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Treatment of Refractory Ulcerative Necrobiosis Lipoidica Diabeticorum With Infliximab Report of a Case FREE

Stephanie W. Hu, BS; Caroline Bevona, MD; Laura Winterfield, MD; Abrar A. Qureshi, MD, MPH; Vincent W. Li, MD, MBA
[+] Author Affiliations

Author Affiliations: Department of Dermatology, Angiogenesis & Wound Healing Center (Ms Hu and Drs Winterfield and Li) and Dermatology-Rheumatology Center (Dr Qureshi), Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Dermatology, Lahey Clinic, Burlington, Massachusetts (Dr Bevona).


Arch Dermatol. 2009;145(4):437-439. doi:10.1001/archdermatol.2009.6.
Text Size: A A A
Published online

ABSTRACT

Background  Necrobiosis lipoidica diabeticorum (NLD) is a rare, granulomatous inflammatory skin disease of unknown origin, sometimes associated with diabetes mellitus. Skin lesions usually develop on the lower extremities and can progress toward ulceration and scarring. Many treatments have been proposed, but few have demonstrated consistent efficacy, and no standard regimens have emerged to date.

Observations  An 84-year-old woman with type 1 diabetes mellitus presented with a 3-year history of chronic right-lower-extremity erythematous papules and plaques that had developed into confluent ulcers with prominent granulation tissue and an orange-yellow hue. The results of a biopsy of the lesion was consistent with a diagnosis of NLD. The wound did not respond to 4 months of intensive local wound care. After the first intravenous infusion of infliximab (5 mg/kg), there was rapid reduction in wound size, pain, and drainage. There was complete wound healing with excellent cosmesis at 6 weeks (total of 3 infusions).

Conclusions  Infliximab should be considered in the treatment of refractory, ulcerative NLD. Its anti–tumor necrosis factor activity may underlie its efficacy in targeting this granulomatous process, and further investigation should be undertaken to confirm these results.

Figures in this Article

Necrobiosis lipoidica diabeticorum (NLD) is a granulomatous condition presenting most commonly as an atrophic plaque with raised borders and telangiectasia, occurring typically on the anterior lower legs of younger women. Aggressive lesions may ulcerate. While two-thirds of cases are found in diabetic patients, there is no correlation with glycemic control, and a clear pathogenetic mechanism for the development of this lesion has thus far been elusive. Accordingly, while NLD appears to have responded to a variety of therapies, consistently effective treatment regimens have yet to be established.

We report a case of a patient with a history of type 1 diabetes mellitus who presented with lower extremity ulcers developing from erythematous papules and plaques that were histopathologically consistent with NLD. The lesions remained refractory to intensive local wound care therapy, but improved dramatically with the initiation of intravenous infliximab, a monoclonal antibody against tumor necrosis factor (TNF), a cytokine involved in the maintenance of granulomas by macrophages.

REPORT OF A CASE

An 84-year-old woman had a 3-year history of chronic right-lower-extremity erythematous papules and plaques, some of which developed into confluent ulcers, extending from the right knee to the medial malleolus, punctuated with islands of normal-appearing skin. Prominent granulation tissue was present at the base of the ulcers, and healed areas harbored an orange-yellow hue. The results of a biopsy of a leg lesion taken during the initial onset of the disease showed an ulcerated epidermis and necrobiotic collagen with sclerosis and palisaded granulomas in the dermis (Figure 1). The dermal interstitial infiltrate consisted of histiocytes, multinucleated giant cells, lymphocytes, and plasma cells. These findings were consistent with a diagnosis of NLD. Her medical history was significant for type 1 diabetes mellitus, 2 prior strokes, idiopathic thrombocytopenic purpura (status post splenectomy), mild renal insufficiency, and hypertension. She also had a history of cholecystitis with subsequent granulomatous inflammation, but no evidence of sarcoidosis.

