NL

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REVIEW
Update on necrobiosis lipoidica: A review of etiology,
diagnosis, and treatment options
Sophia D. Reid, MD,
a
Barry Ladizinski, MD,
b
Kachiu Lee, MD, MPH,
a
Akerke Baibergenova, MD,
c
and Afsaneh Alavi, MD
d
Providence, Rhode Island; Baltimore, Maryland; and Toronto, Ontario, Canada
Necrobiosis lipoidica (NL) is a rare chronic granulomatous disease that has historically been associated with
diabetes mellitus. Debate exists regarding the etiology and pathogenesis of NL with a widely accepted
theory that microangiopathy plays a significant role. NL typically presents clinically as erythematous
papules on the front of the lower extremities that can coalesce to form atrophic telangiectatic plaques. NL is
usually a clinical diagnosis, but if the clinical suspicion is uncertain, skin biopsy specimen can help
differentiate it from sarcoidosis, necrobiotic xanthogranuloma, and granuloma annulare. NL is a difficult
disease to manage despite a large armamentarium of treatment options that include topical and
intralesional corticosteroids, immunomodulators, biologics, platelet inhibitors, phototherapy, and surgery.
Randomized control trials are lacking to evaluate the many treatment methods and establish a standard
regimen of care. Disease complications such as ulceration are common, and lesions should also be
monitored for transition to squamous cell carcinoma, a less common sequelae. ( J Am Acad Dermatol
10.1016/j.jaad.2013.05.034.)
Key words: dermatology; diabetes; necrobiosis lipoidica; treatment.
Necrobiosis lipoidica (NL) is an idiopathic
chronic granulomatous disease of the
dermis, characterized by collagen degener-
ation, granuloma formation, fat deposition, and en-
dothelial wall thickening. Because of its increased
prevalence in diabetic patients, particularly those
who are insulin dependent, etiologic theories re-
garding microangiopathy are most prevalent.
However, the association of poor glycemic control
and the development or progression of NL remains
controversial. Other proposed causes include immu-
noglobulin deposition, trauma, metabolic changes,
and abnormal collagen production. Although the
most common disease association is diabetes, NL has
been described in patients with sarcoidosis, inflam-
matory bowel disease, autoimmune thyroiditis, rheu-
matoid arthritis, monoclonal gammopathy, and
otherwise healthy patients with normal glucose me-
tabolism and no history of autoimmune diseases.
1-5
This review seeks to update the clinician on the
etiology and presentation of NL as well as evidence-
based treatment options.
EPIDEMIOLOGY
NL is a rare disorder with a female predominance
(female to male ratio of 3:1). Age of onset is typically
around the third decade of life in patients with type
1 diabetes and fourth decade in patients with type 2
diabetes and in nondiabetics.
6,7
The incidence of NL
in people with diabetes is only 0.3% to 1.2%.
7
NL
precedes a diagnosis of diabetes in up to 14% of
patients, is diagnosed simultaneously in up to 24%,
and appears after a diagnosis of diabetes in up to
62%.
6,7
Up to half of these patients with diabetes with
NL will eventually become insulin-dependent.
6,8
ETIOLOGY AND PATHOGENESIS
The origin and pathogenesis of NL remains un-
clear with the leading theory involving microangi-
opathy as a result of glycoprotein deposition in the
vasculature resulting in thickening of blood vessels.
9
Boateng et al
9
demonstrated lower oxygen tension of
blood vessels at the site of NL lesions using Doppler
analysis, suggesting that hypoxia is a part of the
pathogenesis.
9
Ngo et al
10
later refuted this study,
From the Department of Dermatology, Brown University, Provi-
dence
a
; Johns Hopkins Bloomberg School of Public Health,
Baltimore
b
; Department of Medicine (Dermatology), University
of Toronto
c
; and Wound Care Clinic, Women’s College Hospital,
Toronto.
d
Funding sources: None.
Conflicts of interest: None declared.
Accepted for publication May 30, 2013.
Reprint requests: Afsaneh Alavi, MD, Wound Care Clinic, Women’s
College Hospital, 76 Grenville St, Toronto, ON M5S 1B1, Canada.
E-mail: afalavi@yahoo.com.
Published online August 19, 2013.
