Ulcerated necrobiosis lipoidica as a rare cause for chronic leg ulcers: case report series of ten patients

Abstract

Necrobiosis lipoidica is a rare granulomatous disorder of the skin. In up to 30% of the affected patients it can lead to ulcerations, which can impair the quality of life and are also very difficult to treat. Its pathogenesis is not fully understood. Only few studies focussing on necrobiosis lipoidica can be found, but none of them focus on ulcerated necrobiosis lipoidica. Therefore, we collected demographic data and comorbidities and assessed treatment options for patients with ulcerated necrobiosis lipoidica. Data of patients who were treated in the wound care centre of the University Hospital of Essen for ulcerated necrobiosis lipoidica over the past 10 years were retrospectively analysed. Hence, data of altogether ten patients (nine women and one man) with ulcerated necrobiosis lipoidica were collected. Of these, 70% of the patients had diabetes mellitus of which 30% had type I diabetes and 40% had type II diabetes; 60% of the patients suffered from arterial hypertension, obesity and hypercholesterolaemia; 40% of the patients suffered from psychiatric disorders such as depression and borderline disorder. Our clinical data demonstrate an association of ulcerated necrobiosis lipoidica and aspects of metabolic syndrome. This leads to a conclusion that ulcerating necrobiosis lipoidica can be seen as part of a generalised inflammatory reaction similar to the inflammatory reaction already known in the pathophysiology of rheumatoid diseases or psoriasis. In patients with clinical atypical painful ulcerations, necrobiosis lipoidica should be considered as a possible differential diagnosis. Therapists should be aware of associated aspects in patients with ulcerated necrobiosis lipoidica who besides diabetes often suffer from other aspects of a metabolic syndrome with increased cardiovascular risk factors. Therefore, these related comorbidities should also be diagnosed and treated.

Introduction

Worldwide, chronic wounds affect a growing number of patients and appear to be an increasing medical and economic problem. The aetiology of these wounds is very heterogeneous. In Europe, the most common manifestation of chronic wounds is chronic leg ulcers caused by vascular diseases. Up to 80% of the chronic leg ulcers are due to chronic venous insufficiency and/or peripheral occlusive arterial diseases 1. Less frequently diagnosed causes are vasculitis, infections, neoplasia, pyoderma gangrenosum, calciphylaxis or drug‐induced ulcerations. Apart from these well‐known causes of ulcerations a large number of other rare diseases such as ulcerated necrobiosis lipoidica exist. Necrobiosis lipoidica is a non‐infectious granulomatous degenerative skin disease, which is characterised by collagen degeneration, fat deposition and thickening of blood vessel walls. It was first described by Urbach in 1929 and named by Oppenheim in 1932 as necrobiosis lipoidica diabeticorum. It is associated with diabetes mellitus, and the extent of this association has been often discussed and varies between 22% and 65% 2, 3. In 1948, Miescher and Lederer described the first case of granulomatosis disciformis chronica et progressiva, a case of necrobiosis lipoidica on a patient without impaired glucose tolerance.

Patients usually present shiny brown‐yellow patches that have developed from small red or violet papules and enlarge over months. Sites most likely to be affected are the shins. The patches have a red advancing indurated border and show central atrophy with a shiny, waxy surface and telangiectasias. Ulcerations appear in around 30% of patients 4. As lesions mature they become less active and more atrophic and thus more susceptible to ulceration as a result of traumata. Until now, the exact aetiology of the ulcerations is not fully understood because the pathogenesis of necrobiosis lipoidica itself is still unknown. Up to date, very few cases of ulcerated necrobiosis lipoidica have been described in literature. In some case reports, associations of this disorder with ulcerative colitis, Crohn's disease and granuloma annulare have been discussed 5, 6, 7. To understand the pathogenesis and improve the treatment of ulcerating necrobiosis lipoidica a larger number of patients needs to be described. Therefore, the goal of this retrospective monocentric study was to examine potentially relevant cofactors in patients with ulcerated necrobiosis lipoidica.

