Lupus ErythematosusLUPUS AT A GLANCEA group of heterogeneous illnesses that havein common the development of immunityto self-nucleic acids and their associatedproteins, with skin-only disease at oneend of the spectrum and severe visceralinvolvement at the other.Skin lesions may be specific to lupus ornonspecific and are seen in other conditionsas well.Acute cutaneous lupus erythematosus(malar rash) is almost always associatedwith underlying visceral involvement,subacute cutaneous lupus patients meetsystemic lupus erythematosus criteria about50% of the time (but typically express onlymild systemic clinical manifestations), andchronic cutaneous lupus (discoid lupuserythematosus, lupus panniculitis, chilblainlupus, and tumid lupus erythematosus)patients most often have skin-only or skinpredominantdisease.Discoid lupus erythematosus causes scarringand can be permanently disfiguring.Subacute cutaneous lupus and acutecutaneous lupus erythematosus are highlyphotosensitive and are characteristicallynonscarring.Lupus erythematosus-nonspecific skinlesions include nonscarring alopecia,mouth ulcers, photosensitivity, Raynaud’sphenomenon, and vasculitis/vasculopathy,among others. They often herald a systemiclupus erythematosus flare.Treatment consists of sunscreens,local and systemic (short-term)glucocorticoids, antimalarials, retinoids,immunosuppressives, thalidomide, andbiologic therapies.Lupus erythematosus occurs much morecommonly in women (9:1 female-male ratio).Both systemic lupus erythematosusand cutaneous lupus erythematosus areassociated with upregulation of class Iinterferon signaling.

LUPUS ERYTHEMATOSUS: ACHALLENGE TO DEFINE, CLASSIFY,AND TREATLupus erythematosus (LE) is the root designation fora diverse array of illnesses that are linked together bythe development of autoimmunity directed predominantlyat the molecular constituents of nucleosomesand ribonucleoproteins. Some patients present withlife-threatening manifestations of systemic LE (SLE);whereas others, who are affected with what likelyrepresents the same basic underlying disease process,express little more than discoid LE (DLE) skin lesionsthroughout their illness. It is convenient to conceptualizeLE as a clinical spectrum ranging from mildlyaffected patients with only localized DLE skin lesionsto those at risk of dying from the systemic manifestationsof LE such as nephritis, central nervous systemdisease, or vasculitis. The pattern of skin involvement

expressed by an individual patient with LE can provideinsight about the position on the spectrum wherethe patient’s illness might best be placed.The nomenclature and classification system originallydevised by James N. Gilliam divides the cutaneousmanifestations of LE into those lesions that showcharacteristic histologic changes of LE (LE-specificskin disease) and those that are not histopathologicallydistinct for LE and/or may be seen as a feature ofanother disease process (LE-nonspecific skin disease).Within this context, the term “LE-specific” relates tothose lesions displaying an interface dermatitis. Theterm cutaneous LE (CLE) is often used synonymouslywith “LE-specific skin disease” as an umbrella designationfor the three major categories of LE-specific skindisease: acute cutaneous LE (ACLE), subacute cutaneousLE (SCLE), and chronic cutaneous LE (CCLE). Thiswill be the framework used in our discussion of theextraordinarily diverse set of cutaneous lesions thatoccur in patients with LE (Table 155-1).The essence of LE is in its heterogeneity, and thechallenge for those who treat it is to recognize clinicallyuseful patterns within the mosaic of features thatconstitute this protean illness. An overview of the systemicmanifestations of LE can be seen in the AmericanCollege of Rheumatology’s (ACR) classification criteriafor SLE,1 which are presented in Table 155-2, andfrom the outline of the systemic manifestations of SLEpresented in Table 155-3.

EPIDEMIOLOGYThe epidemiology and socioeconomic impact of LE ingeneral,2 and CLE specifically,3 have been reviewed. Skin disease is the second most frequent clinical manifestationof LE after joint inflammation. As many as45% of patients with CLE experience some degreeof vocational handicap. A recent quality of life studysuggested that the impact of skin manifestations inpatients with SLE was preceded only by pain andfatigue related to their disease.4 The Dermatology LifeQuality Index and SF-36 have been used to measurequality of life in patients with CLE. Both questionnairesshowed that patients with active skin lesionshad lower quality of life and that patients with associatedalopecia were particularly impacted.5

