IOURNAL of the

AmeRICaN A.CaDemy OF

DerMaTOLOGY VOLUME 25 NUMBER 5 PART 1

NOVEMBER 1991

Continuing medical education Necrobiosis lipoidica Mark H. Lowitt, MD,* and Jeffrey S. Dover, MD Boston, Massachusetts Necrobiosis lipoidica has distinctive clinical andhistopathologic features. Although theories abound, its causeand pathogenesis remainunknown. Despite many reports ofeffective treatments, a critical review of'the literaturesuggests thatnoneisuniformly effective. (J AM ACAD DERMATOL 1991;25:735-48.)

Necrobiosis lipoidica (NL) has a distinctive clinical appearance, unusual histopathologic features, and is strongly associated with diabetes mellitus; its cause, however, remains unknown. Multiple treatment approaches have been attempted withoutconsistentresults. In this review wediscuss the spectrum ofclinical features,histopathologic findings, theories on pathogenesis, differential diagnosis, and reported therapeutic options for this challenging problem.

the condition granulomatosis disciformls chronica et progressiva, now referred to as granulomatosis discifonnis ofMiescher. Wilson-Jones' description" of atypical NL of the face and scalp broadened the spectrum of disease. Because of the significant minority of cases ofnecrobiosis lipoidicadiabeticorum in nondiabetic patients, many investigators now choose to call this condition simply necrobiosis lipoidica (NL).

HISTORY

CLINICAL FEATURES

Oppenheim' first described NL in 1929 and named it dermatitis atrophicans diabetica. In 1932 Urbach- gavethe condition its currentname,necrobiosis lipoidica diabeticorum. He proposed that a circulating diabetic toxin was responsible for the skin lesions. In 1933 Balbi3 suggested that hyperlipidemia in diabetes mellitus played a major role. In 1935 Goldsmith" reported the first caseof NL in a nondiabetic patient."Miescherand Leder,5 in 1948, reported a series of patients without diabetes who had similar lesions, mostlyon the scalp. Theynamed

Typicallesions of NL occur on the pretibial skin as irregular, ovoid plaques with a violaceous, indurated periphery and a yellow central atropic area. Superficial telangiectasia and scattered hyperkeratotic plugs areoften noted? (Fig. 1). The lesions can start as small, finn, red-brown papules that slowly enlargeanddevelop the typical violet-brown periphery and yellow-brown center. S, 9 They are usually multiple and bilateral. Sixteen percent of patients have only oneplaque, and 50% have four to eight.l'' Ulceration occurs in approximately 35% and is often precipitated by minor trauma (Fig. 2). Curiously, theulcers only rarelybecame infected,evenin the presence of diabetes. Partial alopecia, hypohidrosis, and cutaneous anesthesia within the plaques have been reported by several investigators.lv'? Decreased sensitivity to heat and lighttouch in NL lesions was noted in 17 patients, although no comparison with unaffected skinwasmade. 12 In anotherstudy, 11 of 12 patients with NL had impairment of at least one sensory modality in the lesions. These authors'! suggested

TheCME articles are madepossible through an educational grant from the Dermatological Division, Ortho PharmaceuticaI Corporation. Fromthe Department of Medicine, New EnglandDeaconess Hospital and Joslin Diabetes Center, and the Department of Dermatology, Harvard Medical School. Reprint requests: Jeffrey S. Dover, MD, 110 Francis St., Suite 7H, Boston, MA 02215. "'Currently Resident in Dermatology, University of Maryland, Baltimore.

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American Academy of Dermatology

736 Lowitt and Dover

Fig. 1. Typical NL of anterior tibial surface displays a red-brown, atrophic plaque with overlying superficial telangiectasia and visible deeper vessels. (Courtesy B. Fisher, MD, Toronto, Ontario.) Fig. 2. Plaque NL studded with fresh and healed ulcers. Fig. 3. Atypical ulcerated NL of scalp. (Courtesy S. Kang, MD, and S. Moschella, MD, Boston, Mass.)

this cutaneous anesthesia may represent local nerve changes that could also be implicated as a cause of sweat gland dysfunction. Patients may complain of pruritus, dysesthesia, or pain at the site of lesions. Most frequently, however, the lesions of NL are asymptomatic and it is the cosmetic disability that is of greatest concern to the patient. Severe ulcerative NL is not uncommon and often is refractory to medical and surgical treatment. Associated venous insufficiency and local phlebitis make healing even more difflcult.l" Two recent reports document squamous cell carcinoma that arose in sites of preexisting ulcerated NL. In the first case, IS a patient developed squamous cell carcinoma 30 years after the onset of NL and 6 years after ulceration. Kossard et al. 16 reported a patient with bilateral NL who developed bilateral squamous cell carcinoma. Preferential development of NL in areas of increased collagen synthesis has been suggested

by its presence in surgical scars; 4 of 22 lesions were located in surgical scars in one patient'? and in areas of scleroderma in another. IS

CLINICAL VARIANTS The most commonly affected site is the leg. Eighty-five percent of cases involve the legs exclusively, and only 2% have no leg involvement. Other locations include the hands, fingers, forearms, face, and scalp." Lesions in these locations can have a more varied appearance; papules, plaques, or nodules, with or without atrophy may be present, 10 The lesions are often annular, erythematous or brown, and can coalesceto form larger serpiginous plaques that demonstrate little or no atrophy. The most commonly reported atypical locations are the face and scalp, usually in nondiabetic patients- 6,19,20 (Fig. 3). Dowlingand Wilson-Jones-' reported a series of 7 cases that clinicallyresembled annular sar-

Volume 25 Number 5, Part 1 November 1991

coidosis. In hispresentation of 29casesof NL on the face and scalp, Wilson-Jones6described a "nonscarringannularvariant ofnecrobiosis" that affected the face in middle-aged women; he termed this "atypical necrobiosis of the face and scalp."In 30% of the patients the lesions cleared and left hypopigmented macules. Four of 29 patients developed typical NL on the legs, and only 2 had diabetes. Mehregan and Altman'? reported 13patients, predominantly middle-aged women without diabetes, who had similar lesions. Because of the relative absence of necrobiosis histologically, Mehregan and Altman chose to call this disorder "Miescher's granuloma of the face." They considered it to be separate from NL, but within the spectrum of necrobiotic disease. In 1975 O'Brien-' described similar lesions in several patients and called them actinic granuloma. Helander et al.24 reported similar lesions in a young man. Althoughthey believed that the condition was identical to that previously labeledMiescher's granuloma, they considered it a varientof NL. Hanke et al.25 proposed the name annular elastolytic giant cellgranuloma becauseofthe presence ofactinically altered elasticfibers withingiant cells. Debate continuesas to whetherthesevariously nameddisorders represent NL, a variant, or different entities within the spectrum of palisading granulomas. EPIDEMIOLOGY

NL is closely associated with diabetes mellitus. Muller and Winkelmann most clearlydemonstrate this association. to, 26-28 Sixty-five percent of their 171 patients with NL had diabetesmellitus. Of the remainder available for study, 42% (8 of 19) demonstrated abnormal glucose tolerance test results. Fifty-five percent of those with normal glucose tolerancehad a positive familyhistoryofglucose intolerance. Despite the highprevalence ofdiabetes mellitus in patients with NL, necrobiosis is relatively uncommon in diabeticpatients; the reported prevalence is 3 per 1000. Thefemalejmaleratio is 3:1. The age of onsetranges from birth to 76 years,withan average age of 30 in diabetic patients and 41 in nondiabetic patients. Fifty percent of patients with NL demonstrate other diabetic end organ damage. Spontaneous remissions occursin 13% to 19% of patients between 1 and 34 years after onset; however, residual scarring and atrophy remain. The presence or absenceof a smoking historydoes not appear to have an effect on risk. 10

