Lupus Erythematosus
|
Salient features ·
A group of heterogeneous illnesses that have in common
the development of immunity to self-nucleic acids and their associated
proteins, with skin-only disease at one end of the spectrum and severe
visceral involvement at the other. ·
Skin lesions may be specific to lupus or nonspecific,
being seen in other conditions as well. ·
Acute cutaneous lupus erythematosus (malar rash) is
almost always associated with underlying visceral involvement. Subacute
cutaneous lupus patients meet American College of Rheumatology systemic lupus
erythematosus criteria approximately 50% of the time (but typically express
only mild systemic clinical manifestations). Chronic cutaneous lupus (classic
discoid lupus erythematosus, lupus panniculitis, chilblain lupus, and tumid
lupus erythematosus) patients most often have skin-only or skin-predominant
disease. ·
Classical discoid lupus erythematosus causes scarring
and can be permanently disfiguring. Subacute cutaneous lupus and acute
cutaneous lupus erythematosus are highly photosensitive and are
characteristically nonscarring. ·
Lupus erythematosus–nonspecific skin lesions include
nonscarring alopecia, mouth ulcers, photosensitivity, Raynaud phenomenon,
vasculitis/vasculopathy, and bullous systemic lupus erythematosus, among
others. They often herald a systemic lupus erythematosus flare. ·
Treatment consists of physical sun protection, topical
sunscreens, local and short-term systemic glucocorticoids, antimalarials, retinoids,
thalidomide/lenalidomide, conventional immunosuppressives, and biologic
therapies. ·
Lupus erythematosus occurs much more commonly in women
(9:1 female-to-male ratio). ·
Both systemic lupus erythematosus and cutaneous lupus
erythematosus are associated with upregulation of type 1 interferon
signaling.
Introduction
A group of autoimmune connective tissue
disease that have in common the development of immunity to self-nucleic acids
and their associated proteins, with skin-only disease at one end of the
spectrum and severe visceral involvement at the other. |
James N. Gilliam divides the cutaneous
manifestations of LE into those lesions that show characteristic histologic
changes of LE (LE-specific skin disease) and those that are not histopathologically
distinct for LE and/or may be seen as a feature of another disease process
(LE-nonspecific skin disease). Within this context, the term “LE-specific”
relates to those lesions displaying interface dermatitis. The term cutaneous LE
(CLE) is often used synonymously with “LE-specific skin disease” as an umbrella
designation for the three major categories of LE-specific skin disease: acute
cutaneous LE (ACLE), subacute cutaneous LE (SCLE), and chronic cutaneous LE
(CCLE).
Acute cutaneous lupus erythematosus is almost
always associated with underlying visceral involvement and involves
primarily the epidermis and upper dermis. Subacute
cutaneous lupus patients meet systemic lupus erythematosus criteria about 50%
of the time (but typically express only mild systemic clinical manifestations)
and involves primarily the epidermis and upper dermis and is associated
with anti-Ro/SSA autoantibodies. Chronic cutaneous lupus
(discoid lupus erythematosus, lupus panniculitis, chilblain lupus, and tumid
lupus erythematosus) patients most often have skin-only or skin-predominant
disease. Acute and subacute cutaneous lupus erythematosus are highly
photosensitive and are characteristically nonscarring. Discoid lupus
erythematosus involve the epidermis, upper and lower dermis, and
adnexal structures, and causes scarring and can be
permanently disfiguring; the majority of patients do not have clinically significant
systemic disease. Lupus erythematosus tumidus involves the dermis but there is
no prominent epidermal or adnexal involvement. Lupus panniculitis involves the
subcutaneous tissue and may result in disfiguring depressed scars.
Predominant locations of inflammatory infiltrates in subsets of
cutaneous lupus erythematosus
The types of
cutaneous lupus erythematosus are: acute cutaneous lupus erythematosus (ACLE),
subacute cutaneous lupus erythematosus (SCLE), discoid lupus erythematosus
(DLE), lupus erythematosus tumidus (LET) and lupus panniculitis (LEP); the
latter three are forms of chronic cutaneous lupus erythematosus. The primary
locations of the infiltrates are as follows: superficial dermis, ACLE and SCLE;
superficial plus deep dermis and periadnexal, DLE; superficial and
deep dermis,LET; and subcutaneous fat, LEP. The final diagnosis requires
clinicopathological correlation.
Clinical features
ACLE almost always
occurs in the setting of acutely flaring SLE, whereas CCLE often occurs in the
absence of SLE or in the presence of mild smoldering SLE. SCLE occupies an
intermediate position in this clinical spectrum. It is not uncommon to see more
than one subtype of LE-specific skin disease in the same patient, especially in
patients with SLE.
Characteristic sites of involvement for the three
major forms of cutaneous lupus erythematosus (LE)
Comparison of the Major Types of Lupus erythematosus-Specific
Skin Disease
|
Disease Features |
ACLE |
SCLE |
Classic DLE |
|
Clinical features of skin lesions |
|||
|
Induration Dermal atrophy Pigment changes Follicular plugging Hyperkeratosis |
0 0 + 0 + |
0 0 ++ 0 ++ |
+++ +++ +++ +++ +++ |
|
|
|||
|
|
|
|
|
|
Lupus band |
|||
|
Lesional Nonlesional |
++ ++ |
++ + |
+++ 0 |
|
Antinuclear antibodies |
+++ |
++ |
+ |
|
Ro/SS-A antibodies |
|||
|
By immunodiffusion By ELISA |
+ ++ |
+++ +++ |
0 + |
|
Antidouble-stranded DNA antibodies |
+++ |
+ |
0 |
|
Hypocomplementemia |
+++ |
+ |
+ |
|
Risk for developing SLE |
+++ |
++ |
+ |
Discoid lupus erythematosus
DLE is a benign inflammatory disorder of the
skin, characterized by well‐defined
red, scaly plaques, which heal with atrophy, scarring and pigmentary changes.
The histology is characteristic.
Epidemiology
The disease affects twice as many females as
males, with a peak age of onset in the fourth decade in females and slightly
later in males, although it can occur at any age.
Genetic factors:
Familial cases of DLE do occur. A family history is present in 4% of cases.
Pathophysiology
Cutaneous inflammation in DLE is a process in
which interferons (IFNs) – type I and type 3 – induce Th1‐biased
inflammation, with a predominantly lymphocytic infiltration. This inflammatory
pattern mirrors that of the innate immune response to cutaneous viral
infection, followed by epidermal damage, basement‐membrane
thickening and a scarring tissue response associated with a loss of follicular
stem cells. With CD4 and CD8 T cells, natural IFN‐producing
plasmacytoid dendritic cells (PDCs) are the predominant cell type, and numbers
of these correlate with the extent of scarring. IFN‐α,
produced mainly by PDCs, and IFN‐γ
produced by keratinocytes, induces the keratinocytic expression of
proinflammatory chemokines, as well as the apoptosis‐inducing
TNF‐related apoptosis‐inducing
ligand (TRAIL) molecule and its receptors.
