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Necrobiosis lipoidica

Necrobiosis lipoidica
Authors:
Karolyn Wanat, MD
Misha Rosenbach, MD
Section Editor:
Jeffrey Callen, MD, FACP, FAAD
Deputy Editor:
Abena O Ofori, MD
Literature review current through: Jul 2022. | This topic last updated: Oct 14, 2020.

INTRODUCTION — Necrobiosis lipoidica is a rare, chronic granulomatous disease of the skin. Skin involvement usually begins as red-brown or violaceous papules, plaques, or nodules and rapidly progresses to yellow-brown, atrophic, telangiectatic plaques (picture 1A-E). The lower legs, especially the shins, are by far the most common sites of involvement. Ulceration is a common complication, occurring in 10 to 20 percent of patients (picture 1F).

Necrobiosis lipoidica frequently occurs in association with diabetes mellitus, which accounts for the past use of the term "necrobiosis lipoidica diabeticorum" for this disease. The recognition that necrobiosis lipoidica also occurs in the absence of diabetes led to the change in terminology.

The treatment of necrobiosis lipoidica can be challenging. Topical or intralesional administration of corticosteroids is often used as initial therapy.

The clinical manifestations, diagnosis, and management of necrobiosis lipoidica will be reviewed here.

EPIDEMIOLOGY — Necrobiosis lipoidica is a rare disorder that primarily affects young and middle-aged adults but can also occur in children and older adults. In a retrospective study of 171 patients with necrobiosis lipoidica, the average age of onset for patients with diabetes-associated necrobiosis lipoidica was 25 years, and the average age of onset for patients with non-diabetes-associated necrobiosis lipoidica was 46 years [1]. In a separate, retrospective, multicenter study of 236 patients, the mean age at the time of presentation was 45 years for patients with diabetes and 52 years for patients without diabetes [2].

Necrobiosis lipoidica occurs more frequently in women than in men. The largest retrospective studies suggest that females are more commonly affected than males, with a female-to-male ratio ranging from around 3:1 to up to 8:1 [1-4]. The reason for this discrepancy is unclear.

ASSOCIATED DISORDERS — Concurrent type 1 or type 2 diabetes mellitus is common, but not ubiquitous, in patients with necrobiosis lipoidica. The reported prevalences of diabetes in this population vary widely, ranging from 11 to 65 percent [1,5-7]. Necrobiosis lipoidica may also precede a diagnosis of diabetes [1,6]. In a study in which 16 percent of 65 patients with necrobiosis lipoidica met criteria for diabetes or had impaired glucose tolerance at the time of diagnosis, five-year follow-up data on 42 patients who initially were not diabetic and had normal glucose tolerance revealed that 7 percent developed diabetes or abnormal glucose tolerance within five years [6].  

However, among all individuals with diabetes, necrobiosis lipoidica is relatively rare. Estimates of the prevalence of necrobiosis lipoidica among diabetic patients range from 0.3 to 1.2 percent [1,6,8,9]. Necrobiosis lipoidica may be particularly rare among diabetic children; a Scottish study in which health care providers for children with diabetes completed a questionnaire about skin conditions found that only 1 of 1557 children (0.06 percent) had a dermatologist-confirmed diagnosis of necrobiosis lipoidica [10].

Whether necrobiosis lipoidica is a marker of the severity or prognosis of diabetes mellitus is unclear. In a study of over 64,000 patients with type 1 diabetes mellitus from multiple centers, the presence of necrobiosis lipoidica correlated with higher daily insulin requirements [4]. Further study is necessary to clarify whether diabetic patients with necrobiosis lipoidica are at increased risk for renal and retinal complications of diabetes [11,12].

The findings of retrospective studies suggest an association between necrobiosis lipoidica and thyroid disease. A German, multicenter, retrospective study of 100 patients with necrobiosis lipoidica found that 15 percent had thyroid disorders compared with an estimated 5.5 percent in the general population [3]. In another multicenter, retrospective study of 236 patients with necrobiosis lipoidica, 25 percent had thyroid disease [2].  

Further support for an association with thyroid disease was demonstrated in a large retrospective review where 25 percent of patients with type 1 diabetes mellitus and necrobiosis lipoidica had elevated thyroid antibodies, compared with 18 percent of patients with type 1 diabetes mellitus alone [4]. In addition, those patients with necrobiosis lipoidica and type 1 diabetes had an overall increase in risk for celiac disease compared with patients with type 1 diabetes alone (3 versus 1 percent) [4].