Place holder to copy figure label and caption
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 magnification ×20). The dermal interstitial infiltrate consists of histiocytes, multinucleated giant cells, lymphocytes, and plasma cells.

Graphic Jump Location

During the 1-month period before her initial presentation at the Angiogenesis & Wound Healing Center, Brigham and Women's Hospital, the patient experienced a fulminant expansion and ulceration of the lesions, with the ulcers extending over her shin and calf (Figure 2). She was initially treated with intralesional triamcinolone acetonide (5 mg/mL) and intensive local wound management, which included sharp débridement, papain-urea enzymatic débriding ointment, cadexomer iodine antisepsis gel, Prisma Promogran (1% silver-ORC [oxidized regenerated cellulose]-collagen, Johnson & Johnson Wound Management, Somerville, New Jersey) bioactive dressing, and compression strappings. The wounds remained open and inflamed despite 4 months of this treatment regimen.

Place holder to copy figure label and caption
Figure 2.

Multiple ulcers of the right lower extremity from the knee to the posterior aspect of the heel with 2+ pitting edema on the right leg, most marked over the right dorsal aspect of the foot.

Graphic Jump Location

Given the lack of response to intensive local wound care, we theorized that the underlying pathogenic process of NLD might respond to an anti-TNF approach, and we decided to treat the patient with intravenous infliximab at a dose of 5 mg/kg. Before the initiation of anti-TNF treatment, a negative purified protein derivative (tuberculin) test result was confirmed. She received a total of 5 infusions (at weeks 0, 2, 6, 12, and 21). At her first 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 drainage 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 clinical follow-up more than 1 year.

Place holder to copy figure label and caption
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.

Graphic Jump Location

COMMENT

Necrobiosis lipoidica diabeticorum is a chronic granulomatous disease of unknown origin, occurring 3 times more frequently in women than in men,1,2 particularly in patients aged 30 to 40 years, and often on the shins, back of the hands, or the forearms.3 Seventy-five percent of patients with NLD have or will develop diabetes mellitus (type 1 more often than type 2), although only approximately 0.3% of diabetic patients develop NLD.2 Although ulceration has been reported in 13% to 35% of cases, usually in the setting of trauma, spontaneous rapid and fulminant ulceration is uncommon.4,5 Spontaneous remission has been reported in approximately 20% of patients.3

To our knowledge, there is currently no standardized, effective treatment of NLD in clinical practice. First-line therapies include topical and intralesional corticosteroids.2 Smoking cessation and diabetic control may also be effective because reports have documented the beneficial effects of thiazolidinediones in NLD6; however, treatment of a patient's diabetes has not been shown to improve the cutaneous lesions.2 Other therapies that have been tried, with varying degrees of success, include systemic corticosteroids, topical retinoids,7 nicotinamide,8 pentoxifylline,9 aspirin and dipyridamole,10 clofazimine,11,12 hyperbaric oxygen,13,14 fumaric acid esters,15 thalidomide,16 topical tacrolimus,17 mycophenolate mofetil,18 cyclosporine,19,20 and sometimes excision in the case of recalcitrant ulcers. Topical psoralen–UV-A21 and photodynamic therapy22 have been effective, and pulsed dye lasers12 can improve the appearance of telangiectasias. Recently, 7 in a series of 8 patients were reported to show clinical improvement with antimalarial therapy.23

Infliximab is a monoclonal antibody that binds to TNF and is currently approved for the treatment of inflammatory bowel disease, psoriatic arthritis, ankylosing spondylitis, and rheumatoid arthritis. Infliximab blocks soluble and transmembrane-bound TNF and leads to a number of anti-inflammatory effects and cytolysis of inflammatory cells expressing TNF receptors.24,25 Tumor necrosis factor is a proinflammatory cytokine, and blockade results in amelioration of inflammatory conditions, which includes the reduced formation of granulomas.25 As such, infliximab has been shown to be beneficial in chronic cutaneous granulomatous diseases, such as disseminated granuloma annulare and sarcoid,2426 as well as 2 cases of ulcerative NLD.25,27 In both cases of ulcerative NLD, a dose of 5 mg/kg was used. In the article by Drosou et al,25 a 32-year-old woman with extensive ulcerative NLD, who did not respond to 40 mg per day of prednisone, showed complete healing after 2 infusions of infliximab. In the case reported by Kolde et al,27 a 33-year-old man experienced substantial clinical improvement after infliximab therapy; however, treatment was terminated because of reactivation of tuberculosis resulting from the therapy. This highlights the importance of screening for prior exposure to tuberculosis before initiating treatment with infliximab.

