ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Necrobiosis lipoidica

Necrobiosis lipoidica
Literature review current through: Jan 2024.
This topic last updated: Mar 07, 2023.

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, multicenter study of 236 patients, the mean age at the time of presentation was 45 years for patients with diabetes mellitus and 52 years for patients without diabetes [1].

The average age of onset may be younger in individuals with type 1 diabetes mellitus. In a retrospective study of 328 patients with a clinical or biopsy-proven diagnosis of necrobiosis lipoidica, the average age at the time of diagnosis of necrobiosis lipoidica was 27 years among patients with type 1 diabetes mellitus compared with 52 years among patients with type 2 diabetes mellitus and patients without diabetes mellitus [2].

Necrobiosis lipoidica occurs more frequently in females than in males. 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 [1,3-5]. 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 [3,6-8]. Necrobiosis lipoidica may also precede a diagnosis of diabetes [3,7]. 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 [7].

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 [3,7,9,10]. 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 [11].

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 [5]. Further study is necessary to clarify whether diabetic patients with necrobiosis lipoidica are at increased risk for renal and retinal complications of diabetes [12,13].

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 [4]. Data from two larger, retrospective studies from the United States suggest occurrence of thyroid disorders in closer to one-quarter or one-third of patients [1,14].

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 [5]. 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) [5]. Additional studies are necessary to confirm an association between necrobiosis lipoidica and thyroid disease or celiac disease.

Comorbidities are common in patients with necrobiosis lipoidica. Examples of other disorders that have been reported in patients with necrobiosis lipoidica include hypertension, obesity, chronic heart failure, dyslipidemias, coronary artery disease, stroke, and decreased kidney function [14,15].

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 [16,17]. In support of this, lower oxygen tensions within sites of necrobiosis lipoidica have been reported [18]. 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 [19].

Examples of other theories for the pathogenesis of necrobiosis lipoidica include proposals that the disease develops as a consequence of abnormalities of collagen [20-22], impaired neutrophil migration [23], or tissue damage secondary to hyperlipidemia or venous reflux [24]. 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 [25-40]. In patients with other sites of involvement, the pretibial area is usually involved as well [1].

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) [2,3,8]. In retrospective studies, approximately 15 to 33 percent of patients with necrobiosis lipoidica experienced ulceration [1,3,8,41]. Ulceration often followed minor trauma to the affected areas.

Contributing factors to ulceration have not been confirmed. A retrospective study that compared features of ulcerated and nonulcerated disease did not find an association with venous insufficiency, arterial Doppler/ankle brachial index, or transcutaneous oxygen pressure (TcPO2) values [41]. A larger median lesion size was associated with ulceration.

While most patients are asymptomatic, occasional patients experience pruritus or dysesthesia at the sites of skin involvement [42]. Pain may also occur, especially in patients with ulceration [16,41].

Necrobiosis lipoidica can demonstrate the Koebner phenomenon, also known as koebnerization [43-47]. Koebnerization is the development of new areas of skin disease at sites of skin trauma.

Some clinical manifestations may differ between patients with type 1 and type 2 diabetes mellitus. In a retrospective study of 328 patients with necrobiosis lipoidica, patients with type 1 diabetes mellitus were more likely to have atrophy, telangiectasia, hypopigmentation, and macular (flat) lesions than patients with type 2 diabetes mellitus [2].

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 [48]. The presence of mucin among other histopathologic features of necrobiosis lipoidica has been reported in association with autoimmune thyroiditis [49].

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.

Data from a retrospective study of 97 patients with necrobiosis lipoidica suggest histopathologic differences between diabetes-associated and non-diabetes-associated disease [50]. Epidermal acanthosis and neutrophils were more common in patients with diabetes, whereas sarcoidal and tuberculoid granulomas and eosinophils were more common in patients without diabetes [50].

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 [51]. (See 'Differential diagnosis' below.)

Dermoscopy — Several reports suggest that dermoscopy may be a helpful adjunctive tool for the diagnosis of necrobiosis lipoidica [52-56]. (See "Overview of dermoscopy".)

Examples of dermoscopic features of necrobiosis lipoidica that have been described in the literature include [52-54]:

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 [4], 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 [57]. (See "Granuloma annulare: Epidemiology, clinical manifestations, and diagnosis".)

Cutaneous sarcoidosis – Infrequently, cutaneous sarcoidosis may present with necrobiosis lipoidica-like skin lesions [58]. 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) [59]. 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 [60]. 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 [16]. 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 [61]. 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 [7]. 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 [61]. 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 [7]. 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 [62]. 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 to eight 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 [62]. The adverse effects of intralesional corticosteroid therapy are reviewed separately. (See "Intralesional corticosteroid injection", section on 'Adverse effects 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, phototherapy, 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, phototherapy, and oral antimalarials, as next-line therapies. Psoralen plus ultraviolet A (PUVA) photochemotherapy 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 [63-66]. 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 [63]. 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 [64].