Necrobiosis lipoidica 737 NL has also been reported in association with Crohn's disease-? and ulcerative colitis,30 and after jejunal bypass operation.P Several investigators havereported NL and granuloma annulare (GA) in the same patient,12, 20, 32-34 Others have noted progression of atypical GA into NL. 12 Cases of simultaneous cutaneous sarcoid and NL have also been reported.35-38 The multiple reports that document the coexistence of sarcoid, GA, and NL raise the question: are GA, NL, and sarcoid part of a spectrum of the same disease? HISTOPATHOLOGY

In their descriptions of 112 biopsy specimens, Muller and Winkelmann-" noted two major histologic patterns in NL. The first, which was usually presentinpatients with diabetes mellitus, wascalled "palisading granulomatous." The second, named "tuberculoid," wasthe predominant pattern in nondiabeticpatients. (Miescher's granulomas are sometimes considered a subset of this group.) They also described an intermediate group with elements of both patterns. Although now renamed the "necrobiotic"and"granulomatous" reactions, respectively, the two major histologic patterns are still recognized? Thelinkbetweenthe necrobioticpattern and diabetesalthough not asdistinctas wasoncethought, is still recognized. In both histologic types the epidermis is usually normal, although it may be atrophic or even absent in the presence of ulceration. Septal fibrosis is often noted in the subcutaneous fat. The major histologic changes, however, are found in the dermis. In the necrobiotic reaction, large areas of necrobiotic collagen are presentin the lower two thirds of the dermis. Collagen fibers are irregular in size and shape and are frequently associatedwith areas ofhypocellularity. Young collagen fibers are seen adjacent to degenerating collagen (Fig. 4). The term necrobiosis, seemingly an oxymoron, implying both degenerating (necro-) and regenerating (-bio) collagen, best applies to these areas. A characteristic cellular infiltrate that consists of histiocytes, fibroblasts, and lymphoidcellssurrounds the necrobiotic areas and can extend into the adjacent fat. Giant cells are oftenpresent, either alone or as part of granuloma-like complexes. Extracellular lipid deposits are typical and are scattered between degenerating fibers. Blood vessels show endothelial proliferation with wall thickening and occasional luminalocclusion. Notably the vessel wallsare often

Journal of the 738 Lowitt and Dover

American Academy of Dermatology

Fig. 4. "Necrobiotic" type of NL. A, Below a thinned epidermis there are telangiectatic vesselsand poorly defined areas of an almost structureless-appearing dermis.Thesezones of degenerated collagen are surrounded by a palisading arrangement of histiocytes and lymphocytes. (Hematoxylin-eosinstain; X 100.)B,Higher powerreveals collagen to be faintly eosinophilic and relatively hypocellularand palisaded by histiocytes and lymphocytes. (Hematoxylin-eosin stain X 160.) C, At high powernumerousforeign body lipid-containing giant cells, which are thought to impart the yellow color to clinical lesions, are present among the palisading cells. (Hematoxylin-eosin stain; X160.)

infiltrated with periodic acid-Schiff(P AS}-positive, diastase-negative material, presumed to be a neutral glycoprotein. These findings have been confirmed by electron microscopy.I? Necrobiotic areas have bent, curled, and disarrayed collagen fibrils, although they maintain their normal periodicity . Elastin fibers are absent. Sections near necrobiotic areas demonstrate disintegrating elastin fibers, mucopolysaccharide filaments, and thickened basal laminae in large vessels. Vascular changes in NLinclude endothelial swelling, fibrosis, and hyalinization as the most common findings.f? Fibrinoid necrosis, thrombosis and leukocytoclasia are occasionally seen. The most significant vascular changes are seen in necrobiotic NL, whereas in granulomatous NL vessel obliteration is

only occasionally seen and is related to granulomatous inflammation. Changes are most pronounced in the reticular dermis; the papillary areas are preferentially spared. The granulomatous reaction differs from the necrobiotic pattern in several ways. Most notably, it contains little or no necrobiotic material. The epithelioid and giant cells tend to assume a more typically granulomatous configuration (Fig . 5). A moderate to severe inflammatory infiltrate is present near areas of hyalinized collagen, but vascular changes are rare. Dowling and Wilson-Jones' series6• 21 of atypical NL of the face and scalp describe these histologicfeatures as well. Decreased numbers of nerve fibers in lesional areas and in areas of perilesional inflammation have also been noted.f!

Volume 25 Number 5, Part 1 November 1991

Necrobiosis lipoidica 739

Table I. Proposed pathogenetic mechanisms of NL Diabetic/genetic Vascular Microangiopathy Increased fibronectin Increased factor VIII-related antigen Abnormal prostaglandin synthesis Abnormalities of collagen Accelerated collagen aging Increased lysyl oxidase Collagen overhydration Decreased procollagen mRNA Lipid disorders Abnormal leukocyte function Immunemechanisms Immune-mediated vasculopathy Collagen antibodies

A recent study has looked at B cell and T cell subsets in the dermis in patients with NL.42 In all cases but one the lymphoid infiltrates consisted of T cellsin the reticular dermis and in the panniculus. A reexamination of 310 biopsy specimens by Alegre and Winkelmann 42 revealed deep dermal, perivascular lymphoid nodules in 11%. PATHOGENESIS

Despite extensive investigation, the cause of NL remains unknown. Suggestive data have been produced in support of several major theories, yet no single pathogenetic mechanism is universally accepted (Table I). Central to each of the theories is a fundamental, chicken-or-egg question about collagen degeneration. Does it occur first as a consequence of several possible initiating processes and trigger an inflammatory reaction? Or is there an initial inflammatory response, again in response to some as yet unknown trigger, that leads to tissue destruction and ultimately necrobiosis? At present, data exist to support both arguments. Diabetes and heredity Because of the early recognition ofNL's link with diabetes mellitus, explanations of a cause for this link were entertained. The bulk of evidencesuggests that NL and glycemic control are not related. Dandona et a1. 43 studied glycosylated hemoglobin (hemoglobin Ale) in 22 patients with NL. No correlation could be found between the two. Although there have been sporadic reports of NL in nondiabetic

Fig, 5. "Granulomatous" type of NL. A, At lowpower there is a vaguely granulomatous-appearing infiltratein the mid and lower dermis. (Hematoxylin-eosin stain; X40.) D, At higher power not frankly necrobiotic collagen bundles with interstitial hypercellularity are delimited bycircumscribed lymphoid and vaguely granulomatous aggregates containing foreign body and Langhans type giant cells, someof whichare lipidized. (Hematoxylin-eosin stain; X160.)

siblings''" and even in a set of HLA-matched diabetic sisters,45 evidence now suggests that genetic factors do not playa large role in NL. In his 1983 paper, Soler and Mcfxmnachie't" studied HLA typing in 15 diabetic patients with NL compared with 22 without NL. Both groups had high frequencies of HLA-DR4, -B8, and -CW3, and a low incidence of HLA-DR5 and -DR7, consistent with previous reports of HLA patterns in diabetic patients. The only difference between the two groups was a lower frequency of HLA-A2 in patients with NL. The fact that only a single HLA group was different suggests that factors other than genetic probably play the greatest role in NL.

