Crows On 2009

MINI-Symposium: inflammatory skin pathology
Cutaneous histopathology of disease. From a clinical standpoint, the disease may be classified
into systemic (acute), subacute cutaneous and discoid (chronic)
lupus erythematosus forms,1–12 all of which have correlative cutaneous stigmata.

There are other, less common variants of LE which represent
subsets of one or more of these three main categories. The cuta-
A Neil Crowson neous histopathology which correlates with the traditional forms
of LE, along with certain of the novel subtypes, are the principal
Cynthia M Magro subject of this review. In addition to the three main subtypes of
LE, we will discuss the associated vasculopathic lesions, the role
of immunofluorescence microscopy in the diagnosis of LE and
related connective tissue disease syndromes. Consideration will
be also given to recent advances in the pathogenesis of LE, and to
Abstract certain of the uncommon subtypes, namely anti-Ro/SSA-positive
Lupus erythematosus (LE) is an autoimmune connective tissue disease systemic lupus erythematosus (SLE), bullous SLE, lymphomatoid
whose precise aetiological basis is at present uncertain, in which the LE, LE profundus, drug-induced LE, linear cutaneous LE, chil-
clinical presentations range from a skin rash unaccompanied by extra- blains LE and parvovirus B19-associated LE.
cutaneous stigmata to one comprising progressive multisystem disease.
Recent advances in our understanding of the pathophysiological basis
Systemic lupus erythematosus
of LE bring hope for novel therapeutic approaches. Essential to a logical
therapeutic strategy is accurate diagnosis and subclassification. With re- Clinical features
spect to the foregoing, a thorough knowledge of clinical manifestations A diagnosis of SLE is made when a patient manifests four or
and serology is essential. A skin biopsy for routine histology, as well more criteria of the American College of Rheumatology (ACR)1
as the application of direct immunofluorescence microscopy to lesional (Table 1). The incidence of LE, which affects women in 80% of
and/or non-lesional skin, can be a powerful adjunct both to diagnosis cases, ranges from 5.8 in 100,000 in whites to 24.1 in 100,000
and subclassification. From a clinical standpoint, the disease may be in Asiatics13 and is highest in Africans; the incidence in Afri-
classified into systemic (acute), subacute cutaneous and discoid (chron- can–American women in New York City is 1 in 1000.14 The onset
ic) forms, all of which have specific correlative cutaneous histopathology
which calls to mind a distinct set of histological mimics. There are other,
less common, variants of LE, each with its own specific histological dif-
Criteria for systemic lupus erythematosus: Revised
ferential diagnoses. The cutaneous histopathology that correlates with
criteria of the American College of Rheumatology for
the traditional forms of LE, along with certain of the novel subtypes, are
the classification of systemic lupus erythematosus
the subject of this review.
(SLE) (after Tan et al1)
Keywords connective tissue disease; cutaneous; dermatomyositis; 1. Malar rash
histopathology; lupus erythematosus; pathophysiology 2. Discoid rash
3. Photosensitivity
4. Oral ulcers
5. Arthritis
Introduction 6. Serositis: (a) pleuritis or (b) pericarditis
Lupus erythematosus (LE) is an autoimmune disease which 7. Renal disorder:
mainly targets women of childbearing age, although it may occur (a) Proteinuria > 0.5 g/24 h or 3+, persistently or
at both extremes of age and in either sex. The clinical presenta- (b) Cellular casts
tions range from a skin rash unaccompanied by extracutaneous 8. Neurological disorder:
stigmata to one comprising progressive multisystem disease. The (a) Seizures or
diagnosis and subclassification of LE is based on the correlation (b) Psychosis (having excluded other causes, e.g. drugs)
of clinical manifestations with serological abnormalities. The 9. Haematological disorder:
more common clinical features are a photo-induced skin rash, (a) Haemolytic anaemia or
arthralgia, arthritis, fever, Raynaud phenomenon, anaemia, leu- (b) Leucopenia < 4.0 × 109/litre on two or more occasions
copenia, serositis, nephritis and central nervous system (CNS) (c) Lymphopenia < 1.5 × 109/litre on two or more occasions
(d) Thrombocytopenia < 100 + 109/litre
10. Immunological disorders:
A Neil Crowson MD is Clinical Professor of Dermatology, Pathology (a) Positive lupus erythematosus cell or
and Surgery and Director of Dermatopathology at the University (b) Raised antinative DNA antibody binding or
of Oklahoma and Regional Medical Laboratory, and Chairman of (c) Anti-Smith antigen (Sm) antibody or
Pathology, St John Medical Center, Tulsa, OK, USA. (d) False positive serological test for syphilis, present for at
least 6 months
Cynthia M Magro MD is Professor of Pathology and Director of 11. Antinuclear antibody in raised titre
Dermatopathology at the Department of Pathology, Weil College of
Medicine, Cornell University, New York, NY, USA. Table 1
DIAGNOSTIC HISTOPATHOLOGY 15:4 157 © 2009 Elsevier Ltd. All rights reserved.
of SLE is usually in early to mid adulthood, with the peak age at studies, some 20% of SLE patients with antibodies to Ro develop
onset being in the fourth decade of life. Women are hypomethyl- vasculitis.20 Urticarial lesions, including urticarial vasculitis, are
ators of DNA, a biological function that correlates with increased seen in fewer than 10% of SLE cases and are more common in
activity of lymphocytes and is the postulated mechanism of British patients whereby a temporal association with sun expo-
induction of drug-induced LE with certain classical agents such sure is often given.16,21 Patients with SLE express endothelial cell
as hydralazine.15 However, impaired CD4 T-cell methylation is dysfunction22 and may develop thrombosis. In one longitudinal
also held to contribute to the development of SLE and subacute cohort study, 20% of 482 patients developed thrombosis over
cutaneous LE (SCLE). DNA hypomethylation in CD4+ T cells 2936 patient years of follow-up, versus 2.5% of patients with
causes several gene activations and molecule overexpressions, other forms of connective tissue disease.23
and alters cellular function. Aberration of DNA methylation in T This is a disease with substantial financial impact in addition
cells might be responsible for idiopathic lupus and drug-induced to its potentially devastating physical consequences; the direct
lupus. Articular complaints tend to predominate at the outset, and indirect costs of SLE to an American patient were said to be
but 15% of patients present with skin manifestations; ultimately, over US$20,000 per annum in 2004.24
80% of patients will manifest skin involvement, most often in the
context of a faint photodistributed erythema. A malar ‘butterfly Pathophsyiology
rash’ with fine scaling (Table 2) is also characteristic, and is seen The end-organ effects of SLE are reflective of the interactions
in roughly half of patients with SLE.16 Seventy-two per cent of between B and T lymphocytes, likely mediated in part by anti-
116 patients presenting with an acute butterfly rash in one series gen-processing plasmacytoid dendritic cells (PDCs), recognizable
clearly satisfied the ACR criteria for SLE.8 in paraffin-embedded tissue by their expression of CD123. With
Bullous LE, an uncommon concomitant of SLE, is addressed respect to T-cell control of self-tolerance, decreases in a T-cell
below.16 The term ‘Rowell syndrome’4,17 is used to describe SLE fraction termed the T-regulatory (Treg) lymphocytes, which
with an erythema multiforme-like presentation as annular lesions co-express CD4 and CD25, have been described in SLE.25 In
that mimic those seen in SCLE, and is seen in a minority of SLE particular, levels of Treg cells and their activity are reduced in
patients, especially those in whom antibodies to Ro are pres- active versus inactive cases of SLE, and in both active and qui-
ent. In a certain percentage of patients with Rowell syndrome a escent disease compared to normal controls26 or to control cases
drug is a potential factor triggering this erythema multiforme-like of inflammatory skin lesions of other types.27 The loss of T-cell
presentation. A small minority of patients with SLE will have dis- regulation is postulated to presage clinical events in the develop-
coid plaques similar to the skin lesions of discoid lupus erythe- ment of SLE; expansion of autoreactive T-cell clones, which then
matosus (DLE) patients. Vasculopathic lesions are particularly direct polyclonal or oligoclonal B-cell expansion, appears to be
common in patients with SLE, and appear to correlate strongly an early event.28 This function is in turn influenced by the PDC,
with the expression of antibodies to Ro/SSA. These are clinically a professional antigen processing cell that expresses maturation
expressed in internal organs as a vasculitic injury syndrome and and activation markers CD80, CD86 and major histocompatibil-
in the skin as vasculitis, palpable purpura, ulcers, digital infarcts ity complex (MHC) II, in concert with CD123.28 The anomalous
and perniotic lesions of the fingers and toes. The latter also fall Treg status in SLE may reflect an abnormal functional state of
under the designation of ‘chilblains LE’.18,19 In longitudinal cohort the PDC; when such antigen presenting cells from SLE patients
Lupus erythematosus: comparison of clinical and direct immunofluorescence manifestations by subtype
Feature Systemic lupus Subacute cutaneous lupus Discoid lupus

erythematosus (SLE) erythematosus (SCLE) erythematosus (DLE)
Lesional character
Scale Fine, easily detached Fine, easily detached Thick, adherent
Follicular atrophy Absent Absent Present
Photodistribution Present Marked Present
Scarring Absent Absent Present
Atrophy Usually absent Usually absent Present – often marked
Pigmentary alteration Slight Slight Often marked
Telangiectasia Present Present Present
≥ 4 ACR criteria for SLE (incidence) (%) 100 40 10
Positive lupus band test
Lesional skin (%) >90 60 90
Non-lesional sun-protected skin (%) Active disease 90 30 0–10
Inactive disease 30
ACR, American College of Rheumatology.
Table 2
are incubated with Treg cells from healthy control subjects, those iabetes mellitus and multiple sclerosis.37 Beyond autoantibody
d
Tregs become dysfunctional.29 Amongst its other roles, the PDC production, autoreactive B cells serve as adjuvants for T-helper
secretes interleukin (IL)-12 which influences T-cell function. IL- cell activation; regulatory B cells that elaborate IL-10 are regu-
12 in turn upregulates T-cell function and in particular provokes lators of inflammatory responses and therefore are capable of
the elaboration of interferon (IFN)-α, a cytokine associated with downregulating autoimmune disease activity.37 It is possible
the T-helper type 1 (Th1) subset operative in lymphocyte- and therefore to ameliorate end-organ damage in SLE patients with
histiocyte-dominant inflammatory events.28 The critical role of rituximab, a monoclonal antibody that specifically targets B
IFN-α in the pathogenesis of LE is alluded to later in this review. cells expressing CD20.38
It appears that IL-12-mediated, Th1-directed tissue injury is
operative as well in the setting of lupus nephritis.30 Particularly Histopathology (Table 3)
in males younger than 50 years of age, Th1-mediated functions The macular eruption of SLE, or ‘acute cutaneous lupus ery-
dominate in autoimmune diseases, while in women over the age thematosus’ to the clinical dermatologist, manifests subtle light
of 50 autoantibodies appear to be the dominant factor in tissue microscopic findings, resulting in its categorization as one of the
injury.31 In women over the age of 50 with chronic autoimmune so-called ‘invisible dermatoses’. Biopsies exhibit subtle basal
diseases accompanied by fibrotic manifestations, Th2 lymphocyte layer vacuolopathic degeneration of keratinocytes and focal tag-
functions are prominently expressed.31 Increasingly recognized ging of lymphocytes along the dermo-epidermal junction (DEJ)
are autoimmune processes associated with neutrophilic tissue (Figure 1). None of basement membrane zone thickening, kera-
infiltration; these appear to correlate to Th17 activity.31 An eleva- totic follicular plugging or alteration of the epidermal thickness
tion of IL-18 and IL-4 levels in plasma correlates with disease is common, although atrophy, comprising thinning of the epider-
activity; immune complex binding to fixed tissue antigen, typi- mis with loss of the retiform pattern, is seen on occasion. These
cally DNA, enhances Th1 function through the Toll-like receptor changes are difficult to appreciate at scanning magnification, and
(TLR) 9.31 A conversion to a dominant Th2 cytokine milieu may the dermal infiltrate is often sparse. The cornified layer is either
correlate with worsening disease likely due to enhancement of normal or exhibits patchy parakeratosis. Colloid bodies in dermal
antibody function by Th2 cells. papillae, sometimes with subtle subepithelial fibrosis, may be a
High oestrogen levels correlate with disease activity in autoim- clue to antecedent epidermal injury. The dermis typically shows
mune disorders. Oestrogens are potent pro-synthetic molecules
that have a variety of impacts. One of these is the upregulation
of surface expression of the Ro molecule on keratinocytes, a fea-
ture that is also seen in the setting of ultraviolet light exposure Histopathological criteria for subtypes of lupus
and likely explains, at least in part, the female predominance erythematosus (after Magro et al9)
and the lesional distribution in SCLE.31 Oestrogens also increase
the numbers and functionality of autoreactive B cells, in part by Systemic lupus erythematosus
enhancing B-cell survival. Thus, pregnant patients with SLE have • Pauci-inflammatory interface dermatitis
increased severity of disease. Men with SLE have higher ratios of • Slight to absent epidermal atrophy
oestrogen to testosterone, and lower absolute levels of testoster- • Basement membrane zone of normal thickness
one, in their sera.31 Oestrogen receptor signalling downregulates • No follicular plugging
some Th1 functions, while testosterone upregulates them through • Prominent papillary dermal oedema and reticular dermal
a nuclear factor kappa B (NF κ-B) signalling mechanism.31 Phar- mucin accumulation
macological inhibition of NF κ-B activity in animal models results
in decreased susceptibility to SLE.32 Subacute cutaneous lupus erythematosus (SCLE)
Keratinocytes from patients with SLE express higher levels • Prominent suprabasilar exocytosis of lymphocytes
of IL-18 receptor on their cell surfaces in response to IFN-γ or • Dyskeratosis extending into upper spinous layers
tumour necrosis factor (TNF)-α, and are also more likely than • Prominent epidermal atrophy
control keratinocytes to be driven by IL-18 into apoptosis.33 • Follicular plugging or basement membrane zone thickening
Apoptosis, and the phagocytosis of cellular debris by professional minimal or absent
antigen presenting cells, is a key component of the determinant • Mild to moderate mononuclear cell infiltrate confined to the
spread which typifies the course of patients with SLE.34 Genetic superficial dermis
polymorphisms regulate the immune responses to, as well as
the clearance of, nuclear debris, which forms a component of Discoid lupus erythematosus
subsequently created immune complexes.35 Although the genetic • Lymphocyte-rich interface dermatitis
factors that influence lupus susceptibility are complex, it is clear • Less epidermal atrophy than SCLE; sometimes acanthosis
that 10–12% of patients with SLE have a first-order relative with • Prominent basement membrane zone thickening
the disease; genome-wide association studies hold the promise of • Prominent follicular hyperkeratosis
a more complete understanding in the near future.36 • Dense superficial and deep perivascular and periadnexal
One critical result of T-cell upregulation is the induction infiltrates
of autoreactive B-cell clones that generate antibodies directed • Prominent follicular degeneration
against self-antigens. In addition to SLE, other autoimmune • Dermal fibrosis
diseases where B-cell function correlates closely with dis-
ease activity include rheumatoid arthritis, scleroderma, type I Table 3
or absent and when identified ought to prompt consideration of

