Clinical Reference / Therapeutic Strategies / Necrobiosis Lipoidica Diabeticorum

Necrobiosis Lipoidica Diabeticorum


Key Points

  • Necrobiosis lipoidica is an uncommon granulomatous disease that presents with symmetrical yellow/orange-brown atrophic thin plaques with telangiectasias on the anterior shins.
  • Necrobiosis lipoidica occurs uncommonly in patients with diabetes, but when observed it should be viewed as a sign of end-organ damage.
  • Patients with necrobiosis are at high risk of developing complex leg ulcers and the disease is a therapeutic challenge.

Introduction

Necrobiosis lipoidica diabeticorum, also referred to as simply necrobiosis lipoidica (NL), is a rare granulomatous disease of the skin that is fairly consistent in its clinical manifestations. Most patients present with symmetric, distinctive, yellow-brown, slightly atrophic patches on the anterior shins. Early onset lesions may be red-brown or violaceous small papules, nodules or thin plaques, but in most patients the lesions run together and become the standard confluent patches. Over time, as the disease progresses the atrophic nature may become more pronounced with visible telangiectatic vessels, and approximately one-third of patients will develop ulceration within the lesions, which can be devastating.

NL seems to occur more frequently in women than in men (3:1 ratio in small studies), and typically occurs in younger patients at ages between the mid-20s and mid-40s. NL occurs most often in association with diabetes mellitus (thus the historical term “necrobiosis lipoidica diabeticorum”), however it remains a very rare skin manifestation in diabetes, occurring in 0.3-1.2% of patients with diabetes. There is a wide range of data regarding the rates of its association with diabetes, with reports that reveal 11-65% of patients with NL have diabetes; notably, the diagnosis of NL may precede a diagnosis of diabetes. When NL occurs in patients with diabetes, it should be viewed as a sign of end-organ damage.  Diabetic patients with NL are more likely to have retinopathy, nephropathy, and neuropathy due to diabetes, and it is postulated that NL may develop as a result of endovascular damage in these patients. Notably, improved glycemic control and reductions in hemoglobin A1c (HbA1c) are not associated with clinical improvements in lesions of NL.  The etiology of NL remains unclear. The observation of NL in the setting of diabetic patients with end-organ damage has lent credence to the hypothesis that NL represents a skin manifestation of tissue injury due to microvascular damage and potentially abnormal tissue repair function, but the true etiopathogenesis remains elusive.

Clinically patients with NL often present with asymptomatic, well-demarcated yellowish thin, atrophic plaques symmetrically on the anterior shins. The rim of the lesions may have an erythematous-to-violaceous hue. Ectopic NL may occur on the scalp, trunk, upper extremities, or genitalia, but is very uncommon. As lesions persist they usually develop more prominent atrophy and telangiectasias, followed by ulceration in one-third of cases. As with other granulomatous lesions, trauma may play a role in inducing or exacerbating lesions, and koebnerization (extension or development of lesions in response to trauma) has been reported with NL.  Additionally, trauma may precipitate ulceration within previously stable lesions.

The diagnosis is usually made based on the distinctive clinical appearance; biopsy is often not performed but not required. One of the main challenges in managing these patients is that once they have developed ulceration, a biopsy may fail to heal and leads to a chronic wound. On biopsy of NL lesions, the pathology is often squared-off, due to the altered collagen and inflammation. The dermis is filled with alternating bands of inflammatory cells and altered, “necrobiotic” collagen, which appears as homogenized pink bands. The inflammatory component may have palisades of histiocytes and giant cells; plasma cells are often noted near the deeper component. The alternating bands of inflammation and pauci-inflammatory altered collagen have been described as “cake-layering,” and give biopsies of NL a distinctive histological look.

Treatment of NL is challenging, and there is a paucity of high quality data to help guide therapeutic decision-making.  As trauma can cause existing lesions to ulcerate (and perhaps cause extension or development of new lesions), protecting the shins is important and simple. Some have advised investment in shin guards for patients (such as used by field hockey players), especially those with prior ulcerations or severely atrophic, fragile lesions. The initial medical therapy is generally high potency topical corticosteroids applied with occlusion, followed by careful use of intralesional corticosteroid injections.  While steroids can thin the skin, in most cases of NL, halting the active inflammatory process is of more benefit than the risk of steroid-related skin atrophy. Systemic therapeutic options all have very limited evidence to guide their use. PUVA photochemotherapy has been reported as beneficial.

Hydroxychloroquine and other antimalarial agents have been utilized in many granulomatous skin conditions with good results, and case reports support their use in treating NL. Systemic corticosteroids may be used, particularly in ulcerated / severe cases, but tight glycemic control is particularly important in this setting.  Pentoxifylline is used to treat leg ulcers and has a mild anti-inflammatory effect that may help with granulomatous inflammation, and has been reported as beneficial in a case report. Other anti-inflammatory / immunosuppressive agents, particularly the TNF inhibitors, which have been described as beneficial in a number of recent case reports, may be indicated for severe cases. Regardless of the therapy used, if the patient has ulcerations, wound care is an important component of management. Patients with lower leg ulcers require complex, multidisciplinary and multifactorial care, and leg ulcers in the setting of NL have an added degree of difficulty. Mainstays include standard approaches such as maintaining a clean wound free of biofilm or colonization, optimizing the patient’s fluid and nutrition status, and employing gentle compression and calf-pump exercises to prevent lower extremity edema and swelling.