Additional studies are necessary to confirm an association between necrobiosis lipoidica and thyroid disease or celiac disease. Other reported associations include hypertension, obesity, chronic heart failure, and dyslipidemias [13].

PATHOGENESIS — The pathogenesis of necrobiosis lipoidica is unclear. The association with diabetes mellitus has contributed to the theory that microangiopathy secondary to deposition of glycoprotein in blood vessel walls may play a role [14,15]. In support of this, lower oxygen tensions within sites of necrobiosis lipoidica have been reported [16]. However, the validity of this theory was brought into question by a Doppler flowmetry study that found increased blood flow in sites of necrobiosis lipoidica compared with uninvolved skin [17].

Examples of other theories for the pathogenesis of necrobiosis lipoidica include proposals that the disease develops as a consequence of abnormalities of collagen [18-20], impaired neutrophil migration [21], or tissue damage secondary to hyperlipidemia or venous reflux [22]. Further study may help to elucidate the pathogenesis of this disease.

CLINICAL MANIFESTATIONS — Necrobiosis lipoidica usually begins as asymptomatic, well-circumscribed, yellow to pink-brown or red-brown, slightly elevated papules or plaques (picture 2). Erythema or a violaceous skin color may be present at the periphery. Necrobiosis lipoidica is most often found on the pretibial area but can involve the scalp, face, trunk, genitals, or upper extremities [23-38]. In patients with other sites of involvement, the pretibial area is usually involved as well [2].

Over time, the papules or plaques flatten and form broad, yellow-orange patches or thin plaques (picture 1A-C). Atrophy and prominent telangiectasias can develop within the plaques, and the occurrence of erosions or ulceration is a common complication (picture 1D-F) [1,7]. In retrospective studies, approximately 15 to 33 percent of patients with necrobiosis lipoidica experienced ulceration [1,2,7]. Ulceration often followed minor trauma to the affected areas.

While most patients are asymptomatic, occasional patients experience pruritus or dysesthesia at the sites of skin involvement [39]. Pain may also occur, especially in patients with ulceration [14].

Necrobiosis lipoidica can demonstrate the Koebner phenomenon, also known as koebnerization [40-44]. Koebnerization is the development of new areas of skin disease at sites of skin trauma.

HISTOPATHOLOGY — The classic histologic finding of necrobiosis lipoidica is a palisaded and interstitial granulomatous dermatitis involving the dermis with extension into the subcutaneous tissue (picture 3A-C). Granulomas are composed of histiocytes and multinucleated giant cells. The palisaded granulomas are arranged in a horizontal layer, which is described as a "sandwich-like," "tiered cake-like", or "wedding cake-like" arrangement with intermixed layers of altered, homogenized, "necrobiotic" collagen. The amount of necrobiosis can be extensive or minimal.

An associated inflammatory infiltrate composed of lymphocytes, plasma cells, and occasional eosinophils also can be seen. Plasma cells may be clustered towards the deeper dermis or the dermal/subcutaneous junction. Lymphocytic aggregates, occasionally containing germinal centers, also may be present in the deep dermis or subcutaneous tissue in approximately 10 percent of cases [45]. The presence of mucin among other histopathologic features of necrobiosis lipoidica has been reported in association with autoimmune thyroiditis [46].

The duration of necrobiosis lipoidica can influence the histologic findings. Early lesions of necrobiosis lipoidica often exhibit more robust inflammation than is usually detected in later-stage disease. In addition, epidermal atrophy and dermal findings of collagen alteration and necrobiosis with areas of fibrosis tend to be more prominent in older lesions.  

DIAGNOSIS — The diagnosis of necrobiosis lipoidica is made based upon the clinical and histopathologic findings. Although the clinical features alone can be highly suggestive of necrobiosis lipoidica, a skin biopsy is important to confirm the diagnosis. There are no serologic tests that confirm a diagnosis of necrobiosis lipoidica.

Physical examination — A diagnosis of necrobiosis lipoidica is strongly suggested by the detection of one or more atrophic, yellow-orange patches or thin plaques on the pretibial skin, as these features are not typically seen in other granulomatous dermatoses. The clinical diagnosis can be more difficult in patients who present with the pink-brown or red-brown papules or plaques of early-stage necrobiosis lipoidica.

Skin biopsy — A 3 to 5 mm punch biopsy that extends into the subcutaneous fat is the preferred biopsy technique. The characteristic histologic features are often best seen in specimens taken from the edge of a lesion.