Patients and methods

Patients

We collected the data of ten patients with ulcerated necrobiosis lipoidica over a period of 10 years from the dermatologic wound care centre and the outpatient department in the University Hospital in Essen from 2002 to 2012. The group of ten patients with ulcerated necrobiosis lipoidica consisted of one male and nine female patients. The age range during onset of the ulcerations was from 16 to 55 years with a mean of 32·6 years. The diagnosis of necrobiosis lipoidica was proven histologically and/or clinically by the typical clinical appearance with ulcerations that developed on shiny, waxy patches (Figures 1 and 2). Chronic venous insufficiency and peripheral arterial occlusive disease as possible clinical differential diagnoses were excluded by Doppler flowmetry and measurement of the ankle brachial index.

Figure 1.

Patient with very painful ulcerated waxy patches on the shins induced by ulcerated necrobiosis lipoidica diabeticorum.

Figure 2.

Histopathological findings in a patient with ulcerated necrobiosis lipoidica. (A) In the lower magnification, a characteristic sandwich‐like pattern consisting of necrobiotic zones (pink) and the inflammatory infiltrate (blue) can be seen. (B) The inflammatory infiltrate is composed of lymphocytes, multinucleated giant cell and plasma cells.

Cofactors and comorbidities

Epidemiological data were collected by review of patient documents and interview of the patients. The focus was on patient gender and age at onset of the ulcerations. For each patient, comorbidities and cofactors were collected and recorded. Serological parameters that were recorded were glycated haemoglobin (HbA1c) level, C‐reactive protein (CRP) level, leucocyte count and serum creatinine level. The evaluated comorbidities and cofactors included diabetes mellitus, arterial hypertension, obesity, hypercholesterolaemia, renal insufficiency, respiratory diseases, smoking, neoplasias and psychiatric disorders (Table 1).

Table 1.

Overview of cofactors and comorbidities of our patients with ulcerated necrobiosis lipoidica

70% Diabetes mellitus (type I 30% and type II 40%)

60% Obesity

60% Arterial hypertension

60% Hypercholesterolaemia

50% Cigarette smoking

50% Respiratory diseases (asthma bronchiale 30% and COPD 20%)

40% Psychiatric diseases (depression 30% and borderline disorder 10%)

20% Renal insufficiency

COPD, chronic obstructive pulmonary disease.

Statistics

All parameters were recorded and entered in a table analysed with Microsoft® Excel 2000 for statistical analysis.

Results

Location

In all ten patients, ulcers were located at the lower leg. In seven patients, ulcerations were located in the pretibial region and in three patients in the lateral regions of the lower leg. However, in one patient the right upper leg and the lumbar region were also affected.

Pain

All patients described their ulcerations as very painful. Values ranged from 7 to the maximum of 10 points on the visual analogue scale (VAS, range from 0 to 10) with a mean average of 8·5 points on first presentation in the clinic.

Diabetes mellitus

In seven patients, diabetes mellitus was diagnosed prior to or with the onset of the ulcerations. Altogether, three patients suffered from type I diabetes and four patients from type II diabetes. Diabetes mellitus was diagnosed by elevation of HbA1c level ≥6·5% or by a pathological oral glucose tolerance test.

Arterial hypertension

Arterial hypertension was found in six patients when measured on three different days at different times of the day.

Renal dysfunction

An elevated serum creatinine level could be found in two patients. One patient showed a chronic kidney insufficiency stage I and the other showed stage II. None of the patients required dialysis.

Hypercholesterolaemia

Altogether, six patients showed elevated total serum cholesterol levels.

Obesity

A total of six patients were obese at the time of diagnosis of ulcerated necrobiosis lipoidica with a body mass index of at least 30.

Smoking

Six patients were smoking cigarettes on a daily basis.

Respiratory diseases

Accompanying respiratory diseases including bronchial asthma and chronic obstructive pulmonary disease (COPD) could be found in five patients. Three patients had bronchial asthma and two patients had COPD.

Psychiatric disorders

In four patients, a psychiatric disorder could be diagnosed. Three patients were suffering from depression and one patient had a borderline personality disorder.

Other diseases

No malignancies could be detected in the patients in our group. Rheumatoid arthritis, ulcerative colitis, Crohn's disease or other chronic inflammatory diseases also could not be found. None of the patients in this study suffered from thyroid function disorders.

Discussion

In current literature, mostly single case reports of patients with ulcerated necrobiosis lipoidica are found. To the best of our knowledge, no clinical studies or case report series focussing on patients with ulcerated necrobiosis lipoidica exist. Therefore, our case report series is the largest study so far evaluating comorbidities, demographics and treatment options, particularly for patients with ulcerated necrobiosis lipoidica.

