysiologic characteristics.

Ustekinumab to target granulomatous dermatitis in recalcitrant ulcerative necrobiosis lipoidica: case report and proposed mechanism.

We present a 42-year-old woman with no history of diabetes or glucose intolerance who had a 5-year history of ulcerative necrobiosis lipoidica (NL). Despite failure of multiple medications, she experienced clearing of her ulcers after her treatment was changed to ustekinumab. We discuss our patient's disease course and elaborate upon mechanistic reasons for her improvement related to ustekinumab therapy.

Non-infectious granulomatous diseases of the skin and their associated systemic diseases: an evidence-based update to important clinical questions.

Non-infectious granulomatous diseases of the skin are a broad group of distinct reactive inflammatory conditions that share important similarities. As a group, they are relatively difficult to diagnose and distinguish both clinically as well as histologically. Many of these disorders have significant associations with systemic diseases that impact the patient's overall prognosis. In this update, we offer a discussion of emerging concepts and controversies in this field, as presented through evidence-based answers to seven important clinical questions regarding palisading and epithelioid granulomata. These questions offer an opportunity to review ten non-infectious granulomatous conditions that have implications for systemic disease: granuloma annulare, annular elastolytic giant cell granuloma, necrobiosis lipoidica, methotrexate-induced accelerated rheumatoid nodulosis, necrobiotic xanthogranuloma, interstitial granulomatous dermatitis, interstitial granulomatous drug reaction, palisaded neutrophilic granulomatous dermatitis, sarcoidosis, and metastatic Crohn disease. Recent clinical, epidemiologic, and laboratory studies have shed some light on these diseases, the association of these conditions with systemic disorders, and their overall prognoses.

Venous insufficiency in patients with necrobiosis lipoidica.

The pretibial area is the most frequently affected site in necrobiosis lipoidica (NL), but proposed mechanisms of NL cannot fully explain this high frequency. Although a few case reports indicate NL patients are complicated with venous insufficiency, no accurate assessment of the relationship between these two conditions has been performed. By using color Doppler ultrasonographic screening of four NL patients for venous insufficiency, we detected venous insufficiency in at least one leg of each patient. NL lesions were observed on all legs with venous insufficiency, and laboratory examination findings revealed that all the patients had hypercholesterolemia. The skin lesions did not respond satisfactorily to 6-month use of anticholesterolemic medication and elastic stockings. However, these results indicate that both hyperlipidemia and venous reflux, in addition to other pathogenic factors, can trigger tissue damage in the lower legs and lead to the onset of NL.

Skin blood flow in necrobiosis lipoidica diabeticorum.

BACKGROUND: Necrobiosis lipoidica diabeticorum (NLD) is a granulomatous skin reaction found in < 1% of diabetic patients. Our purpose was to determine if NLD represented areas of cutaneous ischemia. METHODS: Using laser Doppler flowmetry, we measured cutaneous blood flow in nine diabetic patients at NLD lesions and at contiguous uninvolved sites. Flow values were also determined at several reference sites noncontiguous with the NLD lesions and compared to age- and sex-matched controls: 24 diabetic subjects without skin abnormalities, 18 diabetic patients with dermopathy, and 40 nondiabetic subjects. RESULTS: NLD lesions exhibited significantly higher blood flow (4.8 +/- 0.7 ml/min/100 g) than areas of unaffected skin close to the lesions (1.2 +/- 0.1 ml/min/100 g) (P < 0.01 for both comparisons). There were no significant differences in flow between normal skin sites in NLD patients and normal sites in diabetic patients without skin lesions. CONCLUSIONS: Our findings refute the hypothesis that NLD is a manifestation of microvascular ischemic disease of the skin. The increased blood flow seen in NLD lesions suggests an ongoing inflammatory process.

Unilateral necrobiosis lipoidica of the ischemic limb--a case report.

A 63-year-old diabetic woman presented with new-onset intermittent claudication of the right calf accompanied by ipsilateral necrobiosis lipoidica (NL). The latter presented the typical appearance of oval, indurated plaques, with brownish-red margins and central atrophy, scattered over the right thigh and calf. Arteriography demonstrated severe obstructive lesions on the right femoral artery. NL and claudication spared the left leg. A possible ischemic pathogenesis of NL emerges from this observation and is supported by recent studies in the literature.

Granuloma annulare and necrobiosis lipoidica tissue reactions as a manifestation of systemic disease.

