Case report

Necrobiosis lipoidica occurring in a patient with rheumatoid arthritis on concurrent tumor necrosis factor-a inhibitor therapy Catherine G. Chung1,2, MD, Abric Rosengrant1, BA, Klaus F. Helm1,2, MD, and David L. Shupp2, MD


Department of Pathology, and Department of Dermatology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA 2

Correspondence Klaus F. Helm, MD Department of Pathology, H179 Penn State Hershey Medical Center 500 University Drive PO Box 850 Hershey PA 17033 USA E-mail: [email protected] Conflicts of interest: None.



Necrobiosis lipoidica (NL) is a chronic granulomatous skin disorder with unclear pathogenesis. Classic, welldeveloped lesions of NL feature patches or plaques with an atrophic, slightly depressed, often shiny yellow–brown center.1 The border of these lesions frequently demonstrates a well-defined inflammatory edge that may be raised and red to purple in color.1,2 The pretibial areas are the most commonly affected location, and less frequently lesions may be seen on the upper extremities, face, and scalp. Up to 35% of cases demonstrate ulceration, frequently following minor trauma.3 The average age of onset is in the fourth decade, but cases occurring in children and the elderly have also been reported.4,5 While the majority of cases are idiopathic, NL has been associated with various systemic and chronic diseases, including diabetes mellitus, sarcoidosis, rheumatoid arthritis (RA), autoimmune thyroid disease, and inflammatory bowel disease.4,6–8 The main histopathologic features of an established lesion of NL are those of horizontally oriented palisading granulomas composed of histiocytes, lymphocytes, and, International Journal of Dermatology 2015, 54, 1294–1296

to a lesser extent, plasma cells that involve the full thickness of the dermis. The process may extend into the subcutaneous adipose tissue as well, lending a clinical and histopathologic picture of panniculitis.1,9 Case Report A 20-year-old woman with a 2-year history of RA presented to her dermatologist for evaluation of enlarging, irregularly shaped, yellow–brown plaques of several months’ duration over the bilateral pretibial areas (Fig. 1). She complained of associated pruritus but had no tenderness or ulceration. She initially attributed the lesions to irritation from wearing ski boots and sought evaluation when they progressed despite discontinuation of ski activities. She otherwise denied any antecedent trauma to the areas or other perceived precipitating factors. She had no personal or family history of diabetes mellitus and no additional medical history. Ongoing immunosuppressive therapy for RA at the time of her initial dermatology visit included adalimumab, methotrexate, and low-dose prednisone, which resulted in good control of her symptoms and disease activity. ª 2014 The International Society of Dermatology

Chung et al.

TNFa inhibitor therapy in NL and RA

Case report


Figure 1 Necrobiosis lipoidica in a patient with concomitant


rheumatoid arthritis. Characteristic yellow–brown plaques with central atrophy on the lower extremities

A biopsy of a representative lesion on the right shin was performed. Microscopic examination demonstrated horizontally oriented palisading histiocytes surrounding degenerated collagen with a superficial and deep perivascular lymphoplasmacytic infiltrate (Fig. 2). Stains for fungal and acid-fast organisms were negative. A colloidal iron stain did not demonstrate any increased dermal mucin. Based on the clinical and histopathologic findings, a diagnosis of NL was made. The patient was treated with topical clobetasol as well as intralesional triamcinolone for the lesions while continuing her systemic regimen for treatment of RA, with resolution of pruritus and modest improvement in the appearance of the lesions. Discussion Treatment of NL often meets with limited or only modest improvement. Reported treatment modalities include topical and intralesional corticosteroids, topical tacrolimus, and various immunosuppressive agents, including cyclosporine, methotrexate, and mycophenolate mofetil.10–18 Other therapies include clofazimine, antimalarial agents, and topical psoralen + ultraviolet A therapy.19–22 Additionally, successful treatment of NL has been reported with anti-tumor necrosis factor (TNF) therapy, including etanercept and infliximab.13,14,23–27 While the exact role of TNF-a in the pathogenesis of NL remains to be elucidated, inhibitors of this proinflammatory cytokine have also been employed with encouraging results in the treatment of other chronic cutaneous granulomatous conditions, including granuloma annulare and sarcoidosis.28,29 Our patient developed progressive lesions of NL despite ª 2014 The International Society of Dermatology

