Necrobiosis Lipoidica

Key points

Etiopathogenesis

The cause and pathogenesis of this disease is not well understood, but many theories have been presented. According to published literature, with small center studies, there is a predominance in females affected by the disease.2, 4, 5, 6, 7 A study performed by Erfurt-Berge and colleagues⁵ in 52 patients with NL found 77% of those affected to be female. This statistic coincides with previous studies that reported a female predominance. Another interesting correlation seen in small trials is

Clinical and histologic presentation

NL is a rare granulomatous disease that generally has an average age of onset between 30 and 40 years of age; but many factors can alter this age of onset allowing it to present at any age, including birth.² The lesions are commonly seen on the bilateral lower extremities, particularly the pretibial surface; however, case reports have identified atypical presentation of lesions on the face, penis, trunk, scalp, and upper extremities. They begin as asymptomatic papules and nodules that erode, in

Systemic associations

NL has been seen in conjunction with multiple systemic diseases, including sarcoidosis, autoimmune thyroiditis, inflammatory bowel disease, ulcerative colitis, and rheumatoid arthritis.³⁷ The association with autoimmune disorders, including type 1 diabetes, allows the theory of immune dysregulation to play a more convincing role in the pathogenesis. The true association of NL with these diseases is difficult to determine as most of the literature is guided by case studies.

The most common

Evaluation and management

Although the diagnosis is often made based on clinical examination, biopsy should be performed to differentiate NL from conditions with similar clinical appearances, including granuloma annulare, and NXG. Biopsies should be repeated in cases of nonhealing ulcerated NL to rule out squamous cell carcinoma. Bakos and colleagues⁴⁵ reported the presence of arborizing telangiectasias, hairpin vessels, and a yellowish background as suggestive findings in early onset NL.⁴⁶

If there is concern for venous

Corticosteroids

Topical, intralesional, and systemic corticosteroids have traditionally been used as the first-line treatement.54, 55, 56 Topical steroids decreased inflammation of active lesions. Intralesional and systemic steroids can rapidly halt progression and produce resolution of lesions in most patients.⁵⁵ Their efficacy most likely lies in their antiinflammatory properties based on these observations. Most patients treated effectively with steroids have nonulcerated lesions as the efficacy of

Ultraviolet light therapy

Phototherapy is used for various inflammatory dermatoses; psoralen-UV-A (PUVA) achieves its effects at the dermal-subdermal junction, where inflammation is evident in NL. In localized applications to lesions, it decreases the active inflamed borders and helps resolve lesions but has no clinical effects on atrophic areas. This finding is supported by a lack of change in ultrasound-determined lesion thickness of atrophic areas in treated lesions.⁷

UVA-1, which supplies a higher proportion of

Immunomodulator

Calcineurin inhibitors inhibit T-cell activation by blocking calcineurin and, thus, the production of cytokines, including interleukin 2 (IL-2) by T-helper cells and clonal T-cell proliferation, resulting in both antiinflammatory and immunomodulator effects. Topical tacrolimus has been shown to be effective in resolving ulceration associated with NL.59, 60, 61, 62 Efficacy is variable in NL plaques without ulceration present with the best response seen in early inflammatory stages. The improved

Biologics

TNF is an important regulator in the formation of granulomas. The monoclonal antibodies adalimumab and infliximab bind directly to soluble TNF alpha to prevent its action. The fusion protein etanercept is a fusion protein consisting of the Fc portion of human IgG1 and TNF receptors that also inhibit soluble TNF function. Both etanercept and infliximab have been repeatedly effective as monotherapy for ulcerating NL.70, 71, 72, 73, 74, 75, 76 From the limited experience, infliximab may produce

Antimalarial

Hydroxychloroquine and chloroquine have antiinflammatory actions and inhibit macrophage chemotaxis, which may prevent further granuloma production in NL. Chloroquine additionally inhibits platelet aggregation by blocking conversion of arachidonic acid to prostaglandins, decreasing the risk of occlusion of cutaneous blood vessels. These mechanisms may explain the response of NL to hydroxychloroquine and chloroquine.77, 78 Effects take 1 to 3 months to be fully realized, and long-term data are

Fumaric acid esters

Fumaric acid esters inhibit inflammatory cytokines and prevent T lymphocyte proliferation. They have been quite effective in case reports and series, leading to complete resolution or healing of NL in patients continuing treatment for 6 months.79, 80, 81 Unfortunately, they are not currently available in the United States or Canada and can be poorly tolerated because of dose-related nausea. The dose used in NL has been the same as traditionally used for psoriasis, starting with 30 mg of

Cutaneous blood flow modulators

Medications targeting the thrombosis in cutaneous blood vessels seen in NL were among the first to be tried but seem to have limited success as monotherapy. Aspirin and dipyridamole inhibit platelet aggregation and decrease blood viscosity. Results are conflicting, with healing of ulcerated NL lesions observed in all 7 patients in 1 case series but not in a subsequent randomized trial compared with placebo.83, 84 Very-low-dose aspirin seemed to have no effect as monotherapy.⁸⁵

Pentoxifylline has

Miscellaneous

Various other treatments have been successful in case reports. Intravenous immunoglobulin (IVIG) has been used to treat a variety inflammatory and granulomatous disorders. IVIG was useful in 2 patients, but 1 patient had an underlying immunoglobulin deficiency and the other patient required addition of corticosteroids for final healing.88, 89 It is, therefore, not likely to be useful as a first-line agent in the absence of a known deficiency. The use of topical tretinoin led to improvement of

Summary

NL is often indolent, and the decision on the treatment is individualized and based on patients’ concerns. There is no gold standard treatment of NL, due to an incomplete understanding of the pathogenesis. The most common treatments of NL are potent topical steroids and calcineurin inhibitors. Physical therapies and immunomodulators are beneficial in some cases. Ulceration is a common complication, and patients need to be monitored for less common sequelae like transition to malignancy.