LES panniculitis .pdf



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Titre: Clinical entity of Lupus erythematosus panniculitis/lupus erythematosus profundus
Auteur: Satoru Arai; Kensei Katsuoka

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Autoimmunity Reviews 8 (2009) 449–452

Contents lists available at ScienceDirect

Autoimmunity Reviews
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / a u t r e v

Clinical entity of Lupus erythematosus panniculitis/lupus
erythematosus profundus
Satoru Arai ⁎, Kensei Katsuoka
Department of Dermatology, Kitasato University School of medicine, Sagamihara, Japan

a r t i c l e

i n f o

Available online 20 January 2009
Keywords:
Panniculitis
Lupus erythematosus
Skin diseases
Lupus erythematosus profundus

a b s t r a c t
We reviewed the clinical and histological characteristics of the 44 cases of lupus erythematosus
profundus (LEP) that have been encountered in our department. The female to male ratio was
4.5:1. The mean age of the females was 36 years, and the mean age of the males was 34 years. The
most common sites were the face (38.4%) and upper limbs (26.0%). Even among the patients with
LEP alone many of the positive patients had low antibody titers of 1:40 or 1:80. In 18 of the 44 cases
SLE was complicated by LEP, and in those cases there was a tendency for LEP to develop during the
course of SLE (11 cases). The important histological findings were lobular panniculitis associated
with mucin deposition (32 cases) and a tendency to be associated with damage to the basal cell
layer. In addition, the direct immunofluorescence test was positive in both the basement
membrane (90.5%) and blood vessels (85.7%) in a high percentage of even the cases of LEP alone.
Based on the above findings, LEP is a cutaneous variant of erythematosus, and the importance of
the histological findings when making the diagnosis of LEP was reconfirmed.
© 2009 Elsevier B.V. All rights reserved.

Contents
1.
2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical findings in LEP . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Background of the disease (presence or absence of complications,
2.2.
Clinical characteristics of LEP . . . . . . . . . . . . . . . . .
2.3.
Association between antinuclear antibody (ANA) and LEP . . . .
2.4.
Clinical characteristics of LEP in the cases associated with SLE . . .
3.
Histological characteristics of lupus erythematosus profundus . . . . .
3.1.
Findings in H&E-stained sections (Table 1) . . . . . . . . . . .
3.2.
Direct immunofluorescence (DIF) study (Table 2) . . . . . . . .
3.2.1.
Positive rate in the basement membrane . . . . . . . .
3.2.2.
Positive rates for blood vessels . . . . . . . . . . . .
4.
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Take
Take-home
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messages . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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449
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1. Introduction

⁎ Corresponding author. 1-15-1 Kitasato, Sagamihara city 228-8555, Japan.
Tel.: +81 42 778 8468; fax: +81 42 778 8628.
E-mail address: satoru@med.kitasato-u.ac.jp (S. Arai).
1568-9972/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.autrev.2008.12.011

Lupus erythematosus profundus (LEP) is a cutaneous
variant of erythematosus, which is principally characterized
by subcutaneous panniculitis. It was first described by Kaposi
in 1883 [1], and the term LEP was proposed by Irgang [2].