Phototherapy – PUVA photochemotherapy, ultraviolet A1 (UVA1) phototherapy, and narrowband ultraviolet B (NBUVB) have been used for necrobiosis lipoidica in clinical practice. PUVA photochemotherapy has most data to support efficacy:

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 [67-70]. 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) [67]. 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 [68]. 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'.)

Other forms of phototherapy – UVA1 phototherapy has been proposed as an alternative form of phototherapy for necrobiosis lipoidica based upon a small, prospective study and a retrospective case series [71,72]. However, availability of UVA1 is primarily limited to specialized centers. (See "UVA1 phototherapy".)

NBUVB phototherapy has greater availability than PUVA photochemotherapy and UVA1 phototherapy but lacks published data to support efficacy for necrobiosis lipoidica. Benefit in a patient with necrobiosis lipoidica-like sarcoidosis is documented in a case report [73]. In our personal experience, NBUVB phototherapy has appeared beneficial in several of our patients with necrobiosis lipoidica. (See "UVB phototherapy (broadband and narrowband)".)

Antimalarials – A few reports document improvement in necrobiosis lipoidica during treatment with hydroxychloroquine or chloroquine [74,75]. 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 [75]. 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 [76-81]. 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 [78]. 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 [81].

Fumaric acid esters Fumaric acid esters may be of benefit in necrobiosis lipoidica [82-84]. 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 [82]. 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 [85,86], a small randomized trial did not support efficacy of combination aspirin and dipyridamole therapy [87]. A small randomized trial that evaluated treatment with aspirin without dipyridamole also did not find benefit of this therapy [88].

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 [89]. 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 [90]. 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 [91,92], pentoxifylline [93], clofazimine [94], fibrinolytic agents [95], pioglitazone, biologic tumor necrosis factor (TNF)-alpha inhibitors [96,97], topical and oral Janus kinase (JAK) inhibitors [98,99], and lasers, including both pulsed dye laser [100,101] and fractional carbon dioxide laser therapy [102,103].

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 [104-107], bovine collagen [108], PUVA photochemotherapy [67], mesh graft transplants and PUVA [109], sequential punch grafting [110], UVA1 phototherapy [111], PDT [78], hyperbaric oxygen [112,113], intralesional infliximab [114], and surgical excision [115]. If surgical excision is performed, lesions should be excised to the level of the periosteum or deep fascia to prevent recurrence [16]. 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 [116], colchicine [117], doxycycline [118], fumaric acid esters [82,84], pentoxifylline [119,120], clofazimine [121], thalidomide [122], intravenous immunoglobulin (in a patient with common variable immunodeficiency) [123], intravenous immunoglobulin and methylprednisolone [124], cyclosporine [125-129], mycophenolate mofetil [130], biologic TNF-alpha inhibitors [96,97,131-138], and ustekinumab [139-141]. Of note, the development of ulcerative necrobiosis lipoidica during hydroxychloroquine and TNF-alpha inhibitor therapy has been reported in a patient with rheumatoid arthritis [142].

Healing of ulcers during treatment with aspirin and dipyridamole has been reported [143]. However, a small, randomized trial did not support the efficacy of this therapy for necrobiosis lipoidica [87].

JAK 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 and tofacitinib are documented in case reports [99,144-147].

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 [148]. 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 [3]. 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 malignancies. Ulceration is estimated to occur in up to one-third of patients [3].

Cases of malignancy, particularly squamous cell carcinoma, have been reported [149,150]. In a retrospective study of 328 patients with necrobiosis lipoidica, six patients developed a malignancy within a necrobiosis lipoidica lesion (six squamous cell carcinomas, one basal cell carcinoma, and one melanoma) [149]. All of the patients with documented malignancies had longstanding, ulcerated disease. (See 'Clinical manifestations' above.)

Suspicion for malignancy should arise when new nodules develop in sites of longstanding necrobiosis lipoidica or ulcers are recalcitrant to treatment [3,151-157]. 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

Epidemiology – 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.)

Associated disorders – 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.)

Clinical manifestations – 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.)

Diagnosis – 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.)

Treatment of nonulcerated disease – 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, phototherapy, systemic medications, and procedural therapies. (See 'Other therapies' above.)

Treatment of ulcerated disease – Treatment of ulcerated necrobiosis lipoidica typically involves wound care measures, treatment of the underlying necrobiosis lipoidica, and pain control (when needed). The best approach to treatment is unclear. (See 'Ulcers' above and 'Our approach' above.)