The diagnosis of necrobiosis lipoidica is strongly supported by the detection of a palisaded and interstitial granulomatous dermatitis that involves the dermis and extends into subcutaneous tissue, necrobiosis of collagen, and an associated inflammatory infiltrate of lymphocytes and plasma cells. However, when the biopsy findings are less classic, it can be difficult to distinguish necrobiosis lipoidica from other noninfectious granulomatous disorders, especially granuloma annulare, which also can present with a palisaded granulomatous dermatitis. A finding of significant mucin in the dermis favors granuloma annulare, as this is not typically seen in necrobiosis lipoidica. Necrobiotic xanthogranuloma is an additional granulomatous disorder that shares histologic features with necrobiosis lipoidica. However, unlike necrobiotic xanthogranuloma, cholesterol clefts are an infrequent finding in necrobiosis lipoidica [47]. (See 'Differential diagnosis' below.)

Dermoscopy — Several reports suggest that dermoscopy may be a helpful adjunctive tool for the diagnosis of necrobiosis lipoidica [48-52]. (See "Overview of dermoscopy".)

Examples of dermoscopic features of necrobiosis lipoidica that have been described in the literature include [48-50]:

Comma-shaped vessels (early lesions)

Irregular pattern of arborizing (branching) vessels (advanced lesions)

Whitish areas (may correspond with degenerated collagen)

Yellow to orange patches (may correspond with granulomatous inflammation)

Further study is necessary to determine the diagnostic value of dermoscopy in the evaluation for necrobiosis lipoidica.

ADDITIONAL EVALUATION — Many patients with necrobiosis lipoidica also have diabetes. Therefore, all patients with necrobiosis lipoidica who lack a preceding history of diabetes should be evaluated for diabetes at the time of diagnosis. (See 'Associated disorders' above and "Screening for type 2 diabetes mellitus".)

Given the possible association between necrobiosis lipoidica and thyroid disease [3], we inquire about signs or symptoms of thyroid dysfunction (eg, heat/cold intolerance, hair loss, dry skin, fatigue) and proceed with laboratory evaluation if the patient history or physical examination suggests the possibility of a thyroid disorder. (See "Laboratory assessment of thyroid function", section on 'Evaluating for thyroid dysfunction'.)

DIFFERENTIAL DIAGNOSIS — The primary disorders in the differential diagnosis of necrobiosis lipoidica consist of other granulomatous disorders involving the skin (eg, granuloma annulare, cutaneous sarcoidosis, necrobiotic xanthogranuloma) and skin conditions with a similar predilection for the lower legs (eg, pigmented purpuric dermatosis, stasis dermatitis). Clinical and pathologic examination is usually sufficient to distinguish necrobiosis lipoidica from other diseases:

Granuloma annulare – Granuloma annulare presents as violaceous or dusky, erythematous papules or annular plaques (picture 4A-C). Unlike necrobiosis lipoidica, yellow discoloration and telangiectasias typically are absent. Classic histologic findings of granuloma annulare include palisaded granulomas with mucin deposition. In contrast, mucin is often absent in necrobiosis lipoidica. There are rare reports of patients who have presented with both disorders [53]. (See "Granuloma annulare: Epidemiology, clinical manifestations, and diagnosis".)

Cutaneous sarcoidosis – Infrequently, cutaneous sarcoidosis may present with necrobiosis lipoidica-like skin lesions [54]. In such cases, the histologic findings are useful for distinguishing between these diseases. Large, well-formed, naked, epithelioid granulomas and absent necrobiosis support a diagnosis of sarcoidosis. Multisystem involvement (lung, eye, lymph nodes, etc) also favors a diagnosis of sarcoidosis. (See "Cutaneous manifestations of sarcoidosis".)

In addition, ulcerative sarcoidosis, a rare subtype of cutaneous sarcoidosis, can share many clinical and histologic features with necrobiosis lipoidica (picture 5) [55]. Patients may develop atrophic, orange-yellow patches at the periphery of the ulcer. In addition, a biopsy taken from the edge of an ulcerative sarcoidosis lesion may demonstrate histologic findings that resemble necrobiosis lipoidica. (See "Cutaneous manifestations of sarcoidosis", section on 'Atrophic and ulcerative sarcoidosis'.)