Journal of the American Academy of Dermatology

740 Lowitt and Dover

Vascular etiologies Because of the blood vessel changes in biopsy specimens, many authors have considered vascular changes as a cause of NL. Vascular changes, however, are absent in onethird of biopsy specimens.-! A linkwithdiabetic microangiopathy has beensuggested, but the affected vessels in NL are usually of larger caliber than those affected in diabetes. Examination of digital blood vessels withnailfoldcapillaroscopy has been performed in diabetic patients with NL. In one study 16 of 17patients had tortuous, narrow capillaries.? The changes observed were similar to those seen in elderly persons with atherosclerotic desease. Lukasiaket al.47 proposed that thisfinding suggests diffuse microvascular disease and presumably an increased riskfor NL. The lack of a control group, however, makes the significance oftheir findings unclear. Anotherstudycomparednailfold changes in patients withdiabetes and in nondiabetic control subjects. 48 No significant difference was seen. It was not stated whether any of these patientshad NL. Basement membrane thickening hasbeenconsistentlynoted and is considered typical of NL, yet its causeis unclear. Koh et al.49 demonstrated an elevation in plasma fibronectin levels in patients with NL, diabetes, and widespread GA versus normal control subjects. Fibronectin, a glycoprotein (a2globulin) produced by fibroblasts, smooth muscle, and endothelial cells, is a component of vascular basement membranes and loose connective tissue, and actsas a substratefor cellattachment. It is suspected that overproductive endothelial cells that produce largeamounts offibronectin (perhaps from an unidentified circulating factor)account forthickening of the basement membrane. Majewski et al.so havealsoreported elevated levels of factor VIII-related antigen in patients with NL. This glycoprotein causes increased plateletadhesion. They suggest that the PAS-positive, diastase-negative material in and aroundblood vessels may be derived from factor VIII-related antigen that mightbindexcessively to basement membrane collagen and cause wall thickening. The same authors also reported elevations in other serum a2globulins in patients with NL. (X2-Macroglobulin can act as a protease inhibitor and therefore might decrease the body's ability to clearfibrin deposits in the basement membrane. In addition, Majewski et a15O, SI speculated that increased globulins causein-

creased plasma viscosity, whichmight lead to small vessel occlusion inareasoflowbloodflow such asthe anteriortibial areas.Rhodes52, 53 suggested that the PAS-positive material may be the same material found in Kimmelstiel-Wilson diabetic kidney disease and in the pancreas of diabetics. Abnormal platelet function that results in increased prostaglandin (thromboxane)synthesis, enhancedplatelet aggregation, and vascular occlusion has been considered as a cause of NL. Elevated thromboxane synthesis has been reported in vitro in platelets fromdiabeticpatientscomparedwith those from nondiabeticpatients. This suggests that poor glycemic control might increase platelet aggregation.P" Takahashi et a1. 55 attempted to link thromboxaneA2synthesis and microvascular disease. Although they found elevated thromboxane synthesis in diabeticpatients,there was no statisticallysignificantdifference in thromboxane synthesis in patients with and without retinopathy. Sweat gland and nerve disturbances

Some authors believe that sweat gland dysfunction in NL results from local nerve damage while others suggest that B cellnodules at the dermoepidermal junction could account for the sweat gland disturbances.V Hatzis et al.13 noted sweatgland abnormalities in NL to be uniformand intense; a typical pattern was found on testing with plastic impression and starch iodine techniques. They suggested that the pattern is so typical in NL (and absent in GA) that this test could be used to help make the diagnosis in histologically similar cases. Boulton et a1. 4 1 reported a decrease in the number of nerves in NL biopsy specimens that may accountfor anesthesia in NL lesions. 11 They postulate that this results from local destruction from the inflammatory process rather than as a primary change. Abnormalities of collagen The abnormal collagen found in NL and other diabeticend organ disease has invitedspeculationof a cause more directly related to the collagen itself. Diaphragmatic samples from three young diabetic patients (on autopsy) showed increased collagen crosslinking that was much greater than expected for their ages. 56 Hamlin et al. suggested that this apparent "aging" of collagen in diabetic patients could account for basement membrane thickening,

Volume 25 Number 5, Part 1 November 1991

atherosclerosis, and diabetic end organ complications. In another study that sought to explain increased collagen crosslinking, lysy1 oxidase, which produces collagen crosslinking by oxidizing lysine and hydroxylysine, was found to be significantlyelevated in NL and in diabetes. 57 Overhydrated collagen can become stiff and is involved in the diabetic stiff hand syndrome.58 The initiating event in overhydration is thought to be hyperglycemia, which diverts glucose metabolism to the polyol pathway by increasing the activity of the enzyme aldose reductase. This leads to an increased production of polyols (e.g. sorbitol) in tissues that osmotically obligates water to enter the tissues. This extra water is thought to overhydrate collagen and cause increased crosslinking. The resultant stiff collagen could account for abnormal vessel walls and tissues that lead to diabetic complications.S9 Whether this occurs specifically in NL, with or without preexisting hyperglycemia, has yet to be determined. Another related collagen abnormality is diabetic thick skin in which large disorganized collagen bundles and increased dermal thickness are present. 60 The relationship of this to NL has not yet been investigated, but the positive response of these conditions to aldose reductase inhibitors raises the question of whether a role may be found for these drugs in the treatment of NL as well.61 Histochemical studies have revealed a decreased concentration of hydroxyproline in affected skin and confirm a decreased collagen content. Compared with normal skin fibroblasts, fibroblasts from affected skin showed a marked decrease in collagen synthesis in vitro. Specifically, a decrease in mRNA from type I procollagen in fibroblasts was noted. Collagen degeneration may result from damage done by local inflammatory cells, but the poor repair and decreased resynthesis of collagen may result from a pretranslational defect, perhaps as a result of local inflammatory cell mediators.P Lipids An association has been noted between NL and familial ,B-lipoproteinemia. 63 The proposed significance is that decreased plasma lipoprotein leads to fewer low-density lipoprotein receptors. The extra circulating low-density lipoprotein, unable to be cleared normally, might need to be disposed of via the reticuloendothelial system. Unequipped to han-

Necrobiosis lipoidica 741 dle such a large amount of lipid, failure of the reticuloendothelial system could result in lipid deposition in tissues. Abnormal leukocyte function Gange et a1. 64 demonstrated impaired neutrophil mobility in vivo in patients with NL and GA. The proposed significance of this finding is that macrophages may then try to assume the role of the defective neutrophils. This results in abnormal accumulations of macrophages and eventual granuloma formation. Similar findings have been described in other granulomatous conditions such as Crohn's disease and chronic granulomatous disease. In two reports Majewski et al.65,66 studied in vitro neutrophil function in patients with NL. They found no impairment of function and no evidence of a circulating factor that could impair normal neutrophils. Whether the previously reported in vivo neutrophil abnormalities result from local lymphokine effect has not yet been confirmed. The same authors-? measured serum ~-glucuronidase activity inpatients with NL. Because this enzyme is involved in glycoprotein and mucopolysaccharide degradation, they speculated that it might be elevated in patients with NL. Results indicated, however, that although significant elevations were found in GA and diabetes, no difference was noted between patients with NL and the normal control group. Immune mechanisms Immune complex disease has proved to be one of the most promising areas of research, although data are somewhat conflicting. The first evidence for immune complexvasculitis in NL came from Dahl and Ullman. 68, 69 With use of direct immunofluorescence microscopy, they found C3, fibrinogen, and immunoglobulins (IgM and IgA) deposited around dermal bloodvesselsin 9 of 12 patients. IgM and C3 were alsoseen at the dermoepidermal junction, and all 12 patients had a large amount of fibrinogen within the necrobiotic areas. Notably, no immune deposits were seen in normal skin from the same patients. They proposed that an antibody-mediated vasculitis may be the initiating event in necrobiosis, either by circulating antigen/antibody complex deposition or by binding of circulating antibodies to vessel wall or tissue antigens. An alternate possibility is that antibodies are present but are not pathogenic. Because 100% of the biopsy specimens had