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

  1. Hashemi DA, Brown-Joel ZO, Tkachenko E, et al. Clinical Features and Comorbidities of Patients With Necrobiosis Lipoidica With or Without Diabetes. JAMA Dermatol 2019; 155:455.
  2. Severson KJ, Costello CM, Brumfiel CM, et al. Clinical and morphological features of necrobiosis lipoidica. J Am Acad Dermatol 2022; 86:1133.
  3. Muller SA, Winkelmann RK. Necrobiosis lipoidica diabeticorum. A clinical and pathological investigation of 171 cases. Arch Dermatol 1966; 93:272.
  4. Erfurt-Berge C, Seitz AT, Rehse C, et al. Update on clinical and laboratory features in necrobiosis lipoidica: a retrospective multicentre study of 52 patients. Eur J Dermatol 2012; 22:770.
  5. Hammer E, Lilienthal E, Hofer SE, et al. Risk factors for necrobiosis lipoidica in Type 1 diabetes mellitus. Diabet Med 2017; 34:86.
  6. Muller SA, Winkelmann RK. Necrobiosis lipoidica diabeticorum histopathologic study of 98 cases. Arch Dermatol 1966; 94:1.
  7. O'Toole EA, Kennedy U, Nolan JJ, et al. Necrobiosis lipoidica: only a minority of patients have diabetes mellitus. Br J Dermatol 1999; 140:283.
  8. Erfurt-Berge C, Dissemond J, Schwede K, et al. Updated results of 100 patients on clinical features and therapeutic options in necrobiosis lipoidica in a retrospective multicentre study. Eur J Dermatol 2015; 25:595.
  9. Peyrí J, Moreno A, Marcoval J. Necrobiosis lipoidica. Semin Cutan Med Surg 2007; 26:87.
  10. Shall L, Millard LG, Stevens A, et al. Necrobiosis lipoidica: the footprint not the footstep. Br J Dermatol 1990; 123:47.
  11. De Silva BD, Schofield OM, Walker JD. The prevalence of necrobiosis lipoidica diabeticorum in children with type 1 diabetes. Br J Dermatol 1999; 141:593.
  12. Verrotti A, Chiarelli F, Amerio P, Morgese G. Necrobiosis lipoidica diabeticorum in children and adolescents: a clue for underlying renal and retinal disease. Pediatr Dermatol 1995; 12:220.
  13. Kelly WF, Nicholas J, Adams J, Mahmood R. Necrobiosis lipoidica diabeticorum: association with background retinopathy, smoking, and proteinuria. A case controlled study. Diabet Med 1993; 10:725.
  14. Severson KJ, Patel MH, Brumfiel CM, et al. Comorbidities and diabetic complications in patients with necrobiosis lipoidica. J Am Acad Dermatol 2022; 86:891.
  15. Jockenhöfer F, Kröger K, Klode J, et al. Cofactors and comorbidities of necrobiosis lipoidica: analysis of the German DRG data from 2012. J Dtsch Dermatol Ges 2016; 14:277.
  16. Reid SD, Ladizinski B, Lee K, et al. Update on necrobiosis lipoidica: a review of etiology, diagnosis, and treatment options. J Am Acad Dermatol 2013; 69:783.
  17. ENGEL MF, SMITH JG Jr. The pathogenesis of necrobiosis lipoidica. Necrobiosis lipoidica, a form fruste of diabetes mellitus. Arch Dermatol 1960; 82:791.
  18. Boateng B, Hiller D, Albrecht HP, Hornstein OP. [Cutaneous microcirculation in pretibial necrobiosis lipoidica. Comparative laser Doppler flowmetry and oxygen partial pressure determinations in patients and healthy probands]. Hautarzt 1993; 44:581.
  19. Ngo B, Wigington G, Hayes K, et al. Skin blood flow in necrobiosis lipoidica diabeticorum. Int J Dermatol 2008; 47:354.
  20. Evans CD, Pereira RS, Yuen CT, Holden CA. Anti-collagen antibodies in granuloma annulare and necrobiosis lipoidica. Clin Exp Dermatol 1988; 13:252.
  21. Holland C, Givens V, Smoller BR. Expression of the human erythrocyte glucose transporter Glut-1 in areas of sclerotic collagen in necrobiosis lipoidica. J Cutan Pathol 2001; 28:287.
  22. Oikarinen A, Mörtenhumer M, Kallioinen M, Savolainen ER. Necrobiosis lipoidica: ultrastructural and biochemical demonstration of a collagen defect. J Invest Dermatol 1987; 88:227.
  23. Gange RW, Black MM, Carrington P. Defective neutrophil migration in granuloma annulare, necrobiosis lipoidica, and sarcoidosis. Arch Dermatol 1979; 115:32.
  24. Nakajima T, Tanemura A, Inui S, Katayama I. Venous insufficiency in patients with necrobiosis lipoidica. J Dermatol 2009; 36:166.