450

S. Arai, K. Katsuoka / Autoimmunity Reviews 8 (2009) 449–452

When LEP occurs in association with systemic erythematosus, it is relatively easy to make the diagnosis. However, when
patients arrive the hospital with a chief complaint of subcutaneous nodules and no other symptoms, the histological
findings are determinative. Some even question whether it is
appropriate to classify LEP as a cutaneous variant of erythematosus in cases in which the autoimmune aspect is unclear, such
as in antinuclear–antibody-negative cases.
Against this background, in the present study we used the
44 cases of LEP encountered in our department from 1970 to
2007 as the basis for a clinical analysis centered on two points,
findings that are important to making the diagnosis of LEP and
whether it is appropriate to classify LEP as a cutaneous variant
of erythematosus.
2. Clinical findings in LEP
2.1. Background of the disease (presence or absence of
complications, etc.)
The 44 LEP patients who were the subjects of the analysis
consisted of 36 females and 8 males. The mean age of the
females was 36± 13 years (range: 14 to 79 years), and the mean
age of the males was 34 ± 14 years (range: 15 to 57 years). In 20
of the cases LEP was associated with a systemic collagen
disease. The systemic collagen disease was SLE in 18 of these 20
cases, systemic sclerosis in 1 case, and dermatomyositis in 1
case, and thus SLE accounted for the association with a systemic
collagen disease in 90% of the cases.
2.2. Clinical characteristics of LEP
The lesions occurred at a single site in 15 of the LEP patients
and at multiple sites in the other 29 LEP patients. LEP was
associated with a collagen disease in 7 of the single-site cases
and in 13 of the multiple-site cases, and there was no difference
in number of LEP sites according to whether LEP was associated
with a collagen disease. Among the 73 sites in the 44 cases, the
head was affected in 16.4% (12 cases: 5 cases associated with a
systemic collagen disease (SCD), 7 cases of LEP alone), the face
in 38.4% (28 cases: 13 cases associated with a SCD and 15 cases
of LEP alone), the trunk in 13.7% (10 cases: 4 cases associated
with a SCD and 6 cases of LEP alone), the upper limbs (Fig. 1) in
26.0% (19 cases: 10 cases associated with a SCD and 9 cases of
LEP alone), lower limbs in 5.5% (4 cases: 2 cases associated with
a SCD and 2 cases of LEP alone), and thus the most common
sites were the face and upper limbs. There were no differences
between sites of occurrence according to whether LEP was
associated with a collagen disease, and no differences were
observed between the two groups in relation to the degree of
depression of the lesions either.

Fig. 1. Lupus erythematosus profundus of the left upper arm.

2.4. Clinical characteristics of LEP in the cases associated with SLE
Since SLE was associated with 18 of the 44 cases of LEP in
this study, we reviewed the clinical characteristics of LEP in
the cases associated with SLE.
First, we reviewed the times when LEP and SLE each
developed. There were only 6 cases in which the two developed
simultaneously, and in approximately 60% of the cases (11
cases) LEP developed during the course of cases in which SLE
had already been diagnosed. The mean interval between the
onset of SLE and the onset of LEP was 7 years. In 1 of the 18 cases
LEP developed first, and SLE was diagnosed 6 years later.
Next, we reviewed four aspects of the 11 cases of the 18 cases
in which LEP was diagnosed during the course of SLE: (1) the
dose of prednisolone (PSL) at the time of the onset of LEP, (2)
the SLE Disease Activity Index (SLEDAI) score, (3) the treatment
of LEP, and (4) whether there had been a recurrence. The mean
dose of PSL at the onset of LEP was 10.8 mg/day (range: 3 to
25 mg/day), and the mean SLEDAI score was 5.0 points,
indicating that the activity of SLE at the onset of LEP was
relatively quiescent. The treatments selected for LEP complicating SLE were an increased dose of PSL (3 cases), dapsone
(3 cases), low-dose cyclophosphamide (1 case), and probucol
(2 cases). However, LEP recurred during the course of treatment
in a large number of the patients, i.e., 5 of them.

2.3. Association between antinuclear antibody (ANA) and LEP
The ANA test was positive in 40 (95.2%) of the 42 patients
whose results were clearly stated. Among the 22 cases that
were not associated with a systemic collagen disease, there
was a low-positive titer of 1:40 in 13 cases, and of 1:80 in 8
cases. As might be expected, in the group in which LEP was
associated with a systemic collagen disease the 17 cases with
titers of 1:80 or more accounted for most of 20 cases.