Granuloma annulare (GA) and necrobiosis lipoidica (NL) are generally considered to be idiopathic cutaneous palisading granulomatous dermatitides. There are sporadic reports of such lesions occurring in patients with coexistent systemic diseases other than diabetes mellitus. Having encountered 49 patients whose skin biopsies showed GA or NL lesions in the setting of extracutaneous disease, the authors set out to assess their clinical and histopathological findings to determine if any parameters were predictive of underlying systemic disease. Fifty-two skin biopsies from 49 patients having either GA or NL in whom there was a clinical history of an associated systemic disease were analyzed by light microscopy. The main systemic disease associations were rheumatologic, endocrine, hematologic, infectious, and inflammatory bowel diseases, ANCA positive vasculitic syndromes, and sarcoidosis. The clinical and histomorphological features were compared with those of a control group of patients whose skin biopsies showed GA or NL and in whom there was no history of extracutaneous disease. For the systemic disease group, patients were selected either retrospectively or prospectively from 160,000 cases accessioned in a 24-month period in the dermatopathology databases of Pathology Services, Inc (Cambridge, MA) and Central Medical Laboratories (Winnipeg, Canada). All systemic disease cases from the former service were analyzed blindly by the second author and from the latter service were analyzed blindly by the first author. Patients in the control group were obtained retrospectively from the Pathology Services Inc. database by the authors. The location of the lesions was atypical in 30 of 34 biopsies from systemic disease patients with a GA tissue reaction versus 10 of 22 biopsies of GA in the control group (P = .001). Six of 18 biopsies from patients with NL tissue reactions in the systemic disease group showed an atypical location, versus only 1 of 9 biopsies of NL from the control group (P = .19). The clinical diagnostic considerations were much broader in the systemic disease group versus the control group and included vasculitis, panniculitis, and connective tissue diseases including morphea in the former. In 22 of 34 GA biopsies and 16 of 18 NL biopsies from the systemic disease group, an active vasculopathy of leukocytoclastic, granulomatous, or thrombogenic subtypes was demonstrable. None of the GA or NL biopsies from the control group showed a similar active vasculopathy. An active vasculopathy was predictive of systemic disease in patients having either a GA-like or an NL-like tissue reaction (P < .001). Fifteen of 34 GA and 7 of 18 NL biopsies in the systemic diseases group showed extravascular neutrophilia in contrast to 3 of 22 GA (P = .02) biopsies and 2 of 9 NL (P = .33) biopsies in the control group. The finding of an active vasculopathy in a skin biopsy specimen showing a GA- or NL-like tissue reaction, particularly in the setting of an atypical clinical presentation both with respect to the location and appearance of lesions, should prompt consideration of an underlying systemic disease, as should extravascular neutrophilia in a skin biopsy showing a GA-like tissue reaction.

Necrobiosis lipoídica: reporte de un caso / Necrobiosis lipoidica: a case report

Presentamos un paciente femenino con necrobiosis lipoídica no relacionada a diabetes mellitus. Los mecanismos etiopatogénicos son aún poco entendidos y la respuesta a las diversas modalidades de tratamiento es inconstante

Necrobiosis lipoidica diabeticorum: association with background retinopathy, smoking, and proteinuria. A case controlled study.

In order to evaluate patients with necrobiosis lipoidica diabeticorum and to compare them with age, sex, and duration of diabetes matched controls, 15 patients with necrobiosis were each matched with 5 control subjects with diabetes mellitus. Complications of diabetes, glycaemic control, and proteinuria were measured. Patients with necrobiosis (mean age 40, range 18-74 years) had a mean duration of diabetes of 14 (range 3-36) years; 8 patients were male, and 7 were female. For necrobiosis versus controls, background retinopathy (67% vs 27%, p = 0.009), proteinuria (53% vs 17%, p = 0.006), and smoking (60% vs 20%, p = 0.003) were all more common with necrobiosis. There were no significant differences between patients with necrobiosis and control patients in the prevalence of vascular disease and neuropathy. Glycosylated haemoglobin concentrations were higher in patients with necrobiosis (p = 0.02). Blood pressure measurements were similar in both groups. We conclude that smoking, proteinuria, and retinopathy were more prevalent in diabetic patients with necrobiosis; the skin lesion may therefore share common aetiological factors which affect the microvascular circulation, leading to damage to basement membranes and vascular endothelial cells.