Initial Evaluation

Differential diagnosis

Lyme disease

Tinea/Dermatophytosis

Psoriasis

Allergic contact dermatitis


Cellulitis / Erysipelas

Granuloma annulare

Treatment

First-line therapy: High potency topical steroids, often applied under occlusion, are utilized initially in most cases.

First steps

  • Topical corticosteroids (clobetasol 0.05% ointment) often under occlusion (with plastic wrap, for instance), or medication-impregnated steroid tape (flurandrenolide tape) applied over the lesions.
  • Intralesional triamcinolone injections (strength varying based on degree of atrophy/ulceration, generally starting with 10-20 mg/mL, up to 40 mg/mL).

Subsequent steps

  • If there is concern for atrophy/skin thinning from the topical steroids, alternate with nonsteroidal/steroid-sparing topicals such as topical tacrolimus (tacrolimus 0.1% or 0.03% ointment) or topical retinoids (tretinoin 0.1% cream) may be used in place of or in addition to steroids.
  • Patients who fail to respond to topical therapy should be referred to an experienced dermatologist.
  • Recalcitrant disease may be approached with antimalarial therapy (hydroxychloroquine 200 mg twice a day / up to 6.5 mg/kg/day dosing) or phototherapy (PUVA three times a week).
  • Alternate options include pentoxifylline 400 mg three times daily or tetracycline-class antibiotics.
  • Severe cases may warrant treatment with systemic immunosuppressive agents such as systemic corticosteroids.
  • Patients with the most severe disease may be candidates for treatment with TNFα inhibitors, particularly infliximab or adalimumab, but data on their use is just emerging and it is essential to weigh the risks and benefits.

Pitfalls

  • Necrobiosis lipoidica can look clinically and histologically identical to ulcerative lesions of cutaneous sarcoidosis. Sarcoidosis rarely presents with ulcerations, but it is worth considering whether patients truly have isolated NL, or whether the skin lesions observed are a cutaneous sign of multiorgan sarcoidosis. If patients have ocular inflammation or pulmonary symptoms, it is worth evaluating them for sarcoidosis.
  • Ulcerated NL can be a management challenge. Patients with diabetes and leg ulcers have a hard time healing typical wounds, and if there is concomitant active granulomatous inflammation from NL, healing may be nearly impossible. Chronic ulcers are then at risk for superinfection, and in patients with impaired circulation and/or impaired sensation from diabetes, there may be a risk for developing osteomyelitis. This should be considered prior to utilizing systemic immunosuppressive agents to treat NL.

Clinical Case

Case 1

  • 48-year-old man
  • Past medical history is notable for diabetes mellitus, with a last HbA1c of 7.7 (elevated)
  • Review of systems reveals no other complaints, including no joint pain, fevers, arthritis, eye symptoms, or recent illness
  • Social history is unremarkable
  • Presents for evaluation of an asymptomatic leg rash which started as a few discrete reddish thin papules and gradually expanded to large patches over the anterior shins bilaterally

Initial evaluation

  • Healthy appearing male
  • Yellow-orange slightly atrophic patches on the anterior shins
  • He has slightly decreased sensation to monofilament testing on the soles of the feet bilaterally

Diagnosis: Necrobiosis lipoidica—and other signs of diabetic end-organ damage (neuropathy)

  • Attempt a KOH scraping to evaluate for presence of dermatophyte infestation (ruling out tinea)
  • Review optimal diabetic care, including diet and exercise, with the patient
  • Adjust his diabetes medications for tighter glycemic control
  • Perform a formal evaluation for neuropathy, creatinine, urine protein/creatinine ratio, and ophthalmological evaluation for signs of diabetic end-organ damage
  • Initiate treatment with high potency topical corticosteroids

Follow-up evaluation

  • The patient reports no improvement with topical corticosteroids
  • Refer to an experienced dermatologist

References

Basoulis D, Fragiadaki K, Tentolouris N, et al. (2016). Anti-TNFα treatment for recalcitrant ulcerative necrobiosis lipoidica diabeticorum: a case report and review of the literature. Metabolism, 65(4): 569-573.

Binamer Y, Sowerby L, El-Helou T. (2012). Treatment of ulcerative necrobiosis lipoidica with topical calcineurin inhibitor: case report and literature review. J Cutan Med Surg, 16(6): 458-461.

Erfurt-Berge C, Dissemond J, Schwede K, et al. (2015). Updated results of 100 patients on clinical features and therapeutic options in necrobiosis lipoidica in a retrospective multicenter study. Eur J Dermatol, 25(6): 595-601.

Feily A, Mehraban S. (2015). Treatment modalities of necrobiosis lipoidica: a concise systematic review. Dermatol Reports, 7(2): 5749.

Peckruhn M, Tittelbach J, Elsner P. (2017). Update: treatment of necrobiosis lipoidica. J Dtsch Dermatol Ges, 15(2): 151-157.

Reid SD, Ladizinski B, Lee K, et al. (2013). Update on necrobiosis lipoidica: a review of etiology, diagnosis, and treatment options. J Am Acad Dermatol, 69(5): 783-791.

Sibbald C, Reid S, Alavi A. (2015). Necrobiosis lipoidica. Dermatol Clin, 33(3): 343-360.