3. Histological characteristics of lupus
erythematosus profundus
3.1. Findings in H&E-stained sections (Table 1)
We reviewed the histological findings in the 40 cases in
which it was possible to evaluate the findings in H&E-stained
sections. For the sake of convenience we reviewed the

S. Arai, K. Katsuoka / Autoimmunity Reviews 8 (2009) 449–452
Table 1
Histopathological characteristic's in LEP (40 cases).
Cases
1. Discoid lupus erythematosus
2. Liquefaction or thickening of the basal cell layer
3. Mucin deposition
4. Hyaline necrosis of fat
5. Lymphocytic aggregation/lymphoid follicles
6. Lobular panniculitis
7. Calcification
8. Fibrin thrombosis

5
19
32
24
28
31
4
4

histological findings by dividing them into 8 categories:
1) discoid LE, 2) liquefaction of the basal cell layer, or thickening
of the basement membrane, 3) mucin deposition, 4) hyaline
necrosis of fat, 5) lymphocytic aggregation/ lymphoid follicles,
6) lobular panniculitis, 7) calcification, and 8) fibrin thrombosis.
According to the results of our study only 5 (12.5%) of the cases
exhibited the typical histological findings of DLE. However, even
among the cases without any epithelial changes clinically,
thickening of the basement membrane or liquefaction of the
basal cell layer was observed in 19 cases (47.5%), and pigment
incontinence was observed in 27 cases (67.5%). Based on the
above, we concluded that the changes in the basal cell layer or
basement membrane described above are important findings
when making the diagnosis of LEP. Hyaline necrosis of fat
(24 cases, 60.0%) and lymphocytic aggregation/ lymphoid
follicles (28 cases, 70.0%), as well as lobular panniculitis
(31 cases, 77.5%), were classified as important histological
findings in LEP. However, based on the results of the present
study showing that mucin deposition was present in a large
number of the cases (32 cases, 80.0%), we concluded that it was
an important finding in terms of making a histological diagnosis
of LEP (Table 1).
3.2. Direct immunofluorescence (DIF) study (Table 2)
We reviewed the results of the direct immunofluorescence
(DIF) study in 37 cases. LEP was associated with SLE in 16 of the
cases, and in the other 21 cases the diagnosis was LEP alone. In
this study we reviewed the DIF findings in regard to deposition
in the basement membrane and in blood vessels (Table 2).
3.2.1. Positive rate in the basement membrane
The basement membrane was DIF-positive in all 16 cases
associated with SLE, and a high proportion of the cases of LEP
alone, 90.5% (19/21), were also positive. The positive rates for
IgM and C3 were highest in both groups.
3.2.2. Positive rates for blood vessels
The blood vessels were DIF-positive in 15 (93.8%) of the 16
cases associated with SLE, and a high proportion of the cases of
LEP alone, 85.7% (18/21), were also positive. The positive rates
of the blood vessels for IgM and C3 were the highest in both
groups, the same as for the basal cell layer or basement
membrane.
4. Discussion
We reviewed the 44 cases of LEP encountered in our
department in regard to whether it is appropriate to classify