Malar, or butterfly rash (localized ACLE), has beenreported in 20%–60% of large cohorts of patients withLE. Limited data suggest that the maculopapularor SLE rash of generalized ACLE is present in about35%–60% of patients with SLE. ACLE, like SLE ingeneral, is much more common in women than men(8:1). All races are affected; however, the early clinicalmanifestations of ACLE can be overlooked in a darkskinnedindividual.Patients presenting with SCLE lesions constitute7%–27% of LE patient populations. SCLE is primarilya disease of white females, with the mean age ofonset in the fifth decade. Drug-induced SCLE patientsare somewhat older at disease onset, perhaps reflectinggreater exposure to drugs for age-related medicalproblems (hypertension, cardiovascular disease).The most common form of CCLE, a classic DLEskin lesion, is present in 15%–30% of SLE populationsselected in various ways. Approximately 5% ofpatients presenting with isolated localized DLE subsequentlydevelop SLE. Rheumatologists have estimated

that SLE patients are sevenfold more common than isolatedcutaneous LE patients. However, dermatologistshave estimated that isolated cutaneous LE patientsmay be 2-3 times more common that SLE patients.Recently published population-based data haveargued strongly that the incidence and prevalence ofisolated forms of cutaneous LE are equivalent to thoseof SLE.6 Although DLE can occur in infants and theelderly, it is most common in individuals between 20and 40 years of age. DLE has a female-male ratio of 3:2to 3:1, which is much lower than that of SLE. All racesare affected, but investigations suggest that DLE mightbe more prevalent in blacks.

ETIOLOGY AND PATHOGENESISThe cause(s) of and pathogenetic mechanisms responsiblefor LE-specific skin disease are not fully understood,although recent work has provided many newinsights. The pathogenesis of LE-specific skin diseaseis inextricably intertwined with SLE pathogenesis.Simply put, SLE is a disorder in which the interplay

between host factors (susceptibility genes, hormonalmilieu, etc.) and environmental factors [ultraviolet(UV) radiation, viruses, and drugs] leads to loss ofself-tolerance, and induction of autoimmunity. This isfollowed by activation and expansion of the immune system,and eventuates in immunologic injury to end organsand clinical expression of disease7 (eFig. 155-0.1 in onlineedition). Recent work has highlighted the important roleof interferon-signaling in the pathogenesis of bothSLE and LE-specific skin disease.

ENVIRONMENTAL FACTORSGenetic predisposition for a lupus diathesis does not,in itself, produce disease. Rather, it appears that inductionof autoimmunity in such patients is triggered bysome inciting event, likely an environmental exposure.Drugs, viruses, UV light, and, possibly, tobacco, havebeen shown to induce development of SLE.Ultraviolet radiation (UVR) is probably the mostimportant environmental factor in the induction phaseof SLE and especially of LE-specific skin disease. UV

light likely leads to self-immunity and loss of tolerancebecause it causes apoptosis of keratinocytes, which inturn, makes previously cryptic peptides available forimmunosurveillance. UVB radiation has been shownto displace autoantigens such as Ro/SS-A and relatedautoantigens, La/SS-B, and calreticulin, from theirnormal locations inside epidermal keratinocytes to thecell surface.13 UVB irradiation induces the release ofCCL27 (cutaneous T cell-attracting chemokine), whichupregulates the expression of chemokines that activate

autoreactive T cells and interferon-(IFN-), producingdendritic cells (DCs), which likely play a centralrole in lupus pathogenesis.14,15

A recent, large, case-control study reported thatsmokers are at a greater risk of developing SLE thanare nonsmokers and former smokers. A cross-sectionalanalysis of a collaborative Web-based database establishedby Werth and colleagues documented thatpatients with treatment resistant CLE were much morelikely to smoke.16 Several authors have shown thatpatients with LE-specific skin disease who smoke areless responsive to antimalarial treatment.17–19

Numerous drugs have been implicated in inducingvarious features of SLE (Table 155-3). The drugsthat induce CLE can be linked by their photosensitizingproperties. It has been suggested that these drugscause an increase in keratinocyte apoptosis, exposureof previously intracellular peptides on epidermal cellsurfaces, and enhance proinflammatory cytokinessuch as TNF-and IFN-.20,21

There has been much speculation about the role ofinfectious agents, particularly viruses, in the inductionof SLE and CLE. Seroconversion to Epstein-Barr virus(EBV) among patients with SLE is nearly universal,and recent data have demonstrated that patients withSLE have defective control of latent EBV infection thatprobably stems from altered T-cell responses againstEBV.