0190-9622/$36.00
Ó2013 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2013.05.034
1

demonstrating that blood flow was higher in
NL lesions as compared with unaffected skin.
Immunohistochemical analysis of tissue from NL
lesions supports the theory of hypoxia, based
on the increased presence of glucose transporter
1 receptors in fibroblasts. However, the increased
presence of these receptors is debatable.
11
CLINICAL
PRESENTATION AND
COMPLICATIONS
NL lesions typically pre-
sent as 1 to 3 asymptomatic,
well-circumscribed papules
and nodules with active ery-
thematous borders that
slowly coalesce into plaques.
The plaques appear viola-
ceous and contain a central
area that initially appears
red-brown, but later pro-
gresses to a yellow-brown
discoloration (Fig 1). The
central area often contains
atrophic, waxy, and eroded
skin. Telangiectasis can de-
velop as a direct result of
collagen degeneration occurring beneath the
epidermis. NL lesions can also exhibit the Koebner
phenomenon, which makes surgical intervention
challenging. Although the majority of lesions are
painless as a result of associated nerve damage, up
to 25% can be exquisitely painful, especially if
ulcerated. NL is generally localized to the bilateral
lower extremities, although lesions on the face,
scalp, trunk, groin, and upper extremities can also
be present. NL is usually diagnosed by physical
examination, but biopsy should be considered if
clinical suspicion is not definite.
Up to 35% of patients with NL will develop
ulcerations secondary to minor trauma (Figs 2
and 3).
6
These ulcerations often prove challenging
to treat. Occasional reports of squamous cell
carcinoma arising in areas of long-term lesions
have also been reported. It is unclear whether
transformation into squamous cell carcinoma is
solely a result of changes of long-standing NL, or
whether chronic ulceration predisposes these
lesions to malignant transformation.
12-14
NL AND DIABETES
There is much debate regarding the nature of the
correlation between NL and diabetes. Studies from
the 1960s established the precedent that over 60% of
patients with NL had diabetes or abnormal glucose
metabolism. This has been challenged by later
studies that were unable to reproduce such a
definitive correlation. A study of 65 patients with
NL by O’Toole et al
15
found that diabetes was present
in only 11%, with an additional 5% being given a
diagnosis of diabetes later in life. Sampling errors
could account for some variation, but debate will
remain until newer studies
are performed. At this time,
most studies continue to cite
a 65% incidence based on the
1966 study by Muller and
Winkelmann.
6,11
Since the
1960s, there have not been
any additional prevalence-
based studies conducted
on NL.
Insulin-dependent (type
1) diabetics have a predispo-
sition to develop NL at a
younger age, with the mean
age of 22 years, as compared
with those with type 2
diabetes and those without
diabetes, who develop NL at
the average age of 49 years.
16
Although NL and diabetes
have historically shared a strong, yet controversial,
correlation with each other, there has not been a
causative relationship established. It is more likely
that the 2 entities are caused by the same underlying
pathophysiology. With only 0.3% to 1.2% of diabetics
developing NL, it begs the question of what factors
increase susceptibility to developing NL versus the
other 99% of diabetics who do not acquire NL.
Genetics do not appear to play a significant role
in disease development (except for rare cases of
familial NL). HLA antigens were compared among
type 1 diabetics and there was no significant
difference in antigen expression between those
with NL and those without.
17
One study of 171
patients with NL showed that a family history of
diabetes was present in 68% of diabetic patients with
NL and 45% of nondiabetic patients with NL who
were aged 45 years and older, again arguing for the
role of glucose metabolism in the disease process.
6
Interestingly, patients who have both NL and
diabetes tend to have an earlier onset of diabetes.
The reason for this is not well understood, but certain
‘‘diabetogenic’’ properties have been proposed to
contribute to earlier-onset diabetes in this patient
population. Diabetics with NL are only slightly more
prone to ulceration compared with nondiabetics,
35% versus 33%, respectively, and nondiabetics are
not more likely to spontaneously clear lesions.
6
CAPSULE SUMMARY
dNecrobiosis lipoidica is difficult to
manage, and there are no established
treatment regimens.
dTraditional therapies include topical and
intralesional steroids,
immunosuppressants, platelet inhibitors,
and phototherapy. Intralesional
infliximab, colchicine, carbon dioxide
laser, photodynamic therapy, and topical
calcineurin inhibitors also have been
used with some efficacy.
dOther experimental treatment options
may be considered if a patient is
unresponsive to conventional therapies.