Figure 2 Biopsy from the pretibial area. Characteristic horizontally oriented palisading histiocytes surrounding degenerated collagen with a superficial and deep perivascular lymphoplasmacytic infiltrate. Hematoxylin and eosin: (a) 940 and (b) 9200

concomitant combination therapy with systemic methotrexate, prednisone, and adalimumab for RA. While NL occurring in the context of RA has been previously reported in the literature,6,9 to the best of our knowledge, this is the first case of NL arising in a patient with RA on concurrent anti-TNF-a therapy. Of interest, Zhang and colleagues13 reported a case of NL in a young woman who responded to etanercept but not adalimumab. With the exception of our current case, this is the only other case of NL treated with adalimumab in the literature. Based on the few reported cases of successful treatment of NL by TNF-a inhibitor therapy, therefore, etanercept or infliximab may provide better efficacy compared to adalimumab in this disease. Lastly, several authors have reported a similar paradoxical onset to our patient of chronic cutaneous granulomatous conditions other than NL in rheumatological patients undergoing treatment International Journal of Dermatology 2015, 54, 1294–1296



Case report

TNFa inhibitor therapy in NL and RA

with anti-TNF-a inhibitors.14,30,31 These cases, along with our current case, suggest a complex role of TNF-a in the recruitment of histiocytes and granuloma formation in specifically inflammatory rheumatological conditions. Further discovery regarding the pathogenesis of chronic granulomatous skin conditions, including NL, in this setting may help to focus future prospective treatments of NL in this subset of patients. References 1 Muller SA, Winkelmann RK. Necrobiosis lipoidica diabeticorum. GP 1966; 34: 93–96. 2 Michaels BD, Mullinax KA, Wells MJ, et al. Tuberous necrobiosis lipoidica. Arch Dermatol 2007; 143: 546– 548. 3 Elmholdt TR, S½rensen HB, Fogh K. A severe case of ulcerating necrobiosis lipoidica. Acta Derm Venereol 2008; 88: 177–178. 4 Muller SA. Dermatologic disorders associated with diabetes mellitus. Mayo Clin Proc 1966; 41: 689–703. 5 Szabo RM, Harris GD, Burke WA. Necrobiosis lipoidica in a 9-year-old girl with new-onset type II diabetes mellitus. Pediatr Dermatol 2001; 18: 316–319. 6 Magro CM, Crowson AN, Regauer S. Granuloma annulare and necrobiosis lipoidica tissue reactions as a manifestation of systemic disease. Hum Pathol 1996; 27: 50–56. 7 Whorwhell PJ, Haboubi NY, Du Boulay C. Nodular necrobiosis in association with ulcerative colitis. Gut 1986; 27: 1517. 8 Jorizzo JL, Olansky AJ, Stanley RJ. Superficial ulcerating necrobiosis in rheumatoid arthritis. Arch Dermatol 1982; 118: 255–259. 9 Kota SK, Jammula S, Kota SK, et al. Necrobiosis lipoidica diabeticorum: a case-based review of literature. Indian J Endocrinol Metab 2012; 16: 614–620. 10 Sparrow G, Abell E. Granuloma annulare and necrobiosis lipoidica treated by jet injector. Br J Dermatol 1975; 93: 85–89. 11 Harth W, Linse R. Topical tacrolimus in granuloma annulare and necrobiosis lipoidica. Br J Dermatol 2004; 150: 792–794. 12 Tidman MJ, Duncan C. The treatment of necrobiosis lipoidica. Br J Diabetes Vasc Dis 2005; 5: 37–41. 13 Zhang KS, Quan LT, Hsu S. Treatment of necrobiosis lipoidica with etanercept and adalimumab. Dermatol Online J 2009; 15: 12.  Perez-Bustillo A, Ruiz-Gonz 14 Suarez-Amor O, alez I, et al. Necrobiosis Lipoidica therapy with biologicals: an ulcerated case responding to etanercept and a review of the literature. Dermatology 2010; 221: 117–121. 15 Clayton TH, Harrison PV. Successful treatment of chronic ulcerated necrobiosis lipoidica with 0.1% topical tacrolimus ointment. Br J Dermatol 2005; 152: 581–582.