Necrobiotic xanthogranuloma – Necrobiotic xanthogranuloma, a disorder commonly associated with immunoglobulin G (IgG) monoclonal gammopathy, can present with yellow patches, plaques, or subcutaneous nodules [56]. Unlike necrobiosis lipoidica, necrobiotic xanthogranuloma often occurs in a periorbital distribution, a finding that is helpful for diagnosis. However, trunk and extremity involvement also can occur. Histopathologic findings that help to identify necrobiotic xanthogranuloma are the presence of larger zones of necrobiosis than are typically seen in necrobiosis lipoidica and cholesterol clefts. (See "Necrobiotic xanthogranuloma".)

Pigmented purpuric dermatosis – Pigmented purpuric dermatosis is a benign cutaneous eruption that, like necrobiosis lipoidica, often presents on the anterior lower legs. The classic clinical findings of petechiae, purpura, and brown discoloration distinguish pigmented purpuric dermatosis from necrobiosis lipoidica. (See "Pigmented purpuric dermatoses (capillaritis)".)

Stasis dermatitis – Stasis dermatitis is an inflammatory skin condition that most often occurs on the lower legs in the setting of chronic venous insufficiency. Stasis dermatitis may present with red to yellowish-brown patches and pitting edema. Clinical and histopathologic features differentiate this disease. (See "Stasis dermatitis".)

TREATMENT — Multiple therapies have been used for necrobiotic lipoidica with inconsistent results. Most data on treatment are derived from case reports, case series, or small uncontrolled studies. High-quality trials to confirm the efficacy of individual therapies are lacking.

Approach to treatment — There is no cure for necrobiosis lipoidica; thus, treatment focuses on management of signs and symptoms of the disease by inhibiting the inflammatory process and healing ulcerations. As a result of the paucity of data to guide evidence-based recommendations for the treatment of necrobiosis lipoidica, uncertainty remains about the best approach to treatment.

Nonulcerated necrobiosis is often asymptomatic and may stabilize over time; thus, deferring treatment is an option. However, many patients desire to proceed with therapy because of the often prolonged course of the disease and the disfiguring nature of the skin lesions. Periodic clinical surveillance for complications of necrobiosis lipoidica, such as ulceration and squamous cell carcinoma, should be performed regardless of whether patients undergo treatment. (See 'Prognosis' below and 'Follow-up' below.)

Our initial therapeutic choice for nonulcerated necrobiosis lipoidica is typically topical treatment with a high-potency topical corticosteroid applied under occlusion. If the response to this treatment is insufficient, our next treatment is usually a trial of intralesional corticosteroid therapy. (See 'First-line treatment' below.)

A variety of other therapeutic options are available for patients who fail local corticosteroid therapy treatment and still desire attempts at therapy. However, patients must be aware that the response to treatment is unpredictable, and the clinician should carefully consider the risk-benefit ratio for treatment. (See 'Other therapies' below.)

Improving control of diabetes mellitus does not appear to affect the course of necrobiosis lipoidica, though high-quality studies to confirm this are lacking [14]. Based upon the other beneficial effects of proper management of diabetes, we encourage all patients with diabetes to optimize control of this disease.

Nonulcerated necrobiosis lipoidica — The goals of treatment of nonulcerated necrobiosis lipoidica are to reduce the risk for ulceration and control active inflammation to improve the appearance of skin lesions.

First-line treatment — Our initial interventions for nonulcerated necrobiosis lipoidica consist of counseling to reduce the risk for ulceration and, if treatment is desired, local administration of corticosteroids to sites of active inflammation. Most often, we begin pharmacologic therapy with a high-potency topical corticosteroid applied under occlusion, particularly for patients with the papules or plaques that characterize early lesions. We find intralesional corticosteroid therapy a useful alternative when we want to concentrate corticosteroid therapy in a precise area (eg, site of inflammation adjacent to an area of prominent atrophy). We also find intralesional corticosteroid useful for the treatment of some topical corticosteroid-resistant lesions.

Avoidance of trauma — The most common complication of necrobiosis lipoidica is ulceration. Once formed, ulcers often heal slowly and can be difficult to treat. In an attempt to reduce the risk for ulceration, we encourage patients to avoid trauma to affected areas. In severe or extensive cases, this may include daily use of thick, padded, protective shin-wear, such as the shin-wear worn by field hockey players. We also encourage patients to moisturize atrophic areas daily to reduce the risk of skin breakdown. (See 'Clinical manifestations' above.)