Predisposing factors
Environmental factors associated with the
onset or exacerbation of discoid lupus erythematosus:
1. Trauma
(11%), including X‐rays and diathermy
2. Stress
(12%)
3. Ultraviolet
exposure (5%), including psoralen with UVA and laser light
4. Infection
(3%), including herpes zoster
5.
Drugs: many drugs are associated with the
precipitation or exacerbation of DLE, including isoniazid, penicillamine,
griseofulvin and dapsone. The drugs that induce CLE can be linked by their photosensitizing
properties. It has been suggested that these drugs cause an increase in
keratinocyte apoptosis, exposure of previously intracellular peptides on
epidermal cell surfaces, and enhance proinflammatory cytokines such as TNF-α
and IFN-α.
6. Seasonal
exacerbation, both in winter (10%) and summer (50%)
7. Cold
exposure (2%, but 17% of patients reported disease exacerbation due to cold)
8. Pregnancy
1% (onset)
9. Pre-menstrual
13% (disease flare)
Clinical features
Most patients have disease limited to the
head and neck (localized DLE), but a few have much more extensive disease,
potentially affecting any area of the skin (disseminated DLE).
Classic DLE
Localized disease
Classic DLE lesions, the most common form of
CCLE, are usually asymmetrically distributed and begin as asymptomatic,
well-defined, elevated, coin-shaped (i.e. discoid) erythematous, flat-topped
plaques covered by a prominent, firmly adherent scale that extends into the
orifices of dilated hair follicles.
DLE lesions typically expand with erythema
and hyper pigmentation at the periphery, leaving hallmark atrophic scarring,
telangiectasia, and hypopigmentation at the centre. When present on
hair-bearing skin (scalp, eyelid margins, and eyebrows), DLE causes scarring
alopecia. Follicular involvement in DLE is a prominent feature. Keratotic plugs
accumulate in dilated follicles that soon become devoid of hair. When the
adherent scale is lifted from more advanced lesions, keratotic spikes similar
in appearance to carpet tacks can be seen to project from the under surface of
the scale (i.e., the “carpet tack” sign). Carpet tack scale is most apparent on
the face and scalp where the follicular orifices are larger. The surface may
present a dirty, brownish yellow appearance that is rough to the touch because
of follicular plugging. Active lesions are intensely
inflammatory, with a pronounced superficial and deep dermal inflammatory
infiltrate. As a result, on palpation, active lesions typically feel thicker
and firmer than surrounding uninvolved skin.
Lesions occur particularly on the cheeks,
bridge of the nose, ears, side of the neck and scalp. A symmetric, hyperkeratotic, butterfly-shaped
DLE plaque is occasionally found over the malar areas of the face and bridge of
the nose. Such lesions should not be confused with the more transient, oedematous,
minimally scaling ACLE erythema reactions that occur in the same areas. Facial
DLE, like ACLE and SCLE, usually spares the nasolabial folds. It may be
difficult to distinguish early lesions of malar DLE from ACLE, but induration
and recalcitrance to topical steroids/calcineurin inhibitors favours the former
diagnosis. When DLE lesions occurs periorally, they resolve with a striking
acneiform pattern of pitted scarring. DLE characteristically affects the
external ear, including the concha or triangular fossa where it presents as
dilated, hyper pigmented follicles. The scalp is involved in 60% of patients
with DLE; irreversible, scarring alopecia resulting from such involvement. The
irreversible, scarring alopecia resulting from DLE differs from the reversible,
nonscarring alopecia that patients with SLE often develop during periods of
systemic disease activity. This type of hair loss, so-called lupus hair, may be
telogen effluvium occurring as the result of flaring systemic disease. In
approximately 7.5% of patients, the lesions on the face resemble rosacea, and
differentiation from true rosacea can be difficult. Usually, there are no
pustules as in true rosacea. Biopsy may be required to distinguish between LE
and rosacea.
Scarring
Discoid
lesions have the potential for scarring, and, with time, a substantial
proportion of patients develop disfiguring scarring. Scarring may be atrophic,
hypertrophic, cribriform or acneform. Pigmentary disturbances are common,
especially in dark‐skinned
people. Patches of leukoderma may be interspersed with hyper pigmented areas. Once
scarring has occurred, no further inflammation is seen, so that if relapse
occurs it usually starts in the reddish zone surrounding the scar.
Calcification may occur in plaques. Lesions on the ear lead to considerable
atrophy and scarring.
Disseminated DLE
Localized DLE lesions occur only on the head
or neck, whereas generalized DLE lesions occur both above and below the neck.
It is unusual for discoid lesions to be present below the neck without lesions
also being present above the neck. This
occurs most often in women, and they are usually cigarette smokers. Generalized
DLE is more commonly associated with underlying SLE and is often more
recalcitrant to standard therapy, frequently requiring layering of antimalarial
and immunosuppressive medications. DLE lesions below the neck most commonly
occur on the extensor aspects of the arms, forearms, and hands, although they
can occur at virtually any site on the body. The palms and soles can be the
sites of painful erosive DLE lesions. On occasion, small DLE lesions occurring
only around follicular orifices appear at the elbow and elsewhere (follicular
DLE). A disseminated variety results in a reticulate telangiectasia, usually
seen on the arms, legs and back of the calves, but potentially widespread. A
more annular variant has been called ‘lupus erythematosus gyrates repens’ and
consists of a migratory gyrate annular erythema with the histological features
of LE.
DLE lesions can be potentiated by sunlight
exposure but to a lesser extent than ACLE and SCLE lesions. DLE, as well as
other forms of CLE, can be precipitated by any form of cutaneous trauma (i.e.,
the Koebner phenomenon or isomorphic effect).
The relationship between classic DLE and SLE
has been the subject of much debate. The following summary points can be made:
(1) 5% of patients presenting with classic localised DLE lesions subsequently develop
evidence of SLE and (2) patients with generalized DLE (i.e., lesions both above
and below the neck) have somewhat higher risk for progressing to SLE, and a
higher risk for developing more severe manifestations of SLE than patients with
localized DLE.
Roughly one-fourth of patients with SLE
develop DLE lesions at some point in the course of their disease, and such
patients tend to have less severe forms of SLE.
Clinical variants
Hypertrophic DLE
Hypertrophic DLE also referred to as
hyperkeratotic or verrucous DLE is a rare variant of CCLE in which the
hyperkeratosis normally found in classic DLE lesions is greatly exaggerated
with thick scales. The extensor aspects of the arms, the upper back, and the
face are the area most frequently affected. It starts as a violaceous, scaly,
tender lesion, which rapidly enlarges, developing a warty hypertrophic surface
with coarse adherent scales, which form a hard brown black tar like plaque. Patients
with hypertrophic DLE probably do not have a greater risk for developing SLE.
Chilblain lupus
This may occur in patients with either DLE or
SLE. Chilblain LE lesions initially develop as purple-red macules, papules, and
plaques on the toes, fingers, and sometimes the nose,
elbows, knees and lower legs. The lesions are brought on or exacerbated by
cold, particularly moist cold climates and are clinically and
histologically similar to idiopathic chilblains (pernio). As they evolve, the lesions may develop a gross and microscopic appearance
consistent with a discoid lesion with the appearance of scarred atrophic
plaques with associated telangiectases. It is possible that chilblain LE begins
as a classic acral, cold-induced lesion that then koebnerizes DLE lesion, thus
explaining the spectrum of clinicohistologic findings, which seem to be based
on when, in the course of the lesion, the biopsy sample is taken.