  25. Alonso ML, Riós JC, González-Beato MJ, Herranz P. Necrobiosis lipoidica of the glans penis. Acta Derm Venereol 2011; 91:105.
  26. Andersen KE. Systemic sarcoidosis with necrobiosis lipoidica-like scalp lesions. Acta Derm Venereol 1977; 57:367.
  27. Dowling GB, Jones EW. Atypical (annular) necrobiosis lipoidica of the face and scalp. A report of the clinical and histological features of 7 cases. Dermatologica 1967; 135:11.
  28. el Sayed F, Elbadir S, Ferrere J, et al. Chronic balanitis: an unusual localisation of necrobiosis lipoidica. Genitourin Med 1997; 73:579.
  29. FORMAN L. Necrobiosis lipoidica diabeticorum of the scalp. Proc R Soc Med 1954; 47:658.
  30. GAETHE G. NECROBIOSIS LIPOIDICA DIABETICORUM OF THE SCALP. Arch Dermatol 1964; 89:865.
  31. Helander I, Niemi KM, Tyrkkö J. Atypical necrobiosis lipoidica of the face. Acta Derm Venereol 1978; 58:276.
  32. Jones EW. Necrobiosis lipoidica presenting on the face and scalp. An account of 29 patients and a detailed consideration of recent histochemical findings. Trans St Johns Hosp Dermatol Soc 1971; 57:202.
  33. Lecroq C, Thomine E, Boullie MC, Lauret P. [Atypical genital necrobiosis lipoidica]. Ann Dermatol Venereol 1984; 111:717.
  34. Lynch M, Callagy G, Mahon S, Murphy LA. Arcuate plaques of the face and scalp. Atypical necrobiosis lipoidica (ANL) of the face and scalp. Clin Exp Dermatol 2010; 35:799.
  35. Mackey JP. Necrobiosis lipoidica diabeticorum involving scalp and face. Br J Dermatol 1975; 93:729.
  36. Sawada Y, Mori T, Nakashima D, et al. Necrobiosis lipoidica of the scrotum. Eur J Dermatol 2011; 21:98.
  37. Shalhoop H. Round, pitting lesions on the lower leg. Necrobiosis lipoidica. JAAPA 2010; 23:14.
  38. Velasco-Pastor AM, Gil-Mateo MP, Martínez-Aparicio A, Aliaga-Boniche A. Necrobiosis lipoidica of the glans penis. Br J Dermatol 1996; 135:154.
  39. Vélez A, Martín-de-Hijas C, del-Río E, Ambrojo P. Ulcerated plaque of the face. Atypical necrobiosis lipoidica. Arch Dermatol 1994; 130:1433, 1436.
  40. Wantzin GL, Siim E, Medgyesi S. An unusual example of necrobiosis lipoidica affecting the face. Br J Plast Surg 1980; 33:61.
  41. Hines A, Butterfield R, Boudreaux B, et al. Characteristics of ulcerated and non-ulcerated necrobiosis lipoidica. Int J Dermatol 2023; 62:790.
  42. Lowitt MH, Dover JS. Necrobiosis lipoidica. J Am Acad Dermatol 1991; 25:735.
  43. Gebauer K, Armstrong M. Koebner phenomenon with necrobiosis lipoidica diabeticorum. Int J Dermatol 1993; 32:895.
  44. Llajam MA. Koebner's phenomenon and necrobiosis lipoidica diabeticorum. Br J Clin Pract 1990; 44:765.
  45. Miller RA. Koebner phenomenon in a diabetic with necrobiosis lipoidica diabeticorum. Int J Dermatol 1990; 29:52.
  46. Patel GK, Harding KG, Mills CM. Severe disabling Köebnerizing ulcerated necrobiosis lipoidica successfully managed with topical PUVA. Br J Dermatol 2000; 143:668.
  47. Schumacher F, Schnyder UW. [Necrobiosis lipoidica and Koebner phenomenon]. Hautarzt 1991; 42:587.
  48. Alegre VA, Winkelmann RK. A new histopathologic feature of necrobiosis lipoidica diabeticorum: lymphoid nodules. J Cutan Pathol 1988; 15:75.
  49. Take N, Mitoma C, Furue M. Necrobiosis lipoidica with mucin deposition in a patient with autoimmune thyroiditis. J Dermatol 2018; 45:e193.
  50. Johnson E, Patel MH, Brumfiel CM, et al. Histopathologic features of necrobiosis lipoidica. J Cutan Pathol 2022; 49:692.
  51. Gibson LE, Reizner GT, Winkelmann RK. Necrobiosis lipoidica diabeticorum with cholesterol clefts in the differential diagnosis of necrobiotic xanthogranuloma. J Cutan Pathol 1988; 15:18.
  52. Pellicano R, Caldarola G, Filabozzi P, Zalaudek I. Dermoscopy of necrobiosis lipoidica and granuloma annulare. Dermatology 2013; 226:319.
  53. Conde-Montero E, Avilés-Izquierdo JA, Mendoza-Cembranos MD, Parra-Blanco V. Dermoscopy of necrobiosis lipoidica. Actas Dermosifiliogr 2013; 104:534.
  54. Bakos RM, Cartell A, Bakos L. Dermatoscopy of early-onset necrobiosis lipoidica. J Am Acad Dermatol 2012; 66:e143.
