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Treatment of Refractory Ulcerative Necrobiosis Lipoidica Diabeticorum with Infliximab Report of a Case

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Treatment of Refractory Ulcerative Necrobiosis Lipoidica Diabeticorum with Infliximab Report of a Case OBSERVATION Treatment of Refractory Ulcerative Necrobiosis Lipoidica Diabeticorum With Infliximab Report of a Case Stephanie W. Hu, BS; Caroline Bevona, MD; Laura Winterfield, MD; Abrar A. Qureshi, MD, MPH; Vincent W. Li, MD, MBA Background: Necrobiosis lipoidica diabeticorum (NLD) agnosis of NLD. The wound did not respond to 4 months is a rare, granulomatous inflammatory skin disease of un- of intensive local wound care. After the first intrave- known origin, sometimes associated with diabetes melli- nous infusion of infliximab (5 mg/kg), there was rapid tus. Skin lesions usually develop on the lower extremi- reduction in wound size, pain, and drainage. There was ties and can progress toward ulceration and scarring. Many complete wound healing with excellent cosmesis at 6 treatments have been proposed, but few have demon- weeks (total of 3 infusions). strated consistent efficacy, and no standard regimens have emerged to date. Conclusions: Infliximab should be considered in the treatment of refractory, ulcerative NLD. Its anti–tumor Observations: An 84-year-old woman with type 1 dia- necrosis factor activity may underlie its efficacy in tar- betes mellitus presented with a 3-year history of chronic geting this granulomatous process, and further investi- right-lower-extremity erythematous papules and plaques gation should be undertaken to confirm these results. that had developed into confluent ulcers with promi- nent granulation tissue and an orange-yellow hue. The results of a biopsy of the lesion was consistent with a di- Arch Dermatol. 2009;145(4):437-439 ECROBIOSIS LIPOIDICA DIA- clonal antibody against tumor necrosis fac- beticorum (NLD) is a tor (TNF), a cytokine involved in the main- granulomatous condi- tenance of granulomas by macrophages. tion presenting most commonly as an atro- REPORT OF A CASE Nphic plaque with raised borders and telangiectasia, occurring typically on the an- terior lower legs of younger women. Ag- An 84-year-old woman had a 3-year his- gressive lesions may ulcerate. While two- tory of chronic right-lower-extremity ery- thirds of cases are found in diabetic patients, thematous papules and plaques, some of there is no correlation with glycemic con- which developed into confluent ulcers, ex- trol, and a clear pathogenetic mechanism for tending from the right knee to the medial the development of this lesion has thus far malleolus, punctuated with islands of nor- been elusive. Accordingly, while NLD ap- mal-appearing skin. Prominent granula- pears to have responded to a variety of thera- tion tissue was present at the base of the pies, consistently effective treatment regi- ulcers, and healed areas harbored an or- mens have yet to be established. ange-yellow hue. The results of a biopsy of a leg lesion taken during the initial on- set of the disease showed an ulcerated epi- Author Affiliations: For editorial comment dermis and necrobiotic collagen with scle- Department of Dermatology, see page 467 rosis and palisaded granulomas in the Angiogenesis & Wound Healing dermis (Figure 1). The dermal intersti- Center (Ms Hu and We report a case of a patient with a his- tial infiltrate consisted of histiocytes, mul- Drs Winterfield and Li) and tory of type 1 diabetes mellitus who pre- tinucleated giant cells, lymphocytes, and Dermatology-Rheumatology sented with lower extremity ulcers devel- plasma cells. These findings were consis- Center (Dr Qureshi), Brigham oping from erythematous papules and tent with a diagnosis of NLD. Her medi- & Women’s Hospital, Harvard Medical School, Boston, plaques that were histopathologically con- cal history was significant for type 1 dia- Massachusetts; and Department sistent with NLD. The lesions remained re- betes mellitus, 2 prior strokes, idiopathic of Dermatology, Lahey Clinic, fractory to intensive local wound care thrombocytopenic purpura (status post Burlington, Massachusetts therapy, but improved dramatically with the splenectomy), mild renal insufficiency, and (Dr Bevona). initiation of intravenous infliximab, a mono- hypertension. She also had a history of cho- (REPRINTED) ARCH DERMATOL/ VOL 145 (NO. 4), APR 2009 WWW.ARCHDERMATOL.COM 437 ©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Figure 3. Shortly after week 2, most of the smaller ulcers were almost completely reepithelialized, and less than 50% of the larger ulcers remained. The ulcer remained completely healed during routine clinical follow-up more than 1 year. Figure 1. Biopsy specimens. The right anterior and medial aspects of the shin showed ulcerated epidermis and necrobiotic collagen with sclerosis and palisaded granulomas in the dermis (hematoxylin-eosin, original of 5 infusions (at weeks 0, 2, 6, 12, and 21). At her first magnification ϫ20). The dermal interstitial infiltrate consists of histiocytes, multinucleated giant cells, lymphocytes, and plasma cells. posttreatment visit (week 2), the surface area of the larger ulcerations