drug-induced LE, GVHD or a morbilliform drug reaction.
Kikuchi disease in the setting of systemic lupus

erythematosus
Kikuchi disease can occur in previously healthy patients or in
patients who have a documented history of SLE, defining a unique
subtype of LE. In Kikuchi disease extracutaneous stigmata domi-
nate the clinical picture specifically in the context of fever, lymph-
adenopathy and cytopenia; however, cutaneous involvement can
occur in 40% of patients. In patients without LE, the disease is typ-
ically self-limiting, resolving within 4 months. The typical manifes-
tations are erythematous macules, papules, patches and plaques
with a head and neck distribution, but the rash can be more gener-
Figure 1 Pauci-inflammatory (cell-poor) vacuolar lymphocytic interface alized with extremity and truncal involvement as well (Figure 4a).
dermatitis in a patient with systemic lupus erythematosus; vacuoles are The pathogenetic mechanisms involved in Kikuchi disease are
noted beneath the epidermis in the basement membrane zone. There is more or less understood. Kikuchi–Fujimoto disease (KFD), or
prominent dermal mucinosis. histiocytic necrotizing lymphadenitis, is a subacute inflammatory
disorder most often seen in young women with clinicopathological
mucin deposition appreciable at a light microscopic level in H&E features suggestive of an infectious aetiology. The most commonly
preparations as beaded basophilic globules and strings between
and adherent to the collagen bundles (Figure 2); these deposits
manifest a blue colour with colloidal iron or Alcian Blue prepara-
tions. This is a most useful morphological finding which favours
a diagnosis of LE over other causes of cell-poor interface der-
matitis, such as morbilliform drug reactions, acute graft versus
host disease (GVHD), acute erythema multiforme, vitiligo and
viral exanthemata.39 Erythrocyte extravasation, telangiectasia
and focal basement membrane zone reduplication around blood
vessels and at the DEJ are common findings in LE. Other features
include rounded histiocytes containing engulfed nuclear debris;
such cells are usually found close to the DEJ and closely resem-
ble the morphology of the LE cell. They are intensely lysozyme
positive. These often represent PDCs deemed integral to patho-
genesis (see Pathophysiology above). On occasion there is an
interstitial histiocytic infiltrate resembling granuloma annulare
(Figure 3). We speculate that these are in fact PDCs, as can be
demonstrated immunohistologically in lesions of LE but not in,
for example, polymorphous light eruption. Eosinophils are rare
Dermal interstitial histiocytoid cell infiltrate in a systemic lupus

erythematosus patient. a Visualized in this acral skin biopsy by
its blue colouration (Alcian Blue-PAS) is intestial MUCIN. b Cells
have expanded cytoplasms as are associated with the infiltrative
Figure 2 Dermal mucinosis in a patient with systemic lupus cells in the granuloma annulare tissue reaction group.
erythematosus is recognized as beaded basophilic strands and
globules between and adherent to collagen bundles (H&E). Figure 3
Asian patient with Kikuchi disease. a One of the hallmarks light microscopically is an interface dermatitis associated with striking apoptotic debris
(b,c). Phenotypic studies reveal a dominance of cytotoxic CD8 lymphocytes, numerous histiocytes highlighted by lysozyme and plasmacytoid
dendritic cells present in varying degrees, the latter highlighted by CD123; the expression of MXA implies an IFN-α-rich microenvironment.
Figure 4
suspected infectious agents in KFD are the human herpesviruses the condition may presage SLE, occur concurrently with SLE and/
EBV, HHV6, HHV7 and HHV8, parvovirus B19, Yersinia, Barton- or develop subsequent to the initial diagnosis of SLE.40,41
ella, Brucella and Toxoplasma organisms. However, there are may LE-associated cutaneous Kikuchi disease has a pathophysi-
citations which suggest an autoimmune-based aetiology, whereby ological basis which closely parallels known pathogenetic
echanisms in SLE, and perhaps Kikuchi disease could be used

m the phenotypic profile shows a cytotoxic CD8-dominant infiltrate
as the more extreme expression of the distinctive phenotypic pro- with numerous CD68-positive scavenger histiocytes along with
file that characterizes SLE. One aspect of the condition is that of CD123-positive PDC forms. There is upregulation of MXA expres-
extensive CD8 T-cell infiltration, plasmacytoid dendritic cell infil- sion in zones of destructive interface change (Figure 4b–d).
tration and enhanced apoptosis with a striking pattern of engulf-
ment of nuclear debris by scavenger histiocytes.
Subacute cutaneous lupus erythematosus
Recent studies suggest that all apoptosis-associated genes,
especially caspases, are upregulated and apoptosis inhibitory Clinical features (see Table 2)
genes, including bcl-2, are downregulated in Kikuchi disease. Not Patients with SCLE manifest a photodistributed, non-scarring
surprisingly, the serum-soluble FAS ligand is markedly elevated papulosquamous and/or annular, polycyclic eruption which may
in patients with Kikuchi disease. occur in isolation or be accompanied by extracutaneous manifes-
Essentially, Kikuchi disease represents an exaggeration of the tations that, when present, are typically mild.2,7 The head and
SLE profile, being that of a cytotoxic CD8 response directed at the neck area is uncommonly involved. As lesions become conflu-
epidermal keratinocytes, a presumptive antigenic source, with ent, a reticulated configuration may become apparent. Uncom-
evidence of an exaggerated IFN-α microenvironment based on mon skin manifestations include pityriasiform lesions,43 mouth
the extent of MXA expression within the epidermis and amidst ulcers, livedo reticularis, periungual telangiectasias, erythro-
perivascular inflammatory cells. The key in making the diag- derma,42 blisters,44 vitiligo-like lesions,45 widespread pruritic
nosis from a histomorphological perspective lies in the extent plaques,46 generalized poikiloderma,47 leucocytoclastic vasculi-
of scavenger histiocyte infiltration and the degree of apoptotic tis48 and a diffuse non-scarring alopecia.4 Anti-Ro/SSA antibod-
debris. The nature of the debris is unclear but probably repre- ies are seen in 50–60% of patients.2,9 Although some patients
sents nuclear fragments of varied origin bound to antibody with have four or more ACR criteria for SLE, large cohort studies indi-
nuclear antigen specificity. cate that patients classified as SCLE clearly do better than those
Most cases of Kikuchi disease show a number of plasmacytoid with SLE.10 It must be kept in mind that in some series, patients
dendritic cells which are a known producer of IFN-α. These cells who are seropositive for antibodies to Ro are more likely to have
are held to play a pivotal role in the pathogenesis of LE and in the SLE than SCLE.49 A patient who has significant extracutaneous
induction of many of the symptoms associated with LE, given the pathology, especially in the context of renal and CNS disease,
role of these cells in the production of IFN-α.42 should not be classified as having SCLE. Ultraviolet light upregu-
In SLE patients, autoantibodies bind to nucleosomes, result- lates surface expression of the Ro antigen50 and provokes apop-
ing in the formation of specific immune complexes that stimulate tosis. Photoreproduction of lesions is significantly more frequent
IFN-α from PDCs. There may be other stimuli to IFN-α produc- in SCLE relative to SLE; photoprovocation of skin lesions in one
tion such as viruses through stimulation of Toll receptors. study was shown in 100% of SCLE patients, 70% of SLE patients,
Genetic aberrations lead to over-expression of IFN-α, an 64% of DLE patients and in no normal controls.51 Photoprotection
event that may be operational in Kikuchi disease with or without is therefore an important therapeutic adjunct and some elderly
concomitant LE. Overall the effect of IFN-α is to provide a cyto- patients with SCLE can be effectively managed with sunblockers
kine cascade that promotes the immune response, resulting in alone.10 It should be emphasized that SCLE in elderly patients is
enhanced local injury. IFN-α plays a role in the acceleration of frequently triggered by drug therapy, the main implicated drugs
cell death of macrophages. It promotes the survival and differ- being thiazides and calcium channel blockers.52–54 A rare case of
entiation of antigen-activated Th1 cells, including CD8 lympho- SCLE is seen as a paraneoplastic phenomenon.55
cytes, an effect possibly reflecting enhancement of expression Under specific conditions, including ultraviolet light exposure,
of functional IL-12R. Type I IFNs can cause maturation of anti- viral infection, alterations of the cytosolic calcium milieu and
gen presenting monocyte-derived dendritic cells and stimulate oestrogen exposure, Ro/SSA particles manifest displaced expres-
B lymphocytes. It might further be postulated that a FAS ligand sion from the nucleus to the cell surface.53,56–61 This is the prob-
polymorphism leading to upregulation of FAS ligand, including able explanation for enhanced photosensitivity of skin lesions in
soluble FAS ligand produced by activated CD8 T cells stimulated anti-Ro/SSA-positive LE patients, the worsening of disease symp-
by autoantigen or viral antigen, may contribute pathogenetically tomatology in connective tissue disease patients experiencing
to the events which define Kikuchi disease. viral illnesses and the association of SCLE with calcium channel
From a histomorphological perspective, Kikuchi disease in blocker therapy. It may also, in concert with the hypomethyl-
the setting of SLE shows a cellular infiltrate where the extent of ation issue discussed above, partly explain the higher incidence
apoptotic debris and histiocytoid forms throughout the infiltrate of SCLE in women.
is striking. However, the baseline histology that is associated
with SLE is present, specifically in regard to an interface der- Histopathology (see Table 3)
matitis typically associated with profound epithelial attenuation, Skin biopsies from patients with SCLE demonstrate an interface
often with extension to the hair follicle. The biopsies are note- dermatitis with suprabasilar exocytosis of lymphocytes showing
worthy for their absence of neutrophilic infiltration, an impor- satellitosis to necrotic keratinocytes (Figure 5) in the absence
tant distinguishing feature from Sweet syndrome which can also of a significant deep perivascular or periadnexal infiltrate or
express leucocytoclasia as a conspicuous morphological finding. follicular plugging. The interface change exhibits a hybrid pat-
Even in those SLE patients who are typically systemically symp- tern comprising cell-poor vacuolar foci alternating with zones
tomatic, the baseline histology can simulate DLE, a phenomenon of lichenoid dermatitis (Figure 5); thus SCLE can be considered
exemplified in the case illustrated in Figure 4. Not unexpectedly, to be one of the lichenoid connective tissue disease syndromes,
allow easy distinction given the findings of antibodies to RNP