Chilblain LE appears to be associated with
anti-Ro/SS-A antibodies. Persistence of
lesions beyond the cold months, a positive ANA, or presence of one of the other
ACR criteria for SLE at the time of diagnosis of chilblain lesions helps to
distinguish chilblain LE from idiopathic chilblains. Approximately 20% of
patients presenting with chilblain LE later develop SLE.
Occasionally, one or more fingers may show a
curious atrophic spindling, sometimes with hyperextension of the terminal
phalanges and dystrophy of the nails.
Lupus erythematosus profundus (panniculitis)
LE profundus/LE panniculitis (Kaposi-Irgang
disease) is a rare form of CCLE typified by inflammatory lesions in the lower
dermis and subcutaneous tissue. Approximately 70% of patients with this type of
CCLE also have typical DLE lesions overlying the panniculitis lesions. Some
have used the term LE profundus to designate those patients who have both LE
panniculitis and DLE lesions, and LE panniculitis to refer to those having only
subcutaneous involvement. Intense inflammation in the
subcutaneous fat leads to indurated plaques
and nodules lying beneath clinically normal skin. The overlying skin often
becomes attached to the subcutaneous nodules and is drawn inward due to atrophy
of fat producing deep depressions. The face, scalp, proximal upper arms, upper
trunk,, breasts, buttocks, and thighs are the sites frequently affected.
Dystrophic calcification frequently occurs in older lesions of LE profundus/LE
panniculitis, and pain associated with such calcification can, at times, be the
dominant clinical problem. Roughly 50% of patients with LE
profundus/panniculitis have evidence of SLE. However, the systemic features of
patients with LE panniculitis/profundus tend to be less severe, similar to
those of patients with SLE who have DLE skin lesions.
Lupus Erythematosus tumidus
Lupus erythematosus tumidus (LET; tumid LE)
is a variant of CCLE in which the dermal findings of DLE, namely, excessive
mucin deposition and superficial perivascular and periadnexal inflammation, are
found on histologic evaluation. The characteristic epidermal histologic changes
of LE-specific skin disease are only minimally expressed, if at all. This
results in succulent, oedematous, urticaria-like plaques with little surface
change. This type of lesion may be much larger and involve the whole of one cheek
or even the whole of a limb or on the trunk. Annular urticaria-like plaques can
also be seen. The paucity of epidermal change often produces confusion
concerning the diagnosis of LET as a form of CCLE. LET appears to be the most
photosensitive subtype of cutaneous lupus, and typically demonstrates a good
response to antimalarials. Additionally, LET lesions tend to resolve completely
without scarring or atrophy.
Mucosal DLE
Mucosal DLE occurs in approximately 25% of
patients with CCLE. The oral mucosa is most frequently affected; however,
nasal, conjunctival, and ano-genital mucosal surfaces can be targeted. In the
mouth, the buccal mucosal surfaces are most commonly involved, with the palate,
alveolar processes, and tongue being sites of less frequent involvement. Discoid
lesions begin as painless erythematous papules, which enlarge into chronic
plaques, usually appearing as erythematous central areas surrounded by well‐demarcated,
irregular, white borders and telangiectasia. The appearance can resemble oral
lichen planus. The surfaces of these plaques overlying the palatal mucosa often
have a honeycomb appearance. Central depression often occurs in older lesions,
and painful ulceration can develop. Rarely, oral mucosal DLE lesions can
degenerate into squamous cell carcinoma, similar to longstanding cutaneous DLE
lesions. Any degree of nodular asymmetry within a mucosal DLE lesion should be
evaluated for the possibility of malignant degeneration. Chronic DLE plaques
also appear on the vermilion border of the lips. At times, DLE involvement of
the lips can present as a diffuse cheilitis, especially on the more sun-exposed
lower lip.
DLE lesions may present on the nasal,
conjunctival, and anogenital mucosa. Perforation of the nasal septum is more
often associated with SLE than DLE. Conjunctival DLE lesions affect the lower
lid more often than the upper lid. Lesions begin as focal areas of nondescript
inflammation most commonly affecting the palpebral conjunctivae or the lid
margin. Scarring becomes evident as lesions mature, and the permanent loss of
eyelashes and ectropion can develop, producing considerable disability.
Erythematous lesions occur on the vulva in
5%, or around the anus.
Histological features
of cutaneous lupus erythematosus
1.
Lymphocytic
interface dermatitis with basal layer degeneration
2. Apoptotic
keratinocytes
3. Degenerative
changes in the connective tissue, consisting of hyalinization, oedema and
fibrinoid change, most marked immediately below the epidermis
4. Basement
membrane thickening (greatest in discoid lupus erythematosus)
5. Perivascular
and periadnexal lymphohistiocytic infiltrate
6. Hyperkeratosis
and Follicular plugging
7. Dermal
mucinosis
8. Epidermal
atrophy
Routine Histopathology
|
CHARACTERISTIC HISTOLOGIC FINDINGS IN CUTANEOUS LUPUS ERYTHEMATOSUS
(LE) |
|||||
|
Histologic finding |
Acute cutaneous LE |
Subacute cutaneous LE |
Discoid lesions of LE |
LE tumidus |
Lupus panniculitis* |
|
Vacuolar
alteration of basal layer |
++ |
++ |
+ |
− |
+/− |
|
Apoptotic
keratinocytes |
+ |
++ |
+ |
− |
+/− |
|
Hyperkeratosis |
− |
−/+ |
+ |
− |
− |
|
Epidermal
atrophy |
+ |
++ |
+/− |
− |
+/− |
|
Pilosebaceous
atrophy |
− |
− |
+ |
− |
− |
|
Follicular
plugging |
− |
+ |
++ |
− |
− |
|
Basement
membrane zone thickening |
+/− |
+ |
++ |
− |
− |
|
Lymphocytic
infiltrate in the upper dermis |
+ |
+ |
++ |
++ |
+/− |
|
Lymphocytic
infiltrate in the lower dermis |
− |
− |
++ |
++ |
+ |
|
Lymphocytic
infiltrate in the subcutis |
− |
− |
+/− |
+/− |
++ |
|
Lymphocytic
infiltrate, periadnexal |
− |
+/− |
++ |
+ |
+/− |
|
Dermal
edema |
+ |
+/− |
+/− |
+/− |
− |
|
Dermal
mucin |
+ |
+ |
+ |
+ |
+/− |
|
Dermal
fibrosis |
− |
− |
+/− |
− |
− |
|
Focal
hemorrhage |
+ |
− |
− |
− |
− |
The table is intended as
a broad overview only. Not every feature will be present in every lesion, some
features may be present that are not indicated as characteristic, and overlap
exists amongst subtypes. [−], not a defining feature; [+/−], a feature that may
be present in some lesions; [+], a feature that is typically present; [++], a
defining feature that may be prominent.