Pathophysiology

The exact underlying pathomechanisms of necrobiosis lipoidica are still unknown. Possible causes that have been discussed so far are microangiopathy caused by diabetes mellitus, antibody‐mediated vasculitis, collagen disorders and disorders of leucocyte function that lead to granuloma formation 2, 3, 4. Molecular pathways that initiate the granuloma formation are still unknown. Recent findings suggest that the pathogenesis is based on stimulation of innate immune cells that lead to release of tumour necrosis factor α (TNF‐α) and interferon (IFN‐γ). Especially, TNF‐α appears to play a major role as a proinflammatory cytokine, which has been implicated in the maintenance of granulomas by macrophages. Dendritic cells and endothelial cells, which are activated by IFN‐γ, are supposed to play a central role in granuloma formation by the secretion of interleukin (IL)‐12 8, 9. There are reported associations with necrobiosis lipoidica and chronic venous insufficiency as well as hypercholesterolaemia. It has been discussed that both can trigger necrobiosis lipoidica and tissue damage 10, 11.

Gender association of ulcerated necrobiosis lipoidica

It is known that necrobiosis lipoidica is more common in women than in men. According to the findings of previous studies on patients with necrobiosis lipoidica, it is found two to three times more often in women than in men 12, 13, 14. In our study population up to 90% of the patients are female. This number does not agree with the findings from the study of Erfurt‐Berge et al. in which 7 of the 13 patients with ulcerated necrobiosis lipoidica were male and 6 female 12. Although the reported number of patients with ulcerated necrobiosis lipoidica in their study is bigger than ours, our study is the first one focussing on cofactors and comorbidities. As gender‐related differences in ulcerations of patients with necrobiosis lipoidica have not been assessed so far in other studies, further investigations and a large number of patients are necessary.

Necrobiosis lipoidica and comorbidities

There have been controversial discussions about the association of diabetes mellitus and necrobiosis lipoidica. Muller and Winkelmann found diabetes mellitus in 65% of 171 patients with necrobiosis lipoidica and an association with abnormal glucose tolerance in 42% of the non‐diabetic cases. In their study, 35% of the diabetic patients and 33% of the non‐diabetic patients with necrobiosis lipoidica had ulcerations within plaques 3. The group of patients with ulcerated necrobiosis lipoidica however had not been analysed separately as in our study. O'Toole et al. found that in a retrospective review of 65 patients in Dublin with necrobiosis lipoidica only 11% had diabetes mellitus and only 5% showed impaired glucose tolerance. Another 11% were diagnosed with diabetes mellitus or impaired glucose tolerance within the 15‐year follow‐up period. Of these 65 patients, 6 had ulcerating necrobiosis lipoidica. Four of these patients had impaired glucose tolerance or diabetes mellitus 2. This group of patients with ulcerated necrobiosis lipoidica has not been described further by O'Toole et al. The recent multicentre study by Erfurt‐Berge et al. showed that of the 52 patients with necrobiosis lipoidica collected over a period of 5 years, 24 patients (46%) had diabetes mellitus 12. In our group of patients with ulcerated necrobiosis lipoidica, 70% showed an association with diabetes mellitus. Altogether, 60% of our patients with ulcerated necrobiosis lipoidica were suffering from arterial hypertension, were obese, smokers and showed hypercholesterolaemia. This is significantly higher than in the study of Erfurt‐Berge et al. in which different comorbidities of patients with necrobiosis lipoidica were evaluated, but not distinguished for patients with ulcerations 12. An association of necrobiosis lipoidica with diabetes mellitus as well as with elevated serum lipids has been described in literature before 15. This association can be explained by the fact that even therapeutically well‐controlled forms of diabetes mellitus cannot achieve an optimal fat and carbohydrate metabolism. This also leads to diabetic microangiopathy and arteriosclerosis, which gives way to arterial hypertension. Lack of exercise and malnutrition can lead to obesity and diabetes mellitus, too. A close association of necrobiosis lipoidica with other diseases of the metabolic syndrome in our cohort is therefore explicable.

