Dermatology Online Journal
Treatment of necrobiosis lipoidica with etanercept and adalimumab
- Author(s): Zhang, Kevin S
- Quan, Long T
- Hsu, Sylvia
- et al.
Treatment of necrobiosis lipoidica with etanercept and adalimumab1. Baylor College of Medicine, Houston, Texas. firstname.lastname@example.org
Kevin S Zhang MD1, Long T Quan MD PhD2, Sylvia Hsu MD1
Dermatology Online Journal 15 (12): 12
2. Carolinas Dermatology Group, Columbia, South Carolina
Necrobiosis lipoidica (NL) is a rare chronic condition presenting as yellow-brown inflammatory plaques with raised borders and an atrophic center. The unilateral or bilateral lesions most commonly occur on the shins and lower extremities. The disease is a granulomatous inflammatory disorder characterized by telangiectasias and collagen degeneration in the dermis and subcutaneous fat . The plaques can leave disfiguring scars. Ulceration occurs in 15 percent of cases, leading to greater risk for secondary infection  and in rare cases, NL leads to squamous cell carcinoma . Necrobiosis lipoidica primarily develops in women between the ages of 30-41, although it is not uncommon in children . Two-thirds of patients with this disease have diabetes mellitus, giving it a prevalence of 0.3 percent in the diabetic population . Necrobiosis lipoidica is found more commonly in the insulin-dependent type of diabetes than the non-insulin-dependent type . Treatments for NL have had limited success, due to the unclear pathogenesis of the disease.
Adalimumab (Humira®, Abbott Laboratories, Abbott Park, IL) and etanercept (Enbrel®, Immunex Corp, Thousand Oaks, CA) both suppress TNF function and inflammation. They are administered in the management of psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. Adalimumab can also be used to treat Crohn disease.
A 29-year-old Caucasian woman presented with necrobiosis lipoidica, confirmed by histopathology. The patient had a history of non-insulin-dependent diabetes, well controlled by glucophage. Her first lesion developed on her dorsal left foot 9 years prior. Since then, the disease had progressed to cover both of her feet, lower extremities, and trunk. The patient had tried topical steroids, intralesional steroids, pentoxifylline, and multiple oral and intravenous antibiotics. She was treated with cyclosporine for one month but discontinued due to side effects. None of the treatments resulted in any improvement of her skin lesions.
Examination revealed multiple erythematous-to-orange, painful plaques on the lower extremities and trunk. On her feet, the plaques were confluent and encompassed both feet.
|Figure 1. Left: Before etanercept treatment. Right: 8 months after treatment, prior to adalimumab treatment.|
The patient was started on subcutaneous etanercept (50 mg) injections twice weekly for 3 months, then weekly after that. She reported significant improvement by two months and complete pain resolution by four months. Due to insurance reasons, the patient was switched to subcutaneous adalimumab (40 mg) injections every other week, 8 months after treatment with etanercept had begun. However, after 3 months of adalimumab, she did not observe improvement. As a result, she switched back to etanercept. She continued for 3 months on etanercept 50 mg twice weekly until her etanercept injections were brought down to once a week. On her final visit 6 months later, the patient had reported progressive improvement since switching back to etanercept. The plaques had flattened and the erythema had improved (Fig. 1). No new plaques have developed since initial treatment. Other than feeling tired the day after injection, the patient experienced no other side effects.
The current treatments for NL have achieved limited efficacy or carry significant side effects. Some treatments focus on improving cutaneous blood flow or wound healing. Corticosteroids, such as intralesional triamcinolone, have been shown to result in modest improvement . Topical tacrolimus ointment has had some success in treating NL . Topical PUVA treatment for ulcerating NL has been shown to reduce pain and heal ulcerations . Other therapies include nicotinamide, clofazimine, chloroquine, and topical tretinoin .
This case utilizes drugs that suppress TNF function. Adalimumab and infliximab are monoclonal antibodies that bind to soluble TNF-α to prevent its interaction with TNF receptors on cell surfaces. 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 fix complement and induce apoptosis in TNF-expressing cells in vitro, while etanercept does not .