in such patients.
Discoid lupus erythematosus

Clinical features (see Table 2)
DLE along with tumid LE are the classic forms of chronic cutane-
ous LE.65 DLE presents as one or more photodistributed scaling
erythematous papules and/or plaques surmounted by an adher-
ent scale extending into patulous follicular orifices. Typically,
involvement is confined to the head and neck region, with a
predilection for periorbital areas and the ears. Women are pref-
erentially affected in a 2–3:1 ratio, with an onset of disease typi-
cally in the fourth decade of life; roughly 5% of patients present
before age 15 or in the eighth decade of life.66 A rash is the most
common, and usually the sole, manifestation of DLE, although
some 15% of patients have a history of Raynaud phenomenon,9
and some have a history of chilblains (perniosis). In one ret-
rospective study of 34 patients with childhood onset of DLE
lesions, almost one in four met criteria for SLE67; in this study
disseminated discoid skin lesions correlated with SLE. Scarring
alopecia tends to supervene in scalp lesions. Typical DLE lesions
range in size from a few millimetres to 15 cm in diameter. The
adherent scale with its prominent keratotic follicular plugs is
similar to carpet tacks – the so-called ‘tin-tack’ sign. Hypertro-
phic, warty lesions are seen most often in the head and neck
region and on the palms and soles. On occasion, itchy lesions
eventuate as prurigo nodularis, while some patients manifest
lesions reminiscent of keratoacanthomata or lichen planus.
Subacute cutaneous lupus erythematosus. a There is a hybrid Lesions tend to expand peripherally, producing an annular mor-
interface dermatitis which is band-like in some areas but phology. Discoid lesions may manifest a seborrhoeic dermatitis-
alternates with a cell-poor vacuolopathic alteration. The infiltrate, like distribution with nasolabial fold and eyebrow accentuation.
confined to the superficial and mid dermis, is associated with Pigmentary alteration, such as areas of leucoderma, slate-grey
dermal oedema and mucinosis. b There is prominent suprabasilar discolouration and/or irregular hyperpigmentation, particularly
exocytosis of lymphocytes with keratinocyte necrosis at all levels in patients of African extraction, may be striking. In all races,
of the epidermis. active lesions tend to be erythematous with hyperpigmentation
at the margin.
Figure 5 Tumid LE is a variant of DLE in which the skin shows a brawny,
indurated morphology due to abundant dermal mucin.68,69 There
which include SCLE, anti-Ro-associated SLE and mixed connec- is a predilection for the lesions to involve the neck, trunk and
tive tissue disease (MCTD).62–64 These three syndromes have upper extremities, sometimes in an annular configuration.69 Lin-
in common antibodies to an extractable nuclear antigen, which ear lesions following the lines of Blaschko may be seen.70–72
is Ro/SSA in patients with LE and ribonucleoprotein (RNP) A similar linear presentation of dermatomyositis (DM) has
in MCTD patients. Histopathological features distinctive from been described, manifesting localization to the trunk and extrem-
lichen planus include parakeratosis, areas of granular cell layer ities, to which the term centripetal flagellate erythema has been
diminution, prominent lymphocyte satellitosis around necrotic applied.73 Involvement of the subcutaneous tissues, or lupus ery-
keratinocytes in the upper spinous layer, the hybrid morphology thematosus profundus, is considered separately below. Although
of the interface dermatitis as illustrated in Figure 5, and mesen- most patients manifest lesional confinement to the head and
chymal mucin deposition. Those cases associated with deeper neck area, a variant termed generalized/disseminated DLE is
perivascular extension or tissue eosinophilia may be of drug- recognized, for which the minimum criterion is the presence of
based aetiology. Epidermal atrophy is typical of SCLE. Basement DLE lesions above and below the neck. Distinctly uncommon
membrane zone thickening is encountered with higher fre- is the presence of one or a few discoid lesions confined to skin
quency and is of greater magnitude compared to SLE, but is not below the neck. Involvement of the oral cavity is seen in 15% of
as pronounced as that seen in lesions of DLE. As with lesions patients in whom, uncommonly, squamous cell carcinoma may
of SLE, mesenchymal mucin is a useful criterion to distinguish supervene. The natural history of the aforementioned subgroups
SCLE from other causes of atrophying lichenoid dermatitis, such of DLE is similar with the patients’ disease largely confined to the
as atrophic lichen planus and lichenoid drug eruption. Patients skin. However, an occasional patient with disseminated lesions
with MCTD can develop a rash which closely resembles that of will manifest haematological and other abnormalities indicative
SCLE clinically and light microscopically, but serology should of supervening SLE.
The incidence of transformation of DLE to SLE is low, prob-

ably on the order of 5%.4 The presence of an antinuclear antigen
(ANA) in low titre does not seem to indicate a high risk of trans-
formation from DLE to SLE, even in patients exposed to trauma,
stress and/or ultraviolet light.74 As discussed below, non-lesional
skin only very rarely shows a positive lupus band test in patients
with DLE; such cases likely represent patients with SLE in whom
there are discoid lesions. Patients with SLE who have classical
discoid lesions are said to have a more indolent form of disease,
and rarely die of internal organ complications11; DLE lesions in
that setting develop in a background of long-standing SLE.
Genotypic analyses reveal the presence of HLA-B8 in SLE and
its absence in DLE.75 Patients who present with discoid lesions
but who evolve quickly into a clinical picture of SLE frequently Figure 7 Discoid lupus erythematosus. A lymphocytic interface
are HLA-B8 positive.75 dermatitis is seen, associated with vacuolar degeneration of basal layer
keratinocytes of the hair follicle and of the interfollicular epidermis with
Histopathology (see Table 3) pronounced keratotic follicular plugging.
Lesions of DLE are typified by an interface dermatitis involving
the hair follicles and epidermis accompanied by a moderate to
heavy superficial and deep perivascular and peri-appendageal of dermal mucin is a useful discriminating feature. In long-stand-
lymphocytic infiltrate (Figure 6). The infiltrate extends into the ing lesions, the inflammatory cell infiltrate subsides and there is
basal layer keratinocytes of adnexae and of the interfollicular epidermal fibroplasia and, in some cases, dermal atrophy.
dermis9; basal layer epithelial destruction and pigmentary incon- At times, lesions of DLE manifest perifollicular and perivascu-
tinence are characteristic. There is marked hyperkeratosis with lar inflammation without an accompanying interfollicular inter-
keratotic follicular plugging. The epidermis exhibits variable acan- face dermatitis; we have applied the term folliculotropic DLE to
thosis and atrophy, a characteristic finding in DLE (Figure 7). Pro- such cases. Connective tissue disease serology and lupus band
nounced acanthosis usually reflects greater lesional age and may testing are typically negative, and most patients do not manifest
simulate squamous cell carcinoma76; such cases are designated extracutaneous stigmata to suggest a systemic connective tis-
as hypertrophic DLE (Figure 8). Basement membrane zone thick- sue disease diathesis. Such cases may be difficult to distinguish
ening, initially comprising a fine fibrillar reduplication of basal from Jessner lymphocytic infiltrate of skin and sometimes from
lamina visible only in special stains, progresses to form a broad delayed type hypersensitivity reactions. Features favouring follic-
eosinophilic homogeneous 5–15 μm band of basement membrane ulotropic DLE include the presence of dermal mucin deposition,
material discernable by routine light microscopic assessment. the absence of tissue eosinophilia and the presence of follicular
Significant dermal mucin deposition is usually present in lesions epithelial destruction.
of DLE. In some cases showing florid lymphoid hyperplasia, the The designation ‘tumid LE’ has been used traditionally for
distinction from a lesion of nodular lymphocytoma cutis due to a cases showing marked mesenchymal mucin deposition (Figure 9);
drug or insect bite reaction may be difficult; however, the presence the definition has expanded in recent years to cover striking
Figure 6 Discoid lupus erythematosus. A superficial and deep

perivascular and periadnexal lymphocytic interface dermatitis is seen,
associated with vacuolar degeneration of basal layer keratinocytes,
dermal oedema and mucinosis. Extension of the lymphocytic infiltrate
to the deep reticular dermis is noteworthy, a feature which would Figure 8 Hypertrophic discoid lupus erythematosus. There
be unusual in systemic lupus erythematosus or subacute lupus is a lymphocytic interface dermatitis accompanied by
erythematosus. pseudoepitheliomatous hyperplasia.
lymphocyte-rich variants of LE without a significant supervening and/or interfollicular lymphocytic migration into the epidermis,
interfollicular and follicular interface component associated with we use the designation of DLE (non-scarring DLE) and not that of
epithelial destruction. We have used an alternative designation, Jessner lymphocytic infiltrate of skin. There is a recent report of
namely non-scarring folliculotropic DLE.68–79 Lesions tend to tumid LE occurring in carriers of X-linked chronic granulomatous
resolve completely with local therapy and/or plaquenil in the disease.82
absence of either scarring or atrophy.79 A characteristic feature
of this variant of LE is the lack of any serological stigmata of
Vasculopathic lesions in the setting of lupus
collagen vascular disease, no extracutaneous manifestations and,
erythematosus
due to the lack of true epithelial destruction and any association
with SLE, the lupus band test is negative. A recent study compar- Vascular lesions are largely confined to patients with SLE. They
ing tumid LE to Jessner lymphocytic infiltrate of the skin found fall primarily into the categories of immunologically-mediated
little difference between the two entities, suggesting that they are inflammatory vasculitic lesions and pauci-inflammatory throm-
closely allied on a narrow spectrum.80 Others have concluded that botic lesions triggered by underlying procoagulant and/or hyper-
the two entities are likely the same.81 From a histomorphologi- viscosity states associated with LE. All calibres and types of
cal perspective, if there is any evidence of epithelial destruction vessels are affected, ranging from capillaries to medium sized
arteries and veins in all organs, including the cutaneous, cen-
tral nervous, cardiopulmonary, genitourinary and gastrointesti-
nal systems. Cutaneous vasculitis and thrombotic vasculopathic
lesions may be a harbinger of more serious extracutaneous organ
involvement. One cohort of 667 SLE patients showed an inci-
dence of vasculitis of 36%, of whom 61% had a single episode.
Vasculitis involved the skin in isolation in 82%, viscera in isola-
tion in 12.4%, and skin and viscera in combination in 5%.83
Leucocytoclastic vasculitis
The most common vasculitic lesion in the setting of SLE is a leu-
cocytoclastic vasculitis (LCV) (Figure 10), which may be confined
to the skin, but also tends to involve pulmonary interalveolar sep-
tal and renal glomerular capillaries, manifesting as haemoptysis
and haematuria, respectively. With respect to LCV involving the
skin, as with cutaneous LCV in association with other systemic
diseases, the histological presentation is as a severe pandermal
vasculitis often accompanied by thrombosis with resultant cuta-
neous infarction. Rarely, a systemic macroscopic polyarteritis
nodosa-like vasculitis involves the extracutaneous vasculature;
however, the skin involvement with this form of vasculitis is a
small vessel LCV rather than a subcuticular arteritis. Recently
described is a form of folliculocentric purpura which correlates
histologically either to LCV or to a Sweet-like vascular injury
pattern comprising perivascular and intramural lymphoid cuffs
with peripheral neutrophilia and absent fibrin deposition, either
of which occurs in a folliculocentric disposition.84
Discoid lupus erythematosus, tumid type. a A lymphocytic

