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Home , Necrobiosis, Necrobiosis lipoidica, Ulcer (dermatology)

OBSERVATION Treatment of Refractory Ulcerative 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: diabeticorum (NLD) agnosis of NLD. The wound did not respond to 4 months is a rare, granulomatous inflammatory of un- of intensive local wound care. After the first intrave- known origin, sometimes associated with melli- nous infusion of infliximab (5 mg/kg), there was rapid tus. Skin usually develop on the lower extremi- reduction in wound size, , 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- 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 and plaques gation should be undertaken to confirm these results. that had developed into confluent with promi- nent granulation tissue and an orange-yellow hue. The results of a of the 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 by macrophages. tion presenting most commonly as an atro- REPORT OF A CASE phicN plaque with raised borders and , 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 and necrobiotic with scle- Department of , 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 (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-

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©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 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 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 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 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 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

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©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 , ankylosing spondy- Organogenesis. Dr Qureshi has served as a speaker for litis, and . 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. 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Treatment of necrobiosis lipoidica dia- etanercept injections (25 mg) into the dermis, with com- beticorum by hyperbaric oxygen. Acta Derm Venereol. 1993;73(6):447-448. plete resolution after 8 months. Mechanistically, inhibi- 15. Kreuter A, Knierim C, Stucker M, et al. Fumaric acid esters in necrobiosis li- poidica: results of a prospective non-controlled study. Br J Dermatol. 2005; tion of the granulomatous process underlying NLD may 153(4):802-807. serve as the basis for the efficacy of other agents as well: 16. Kukreja T, Petersen J. Thalidomide for the treatment of refractory necrobiosis both thalidomide and pentoxifylline have been shown to lipoidica. Arch Dermatol. 2006;142(1):20-22. 28,29 17. Harth W, Linse R. Topical tacrolimus in granuloma annulare and necrobiosis antagonize this TNF. lipoidica. Br J Dermatol. 2004;150(4):792-794. Given the marked response of infliximab therapy in our 18. Reinhard G, Lohmann F, Uerlich M, Bauer R, Bieber T. Successful treatment of patient with recalcitrant ulcerative NLD, we believe that ulcerated necrobiosis lipoidica with mycophenolate mofetil. Acta Derm Venereol. 2000;80(4):312-313. an anti-TNF approach holds promise in the treatment of 19. Stinco G, Parlangeli ME, De Francesco V, Frattasio A, Germino M, Patrone P. this disease, and infliximab should be considered as a thera- Ulcerated necrobiosis lipoidica treated with cyclosporine A. Acta Derm Venereol. 2003;83(2):151-153. peutic option for patients with this condition. Because the 20. Stanway A, Rademaker M, Newman P. Healing of severe ulcerative necrobiosis current literature on therapy of this disease lacks con- lipoidica with cyclosporine. Australas J Dermatol. 2004;45(2):119-122. trolled studies, further investigation is warranted to estab- 21. De Rie MA, Sommer A, Hoekzema R, Neumann HA. Treatment of necrobiosis lipoidica with topical psoralen plus ultraviolet A. Br J Dermatol. 2002;147(4):743-747. lish the efficacy of the anti-TNF approach (infliximab or 22. Heidenheim M, Jemec GBE. Successful treatment of necrobiosis lipoidica diabeti- other anti-TNF agents) in NLD and to better define the op- corum with photodynamic therapy. Arch Dermatol. 2006;142(12):1548-1550. timal dose and duration of treatment. 23. Durupt F, Dalle S, Debarbieux S, Balme B, Ronger S, Thomas L. Successful treat- ment of necrobiosis lipoidica with antimalarial agents. Arch Dermatol. 2008; 144(1):118-119. Accepted for Publication: September 29, 2008. 24. Hertl MS, Haendle I, Schuler G, Hertl M. Rapid improvement of recalcitrant dis- seminated granuloma annulare upon treatment with tumour necrosis factor-␣ Correspondence: Vincent W. Li, MD, MBA, Depart- inhibitor, infliximab. Br J Dermatol. 2005;152(3):552-555. ment of Dermatology, Angiogenesis and Wound Heal- 25. Drosou A, Kirsner RS, Welsh E, Sullivan TP, Kerdel FA. Use of infliximab, an an- ing Center, 221 Longwood Ave, Boston, MA 02115 titumor necrosis alpha antibody, for inflammatory dermatoses. J Cutan Med Surg. 2003;7(5):382-386. ([email protected]). 26. Haley H, Cantrell W, Smith K. Infliximab therapy for sarcoidosis ( pernio). Author Contributions: All authors had full access to all Br J Dermatol. 2004;150(1):146-149. of the data in the study and take responsibility for the 27. Kolde G, Muche JM, Schulze P, Fischer P, Lichey J. Infliximab: a promising new treatment option for ulcerated necrobiosis lipoidica. Dermatology. 2003;206 integrity and accuracy of the case series. Study concept (2):180-181. and design: Bevona, Qureshi, and Li. Acquisition of data: 28. Pollice PF, Rosier RN, Looney RJ, Puzas JE, Schwarz EM, O’Keefe RJ. Oral pen- toxifylline inhibits release of tumor necrosis factor-alpha from human periph- Hu, Bevona, Qureshi, and Li. Drafting of the manuscript: eral blood monocytes: a potential treatment for aspetic loosening of total Hu and Bevona. Critical revision of the manuscript: Hu, components. J Joint Surg Am. 2001;83(7):1057-1061. Bevona, Li, Qureshi, and Winterfield. Administrative, tech- 29. Rowland TL, McHugh SM, Deighton J, Dearman RJ, Ewan PW, Kimber I. Differ- ential regulation by thalidomide and dexamethasone of cytokine expression in nical, and material support: Hu, Bevona, Qureshi, and Li. human peripheral blood mononuclear cells. Immunopharmacology. 1998;40 Study supervision: Qureshi and Li. (1):11-20.

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