Topical corticosteroids — Topical corticosteroids are commonly prescribed for the treatment of necrobiosis lipoidica. However, the use of these agents is primarily based upon clinical experience, as there are few data to support their efficacy [57]. In one retrospective review of 65 patients with necrobiosis lipoidica, among the 22 patients treated with potent topical corticosteroids (regimen not specified), one-third had documented improvement [6]. In addition, a case report documents treatment of the upper one-third of an area of necrobiosis lipoidica on a patient's shin with topical clobetasol applied under occlusion nightly for three weeks resulting in thinning and softening of the treated area [57]. Subsequent treatment of the entire affected area on the patient's shin for an additional three weeks resulted in similar results. Recurrence was not evident at a follow-up visit three months after treatment.

We typically prescribe a high-potency topical corticosteroid (eg, clobetasol 0.05% cream or ointment (table 1)) and instruct the patient to apply the medication to areas of active inflammation (ie, sites of erythema or elevated papules or plaques) under an occlusive dressing (eg, plastic wrap or hydrocolloid dressing) nightly for three to four weeks. We instruct patients to avoid areas of skin atrophy. After this time period, we re-evaluate the site for the response to treatment. A response to treatment is indicated by a reduction in erythema and flattening of the treated lesions.

If a complete response is obtained (erythema resolved and lesion completely flattened), we reduce the frequency of treatment to application on two consecutive days per week (eg, weekends) for one month. Provided relapse does not occur by the end of this period, we discontinue treatment.

If a patient has only a partial response to topical corticosteroid treatment after the initial three- to four-week treatment cycle, we proceed with an additional month of treatment with a potent topical corticosteroid without occlusion, attempt intralesional corticosteroid treatment, or try other treatments.

Because atrophy is a manifestation of necrobiosis lipoidica that can also be induced by corticosteroid therapy and may contribute to ulceration, close follow-up during topical steroid therapy is essential to prevent the development of corticosteroid-induced atrophy. The adverse effects of topical corticosteroid therapy are reviewed in greater detail separately. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

Intralesional corticosteroids — Intralesional corticosteroid therapy is a common treatment for necrobiosis lipoidica. Similar to topical corticosteroids, there are few data on efficacy. Among eight patients who received treatment with intralesional triamcinolone (regimen unspecified) in a retrospective review of 65 patients with necrobiosis lipoidica, four had clearance or great improvement of the cutaneous lesions [6]. In an uncontrolled study, a series of intralesional injections of triamcinolone acetonide (5 mg/mL) using a needleless jet injector was associated with gradual resolution of necrobiosis lipoidica in three of five patients and partial improvement in one patient [58]. None of the three patients who achieved resolution demonstrated recurrences within follow-up periods of 1 to 12 months.

When treating with intralesional corticosteroids, we typically use triamcinolone acetonide at a concentration of 5 to 10 mg/mL. We avoid injecting areas of atrophy due to concern about a risk for promoting ulceration, and in lesions with atrophic centers, we limit injections to the inflamed peripheral border of the lesions to avoid the atrophic areas. Individual injections are placed approximately 1 cm apart, with approximately 0.1 cc injected at each injection point. We limit the total dose administered per treatment session to no more than 40 mg.  

We re-evaluate the treated site after approximately six weeks for resolution of erythema and flattening of previously raised papules or plaques. If only a partial response is achieved and corticosteroid-induced atrophy is not evident, we repeat treatment. If no response is evident after two to three treatment sessions, we discontinue intralesional corticosteroid therapy.

There is some discomfort associated with intralesional corticosteroid injections. Similar to topical corticosteroids, cutaneous atrophy and hypopigmentation are potential adverse effects. It is worth noting that in the study in which a needleless jet injector was used to inject triamcinolone acetonide, one patient developed multiple small ulcers at injection sites that healed spontaneously within three months and did not recur with subsequent injections [58]. The adverse effects of intralesional corticosteroid therapy are reviewed separately. (See "Intralesional corticosteroid injection", section on 'Side effects, complications, and pitfalls'.)