interface dermatitis is subtle or absent. b Dermal mucinosis is
striking (Alcian Blue-PAS stain). Figure 10 Systemic lupus erythematosus with leucocytoclastic vaculitis
characterized by disintegrating angiocentric neutrophilic infiltrates with
Figure 9 mural fibrin deposition.
Urticarial vasculitis
Although a distinctive clinicopathological entity, urticarial vas-
culitis is considered a non-specific finding that occasionally
accompanies SLE. It is characterized clinically by urticarial
lesions which persist for longer than 24 hours and leave a pig-
mented residuum. Histologically there is erythrocyte extravasa-
tion, slight leucocytoclasia and neutrophilic infiltration of vessel
walls with minimal fibrin deposition. Extracutaneous manifes-
tations include involvement of synovia, kidneys and ophthal-
mological, respiratory, central nervous and gastrointestinal
systems.21 Hypocomplementaemia is the best predictor of sys-
temic sequelae asssociated with urticarial vasculitis. Its patho-
genetic basis is complement activation triggered by immune
complexes.
Lymphocytic vasculitis
The other main vasculitic reaction pattern is a lymphocytic
vasculitis. This form of vasculitis may be associated with
concomitant cyrofibrinogenemia and/or an antiphospholipid
(APL) antibody, especially one with lupus anticoagulant
activity. Accompanying vascular thrombosis may be a clue to
the presence of APL antibody as discussed below, although
its basis may be one attributable to anti-endothelial cell anti-
bodies. It may be pauci-inflammatory or be associated with
angiocentric lymphocytic infiltrates (Figure 11). If there is
no concomitant necrosis of the vessel to warrant the desig-
nation of vasculitis, this type of vascular lesion is usually
attributable to the presence of procoagulant factors, such as
an APL antibody and plasminogen activator antibody, or an
acquired hyperviscosity state such as cryoglobulinaemia or
cryofibrinogenaemia.
Livedoid vasculopathy
Patients with SLE, particularly in the setting of APL antibody,
may manifest a peculiar form of deep-seated thrombogenic vas-
cular injury pattern which presents clinically as livedo reticu-
laris – a net-like pattern of bluish discolouration of the skin
frequently localized to an extremity. Often frustrating to the
pathologist is the seeming lack of abnormality in the correspond-
Biopsy from patient who presented with photodistributed
ing punch biopsy. Generally speaking, thrombosis is visible only
haemorrhagic livedo, showing an interface dermatitis along
in small and intermediate-sized vessels in the subcutis or deep
with a positive lupus band test typical of lupus erythematosus
reticular dermis; the superficial vascular plexus often merely
(LE). However, there was also a concomitant thrombogenic
shows compensatory ectasia but thrombi may be seen there as
lymphocytic vasculitis. The patient died of catastrophic
well (Figure 12). Therefore, a deep-seated thromobogenic vascu-
antiphospholipid syndrome associated with an occlusive
lopathy should be suspected in this clinical setting, even when
vasculopathy affecting her intestine. Underlying antiphospholipid
telangiectasia is the only histological abnormality. Skin biopsies
antibody syndrome must always be considered when a biopsy
from SLE patients with haemorrhagic and ulcerating livedo of the
of LE showing a typical interface dermatitis also demonstrates
lower extremities often reveal bland luminal thrombi occluding
vascular thrombosis.
vessels throughout the dermis with concomitant necrosis of the
epidermis and dermis.
Figure 11
Antiphospholipid antibody syndrome

which have been identified in roughly 20–35% of patients with
An under-recognized manifestation of SLE in the skin is, in our SLE,86 but which are not unique to SLE. The presence of an APL
experience, the vasculopathic lesion which correlates with the pres- antibody does not specifically signify thrombotic complications
ence of an APL antibody. The APL antibodies are a heterogeneous related to the APL. The APLs are seen in virtually any of the
group of autoantibodies directed against anticardiolipin, antipho systemic connective tissue diseases, with lymphoproliferative
sphatidylinositol, antiphosphatidylethanolamine, antiphospha- diseases and with liver disease, and in the setting of chronic
tidylcholine, anti-β2-glyorpotein and antiphosphatidylserine,85 infection and the intake of certain drugs.87
vasculitis. In this regard, the anti-endothelial cell antibody assay

using patient serum incubated with generic umbilical endothelial
cells is characteristically positive in these patients (Figure 13). A
‘two-hit’ hypothesis is favoured, whereby underlying endothelial
damage in the presence of an APL is needed to provoke throm-
bosis.89 There is evidence that APL antibodies from patients with
autoimmune disorders are directed against a complex antigen of
which β2-glycoprotein-1 is an essential component. In contrast,
APL antibodies from patients with infections, including syphilis
and human immunodeficiency virus (HIV), bind directly to the
phospholipid even in the absence of β2-glycoprotein. It has been
suggested that APL antibodies directed against phosphatidyletha-
nolamine or cardiolipin could downregulate the expression of
anticoagulant activities of the protein C pathway, creating a state
of relative activated protein C resistance. β2-Glycoprotein is a
lipid-binding inhibitor of platelet aggregation and of prothrom-
bin, and is therefore a natural anticoagulant, hence, antibod-
ies to β2-glycoprotein would logically promote thrombosis. An
additional mechanism of thrombosis relates to APL antibodies
directed against heparin sulphate in the region recognized by
antithrombin III, which could promote coagulation by prevent-
ing heparin-induced formation of antithrombin III–thrombin
complexes.
Figure 12 Deep-seated thrombogenic lymphocytic vasculitis in a biopsy
Dermatopathological and dermatological presentations
from a patient with livedo reticularis.
In addition to livedoid vasculopathy, perniotic nodules,19 pur-
puric cutaneous infarction90 and Degos disease-like skin infarcts
Pathogenetic basis which heal to from porcelain scars,91 patients can present clini-
One of the greatest predictors that an APL will be associated cally with cutaneous papules and nodules.92
with thrombosis is whether or not the lupus anticoagulant assay The characteristic light microscopic finding encountered in
is positive. The so-called lupus anticoagulant, first identified in APL antibody syndrome is that of occlusive pan-dermal and
1952,88 reacts with the negatively charged phospholipid portion subcutaneous arterial and venous thrombi.92,93 An accompany-
of the prothrombin activator complex to produce a prolongation ing intramural and perivascular lymphocytic infiltrate may be
of the in vitro clotting assays, such as activated partial throm- present (Figure 14), however the classic morphology is typically
boplastin time, the dilute Russell viper venom time, the kaolin in the context of pauci-inflammatory thrombogenic vasculopa-
clotting time and the prothrombin time. A clinical paradox is the thy (Figure 14a). As the APL has anti-endothelial cell properties,
fact that these patients tend not to suffer a bleeding diathesis, but there is often endothelial cell injury with variable mural fibrin
rather experience arterial and venous thrombosis, which occur deposition. Reactive angioendotheliomatosis resembling stasis
in 25–50% of patients with lupus anticoagulant, manifesting as dermatitis is characteristic of lower extremity lesions and lesions
a higher frequency of vascular events, including migraine head-
aches and livedo reticularis.
Predictors of thrombosis include APLs of IgG subtype and
the presence of antibodies to β2-glycoprotein. The simultane-
ous presence of circulating lupus anticoagulant and high titres of
both anticardiolipin antibody and antibodies to β2-glycoprotein-1
identifies a subset of patients with primary APL syndrome who
have a more severe clinical course. In contrast, patients with
antibodies to prothrombin in the setting of lupus anticoagulant
activity have a much weaker association with thrombosis, but
are instead prone to serious bleeding events.
Mechanisms of thrombosis include complement-mediated
injury via APL antibodies binding to complexes comprising a pro-
tein cofactor (i.e. β2-glycoprotein, kininogen and thrombin) and
surface (i.e. endothelial cell and platelet) phospholipids, hence
leading to platelet aggregation and endothelial dysfunction, Figure 13 Patient’s serum incubated with generic endothelial cells
respectively. C5b-9 is the effector mechanism of microvascular along with fluoresceinated human anti-IgG. The assay is positive as
injury. In addition, by damaging endothelium, the exposure of characterized by a striking granular nuclear staining pattern within the
hidden antigens to which the patients may develop antibod- substrate endothelial cells. This particular assay is corroborative of the
ies can theoretically occur, leading to a true immune-based presence of anti-endothelial cell antibodies.
Biopsy of a foot ulcer in a patient with systemic lupus erythematosus and concomitant high levels of antiphospholipid antibodies. a Striking
occlusive thrombogenic vasculopathy, accompanied by b prominent deposits of C5b-9 in vessels. It appears that immune-mediated endothelial
cell injury, as revealed by c a positive anti-endothelial cell antibody assay, may contribute directly to vascular thrombosis and be associated
with d mural deposits of C4d.
Figure 14
from acral sites in patients with APL antibody syndrome,94 where be the defining morphology in lesions of livedo reticularis. Direct
luminal thrombosis is seen amidst glomeruloid congeries of pro- immunofluorescent findings will demonstrate a positive lupus
liferating blood vessels. In contradistinction, in reactive ango- band test, typically with all classes of immunoglobulin deposited
endotheliomatosis related to stasis, neovascularization without along the DEJ. In addition, one of the most characteristic immu-
supervening fibrin deposition is typical. An endarteritis obliter- nofluorescent findings is in the context of C5b-9 within the cuta-
ans phenomenon can be observed in livedo reticularis and may neous vasculature. APL antibody syndrome, along with diabetes
mellitus and porphyria, is among the disorders associated with
the greatest extent of C5b-9 deposition in vessels.
Serological considerations in the diagnosis of connective

tissue disease states
Connective tissue disease patients have antibodies to one or more
cellular constituents, including antigens resident in the nucleus,
cytosol and plasmalemma. The significance of seropositivity for
antibodies to the cellular antigens depends upon the total quan-
tity of antibody present, as indicated by the titre and nature of
the assay used, as well as by the specificity of the antibody. With
respect to the former, most reference commercial laboratories
employ enzyme-linked immunosorbent assay (ELISA) technol-
ogy, which is more sensitive, but less specific, than the older
immunodiffusion methodologies.95 The nature of the antigen
Figure 15 In patients with antibodies to an extractable nuclear antigen specificity as it relates to specific diagnostic categories of connec-
such as anti-Ro and/or anti-RNP, a striking pattern of granular nuclear tive tissue disease is represented in Table 4. The immunofluores-
decoration of keratinocytes is observed. cence appearance of the ANA pattern generated by the overlay
induced SLE. A nuclear membrane decoration pattern reflects

antibodies to DNA or, rarely, to laminin, and correlates with SLE.
A fine speckled nuclear pattern (Figure 15) reflects antibodies to
extractable nuclear antigens (ENAs) Ro/SSA, La/SSB, U1RNP,
Ku and Scl-70, the combinations of which are important for pre-
cise disease classification (Table 4). A coarse speckled pattern
correlates with anticentromere antibodies, and thus with sclero-
derma, as does a nucleolar pattern. Some antibodies, such as
those to Smith (Sm) and to double-stranded DNA (dsDNA), are
reasonably specific for SLE.
Although a comprehensive review of the structure and func-
tion of the ENAs is beyond the scope of this review, a knowl-
edge of the expression pattern of the small ribonucleoprotein
particle Ro/SSA is core to understanding the clinical expression
of the anti-Ro/SSA-positive LE subset. All of U1RNP, Sm, Ro
and La are small ribonuclear protein macromolecules resident
in the cytoplasms and nuclei of eucaryotic cells.96 The Ro/SSA
antigen is a 60 kDa protein attached to small RNAs to produce
a 100 kDa complex with both a nuclear and cytoplasmic local-
ization in normal adult and neonatal skin, although the extent
of nuclear staining in adults is greater compared to the expres-
sion within the cytoplasm.97,98 Antibodies to Ro/SSA are found
in patients with LE99–103 and in primary and secondary Sjögren
syndrome,100,104–107 but are also expressed on occasion in cases
of scleroderma,108 rheumatoid arthritis109,110 and primary bili-
ary cirrhosis.111 The manifestations of anti-Ro/SSA antibodies
are heterogeneous,112,113 with some patients having an unclas-
sifiable connective tissue disease.112–114 Anti-Ro antibodies are
commonly seen in patients with SCLE.2 Under specific condi-
tions, including ultraviolet light exposure, viral infection, altera-
In the setting of dermatomyositis, a prominent pattern of tions of the cytosolic calcium milieu, and under the influence of
vascular C5b-9 is noted in muscle. oestrogens, Ro/SSA particles manifest upregulated or displaced
expression from the nucleus to the cytosol and from the cyto-
Figure 16 sol to the cell surface.53,56–61 This is the probable explanation
for enhanced photosensitivity or photoreproduceability of skin
of patient serum on a Hep2 cell- or mouse epithelial cell-bearing lesions in anti-Ro/SSA-positive LE patients, as well as the wors-
glass slide correlates with antibody specificity and with the direct ening of disease symptomatology in connective tissue disease
immunofluorescence findings in patient skin biopsy material. patients experiencing viral illnesses. Outside of SCLE, the pres-
Specifically, a homogeneous nuclear pattern reflects anti-DNA ence of anti-Ro/SSA antibodies appears to define a subset of SLE
or antihistone antibodies, and thus points either to SLE or drug- patients with a higher incidence of cardiac conduction defects,115
Seropositivity* by connective tissue disease classification (after Crowson and Magro78)
ANA C ssDNA dsDNA Sm SSA/Ro SSB/La NRNP Histone Scl 70
SLE 95–100 0–10 70 70 <30** 40 10–20 40–50 30 0

