Necrobiosis lipoidica diabeticorum

The patient had necrobiosis lipoidica diabeticorum, a cutaneous disease seen primarily in diabetic patients. Because the condition is occasionally found in patients without diabetes, the shorter term necrobiosis lipoidica (NL) is now used to encompass all patients with the clinical lesions regardless of the presence (or absence) of diabetes. NL usually affects the pretibial regions and may result in chronic ulcerations that typically respond poorly to standard local treatments.


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NL is seen in 0.3% of diabetic patients. In 60% of patients, a diagnosis of diabetes precedes the onset of NL, 25% develop NL and diabetes concomitantly, and 15% have NL prior to the onset of diabetes. Diabetes control appears to have no correlation with the onset, severity, or course of the skin disease. Diabetic patients with NL have a higher rate of systemic complications, such as peripheral neuropathy, retinopathy, and limited joint mobility.

NL occurs three times more often in women than in men; the average age of onset is 30 years. The disease can be seen, however, at any age and in all races. NL tends to be chronic with variable progression and scarring. Rarely, squamous cell carcinoma develops in older NL lesions.

In the majority of cases, patients report the sudden appearance of 1- to 3-mm, well-circumscribed papules or nodules in the pretibial areas. These lesions expand over the ensuing months to form asymptomatic, well-demarcated, shiny, waxy, round patches. Most patches are red-brown initially before they progress to yellow, depressed atrophic plaques surrounded by raised, violaceous rims. Numerous telangiectatic vessels can be seen on the lesions’ surface. Many NL patients have multiple lesions on both legs. The major complaint is usually the unsightly cosmetic appearance. Rarely, lesions appear on the face, scalp, trunk, and upper extremities. These lesions are usually more annular or serpiginous in configuration and less atrophic. Intralesional ulcerations are seen in 35% of NL patients and are especially likely to develop after trauma. In patients with severe ulcerations, 75% experience no pain (a result of cutaneous nerve damage), while 25% report severe pain, pruritus, or dysesthesia. Decreased sensation to pinprick and fine touch, hypohidrosis, and partial alopecia can be found within NL plaques.

The clinical appearance of NL is usually distinctive. Be aware, however, that some patients with NL will present atypically, and early forms of the disease may not be easily recognizable. The differential diagnosis includes granuloma annulare, xanthoma, necrobiotic xanthogranuloma, sarcoidosis, diabetic dermopathy, stasis dermatitis, erythema nodosum, morphea, lichen sclerosus, sclerosing lipogranuloma, and lupus.

The exact etiology of NL is unknown. The pathogenesis has been most often linked to diabetic microangiopathy with deposition of glycoprotein in the affected blood-vessel walls. The vascular changes may also reflect deposition of immunoglobulins, complement, and fibrinogen. An antibody-mediated vasculitis may be involved. Alternatively, NL may be primarily a disorder of collagen degeneration in which the body seemingly is having difficulty getting rid of the old connective tissue, with inflammation occurring as a secondary event. In this scenario, abnormal and defective collagen fibrils trigger the immune reaction, which features a granulomatous WBC response, thickening of the blood-vessel walls, and fat deposition. As has happened in many cases of sarcoidosis, polymerase chain reaction testing may in the future reveal that a specific organism is responsible for eliciting this granulomatous response.1

If the NL patient has no previous history of diabetes, a test for glucose intolerance is warranted. Otherwise, no specific testing is required. A skin biopsy is indicated only if there is uncertainty about the clinical diagnosis because even this simple surgical procedure can trigger chronic ulcerations. A specimen from the palpable inflammatory border will yield the best pathologic results. On microscopic examination, palisading granulomas are visible in the dermis and subcutaneous tissues are admixed with areas of collagen degeneration. Histiocytes, multinucleated lymphocytes, and an occasional plasma cell or eosinophil are found in the granulomas. Additionally, there is thickening of the blood-vessel walls and endothelial-cell swelling. Immunofluorescence reveals immunoglobulins M and A, as well as complement 3 and fibrinogen in the blood-vessel walls.

No treatment has been proven to be effective in large clinical studies. As previously noted, control of blood glucose levels in diabetic patients does not have a significant effect on the course of NL. Protecting the legs from localized trauma, including possible use of elastic support stockings and leg rest, is advisable. Spontaneous remission has been reported in 15% of affected patients.

The standard initial treatment is a short course of moderate-strength topical corticosteroids to lessen the inflammation of active early lesions and active borders of enlarging lesions. Corticosteroid injection into the active borders has also been utilized. However, use of these agents must be monitored, as steroids can exacerbate the atrophy that is inherent with NL. Topical calcineurin inhibitors can also be used. Topical pimecrolimus or tacrolimus applied twice daily has been reported to improve NL lesions.2 Reports of success in a few patients whose ulcerations were treated with local granulocyte-macrophage colony-stimulating factor bovine collagen are encouraging.3

If ulcerations persist, systemic therapy may be indicated. Niacinamide is a safe option that has achieved some success; one proposed mechanism involves inhibition of lymphokine release and decreased macrophage migration. Antiplatelet aggregation therapy with aspirin, dipyridamole, or pentoxifylline has had varied results. Oral cyclosporine at doses of 2.5 mg/kg/day appears helpful in cases of resistant NL.

A host of agents have been tried in anecdotal and/or uncontrolled studies of NL, including psoralen plus UVA, mycophenolate mofetil, stanozolol, inositol niacinate, infliximab, nicofuranose, and ticlopidine, as well as laser therapy. Some of these agents have potential side effects, such as hepatotoxicity with stanozolol and agranulocytosis with ticlopidine, and they must be used only after weighing benefits and risks. Surgical excision and grafting has not been universally successful, as recurrence is possible and poor healing of the graft site is not uncommon.

We prescribed twice-daily application of topical pimecrolimus along with oral dicloxacillin for the slow-healing, shallow ulcer on our patient’s shin. No other systemic therapies were initiated. The patient was satisfied with the results.

Dr. Burkhart is clinical professor of dermatology at the University of Toledo College  of Medicine in Ohio and clinical assistant professor of dermatology at Ohio University College of Osteopathic Medicine, in Athens. He has no relationships to disclose relating to the content of this article.

References

  1. Burkhart CG, Burkhart CN. Propionibacterium acnes: an indigenous bacterium may be pathogenic in several cutaneous disease states. Arch Dermatol. 2001:137:1250.
  2. Landers MC, Skokan M, Law S. Storrs F. Cutaneous and pulmonary sarcoidosis in association with tattoos. Cutis. 2005;75:44-48.
  3. Evans AV, Atherton DJ. Recalcitrant ulcers in necrobiosis lipoidica diabeticorum healed by topical granulocyte-macrophage colony-stimulating factor. Br J Dermatol. 2002;147:1023-1025.