Other therapies — For patients with nonulcerated necrobiosis lipoidica who cannot be managed adequately with local corticosteroids but still desire treatment, other interventions, such as topical tacrolimus, topical psoralen plus ultraviolet A (PUVA) photochemotherapy, systemic medications, and procedural therapies, may be beneficial. Data to support the efficacy of these interventions are limited and insufficient for conclusions on the comparative efficacy of treatments. We favor generally well-tolerated therapies, including topical tacrolimus, PUVA photochemotherapy, and oral antimalarials as next-line therapies. PUVA is the most studied of these treatments. Newer data suggest that photodynamic therapy (PDT) may be effective for necrobiosis lipoidica. Fumaric acid esters are also reported to improve necrobiosis lipoidica but are not available in the United States:

Topical tacrolimus – Case reports document improvement in necrobiosis lipoidica during treatment with tacrolimus 0.1% ointment [59-62]. As an example, in a case report, twice-daily application for eight weeks and once-daily application for eight weeks led to significant improvement in nonulcerated necrobiosis lipoidica on the arm and lower leg [59]. In a case series, twice-daily application of tacrolimus 0.1% ointment for eight weeks to nonulcerated necrobiosis lipoidica in two patients was followed by a considerable reduction in clinical inflammation in one patient and a more modest reduction of inflammation in the other patient [60].

PUVA photochemotherapy Several prospective uncontrolled studies suggest a beneficial effect of topical PUVA photochemotherapy, with partial improvement observed in 50 percent or more of treated patients [63-66]. In one of the largest prospective studies, 30 patients who previously failed local corticosteroid therapy were treated with topical PUVA twice weekly for as long as improvement continued. The mean number of treatments given was 20 (range 5 to 42) [63]. At the end of the study, 16 patients (53 percent) had improvement in ulceration or erythema, including five patients (17 percent) who achieved complete resolution of ulceration and erythema after a mean of 22 exposures (range 15 to 30). PUVA treatment did not have an effect on atrophy.

The long-term efficacy of topical PUVA was evaluated in a prospective study of 10 women with nonulcerated necrobiosis lipoidica who were treated with topical PUVA three times weekly and had follow-up periods of 12 to 24 months [64]. It is worth noting that five patients also received oral pentoxifylline (800 mg per day). All 10 patients achieved almost complete remission (softening of skin lesions, absence of hyperpigmentation, absence of lesion progression) after a mean of 47 treatment sessions. Two patients with insulin-dependent diabetes-associated necrobiosis lipoidica experienced recurrences at 8 and 12 months after treatment. The recurrences responded to reinitiation of PUVA treatment.

Treatment regimens for PUVA for necrobiosis lipoidica have varied, with frequencies ranging from one to three times per week seeming effective in uncontrolled studies. We usually administer topical PUVA two to three times per week. Typically, a topical form of 8-methoxypsoralen is applied directly to the lesions followed by exposure of the skin to ultraviolet A (UVA) light. The dose of PUVA is titrated upward as tolerated. Erythema, hyperpigmentation, and blistering are potential side effects of topical PUVA therapy. (See "Psoralen plus ultraviolet A (PUVA) photochemotherapy", section on 'Topical PUVA'.)

Antimalarials – A few reports document improvement in necrobiosis lipoidica during treatment with hydroxychloroquine or chloroquine [67,68]. In a review of eight consecutive women treated for necrobiosis lipoidica with chloroquine (200 mg per day) or hydroxychloroquine (400 mg per day) for 2 to 12 months (all but one without ulceration), seven demonstrated clinical improvement (improvement in erythema, skin infiltration, lesion spread) within the first six months of therapy [68]. Four patients had failed previous treatment with topical corticosteroids. Relapses may occur after the discontinuation of therapy.

Photodynamic therapy – Variable responses have been obtained with photodynamic therapy (PDT) for nonulcerated or ulcerated necrobiosis lipoidica [69-74]. In a retrospective study of 18 patients with necrobiosis lipoidica (including four patients with partially ulcerated lesions), multiple cycles of PDT with methyl aminolevulinate and red light or 5-aminolevulinic acid and red light was associated with a complete response in 1 patient, partial response in 6 patients, and no response in 11 patients [71]. The complete responder and two of the partial responders had ulcerated necrobiosis lipoidica. In a retrospective review of 65 patients (80 total treatments), the use of PDT with curettage and application of 16% methyl aminolevulinate followed by red light or daylight exposure resulted in improvement in necrobiosis lipoidica. A total cure was observed in 66 percent of all treatment series, with a 64 percent cure rate with conventional PDT and 80 percent with daylight PDT [74].

Fumaric acid esters Fumaric acid esters may be of benefit in necrobiosis lipoidica [75-77]. A prospective uncontrolled study in which 18 patients were treated with oral fumaric acid esters for at least six months after failing other treatments offers support for fumaric acid ester treatment [75]. Among the 15 patients who completed the study, all improved, exhibiting marked reductions of active disease. In addition, the four patients with ulcerated lesions experienced complete healing of ulcerations. Side effects included nausea, gastrointestinal effects, flushing, and moderate lymphocytopenia. Fumaric acid esters are not available in the United States.