SCLE 70 0 10–20 0 0 60–80 10 0 0 0
DLE 20–30 10–20 10–20 0 10–20 10 0 0 0
CRST 90 90 0 0 0 0 0 0 0 0
PSS 70 10 10–20 0 0 10 10 20 0 30
MCTD 95–100 0 30 0 0-5 0 0 100 0 0
ANA, antinuclear antibody; C, complement; CRST, CREST syndrome; DLE, discoid lupus erythematosus; dsDNA, double-stranded DNA; MCTD, mixed connective
tissue disease; NRNP, nuclear ribonucleoprotein; PSS, progressive systemic sclerosis/scleroderma; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic
lupus erythematosus; ssDNA, single-stranded DNA.
*Expressed as percentage of cases.
**Dependent upon ethnicity.
Table 4
secondary Sjögren syndrome,104,105 myocarditis,103 hyper-γ- IgM decoration along the DEJ is common in sun-exposed skin
globulinemia,116 thrombocytopenia,103 positive rheumatoid fac- of patients who do not have LE, such as in lesions of actinic
tor,103,114 pulmonary fibrosis and chilblains.19,117 As discussed keratosis and rosacea, and in 20% of normal skin specimens
in detail below, the demonstration of vascular C5b-9 not only in from healthy young adults. One study of sun-exposed normal
the skin but also lung tissue in such patients9 recapitulates the skin showed a weak interrupted linear and granular pattern of
pattern seen in patients with DM (Figure 16)118 and serves to DEJ deposition of IgM and Clq in 25% of samples,128,129 while
implicate a humoral-based microangiopathy in the pathogenesis deposition of IgG, IgA and C3 was seen in less than 5% of cases.
of both disease processes. In comparing the immunofluorescence profile of DM to LE, we
In all cases of connective tissue disease, the serological status found weak discontinuous DEJ deposition of IgM on sun-exposed
of the patient must be correlated to the clinical, histological and lesional skin in over 50% of DM patients, but never of sufficient
tissue immunofluorescence findings to ensure proper interpreta- intensity to warrant designation as a positive LBT using the strict
tion and classification. criteria outlined above.130 Up to 13.5% of patients with systemic
scleroderma manifest a positive LBT, a finding which appears to
herald a more aggressive course.131,132 Biopsied lesions of cuta-
Role of immunofluorescence testing in the diagnosis
neous vasculitis, irrespective of cause, may also exhibit a posi-
of lupus erythematosus and other connective tissue
tive LBT.
diseases
In sun-protected skin, an interrupted band of IgM of at least
The lupus band test (LBT) and its adjunct, the corresponding moderate intensity is sufficient for designation as a positive LBT,
deposition pattern of the supramolecular membrane attack com- assuming that the biopsy is not a lesion of lichen planus, where
plex of complement C5b-9, are valuable in establishing the pres- granular deposition of IgM as an interrupted band along the DEJ
ence in any given patient of a connective tissue disease, and for is seen at sites of colloid body deposition. The deposition of IgG
furthering precise classification of the disease process. We con- is usually less intense than that of IgM. As false-positive results
cur with the view that immunofluorescence should always be are practically non-existent, however, it is likely adequate to see
performed in conjunction with conventional histology to boost an interrupted weak band of IgG deposition, even in sun-exposed
sensitivity and specificity of diagnosis.119 skin.9,126 The concomitant deposition of IgA greatly enhances the
specificity of the assay. We have seen many examples of posi-
Lupus band test tive LBTs composed of fine granules of IgM isotype unaccompa-
Definition: the LBT was introduced in 1963 by Burnham and co- nied by the deposition of any additional immunoglobulins: these
workers,120 who referred to the deposition of IgG, IgA and IgM patients had other forms of autoimmune disease, such as alope-
along the DEJ in lesional skin. The definition has since expanded cia areata, a subgroup of patients with female pattern hair loss;
to encompass lesional and non-lesional skin in sun-exposed and idiopathic and autoimmune associated small fibre neuropathy;
sun-protected sites.121–126 or apparent drug hypersensitivity. An example of a positive LBT
of IgM isotype in the setting of idiopathic small fibre neuropathy
Baseline criteria: the most frequent immunoglobulin class depos- is shown in Figure 17; the specimen was obtained from non-
ited is IgM, while the least frequently deposited is IgA. In DEJ lesional skin of the leg. An IgM variant of a positive LBT is more
lesions, the frequency of IgG deposition is low compared to that likely to be indicative of LE if it is intense and associated with
of IgM, which is seen in 90% of lesional skin biopsies. The depo- a vertical fibril-like staining pattern as well. Hence the clinician
sition of various immunoreactants in clinically normal deltoid must be alerted with regards to the relative lack of specificity of
area skin from patients with SLE and other rheumatic diseases the IgM variant of the positive LBT (Figure 17).
in one study demonstrated DEJ deposition in 73% of patients Our view is that sun-exposed lesional skin should be used to
with SLE and in 36% of the other patients, yielding a specificity substantiate an initial diagnosis of LE so as to avoid the prob-
of 64% and a predictive value of 57%. The predictive value for lem of false-negative results due to reduced sensitivity in sun-
SLE was greater with C4 (100%), properdin (91.3%) and IgA protected skin. After the diagnosis of LE is made, a biopsy of
(86.2%) than with IgM (59%). The specificity and predictive non-lesional skin may be performed to further assist in subclas-
value increases with the number of immunoreactants detected at sification and prognostication, as discussed below.
the DEJ.120–125,127 The pattern of deposition is typically as gran-
ules or closely spaced vertically oriented fibrils; occasionally it Rate of positivity according to the subtype of LE: in sun-exposed
manifests as a thick, homogeneous band. We do not designate as non-lesional skin the LBT is positive in 70–80% of patients with
a positive LBT a sharply-defined thin linear band of decoration SLE, while it is negative in patients with DLE and SCLE. A posi-
similar to that seen in bullous pemphigoid. Globular subepider- tive LBT in sun-protected non-lesional skin of SLE patients, seen
mal deposits positive for complement and or immunoglobulin, in roughly 55% of cases, correlates with severe extracutane-
while indicative of an antecedent keratinocyte injury, are not ous disease, particularly of renal origin, and with antibodies to
specific as to cause. dsDNA.126,133,134
The degree of deposition which warrants designation as a pos-
itive LBT is controversial; differences in criteria partly explain Genesis of the LBT: in biopsies of sun-exposed forearm skin,
the disparity of results in various series. To be considered a early studies demonstrated a positive LBT in 77% of cases, ver-
positive LBT, deposition of IgM in sun-exposed skin should sus 33% of non-sun-exposed buttock skin.135 It was therefore
assume a continuous band over at least 50% of the width of the postulated that ultraviolet light plays a role in the denaturing
biopsy specimen and be at least moderate in intensity.126 Weak of keratinocyte DNA, which then diffuses across the basement
C5b-9 in the subclassification of lupus erythematosus and other