Treatment

Treatment of the ulcerations in patients with necrobiosis lipoidica is very difficult and relapses occur frequently. No known standardised effective treatment for ulcerated necrobiosis lipoidica is available until today. There are a number of treatment options described in literature that are not evidence‐based. The main reason is the low number of cases, especially of ulcerating necrobiosis lipoidica, and the remarkable number of side effects of most therapies that a lot of patients are not willing to tolerate, considering that—in many cases—just the non‐ulcerated patches do not cause strain. Recorded treatment options are intralesional and topical steroids or tacrolimus 16, topical PUVA 17, 18 or UVA1 19, 20, systemic steroids, doxycycline 21, antimalarial drugs 22, fumaric acid esters (FAEs) 23, pentoxifylline 24, cyclosporine A 25, biological agents 26, 27 and surgery with excision followed by skin grafting (Tables 2 and 3).

Table 2.

Topical therapies of ulcerated necrobiosis lipoidica

CO2 laser

Photodynamic therapy (PDT)

Phototherapy (PUVA and UVA1)

Surgical excision (with or without skin grafting)

Topical calcineurin inhibitors

Topical steroids

Table 3.

Systemic therapies of ulcerated necrobiosis lipoidica

Biologics

Cyclosporine A

Doxycycline

Fumaric acid esters

Glucocorticosteroids

Hydroxychloroquine

Intravenous immunoglobulin (IVIG)

Pentoxifylline

The foundation of any therapy of ulcerated necrobiosis lipoidica is good and regular wound care. The ulcers can be treated, for example, with antiseptic solutions and non‐adhesive wound dressings, especially foams. As an example of a more invasive treatment, one of our patients with non‐insulin‐dependent diabetes mellitus type II showed complete healing under good control of diabetes after surgical excision, wound bed preparation with negative pressure therapy and subsequent transplantation of a mesh graft. A good control of diabetes mellitus is essential for proper wound healing conditions. In this respect, most of our patients showed a lack of compliance or adherence, despite the psychological strain caused by the cosmetically disfiguring ulcerations and the pain. In addition, regular follow‐up is necessary because it has been shown that long‐standing chronic ulcerating lesions of necrobiosis lipoidica can lead to squamous cell carcinoma owing to malignant transformation as described in several case reports 28, 29, 30. In addition, an adequate pain therapy is necessary, because all patients in our group described their ulcerations as very painful. Besides non‐steroidal anti‐inflammatory drugs and opioids, a topical pain therapy with morphine‐containing hydrogel can reduce the pain significantly 31. In most of our cases, a therapy with topical glucocorticosteroids was started as an initial treatment and then intralesional injections of glucocorticosteroids were tried. In the past years, more patients were successfully treated with topical tacrolimus as well 16, 32. Compression therapy was performed on all of our patients to support ulcer healing, because previous reports have shown that chronic venous insufficiency, even if there are no clinical signs of stasis, can trigger tissue damage in the lower leg maintaining ulcerations caused by necrobiosis lipoidica 10. The fact that necrobiosis lipoidica almost exclusively appears on the lower legs and not in other body parts leads to the assumption that stasis plays a role in the formation of necrobiosis lipoidica plaques and ulcerations. Most of our patients as well as many cases reported in literature showed good response to oral corticosteroids 33, 34. Glucocorticosteroids are effective only if inflammation is present; in older atrophied lesions no effect is to be expected. Because of the various side effects like overall hyperglycaemia, obesity, depression and rise of liver enzymes, this therapy should be limited and a maintenance therapy is needed. One of our patients was treated successfully with cyclosporine A, which led to a good response with complete healing of the ulcers 25. Cyclosporine A is a calcineurin inhibitor, which reduces the activity of T helper cells, natural killer cells and monocytes. Non‐cell‐mediated effects are reduced expression of adhesion molecules and reduced histamine liberation. In our patient, new ulcers developed 1 year later. This leads to the conclusion that although cyclosporine A can be very effective in the treatment of ulcerated necrobiosis lipoidica, a long‐term maintenance therapy is needed to retain the effect. In a similar manner, there is increasing evidence that TNF‐α plays a major role in granuloma formation. Therefore, TNF‐α inhibitors such as infliximab and etanercept have been described as being successful in the treatment of granulomatous inflammatory diseases such as ulcerative colitis and sarcoidosis. Similarities in the profile of cytokine changes and the combined occurrence of different diseases such as rheumatoid arthritis, ankylosing spondylitis, chronic inflammatory bowel diseases, uveitis and psoriasis in the same patient have led to the hypothesis that there is a family of cytokine‐mediated diseases with the same underlying pathological process of cytokine dysregulation in which TNF‐α plays a key role. The affected diseases are summoned as TNF‐α‐related chronic inflammatory diseases (TRECIDs) and can be treated successfully with TNF‐α antagonists 35. TNF‐α is a proinflammatory cytokine that has been implicated in the maintenance of granulomas by macrophages. The inhibition of this cytokine can be achieved with TNF‐α antagonists. Thus, biological agents such as infliximab, etanercept and adalimumab have been successfully used for the treatment of granuloma annulare, sarcoidosis and also necrobiosis lipoidica. Adalimumab and infliximab are monoclonal antibodies that bind to soluble TNF‐α. Etanercept is a fusion protein consisting of the Fc portion of human IgG1 and TNF receptors that also inhibits soluble TNF function. Adalimumab and infliximab have complementary effects and induce apoptosis in TNF‐expressing cells in vitro, whereas etanercept does not 36. The use of these drugs is off‐label, because they are only approved for the treatment of rheumatoid diseases and therapy‐refractory psoriasis. In literature, several cases have been described in which ulcerated necrobiosis lipoidica had been successfully treated with infliximab or etanercept. In one case infliximab therapy had to be stopped because of exacerbation of miliary tuberculosis 37. A comparison showed faster healing of the ulcerations under treatment with infliximab compared with etanercept. In several cases, adalimumab had less or no effect on healing of ulcerated necrobiosis lipoidica compared with infliximab or etanercept 38. One should always be aware of potential side effects of these drugs, especially the increased risk of secondary malignancies. Long‐time use of biological agents can lead to endogenous anti‐TNF‐α antibodies inducing non‐responsiveness 39. The good response to TNF‐α antagonists suggests a strong role for TNF‐α‐mediated inflammation in ulcerated necrobiosis lipoidica. Another treatment option is fumaric acid esters (FAE), which are approved for the treatment of psoriasis 13, 23. Kreuter et al. performed a prospective non‐controlled study with 18 patients having necrobiosis lipoidica who were treated with FAE in the standard dosage for psoriasis for 6 months. Altogether, four of the patients had ulcerated patches of necrobiosis lipoidica and all four of them showed complete healing. In all the participating patients who completed the therapy a clinical and histological improvement of necrobiosis lipoidica could be detected. Possible adverse effects that were reported were gastrointestinal symptoms, flush and reversible lymphocytopenia. FAE interfere with granuloma formation. Dendritic cells and endothelial cells are also supposed to play a central role in granuloma formation. FAE are known to affect dendritic cells by inhibiting the production of IL‐12 by activated dendritic cells and induction of anti‐inflammatory cytokines such as IL‐4 8, 9. In endothelial cells, FAE inhibit the expression of ICAM‐1 and VCAM‐1 and the activation of NFκβ 40, 41. The complete mechanism is still unknown.