Other – Concern about a role for angiopathy in the pathogenesis of necrobiosis lipoidica led to investigation of the efficacy of antiplatelet therapies, such as aspirin, dipyridamole, and ticlopidine, for necrobiosis lipoidica. Although improvement of ulcerated or nonulcerated necrobiosis lipoidica with these agents has been reported anecdotally [78,79], a small randomized trial did not support efficacy of combination aspirin and dipyridamole therapy [80]. A small randomized trial that evaluated treatment with aspirin without dipyridamole also did not find benefit of this therapy [81].

Infrequently, systemic glucocorticoids are used for attaining control of necrobiosis lipoidica. Treatment of six patients with nonulcerated necrobiosis lipoidica with oral 6-methylprednisolone (1 mg/kg per day for one week and 40 mg per day for four weeks followed by a rapid taper to treatment cessation over two weeks) was associated with dramatic improvement within the first few weeks of treatment [82]. Clinical signs of erythema and granulomatous infiltration resolved completely in all patients, and no recurrences were observed during follow-up periods of 4 to 10 months. A case report also documents a dramatic response during systemic glucocorticoid treatment [83]. Systemic glucocorticoid therapy may increase blood glucose levels and should be used with caution in patients with diabetes mellitus.

Other treatments that have been reported to be useful for necrobiosis lipoidica in small numbers of patients include topical tretinoin [84,85], pentoxifylline [86], clofazimine [87], fibrinolytic agents [88], pioglitazone, ultraviolet A1 (UVA1) phototherapy (with a report demonstrating 31 percent of patients with beneficial outcome) [89,90], biologic tumor necrosis factor (TNF)-alpha inhibitors [91,92], and lasers, including both pulsed dye laser [93,94] and fractional carbon dioxide laser therapy [95,96].  

Ulcers — The treatment of ulcerated necrobiosis lipoidica can be challenging. Treatment typically involves wound care measures, treatment of the underlying necrobiosis lipoidica, and pain control (when needed). The best approach to treatment is unclear.

Wound care — Wound care is an important part of the management of ulcers in necrobiosis lipoidica. In addition to employing basic principles of wound care, we aim to facilitate wound healing by minimizing exposure to factors that may inhibit wound healing, such as malnutrition and lower extremity edema. Compression stockings and leg elevation can aid in the management of lower extremity edema. (See "Basic principles of wound healing" and "Basic principles of wound management".)

Therapeutic interventions — Data on therapies to heal necrobiosis lipoidica ulcers are limited. Examples of local therapies that have been linked to improvement in ulcerations in small numbers of patients include topical tacrolimus [97-100], bovine collagen [101], PUVA photochemotherapy [63], mesh graft transplants and PUVA [102], UVA1 phototherapy [103], PDT [71], hyperbaric oxygen [104,105], intralesional infliximab [106], and surgical excision [107]. If surgical excision is performed, lesions should be excised to the level of the periosteum or deep fascia to prevent recurrence [14]. The possibilities of surgery-induced koebnerization and poor cosmetic outcomes may be a concern.

Improvement in ulceration has also been observed during systemic treatment with hydroxychloroquine [108], colchicine [109], doxycycline [110], fumaric acid esters [75,77], pentoxifylline [111,112], clofazimine [113], thalidomide [114], intravenous immunoglobulin (in a patient with common variable immunodeficiency) [115], intravenous immunoglobulin and methylprednisolone [116], cyclosporine [117-121], mycophenolate mofetil [122], biologic TNF-alpha inhibitors [91,92,123-129], and ustekinumab [130,131]. Of note, the development of ulcerative necrobiosis lipoidica during hydroxychloroquine and TNF-alpha inhibitor therapy has been reported in a patient with rheumatoid arthritis [132].

Healing of ulcers during treatment with aspirin and dipyridamole has been reported [133]. However, a small, randomized trial did not support the efficacy of this therapy for necrobiosis lipoidica [80].

Janus kinase inhibitors, which have also been utilized for the treatment of other granulomatous diseases, have been proposed as a potential treatment for recalcitrant, ulcerative necrobiosis lipoidica. Responses to oral ruxolitinib are documented in case reports [134,135].

Our approach — In contrast to nonulcerated necrobiosis lipoidica, for which deferring treatment is an option, we take a more aggressive approach to the treatment of ulcerated disease. Our initial treatment usually consists of multimodality therapy including application of a high-potency topical corticosteroid or topical tacrolimus to the affected skin around the ulcer in combination with topical PUVA photochemotherapy, an oral antimalarial, an oral tetracycline antibiotic, or oral pentoxifylline.