  55. Lallas A, Zaballos P, Zalaudek I, et al. Dermoscopic patterns of granuloma annulare and necrobiosis lipoidica. Clin Exp Dermatol 2013; 38:425.
  56. Balestri R, La Placa M, Bardazzi F, Rech G. Dermoscopic subpatterns of granulomatous skin diseases. J Am Acad Dermatol 2013; 69:e217.
  57. Souza FH, Ribeiro CF, Pereira MA, et al. Simultaneous occurrence of ulcerated necrobiosis lipoidica and granuloma annulare in a patient: case report. An Bras Dermatol 2011; 86:1007.
  58. Chiba T, Takahara M, Nakahara T, et al. Cutaneous sarcoidosis clinically mimicking necrobiosis lipoidica in a patient with systemic sarcoidosis. Ann Dermatol 2012; 24:74.
  59. Yoo SS, Mimouni D, Nikolskaia OV, et al. Clinicopathologic features of ulcerative-atrophic sarcoidosis. Int J Dermatol 2004; 43:108.
  60. Spicknall KE, Mehregan DA. Necrobiotic xanthogranuloma. Int J Dermatol 2009; 48:1.
  61. Goette DK. Resolution of necrobiosis lipoidica with exclusive clobetasol propionate treatment. J Am Acad Dermatol 1990; 22:855.
  62. Sparrow G, Abell E. Granuloma annulare and necrobiosis lipoidica treated by jet injector. Br J Dermatol 1975; 93:85.
  63. Patsatsi A, Kyriakou A, Sotiriadis D. Necrobiosis lipoidica: early diagnosis and treatment with tacrolimus. Case Rep Dermatol 2011; 3:89.
  64. Harth W, Linse R. Topical tacrolimus in granuloma annulare and necrobiosis lipoidica. Br J Dermatol 2004; 150:792.
  65. Barth D, Harth W, Treudler R, Simon JC. [Topical tacrolimus in necrobiosis lipoidica]. Hautarzt 2011; 62:459.
  66. Koura-Nishiura A, Yoneda K, Nakai K, et al. Clearance of atypical facial necrobiosis lipoidica with tacrolimus ointment. J Eur Acad Dermatol Venereol 2016; 30:383.
  67. De Rie MA, Sommer A, Hoekzema R, Neumann HA. Treatment of necrobiosis lipoidica with topical psoralen plus ultraviolet A. Br J Dermatol 2002; 147:743.
  68. Narbutt J, Torzecka JD, Sysa-Jedrzejowska A, Zalewska A. Long-term results of topical PUVA in necrobiosis lipoidica. Clin Exp Dermatol 2006; 31:65.
  69. McKenna DB, Cooper EJ, Tidman MJ. Topical psoralen plus ultraviolet A treatment for necrobiosis lipoidica. Br J Dermatol 2000; 143:1333.
  70. Patel GK, Mills CM. A prospective open study of topical psoralen-UV-A therapy for Necrobiosis lipoidica. Arch Dermatol 2001; 137:1658.
  71. Beattie PE, Dawe RS, Ibbotson SH, Ferguson J. UVA1 phototherapy for treatment of necrobiosis lipoidica. Clin Exp Dermatol 2006; 31:235.
  72. Attili SK, Dawe RS, Ibbotson SH. Ultraviolet A1 phototherapy: One center's experience. Indian J Dermatol Venereol Leprol 2017; 83:60.
  73. Kuroda K, Hamada T, Shiomi M, Iwatsuki K. Narrow-band UVB for pretibial (necrobiosis lipoidica-like) involvement of cutaneous sarcoidosis: a promising therapeutic option. Eur J Dermatol 2017; 27:537.
  74. Nguyen K, Washenik K, Shupack J. Necrobiosis lipoidica diabeticorum treated with chloroquine. J Am Acad Dermatol 2002; 46:S34.
  75. Durupt F, Dalle S, Debarbieux S, et al. Successful treatment of necrobiosis lipoidica with antimalarial agents. Arch Dermatol 2008; 144:118.
  76. Truchuelo T, Alcántara J, Fernández-Guarino M, et al. Photodynamic therapy for necrobiosis lipoidica is an unpredictable option: three cases with different results. Int J Dermatol 2013; 52:1589.
  77. Kosaka S, Kawana S. Case of necrobiosis lipoidica diabeticorum successfully treated by photodynamic therapy. J Dermatol 2012; 39:497.
  78. Berking C, Hegyi J, Arenberger P, et al. Photodynamic therapy of necrobiosis lipoidica--a multicenter study of 18 patients. Dermatology 2009; 218:136.
  79. De Giorgi V, Buggiani G, Rossi R, et al. Successful topical photodynamic treatment of refractory necrobiosis lipoidica. Photodermatol Photoimmunol Photomed 2008; 24:332.
  80. Heidenheim M, Jemec GB. Successful treatment of necrobiosis lipoidica diabeticorum with photodynamic therapy. Arch Dermatol 2006; 142:1548.
  81. Kaae J, Philipsen PA, Wulf HC. Photodynamic therapy of necrobiosis lipoidica using methyl aminolevulinate: A retrospective follow-up study. Photodiagnosis Photodyn Ther 2018; 22:223.