forms of connective tissue disease
The C5b-9 assay is a useful adjunct in the subclassification of con-
nective tissue disease.9,136,137 Dako anti-C5b-9 aE11 is a monoclo-
nal mouse antihuman antibody targeted against the neo-epitope
resident on activated C9 of the terminal complement complex
comprising complement fractions C5b, C6, C7, C8 and C9. The
supramolecular structure C5b-9 forms following activation of the
classical or alternate pathways, and induces plasmalemmal pores
which lead to cell injury118,130 and permit access of other antibod-
ies to the cytosol and to the nucleus of keratinocytes and endo-
thelia (Figure 18). The method used is a ‘sandwich’ technique
which, by definition, is an indirect immunofluorescence method,
even though patient skin is employed as the substrate.126 It is
indirect because anti-C9 itself is invisible since it is not tagged
with any type of fluorochrome. However, there is subsequent
Figure 17 Positive lupus band test (LBT). There is a continuous band of
application of a fluorescein-labelled human anti-IgG which then
intense fine granular and fibril-like staining along the dermo-epidermal
binds the anti-C9, resulting in a positive bright reaction.
junction for IgM. When IgM is seen in isolation without concomitant
IgG and IgA, the specificity of underlying lupus erythematosus is
Systemic lupus erythematosus:
significantly less compared to positive lupus bands associated with all
Lesional skin – intense granular deposition of C5b-9 along the
three classes of immunoglobulin. An IgM variant of a positive LBT can
DEJ is seen in 80% of cases.9 Granular nuclear and cytoplas-
be seen in many autoimmune conditions and as a non-specific finding
mic deposits of IgG and C5b-9 are also observed in keratinocytes
on sun-exposed skin of healthy adults.
in patients with antibodies to one of the ENAs: Ro, La, Sm or
U1RNP. Vascular decoration for C5b-9 is observed in SLE patients
membrane zone and becomes trapped due to the natural avid- with antibodies to Ro/SSA, in patients in whom there is a circu-
ity of native DNA for type IV collagen. This DNA then binds lating lupus anticoagulant, or when vasculitis is demonstrated in
with ANAs, being visualized as the granular deposits which con- the biopsy.62,138
stitute the positive LBT. Another source of immunoreactivity is Non-lesional skin – deposition of C5b-9 along the DEJ and
that due to circulating immune complexes comprising DNA and within blood vessels is usually absent or weak in SLE patients
ANAs. Antibodies directed against basement membrane zone lacking an anti-ENA antibody, whereas in SLE patients with an
components do not to play a significant role in the genesis of a antibody to an ENA, immunoreactivity for C5b-9 and IgG within
positive LBT.126,135 keratinocytes is common.9 C5b-9 deposits are also seen in the
cutaneous vasculature in patients with anti-Ro-associated SLE.62
Relationship of the LBT to disease severity in SLE: the relation-
ship between a positive LBT and the severity of renal disease in Subacute cutaneous lupus erythematosus: deposition of C5b-
SLE is controversial. Some authors suggest a significant relation- 9 along the DEJ is observed in 66% of SCLE patients. A more
ship between a positive LBT in non-lesional sun-protected skin specific finding is the presence of granular nuclear and/or
and renal pathology, with 70% of such patients having active cytoplasmic epidermal decoration for IgG138 and C5b-9,9,130 an
nephritis, and with serious renal disease being three times more immunofluorescence profile independent of serological findings
common. The deposition of IgG in non-lesional sun-protected
skin correlates with anti-nDNA antibodies and with a higher
incidence of renal disease.123,124,133,134 A negative LBT, however,
does not exclude active renal disease. Patients with pure IgM
deposition in clinically normal skin have anti-nDNA antibod-
ies restricted to the IgM class and tend to have a more benign
course.133 Several studies have correlated a positive LBT on but-
tock skin with active systemic disease. As C1q avidly binds to
DNA, C1q deposition along the DEJ in the skin of SLE patients
may reflect the presence of DNA at the DEJ; such patients have a
higher index of disease activity.133,134
The recommended site for a sun-exposed non-lesional skin
biopsy to establish an initial diagnosis of SLE is the shoulder. The
upper arm and the extensor aspect of the forearm are positive in
67% of cases. The volar aspect of the forearm or the upper third
of the extensor aspect of the forearm are the typical sites chosen
to represent sun-protected non-lesional skin; the volar aspect of Figure 18 C5b-9 is the effector mechanism of microvascular injury in the
the forearm is positive in 50% of cases. Buttock skin generates a skin. Photomicrograph showing striking deposits of C5b-9 along the
positive LBT in 35–40% of patients with active SLE.125 dermo-epidermal junction and in blood vessels.
observed in patients with and without antibodies to Ro130 (see In the appropriate clinical setting, the constellation of a nega-
Figure 12). There is usually absent vascular decoration except in tive LBT, C5b-9 deposition along the DEJ and within blood ves-
patients who have drug-associated SCLE.53 In vivo keratinocyte sels, with variable keratinocyte decoration for C5b-9 and IgG in
fluorescence seen using standard LBT reagents is associated with the absence of antibodies to Ro/SSA or RNP is highly suggestive
ANA by serological testing in 70% of patients; the positive pre- of DM.
dictive value of an in vivo ANA for systemic connective tissue
disease is 75%.139 Of 20 of 28 patients with positive keratinocyte Genesis of C5b-9 decoration and its significance: in the setting
fluorescence for autoantibodies IgG, IgA, IgM or C3, 17 had an of LE or MCTD, DEJ deposition of C5b-9 may reflect activation
antibody to an ENA. Nine of these 17 patients were proven to within the basement membrane zone of the complement path-
have SLE, three had MCTD, three had an overlap syndrome and way due to the deposition of immune complexes or by passively
one each had Sjögren disease or CREST syndrome.139 C5b-9 in absorbed keratinocyte-derived DNA complexed with an ANA. In
keratinocytes is much more specific than IgG decoration of kera- the setting of DM, we have postulated that the mechanism of
tinocytes. In our experience, IgG in keratinocytes without C5b-9 is deposition may relate to non-specific trapping of C5b-9 passing
not associated with antibodies to an ENA but may be indicative across damaged dermal papillae capillaries.118,130 Once depos-
of a positive ANA. ited, C5b-9 may contribute to epidermal injury.118,130 The epider-
mal deposition of C5b-9 in SCLE, anti-Ro/SSA-positive SLE, MCTD
Discoid lupus erythematosus: intense granular decoration for and ANA-positive DM correlates strongly with an antibody to an
C5b-9 along the DEJ is seen in 60% of cases. Decoration of epider- ENA.62,63,118,130 Antibodies to ENAs in DM include those that are
mal keratinocytes or endothelia for either IgG or C5b-9 is typically directed against histidyl-transfer RNA synthetase, and four other
absent.130 aminoacyl transfer RNA synthetases, namely threonine, glycine,
isoleucine and alanine.118,130,140 Relocation of nuclear and cyto-
Mixed connective tissue disease: granular nuclear and cytoplas- plasmic Ro/SSA antigens to the cell surface has been implicated
mic keratinocyte deposition of C5b-9 and IgG is seen in 100% of as a key event which allows the binding of autoantibodies. Ultra-
cases, corresponding to antibodies to RNP, which are a defin- violet light exposure, viral infection and oestrogen treatment of
ing feature of this disease process. Intense granular deposits are cultured keratinocytes have been shown to displace Ro antigen
seen along the DEJ in almost all cases, usually in concert with to the cell membrane.59,60,141,142 A similar mechanism of surface
granular vascular decoration.63 The immunofluorescence profile displacement has been shown for RNP and may also occur with
is virtually indistinguishable from that of anti-Ro/SSA-positive DM-associated ENAs.118,130 The presence of C5b-9 in keratino-
SLE62 (Figure 19). cytes suggests a role for complement-induced pores in the prop-
agation of keratinocyte injury. Most studies indicate that C5b-9
Dermatomyositis: the typical finding in dermatomyositis is binding to keratinocytes is not cytotoxic and that the principal
C5b-9 deposition as a continuous granular band along the DEJ mechanism of injury is antibody-dependent cellular immunity.
of lesional sun-exposed and sun-protected skin. In over 90% of However, it is possible that C5b-9 may be capable of lysing cells
cases there is granular vascular staining which is most conspicu- whose repair mechanisms have been previously or concurrently
ous in dermal papillae capillaries. Granular keratinocyte nuclear suppressed.143,144 The pores may also allow circulating antibod-
staining for C5b-9 or IgG is observed only in those patients in ies access to the cytoplasmic and nuclear antigens of the Ro/
whom there is a positive ANA.9,118 SSA, RNP and histidyl-transfer RNA synthetase complexes seen
in SCLE and anti-Ro/SSA-associated SLE, MCTD- and anti-Jo1-
associated DM, respectively. Intracellular decoration may reflect
an in vivo phenomenon initiated by complement-mediated pore
formation.9,63,118,130 Deposition of C5b-9 in dermal blood vessels
in anti-Ro/SSA-associated SLE, DM and MCTD suggests that the
endothelium is a prime antigenic target in these connective tissue
diseases.9,62,63,118
Uncommon subtypes of lupus erythematosus

Anti-Ro/SSA associated systemic lupus erythematosus
Antibodies to Ro/SSA are found in patients with SCLE, comple-
ment deficiency LE, SLE, neonatal LE and Sjögren syndrome.
We recently described the dermatopathological findings from a
group of anti-Ro/SSA-positive SLE patients whose variable clini-
cal manifestations included SCLE-like rashes, malar erythema,
a DM-like rash and vascular disease involving the skin, heart,
pulmonary and nervous systems.62 The sequela of vasculopathy
in the lungs is interalveolar septal capillary drop out (personal
Figure 19 Bullous systemic lupus erythematosus. A neutrophilic and observations), while microvascular injury in the skeletal muscle
eosinophilic interface dermatitis is seen; focally there are dermal produces a pattern of myositis resembling DM.62,145 In vitro stud-
papillae micro-abscesses reminiscent of dermatitis herpetiformis. ies showing endothelial localization of the Ro/SSA antigen,141
and the correlation of serum C5b-9 levels with evidence of active dermatitis herpetiformis (Figure 19). Also present may be his-
CNS disease,138,146 suggest that humoral injury mediated by tiocytes containing the engulfed nuclear debris of disintegrating
anti-Ro/SSA antibody binding to endothelial Ro antigen may be neutrophils. Tissue eosinophilia may be present and may be a
operative. In patients with Sjögren syndrome, but seemingly not prominent finding that provokes consideration of bullous pem-
in a cohort of SLE patients, the degree of skin disease activity phigoid; outside of the context of drug-induced LE, eosinophilis
appeared to correlate with the levels of antibodies to Ro/SSA.147 are otherwise uncommon in LE lesions. There is mesenchymal
Simmons-O’Brien et al113 explored the heterogeneous clinical mucinosis.149,150 We have encountered a recent case of bullous
features of 100 patients with anti-Ro/SSA antibodies and found SLE associated with concomitant vasculitis. A non-bullous neu-
the latter to be a marker for specific cutaneous and extracutane- trophilic dermatosis has been described in patients with SLE152
ous manifestations, namely vasculitis, SCLE-like rashes, malar and SCLE.153
erythema and pulmonary disease. Sixty-five per cent of their
patients had progressive disease with 20% dead at 10 years’ fol- Immunofluorescent studies: the direct immunofluorescence
low-up. While anti-Ro antibodies may be a marker for an indo- examination of lesional skin reveals a continuous band of IgG
lent connective tissue disease, namely SCLE, in some patients deposition along the DEJ. This band may appear homogeneous
it may herald the onset of serious complications relating to a with a 400× objective (Figure 20), but 1000× oil-immersion
systemic vascular injury syndrome.62 microscopy often reveals, in addition to a homogeneous lin-
ear band, a superimposed granular band. In our experience, it
Histomorphology: the photodistributed eruption of anti-Ro/ is more common to observe a granular deposition pattern as
SSA-positive SLE is characterized by an interface dermatitis with opposed to a homogeneous linear one. If a homogeneous linear
concomitant mucin deposition. There may be marked epidermal band is noted, the band appears much wider due to the super-
atrophy, hence defining a pattern resembling SCLE. In patients vening granular pattern of deposition that occurs. This particular
with secondary Sjögren syndrome, it is characteristic to see a morphology is in contradistinction to the well-defined thin linear
lymphocytic eccrine hidradentitis. There may be accompanying band seen with bullous pemphigoid and epidermolysis bullosa
superficial vasculopathic changes similar to those encountered in aquisita (EBA).126 Co-dominant expression of IgA and IgM is
DM, including telangiectasia, endothelial cell necrosis, luminal seen; there is an increased incidence of IgA deposition in bullous
deposits of fibrin and vascular density reduction. Primary vas- versus non-bullous SLE (76% vs 17%). Salt split skin studies in
culopathic reaction patterns include lymphocytic vasculitis, LCV bullous SLE reveal localization of immunoreactivity to the blis-
and a pauci-inflammatory thrombotic vasculopathy.62 ter floor consistent with antigenic localization to the sublamina
densa region, similar to that of EBA and unlike that of bullous
Bullous systemic lupus erythematosus pemphigoid in which immunoreactivity localizes to the roof.
A distinctive cutaneous manifestation of SLE, bullous SLE, typi- Immunogold electron microscopy performed on perilesional skin
cally occurs in patients who have had one or more features of shows localization of immunoreactants to the sublamina densa
SLE preceding the eruption by months to years. The skin erup- region.149–151
tion comprises bullae arising either on a background of diffuse
erythema or on an urticarial base resembling bullous pemphigoid, Immunoblot analysis: by immunoblot analysis, IgG is shown
or as grouped vesicular lesions mimicking dermatitis herpetifor- to bind to two distinct protein bands with molecular weights of
mis (Figure 19).148,149 The eruption is generalized, but tends to 290 and 145 kDa. These migrate with bands previously reported
preferentially involve the trunk and flexural surfaces. Although a for EBA and have specificity for type VII collagen.154–158 There
bullous eruption confined to the face has been described, there is appears to be immunogenic heterogeneity in bullous SLE, with
some controversy as to whether this truly represents bullous SLE.
The criteria proposed for the diagnosis of bullous SLE include:
(1) a diagnosis of SLE by criteria of the ACR; (2) a widespread,
non-scarring, vesiculobullous eruption; (3) subepidermal blisters
with dermal inflammation characterized by neutrophilic papil-
lary micro-abscesses similar to those of dermatitis herpetiformis;
and (4) direct immunoflourescence demonstration of linear or
granular IgG and/or IgM in lesional or non-lesional skin. The
newly revised criteria do not require salt split skin dermal bind-
ing of immunoreactants, a homogeneous linear staining pattern
along the DEJ or demonstration of antibodies to type VII colla-
gen.150 As discussed below, while in most patients antigenicity
lies in the non-collagenous domain of type VII collagen, some
patients have antigen specificity to other components of the base-
ment membrane zone.126,151
Histomorphology: skin biopsies show a neutrophilic interface Figure 20 Biopsy shows an intense homogeneous and granular staining
dermatitis which is often associated with effacement of the rete pattern along the dermo-epidermal junction with granular decoration
ridges, a morphology reminiscent of linear IgA disease and/or of keratinocyte nuclei and cytoplasms. The immunoreactant illustrated
with dermal papillary neutrophilic micro-abcesses cognate to is IgG.
some patients manifesting epidermal decoration with salt split and numerous Sezary cells are present; clinically the lesions are
skin in the face of absent antibodies to type VII collagen. In most typical of SCLE. The third picture is one which mimics an angio-
patients, however, the pathogenetic basis is held to reflect anti- immunoproliferative lesion by virtue of dense angiocentric lym-
bodies to the non-collagenous component of type VII collagen. phoid infiltrates accompanied by thrombosis.160
This region is composed of fibronectin type III homology units The lymphocytes are atypical, manifesting polylobated nuclear
which may contribute to intermolecular cross-linking and base- contours. Usually this pattern is accompanied by an interface
ment membrane adhesion functions. Fusion protein analysis dermatitis resembling either DLE or SCLE; lesions also resemble
shows that sera from patients with bullous SLE react with two DLE or SCLE on clinical grounds. Lymphomatoid vasculitis160,161
separate 100 amino acid-containing regions within the fourth is also a characteristic finding seen in patients with LEP, as dis-
(E-1) and eighth (E-2) fibronectin homology repeats, sequences cussed below. The final pattern comprises dense infiltration of
which appear to influence adhesion between type VII collagen the fat lobule by lymphocytes with variable lymphoid atypia and
and other basement membrane zone proteins.154–157 Antibodies fat necrosis; such lesions are categorized as LEP, and will be
binding to the non-collagenous component of type VII collagen considered separately.
activate the complement cascade sequence and thereby generate
C5a, a major neutrophil chemoattractant and leucocyte-activating Lupus erythematosus profundus
complement peptide. It is also possible that the deposition of Clinical features: LEP is a distinctive cutaneous marker of LE
IgA along the DEJ contributes to neutrophilic infiltration. Not all which characteristically affects the head and neck area, partic-
patients with bullous SLE have antibodies to type VII collagen, ularly the cheeks, the upper arms, trunk and buttocks.162 The
and conversely there are patients with antibodies to type VII col- clinical presentation is one of tan to violaceous plaques, mainly
lagen who have neither bullous SLE nor EBA. afflicting women in the third to fifth decades,4 although LEP may
also be seen in infancy. Lesions are typically symmetrical, may
Lymphomatoid lupus erythematosus ulcerate and generally heal with atrophy. LEP may herald the
Dense lymphoid infiltrates in concert with variable cytological onset of LE, occur in isolation or develop in patients with an
atypia of lymphocytes can be observed in lesions of LE; such established history of LE. In most instances it occurs simultane-
findings do not usually signify progression to lymphoma.159 ously with other cutaneous and extracutaneous manifestations.
Clinically the lesions are within the spectrum of DLE, SCLE and Originally held to represent a manifestation of DLE confined to
LE profundus (LEP) (see below). There are four primary light the skin,163 other studies have shown LEP to occur with roughly
microscopic patterns encompassing lymphomatoid LE. One is equal frequency in the setting of SLE.164–169 A recent study indi-
characterized by dense lymphoid infiltrates in a perifollicular and cates a relatively low frequency of association with SLE and a
perivascular array with minimal involvement of the interfollicu- paucity of serological abnormalities typically associated with a
lar epidermis. We designate such lesions as representing follicu- connective tissue disease diathesis170; 50% of patients had no
lotropic lymphomatoid DLE (Figure 21).159 The two characteristic other clinical features of LE.170 Paediatric patients with APL anti-
clinical presentations are indurated follicular papules in the malar body syndrome and/or hereditary complement deficiency171 may
area versus infiltrative transient urticarial plaques involving the present with LEP. LEP affects approximately 1–2% of patients
upper back and anterior chest. The second histological presenta- with LE.162,167 Drugs can induce LEP; typical is a case report of
tion resembles lichenoid SCLE; however, the band-like infiltrate IFN-β-induced LEP in a patient with multiple sclerosis.172
is of greater intensity, there are foci of striking epitheliotropism
Histomorphology of LEP comprises infiltration of the subcutane-
ous fat lobules by lymphocytes, histiocytes and plasma cells with
an interposed zone of granular necrobiotic alteration (Figure 22).
Nodules of centroblasts and centrocytes with admixed tingable
body macrophages recapitulate lymphoid follicles.173 The histio-
cytes include those whose cytoplasm contains nuclear debris and
others with serpentine nuclear contours174 which on occasion
aggregate to form areas of granulomatous inflammation adjacent
to the septae in LEP.164 Endothelial necrosis, segmental depos-
its of fibrin, occlusive luminal thrombi of interstitial capillaries
and venules, and obliterative lymphocytic angiotropism may be
seen, suggesting that a micro-angiopathy is integral to the his-
topathology.164,168 It has been our experience that a significant
percentage of cases of LEP will manifest lymphoid atypia and the
intense lobular infiltration of the panniculus, making the light
microscopic distinction from panniculitis-like T-cell lymphoma/
subcutaneous T-cell lymphoma (SCTCL) difficult. We have also
Figure 21 Folliculotropic lymphomatoid discoid lupus erythematosus. found that features traditionally associated with LEP, such as
The Biopsy shows an exuberant perivascular and peri-adnexal dermal mucin deposition, focal interface change, extensive lobu-
lymphocyte infiltrate with an expansile morphology, hence imparting lar fat necrosis, histiocytes containing engulfed nuclear debris
a lymphomatoid quality to the infiltrate. The infiltrate is without and vasculitis are common in lesions of SCTCL.174 However, in
significant atypia. SCTCL, zones of B-cell infiltration, including germinal centre
the lesions appear similar to those of LEP; however, atrophy is