451

LEP as a cutaneous variant of erythematosus, and in regard to the
presence of characteristic clinical and histological findings.
The most common sites of involvement in the case of LEP
were the face and upper limbs. There is a report stating that
the most common sites of LEP are the upper limbs, thighs and
buttocks [3], but lesions occurred in the lower limbs in only 4
of the cases in our series. Moreover, ulceration has been
reported to occur in 28% [3] of the patients, but it only
occurred in 3 of the cases seen in our department, and thus
there were large discrepancies from earlier reports. The
mechanism responsible for LEP leading to ulceration is
unknown, but in the present study as well it appeared to be
secondary ulceration due to impaired circulation as a result of
the fibrin thrombosis (4 cases) or extensive tissue hyaline
necrosis of fat. Because of the small number of cases of LEP
ulceration in Japan, a racial influence is also suspected.
Mucin deposition in the dermis or between fat lobules was
a prominent histological finding in many cases. Moreover,
even when the only finding clinically was subcutaneous
induration, thickening of the basement membrane or liquefaction of the basal layer was observed histologically in 19
cases (47.5%), and pigment incontinence was seen in 27 cases
(67.5%). Both have already been reported as histological
findings associated with LEP [4,5], but great importance has
never been attached to them as findings that can be used to
diagnose LEP histologically. LEP is difficult to diagnose on the
basis of the clinical findings alone, and if the mucin deposition
and above-described changes in the basal cell layer or
basement membrane are observed in addition to lobular
panniculitis and hyaline necrosis of fat, we think they can
serve as important histological evidence of LEP, because they
provide a basis for ruling out other forms of panniculitis.
The DIF-positive rates in this study were high. The rate was
90.5% in the basement membrane even in the LEP alone cases,
and blood vessels in the dermis were positive in 85.7%.
Although it is not possible to perform DIF tests in every
institution, DIF tests make it possible to strengthen the basis for
the histological diagnosis in cases that are strongly suspected of
being LEP based on the findings in H&E-stained sections [6].
The ANA test was positive in 95.4% (21/22) of even the
cases of LEP alone. The antibody titer was weakly positive,
1:40 (13 cases) or 1:80 (8 cases), in many of the cases. There
is a report that many LEP cases are ANA-negative, and that in
many of the positive cases the titers are low [3]. The ANA titer
alone cannot serve as a basis for diagnosing LEP, but we
consider it an auxiliary test when diagnosing LEP.
In the present study 18 of the 44 LEP cases (40.9%) were
associated with SLE. Since the rates in previous reports were
10% [3] and 22.2% [5], the rate of association with SLE in our
Table 2
Direct immunofluorescence test in LEP (37 cases).

IgG
IgA
IgM
C1q
C3
C4
Fib

Basement membrane (cases)

Blood vessels (cases)

Without SLE

With SLE

Total

Without SLE

With SLE

Total

11
6
11
7
14
4
3

9
8
16
6
13
10
9

20
14
27
13
27
14
12

4
5
8
7
13
4
5

7
5
13
8
12
5
8

11
10
21
15
25
9
13

452

S. Arai, K. Katsuoka / Autoimmunity Reviews 8 (2009) 449–452

department was twice high. The frequency of occurrence of
LEP in SLE, on the other hand, has been reported to be 2% [7]
to 4.5% [8], and it is an uncommon skin manifestation. Also,
when we reviewed the 18 LEP cases associated with SLE, there
were many cases in which LEP occurred during the course of
SLE, and there was a tendency for LEP alone to occur in the
cases in which the activity of SLE was relatively quiescent.
There were also many cases of recurrence even when the
steroid dose was increased and when immunosuppressive
drugs and dapsone were used in combination.
As reported above, we reviewed the clinical and histological findings in 44 cases of LEP. Based on the results of this
study, it is appropriate to classify LEP as a cutaneous variant of
erythematosus, and it was reconfirmed that the histological
findings are important to the diagnosis of LEP.

References
[1] Kaposi M. Pathologie und therapie der Hautkrankheiten, ed 2. Vienna,
Urban & Schwarzenberg,1883, P642.
[2] Irgang S. Lupus erythematosus profundus: report of an example with clinical
resemblance to Darier–Roussy sarcoid. Arch Dermat & Syph 1940;42:97–108.
[3] Martens PB, Moder KG, Ahmed I. Lupus panniculitis: clinical perspectives
from a case series. J Rheumatol 1999;26:68–72.
[4] Peters MS, Su WPD. Lupus erythematosus panniculitis. Med Clin North
Am 1989;73:1113–26.
[5] Massone C, Kodama K, Salmhofer W, Abe R, Shimizu H, Parodi A, et al. Lupus
erythematosus panniculitis (lupus profundus): clinical, histopathological,
and molecular analysis of nine cases. J Cutan Pathol 2005;32:396–404.
[6] Sánchez NP, Peters MS, Winkelmann RK. The histopathology of lupus
erythematosus panniculitis. J Am Acad Dermatol 1981;5:673–80.
[7] Díaz-Jouanen E, DeHoratius RJ, Alarcón Segovia D, Messner RP. Systemic
lupus erythematosus presenting as panniculitis (lupus profundus). Ann
Intern Med 1975;82:376–9.
[8] Tuffanelli DL. Lupus erythematosus panniculitis (profundus). Arch
Dermatol 1971;103:231–42.