Interestingly, one case of an NLD lesion in a 35-year-old woman with well-controlled type 1 diabetes mellitus was previously reported to be treated successfully with etanercept, another TNF antagonist in the form of a dimeric fusion protein that binds the cytokine.8 Initial improvement was seen by the first month of intralesional etanercept injections (25 mg) into the dermis, with complete resolution after 8 months. Mechanistically, inhibition of the granulomatous process underlying NLD may serve as the basis for the efficacy of other agents as well: both thalidomide and pentoxifylline have been shown to antagonize this TNF.28,29

Given the marked response of infliximab therapy in our patient with recalcitrant ulcerative NLD, we believe that an anti-TNF approach holds promise in the treatment of this disease, and infliximab should be considered as a therapeutic option for patients with this condition. Because the current literature on therapy of this disease lacks controlled studies, further investigation is warranted to establish the efficacy of the anti-TNF approach (infliximab or other anti-TNF agents) in NLD and to better define the optimal dose and duration of treatment.

ARTICLE INFORMATION

Correspondence: Vincent W. Li, MD, MBA, Department of Dermatology, Angiogenesis and Wound Healing Center, 221 Longwood Ave, Boston, MA 02115 (vincentli@earthlink.net).

Accepted for Publication: September 29, 2008.

Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity and accuracy of the case series. Study concept and design: Bevona, Qureshi, and Li. Acquisition of data: Hu, Bevona, Qureshi, and Li. Drafting of the manuscript: Hu and Bevona. Critical revision of the manuscript: Hu, Bevona, Li, Qureshi, and Winterfield. Administrative, technical, and material support: Hu, Bevona, Qureshi, and Li. Study supervision: Qureshi and Li.

Financial Disclosure: Dr Li has served as a consultant for Johnson & Johnson/Ethicon, Genentech, and Organogenesis. Dr Qureshi has served as a speaker for Abbott, Amgen, and Genentech.