had decreased by approximately 50%, and the smaller lesions had almost completely reepithelialized (Figure 3). She also reported decreased pain and drain- age in the involved areas. Complete wound healing was achieved at week 6 of infliximab therapy, with excellent cosmesis. The patient experienced no adverse effects from infliximab and no recurrence of the lesions during clini- cal follow-up more than 1 year. COMMENT Necrobiosis lipoidica diabeticorum is a chronic granulo- matous disease of unknown origin, occurring 3 times more frequently in women than in men,1,2 particularly in pa- Figure 2. Multiple ulcers of the right lower extremity from the knee to the posterior aspect of the heel with 2ϩ pitting edema on the right leg, most tients aged 30 to 40 years, and often on the shins, back of 3 marked over the right dorsal aspect of the foot. the hands, or the forearms. Seventy-five percent of pa- tients with NLD have or will develop diabetes mellitus (type 1 more often than type 2), although only approximately lecystitis with subsequent granulomatous inflamma- 0.3% of diabetic patients develop NLD.2 Although ulcer- tion, but no evidence of sarcoidosis. ation has been reported in 13% to 35% of cases, usually in During the 1-month period before her initial presen- the setting of trauma, spontaneous rapid and fulminant ul- tation at the Angiogenesis & Wound Healing Center, ceration is uncommon.4,5 Spontaneous remission has been Brigham and Women’s Hospital, the patient experi- reported in approximately 20% of patients.3 enced a fulminant expansion and ulceration of the le- To our knowledge, there is currently no standard- sions, with the ulcers extending over her shin and calf ized, effective treatment of NLD in clinical practice. First- (Figure 2). She was initially treated with intralesional line therapies include topical and intralesional cortico- triamcinolone acetonide (5 mg/mL) and intensive local steroids.2 Smoking cessation and diabetic control may also wound management, which included sharp de´bride- be effective because reports have documented the ben- ment, papain-urea enzymatic de´briding ointment, ca- eficial effects of thiazolidinediones in NLD6; however, dexomer iodine antisepsis gel, Prisma Promogran (1% treatment of a patient’s diabetes has not been shown to silver-ORC [oxidized regenerated cellulose]-collagen, improve the cutaneous lesions.2 Other therapies that have Johnson & Johnson Wound Management, Somerville, been tried, with varying degrees of success, include sys- New Jersey) bioactive dressing, and compression strap- temic corticosteroids, topical retinoids,7 nicotinamide,8 pings. The wounds remained open and inflamed de- pentoxifylline,9 aspirin and dipyridamole,10 clofaz- spite 4 months of this treatment regimen. imine,11,12 hyperbaric oxygen,13,14 fumaric acid esters,15 Given the lack of response to intensive local wound thalidomide,16 topical tacrolimus,17 mycophenolate care, we theorized that the underlying pathogenic pro- mofetil,18 cyclosporine,19,20 and sometimes excision in the cess of NLD might respond to an anti-TNF approach, and case of recalcitrant ulcers. Topical psoralen–UV-A21 and we decided to treat the patient with intravenous inflix- photodynamic therapy22 have been effective, and pulsed imab at a dose of 5 mg/kg. Before the initiation of anti- dye lasers12 can improve the appearance of telangiecta- TNF treatment, a negative purified protein derivative (tu- sias. Recently, 7 in a series of 8 patients were reported to berculin) test result was confirmed. She received a total show clinical improvement with antimalarial therapy.23 (REPRINTED) ARCH DERMATOL/ VOL 145 (NO. 4), APR 2009 WWW.ARCHDERMATOL.COM 438 ©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Infliximab is a monoclonal antibody that binds to TNF Financial Disclosure: Dr Li has served as a consultant and is currently approved for the treatment of inflamma- for Johnson & Johnson/Ethicon, Genentech, and tory bowel disease, psoriatic arthritis, ankylosing spondy- Organogenesis. Dr Qureshi has served as a speaker for litis, and rheumatoid arthritis. Infliximab blocks soluble and Abbott, Amgen, and Genentech. transmembrane-bound TNF and leads to a number of anti- inflammatory effects and cytolysis of inflammatory cells ex- 24,25 pressing TNF receptors. Tumor necrosis factor is a pro- REFERENCES inflammatory cytokine, and blockade results in amelioration of inflammatory conditions, which includes the reduced 1. Huntley AC. The cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol. 25 formation of granulomas. As such, infliximab has been 1982;7(4):427-455. shown to be beneficial in chronic cutaneous granuloma- 2. Peyri J, Moreno A, Marcoval J. Necrobiosis lipoidica. Semin Cutan Med Surg. 2007;26(2):87-89. tous diseases, such as disseminated granuloma annulare and 3. Körber A, Dissemond J. Necrobiosis lipoidica diabeticorum. CMAJ. 2007;177(12): sarcoid,24-26 as well as 2 cases of ulcerative NLD.25,27 In both 1498. cases of ulcerative NLD, a dose of 5 mg/kg was used. In 4. Kalus AA, Chien AJ, Olerud JE. Diabetes mellitus and other endocrine diseases. 25 In: Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, eds.
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