742

Lowitt and Dover

large amounts offibrinogen, they suggested that this finding may be useful in diagnosis of NL, in casesin which light microscopy is insufficient to exclude other similar disorders. Many of Dahl's speculations70 on the pathogenesis of GA can be appliedto NL as well. Nieboer and Kalsbeek's subsequent study"! of 9 patients with NL, 18 withGA, and 2 with granulomatosis disciformis of Miescher onlypartially con:firmed Dahl's findings." IgM was found in the epithelialbasementmembrane in 3 of 9, in vessel walls in 2 of 9, but in none of the necrobiotic areas. Fibrinogen was again noted in 9 of 9 necrobiotic areas and vessel walls. Complement (C3c, C3d, and C5) was seenin 2 of 9 basementmembranes and in 1 of 9 vessel walls. Examination of uninvolved skin showed basically negative findings, although some tissue showed nonspecific staining with IgM, complement, fibrin, and albumin. Patterns in NL were similar to those in GA and Miescher's granuloma. The pattern of complement deposition suggests alternate pathway activation. Laukkanen et a1. 72 refuted previous evidence based on immunotluorescent studies in 14 patients withNL. No immunoglobulins weredetected in lesional skin. C3 and IgM deposition was demonstratedin 30% ofpatients afterinjection of histamine intonormal skin. Traumawasa triggeringfactor for the development of NL in 64% of patients. Quimby et al. 40 recently reported that 11 of 12 patients with NL demonstrated immunoreactants (primarily fibrin, C3, and IgM) in vessel walls and involved skin. Vessels in uninvolved skin were also foundto have deposits. The vasculardeposition correlated well with the histologic findings of vasculopathy and occlusion. Quimby et al. postulated a causal link between immune deposition and disease and noted a stronger association of immune deposition with type I than withtype II diabetesmellitus. Evanset al.73 measured serumantibodies to collagen in 32 patients with NL and in 31 normal control subjects and found nosignificant difference between the twogroups. Because these antibodies may result from ingested collagen in westerndiets,they are not specifically directed against necrobiotic human collagen and therefore donot playa pathogenic rolein NL. DIFFERENTIAL DIAGNOSIS Althoughthe clinical appearanceof classicNL is distinctive, early or atypical NL can be difficult to

Journal of the American Academy of Dermatology

recognize. Early NL and GA can be virtuallyindistinguishable. As the lesions enlarge they become more distinctive; GA remains without epidermal change, atrophy, or the yellow color of NL. The typicallocation of GA on the dorsa of hands,fingers, and feet is helpful in distinguishing the two.?" Pigmented pretibial patches occur in diabetic patientsas flat, atrophic, hyperpigmented lesions without the typical red or yellow of NL. 75 Sarcoidosis, whichmay presentas annular/serpiginous groupsof red-brown papuleson the scalp, face, or extremities, can appear similar to granulomatous or atypical NL. Severalexamples of NL-likelesions in patients with sarcoidosis have been reported. 20, 76 Rheumatoid nodules can have a clinical appearance similar to NL, but generally they appear as subcutaneous nodules on the extensor aspects of joints in the settingofsevere arthrltis.??: 78 Necrobioticxanthogranuloma is characterizedby yellow, indurated plaques and nodules with atrophyand ulcerationthat involve the periorbital areas; it is always associated with paraproteinemia. 79·81 Other conditions that can clinically resembleNL include morphea, stasis dermatitis, migratory subacute nodular panniculitis, erythema nodosum, erythema induratum, lichen sclerosus et atrophicus, tertiary syphilis, radiodermatitis, sclerosing lipogranuloma, and Hansen's disease with central lesional anesthesia. u, 26, 44,77, 82 Histologically, NL can be difficult to distinguish fromGA. NL demonstrates moregiant cells, greater vascular changes, more collagen degeneration and lipid deposition with less (or no) mucin deposition, although histologic patterns in GA can be variable.?: 83,84 NL is more likely to ulcerate and to demonstrate atrophy and telangiectasia. 34 The presenceof fibrinogen onimmunofluorescent stainingin NL may be useful in diagncsis.s? The pattern of sweat glandchangesin NL and GA may be used to distinguish between the two as well. Intense and uniformhypohidrosis is seenin NL, whereasGA lesions demonstratenormalcentralsweatingbut cornplete anhidrosis along the papular border.P The well-defined granulomas found in granulomatous NL may resemble those of sarcoidosis, but sarcoidosis usually does not demonstrate the necrobiosis, hyalinization, and lipiddepositions of NL. 85 Several cases have been reported in which NL, GA, and rheumatoid nodules could not be distinguished histologically.e" The presence of cholesterol clefts suggests necrobiotic xanthogranuloma. 86

Volume 25 Number 5, Part I November 1991

TREATMENT

A consistently effective treatment for NL has yet to be found. It is well accepted that control of NL does not relate to diabetic glycemic control. 10, 43 Reported effective treatments for NL have included a variety of topical, oral and surgical approaches (Tables II and III).. Corticosteroids

Potent topical corticosteroids applied to early lesions or the inflammatory rim surrounding developed NL lesions are thought to help in controlling disease progression (Fig. 6), but nocontrolledstudies have been published.?" 87 Intralesional injections of corticosteroids into the active border of NL lesions are also thought to be helpful.v- 88 In 1966 Muller and Winkelmann10 reportedimprovement in 7 of 14 patients treated with this method. Sparrow and Abe1l89 treated five patients with nonulcerative NL with intralesionaltriamcinolone acetatebyjet injector. Three ofthefivepatientsshowed "improvement" after several treatments. Fibrinolytics

On the assumption that angiopathy is associated with poor fibrinolysis, Rhodes53, 90 treated 30 NL patients withfibrinolytic agents. Stanozolol wasthe first agent utilized, and it producedgood clinical resultsbutunacceptablehepatictoxicity. Whentreated with inositol niacinate and tetranicotinoyl fructose, 2 of 30 patients cleared completely and 24 showed some improvement within 6 months. Pentoxifylline has beenshown to havefibrinolytic activity in additionto its better recognized effects of increasingerythrocytedeformabilityanddecreasing platelet aggregation. Littler and Tschen91 treated one patient with ulcerative NL with pentoxifylline with good results. Pentoxifylline's mechanism of fibrinolysisisunclear,but it isspeculated that the drug may increase prostaglandin 12 (PGh), which can cause fibrinolysis. It may increasesecretion of plasminogen activator, increase endothelial protein C release, or decrease antiplasmin activator, all of which would increasefibrinolysis. Antiplatelet agents Aspirin/dipyridamole. The treatment of NL with antiplatelet agents has been the subjectof considerable debate. On the assumption that abnormal platelet aggregation and prostaglandin secretion might play a role in the genesis of NL, aspirin in

