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Selective case study describing the use of Apligraf on necrobiosis lipoidica associated with diabetes Necrobiosis lipoidica is a rare skin disease characterised by large, well-demarcated, symmetrical plaques with overlying telangiectasias and atrophic, fibrotic features. The disease is associated with diabetes mellitus (1 in 300 cases), but can also be linked to other diseases such as rheumatoid arthritis. Women are three times more likely to develop necrobiosis lipoidica compared to men. Ulcerations are the most serious type of complications in necrobiosis lipoidica, and they occur most frequently on the legs of patients. However, the aetiology of necrobiosis lipoidica still remains unclear. Although many studies have been conducted in order to determine necrobiosis lipoidica’s pathophysiology, a clear and definite path to disease has not been recorded. In this case study, a patient with necrobiosis lipoidica that had been refractory to conventional therapy received treatment with Apligraf® bioengineered wound dressings. Apligraf was shown to be effective in managing the patient’s multiple hard-to-heal wounds. It was more successful than previous therapies in achieving granulation tissue formation and wound volume reduction, in addition to being a more rapid form of treatment.

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ecrobiosis lipoidica is a rare skin disease that is generally characterised by chronic wounds below the knee, many of which are unremitting to multiple modes of therapy. Greater than 75% of necrobiosis lipoidica sufferers are either currently diagnosed or will someday be diagnosed with diabetes. Many patients also have concurrent impaired glucose intolerance and/or a strong family history of diabetes. Despite the strong correlation with diabetes, less than one percent of the entire diabetic population will develop this condition. Gender comparison indicates that females have a higher incidence of the disease than men at a ratio of 3 to 1.1 While related to diabetes, the clinical features of necrobiosis lipoidica resemble a process far differ-

ent than that of a typical diabetic foot ulcer. Necrobiosis lipoidica initially presents as small redbrown papules and nodules that may mimic sarcoid or granuloma annulares. Over time, the lesions expand into indurated, well-demarcated, yellow-red or yellow-brown plaques with central epidermal atrophy and telangiectasias. In up to one-third of the cases, the atrophied lesions can lead to serious complications such as ulcerations. The majority of the lesions will present on the anterior tibial region of the lower leg. The aetiology of necrobiosis lipoidica still remains unclear, despite numerous studies aimed at delineating the root cause of the disorder. Recent evidence suggests that microangiopathy (abnormal collagen production) and immune complex vasculitis, along with the involvement of T cells and

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H.L. Penny,1 DPM, DABPM, FAPWHc; M. Faretta,2 APWH Student Member; M. Rifkah,3 APWH Student Member; A. Weaver,4 Pre-medical Student; A. Swires,1 RN, BSN; J. Spinazzola,5 DO, APWH, Medical Resident; 1 University of Pittsburgh Medical Centre Altoona, Altoona, US; 2 The Commonwealth Medical College, Scranton, US;

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necrobiosis lipoidica; Apligraf; diabetes; leg ulcers

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practice 3 Marshall University School of Medicine, Huntington, US; 4 Juniata College, Duncansville, US; 5 Penn State Hershey Medical Center, Hershey, US. Email: [email protected]

Fig 1. Wound appearance on first day of application of Apligraf

Fig 2. Wound application at second application, 6 weeks after initial application.

Case Study The patient was a 13 year-old female with a 10-year history of necrobiosis lipoidica located bilaterally on the lower extremities; she was refractory to multiple modes of treatment. Her initial diagnosis was made at the age of three. Six years later, she was diagnosed with type 1 diabetes. The patient received

Fig 3. Wound 3 appearance 5 weeks after Apligraf treatment

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Declaration of interest: There were no external sources of funding for this study. The author has no conflicts of interest to declare with regard to the manuscript or its content.