nevertheless a feature. From a light microscopic perspective,
there is infiltration of the fat by a mixture of T cells. There is
usually no B-cell component and the extent of fat necrosis and
vasculitic changes seen in both LEP and SCTCL are not seen.
Erythrocyte phagocytosis by histiocytes can be observed.174,175
Immunofluorescent studies: in our hands, a positive LBT in

cases of LEP is seen in two settings: (1) when the skin biopsy
shows concomitant interface changes; and (2) when the LEP
lesion arises in concert with symptomatology indicative of
SLE.174
Phenotypic studies: in LEP the infiltrate within the subcutis

comprises both T and B cells. The B cells may be closely aggre-
gated to produce structures resembling germinal centres. Ger-
minal centres are not a feature of either atypical lymphocyctic
lobular panniculitis or subcutaneous panniculitis-like T-cell lym-
phoma. In addition, there is often a dominance of CD4 cells over
those of CD8 subset in contrast with the extensive CD8-positive
infiltration of the subcutaneous tissue seen in lesions of pannicu-
litis-like T-cell lymphoma. There can be a substantial reduction
in the pan T-cell markers CD7 and CD62, and there can be some
diminution in the expression of CD5. These three markers are
also characteristically lost in the setting of atypical lymphocytic
lobular panniculitis and subcutaneous panniculitis-like T-cell
lymphoma.174,175
Molecular studies: While polyclonality is typical, monoclonality

can be seen.174,175 An example of monoclonality in a patient with
classic features of LEP is shown in Figure 23.
Drug-induced lupus erythematosus (Table 5)

A diagnosis of drug-induced LE (DIL) should be entertained
when a patient who does not have idiopathic LE develops a
positive ANA and at least one clinical manifestation of LE while
Lupus erythematosus profundus. a Lymphocytic infiltration of
ingesting a drug; this diagnosis is substantiated if the symptoms
the fat lobule is accompanied by zones of granular eosinophilic
abate after drug discontinuance. The clinical stigmata of DIL vary
necrosis of the fat lobule. b End-stage lesions show waning of
with drugs from different classes. Generally, skin disease is less
the lymphocytic infiltration of the fat lobule and more intense
frequent and pulmonary manifestations are more common than
interstitial granular eosinophilic necrosis of the fat lobule.
in idiopathic SLE. The prototypic agents generate two distinc-
tive serological profiles: chlorpromazine and hydralazine are
associated with antihistone antibodies, while procainamide and
Figure 22
quinidine generate anti-H2a-H2b-DNA antibodies directed at a
histone–DNA complex.176 Procainamide and hydralazine inhibit
formation, along with the presence of erythrocyte phagocytosis T-cell DNA methylation, thereby provoking autoreactivity in
by macrophages are additional light microscopic clues. There cloned T-helper (Th) lymphocytes.177 They appear to share with
are two additional morphological nuances worthy of mention. other DNA methylation inhibitors an ability to induce autolo-
First is the pattern of interface change in SCTCL, which is more gous B-cell differentiation.15 The mechanism by which this leads
in the context of epidermotropism, and typically the epidermis to an LE-like syndrome may relate to upregulated gene expres-
is unaltered in thickness and/or may be slightly hyperplastic. sion associated with DNA hypomethylation, as has been shown
Second, the nature of the interstitial mucin deposition is one in T cells of patients with active SLE. Alternatively, alteration
whereby plump, rounded histiocytes are found amidst the areas of the normal interaction of DNA and histones could result in
of interstitial dermal mucinosis. exposure to epitopes to which the host is not immunologically
Another important diagnostic consideration that enters into tolerant.15,178–180 We reported a group of patients who expressed
the differential diagnosis of LEP is so-called atypical lymphocytic an SCLE-like illness due to intake of calcium channel block-
lobular panniculitis. This is a recently recognized form of sub- ers.53,54 This form of DIL has also been reported in the setting of
cutaneous T-cell dyscrasia that likely represents the prodromal therapy with docetaxol (Taxotere®), thiazide diuretics181,182 and
waxing and waning phase that may presage SCTCL. In this entity antihistamines.183
Figure 23 Lupus profundus. Molecular studies on

biopsy from a 38-year-old woman with upper arm
subcutaneous nodules characteristic for lupus
profunudus. Two distinct populations of T cells are
seen amidst a polyclonal background. Clonality can
occur in lesions of lupus profundus. The biopsy showed
a striking interstitial lymphocytic infiltrate within the
fat and there were scattered germinal centres. From
a phenotypic perspective, the infiltrate was CD4
dominant. In atypical lymphocytic lobular panniculitis
and panniculitis-like T-cell lymphoma, germinal centres
would be very uncommon and there would not be a
dominance of CD4 lymphocytes, as noted here.
It is postulated that drug-induced perturbation of lymphocyte thickening. In drug-induced SCLE, the findings are similar to
function might generate an immunological milieu permissive idiopathic SCLE, however there may be a deeper perivascular
to the development of autoantibodies against ribonucleopro- extension of the infiltrate. In both forms of DIL, interstitial and
teins.184–187 The depression in T-suppressor (Ts) lymphocyte perivascular eosinophils may be seen and are an important clue
activity reported with SLE has been attributed to deficient func- to a drug-based aetiology.52,53,183
tion of the 2H4+ T-cell subset, inducers of Ts cell activity. Drugs
causative of DIL, including methyldopa, procainamide, chlor- Linear cutaneous lupus erythematosus
promazine and hydralazine,175 may abrogate Ts cell activity in Cutaneous lesions of LE which follow a linear distribution are
a fashion similar to that seen in idiopathic LE.187–192 Suppression uncommon. The lesions may follow the lines of Blaschko, pos-
by calcium channel blockers of pathways which lead to apopto- sibly representing the clinical expression of a genetically pro-
sis in lymphocytes, apparently through enhanced bcl-2 expres- grammed clone of altered cells following the lines of Blaschko
sion,193 would be expected to expand the lymphocyte pool. The during early embryogenesis. Other linear skin lesions include
second mechanism involves the lowering by this class of drugs lichen striatus, a multilinear variant referred to as ‘Blaschki-
of cytosolic calcium concentration in keratinocytes and lympho- tis’, psoriasis, inflammatory linear verruocus epidermal nevus,
cytes. The effect on Ro/SSA expression of lowered calcium con- incontinentia pigmenti and scleroderma. Most cases repre-
centration, namely displacement of Ro/SSA antigen to the cell sent a linear variant of DLE with a predilection to involve the
surface, might promote binding of antibody to the cell surface face.71,72
with injury mediated by antibody-dependent cellular cytotoxic
mechanisms in concert with C5b-9-mediated membrane pore Chilblains lupus erythematosus
formation.53,56–61,118,126 In chilblains LE, patients with known LE manifest violaceous
papules and nodules localized to acral sites in temporal asso-
Histomorphology: Skin biopsies in DIL show features resem- ciation with cold exposure and dampness.18 Histologically, the
bling the type of LE syndrome provoked by the drug. For exam- biopsies are remarkable for a vacuolar interface dermatitis with
ple, in drug-induced SLE, the classical histopathology comprises variable epithelial atrophy. A striking lymphocytic vascular reac-
a cell-poor vacuolopathic lymphocytic interface injury pattern tion is present involving venules throughout the dermis. There is
associated with a superficial disposition of the infiltrate, and concomitant mural and luminal fibrin deposition within reticu-
absent keratotic follicular plugging or basement membrane zone lar dermal-based blood vessels. In chilblains unassociated with
LE or other systemic disorders, there is striking papillary dermal
oedema.19 A similar pattern of superficial and deep perivascular
lymphocytic infiltration is present; however, deposits of fibrin
Drug classes associated with lupus erythematosus are not encountered in reticular dermal blood vessels, unlike
(after Crowson and Magro28) their almost ubiquitous presence in chilblains LE. There appears
to be an association between chilblains LE and the presence of
• Antihypertensive anti-Ro/SSA antibodies.62
• Antipsychotic
• Anticonvulsant Parvovirus B19-induced systemic connective diseases includ-
• Antihistaminic ing lupus erythematosus
• Anti-inflammatory There is an emerging literature precedent on the role of parvovi-
• Antimicrobial rus B19 and cytomegalovirus as potential triggers to SLE, sclero-
• Immunosuppressive derma, DM, rheumatoid arthritis and ANCA-positive vasculitis.194
• Antihormonal The basis for the association is both in the context of seropositiv-
• Recombinant cytokines ity and the identification of viral RNA via an in situ methodology
• Docetaxol (Taxotere®) and/or solution phase PCR for viral DNA. The main virus associ-
ated with lupus-like reactions is parvovirus B19. There is a mis-
Table 5 conception that a negative IgM antibody titre would refute a role
for parvovirus B19 as an inciting trigger. In our experience, in