Necrobiosis lipoidica—a systemic inflammatory disease?

Our results show a strong correlation between ulcerating necrobiosis lipoidica and aspects of metabolic syndrome. All patients in our study showed one or more cardiovascular risk factors. Without dispute there is a strong correlation for necrobiosis lipoidica particularly with diabetes mellitus. A study using Doppler flowmetry showed that necrobiosis lipoidica is improbable to be due to microvascular ischaemia, but rather can be caused by inflammation 42. This suggests that ulcerating necrobiosis lipoidica can be seen as part of a generalised inflammatory reaction due to a systemic metabolic syndrome. Other inflammatory skin diseases such as psoriasis have already been shown to be part of a systemic TH1‐mediated inflammation with increased levels of TNF‐α and IL‐6, leading to TNF‐α‐induced insulin resistance, arteriosclerosis and subsequent cardiovascular events 43. Improvement and healing of the ulcerations after treatment with TNF‐α antagonists underline this hypothesis.

Conclusion

Necrobiosis lipoidica is a rarely diagnosed skin disorder. Especially, atypical cases with ulcerations are often misdiagnosed and the patient treated for more common diseases such as venous leg ulcers or vasculitis. Because of the severe impact in quality of life as well as possible complications such as infection and malignant transformation, early diagnosis and therapy are necessary. The results of our study suggest an association of ulcerated necrobiosis lipoidica with some aspects of metabolic diseases. Therefore, metabolic diseases in patients with ulcerated necrobiosis lipoidica should be diagnosed and treated early.