Histologic
findings in cutaneous LE depend in large part on the subtype. However, in
practice, an overlap in histologic findings occurs among the various clinical
phenotypes, particularly ACLE, SCLE and discoid lesions. Some of the more
distinctive histologic features of cutaneous LE are basal cell damage (also
referred to as vacuolar degeneration, hydropic change, or interface
dermatitis), lymphohistiocytic inflammatory infiltrates and, primarily in
discoid lesions, periadnexal inflammation, follicular plugging, and scarring.
The
LE-specific skin disease histopathology is a distinctive constellation of
hyperkeratosis, follicular plugging, epidermal atrophy, vacuolar basal cell
degeneration, dermal-epidermal junction basement membrane thickening, dermal
edema, dermal mucin deposition, and lymphohistiocytic infiltration of the
dermal-epidermal junction and dermis, focused in a superficial and deep
perivascular and periappendageal distribution.
The histopathologic changes in ACLE lesions
are generally less impressive than those in SCLE and DLE lesions, and are
mainly those of cell-poor interface dermatitis. The lymphohistiocytic cellular
infiltrate is relatively sparse, but more dermal oedema and epidermal
atrophy. Some authors have noted an
increase in the number of neutrophils in the infiltrate. A mild degree of focal
vacuolar alteration of basal keratinocytes can be seen, in addition to
telangiectases and extravasation of erythrocytes. One may see individually
necrotic keratinocytes, and in its most severe form, ACLE can display extensive
epidermal necrosis similar to TEN. The upper dermis usually shows pronounced
mucinosis and may be very helpful in distinguishing ACLE from other causes of
cell-poor interface dermatitis.
SCLE also
frequently presents as interface dermatitis, with foci of vacuolar alteration
of basal keratinocytes alternating with areas of lichenoid dermatitis.
Pronounced epidermal atrophy is often present. Dermal changes include edema,
prominent mucin deposition, and sparse lymphohistiocytic cell infiltration
usually limited to areas around blood vessels and periadnexal structures in the
upper one-third of the dermis. In contrast to discoid lesions, SCLE lesions
tend to have little or no hyperkeratosis, basement membrane thickening,
periadnexal infiltrate, follicular plugging, deep dermal infiltrate, or
scarring.
In classic DLE lesions, epidermal changes
include hyperkeratosis, follicular plugging, epidermal atrophy, and interface
dermatitis. The epidermal basement membrane is markedly thickened. Dermal
changes include a dense lymphohistiocytic cell infiltration predominantly in the
periappendageal and perivascular areas, oedema and hyalinization of the
connective tissue immediately below the epidermis and dermal mucin deposition.
The infiltrate is often quite dense and typically extends well into the deeper
reticular dermis and/or subcutis, which may help to distinguish it from ACLE or
SCLE. In chronic scarring DLE lesions, the dense inflammatory cell infiltrate
subsides and is replaced by dermal fibroplasia.
The
histopathology of hypertrophic DLE lesions is similar to that of classic DLE
lesions except for a much greater degree of epidermal acanthosis and
hyperkeratosis.
Chilblain LE
shows interface dermatitis, with superficial and deep perivascular lymphocytic
infiltration much like classic DLE. However, a lymphocytic vasculitis and
fibrin within the lumina of dermal blood vessels are present in addition.
LE tumidus
has prominent dermal mucin deposition and lymphocytic infiltrates with a lack
of epidermal change.
While
changes of lupus panniculitis are most prominent in the subcutis, an overlying
change of discoid lesion can be found in many cases.
This algorithm is intended
as a guide to diagnosis and should be individualized for each situation. For
example, lesional biopsy for direct immunofluorescence (DIF) may be performed
at the same time as a lesional biopsy for routine histology. Less definitive
histologic findings might sometimes be acceptable if the patient is already
known to have SLE.
Examination of the skin
for deposits of immunoreactants is called direct immunofluorescence (DIF). DIF
of lesional skin does not replace routine histologic staining as the method of
choice for establishing a diagnosis of cutaneous LE. However, in those cases
where the routine histopathology is equivocal, DIF can be a valuable asset in
establishing a diagnosis.
The
most characteristic DIF finding in cutaneous LE is antibody deposition at the
dermal–epidermal junction and around hair follicles.
Immunohistology shows the presence of primarily of IgG and/or IgM, occasionally IgA and
complement at the dermal–epidermal junction, in skin lesions present for 6
weeks or more, in approximately 80% of patients. Homogeneous, granular or
thready patterns occur, but the deposition is usually homogeneous in older
lesions. They are more frequent on the face (80%) than those on the trunk (20%)
and in untreated lesions, and decrease after treatment with topical
corticosteroids. They do not occur in uninvolved skin, unlike the majority of
cases of SLE. C1q deposits are found in 29% of patients with immunofluorescent-
positive DLE, compared with 90% in SLE, and the presence of such deposits
implies an increased risk of eventual systemic disease. In scarring alopecia
caused by LE, the deposits occur around hair follicles, a feature not seen in
other types of scarring alopecia.
Some investigators
have reported that in SCLE, granular deposits of IgG and IgM are observed
primarily within the epidermis rather than at the dermal–epidermal junction.
There is evidence that the epidermal deposits are due to anti-SSA/Ro
autoantibodies depositing directly within the skin.
In active lesions of ACLE, SCLE
and DLE, DIF of lesional skin is positive in the majority of cases. In general,
a positive DIF supports the diagnosis of cutaneous LE, but a negative DIF does not
exclude the diagnosis. It has been noted that DIF is most likely to be positive
in well-established, active lesions. DIF is often negative or nonspecific in LE
tumidus. In lupus panniculitis, DIF may show immunoreactants around dermal
vessels, but granular deposits at the dermal–epidermal junction are not
uniformly present.
Laboratory
abnormalities in DLE
ANA are present in low titre in 30%–40% of
patients with DLE; the ‘homogeneous’ type of antinuclear factor being twice as
frequent as the ‘speckled’ type. Antinuclear antibodies (ANA) are more common
in older patients, in those who have had the disease for a long time and when
there is extensive skin involvement. They are also more common in patients with
chiblains, Raynaud’s phenomenon and joint pains. However, fewer than 5% have
the higher ANA levels that are characteristic of patients with overt SLE
(>1:320). Antibodies to single-stranded DNA (IgM in 20%) occur in nearly
one-fifth and may indicate widespread and progressive disease, but antibodies to
dsDNA are distinctly uncommon. A small percentage of patients with DLE have
low-grade anaemia, biologic false-positive serologic tests for syphilis (VDRL
rapid plasma reagent), positive rheumatoid factor tests, slight depressions in
serum complement levels, modest elevations in γ globulin, and modest
leukopenia. It has been suggested that such findings are risk factors for the
development of SLE.
Disease course and
prognosis
The untreated skin lesions of DLE tend to be
persistent. With treatment, the more tumid lesions with little scaling may
clear completely in the course of a month or two. Longstanding Lesions with
much scaling and some scarring are slower to remit. Ultimately, scarring is
found in 57%, with scarring alopecia in 35%; 35% also have pigmentary
abnormalities. Areas of activity at the edge of such scars may take years to
settle. Spontaneous remission occurs occasionally, and the disease activity can
recrudesce at the sites of older, inactive lesions. Rebound after
discontinuation of treatment is typical, and slower taper of medications during
periods of inactivity is recommended. Long duration and lack of remission are
related to Raynaud’s phenomenon, scalp involvement and chilblain-like lesions.
