Necrobiosis lipoidica

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Necrobiosis lipoidica

Arif M. Aslam and Ian Coulson

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

(From Pei-Shan Yen, Kuo-Hsien Wang, Wei-Yu Chen, Ya-Wen Yang, Wen-Tsao Ho, 2011. The many faces of necrobiosis lipoidica: a report of three cases with histologic variations. Dermatologica Sinica 29 (2), 67–71.)

Necrobiosis lipoidica (NL) is a chronic cutaneous granulomatous condition with degenerative connective tissue changes. The pathophysiology remains unknown but both granulomatous and angiopathic mechanisms have been proposed. It is seen in 1 in 300 diabetics but may be unassociated with glucose intolerance. NL initially appears as an atrophic plaque found over pretibial sites. Ulceration may occur after trauma, with ensuing pain. NL may rarely be complicated by squamous cell carcinoma.

Management strategy

Smoking cessation and avoiding trauma to the affected shins are key factors to avoid transformation from an unsightly plaque into a painful, recalcitrant ulcer. The progression of new lesions may be halted by intralesional or occluded potent topical corticosteroids applied to the margins of the lesions. Once atrophy has developed there is little that will reverse this, although topical retinoids may be tried. Telangiectasia is often marked and has been treated with pulsed dye laser. Extensive lesions may justify trials of nicotinamide or prednisolone. Antiplatelet therapy in the form of aspirin, dipyridamole, or ticlopidine has its enthusiasts, though responses are inconclusive. Topical psoralen and UVA (PUVA) has received recent interest and may arrest progression and improve the appearance. A variety of systemic anti-inflammatory and immunosuppressive agents have received recent attention, including mycophenolate mofetil, fumaric acid esters, cyclosporine, antimalarials, thalidomide, and pentoxifylline. Infliximab and etanercept have also been proposed.

The chronically ulcerated lesion is a challenge; antibiotics deal with secondary infection, appropriate dressings may be required, and growth factors such as becaplermin and granulocyte–macrophage colony-stimulating factor (GM-CSF) may accelerate healing. As diabetics may have coexisting large vessel atherosclerosis that may contribute to ulceration, non-invasive arterial studies or angiography need to be considered if clinically indicated. Venous hypertension may also contribute to the localization and ulceration of necrobiosis. Excision and grafting may transform the patient’s quality of life and improve cosmesis.

Work with the diabetes specialist to optimize diabetic control.

Specific investigations

Two-hour postprandial glucose

Consider angiography or venous circulation studies

Consider a biopsy to exclude sarcoidosis, which may mimic necrobiosis lipoidica, or, if clinical features suggest, the rare development of squamous cell carcinoma

Squamous cell carcinoma arising in an area of long-standing necrobiosis lipoidica.

Lim C, Tschuchnigg M, Lim J. J Cutan Pathol 2006; 33: 581–3.

Case report of a squamous cell carcinoma arising de novo in an area of NL.

Carcinoma cuniculatum arising in necrobiosis lipoidica.

Porneuf M, Monpoint S, Barnéon G, Alirezai M, Guillot B, Guilhou JJ. Ann Dermatol Venereol 1991; 118: 461–4.

Although rare, squamous cell carcinomas may complicate any condition in which papillary dermal scarring is appreciable.

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

Naschitz JE, Fields M, Isseroff H, Wolffson V, Yeshurun D. Angiology 2003; 54: 239–42.

A possible ischemic pathogenesis of NL emerges from a case of unilateral large vessel arteriosclerotic ischemia with ipsilateral NL.

The author has experience of a severely ulcerated area of NL that only started to heal after the disobliteration of severe femoropopliteal atheroma.

Dermatoscopy of early onset necrobiosis lipoidica.

Bakos RM, Cartell A, Bakos L. J Am Acad Dermatol 2012; 66: e143–4.

Dermatoscopy may be a useful tool for evaluating early onset NL before biopsy. The presence of branching telangiectasia, hairpin-like vessels and a yellow background may suggest this diagnosis.

First-line therapies

Stop smoking and optimize diabetic control	C
Intralesional or topical corticosteroids under occlusion	D

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

Kelly WF, Nicholas J, Adams J, Mahmood R. Diabet Med 1993; 10: 725–8.

The patient should stop smoking and control diabetes mellitus with vigilance. Fifteen diabetic patients with NL were each matched with five control subjects with diabetes mellitus. Background retinopathy, proteinuria, and smoking were all more common with NL. No differences were noted between those with NL and controls in the prevalence of vascular disease and neuropathy. Glycosylated hemoglobin concentrations were higher in patients with NL.