JAMACAD DERMATOL
2Reid et al

Maintaining adequate glucose control is a highly
debated topic in the management of NL, with current
consensus agreeing that it is not an essential
component of treatment. Glucose control has only
been beneficial in a few cases,
8
with most studies
supporting the more current idea that glucose
regulation does not affect the presence or progres-
sion of NL.
One study reported clearance of NL lesions in
patients with diabetes after pancreatic transplanta-
tion, but not kidney transplantation, although it is
unclear if resolution can be attributed to the
transplantation itself or to the immunosuppressive
medications that were initiated posttransplanta-
tion.
18
More studies are needed to further elucidate
this relationship. Nonetheless, it is still recommen-
ded that patients with NL maintain acceptable
glucose levels to prevent other complications of
diabetes.
TREATMENT OPTIONS
NL has historically been a difficult disease to
treat, with current therapeutic options producing
minimal and inconsistent results. A multitude of case
reports have described the use of several treatments
(Table I), but large randomized placebo-controlled
trials are lacking.
Lifestyle modifications are important to minimize
risk of NL complications, primarily the avoidance of
trauma. Once ulcerated, healing may be difficult. A
palpable dorsalis pedis or posterior tibialis pulse
indicates adequate blood flow for healing, but does
not exclude the presence of arterial disease in
diabetic patients.
19
In high-risk cases, measuring
toe pressure is helpful because 80% of diabetics
Fig 2. Necrobiosis lipoidica (NL). The central area often
contains atrophic, waxy, eroded skin.
Fig 1. Necrobiosis lipoidica. Well-defined plaques with
central area that initially appears red-brown, but later
progresses to yellow-brown coloration. Central area of
lesions often contains atrophic, waxy, eroded skin.
JAMACAD DERMATOL Reid et al 3

and 20% of nondiabetics have calcified arterial
vessels that can lead to falsely elevated ankle
brachial index levels.
20
Identifying infected lesions
is important so proper dressing-containing antisep-
tics, such as micronized silver, slow-release iodine,
or chlorhexidine can be used.
21
Deep infection
usually requires systemic antimicrobial therapy.
The mainstay of treatment for NL includes topical
and intralesional corticosteroids. Several case studies
have shown that the use of intralesional triamcino-
lone, topical clobetasol, and short courses of
systemic steroids can be efficacious.
8
Steroid use in
diabetic patients should be monitored to prevent
glucose dysregulation, particularly when used over
large surface areas. Steroids should also not be
applied to atrophic areas given lack of efficacy and
possibly worsening of atrophy. Steroids should
instead be applied to the active borders of lesions
to reduce inflammation and halt progression.
Intralesional infliximab has been reported to
clear NL lesions, but recurrences were common.
22
Other tumor necrosis factor-alfa inhibitors, such as
etanercept and thalidomide, have been used with
some success, although dosing regimens are not well
defined.
23
Pioglitazone, a peroxisome proliferator
eactivated receptor-gamma agonist that also has an
inhibitory effect on tumor necrosis factor-alfa helped
improve NL lesions in 1 report, but did not prevent
new lesions from developing.
24
Hyperbaric oxygen
use has produced moderate results.
25
Topical tretinoin has been shown to improve the
atrophic nature of NL lesions by promoting collagen
formation and angiogenesis.
26
Topical tacrolimus
was used to treat 2 patients with ulcerated NL with
somewhat beneficial results in ulcers, but no
significant response in residual lesions.
27
Topical
tacrolimus has also been used in nonulcerated NL
lesions and a significant decrease in size of lesions
was noted, with no new areas of recurrence at
1-year follow-up.
28
Use of topical bovine collagen
helped with wound resolution in a nondiabetic
male.
29
One trial with an aspirin and dipyridamole
combination versus placebo showed no significant
improvement.
30
Another trial examined the use of
acetylsalicylic acid versus placebo, with lesions
worsening in both groups.
31
However, a small study
suggested that a healing effect may be conferred with
antiplatelet therapy in patients with ulcerated lesions
and high thromboxane levels.