REFERENCES

Huntley  AC The cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol 1982;7 (4) 427- 455
PubMed Link to Article
Peyri  JMoreno  AMarcoval  J Necrobiosis lipoidica. Semin Cutan Med Surg 2007;26 (2) 87- 89
PubMed Link to Article
Körber  ADissemond  J Necrobiosis lipoidica diabeticorum. CMAJ 2007;177 (12) 1498
PubMed Link to Article
Kalus  AAChien  AJOlerud  JE Diabetes mellitus and other endocrine diseases.  In: Wolff  K, Goldsmith  LA, Katz  SI, Gilchrest  BA, Paller  AS, Leffell  DJ, eds. Fitzpatrick's Dermatology in General Medicine. New York, NY: McGraw-Hill; 2008: 1467-1470
Lowitt  MHDover  JS Necrobiosis lipoidica. J Am Acad Dermatol 1991;25 (5, pt 1) 735- 748
PubMed Link to Article
Boyd  AS Thiazolidinediones in dermatology. Int J Dermatol 2007;46 (6) 557- 563
PubMed Link to Article
Boyd  AS Tretinoin treatment of necrobiosis lipoidica diabeticorum. Diabetes Care 1999;22 (10) 1753- 1754
PubMed Link to Article
Zeichner  JAStern  DWKLebwohl  M Treatment of necrobiosis lipoidica with the tumor necrosis factor antagonist etanercept. J Am Acad Dermatol 2006;54 (3) (suppl 2)S120- S121
PubMed Link to Article
Noz  KCKorstanje  MJVermeer  BJ Ulcerating necrobiosis lipoidica effectively treated with pentoxifylline. Clin Exp Dermatol 1993;18 (1) 78- 79
PubMed Link to Article
Heng  MCSong  MKHeng  MK Healing of necrobiotic ulcers with antiplatelet therapy: correlation with plasma thromboxane levels. Int J Dermatol 1989;28 (3) 195- 197
PubMed Link to Article
Arbiser  JLMoschella  SL Clofazimine: a review of its medical uses and mechanisms of action. J Am Acad Dermatol 1995;32 (2, pt 1) 241- 247
PubMed Link to Article
Mensing  H Clofazimine: therapeutic alternative in necrobiosis lipoidica and granuloma annulare. Hautarzt 1989;40 (2) 99- 103
PubMed
Bouhanick  BVerret  JLGouello  JPBerrut  GMarre  M Necrobiosis lipoidica: treatment by hyperbaric oxygen and local corticosteroids. Diabetes Metab 1998;24 (2) 156- 159
PubMed
Weisz  GRamon  YWaisman  DMelamed  Y Treatment of necrobiosis lipoidica diabeticorum by hyperbaric oxygen. Acta Derm Venereol 1993;73 (6) 447- 448
PubMed
Kreuter  AKnierim  CStucker  M  et al.  Fumaric acid esters in necrobiosis lipoidica: results of a prospective non-controlled study. Br J Dermatol 2005;153 (4) 802- 807
PubMed Link to Article
Kukreja  TPetersen  J Thalidomide for the treatment of refractory necrobiosis lipoidica. Arch Dermatol 2006;142 (1) 20- 22
PubMed Link to Article
Harth  WLinse  R Topical tacrolimus in granuloma annulare and necrobiosis lipoidica. Br J Dermatol 2004;150 (4) 792- 794
PubMed Link to Article
Reinhard  GLohmann  FUerlich  MBauer  RBieber  T Successful treatment of ulcerated necrobiosis lipoidica with mycophenolate mofetil. Acta Derm Venereol 2000;80 (4) 312- 313
PubMed Link to Article
Stinco  GParlangeli  MEDe Francesco  VFrattasio  AGermino  MPatrone  P Ulcerated necrobiosis lipoidica treated with cyclosporine A. Acta Derm Venereol 2003;83 (2) 151- 153
PubMed Link to Article
Stanway  ARademaker  MNewman  P Healing of severe ulcerative necrobiosis lipoidica with cyclosporine. Australas J Dermatol 2004;45 (2) 119- 122
PubMed Link to Article
De Rie  MASommer  AHoekzema  RNeumann  HA Treatment of necrobiosis lipoidica with topical psoralen plus ultraviolet A. Br J Dermatol 2002;147 (4) 743- 747
PubMed Link to Article
Heidenheim  MJemec  GBE Successful treatment of necrobiosis lipoidica diabeticorum with photodynamic therapy. Arch Dermatol 2006;142 (12) 1548- 1550
PubMed Link to Article
Durupt  FDalle  SDebarbieux  SBalme  BRonger  SThomas  L Successful treatment of necrobiosis lipoidica with antimalarial agents. Arch Dermatol 2008;144 (1) 118- 119
PubMed Link to Article
Hertl  MSHaendle  ISchuler  GHertl  M Rapid improvement of recalcitrant disseminated granuloma annulare upon treatment with tumour necrosis factor-α inhibitor, infliximab. Br J Dermatol 2005;152 (3) 552- 555
PubMed Link to Article
Drosou  AKirsner  RSWelsh  ESullivan  TPKerdel  FA Use of infliximab, an antitumor necrosis alpha antibody, for inflammatory dermatoses. J Cutan Med Surg 2003;7 (5) 382- 386
PubMed Link to Article
Haley  HCantrell  WSmith  K Infliximab therapy for sarcoidosis (lupus pernio). Br J Dermatol 2004;150 (1) 146- 149
PubMed Link to Article
Kolde  GMuche  JMSchulze  PFischer  PLichey  J Infliximab: a promising new treatment option for ulcerated necrobiosis lipoidica. Dermatology 2003;206 (2) 180- 181
PubMed Link to Article
Pollice  PFRosier  RNLooney  RJPuzas  JESchwarz  EMO'Keefe  RJ Oral pentoxifylline inhibits release of tumor necrosis factor-alpha from human peripheral blood monocytes: a potential treatment for aspetic loosening of total joint components. J Bone Joint Surg Am 2001;83 (7) 1057- 1061
PubMed
Rowland  TLMcHugh  SMDeighton  JDearman  RJEwan  PWKimber  I Differential regulation by thalidomide and dexamethasone of cytokine expression in human peripheral blood mononuclear cells. Immunopharmacology 1998;40 (1) 11- 20
PubMed Link to Article