Necrobiosis lipoidica 743

Table II. Treatmentof NL A. Medical Corticosteroids Topical Intralesional Fibrinolytic agents Inositol niacinate Tetranicotinoyl fructose Nicotinamide Pentoxifylline Heparin (perilesional) Antiplatelet agents Aspirin Dipyridamole Ticlopidine Clofazimine B. Surgical Excision and split-thickness grafting Temporary porcine grafting Allografted cultured keratinocytes

combination with dipyridamole has been administered. Although some good results have been reported, the only studies that showa favorable effect have been anecdotal or uncontrolled. In one report ulcer healing was noted in two of three female diabetic patients with NL treated with aspirin (1.5 to 4.5 gm/day).92 In another trial six of seven patients treated with lower doses of aspirin (3.4 mg/kg every 48 hours) showed "good" or "reasonable" responses.93 Low-dose aspirin waschosen on the assumption that it might inhibit thromboxane Azmorethan PGE2 and alterthe balance to favor inhibition of aggregation. In another study skinblood flow in 10patients with diabetes mellitus and NL was measured during aspirin therapy (40 tag] day) and 3 months after cessation of the therapy" Surprisingly, skin blood flow in lesional areas increased after aspirin was stopped. This suggeststhat low-dose aspirin might actually be harmful byoverinhibiting the vasodilator effects ofPGE2 and decreasing skin blood flow. A reportof one patient withulcerative NL treated withdipyridamole alone (225 rug/day) noted improvement in 3 weeka'" Platelet survival timewas studied in 10 patientswithNL before andaftercombined treatment with aspirin (325 mg/day) and dipyridamole (75 mg/day).96 Abnormally short platelet half-lives were notedin 55% of patients, but after treatment withaspirin/dipyridamole theplateletsurvival time increased in 75% of cases. No significant clinical

Journal of the American Academy of Dermatology

744 Lowitt and Dover Table III. Medical treatment of NL Author (Ref. No.)

Eldor et al. (1978)92 Karkavitsas et al. (1982)93

Beck and Bjerring (1988)94

Fjellner (1978)95 Quimby et al. (1989)96 Heng et al. (1989)97

Statham et al. (1981)99

Beck et al. (1985)101 Bonnetblanc et al.

(1986)102 Rhodes (1986)103

Controlled trial

Drug regimen

Aspirin 1.5-4.5 gm/day Aspirin 3.4 mg/kg q 48 hr Aspirin 40 mg/day Dipyridamole 225 mg/day Aspirin 325 rug/day + dipyridamole 75 mg/day Aspirin 80 mg/day + dipyridamole 75 mg t.i.d. Aspirin 300 mg tid + dipyridamole 75 mg t.i.d. vs placebo Aspirin 40 rug/day vs placebo Ticlopidine 250-500 mg/day Ticlopidine dose unspecified

Results

3

No

2/3 of patients showed

7

No

6/7 showed "good" or

10

No

1

No

10

No

7

No

12

Yes

16

Yes

2

No

33

No

healing of ulcers

"reasonable" response Skin blood flow in lesions increased after stopping aspirin Ulcerated NL improved No clinicalchange but platelet half-life increased in 75% Ulcerated lesions healedin 2-4 wk; no change in nonulcerated lesions No significant difference between the two groups No significant difference between the two groups 1/2 of the patients improved 9/33 resolved in 6-9 mo; 17/33 improved slightly 8/13 showed decreased pain, resolved ulceration, or decreased erythema

Handfield-Jones et al

Nicotinamide 500 mg t.i.d,

13

No

Muller and Winkelmann (1966) 10 Sparrow and Abell

Steroid injectionsdose unspecified Perilesional triamcinolone acetonide 0.1 ml (5 mg/ml) by jet injector q 6-8 wk Occlusive clobestasol propionate for 6 wk Inositol niacinate

14

No

7/14 improved

5

No

3/5 improved

1

No

Complete clearing

(1988)110

(1975)89

Goette (1990)87 Rhodes (1976)90

Littler and Tschen?'

2/3 cleared

completely

1 gm t.i.d.;

tetranicotinoyl fructose 500 mg t.i.d, Pentoxifylline 400 mg t.i.d.

change in the NL lesions was appreciated. In a recent study seven patients with ulcerated NL were treated with the aspirin/dipyridamole combination (80 mg and 75 mg three times daily). 97 All patients

30

No

1

No

24/30 improved

somewhat

Good results

showed healing of ulcers, as well as diminution of pain, in 2 to 4 weeks. Established, nonulcerated NL lesions showed no change. Before therapy all patients were found to have elevated thromboxane B2

Volume 25 Number 5, Part 1 November 1991

levels. After treatment, thromboxane B2 levels decreased dramatically in all patients. Halushka et al. 54 suggested that the lesions healed because of aspirin's effect on thromboxane A2' Despite these promising findings, results from the only two controlled trials are not encouraging. Statham et al. 98,99 performed a randomized, double-blind study of 12 patients with NL. Seven received aspirin (300 mg three times daily) and dipyridamole (75 mg three times daily) for 8 weeks. Five patients were treated with a placebo. Only one of the 12 patients showed improvement of NL lesions, but this patient was found to be in the placebo group. Critics of this study suggested that the dose of aspirin may have been too high, thus also blocking PGE2 production by the endothelium.P? It might also be speculated that 8 weeks may not have been long enough to see noticeable improvement in the treatment group. Beck et a1. IOI conducted the largest randomized double-blind trial to date, also with discouraging results. Sixteen patients received either aspirin (40 mg/ day) or placebo. Although in vitro platelet aggregation showed inhibition in the aspirin-treated group, no significant improvement of lesion was noted. The lesions, in fact, became larger in both groups. Ticlopidine. Tic1opidine, a potent antithrombotic agent that increases PGI2 synthesis in vitro, has been used in treatment of NL. Bonnetblanc et al.102 treated two patients, in both of whom aspirin/dipyridamole had failed, with ticlopidine (250 to 500 mg daily). One patient's lesions disappeared after treatment, but the second patient showed no improvement. Rhodes'P treated 33 NL patients with ticlopidine. Nine cleared completely within 6 to 9 months. Seventeen of 33 were somewhat improved, and only 7 demonstrated no benefit. They also documented an elevation in lysyl oxidase levels in patients with NL that could explain increased collagen crosslinking in these patients. They noted that enzyme levelsdropped in 5 of the 33 patients treated. Despite these data, they discontinued the use of ticlopidine because of its association with agranulocytosis.If a similar, less toxic drug became available, a randomized study in treatment of NL would be of great interest. Surgical treatments Ulcerative NL usually responds to routine ulcer treatment, albeit slowly, but surgical intervention occasionally becomes necessary.P" In Dubin et al.'s review L05 of surgical therapy for NL, excision to deep fascia or periosteum followed by split-

Necrobiosis lipoidica 745

Fig. 6. Areas of early NL treated for 4 weeks with betamethasone dipropionate (Diprolene) (outlined in pen).