  82. Kreuter A, Knierim C, Stücker M, et al. Fumaric acid esters in necrobiosis lipoidica: results of a prospective noncontrolled study. Br J Dermatol 2005; 153:802.
  83. Gambichler T, Kreuter A, Freitag M, et al. Clearance of necrobiosis lipoidica with fumaric acid esters. Dermatology 2003; 207:422.
  84. Eberle FC, Ghoreschi K, Hertl M. Fumaric acid esters in severe ulcerative necrobiosis lipoidica: a case report and evaluation of current therapies. Acta Derm Venereol 2010; 90:104.
  85. Rhodes EL. Necrobiosis lipoidica treated with ticlopidine. Acta Derm Venereol 1986; 66:458.
  86. Eldor A, Diaz EG, Naparstek E. Treatment of diabetic necrobiosis with aspirin and dipyridamole. N Engl J Med 1978; 298:1033.
  87. Statham B, Finlay AY, Marks R. A randomized double blind comparison of an aspirin dipyridamole combination versus a placebo in the treatment of necrobiosis lipoidica. Acta Derm Venereol 1981; 61:270.
  88. Beck HI, Bjerring P, Rasmussen I, et al. Treatment of necrobiosis lipoidica with low-dose acetylsalicylic acid. A randomized double-blind trial. Acta Derm Venereol 1985; 65:230.
  89. Petzelbauer P, Wolff K, Tappeiner G. Necrobiosis lipoidica: treatment with systemic corticosteroids. Br J Dermatol 1992; 126:542.
  90. Taniguchi Y, Sakamoto T, Shimizu M. A case of necrobiosis lipoidica treated with systemic corticosteroid. J Dermatol 1993; 20:304.
  91. Boyd AS. Tretinoin treatment of necrobiosis lipoidica diabeticorum. Diabetes Care 1999; 22:1753.
  92. Heymann WR. Necrobiosis lipoidica treated with topical tretinoin. Cutis 1996; 58:53.
  93. Basaria S, Braga-Basaria M. Necrobiosis lipoidica diabeticorum: response to pentoxiphylline. J Endocrinol Invest 2003; 26:1037.
  94. Mensing H. [Clofazimine--therapeutic alternative in necrobiosis lipoidica and granuloma anulare]. Hautarzt 1989; 40:99.
  95. Rhodes EL. Fibrinolytic agents in the treatment of necrobiosis lipoidica. Angiology 1978; 29:60.
  96. Conte H, Milpied B, Kaloga M, et al. Treatment of pre-ulcerative necrobiosis lipoidica with infliximab. Acta Derm Venereol 2011; 91:587.
  97. Zeichner JA, Stern DW, Lebwohl M. Treatment of necrobiosis lipoidica with the tumor necrosis factor antagonist etanercept. J Am Acad Dermatol 2006; 54:S120.
  98. Nugent S, Coromilas AJ, English JC 3rd, Rosenbach M. Improvement of necrobiosis lipoidica with topical ruxolitinib cream after prior nonresponse to compounded topical tofacitinib cream. JAAD Case Rep 2022; 29:25.
  99. Damsky W, Singh K, Galan A, King B. Treatment of necrobiosis lipoidica with combination Janus kinase inhibition and intralesional corticosteroid. JAAD Case Rep 2020; 6:133.
  100. Gutierrez D, Steuer AB, Marji JS, Cindy Bae YS. Treatment of Necrobiosis Lipoidica With Pulsed Dye Laser. Dermatol Surg 2020; 46:1468.
  101. Bergqvist E, Bergqvist G. The long-term effect of pulsed dye laser on Necrobiosis Lipoidica: A case study. J Cosmet Laser Ther 2019; 21:17.
  102. Buggiani G, Tsampau D, Krysenka A, et al. Fractional CO2 laser: a novel therapeutic device for refractory necrobiosis lipoidica. Dermatol Ther 2012; 25:612.
  103. Zaouak A, Ben Brahim E, Daoued F, et al. Unconventional use of fractional ablative CO2 laser in necrobiosis lipoidica. J Cosmet Laser Ther 2019; 21:82.
  104. Clayton TH, Harrison PV. Successful treatment of chronic ulcerated necrobiosis lipoidica with 0.1% topical tacrolimus ointment. Br J Dermatol 2005; 152:581.
  105. Binamer Y, Sowerby L, El-Helou T. Treatment of ulcerative necrobiosis lipoidica with topical calcineurin inhibitor: case report and literature review. J Cutan Med Surg 2012; 16:458.
  106. Maus EA. The importance of challenging your diagnosis even in straightforward cases. BMJ Case Rep 2012; 2012.
  107. Ginocchio L, Draghi L, Darvishian F, Ross FL. Refractory Ulcerated Necrobiosis Lipoidica: Closure of a Difficult Wound with Topical Tacrolimus. Adv Skin Wound Care 2017; 30:469.