Relapses can occur with sun- light, cold, trauma or mental stress after months
or years of remission. In spite of the chronic and relapsing nature of the
condition, the patient usually remains in good health.
Despite the fact that over half of patients
have haematological and serological abnormalities, the risk of developing overt
SLE is low. The risk is higher in patients with disseminated DLE than in DLE
confined to the head and neck. Patients presenting with localized DLE have only
a 5% chance of subsequently developing clinically significant SLE disease
activity. Generalized DLE and persistent, low-grade laboratory abnormalities
appear to be risk factors for such disease progression. Females developing DLE
before the age of 40 years, with HLA-B8 in their histocompatibility type, have
an increased risk of ‘converting’ to SLE. Patients with DLE showing signs of
nephropathy, arthralgia and ANA titres of 1: 320 or more should be carefully
monitored.
Neoplastic change in
DLE
Squamous cell and, less commonly, basal cell
carcinomas occasionally occur in the scars of DLE, particularly on the scalp,
ears, lips and nose. They are said to be more common in middle-aged males.
Management
The initial management of patients with any
form of CLE should include an evaluation to rule out underlying SLE disease
activity at the time of diagnosis. All patients with CLE should receive
instruction about protection from sunlight and artificial sources of UVR and
should be advised to avoid the use of potentially photosensitizing drugs such
as hydrochlorothiazide, tetracycline, griseofulvin,
and piroxicam. With regard to
specific medical therapy, local measures should be maximized and systemic
agents used if significant local disease activity persists or systemic activity
is superimposed.
ACLE lesions usually respond to the systemic
immunosuppressive measures required to treat the underlying SLE disease activity
that so frequently accompanies this form of CLE (e.g., systemic
glucocorticoids, azathioprine,
and cyclophosphamide).
Increasing evidence suggests that aminoquinoline antimalarial agents such as hydroxychloroquine can
have a steroid-sparing effect on SLE, and these drugs can be of value in ACLE.
The local measures discussed in Local Therapy below can also be of value in
treating ACLE. Because the lesions of SCLE and CCLE are often found in patients
who have little or no evidence of underlying systemic disease activity, unlike
the lesions of ACLE, nonimmunosuppressive treatment modalities are preferred
for SCLE and CCLE. For the most part, SCLE and CCLE lesions respond equally to
such agents.
Local Therapy
Topical
Glucocorticoids
Topical or intralesional
corticosteroids are a mainstay of therapy. They offer a high degree of safety
as well as the potential for a relatively rapid response. The systemic side
effects of corticosteroids are largely avoided, although the cutaneous side
effects are not. It is frequently the case that topical corticosteroids need to
be of high potency in order for a response to occur, and discoid lesions are
one of the few instances where it may be appropriate to use high-potency
corticosteroids on the face. Patients should be instructed about the risks and
benefits of therapy, the need to limit the application to affected areas, and
the need for monitoring for cutaneous side effects. Super
potent topical class I agents, such as clobetasol propionate
0.05% or betamethasone dipropionate
0.05%, produce the greatest benefit in CLE. Twice-daily application of the
super potent preparations to lesional skin for 2 weeks followed by a 2-week
rest period can minimize the risk of local complications such as steroid
atrophy and telangiectasia. Alternatively, a topical calcineurin inhibitor can
be used daily during the 2-week rest period from topical corticosteroids.
Ointments are more effective than creams for more hyperkeratotic lesions such
as hypertrophic DLE. Occlusive therapy with glucocorticoid can potentiate the
beneficial effects of topical glucocorticoids but also carries a higher risk of
local side effects. Class I or class II topical glucocorticoid solutions and
gels are best for treating the scalp. Unfortunately, even the most aggressive
regimen of topical glucocorticoids by itself does not provide adequate
improvement for most patients with SCLE and CCLE.
Intralesional
Glucocorticoids
Intralesional glucocorticoids (e.g., triamcinolone acetonide
suspension, 2.5–5.0 mg/mL for the face with higher concentrations allowable in
less sensitive sites) are more useful in the management of DLE than SCLE.
Intralesional glucocorticoids themselves can produce cutaneous and subcutaneous
atrophy (deep injections into the subcutaneous tissue enhance this risk). A
30-gauge needle is preferred because it produces only mild discomfort on
penetration, especially when injected perpendicularly to the skin. The active
borders of lesions should be thoroughly infiltrated. Intralesional therapy is
indicated for active discoid lesions, hyperkeratotic
lesions, LE tumidus lesions, and lesions that
are unresponsive to topical glucocorticoids. The
injections may be repeated monthly while the lesions are active.
Topical Calcineurin
Inhibitors
Pimecrolimus 1%
cream and tacrolimus
0.1% ointment have demonstrated efficacy in the treatment of ACLE, DLE, and
SCLE.
Systemic Therapy
Antimalarials
Antimalarial therapy has been
used for more than a half-century for cutaneous LE, and it remains the gold
standard for systemic therapy. One or a combination of the
aminoquinoline antimalarials can be effective for approximately 75% of patients
with CLE who have failed to benefit adequately from the local measures. The
risks of retinal toxicity should be discussed with the patient, and a pre treatment
ophthalmologic examination should be performed. However, the risk of
antimalarial retinopathy is extremely rare, particularly in the first 10 years
of therapy, if recommended daily dose maximum levels of these agents are not
exceeded (hydroxychloroquine,
6.5 mg/kg/day based on ideal body weight; chloroquine, 3
mg/kg/day). Patients should have follow-up ophthalmologic evaluations every
6–12 months while on therapy.
Hydroxychloroquine sulfate is the
most commonly chosen antimalarial, as it is usually well tolerated. Chloroquine
and quinacrine (mepacrine) are alternatives. Hydroxychloroquine sulfate
(Plaquenil), 6–6.5 mg/kg, should be given daily, either once daily or in two
divided doses to prevent GI side effects. Patients should be informed about 2–3
month delayed onset of therapeutic benefit. If no response is seen after 8–12
weeks, quinacrine hydrochloride, 100 mg/day, can be added to the hydroxychloroquine
without enhancing the risk of retinopathy (quinacrine does not cause
retinopathy). Quinacrine can turn the skin yellow,
although it does not invariably do so. If, after 4–6 weeks, adequate
clinical control has not been achieved, consideration should be given to
replacing the hydroxychloroquine with chloroquine diphosphate. For chloroquine, the usual dose is 125–250 mg/day, with
the eye toxicity-minimizing dose being no more than 3 mg/kg ideal body weight/day. Doses may need to be
adjusted for patients with decreased renal or hepatic function. In 2016, the American Academy of Ophthalmology recommended
a maximum dose of <5 mg/kg real weight/day of hydroxychlorquine and
<2.3 mg/kg real weight/day for chloroquine. In general, chloroquine
is felt to be more efficacious than hydroxychloroquine in treating CLE, perhaps
due to the earlier therapeutic responses that might occur as a result of the
shorter time period required to reach steady state blood levels with chloroquine
as compared to hydroxychloroquine.