CLINICAL FINDINGS(eFig. 155-0.2 in online edition)

CUTANEOUS LESIONSeTable 155-3.1 in online edition compares the key clinical,histopathologic, and laboratory features of patientspresenting with ACLE, SCLE, and CCLE (classic DLE)

subtypes of LE-specific skin disease, because the typeof skin involvement in LE can reflect the underlyingpattern of SLE activity. In fact, the designations acute,subacute, and chronic, in regard to CLE, refer to thepace and severity of any associated SLE and are notnecessarily related to how long individual lesions havebeen present. For example, ACLE almost always occursin the setting of acutely flaring SLE, whereas CCLEoften occurs in the absence of SLE or in the presenceof mild smoldering SLE. SCLE occupies an intermediateposition in this clinical spectrum. Subclassification,although important for assigning risk, is sometimesdifficult, as it is not uncommon to see more than onesubtype of LE-specific skin disease in the same patient,especially in patients with SLE.

ACUTE CUTANEOUS LUPUS ERYTHEMATOSUS.Although ACLE localized to the face is theusual pattern of presentation, ACLE can assume a generalizeddistribution. Localized ACLE has commonlybeen referred to as the classic butterfly rash or malarrash of SLE (Fig. 155-1). In localized ACLE, confluentsymmetric erythema and edema are centered over themalar eminences and bridges over the nose (unilateralinvolvement with ACLE has been described). Thenasolabial folds are characteristically spared. The forehead,chin, and V area of the neck can be involved, andsevere facial swelling may occur. Occasionally, ACLEbegins as small macules and/or papules on the facethat later may become confluent and hyperkeratotic.Generalized ACLE presents as a widespread morbilliform

or exanthematous eruption often focused over theextensor aspects of the arms and hands and characteristicallysparing the knuckles (Fig. 155-2A). Althoughperivascular nail fold erythema and telangiectasia canoccur (see Fig. 155-2B), they are considerably morecommon and occur in more exaggerated forms in dermatomyositis(see Fig. 157-5). Generalized ACLE hasbeen indiscriminately referred to as the maculopapularrash of SLE, photosensitive lupus dermatitis, and SLE rash.An extremely acute form of ACLE is rarely seen thatcan simulate toxic epidermal necrolysis (TEN). Thisform of LE-specific vesiculobullous disease resultsfrom widespread apoptosis of epidermal keratinocytes,and eventuates in areas of full-thickness epidermalskin necrosis, which is subsequently denuded.It can be differentiated between true TEN because it

occurs on predominantly sun-exposed skin and has amore insidious onset.30 The mucosa may or may not beinvolved, as in TEN.ACLE is typically precipitated or exacerbatedby exposure to UV light. This form of CLE can bequite ephemeral, lasting only hours, days, or weeks;however, some patients experience more prolongedperiods of activity. Postinflammatory pigmentarychange is most prominent in patients with heavilypigmented skin. Scarring does not occur in ACLEunless the process is complicated by secondary bacterialinfection.

SUBACUTE CUTANEOUS LUPUS ERYTHEMATOSUS.A disease presentation dominated bySCLE lesions marks the presence of a distinct subset ofLE having characteristic clinical, serologic, and geneticfeatures. Although a finding of circulating autoantibodiesto the Ro/SS-A ribonucleoprotein particlestrongly supports a diagnosis of SCLE, the presence ofthis autoantibody specificity is not required to make adiagnosis of SCLE.SCLE initially presents as erythematous maculesand/or papules that evolve into hyperkeratotic papulosquamousor annular/polycyclic plaques (Fig.155-3). Whereas most patients have either annularor papulosquamous SCLE, a few develop elementsof both morphologic varieties. SCLE lesions arecharacteristically photosensitive and occur in predominantlysun-exposed areas (i.e., upper back,shoulders, extensor aspects of the arms, V area ofthe neck, and, less commonly, the face). SCLE lesionstypically heal without scarring but can resolve withlong-lasting, if not permanent, vitiligo-like leukoderma,and telangiectasias.Several variants of SCLE have been described. Onoccasion, SCLE lesions present initially with an appearanceof erythema multiforme. Such cases are similar toRowell syndrome (erythema multiforme-like lesionsoccurring in patients with SLE in the presence of La/SS-B autoantibodies). As a result of intense injury toepidermal basal cells, the active edge of an annular