PROGNOSIS — Necrobiosis lipoidica usually exhibits a chronic course characterized by slow progression and eventual stabilization over the course of years [136]. Occasionally, spontaneous resolution occurs as demonstrated by a retrospective study of 171 patients with necrobiosis lipoidica, in which 21 of 111 patients with diabetes-associated necrobiosis lipoidica (19 percent) and 8 of 60 patients without diabetes (13 percent) achieved spontaneous resolution [1]. The mean times to resolution were 12 and 8 years, respectively (range 1 to 34 years).

Potential complications of necrobiosis lipoidica are ulcers (common) and squamous cell carcinoma (rare). Ulceration occurs in up to one-third of patients [1]. (See 'Clinical manifestations' above.)

Suspicion for squamous cell carcinoma should arise when new nodules develop in sites of long-standing necrobiosis lipoidica or ulcers are recalcitrant to treatment [1,137-143]. A biopsy should be performed in such cases.

FOLLOW-UP — The appropriate frequency of follow-up varies based upon the severity of disease, the presence of ulceration, the rate of disease progression, and need for monitoring of treatment. We often see patients at least every three months when evaluating the efficacy of new treatments.

Patients should be instructed to return for follow-up if changes occur (exacerbations, nodules, ulcers, etc). We typically see our patients for clinical examination at least once yearly.

Standard recommendations for evaluating for subsequent development of diabetes in patients without diabetes at the time of diagnosis have not been established. We typically re-evaluate these patients for diabetes once yearly. (See 'Associated disorders' above and "Screening for type 2 diabetes mellitus".)

SUMMARY AND RECOMMENDATIONS

Necrobiosis lipoidica is a rare, chronic granulomatous disease of the skin. Necrobiosis lipoidica can occur in males, females, children, and adults, but is most common in young to middle-aged adult women. (See 'Epidemiology' above.)

There is a strong relationship between necrobiosis lipoidica and diabetes mellitus. It is estimated that between 11 and 65 percent of patients with necrobiosis lipoidica also have diabetes mellitus. Patients with necrobiosis lipoidica who do not have a known history of diabetes should be evaluated for this disorder. (See 'Associated disorders' above.)

Necrobiosis lipoidica most commonly occurs on pretibial skin. Less frequently, lesions develop on the scalp, face, trunk, genitals, or upper extremities. (See 'Clinical manifestations' above.)

The initial skin eruption of necrobiosis lipoidica is typically single or multiple, yellow to pink-brown or red-brown, slightly elevated papules or plaques (picture 2). Over time the papules and plaques evolve to yellow-orange patches or thin plaques with atrophy and telangiectasias (picture 1A-E). (See 'Clinical manifestations' above.)

Necrobiosis lipoidica is often asymptomatic. However, some patients experience pruritus, pain, or dysesthesia. (See 'Clinical manifestations' above.)

The diagnosis of necrobiosis lipoidica is made based upon clinical and histologic findings. Biopsies taken from the edge of a lesion are most likely to demonstrate classic histologic findings of a palisaded and interstitial granulomatous dermatitis, necrobiosis of collagen, and an associated inflammatory infiltrate with lymphocytes and plasma cells. (See 'Histopathology' above and 'Diagnosis' above.)

Although nonulcerated necrobiosis lipoidica is a benign condition, patients with necrobiosis lipoidica often desire treatment because of the negative cosmetic effects or associated symptoms. Data on treatment efficacy are limited and responses to treatment are variable. (See 'Approach to treatment' above.)

For patients who desire treatment for nonulcerated necrobiosis lipoidica, we suggest a high-potency topical corticosteroid applied under occlusion as initial treatment (Grade 2C). Intralesional injection of corticosteroids is an additional option for treatment. (See 'First-line treatment' above.)

Limited data suggest that other treatments may be useful for necrobiosis lipoidica, such as topical tacrolimus, psoralen plus ultraviolet A (PUVA) photochemotherapy, systemic medications, and procedural therapies. (See 'Other therapies' above.)

There are rare reports of squamous cell carcinoma in sites of necrobiosis lipoidica. The possibility of squamous cell carcinoma should be considered in patients who develop nodules within longstanding lesions or refractory ulcers. (See 'Prognosis' above and 'Follow-up' above.)

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References