32
Some reports have also demonstrated beneficial
outcomes with stanozolol, ticlopidine, inositol
nicotinate, pentoxifylline, and prostaglandin E1.
8
Granulocyte-macrophage colony-stimulating factor
was found to be effective in patients with ulcerated
NL, but platelet-derived growth factor did not confer
any benefit.
33
Clofazimine was shown to be effective in 60% of
patients with either granuloma annulare or NL,
34,35
however, doses above 100 mg daily should not
exceed a 3-month time period because of potential
adverse effects.
36
Some side effects are mild such as
skin discoloration, ichthyosis, nausea, and vomiting,
however more serious side effects can ensue such as
small bowel enteropathy, ileus, and splenic infarc-
tion from crystal deposition.
36
Some reports have
also demonstrated complete resolution of lesions
with chloroquine.
11,37
Oral cyclosporine has consistently shown benefi-
cial results in healing NL ulcerations,
38-41
but
recurrences are common upon discontinuation.
38-40
Mycophenolate mofetil, another immunosuppres-
sant, was used successfully in a patient with
ulcerated NL, but the lesion recurred after cessation
of therapy.
42
One study of 10 patients with refractory NL treated
with psoralen plus ultraviolet A showed 100%
remission rate after an average of 47 sessions, with
similar findings in subsequent studies.
43,44
Other
reports using psoralen plus ultraviolet A with fewer
treatment sessions were not as successful.
45
Methyl
aminolevulinate photodynamic therapy has been
tried, but was not effective.
46
Surgery is a less favored option, given the risk of
koebnerization and disfiguring results. Lesions are
Fig 3. Necrobiosis lipoidica (NL). Ulceration occurs in up
to 35% of patients with NL and develops within existing NL
plaques.
JAMACAD DERMATOL
4Reid et al

Table I. Treatment options for necrobiosis lipoidica
Treatment options Treatment Study type No. of patients Results Author/year
Behavioral and lifestyle modifications Glycemic control Case report 1 1/1 Improved Kota et al
8
/2012
Topical and intralesional agents Topical steroid Case report
Retrospective
1
1
1/1 Improved
1/1 No change
Goette
53
/1990
Smith
42
/1997
Topical calcineurin inhibitors Case series
Case report
Case report
Case report
Case series
2
1
1
1
6
2/2 Improved after 8 and 14
wk; 1 recurred at 1 y
1/1 Improved after 16 wk; no
recurrence at 1 y
1/1 Improved after 12 wk
1/1 Resolution of ulcerated
area after 4 wk only,
underlying NL still present
4/6 Partial resolution after 8
wk; 2 with no change
Binamer et al
29
/2012
Patsatsi et al
28
/2011
Barth et al
54
/2011
Clayton et al
55
/2005
Harth et al
56
/2004
Intralesional steroids Case series
Retrospective
4
2
3/4 Improved, 1/4 with
partial resolution
2/2 Without change
Sparrow et al
57
/1975
Smith
42
/1997
Intralesional infliximab
administered weekly 33
doses
Case series 2 2/3 Improved Barde et al
23
/2011
Bovine collagen Case report 1 1/1 Resolution after 6 wk; no
recurrence at 5 mo
Spenceri et al
30
/1997
Systemic agents Aspirin 325-365 mg daily RCT 16 16/16 Showed worsening of
lesions, regardless of
randomization
Beck et al
31
/1985
Dipyridamole 1aspirin Case series
RCT
Case report
Case report
7
14
1
1
7/7 Resolution of ulceration
14/14 With no change,
regardless of randomization
1/1 No change
1/1 Improved
Heng et al
33
/1989
Statham et al
58
/1981
Statham et al
59
/1980
Eldor et al
60
/1978
Dipyridamole 1intralesional
triamcinolone
Case report 1 1/1 Improvement after 2 wk Jiquan et al
61
/2008
Pentoxifylline 400 mg 3 times
daily
Case report
Case report
Retrospective
1
1
2
1/1 Partial improvement after
3mo
1/1 No change
2/2 Minimal improvement
Stanway et al
39
/2004
Kostler et al
62
/2003
Smith
42
/1997
Nicotinic acid Case series
Prospective
2
13
2/2 Resolution of ulceration,
NL still present