Hydroxychloroquine and chloroquine should not
be used simultaneously because of enhanced risk for retinal toxicity. There is
some evidence that chloroquine may be more retinotoxic than hydroxychloroquine.
As the response to antimalarials
is relatively slow, so for patients who are beginning therapy for cutaneous LE,
topical or intralesional therapy should usually be given along with
antimalarial therapy. However, some patients do not respond either to single
antimalarial therapy or to the combination of quinacrine with either
hydroxychloroquine sulfate or chloroquine.
Multiple side effects other than retinal
toxicity are associated with the use of antimalarials. Quinacrine is associated
with a higher incidence of side effects, such as headache, gastrointestinal
intolerance, hematologic toxicity, pruritus, lichenoid drug eruptions, and
mucosal or cutaneous pigmentary deposition, than is either hydroxychloroquine or chloroquine.
Quinacrine commonly produces a yellow discoloration of the entire skin and
sclera in fair-skinned individuals, which is completely reversible when the
drug is discontinued. Quinacrine can produce significant hemolysis in patients
with glucose-6-phosphate
dehydrogenase deficiency (this adverse effect has also been reported to occur
rarely with hydroxychloroquine and chloroquine). Each of the aminoquinoline antimalarials
can produce bone marrow suppression, including aplastic anemia, although this
effect is exceedingly rare with the current dosage regimens. Toxic psychosis,
grand mal seizures, neuromyopathy, and cardiac arrhythmias occurred with the
use of high doses of these drugs in the past; these reactions are uncommon with
the lower daily dose regimens used today.
Before therapy with hydroxychloroquine and
chloroquine is
begun, complete blood cell counts, as well as liver and renal function tests,
should be performed; these tests should be repeated 4–6 weeks after therapy has
been initiated, and every 4–6 months thereafter. A screen for hematologic
toxicity when quinacrine is used is recommended more often. Patients with overt
or subclinical porphyria cutaneatarda are at particularly high risk for
developing acute hepatotoxicity, which often simulates an acute surgical
abdomen, when treated with therapeutic doses of antimalarials for CLE. It is
also recommended to check urine levels of β-human chorionic gonadotropin initially
in women with childbearing potential; although recent evidence indicates that
the risk to pregnant women of currently recommended dose regimens of
antimalarials is minimal.
Options for Antimalarial-Refractory
Disease
Disease that is refractory to
antimalarials is often refractory to other therapies as well. Nonetheless, it
is reasonable to seek a therapy that will work well, if the risks of therapy
are deemed to be worth the potential benefits. In antimalarial-resistant
patients, therapeutic options include oral retinoids, thalidomide or
lenalidomide, immunosuppressive agents such as mycophenolate mofetil,
azathioprine or methotrexate, apremilast, ustekinumab, sulfasalazine, and
systemic corticosteroids.
Dapsone has been used, but
usually with little success except in the rare subset of bullous eruption of
SLE. Both retinoids and thalidomide are potent teratogens, making them
difficult choices in women of childbearing potential. Thalidomide also
frequently causes a peripheral neuropathy. For that reason, some clinicians
have advocated giving thalidomide in low or intermittent dosing in an attempt
to minimize toxicity. Lenalidomide, a thalidomide derivative, has led to
improvement of refractory CLE and there may be a lower risk of developing
peripheral neuropathy.
Systemic
Glucocorticoids
Every effort should be made to avoid the use
of systemic glucocorticoids in patients with LE limited to the skin. However,
in occasional patients who have especially severe and symptomatic skin disease,
intravenous pulse methylprednisolone has
been used. In less acute cases, moderate daily doses of oral glucocorticoids (prednisone,
20–40 mg/day, given as a single morning dose) can be used as supplemental
therapy during the loading phase of therapy with an antimalarial agent. The
dose should be reduced at the earliest possible time because of the
complications of long-term glucocorticoid therapy, especially avascular
(aseptic) bone necrosis, a side effect to which patients with LE are particularly
susceptible.
Because steroid-induced bone loss occurs most
rapidly in the first 6 months of use, all patients who do not have
contraindications should begin agents to prevent osteoporosis with the
initiation of steroid therapy. When the disease activity is controlled, the
daily dosage should be reduced by 5- to 10-mg decrements until activity flares
again or until a daily dosage of 20 mg/day is achieved. The daily dose should
then be lowered by 2.5-mg decrements (some physicians prefer to use 1-mg dose
decrements below 10 mg/day). Alternate-day glucocorticoid therapy has not been
successful in suppressing disease activity in most patients with CLE or SLE. Prednisolone
rather than prednisone
should be used in patients who have significant underlying liver disease,
because prednisone requires hydroxylation in the liver to become biologically
active. Any amount of prednisone given as a single oral dose in the morning has
less adrenal-suppressing activity than the same amount given in divided doses
throughout the day. However, any given amount of this drug, taken in divided
doses, has a greater LE-suppressing activity than does the same amount of drug
given as a single morning dose.
Other
Immunosuppressives
Mycophenolate mofetil (MMF) (2.5–3.0 g/day orally) is
a purine analogue similar to azathioprine, but with more specific inhibition of
the de novo pathway in lymphocytes. This characteristic may allow for more efficacies
and less toxicity in treating severe, recalcitrant CLE.
Methotrexate
(7.5–25.0 mg orally 1 day per week) is effective for severe refractory CLE. A
double-blind, randomized, placebo-controlled trial in patients with SLE showed
that moderate doses of methotrexate (15–20 mg weekly) effectively controlled
cutaneous and articular activity and permitted a reduction in prednisone
dose.
Scarred lesions may be camouflaged.
Vasodilator drugs, particularly calcium‐channel
blockers such as nifedipine, are helpful in those with Raynaud phenomenon and
chilblain lesions.
Adjunctive Therapy
Sun protection is a vital part of
therapy for many patients because the sun exacerbates or initiates their skin
lesions. For others, sun protection is important for cancer prevention,
particularly in hypo pigmented skin or in chronic discoid lesions, where the
risk of skin cancer development may be higher. Cancer prevention is also
essential for patients who are on immunosuppressive therapy. Lastly, it has
been reported that sun exposure can exacerbate systemic disease in patients who
have SLE. Therefore, there are a variety of reasons why sun protection should
be emphasized, even in persons whose skin lesions are not induced or
exacerbated by sun exposure.
Sunscreens should be applied to
exposed skin daily, and more often if sun sensitivity is great or sun exposure
is intense or prolonged. The application of sunscreen
should be frequent – preferably every 2–3 h in bright sunlight. Broad-spectrum, water-resistant sunscreens [SPF ≥30
with an efficient UVA blocking agent such as a photostabilized form of
avobenzone, micronized titanium dioxide or micronized zinc oxide are preferred. Protective clothing is important to emphasize, as
the proper protective clothing is often significantly more effective than
sunscreens. Wear tightly woven clothing and broad-brimmed
hats. Sun avoidance is even more effective than
protective chemicals and clothing. Midday sun is particularly high in UVB, a
spectrum of UV radiation to which many patients are susceptible. It is more
difficult to minimize UVA exposure, as UVA is present in substantial quantities
throughout the day and can penetrate some types of window glass.