thickness skin grafting appeared to be successful in most cases. In their own series of six patients treated with excision to deep fascia and grafting, all six were free of recurrence from 6 months to several years. One patient who underwent excision only down to the subcutaneous fat (and not to fascia) demonstrated recurrence. Temporary porcine grafts followed by autologous skin grafting yielded good results in a patient with severe ulceration.t''? The porcine grafts, placed daily for 11 days, were used to stimulate growth of granulation tissue to create a more favorable environment for the placement of the final autologous graft. Success has been reported in one patient with ulcerative NL with use of intravenous PGE I (40 /.lg per day for 21 days) followed by excision and transposed skin flap. I08 Because. skin flaps are technically difficult in diabetic patients, the vasodilator effects of PGEI infusion are thought to have played a role in flap survival. Successful treatment of ulcerated NL with allografted cultured keratinocytes has been reported (T.J. Phillips, personal communication, January 1990). In view of the difficulties posed by treatment of NL and its predisposition for sites of leg injury, efforts should also be made when possible to educate patients at risk about avoidance of anterior tibial trauma.F Other agents Nicotinamide has been shown in vitro to suppress lymphocytic transformation to various stimuli. Handfield-Jones et ap09, 110treated 13 NL patients, 11 of them diabetic, with nicotinamide (500 mg three times daily for I month). Eight noted some improvement (decreased pain, resolution of ulceration, or decreased erythema). Side effects were

746 Lowitt and Dover minimal. No significant change in diabetic control was noted during treatment. Although a controlled trial has yet to be completed, these preliminary results are encouraging. Nicotinamide has also been used successfully in GA, presumably by inhibiting release of lymphokines and by decreasing macrophage migration. Other effective treatments described include perilesional heparin injectionl"! and clofazimine.U'' Whether or not the lesions are being treated, cover-up makeup can be of great utility. SUMMARY

After reviewing the history, presentation, proposed pathogenetic mechanisms, and treatment of NL, a multitude of questions remain. What is the primary event leading to disease? Is necrobiotic collagen the stimulus for an inflammatory reaction, or simply a by-product of the inflammation itself? Can we combine the accumulated data that suggest immunologic, vascular, and histochemical causes into a united theory? Answers to some of these questions may help in the development of more consistently successful treatments for this condition. We thank Dr. Cynthia M. Magro for providing the histopathology and Dr. Tania J. Phillips for critically reviewing the manuscript. REFERENCES 1. Oppenheim M. Eigentumlich disseminierte degeneration des bindegewebesder haut bie einemdiabetiker.Z Hautkr 1929-1930;32:179. 2. Urbach E. Beitrage zu einer physiologischen und patho1ogischin chemi der haut: eine neue diabetische steffwechseldermatose, nekrobiosis lipoidica diabeticorum. Arch Dermatol Syph 1932;166:273. 3. Balbi E. Richerche intorno alla patogenesidella necrobiosislipoidicadiabeticorum.G Ita1Dermat Sif 1933;74:14. 4. Goldsmith WN. Necrobiosis lipoidica.Proc R Soc Med 1935;28:363. 5. MiescherG, Leder M. Granulomatosis disciformis chronica et progressive (atypische tuberkulose). Dermato1ogica 1948:97:25. 6. Wilson-Jones E. Necrobiosis lipoidica presenting on the face and scale. Trans St Johns Hosp Dermatol Soc 1971;57:202-20. 7. Lever WF, Schaumburg-Lever G, Histopathology of the skin. 6th ed, Philadelphia: JB Lippincott, 1983:23643. ' 8. Narva WM, Benoit FL, Ringrose EJ. Necrobiosis lipoidica diabeticorum with apparently normal carbohydrate tolerance, Arch Intern Moo 1965;115:718-22. 9. Binkley GW. Dermopathyin the diabeticsyndrome.Arch Dermato11965;92:625-34. 10. Muller SA, Winkelmann RK. Necrobiosis lipoidicadiabeticorum.A clinicaland pathologicalinvestigation of171 cases. Arch DermatoI1966;93:272-81. 11. Mann RJ, Harman RRM. Cutaneous anesthesia in necrobiosis lipoidica, Br J Dermatol 1984;110:323-5.

Journal of the American Academy of Dermatology 12. Binazzi M, SimonetteV. Granuloma annu1are, necrobiosis Iipoidica, and diabeticdisease. Int J Dermatol 1988; 27:576-9. 13. Hatzis J, Varelzidis A, ToscaA, et al. Sweatglanddisturbancesin granuloma annulare and necrobiosis lipoidica. Br J Dermato11983;108:705-9. 14. MarkeyAC, Tidman MJ, RowePH, et al, Aggressive ulcerative necrobiosis lipoidica associated with venous insufficiency, giant-cell phlebitis and arteritis. Clin Exp Dermatol 1988;13:183-6. 15. ClementM, Guy R, PembrokeAC. Squamouscellcarcinomaarising in long-standing necrobiosis lipoidica. Arch Dermatol 1985;121:24-5. 16. Kossard S, Collins E, Wargon 0, et al. Squamouscarcinomasdeveloping in bilaterallesions of necrobiosis lipoidica. Australas J Dermato11987;28:l4-7. 17. Sah1 W1. Necrobiosis lipoidica diabeticorum, Localization in surgicalscars. J Cutan Pathol1978;5:249-53. 18. Wantzin GL, Kobayae T. Necrobiosis lipoidica in a patient withgeneralized scleroderma: a casereport. Acta Derm Venereal (Stockh) 1980;60:73-6. 19. MackeyJP. Necrobiosis lipoidica diabeticoruminvolving scalp and face. Br J Dermato11975;93:729-30. 20. BurtonJL. Granulomaannu1are, rheumatoidnodules and necrobiosis lipoidica. Br J Dermatol 1977:97(suppl 15): 52-4. 21. Dowling GB, Wilson-Jones E. Atypical (annular) necrobiosis lipoidica of the face and scalp.A report of the clinical and histological features of 7 cases. Derrnatologica 1967;135:11-26. 22. Mehregan AH, Altman 1. Miescher's granuloma of the face. A varient of the necrobiosis lipoidica-granuloma annulare spectrum. Arch DermatoI1973;107:62-4. 23. O'Brien JP. Actinic granuloma. Arch Dermatol 1973;111 :460-6. 24. Helander I, Nieme KM, Tyrkko J. Atypical necrobiosis lipoidica of the face. Acta Derm Venereol (Stockh) 1978;58:276-7. 25. Hanke CW, Bailin PL, Roenigk HH Jr. Annular elastolytic giant cell granuloma. J AM ACAD DERMATOL 1979;1:413-21. 26. Muller SA, WinkelmannRK. Necrobiosis lipoidica diabeticorum. Results of glucose-tolerance tests in nondiabetic patients. JAMA 1966;195:433-6. 27. Muller LSA, Winkelmann RK. Atypicalformsof necrobiosis lipoidica diabeticorum. A reportofthree cases. Arch PathoI1966;81:352-61. 28. Muller SA, WinkelmannRK. Necrobiosis lipoidica diabeticorum. Histopathologic study of 98 cases. Arch Dermatol 1966;94:1-10. 29. DuBoulay C, Whorwhell PJ "Nodularnecrobiosis": a new cutaneous manifestation of Crohn's disease? Gut 1982; 23:712-5. 30. Whorwell PJ, HaboubiNY, DuBoulayC.Nodularnecrobiosis in association with ulcerative colitis. Gut 1986; 27:1517. 31. CleggDO, Zone JJ, Piepkorn MW. Necrobiosis lipoidica associated with jejunoileal bypasssurgery. Arch Dermatol1982;118:135-6. 32. Schwartz ME. Necrobiosis lipoidica and granuloma annulare. Simultaneous occurrence in a patient. Arch Dermatol1982;1l8:192-3. 33. Cohen IlK. Necrobiosis lipoidica and granuloma annulare. J AM ACAD DERMATOL 1984;10:123-4. 34. FeldmanFF. Granulomaannulareand necrobiosis lipoidica in the same patient. Arch DermatoI1968;98:677-8.