Take-home messages
• The histopathological findings and direct immunofluorescence study are important for making the diagnosis of LEP.
• Regarding the histopathological examination, findings of
lobular panniculitis and hyaline necrosis of fat together with
mucin deposition and basement membrane degeneration
are important factors in making the diagnosis of LEP.
• Direct immunofluorescence study was highly positive at the
epidermal basement membrane and dermal blood vessels.
• In LEP associated with SLE, LEP tended to appear at the
course of SLE.

IgA antiphospholipid antibodies are an independent risk factor for thrombosis
Antiphospholipid syndrome (lupus anticoagulant, anti-cardiolipin and anti-beta(2)-glycoprotein antibodies, mostly IgG isotype)
are strong risk factors for thrombosis. Because a paucity of information on IgA isotype exists in the literature, Shen YM. et al. (Lupus
2008; 17: 996–1003) retrospectively evaluated the thrombotic significance of IgA antiphospholipid antibodies. The authors included
472 patients with clinical information on thrombotic events and complete laboratory work-up for antiphospholipid antibodies
syndrome. Odds ratio (OR) of various antiphospholipid antibodies for thrombosis were calculated by univariate and multivariate
analyses. Lupus anticoagulant alone was detected in 57 (12%) patients, ELISA-based antibodies (IgG, IgM, IgA) against cardiolipin,
phosphatidylserine or beta(2)-glycoprotein-1 alone were detected in 131 (28%) patients, whereas 80 (17%) patients had both.
Antibody isotype distribution was IgG 32%, IgM 60%, and IgA 56%. Univariate analysis showed a statistically significant risk of
thrombosis in patients with elevated titers of IgA of any ELISA-based antiphospholipid antibodies (OR 1.77). Stepwise logistic
regression (multivariate) analysis identified elevated titers of any ELISA-based IgA antiphospholipid antibodies as an independent
risk factor for thrombosis (OR 1.6) in the entire cohort, and in the subgroup of patients without concurrent presence of lupus
anticoagulant (OR 1.8). IgA antiphospholipid antibodies appear to be a significant independent risk factor for thrombosis, thereby
meriting evaluation in patients with unexpected thrombosis.

Antigen-specific peripheral shaping of the natural regulatory T cell population
Although regulatory T (Treg) cells are thought to develop primarily in the thymus, the peripheral events that shape the protective
Treg cell population are unclear. Here, Lathrop SK. et al. (J Exp Med 2008; 205: 3105–17) analyzed the peripheral CD4+ Tcell receptor
(TCR) repertoire by cellular phenotype and location in mice with a fixed TCRbeta chain. The authors found that Treg (Foxp3+) cells
showed a marked skewing of TCR usage by anatomical location in a manner similar to antigen-experienced (CD44highFoxp-) but not
naïve (CD44low Foxp3-) cells, even though CD44high and Treg cells used mostly dissimilar TCRs. This was likely unrelated to
peripheral conversion, which they estimate generates only a small percentage of peripheral Treg cells in adults. Conversion was
readily observed, however, during the immune response induced by Foxp3-cells in lymphopenic hosts. Interestingly, the converted
Foxp3+ and expanded Foxp3- TCR repertoires were different, suggesting thet generation of Foxp3+ cells is not an automatic process
upon antigen activation of Foxp3- Tcells. Retroviral expression of these TCRs in primary monoclonal Tcells confirmed that conversion
did not require prior cellular conditioning. Thus, these data demonstrate that TCR specificity plays a crucial role in the process of
peripheral conversion and in shaping the peripheral Treg cell population to the local antigenic landscape.


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