  108. Spenceri EA, Nahass GT. Topically applied bovine collagen in the treatment of ulcerative necrobiosis lipoidica diabeticorum. Arch Dermatol 1997; 133:817.
  109. Köstler E, Wollina U. Ulcerated necrobiosis lipoidica: a combined treatment approach with dermatosurgery and PUVA. Int J Low Extrem Wounds 2003; 2:243.
  110. Fulgencio-Barbarin J, Conde Montero E. Sequential punch grafting for treatment of ulcerative necrobiosis lipoidica. J Tissue Viability 2022; 31:560.
  111. Radakovic S, Weber M, Tanew A. Dramatic response of chronic ulcerating necrobiosis lipoidica to ultraviolet A1 phototherapy. Photodermatol Photoimmunol Photomed 2010; 26:327.
  112. Bouhanick B, Verret JL, Gouello JP, et al. Necrobiosis lipoidica: treatment by hyperbaric oxygen and local corticosteroids. Diabetes Metab 1998; 24:156.
  113. Weisz G, Ramon Y, Waisman D, Melamed Y. Treatment of necrobiosis lipoidica diabeticorum by hyperbaric oxygen. Acta Derm Venereol 1993; 73:447.
  114. Barde C, Laffitte E, Campanelli A, et al. Intralesional infliximab in noninfectious cutaneous granulomas: three cases of necrobiosis lipoidica. Dermatology 2011; 222:212.
  115. Dubin BJ, Kaplan EN. The surgical treatment of necrobiosis lipoidica diabeticorum. Plast Reconstr Surg 1977; 60:421.
  116. Kavala M, Sudogan S, Zindanci I, et al. Significant improvement in ulcerative necrobiosis lipoidica with hydroxychloroquine. Int J Dermatol 2010; 49:467.
  117. Schofield C, Sladden MJ. Ulcerative necrobiosis lipoidica responsive to colchicine. Australas J Dermatol 2012; 53:e54.
  118. Mahé E, Zimmermann U. [Significant improvement in ulcerative necrobiosis lipoidica with doxycycline]. Ann Dermatol Venereol 2011; 138:686.
  119. Noz KC, Korstanje MJ, Vermeer BJ. Ulcerating necrobiosis lipoidica effectively treated with pentoxifylline. Clin Exp Dermatol 1993; 18:78.
  120. Littler CM, Tschen EH. Pentoxifylline for necrobiosis lipoidica diabeticorum. J Am Acad Dermatol 1987; 17:314.
  121. Benedix F, Geyer A, Lichte V, et al. Response of ulcerated necrobiosis lipoidica to clofazimine. Acta Derm Venereol 2009; 89:651.
  122. Kukreja T, Petersen J. Thalidomide for the treatment of refractory necrobiosis lipoidica. Arch Dermatol 2006; 142:20.
  123. Barouti N, Cao AQ, Ferrara D, Prins C. Successful treatment of ulcerative and diabeticorum necrobiosis lipoidica with intravenous immunoglobulin in a patient with common variable immunodeficiency. JAMA Dermatol 2013; 149:879.
  124. Batchelor JM, Todd PM. Treatment of ulcerated necrobiosis lipoidica with intravenous immunoglobulin and methylprednisolone. J Drugs Dermatol 2012; 11:256.
  125. Aslan E, Körber A, Grabbe S, Dissemond J. [Successful therapy of ulcerated necrobiosis lipoidica non diabeticorum with cyclosporine A]. Hautarzt 2007; 58:684.
  126. Smith K. Ulcerating necrobiosis lipoidica resolving in response to cyclosporine-A. Dermatol Online J 1997; 3:2.
  127. Stanway A, Rademaker M, Newman P. Healing of severe ulcerative necrobiosis lipoidica with cyclosporin. Australas J Dermatol 2004; 45:119.
  128. Stinco G, Parlangeli ME, De Francesco V, et al. Ulcerated necrobiosis lipoidica treated with cyclosporin A. Acta Derm Venereol 2003; 83:151.
  129. Darvay A, Acland KM, Russell-Jones R. Persistent ulcerated necrobiosis lipoidica responding to treatment with cyclosporin. Br J Dermatol 1999; 141:725.
  130. Reinhard G, Lohmann F, Uerlich M, et al. Successful treatment of ulcerated necrobiosis lipoidica with mycophenolate mofetil. Acta Derm Venereol 2000; 80:312.
  131. Hu SW, Bevona C, Winterfield L, et al. Treatment of refractory ulcerative necrobiosis lipoidica diabeticorum with infliximab: report of a case. Arch Dermatol 2009; 145:437.
  132. Kolde G, Muche JM, Schulze P, et al. Infliximab: a promising new treatment option for ulcerated necrobiosis lipoidica. Dermatology 2003; 206:180.
  133. Leister L, Körber A, Dissemond J. [Successful treatment of a patient with ulcerated necrobiosis lipoidica non diabeticorum with adalimumab]. Hautarzt 2013; 64:509.