Volume25 Number 5, Part 1 November 1991 35. Savin JA. Diabetes mellitus, sarcoidosis, ?necrobiosis lipoidica. Proc R Soc Med 1969;62:350. 36. Graham-Brown RAC, Shuttleworth D, SarkanyI. Coexistence ofsarcoidosis and necrobiosis lipoidica of the legs. A reportoftwo cases. ClinExp DermatoI1985;10:274-8. 37. MonkBE,DuVivier AWP. Necrobiosis lipoidica andsarcoidosis. Clin Exp DermatoI1987;12:294-5. 38. Andersen KE. Systemic sarcoidosis with necrobiosis lipoidica-Iike scalplesions. Acta Derm Venereal (Stockh) 1977;57:367-9. 39. Kobayasi T, Sanielsen L, Asboe-Hansen G. Ultrastructure of necrobiosis lipoidica diabeticorum. Acta Derm Venereol (Stockh) 1974;54:427-31. 40. Quimby SR, Muller SA, Schroeter AL. The cutaneous immunopathology of necrobiosis lipoidica diabeticorum. Arch DermatoI1988;124:1364-71. 41. Boulton AJM, CutfieldMB,Abouganem D, et aI.Necrobiosis lipoidica diabeticorum: a clinicopathologic study.J AM ACAD DERMATOL 1988;18:530-7. 42. AlegreVA,Winkelmann RK. A newhistopathologic feature of necrobiosis lipoidica diabeticorum: lymphoid nodules. J Cutan PathoI1988;15:75-7. 43. Dandona P, Freedman D, Barter S, et aI. Glycosylated haemoglobin in patients with necrobiosis lipoidica and granuloma annulare. Clin Exp Dermatol 1981;6:299302. 44. FindlayGH, Morrison JGL, DeBeer HA. Non-diabetic necrobiosis Iipoidica. Hitherto unrecognized papuloneerotic, nodule-ulcerative andfamilial forms of thedisease. S Afr Med J 1981;59:323-6. 45. Seviour PW, Elkeles RS. Necrobiosis Iipoidica in two diabetic sisters. Clin Exp DermatoI1985;10:159-61. 46. Soler NG, McConnachie PRo HLA antigens and necrobiosis Iipoidica diabeticorum-a comparison between insulin-dependent diabetics with and without necrobiosis. Postgrad Med J 1983;59:759-62. 47. Lukasiak B, Wnorowski J, Rozanski J. Capillaroscopic changes in the courseof necrobiosis lipoidica. Pol Med J 1969;8:230-7. 48. Trapp RG, Soler NG, Spencer-Green G. Nailfold capillaroscopy intypeI diabetics withvasculopathy andlimited joint mobility. J Rheumatol1986;13:917-20. 49. KohMS,Majewski BBJ,BarterS, et aI.Increased plasma fibronectin in diabetesmellitus, necrobiosis Iipoidica and widespread granuloma annulare. Clin Exp Dermatol 1984;9:293-7. 50. Majewski BBJ,Koh MS, Barter S, et aI.Increased factor VIII-related antigen in necrobiosis lipoidica and widespread granuloma annulare without associated diabetes. Br J DermatoI1982;107:641-5. 51. Majewski BBJ, Barter S, Rhodes EL. Serum alpha-2 globulin levels in granuloma annulare and necrobiosis lipoidica. Br J DermatoI1981;105:557-62. 52. Rhodes EL. Thoughtson the diabeticstate.Br J Dermatol 1966;78:577-80. 53. Rhodes EL. Fibrinolytic agentsin the treatmentofnecrobiosis lipoidica. Angiology 1978;29:60-4. 54. HalushkaPV,RogersRC, Loadholdt CB,et aI.Increased plateletthromboxane synthesis in diabetes mellitus. J Lab Clin Med 1981;97:87-96. 55. TakahashiR, Shiraki M, Morita I, et aI.Plateletthromboxane synthesizing activity in non-insulin-dependent diabetes: correlation with diabeticretinopathy and diabetic treatment. Prostaglandins Leukotrienes Med 1985;17: 149-58. 56. Hamlin CR, Kohn RR, Luschin JH. Apparent acceler-

Necrobiosis lipoidica 747 ated agingof human collagenin diabetesmellitus. Diabetes 1975;24:902-4. 57. Yuen CT, Easton D, Misch KJ, et al. Increasedactivity of serumamineoxidases in granuloma annulare,necrobiosis lipoidica and diabetes. Br J Derrnatol 1987;116: 643-9. 58. Sibbitt WL. Diabeticstiff hand syndrome. Int Med Specialist 1989;10:71-86. 59. Eaton RP. The collagen hydration hypothesis: a newparadigm for the seconodary complications of diabetesmellitus. J Chronic Dis 1986;39:763-6. 60. Hanna W, Friesen D, Bombardier C, et aI. Pathologic features of diabetic thick skin. J AM ACAD DERMATOL 1987;16:546-53. 61. Eaton RP, Sibbit WL, Harsh A. The effect of an aldose reductaseinhibiting agent on limitedjoint mobility in diabetic patients. JAMA 1985;253:1437-40. 62. Oikarinen A, Mortenhumer M, Kallioinen M, et aI. Necrobiosis lipoidica: ultrastructural and biochemical demonstration of a collagen defect. J Invest Dermatol 1987;88:227-32. 63. Igisu K, SomeyaT, Tamaki K. Necrobiosis Iipoidica diabeticorum associated with familial hypo-beta-lipoproteinemia, Int J DermatoI1987;26:647-8. 64. Gange RW, BlackMM, Carrington P. Defective neutrophil migration in granulomaannulare, necrobiosis lipoidica, and sarcoidosis. Arch DermatoI1979;115:32-5. 65. Majewski BBl, Rhodes EL, Watson B. Neutrophil mobility in granuloma annulare and necrobiosis lipoidica. Clin Exp DermatoI1981;6:583-90. 66. Koh MS, Majewski BBJ, Barter S, et al. Polymorphonuclear and mononuclear leucocyte function in necrobiosis lipoidica and granuloma annulare. Arch Dermatol Res 1983;275:45-7. 67. Koh MS, Majewski BBJ, Barter S, et al. Serum beta-glucuronidase activityin human diabetesmellitus, granuloma annulare and necrobiosis lipoidica, Clin Exp Dermatol 1983;8:299-304. 68. Dahl MV, Ullman S. Direct immunofluorescence in granuloma annulare land necrobiosis lipoidica. Clin Res 1976;24:95A. 69. Ullman S, Dahl MY.Necrobiosis Iipoidica, An immunofluorescence study.Arch Dermatol 1977;113:1671-73. 70. Dahl MV.Speculations onthe pathogenesis of granuloma annulare, Australas J DermatoI1985;26:49-57. 71. Nieboer C, Kasbeek GL. Direct immunofluorescence studies in granuloma annulare, necrobiosis lipoidica and granulomatosis disciformis Miescher. Dermatologica 1979;158:427-32. 72. LaukkanenA, Fraki JE, Vaatainen N, et al. Necrobiosis lipoidica: clinical and immunofluorescent study. Dermatologica 1986;172:89-92. 73. EvansCD, Pereira RS, Yuen CT, et al. Anti-collagen antibodies in granulomaannulare and necrobiosis lipoidica, Clin Exp DermatoI1988;13:252-4. 74. FitzpatrickTB, PolanoML, SuurmondD. Coloratlasand synopsis of clinical dermatology. New York: McGrawHill, 1983:100-1. 75. Bauer M, Levan NE. Diabetic dermangiopathy. A spectrum including pigmented pretibial patches and necrobiosis lipoidica diabeticorum. Br J Dermatol 1970;83:52835. 76. Saxe N, Benatar SR, BokL, et al. Sarcoidosis withlegulcers and annular facial lesions. Arch Dermatol 1984; 120:93-6. 77. Jelinek lE. Cutaneous markers of diabetes mellitus and