[Cutaneous microcirculation in pretibial necrobiosis lipoidica. Comparative laser Doppler flowmetry and oxygen partial pressure determinations in patients and healthy probands]. / Kutane Mikrozirkulation bei prätibialer Nekrobiosis lipoidica. Vergleichende Laser-Doppler-Fluxmetrie und Sauerstoffpartialdruckmessungen bei Patienten und Hautgesunden.

Necrobiosis lipoidica (NL) is a chronic, skin disease usually localized pretibially and often associated with diabetes mellitus. Primary vascular disturbances are considered pathogenetic for NL. In order to determine microcirculatory alterations in "idiopathic" NL linked with neither arterial hypertension nor diabetes mellitus, we performed simultaneous measurements of laser-Doppler flux (LDF) and oxygen tension (pcuO2) in 10 non-diabetic patients with NL and in 10 age- and sex-matched healthy volunteers. We examined the centre of the pretibial NL plaque, its border and the non-affected skin of the proximal lower leg at probe temperatures of 36 degrees C (flux) and 37 degrees C (pcuO2). Corresponding sites and temperatures were chosen for the controls. In addition, the degrees of hyperaemia caused by arterial occlusion (3 min) and during local heating (42 degrees C) were continuously measured. The initial pcuO2 values were found to be lowered, in contrast to increased fluxes within and around the NL lesions. In addition, responses of both flux and pcuO2 to the hyperaemic stimuli were weaker than in the corresponding skin of the healthy controls. Only minor differences from controls or none at all were found in clinically unaffected lower leg skin of the patients. Our results indicate a local alteration of microcirculation in patients with "idiopathic" NL that occurs independently of diabetes.

Skin blood flow in necrobiosis lipoidica during treatment with low-dose acetylsalicylic acid.

Skin blood flow was measured by the laser Doppler technique in lesional and clinically normal skin of 10 diabetic patients with necrobiosis lipoidica during and after treatment with 40 mg acetylsalicylic acid (ASA) daily. The measurements showed that the blood flow during ASA treatment was significantly decreased in the central lesional skin without changes in the peripheral part of the lesions and normal skin. In view of these findings we suggest that low-dose ASA may not be the best treatment for necrobiosis lipoidica.

Cutaneous anaesthesia in necrobiosis lipoidica.

Cutaneous sensation in plaques of necrobiosis lipoidica was assessed in five non-diabetic and seven diabetic patients. Eleven of the twelve showed partial or complete anaesthesia of the affected skin. These findings are important in the differential diagnosis of tuberculoid leprosy. Further studies of nerve function in cutaneous granulomas need to be carried out.

Sweat gland disturbances in granuloma annulare and necrobiosis lipoidica.

We studied sweat gland distribution, density and activity in thirteen cases of granuloma annulare and ten cases of necrobiosis lipoidica, using a combination of the plastic impression and starch-iodine methods. The pattern of sweat gland disturbance in the two diseases was entirely different. In necrobiosis lipoidica an intense and uniform hypohidrosis was detected throughout the lesion, whereas in granuloma annulare the disturbance followed the morphology of the lesion (the papular border showed complete anhidrosis, whereas the flat central part of the lesion showed only moderate hypohidrosis or normal sweating). The method assigns numerical values to the 'relative density' and the 'relative activity' of the functioning sweat glands compared with normal skin, thus permitting statistical evaluation of the results.

[Peripheral blood flow in patients with necrobiosis lipoidica (diabeticorum)]. / Untersuchungen zur peripheren Durchblutung bei Patienten mit Necrobiosis lipoidica (diabeticorum).

For the judgment of the peripheral blood supply 16 insulin-dependent diabetics with necrobiosis lipoidica at the lower extremities were compared with 15 insulin-dependent diabetics without necrobiosis lipoidica. The vascular changes in form of retinopathy, nephropathy, neuropathy, hypertension, the results of the radiologically provable vascular changes, oscillograms and impedance plethysmograms as well as the results of the muscle and skin clearance and angioscintigraphy were evaluated. The at last mentioned methods give an insight into the microangiopathy. The apparantly contradicting findings of the muscle clearance (smaller blood supply) and of the skin clearance (increased blood flow) find their explanation by the angioscintigraphically proved different regional parameters of blood flow in the necrobiotic regions. The angiopathic findings are characterized by the enrichment of activity in the marginal seam as a sign of hyperemia and decreased accumulation in the centre as an expression of necrobiosis. The changes of the connective tissue and their causes of development are discussed. Angiopathic and traumatic influences conditioned by metabolism, apart from local peculiarities are taken into consideration.