Figures

Place holder to copy figure label and caption
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 magnification ×20). The dermal interstitial infiltrate consists of histiocytes, multinucleated giant cells, lymphocytes, and plasma cells.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Multiple ulcers of the right lower extremity from the knee to the posterior aspect of the heel with 2+ pitting edema on the right leg, most marked over the right dorsal aspect of the foot.

Graphic Jump Location
Place holder to copy figure label and caption
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.

Graphic Jump Location

Tables

References

Huntley  AC The cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol 1982;7 (4) 427- 455
PubMed Link to Article
Peyri  JMoreno  AMarcoval  J Necrobiosis lipoidica. Semin Cutan Med Surg 2007;26 (2) 87- 89
PubMed Link to Article
Körber  ADissemond  J Necrobiosis lipoidica diabeticorum. CMAJ 2007;177 (12) 1498
PubMed Link to Article
Kalus  AAChien  AJOlerud  JE Diabetes mellitus and other endocrine diseases.  In: Wolff  K, Goldsmith  LA, Katz  SI, Gilchrest  BA, Paller  AS, Leffell  DJ, eds. Fitzpatrick's Dermatology in General Medicine. New York, NY: McGraw-Hill; 2008: 1467-1470
Lowitt  MHDover  JS Necrobiosis lipoidica. J Am Acad Dermatol 1991;25 (5, pt 1) 735- 748
PubMed Link to Article
Boyd  AS Thiazolidinediones in dermatology. Int J Dermatol 2007;46 (6) 557- 563
PubMed Link to Article
Boyd  AS Tretinoin treatment of necrobiosis lipoidica diabeticorum. Diabetes Care 1999;22 (10) 1753- 1754
PubMed Link to Article
Zeichner  JAStern  DWKLebwohl  M Treatment of necrobiosis lipoidica with the tumor necrosis factor antagonist etanercept. J Am Acad Dermatol 2006;54 (3) (suppl 2)S120- S121
PubMed Link to Article
Noz  KCKorstanje  MJVermeer  BJ Ulcerating necrobiosis lipoidica effectively treated with pentoxifylline. Clin Exp Dermatol 1993;18 (1) 78- 79
PubMed Link to Article
Heng  MCSong  MKHeng  MK Healing of necrobiotic ulcers with antiplatelet therapy: correlation with plasma thromboxane levels. Int J Dermatol 1989;28 (3) 195- 197
PubMed Link to Article
Arbiser  JLMoschella  SL Clofazimine: a review of its medical uses and mechanisms of action. J Am Acad Dermatol 1995;32 (2, pt 1) 241- 247
PubMed Link to Article
Mensing  H Clofazimine: therapeutic alternative in necrobiosis lipoidica and granuloma annulare. Hautarzt 1989;40 (2) 99- 103
PubMed
Bouhanick  BVerret  JLGouello  JPBerrut  GMarre  M Necrobiosis lipoidica: treatment by hyperbaric oxygen and local corticosteroids. Diabetes Metab 1998;24 (2) 156- 159
PubMed
Weisz  GRamon  YWaisman  DMelamed  Y Treatment of necrobiosis lipoidica diabeticorum by hyperbaric oxygen. Acta Derm Venereol 1993;73 (6) 447- 448
PubMed