  134. Zhang KS, Quan LT, Hsu S. Treatment of necrobiosis lipoidica with etanercept and adalimumab. Dermatol Online J 2009; 15:12.
  135. Fertitta L, Vignon-Pennamen MD, Frazier A, et al. Necrobiosis lipoidica with bone involvement successfully treated with infliximab. Rheumatology (Oxford) 2019; 58:1702.
  136. Sandhu VK, Alavi A. The role of anti-tumour necrosis factor in wound healing: A case report of refractory ulcerated necrobiosis lipoidica treated with adalimumab and review of the literature. SAGE Open Med Case Rep 2019; 7:2050313X19881594.
  137. Nunes de Mattos AB, Brummer CF, Funchal GDG, Nunes DH. Perforating necrobiosis lipoidica: good response to adalimumab. An Bras Dermatol 2019; 94:769.
  138. Vetos D, Wu DJ, Downing MB, Rajpara A. Adalimumab for treatment of severe ulcerative sarcoidosis. Dermatol Online J 2021; 27.
  139. Hassoun LA, Sivamani RK, Sharon VR, et al. Ustekinumab to target granulomatous dermatitis in recalcitrant ulcerative necrobiosis lipoidica: case report and proposed mechanism. Dermatol Online J 2017; 23.
  140. Pourang A, Sivamani RK. Treatment-resistant ulcerative necrobiosis lipoidica in a diabetic patient responsive to ustekinumab. Dermatol Online J 2019; 25.
  141. Beatty P, Killion L, Blake C, et al. Ulcerating necrobiosis lipoidica successfully treated with ustekinumab. Australas J Dermatol 2021; 62:e473.
  142. Fehlman JA, Burkemper NM, Missall TA. Ulcerative necrobiosis lipoidica in the setting of anti-tumor necrosis factor-α and hydroxychloroquine treatment for rheumatoid arthritis. JAAD Case Rep 2017; 3:127.
  143. Heng MC, Song MK, Heng MK. Healing of necrobiotic ulcers with antiplatelet therapy. Correlation with plasma thromboxane levels. Int J Dermatol 1989; 28:195.
  144. Lee JJ, English JC 3rd. Improvement in Ulcerative Necrobiosis Lipoidica After Janus Kinase-Inhibitor Therapy for Polycythemia Vera. JAMA Dermatol 2018; 154:733.
  145. Barbet-Massin MA, Rigalleau V, Blanco P, et al. Remission of necrobiosis lipoidica diabeticorum with a JAK1/2 inhibitor: A case report. Diabetes Metab 2021; 47:101143.
  146. Janßen S, Jansen TM. Ulcerated necrobiosis lipoidica successfully treated with tofacitinib. Int J Dermatol 2022; 61:739.
  147. Erfurt-Berge C, Sticherling M. Successful treatment of ulcerative necrobiosis lipoidica with janus kinase inhibitor. J Eur Acad Dermatol Venereol 2020; 34:e331.
  148. Kalus AA, Chien AJ, Olerud JE. Diabetes mellitus and other endocrine diseases. In: Fitzpatrick's Dermatology in General Medicine, 8th ed, Goldsmith LA, Katz SI, Gilchrest BA (Eds), McGraw-Hill, 2012. Vol 2, p.1840.
  149. Harvey JA, Severson KJ, Brumfiel CM, et al. Necrobiosis lipoidica-associated cutaneous malignancy. J Am Acad Dermatol 2022; 86:1428.
  150. Souza MEV, Recuero JK, Santos MF, Bonamigo RR. Squamous cell carcinoma superimposed on necrobiosis lipoidica: a rare complication. An Bras Dermatol 2020; 95:775.
  151. Beljaards RC, Groen J, Starink TM. Bilateral squamous cell carcinomas arising in long-standing necrobiosis lipoidica. Dermatologica 1990; 180:96.
  152. Clement M, Guy R, Pembroke AC. Squamous cell carcinoma arising in long-standing necrobiosis lipoidica. Arch Dermatol 1985; 121:24.
  153. Gudi VS, Campbell S, Gould DJ, Marshall R. Squamous cell carcinoma in an area of necrobiosis lipoidica diabeticorum: a case report. Clin Exp Dermatol 2000; 25:597.
  154. Imtiaz KE, Khaleeli AA. Squamous cell carcinoma developing in necrobiosis lipoidica. Diabet Med 2001; 18:325.
  155. Lim C, Tschuchnigg M, Lim J. Squamous cell carcinoma arising in an area of long-standing necrobiosis lipoidica. J Cutan Pathol 2006; 33:581.
  156. McIntosh BC, Lahinjani S, Narayan D. Necrobiosis lipoidica resulting in squamous cell carcinoma. Conn Med 2005; 69:401.
  157. Santos-Juanes J, Galache C, Curto JR, et al. Squamous cell carcinoma arising in long-standing necrobiosis lipoidica. J Eur Acad Dermatol Venereol 2004; 18:199.
Topic 89276 Version 9.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