Granuloma annulare and necrobiosis lipoidica treated by jet injector.

Sparrow G, Abell E. Br J Dermatol 1975; 93: 85–9.

Three of five cases of NL underwent complete resolution and one had partial improvement with 5 mg/mL triamcinolone injection to the edges of lesions. No serious complications of this type of treatment were observed.

Treatment of psoriasis and other dermatoses with a single application of a corticosteroid left under a hydrocolloid occlusive dressing for a week.

Juhlin L. Acta Derm Venereol 1989; 69: 355–7.

A 0.1% betamethasone alcoholic lotion under a hydrocolloid dressing was an effective, well-tolerated treatment, and three applications only were required.

Second-line therapies

Systemic corticosteroids	D
Aspirin and dipyridamole	C
Ticlopidine	D
Nicotinamide	D
Clofazimine	D
Topical PUVA	D
Topical tacrolimus	E

Necrobiosis lipoidica: treatment with systemic corticosteroids.

Petzelbauer P, Wolff K, Tappeiner G. Br J Dermatol 1992; 126: 542–5.

Oral methylprednisolone was given to six patients with non-ulcerating NL for 5 weeks; in all cases there was cessation of disease activity during the 7-month follow-up period. Initial dosage was 1 mg/kg daily for 1 week, then 40 mg daily for 4 weeks, followed by tapering and termination in 2 weeks. All, including the diabetics, tolerated the treatment well. There was no improvement in atrophy. Benefit was maintained at the end of the 7-month follow-up period.

Careful monitoring of blood glucose is mandatory in all diabetic patients with NL treated with systemic corticosteroids.

Ulcerating necrobiosis lipoidica effectively treated with pentoxifylline.

Noz KC, Korstanje MJ, Vermeer BJ. Clin Exp Dermatol 1993; 18: 78–9.

Ulcerated NL healed completely within 8 weeks of administration of 400 mg pentoxifylline twice daily.

Healing of necrobiotic ulcers with antiplatelet therapy. Correlation with plasma thromboxane levels.

Heng MC, Song MK, Heng MK. Int J Dermatol 1989; 28: 195–7.

NL in diabetics has been considered to be a cutaneous manifestation of diabetic microangiopathy. Seven diabetic patients with necrobiotic ulcers of recent onset that healed after administration of 80 mg/day of acetylsalicylic acid and 75 mg three times daily of dipyridamole had elevated thromboxane levels. Healing was associated with depression of the elevated thromboxane levels in all seven patients.

Treatment of necrobiosis lipoidica with low-dose acetylsalicylic acid. A randomized double-blind trial.

Beck HI, Bjerring P, Rasmussen I, Zachariae H, Stenbjerg S. Acta Derm Venereol 1985; 65: 230–4.

No response was seen with the use of 40 mg acetylsalicylic acid daily for 24 weeks, despite documented platelet aggregation inhibition.

A randomized double blind comparison of an aspirin dipyridamole combination versus a placebo in the treatment of necrobiosis lipoidica.

Statham B, Finlay AY, Marks R. Acta Derm Venereol 1981; 61: 270–1.

Fourteen patients with a clinical and histologic diagnosis of NL were treated in a double-blind control study with either an aspirin–dipyridamole combination or a matching placebo for an 8-week period. None of the patients in the aspirin–dipyridamole group showed a significant improvement.

Necrobiosis lipoidica treated with ticlopidine.

Rhodes EL. Acta Derm Venereol 1986; 66: 458.

When 33 patients were given an unstated dose of this antiplatelet agent, NL cleared in nine and improved in 17 patients. The author warns that cases of agranulocytosis have been reported with ticlopidine.

High dose nicotinamide in the treatment of necrobiosis lipoidica.

Handfield-Jones S, Jones S, Peachey R. Br J Dermatol 1988; 118: 693–6.

An open study of high-dose nicotinamide in the treatment of 15 patients with NL. Of 13 patients who remained on treatment for more than 1 month, eight improved. A reduction in pain, soreness, and erythema, and the healing of ulcers if present, was noted. There were no significant side effects, particularly with respect to diabetic control. Lesions tended to relapse if treatment was stopped.

Clofazimine – therapeutic alternative in necrobiosis lipoidica and granuloma annulare.

Mensing H. Int J Dermatol 1989; 28: 195–7.

Ten patients with NL were treated with clofazimine 200 mg orally daily. Six of 10 patients responded; three of the responders achieved complete remission of the dermatosis. All the patients treated had reddening of the skin, but this was reversible after the end of therapy, as were the other side effects (i.e., diarrhea and dryness of the skin).

Topical PUVA treatment for necrobiosis lipoidica.