UV-blocking films should be applied to home and automobile windows, and acrylic
diffusion shields should be placed over fluorescent lighting. Education on the optimal use of sunscreens and protective
clothing and effective approaches to sun avoidance is important for most
patients with lupus. Careful attention should be given to vitamin D and calcium
intake.
For some patients, cosmetic
cover-up is the most helpful therapeutic intervention. Particularly in
situations where the disease activity has subsided but dyspigmentation remains,
cosmetic camouflage of the hyper pigmentation or hypo pigmentation may be the
best approach. Corrective camouflage cosmetics such as
Dermablend® and Covermark® offer the dual benefit of being highly effective
physical sunscreens as well as aesthetically pleasing cosmetic masking agents.
It has been observed that a large
number of cigarette smokers are represented amongst patients who present with
cutaneous lupus and that smokers may have more extensive cutaneous disease and
may be more refractory to therapy. Thus, smoking cessation represents a useful
adjunctive therapy in some individuals.
Therapeutic ladder
First line
Topical therapy can frequently control and
sometimes clear lesions without the need for systemic treatment; potent topical
corticosteroid such as 0.1% betamethasone 17‐valerate
cream alone can be effective without inducing epidermal atrophy. Intralesional
corticosteroid injections are helpful in resistant cases, even on the lips,
mouth and ears. Topical calcineurin inhibitors, such as tacrolimus, provide a
useful alternative to corticosteroids in those with localized disease.
Second line
For patients with severe, extensive or
scarring disease, particularly affecting the scalp, oral prednisolone is often
the most helpful initial treatment. A dosage of 0.5 mg/kg, rapidly tapered over
6 weeks is quickly effective, minimizes scarring and allows the slower acting
agents such as antimalarials to work. Long‐term
therapy with oral corticosteroids is best avoided because of side effects, but
may be necessary in a small number of patients resistant to other maintenance
therapy. In such circumstances, patients should also receive bone protection
with biphosphonates or related drugs to avoid osteoporosis. Methylprednisolone
500–1000 mg/day for 2 or 3 days, given as an intravenous pulse therapy, may
help resistant lesions.
First‐line
systemic treatment for on-going use should be with one of the oral
antimalarials. Most would start therapy with hydroxychloroquine, initially at
200 mg twice daily, reducing to 200 mg/day once a response is achieved.
Chloroquine phosphate is equally effective, usually at a dosage of 250 mg twice
daily, but hydroxychloroquine is used first by most prescribers because side
effects, particularly eye toxicity, are less likely provided that the dosage
limitations of 6.5 mg/kg lean body weight are adhered to. The comparable safe
daily dosage for chloroquine is unclear, but is probably around 4 mg/kg/day of
chloroquine base. Cumulative toxicity is rarely a problem with
hydroxychloroquine, although it can occur with chloroquine. For this reason,
courses of treatment lasting approximately 6 months are preferred, but this may
not be possible in the most severely affected patients who will require on-going
therapy. Quinacrine is also useful, and is safe from an ophthalmological point
of view, but it is often reserved for later use (because of yellow
discoloration of the skin). It may be used alone, or as part of a combination
of antimalarials, which may be more effective than the equivalent amount of
each drug given individually. Monitoring during therapy should include taking
an ophthalmic history and testing reading ability with appropriate charts (e.g.
Snellen).
Side effects of
antimalarials
Mild
1. Nausea
and vomiting
2. Abdominal
pain
Severe
1. Corneal
deposits
2. Retinopathy
3. Pigmentation
of the palate, nails and legs
4. Bleaching
of hair
5. Exfoliative
dermatitis
6. Lichenoid
rashes
7. Myasthenia
8. Extrapyramidal
involuntary movements
9. Neuropathy
10.
Psychiatric syndromes
11.
Myopathy
Third line
For cases not responding to topical steroids,
antimalarials and sunscreens, methotrexate and mycophenolate are the most
effective third line agents.
In the future, immune response modifiers such as tocilizumab
(anti-IL-6R), anifrolumab (anti-IFN-αR), and
ustekinumab or Janus kinase (JAK) inhibitors may play a role in the treatment
of cutaneous LE.
|
THERAPY
OF CUTANEOUS LUPUS ERYTHEMATOSUS |
|
Local therapy |
|
1. Sun protection (2) 2. Topical and
intralesional corticosteroids (2) 3. Topical calcineurin
inhibitors (2) 4. Topical retinoids (3) |
|
Systemic antimalarial therapy |
|
1. Hydroxychloroquine
(200 mg po daily–BID in adults; up to 6.5 mg/kg ideal body weight/day) (2)§ 2. Chloroquine (125–250
po daily in adults; up to 3.5–4 mg/kg ideal body weight/day) (2)§ 3. Quinacrine (100 mg po
daily) (2) 4. Combination of
hydroxychloroquine or chloroquine and quinacrine (2) |
|
Systemic therapy for
antimalarial-resistant cutaneous disease |
|
1. Retinoids (e.g.
acitretin, isotretinoin) (2) 2. Thalidomide (50–100 mg
po daily for clearing and, if necessary, 25–50 mg po daily–twice weekly for
maintenance)* (2) 3. Lenalidomide (3) 4. Dapsone (primarily for
bullous eruption of SLE) (2) 5. Immunosuppressive
agents (e.g. mycophenolate mofetil, azathioprine, methotrexate) (2) 6. Sulfasalazine (2) 7. Systemic
corticosteroids (3)
§ In 2016, the American Academy of
Ophthalmology recommended a maximum dose of ≤5 mg/kg real weight/day of hydroxychloroquine and
≤2.3 mg/kg real weight/day for chloroquine. * Concurrently with antimalarial as
latter may reduce thrombosis risk. |
Key to evidence-based
support: (1) prospective controlled trial; (2) retrospective study or large
case series; (3) small case series or individual case reports. BID, twice
daily.
S2k guideline for treatment of cutaneous lupus erythematosus –
guided by the European Dermatology Forum (EDF) in cooperation with the European
Academy of Dermatology and Venereology (EADV),2016.
Preventive measures and risk factors
Recommendations
• It is recommended to performing patient’s
past and present drug history, particularly in patients with SCLE.
• It is recommended to avoid unprotected UV
exposure and to use daily preventive (chemical and physical) measures in all
patients with CLE.
• Vitamin D supplementation is suggested in
all patients with CLE.
• Cessation of smoking (active and passive)
is recommended in all patients with CLE.
• It is recommended to avoid isomorphic
trigger factors, especially in patients with DLE.
Pregnancy or hormonal therapy
Recommendations
• In patients with CLE and associated
antiphospholipid syndrome, it is not recommended to take hormonal contraception
containing oestrogen.
• Oestrogen replacement therapy for patients
with CLE is not suggested.
• In active disease during pregnancy or
breastfeeding, HCQ as first-line treatment for CLE at usual dosage is recommended.
• It is recommended to continue the
maintenance of HCQ treatment during pregnancy, but it is also recommended to
switch from CQ to HCQ in this period.