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Lowitt and Dover the role of microangiopathy. In: The skin and diabetes. Philadelphia: Lea & Febiger, 1986:31-69. Jorizzo JL, Olansky AJ, Stanley RJ. Superficial ulcerating necrobiosis in rheumatoid arthritis. A variant of the necrobiosis lipoidica-rheumatoid nodule spectrum? Arch DermatoI1982;1l8:255-9. Macfarlane AW, Verbov JL. Necrobiotic xanthogranuloma with paraproteinaemia. Br J Dermatol 1985;113: 339-43. Holden CA, Winkelmann RK, Jones EW. Necrobiotic xanthogranuloma: a report of four cases. Br J Dermatol 1986;114:241-50. Kossard S, Winkelmann RK. Necrobiotic xanthogranuloma with paraproteinemia. J AM ACAD DERMATOL 1980;3:257-70. Bowers RE. Sclerosing lipogranuloma. ?Necrobiosis Iipoidica. Proc R Soc Med 1975;68:450-1. Laymon CW, Fisher 1. Necrobiosis lipoidica (diabeticorum?) Arch Dermatol Symph 1949;59:150-67. Dabsld K, Winkelmann RK. Generalized granuloma annulare: histopathology and immunopathology. Systematic review of 100 cases and comparison with localized granuloma annulare. J AM ACAD DERMATOL 1989;20:28-47. Mehregan AH, Pincus H. Necrobiosis lipoidica with sarcoid reaction. Arch DermatolI961;93:729-30. Gibson LE, Reizner GT, Winkelmann RK. Necrobiosis Iipoidica diabeticorum with cholesterol clefts in the differential diagnosis of necrobiotic xanthogranuloma. J Cutan PathoI1988;15:18-21. Goette DK. Resolution of necrobiosis lipoidica with exclusive (sic) clobestasol propionate treatment. JAM ACAD DERMATOL 1990;22:855-6. Marten RH, Dulake M. Hydrocortisone in necrobiosis lipoidica diabeticorum. Br J Dermatol 1957;69:395-9. Sparrow G, Abell E. Granuloma annulare and necrobiosis lipoidica treated by jet injector. Br J Dermatol 1975; 93:85-9. Rhodes EL. Fibrinolytic agents in the treatment of necrobiosis lipoidica. Br J DermatoI1976;95:673-4. Littler CM, Tschen EH. Pentoxifylline for necrobiosis lipoidica diabeticorum. J AM ACAD DERMATOL 1987;17: 314-6. Eldor A, Diaz EG, Naparstek E. Treatment of diabetic necrobiosis with aspirin and dipyridamole. N Eng! J Med 1978;298:1033. Karkavitsas K, Miller JA, Dowd PM, et al. Aspirin in the management of necrobiosis lipoidica. Acta Derm Venereol (Stockh) 1982;62:183. Beck H, Bjerring P. Skin blood flow in necrobiosis lipoidica during treatment with low-dose acetylsalicylic acid. Acta Derm Venereal (Stockh) 1988;68:364-5. Fjellner B. Treatment of diabetic necrobiosis with aspirin or dipyridamole. N Engl J Med 1978;299:1366.

Journal of the American Academy of Dermatology

96. Quimby SR, Muller SA, Schroeter AL, et a1. Necrobiosis lipoidica diabeticorum: platelet survival and response to platelet inhibitors. Cutis 1989;43:213-6. 97. Heng MC, Song MK, Heng MK. Healing of necrobiotic ulcers with antiplatelet therapy. Correlation with plasma thromboxane levels. Int J DermatolI989;28:195-7. 98. Statham BN, Finlay AY, Marks R. Aspirin and dipyridamole ineffective in treatment of necrobiosis lipoidica. N Engl J Med 1980;303:1419. 99. Statham B, Finlay AY, Marks R. A randomized double blind comparison of an aspirin dipyridamole combination versus a placebo in the treatment of necrobiosis lipoidica, Acta Derm Venereal (Stockh) 1981;61:270-1. 100. Dahl MV. Immunofluorescence,necrobiosislipoidica, and blood vessels. Fluorescent lights in the tunnels. Arch Dermatol 1988;124:1417-9. 101. Beck H, Bjerring P, Rasmussen I, et al. Treatment of necrobiosislipoidica with low-dose acetylsalicylic acid. A randomized double-blind trial. Acta Derm Venereol (Stockh) 1985;65:230-4. 102. Bonnetblanc JM, Julia A, Rigaud M. Antithrombotic agents in necrobiosis lipoidica diabeticorum. Acta Derm Venereol (Stockh) 1986;66:90. 103. Rhodes EL. Necrobiosis lipoidica treated with ticlopidine. Acta Derm Venereol (Stockh) 1986;66:458. 104. Hanke CW, Bergfeld WF. Treatment with benzoyl peroxide of ulcers on legs with lesionsof necrobiosislipoidica diabeticorum. J Dermatol Surg Oncol 1978;4:701-4. 105. Dubin BJ, Kaplan EN. The surgical treatment of necrobiosis lipoidica diabeticorum. Plast Reconstr Surg 1977; 60:421-8. 106. Marr TH, Traisman HS, Griffith BH, et a1. Necrobiosis lipoidicadiabeticorum ina juvenile diabetic. Treatment by excision and skin grafting. Cutis 1977;19:348-50. 107. YoushockE, Beninison J. Necrobiosis lipoidica:treatment with porcine dressings, split-thickness skin grafts and pressure garments. A case report and review of review of treatment modalities. Angiology 1985;36:821-6. 108. Sawada Y. Successful treatment of ulcerated necrobiosis lipoidicadiabeticorum with prostaglandin E] and skin flap transfer. A case report. J Dermatol (Tokyo) 1985;12:44954. 109. Handfield-Jones S, Jones SK, Peachey RDG. Nicotinamide treatment in diabetes. Br J DermatolI987;116:27786. 110. Handfield-Jones S, Jones S, Peachey R. High dose nicotinamide in the treatment of necrobiosis lipoidica, Br J DermatoI1988;118:693-6. 111. Wilkin JK. Perilesional heparin injections for necrobiosis lipoidica. JAM ACAD DERMATOL 1983;8:904. 112. Mensing H. Clofazimine therapy: an alternative treatment for necrobiosis lipoidica and granuloma annulare. Hautarzt 1989;40:99-103.