Immunohistochemistry as a diagnostic adjunct in the
virtually all cases the IgM titre is characteristically negative; how-
evaluation of potential biopsies of lupus erythematosus
ever, there is seropositivity for IgG antibodies to parvovirus B19
in high titre indicative of recent re-exposure or persistent high A Th1 dominant cytokine milieu is common in lesions of SLE,
viral load. Dermatopathological clues to parvovirus B19-induced although there may be a reduction in this cell population with
LE include the presence of a pronounced interstitial lymphohis- progressive disease.
tiocytopathy,194,195 while clues to parvovirus B19-induced DM are In a recent study, we examined 60 cases represented by
the presence of a lymphocytic vasculitis and a prominent inter- biopsy material with classic features of DM, SLE, DLE and
face dermatitis194,195 in a patient with documented DM on clinical SCLE for expression of CD3, CD4, CD8, CD20, CD45RA, CD83,
and/or serological grounds. Essentially, a viral-based aetiology CD123, cutaneous lymphocyte antigen (CLA), FoxP3, CXCR3 and
should be explored in any case of classic DM in which there MXA.197 The purpose of the study was to determine the phe-
is a striking lymphocytic component. A concomitant histiocytic notypic profile of each of these distinctive subtypes of collagen
infiltrate assuming an interstitial pattern is one of the less well vascular disease and then assess for any discernible differences
recognized clues to systemic connective tissue disease associated that could aid in the potential distinction of DM, SLE, DLE and
with viral disease,196 but is not, in isolation, diagnostic. SCLE. MXA, which is a signature marker of IFN-α expression
was seen in many cases with positivity found within endothe-
Rowell syndrome lium, keratinocytes and inflammatory cells. Vascular expres-
Rowell syndrome is characterized by clinical lesions resembling sion was greatest in DM, while upregulation of MXA expression
erythema multiforme occurring in patients with an established was observed in areas of interface dermatitis in cases of SLE,
history of LE. Often, these patients have a history of chilblains SCLE and DLE (Figure 25). DM cases had the highest number of
LE and are anti-Ro antibody positive. The actual trigger to ery- CD4 lymphocytes; CD8 lymphocytes were greatest in SLE. The
thema multiforme is variable and includes light exposure and greatest extent of CD20 B-cell infiltration was noted in lesions
drug hypersensitivity (Figure 24). of DLE. CD123 plasmacytoid dendritic cells were seen in most
cases of DM, SLE, SCLE and DLE, being greatest in SCLE and in
a subgroup of SLE patients with Kikuchi disease (Figure 26). In
general, regulatory T cells are fewer in biopsies of LE and DM
compared to other forms of inflammatory dermatitis reflecting a
form of type IV hypersensitivity,198 although their numbers are
most diminished in the setting of SLE (Figure 27). An interesting
potential differentiator that favours DM is strong expression of
MXA in vascular endothelium. Another important distinguishing
feature is a reduction in the expression of CLA within the T-cell
dominant infiltrate in lesions of LE compared to other forms of
T-cell rich cutaneous inflammation199 (Figure 28).
Recently published is the utility of C3d and C4d via an immu-
nohistochemical methodology in the evaluation of collagen vas-
cular disease.200 Essentially, intense C3d without C4d is typical
of DLE, combined C3d and C4d along the DEJ is characteristic of
SLE and C4d along the DEJ is characteristic of DM (Figure 29).
Rowell syndrome. a Systemic lupus erythematosus in a patient who

developed violaceous desquamating plaques. b On biopsy these
showed a pattern reminiscent of erythema multiforme. Figure 25 Prominent MXA expression in a region of follicular interface
dermatitis. MXA is a signature for interferon-α and is typically
Figure 24 upregulated in the epidermis.
Figure 26 Biopsy of subacute cutaneous lupus erythematosus. There

are numerous CD123-positive plasmacytoid dendritic cells in the Figure 28 Reduction in the staining of cutaneous lymphocyte antigen
epidermis and dermis. amidst T cells in the dermis in biopsies of lupus erythematosus.
Note that while there are many cells which are positive for cutaneous
lymphocyte antigen (CLA), there are still a number which are negative.
While Cd4 may decorate the nuclei of keratinocytes in cases of In a biopsy of lichen planus, this pattern of reduction would not
SCLE, this staining pattern is difficult to interpret and must be be seen. Essentially, the CLA would mirror the CD3. This diminution
examined under oil where a distinct, grannular, appearance is in dermal staining for CLA may be a useful finding when trying to
noted within the nucleus200 (Figure 30). establish the basis for a lichenoid infiltrate.
Molecular and genetic basis of lupus erythematosus

an association between SLE and variation in the HLA region on
In the last few years, striking advances in our understanding of chromosome 6.202 The most common European haplotype asso-
the molecular basis of LE have been made. A genetic basis for ciated with SLE is AH8.1.202 Abnormalities in the C4 gene are
LE has long been suspected. One of the first clues that there also associated with SLE. C4 is encoded by two genes, C4a and
was a genetic basis for LE was established many years ago, and C4b. C4a has enhanced abilities to bind immune complexes.204
was based on the dramatically higher incidence of LE in mono- The C4 genes are inherited in a discrete RCCX module which
zygotic twins compared to dizygotic twins.200–202 Several novel contains one C4 gene along with three neighbouring genes. The
candidate genes have been established via mapping studies. In class III MHC genes carry between two and eight C4 genes. Car-
a small percentage of cases, highly penetrant mutations such as rying fewer than two copies of C4a is a risk factor for SLE.204 The
homozygous deficiencies of C1q, C2 and C4 and mutations in the identification of ITGAM as a major susceptibility gene was dem-
DNA exonuclease TREX1 have been implicated.203,204 There is onstrated. This gene encodes the integrin gN protein that dimer-
izes with integrin B2 to form the cell surface receptor known as
complement receptor 3 or Mac-1. CR3 is expressed on neutro-
phils, macrophages and dendritic cells and can bind a variety
of ligands, including intercellular adhesion molecule (ICAM)-1
and the C3d fragment of activated complement C3. The sequelae
could be an influence in leucocyte trafficking and CR3-mediated
uptake of apoptotic cells or immune complexes.205 There is a
general upregulation of IFN-inducible genes in SLE. IRF5 encodes
an IFN-induced transcription factor responsible for mediating the
expression in many of the genes. Polymorphism at SNP rs2004640
creates a novel splice site in exon B, allowing the expression of
a novel IRF5 isoform. A second mutation, rs10954213, creates
a function polyadenylation site and hence a shorter and more
stable gene transcript. IFNs are typically produced in response to
infection. Large amounts are produced by plasmacytoid dendritic
cells stimulated by viral RNA and DNA through Toll receptors
7 and 9.205,206 In SLE they may also be triggered in response to
Figure 27 Regulatory T cells may be diminished in biopsies of lupus nucleic acid antigens released apoptotic cells. IFNs exert many
erythematosus, especially aggressive variants of systemic lupus downstream effects on the immune system, stimulating the Th1
erythematosus where it may define less than 5% of the cell population. pathways and sustaining activated T cells, and also lowering
However, in this biopsy of systemic lupus erythematosus, there are a the threshold for B-cell activation through the B-cell receptor
number of regulatory T cells. and promoting B-cell survival and differentiation. Three genes
Figure 30 Biopsy showing speckled granular staining for C4d within

epidermal keratinocytes.
genetic abnormalities in IRF5, Stat 4 and IRF7.205,206 Finally there

is an overreactive response to antigen binding to the B-cell recep-
tor related to genetic abnormalities in the BCR. It might be sur-
mised that the abnormalities in T-cell responses to antigen could
also play a role in LE given the T-cell dominant nature of the
infiltrate, epidermal-mediated destruction by CD8 lymphocytes,
restricted T-cell dominant repertoires identified in tissue samples
and diminished T-regulatory activity in active SLE; however, the
apparent risk associated with shared T-cell regulating genes is
held to be modest.200–211
This biopsy of systemic lupus erythematosus shows prominent Conclusion

granular deposits of both a C3d and b C4d along the dermo-
Recent advances in our understanding of the pathogenesis of the
epidermal junction.
connective tissue diseases have been paralleled by the elucida-
tion of specific histomorphological features which are manifested
Figure 29 by them. Careful attention to detail in the interpretation of rou-
tinely processed skin biopsy material can prompt specific relevant
involved in BCR signalling are strongly associated with SLE and questions concerning serological status and clinical presentation.
include BLK, BANK1 and LYN.207,208 All three of these genes are When these data are correlated with routine and immunofluo-
important in controlling activation of B cells following signalling rescence studies of skin biopsy material, the dermatopathologist
through the BCR. The role of BLK is least well understood. BLK can play a pivotal role in the diagnosis, proper classification,
knockout mice appear to have a relatively normal B-cell pheno- prognostication and treatment of the individual patient with
type. BANK is a scaffold protein that acts downstream of LYN by connective tissue disease. ◆
mediating an interaction between LYN and IP. Stat 4 may play a
role in the differentiation of the potentially pathogenic Th17 T-
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MINI-Symposium: inflammatory skin pathology

lupus erythematosus forms,1–12 all of which have correlative cutaneous stigmata.

Lupus erythematosus: comparison of clinical and direct immunofluorescence manifestations by subtype

Feature Systemic lupus Subacute cutaneous lupus Discoid lupus

ACR, American College of Rheumatology.

or absent and when identified ought to prompt consideration of

Kikuchi disease in the setting of systemic lupus

Dermal interstitial histiocytoid cell infiltrate in a systemic lupus

­ echanisms in SLE, and perhaps Kikuchi disease could be used

allow easy distinction given the findings of antibodies to RNP

Discoid lupus erythematosus

The incidence of transformation of DLE to SLE is low, prob-

Figure 6 Discoid lupus erythematosus. A superficial and deep

Discoid lupus erythematosus, tumid type. a A lymphocytic

Antiphospholipid antibody syndrome

­vasculitis. In this regard, the anti-endothelial cell antibody assay

Serological considerations in the diagnosis of connective

induced SLE. A nuclear membrane decoration pattern reflects

Seropositivity* by connective tissue disease classification (after Crowson and Magro78)

ANA C ssDNA dsDNA Sm SSA/Ro SSB/La NRNP Histone Scl 70

SLE 95–100 0–10 70 70 <30** 40 10–20 40–50 30 0

C5b-9 in the subclassification of lupus erythematosus and other

Uncommon subtypes of lupus erythematosus

the lesions appear similar to those of LEP; however, atrophy is

Immunofluorescent studies: in our hands, a positive LBT in

Phenotypic studies: in LEP the infiltrate within the subcutis

Molecular studies: While polyclonality is typical, monoclonality

Drug-induced lupus erythematosus (Table 5)

Figure 23 Lupus profundus. Molecular studies on

for parvovirus B19 as an inciting trigger. In our experience, in

Rowell syndrome. a Systemic lupus erythematosus in a patient who

Figure 26 Biopsy of subacute cutaneous lupus erythematosus. There

Molecular and genetic basis of lupus erythematosus

Figure 30 Biopsy showing speckled granular staining for C4d within

genetic abnormalities in IRF5, Stat 4 and IRF7.205,206 Finally there

This biopsy of systemic lupus erythematosus shows prominent Conclusion

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echanisms in SLE, and perhaps Kikuchi disease could be used

vasculitis. In this regard, the anti-endothelial cell antibody assay