McKenna DB, Cooper EJ, Tidman MJ. Br J Dermatol 2000; 143: 71.

Four of eight patients with NL responded favorably to topical PUVA using a 0.15% methoxsalen emulsion, with weekly treatments, starting with 0.5 J/cm² with 20% incremental increases until erythema developed at the edge of the lesions. The mean number of treatments administered was 39.

Successful treatment of chronic ulcerated necrobiosis lipoidica with 0.1% topical tacrolimus ointment.

Clayton T, Harrison P. Br J Dermatol 2005; 152: 581–2.

A case report of ulcerated NL that healed successfully with 0.1% tacrolimus ointment applied twice daily for 1 month.

Third-line therapies

Topical retinoids	E
Cyclosporine	E
Heparin	E
Chloroquine	E
Mycophenolate mofetil	E
Infliximab	E
Etanercept	E
Fumaric acid esters	D
Promogran for ulceration	E
GM-CSF for ulceration	D
Becaplermin for ulceration	E
Pentoxifylline	E
Photodynamic therapy	E
Pulsed dye laser for telangiectasia	E
Surgery for ulceration	E
Thalidomide	E
Intravenous immunoglobulins and methylprednisolone	E
Ultraviolet A1 phototherapy	E

Necrobiosis lipoidica treated with topical tretinoin.

Heymann WR. Cutis 1996; 58: 53–4.

A case is presented in which atrophy was diminished by the application of topical tretinoin.

Persistent ulcerated necrobiosis lipoidica responding to treatment with cyclosporine.

Darvay A, Acland KM, Russell-Jones R. Br J Dermatol 1999; 141: 725–7.

In two patients with severely ulcerated NL the ulceration healed completely after 4 months of cyclosporine therapy, and both patients have remained free of ulceration since. Effective doses were between 3 and 5 mg/kg daily. Three other reports of the effective use of cyclosporine therapy in ulcerated NL now exist.

Minidose heparin therapy for vasculitis of atrophie blanche.

Jetton RL, Lazarus GS. J Am Acad Dermatol 1983; 8: 23–6.

The authors speculate that subcutaneous heparin 5000 IU twice daily may help NL because it helped the vasculitis associated with atrophie blanche. A subsequent letter informs that perilesional low-dose heparin has been successfully used in NL by Russian dermatologists.

Necrobiosis lipoidica diabeticorum treated with chloroquine.

Nguyen K, Washenik K, Shupack J. J Am Acad Dermatol 2002; 46: S34–36.

A single report of the first case of successful treatment of NL with oral chloroquine.

Successful treatment of ulcerated necrobiosis lipoidica with mycophenolate mofetil.

Reinhard G, Lohmann F, Uerlich M, Bauer R, Bieber T. Acta Derm Venereol 2000; 80: 312–13.

A 61-year-old woman with NL for over 30 years was started on mycophenolate mofetil 0.5 g twice daily and the lesions regressed within 4 weeks. The dose was reduced to 0.5 g over the next four months and then stopped. Within 14 days of stopping mycophenolate mofetil the ulceration recurred.

Infliximab: a promising new treatment option for ulcerated necrobiosis lipoidica.

Kolde G, Muche JM, Schulze P, Fischer P, Lichey J. Dermatology 2003; 206: 180–1.

A 33-year-old man with insulin-dependent diabetes mellitus and ulcerated NL was treated with infliximab monotherapy 5 mg/kg infusions each month. By the second infusion the ulceration had healed, but subsequent infusions were stopped because of the development of miliary tuberculosis. The NL did not recur on stopping infliximab.

Ulcerative necrobiosis lipoidica: is there a place for anti-TNFα treatment?

Guedes R, Leite I, Baptista A, Roche N. Case Report Med 2012; 854738 [Epub].

A 65-year-old female patient who previously failed to respond to potent topical steroids, topical 0.1% tacrolimus and cyclosporine received 50 mg subcutaneous etanercept once weekly. After 8 weeks of therapy all the ulcerative lesions had healed.

Clearance of necrobiosis lipoidica with fumaric acid esters.

Gambichler T, Kreuter A, Freitag M, Pawlak FM, Brockmeyer NH, Altmeyer P. Dermatology 2003; 207: 422–4.

A 50-year-old woman with a 15-year history of recalcitrant NL was treated with Fumaderm Initial (30 mg dimethylfumarate), starting at one tablet daily increased at weekly intervals up to three tablets daily. After the third week, Fumaderm (120 mg dimethylfumarate) was started at one tablet daily and increased to a maximum dose of two tablets daily. After 6 months of treatment the NL had resolved apart from skin atrophy. Remission was maintained over a 6-month follow-up period.