Our patient showed improvement after systemic treatment with etanercept with minimal side effects. A case study by Zeichner et al. treated NL in a 35-year-old woman for 8 months using etanercept injections and also recorded improvement without side effects . However, these injections were given intralesionally and not systemically as in our case. In addition, two cases have demonstrated some success treating NL using infliximab. Drosou et al. administered infliximab along with prednisone . The treatment by Kolde et al. resulted in improvement as well but the patient contracted tuberculosis after 2 months . The relative efficacy of etanercept and the minimal adverse effects suggest that it is a worthy mode of treatment for NL.
Etanercept had a greater efficacy than adalimumab in our patient, but the reasons remain unclear. Ebert et al. suggests that TNF-α sensitive disorders may not actually be triggered by TNF-α. This is due to the fact that patients with ulcerative colitis that are non-responsive to anti-TNF-α antibodies already have high levels of endogenous anti-TNF-α antibodies, which should neutralize any diseases mediated by TNF-α . In addition, reports have demonstrated that endogenous antibodies to anti-TNF-α drugs play a role in inducing non-responsiveness . Evaluating differences in physiological response to adalimumab, infliximab, and etanercept may provide insight into the pathogenesis and treatment of NL.
References1. Alegre VA, Winkelmann RK. A new histopathologic feature of necrobiosis lipoidica diabeticorum: lymphoid nodules. J Cutan Pathol 1988;15:75-7. [PubMed]
2. Markey AC, Tidman MJ, Rowe PH et al. Aggressive ulcerative necrobiosis lipoidica associated with venous insufficiency, giant-cell phlebitis and arteritis. Clin Exp Dermatol 1988;13:183-6. [PubMed]
3. Santos-Juanes J, Galache C, Curto JR et al. Squamous cell carcinoma arising in long-standing necrobiosis lipoidica. J Eur Acad Dermatol Venereol 2004;18:199-200. [PubMed]
4. DeSilva BD, Schofield OM, Walker JD. The prevalence of necrobiosis lipoidica in children with type 1 diabetes. Br J Dermatol 1999;141:593-4. [PubMed]
5. Lowitt MH, Dover JS. Necrobiosis lipoidica. J Am Acad Dermatol 1991;25:735-48. [PubMed]
6. Sparrow G, Abell E. Granuloma annulare and necrobiosis lipoidica treated by jet injector. Br J Dermatol 1975;93:85-9. [PubMed]
7. Harth W, Linse R. Topical tacrolimus in granuloma annulare and necrobiosis lipoidica. Br J Dermatol 2004;150:792-4. [PubMed]
8. Patel GK, Harding KG, Mills CM. Severe disabling koebnerising ulcerated necrobiosis lipoidica successfully managed with topical PUVA. Br J Dermol 2000;143:668-9. [PubMed]
9. Tidman MJ, Duncan C. The treatment of necrobiosis lipoidica. Br J Diabetes Vasc Dis 2005;5(1):37-41. DOI: 10.1177/14746514050050010701
10. Mitoma H, Horiuchi T, Tsukamoto H, Tamimoto Y, Kimoto Y, Uchino A, To K, Harashima S, Hatta N, Harada M. Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor alpha-expressing cells: comparison among infliximab, etanercept, and adalimumab. Arthritis Rheum 2008;58(5):1248-57. [PubMed]
11. Zeichner JA, Stern DW, Lebwohl M. Treatment of necrobiosis lipoidica with the tumor necrosis factor antagonist etanercept. J Am Acad Dermatol 2006;54(3 Suppl 2):S120-1. [PubMed]
12. Drosou A, Kirsner R S, Welsh Esperanza. Use of Infliximab, an Anti-Tumor Necrosis Alpha Antibody, for Inflammatory Dermatoses. J Cutan Med Surg 2003;7(5):382-386. [PubMed]
13. Kolde G, Muche JM, Schulze P, Fischer P, Lichey J. Infliximab: a promising new treatment option for ulcerated necrobiosis lipoidica. Dermatology 2003;206(2):180-1. [PubMed]
14. Ebert EC, Das KM, Mehta V, Rezac C. Non-response to infliximab may be due to innate neutralizing anti-tumour necrosis factor-alpha antibodies. Clin Exp Immunol 2008;154(3):325-31. [PubMed]
15. Radstake TR, Svenson M, Eijsbouts AM, van den Hoogen FH, Enevold C, van Riel PL, Bendtzen K. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis 2008 [Epub ahead of print]. Available from: BMJ Journals. www.ard.bmj.com. [PubMed]
© 2009 Dermatology Online Journal