8/13 Partial improvement
Smith
42
/1997
Handfield-Jones et al
63
/1988
Continued
JAMACAD DERMATOL Reid et al 5

Table I. Cont’d
Treatment options Treatment Study type No. of patients Results Author/year
Niacinamide Retrospective 2 2/2 No effect Smith
42
/1997
Cyclosporine Case report
Case report
Case series
Case series
1
1
2
2
1/1 Improved after 8 mo,
recurred 3 mo after cessation
of therapy
1/1 Resolution of ulceration
after 3 mo, NL still present
2/2 Resolution of ulceration,
NL still present
2/2 Resolution of ulceration,
NL still present
Stanway et al
39
/2004
Stinco et al
40
/2003
Darvay et al
41
/1999
Smith/1997
42
Antimalarials Case series 8
1
6/6 Treated with chloroquine
improved after 6 mo; 1/2
treated with hydroxychloro-
quine improved after 6 mo
1/1 Treated with chloroquine,
improved
Durupt et al
38
/2008
Nguyen et al
70
/2002
Colchicine 1000 mg daily Case report 1 1/1 Resolution of ulceration,
underlying NL still present
Schofield et al
71
/2012
Clofazimine 100 mg daily Case report 1 1/1 Ulceration healed, NL still
present
Benedix et al
37
/2009
Fumaric acid Case series 4 4/4 No effect Breuer et al
72
/2005
Mycophenolate mofetil Case report 1 1/1 Ulceration healed,
recurred after cessation of
therapy
Reinhard et al
43
/2000
Pioglitazone Case report 1 1/1 Regression of lesions,
appearance of new lesions
Boyd
25
/2007
JAMACAD DERMATOL
6Reid et al

Physical modalities PUVA 4 J/cm
2
Prospective
Prospective
Case report
Prospective
Case series
Prospective
Prospective
Case report
Retrospective
10
6
1
30
6
7
10
1
2
10/10 Improved with good
responses, 2 recurred at 8 mo
1/6 Complete resolution; 5/6
at least mild improvement
1/1 Partial remission
5/30 Complete resolution,
11/30 some improvement,
10/30 some improvement,
4/30 worsening
6/6 With significant clearing
2/7 Complete resolution, 4/7
some improvement, 1/7
no change
6/10 Improvement, 4/10 no
change
1/1 Improved
2/2 Minimal improvement
Narbutt et al
44
/2006
Beattie et al
64
/2006
Kostler et al
62
/2003
De Rie et al
46
/2002
Ling et al
45
/2002
Patel et al
65
/2001
McKenna et al
66
/2000
Patel et al
65
/2000
Smith
42
/1997
PDT Retrospective 18 7/18 With some response Berking et al
67
/2009
Hyperbaric oxygen Case study
Case study
1
1
1/1 Improved
1/1 Improvement in
ulceration, underlying
lesion still present
Bouhanick et al
26
/1998
Weisz et al
68
/1993
CO
2
laser Prospective 11 9/11 Improved; 2/11 no
change
Buggiani et al
69
/2012
CO
2
, Carbon dioxide; NL, necrobiosis lipoidica; PDT, photodynamic therapy; PUVA, psoralen plus ultraviolet A; RCT, randomized controlled trial.
JAMACAD DERMATOL Reid et al 7

excised to the level of the periosteum or deep fascia
to prevent recurrences.
47-49
Skin grafting is often
required to close defects that remain after removal of
the affected areas with mildly impressive cosmetic
results. Pulse dye lasers have also been used to treat
the telangiectatic component of NL.
50-52
Beneficial
cosmetic results were reported in 1 study and
harmful skin breakdown observed in another
study.
50,51
Further research is needed to determine
the optimal settings to treat NL.
CONCLUSION
Despite years of research, the origin of NL
remains unknown. The relationship between NL
and diabetes continues to be investigated, with
more current literature suggesting a lesser correla-
tion. Further, no effective treatment regimens have
been established. Currently, there are several
off-label treatment options with varying results that
can be offered to patients. The condition may also
resolve spontaneously without treatment, although
few epidemiologic studies have examined the rates
of resolution. It is important to monitor lesions for
signs of ulceration and treat aggressively to decrease
potential malignant transformation.
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