Fumaric acid esters in necrobiosis lipoidica: results of a prospective noncontrolled study.

Kreuter A, Knierim C, Stücker M, Pawlak F, Rotterdam S, Altmeyer P, et al. Br J Dermatol 2005; 153: 802–7.

Eighteen patients with NL were given the standard Fumaderm regimen as used in psoriasis for at least 6 months. Three discontinued therapy, but the rest gained significant clinical, ultrasonographic, and histological improvement.

The management of hard-to-heal necrobiosis with Promo-gran.

Omugha N, Jones AM. Br J Nurs 2003; 15: S14–20.

A single case study with non-healing ulcerated NL of 3 years’ duration. Treatment with a new protease-modulating matrix (freeze-dried matrix composed of collagen and oxidized regenerated cellulose) resulted in complete healing of the ulcer after 8 weeks, where other dressing regimens had failed to effect healing over a period of 2.5 years.

Healing of chronic leg ulcers in diabetic necrobiosis lipoidica with local granulocyte–macrophage colony-stimulating factor treatment.

Remes K, Ronnemaa T. J Diabetes Complications 1999; 13: 115–18.

Topical recombinant human GM-CSF healed two patients with ulcerated NL within 10 weeks. A reduction in the size of the ulcers was already evident after the first topical applications. The ulcers have remained healed for more than 3 years.

Becaplermin and necrobiosis lipoidicum diabeticorum: results of a case control pilot study.

Stephens E, Robinson JA, Gottlieb PA. J Diabetes Complications 2001; 15: 55–6.

Five patients with type 1 diabetes mellitus and NL were treated with topical becaplermin gel (recombinant platelet-derived growth factor). The index patient had ulcerated NL, and this healed. Three of the five patients with non-ulcerated NL reported a subjective improvement in sensation and lightening of color of the lesions. However, serial photographs and measurements over the 5-month treatment period showed no significant change in the size of the treated areas.

Necrobiosis lipoidica diabeticorum: response to pentoxiphylline.

Brasaria S, Braga-Brasaria M. J Endocrinol Invest 2003; 26: 1037–40.

A case report of a 20-year-old diabetic with ulcerating NL almost completely healing after 6 months of pentoxyfylline 400 mg three times daily.

Successful treatment of necrobiosis lipoidica diabeticorum with photodynamic therapy.

Heidenheim M, Jemec G. Arch Dermatol 2006; 142: 1548–50.

A case report of a 60-year-old woman who received six treatments with methylaminolevulinate photodynamic therapy, spaced at 1-week intervals. Both clinical and histological clearance was reported.

Necrobiosis lipoidica diabeticorum treated with the pulsed dye laser.

Moreno-Arias GA, Camps-Fresneda A. J Cosmet Laser Ther 2001; 3: 143–6.

A single report of the successful eradication of unsightly telangiectasia, a prominent feature of mature NL.

The surgical treatment of necrobiosis lipoidica diabeticorum.

Dubin BJ, Kaplan EN. Plast Reconstruct Surg 1977; 60: 421–8.

Seven cases treated by excision of the lesions down to the deep fascia, ligation of the associated perforating blood vessels, and the use of split-skin grafts to cover the defects. There were no recurrences.

Thalidomide for the treatment of refractory necrobiosis lipoidica.

Kukreja T, Peterson J. Arch Dermatol 2006; 142: 20–2.

A 51-year-old woman was treated successfully with a dose of thalidomide 150 mg daily, tapering to 50 mg twice weekly. A response was seen after 4 months and maintained after 2 years.

Treatment of ulcerated necrobiosis lipoidica with intravenous immunoglobulin and methylprednisolone.

Batchelor JM, Todd PM. J Drugs Dermatol 2012; 11: 256–9.

The authors report a case of a female patient with recalcitrant ulcerated NL that was resistant to several systemic agents but who initially responded to intravenous immunoglobulin. However this became less effective over time but a course of intravenous methylprednisolone led to regression.

Dramatic response of chronic ulcerating necrobiosis lipoidica to ultraviolet A1 phototherapy.

Radakovic S, Weber M, Tanew A. Photodermatol Photoimmunol Photomed 2010; 26: 327–9.

A 52-year-old female patient with a more than 30-year history of NL had failed to respond to multiple systemic therapies. However, there was a rapid improvement when UVA1 phototherapy was initiated. After 22 irradiations and a total exposure dose of 1480 J/cm² the lesions healed completely. In the follow-up of 6 months, two minor recurrences were treated successfully with UVA1 phototherapy.

Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e