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release of pro-inflammatory cytokines, are possibly implicated in the pathophysiology of necrobiosis lipoidica. Current studies are also determining that the degree of hyperglycaemia and diabetic control do not correlate with the presence or severity of necrobiosis lipoidica.2 Traditionally, the treatment of necrobiosis lipoidica has been one of chronic, suboptimal therapy that has not been uniformly successful across the patient population.3 First-line therapy generally begins with the application of a topical steroid at the lowest effective potency. Steroid strength is then slowly increased over the course of several weeks for refractory cases, carefully monitoring for atrophy of the skin. Intralesional injections of steroids have also been found to be beneficial against ongoing inflammation, but have been found to provide no benefit, and may actually worsen atrophic lesions. In some cases, systemic steroids have been found to halt both disease progression and recurrences, but again provide no resolution of concurrent atrophic skin lesions.4 Additional therapies have been attempted, but none have been shown to consistently provide benefits to large populations. Two therapies with similar mechanisms of action, Tacrolimus and Cyclosporine have been attempted with positive outcomes. In both situations, these two drugs have shown successful treatment of ulcerated necrobiosis lipoidica.5,6 Several other therapies such as antimalarial drugs (Chloroquine), hyperbaric oxygen, granulocyte-macrophage colony stimulating factor, and TNFα inhibitors (Infliximab) have all been shown to demonstrate benefit in small case studies. Unfortunately, none of the aforementioned therapies have been proven to show consistent efficacy in a large population study.7-10 There have also been implications of PUVA therapy, a novel type of therapy that combines oral or topical psoralen medication with ultraviolet A light. This type of therapy, although unique has yet to have solid long-term results with some necrobiosis lipoidica patients exhibiting a recurrence of disease after 8–12 months.11 Apligraf® is a living, bi-layered wound dressing that serves as a skin substitute. This bioengineered wound dressing contains living cells and proteins such as type-I collagen, fibroblasts, and matrix proteins. It has been FDA approved for the treatment of diabetic foot ulcers, as well as venous leg ulcers.

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practice Fig 5. Measurements of wound 1 dimensions showing progression of healing over course of treatment Wound 1: Dimensions before and after Apligraf treatment 12 10

Area (cm2) Volume (cm3)

8 6 4 2 First Application

Second Application

Fig 6. Measurements of wound 2 dimensions showing progression of healing over course of treatment Wound 2: Dimensions before and after Apligraf treatment 12 10

Area (cm2) Volume (cm3)

8 6 4 2 0

Initial Assessment

First Application

Second Application

Table 1: Initial assessment of wound dimensions Length

Width

Depth

Wound Notes

Wound 1 (LLE proximal)

3.7 cm

3.0 cm

0.1 cm

Complete basic granulation tissue

Wound 2 (LLE middle)

3.4 cm

3.0 cm

0.2 cm

40% nonviable tissue 60% granulation tissue

Wound 3 (LLE distal)

0.4 cm

0.3 cm

0.2 cm

100% nonviable tissue

treatment at a different institution prior to presenting at our wound clinic. Past treatment for the patient’s necrobiosis lipoidica included both topical and systemic steroids, as well as intralesional injections, yet no longterm positive outcomes were reported with these measures. She also received oral formulations of niacinamide, pentoxifylline, and zinc. However, she was refractory to these treatments, with poor longterm outcomes, leading to her decision to present to our wound clinic. S14

Fig 4. Wound 3 appearance 10 weeks after Apligraf treatment and 16 weeks after initiation of Apligraf to wounds 1 and 2.

Methods Initially, the wounds were treated with Collagenase Santyl Ointment, Fibracol, Solosite, and an Unna boot dressing. Three individual wounds on the left lower extremity (LLE) were then evaluated and chosen for the trial with the Apligraf wound dressing: Necrotic areas of the wound were debrided where indicated. Once healthy, granulated tissue was exposed, the Apligraf wound dressing was applied per the product protocol. Adaptic dressings were applied over the wounds and covered with Acticoat® absorbent dressings in order to decrease bioburden. At each dressing change, the patient was also wrapped in an Unna boot in order to augment venous return and keep the dressings in place. During each office visit, multiple aspects of the wounds were examined and recorded: wound dimensions, percentage of non-viable tissue within the wounds, exudate volumes, signs of infection, and pain.

Results On the first day of the application of Apligraf (Fig 1), wound 1 measured 1.0cm x 1.5cm x 0.1cm, while wound 2 measured 3.4cm x 3.0cm x 0.1cm (length, width, depth, respectively). Apligraf was only applied to wounds 1 and 2, as wound 3 did not yet have viable tissue for the application of wound dressing. At the second application of Apligraf (Fig 2), six weeks after the initial application, wounds 1 and 2 were completely resolved. At this stage, given that wound 3 now had viable tissue for Apligraf wound dressing placement, Apligraf was applied to the wound. Five weeks following the initial application of Apligraft to wound 3, the patient presented with an infected wound (Fig 3). She was placed on oral cefadroxil, and the wound was covered with PolyMem silver dressing to decrease bio-burden and

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Initial Assessment

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practice

Conclusion

Table 2. First application. Length

Width

Depth

Wound 1 (LLE proximal)

1.0 cm

1.5 cm

0.1 cm

Wound 2 (LLE middle)

3.4 cm

3.0 cm

0.1 cm

Wound 3 (LLE distal)

1.3 cm

1.5 cm

0.1 cm

Table 3. Second application (only to wound 3) – six weeks after initial application.