Kreuter  AKnierim  CStucker  M  et al.  Fumaric acid esters in necrobiosis lipoidica: results of a prospective non-controlled study. Br J Dermatol 2005;153 (4) 802- 807
PubMed Link to Article
Kukreja  TPetersen  J Thalidomide for the treatment of refractory necrobiosis lipoidica. Arch Dermatol 2006;142 (1) 20- 22
PubMed Link to Article
Harth  WLinse  R Topical tacrolimus in granuloma annulare and necrobiosis lipoidica. Br J Dermatol 2004;150 (4) 792- 794
PubMed Link to Article
Reinhard  GLohmann  FUerlich  MBauer  RBieber  T Successful treatment of ulcerated necrobiosis lipoidica with mycophenolate mofetil. Acta Derm Venereol 2000;80 (4) 312- 313
PubMed Link to Article
Stinco  GParlangeli  MEDe Francesco  VFrattasio  AGermino  MPatrone  P Ulcerated necrobiosis lipoidica treated with cyclosporine A. Acta Derm Venereol 2003;83 (2) 151- 153
PubMed Link to Article
Stanway  ARademaker  MNewman  P Healing of severe ulcerative necrobiosis lipoidica with cyclosporine. Australas J Dermatol 2004;45 (2) 119- 122
PubMed Link to Article
De Rie  MASommer  AHoekzema  RNeumann  HA Treatment of necrobiosis lipoidica with topical psoralen plus ultraviolet A. Br J Dermatol 2002;147 (4) 743- 747
PubMed Link to Article
Heidenheim  MJemec  GBE Successful treatment of necrobiosis lipoidica diabeticorum with photodynamic therapy. Arch Dermatol 2006;142 (12) 1548- 1550
PubMed Link to Article
Durupt  FDalle  SDebarbieux  SBalme  BRonger  SThomas  L Successful treatment of necrobiosis lipoidica with antimalarial agents. Arch Dermatol 2008;144 (1) 118- 119
PubMed Link to Article
Hertl  MSHaendle  ISchuler  GHertl  M Rapid improvement of recalcitrant disseminated granuloma annulare upon treatment with tumour necrosis factor-α inhibitor, infliximab. Br J Dermatol 2005;152 (3) 552- 555
PubMed Link to Article
Drosou  AKirsner  RSWelsh  ESullivan  TPKerdel  FA Use of infliximab, an antitumor necrosis alpha antibody, for inflammatory dermatoses. J Cutan Med Surg 2003;7 (5) 382- 386
PubMed Link to Article
Haley  HCantrell  WSmith  K Infliximab therapy for sarcoidosis (lupus pernio). Br J Dermatol 2004;150 (1) 146- 149
PubMed Link to Article
Kolde  GMuche  JMSchulze  PFischer  PLichey  J Infliximab: a promising new treatment option for ulcerated necrobiosis lipoidica. Dermatology 2003;206 (2) 180- 181
PubMed Link to Article
Pollice  PFRosier  RNLooney  RJPuzas  JESchwarz  EMO'Keefe  RJ Oral pentoxifylline inhibits release of tumor necrosis factor-alpha from human peripheral blood monocytes: a potential treatment for aspetic loosening of total joint components. J Bone Joint Surg Am 2001;83 (7) 1057- 1061
PubMed
Rowland  TLMcHugh  SMDeighton  JDearman  RJEwan  PWKimber  I Differential regulation by thalidomide and dexamethasone of cytokine expression in human peripheral blood mononuclear cells. Immunopharmacology 1998;40 (1) 11- 20
PubMed Link to Article

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