• In active disease or during flares, dapsone
for HCQ-refractory CLE patients as an alternative treatment during pregnancy or
breastfeeding is suggested.
• It is recommended that systemic
corticosteroids (prednisone and methylprednisolone) should be given in a dose
of not more than 10 - 15 mg per day during pregnancy or breastfeeding.
• Methotrexate (MTX), mycophenolate mofetil
(MMF) or mycophenolate acid (MPA), retinoids and thalidomide or lenalidomide in
women of childbearing age without effective contraception is not recommended.
• It is recommended that a pregnant or
breastfeeding patient with severe CLE and/or anti-Ro/SSA antibodies should be
treated by a multidisciplinary approach.
Topical corticosteroids
Recommendations
• Topical corticosteroids as first-line
treatment for a time limited up to some weeks in all CLE lesions are
recommended.
• In patients with widespread disease and/or
the risk of scarring, it is recommend concomitant treatment with antimalarials
Topical Calcineurin Inhibitors
Recommendations
• In active, oedematous CLE lesions,
particularly on the face, it is recommended calcineurin inhibitors (0.1%
tacrolimus ointment) as an alternative first-line or as a second-line topical
treatment option.
• In patients with widespread disease and/or
the risk of scarring, it is recommended concomitant treatment with
antimalarials.
Topical retinoids and other topical agents
Recommendations
• In therapy-refractory hyperkeratotic
lesions of CLE, it is suggested topical retinoids as second-line treatment.
• It is suggested R-salbutamol as second-line
topical treatment for therapy-refractory DLE.
• Imiquimod is not recommended as topical
treatment in CLE.
UV treatment, cryotherapy and lasers
Recommendations
• It is not recommended any UV light as
treatment for patients with CLE.
• It is not recommended cryotherapy on any
CLE lesion.
• It is not recommended laser treatment on
any active CLE lesion. Laser treatment might be an additive option in carefully
selected lesions (e.g. telangiectasia).
Antimalarials
Recommendations
• It is recommended that antimalarials as
first-line and long term systemic treatment in all CLE patients with severe or
widespread skin lesions, in particular in patients with the risk of scarring and
development of systemic disease.
• It is recommended to apply HCQ in a maximum
daily dose of 5 mg/kg real bodyweight or CQ in a maximum daily dose of 2.3
mg/kg real bodyweight. A combination of HCQ with CQ must be avoided due to the
risk of irreversible retinopathy.
• In refractory cases, it is recommended to
add quinacrine to either HCQ or CQ.
• In cases of contraindication for HCQ or CQ
(e.g. retinopathy), monotherapy with quinacrine is recommended.
• Ophthalmological consultation is
recommended in all CLE patients treated with HCQ or CQ at baseline, annually
after 5 years of starting treatment or earlier in the presence of risk factors.
• it is suggested measuring HCQ or CQ blood
levels in therapy-refractory patients.
• Determination of G6PD activity is suggested
before antimalarial treatment.
Systemic corticosteroids
Recommendations
• In severe or widespread active CLE lesions,
systemic corticosteroids are recommended as first-line treatment in addition to
antimalarials.
• It is recommended to taper
the dose of systemic corticosteroids to a minimum with the aim to discontinue
the administration, as soon as the disease being treated is under control.
• Long-term therapy with corticosteroids in
CLE without systemic involvement is not recommended due to the well-known
serious side-effects.
Methotrexate (MTX)
Recommendation
• It is recommended MTX up to 20 mg per week
as a second-line treatment, primarily in patients with SCLE, preferably
subcutaneously and in addition to antimalarials.
Retinoids
Recommendation
• It is recommended retinoids as second-line
systemic treatment in selected CLE patients unresponsive to other treatments,
preferably in addition to antimalarials.
Dapsone
Recommendations
• It is suggested dapsone as first-line
treatment in Bullous LE.
• It is recommended dapsone as second-line
treatment in refractory CLE, preferably in addition to antimalarials.
• It is recommended to start dapsone with a
low-dose treatment (50 mg/day) and to increase it to a maximum of 1.5 mg/kg
according to clinical response and side-effects. Determination of G6PD activity
must be performed prior to therapy
Mycophenolate mofetil (MMF)
Recommendations
• It is recommended MMF as third-line
treatment in refractory CLE patients, preferably in addition to antimalarials.
• It is recommended 2 x 500 mg MMF per day as
starting dose that can be increased up to 3 g per day depending on the clinical
response.
• It is suggested MPA as an alternative
treatment for MMF.
Azathioprine, cyclophosphamide and cyclosporine
Recommendations
• It is not suggested azathioprine for the
treatment of CLE without systemic involvement.
• It is not suggested cyclophosphamide for
CLE without systemic involvement.
• It is not suggested cyclosporine for CLE
without systemic involvement
Thalidomide and Lenalidomide
Recommendations
• It is recommended thalidomide for selected
refractory CLE patients, preferably in addition to antimalarials.
• It is suggested a starting dose of 100 mg
per day and, after clinical effectiveness, taper to a minimum dose. The
sedative and prothrombotic effect should be taken into consideration. Due to
high incidence of polyneuropathy, electrophysiological examination of the peripheral
nerves must be performed prior to use and during treatment according to
clinical symptoms. Any sign of polyneuropathy should indicate the stop of the
drug.
• It is not suggested lenalidomide for the
treatment of CLE.
Antibiotics
Recommendation
• It is not recommended
antibiotics/antimicrobials (clofazimine/sulfasalazine/cefuroxime axetil) for
the treatment of CLE.
Intravenous immunoglobulins (IVIG)
Recommendation
• It is not suggested the use of IVIG for the
treatment of CLE.
Belimumab
Recommendation
• It is not suggested belimumab for the
treatment of CLE without systemic involvement.
Rituximab
Recommendation
• It is not suggested rituximab for the
treatment of CLE.
Anti-CD4 antibodies
Recommendation
• It is not recommended anti-CD4 antibodies
for the treatment of CLE.
Further biological drugs
Recommendations
• It is not recommended anti-TNF-a antibodies
for the treatment of CLE.
• It is not recommended IFN-a for the
treatment of CLE.
• It is not recommended leflunomide for the
treatment of CLE.
• It is not suggested danazol for the
treatment of CLE.
• It is not recommended extracorporeal
photopheresis for the treatment of CLE
Summary
Topical corticosteroids are the mainstay of
treatment for all different subtypes of the disease, but they are of limited
value because of their well-known side-effects, such as atrophy and
telangiectasia. A safe and effective alternative topical treatment for CLE is
the calcineurin inhibitors tacrolimus and pimecrolimus. Irrespective of the
subtype of the disease, antimalarials, such as HCQ or CQ, are the first-line
systemic treatment for disfiguring and widespread skin manifestations and for
the prevention of systemic disease. Systemic corticosteroids can be used
additionally in patients with highly acute and severe skin lesions, but should
be time-limited due to the well-known side-effects. Further second line
treatment options include MTX, retinoids and dapsone; MMF and MPA are
third-line treatment options. Biologicals, such as belimumab or sirukumab, are
promising new therapeutic options, but their efficacy and safety in the
treatment of patients with CLE still needs to be evaluated in clinical trials.