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16 Darvay A, Acland KM, Russell-Jones R. Persistent ulcerated necrobiosis lipoidica responding to treatment with cyclosporin. Br J Dermatol 1999; 141: 725–727. 17 Reinhard G, Lohmann F, Uerlich M, et al. Successful treatment of ulcerated necrobiosis lipoidica with mycophenolate mofetil. Acta Derm Venereol 2000; 80: 312–313. 18 West EA, Warren RB, King CM. A case of recalcitrant necrobiosis lipoidica responding to combined immunosuppression therapy. J Eur Acad Dermatol Venereol 2007; 21: 830–831. 19 Patel GK, Harding KG, Mills CM. Severe disabling koebnerising ulcerated necrobiosis lipoidica successfully managed with topical PUVA. Br J Dermol 2000; 143: 668–669. 20 Benedix F, Geyer A, Lichte V, et al. Response of ulcerated necrobiosis lipoidica to clofazimine. Acta Derm Venereol 2009; 89: 651–652. 21 Durupt F, Dalle S, Debarbieux S, et al. Successful treatment of necrobiosis lipoidica with antimalarial agents. Arch Dermatol 2008; 144: 118–119. 22 Narbutt J, Torzecka JD, Sysa-Jedrzejowska A, et al. Long-term results of topical PUVA in necrobiosis lipoidica. Clin Exp Dermatol 2006; 31: 65–67. 23 Drosou A, Kirsner RS, Welsh E, et al. Use of infliximab, an anti-tumor necrosis alpha antibody, for inflammatory dermatoses. J Cutan Med Surg 2003; 7: 382–386. 24 Kolde G, Muche JM, Schulze P, et al. Infliximab: a promising new treatment option for ulcerated necrobiosis lipoidica. Dermatology 2003; 206: 180–181. 25 Cummins DL, Hiatt KM, Mimouni D, et al. Generalized necrobiosis lipoidica treated with a combination of splitthickness auto-grafting and immunomodulatory therapy. Int J Dermatol 2004; 43: 852–854. 26 Zeichner JA, Stern DW, Lebwohl M. Treatment of necrobiosis lipoidica with the tumor necrosis factor antagonist etanercept. J Am Acad Dermatol 2006; 54: S120–S121. 27 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: 437–439. 28 Supack J, Siu K. Resolving granuloma annulare with etanercept. Arch Dermatol 2006; 142: 394–395. 29 Haley H, Cantrell W, Smith K. Infliximab therapy for sarcoidosis (lupus pernio). Br J Dermatol 2004; 150: 146–149. 30 Toussirot E, Pertuiset E, Kantelip B, et al. Sarcoidosis occurring during anti-TNF-alpha treatment for inflammatory rheumatic disease: report of two cases. Clin Exp Rheumatol 2008; 26: 471–475. 31 Voulgari PV, Markatseli TE, Exarchou SA, et al. Granuloma annulare induced by anti-tumour necrosis factor therapy. Ann Rheum Dis 2008; 67: 567–570.

ª 2014 The International Society of Dermatology

Necrobiosis lipoidica occurring in a patient with rheumatoid arthritis on concurrent tumor necrosis factor-α inhibitor therapy.

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