Apligraf was effective in managing the patient’s multiple ulcerations due to necrobiosis lipoidica, and is hence an effective treatment option for this type of wound that had previously been refractory to other forms of treatment. The Apligraf treatment protocol not only avoided further complications but proved to be more successful than previously attempted therapies. Apligraf achieved both granulation tissue formation and wound volume reduction, doing so in a more rapid pace than the aforementioned therapies. Whereas prior treatments were conducted in a 6–12 month span, our initial application of Apligraf resolved wounds 1 and 2 in 45 days, with wound 3 resolving in 68 days. The delay in healing wound 3 is due to the hypergranulation that occurred at the wound site,

as well as the presence of a superficial skin infection around the periwound. These two reasons could be attributed to the delay of wound closure at the site of wound 3. In this case study, Apligraf was used as an off-label treatment. The treatment protocol with Apligraf application we used in this present case study may be a future indication for the treatment of necrobiosis lipoidica. n

References 1 Cohen, O.,Yaniv, R., Karasik, A., Trau, H. Necrobiosis lipoidica and diabetic control revisited. Med Hypotheses 1996; 46: 4, 348–350. 2 Dandona, P., Freedman, D., Barter, S. et al. Glycosylated haemoglobin in patients with necrobiosis lipoidica and granuloma annular. Clin Exp Dermatol 1981; 6: 3, 299–302. 3 Lowitt, M., Dover, J. Necrobiosis lipoidica. J Am Acad Dermatol 1991; 25: 735–748. 4 Petzelbauer, P., Wolff, K., Tappeiner, G. Necrobiosis

necrobiosis lipoidica with antimalarial agents. Arch Dermatol 2008; 144: 1, 118–119. 8 Remes, K., Rönnemaa, T. Healing of chronic leg ulcers in diabetic necrobiosis lipoidica with local granulocyte-macrophage colony stimulating factor treatment. J Diabetes Complications 1999; 13: 2, 115–118. 9 Bouhanick, B.,Verret, J., Gouello, J. et al. Necrobiosis lipoidica: treatment by hyperbaric oxygen and local corticosteroids. Diabetes Metab. 1998; 24: 2, 156-159.

Width

Depth

0.0 cm

0.0 cm

0.0 cm

Wound 2 (LLE middle)

0.0 cm

0.0 cm

0.0 cm

Wound 3 (LLE distal)

1.8 cm

2.0 cm

0.2 cm

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10 Hu, S., Bevona, C., Winterfield, L. et al. Treatment of refractory ulcerative necrobiosis lipoidica diabeticorum with infliximab: report of a case. Arch Dermatology 2009; 145: 4, 437–439. 11 Narbutt, J., Torzecka, JD., Sysa-Jedrzejowska, A., Zalewska, A. Long-term results of topical PUVA in necrobiosis lipoidica. Clin Exp Dermatol 2006; 31: 1, 65–67.

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lipoidica: treatment with systemic corticosteroids. Br J Dermatol 1992; 126: 6, 542–545. 5 Clayton, T., Harrison, P.V. Successful treatment of chronic ulcerated necrobiosis lipoidica with 0.1% topical tacrolimus ointment. Br J Dermatol 2005; 152: 3, 581–582. 6 Stanway, A., Rademaker, M., Newman, P. Healing of severe ulcerative necrobiosis lipoidica with cyclosporin. Australas J Dermatol 2004; 45: 2, 119–122. 7 Durupt, F., Dalle, S., Debarbieux, S. et al. Successful treatment of

Length Wound 1 (LLE proximal)

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absorb drainage. Small vesicles that could have contributed to heat rash were noted. Calmoseptine was applied to the rash area. Cast padding and Unna’s boot were then applied. Ten weeks after application of Apligraf to wound 3, and 16 weeks after application of Apligraft to wounds 1 and 2, all wounds had completely resolved. The progression of healing over the course of treatment of wounds 1 and 2 are shown in Fig 5 and 6.

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