SCLE lesion occasionally undergoes a vesiculobullouschange that can subsequently produce a strikinglycrusted appearance. Such lesions can mimic Stevens-Johnson syndrome/TEN. Pathogenesis is similar tothat described above for TEN-like ACLE. Rarely, SCLEpresents with exfoliative erythroderma or displays acurious acral distribution of annular lesions. Pityriasiformand exanthematous variants of SCLE have beenreported. The skin lesions of neonatal LE (transient,photosensitive, nonscarring LE-specific skin lesions inneonates who have received IgG anti-Ro/SS-A, and,occasionally, other autoantibody specificities transplacentally)share many features with SCLE.Unlike ACLE skin lesions, SCLE lesions tend to beless transient than ACLE lesions and heal with morepigmentary change. They are also less edematous andmore hyperkeratotic than ACLE lesions. SCLE morecommonly involves the neck, shoulders, upper extremities,and trunk, whereas ACLE more commonly affectsthe malar areas of the face. When the face is involvedwith SCLE, it is most often the lateral face, with sparingof the central, malar regions. In comparison toSCLE lesions, DLE lesions are generally associatedwith a greater degree of hyper- and hypopigmentation,atrophic dermal scarring, follicular plugging, andadherent scale. A consistent clinical difference is thatDLE lesions are characteristically indurated, whereasSCLE lesions are not; this difference reflects the greaterdepth of inflammation seen histopathologically in DLElesions.Approximately one-half of patients with SCLE meetthe ACR’s revised criteria for the classification of SLE.However, manifestations of severe SLE, such as nephritis,central nervous system disease, and systemic vasculitis,develop in only 10%–15% of patients withSCLE. It has been suggested that the papulosquamoustype of SCLE, leu-kopenia, high titer of antinuclearantibody (ANA) (1:640), and anti-dsDNA antibodiesare risk factors for the development of SLE in a patientpresenting with SCLE lesions.

SCLE can overlap with other autoimmune diseases,including Sjögren’s syndrome, rheumatoid arthritis,and Hashimoto’s thyroiditis. Other disorders thathave been anecdotally related to SCLE are Sweetsyndrome, porphyria cutanea tarda, gluten-sensitiveenteropathy, and Crohn’s disease. There has alsobeen the suggestion that SCLE can be associated withinternal malignancy (breast, lung, gastric, uterine,hepatocellular, and laryngeal carcinomas as well aswith Hodgkin lymphoma).31

CHRONIC CUTANEOUS LUPUSERYTHEMATOSUSClassic DLE. Classic DLE lesions, the most commonform of CCLE, begin as red-purple macules, papules,or small plaques and rapidly develop a hyperkeratoticsurface. Early classic DLE lesions typically evolve intosharply demarcated, coin-shaped (i.e., discoid) erythematousplaques covered by a prominent, adherentscale that extends into the orifices of dilated hair follicles(Fig. 155-4).DLE lesions typically expand with erythema andhyperpigmentation at the periphery, leaving hallmarkatrophic central scarring, telangiectasia, and hypopigmentation(Fig. 155-5). DLE lesions at this stage can

merge to form large, confluent, disfiguring plaques.DLE in persons of certain ethnic backgrounds, such asAsian Indians, can present clinically as isolated areasof macular hyperpigmentation. When present on hairbearingskin (scalp, eyelid margins, and eyebrows),DLE causes scarring alopecia, which can lead to disfigurementand markedly impact quality of life. Follicularinvolvement in DLE is a prominent feature. Keratoticplugs accumulate in dilated follicles that soon becomedevoid of hair. When the adherent scale is lifted frommore advanced lesions, keratotic spikes similar inappearance to carpet tacks can be seen to project fromthe undersurface of the scale (i.e., the “carpet tack”sign). DLE lesions can be difficult to diagnose in Caucasianpatients because the characteristic peripheralhyperpigmentation is often absent. Such lesions areoften confused with actinic keratoses, squamous cellcarcinoma, or acne.DLE lesions are most frequently encountered on theface, scalp, ears, V area of the neck, and extensor aspectsof the arms. Any area of the face, including the eyebrows,eyelids, nose, and lips, can be affected. A symmetric,hyperkeratotic, butterfly-shaped DLE plaque isoccasionally found over the malar areas of the face andbridge of the nose. Such lesions should not be confusedwith the more transient, edematous, minimally scalingACLE erythema reactions that occur in the same areas.Facial DLE, like ACLE and SCLE, usually spares thenasolabial folds. It may be difficult to distinguish earlylesions of malar DLE from ACLE, but induration andrecalcitrance to topical steroids/calcineurin inhibitorsfavors the former diagnosis. When DLE lesions occurperiorally, they resolve with a striking acneiform patternof pitted scarring. DLE characteristically affects theexternal ear, including the outer portion of the externalauditory canal (Fig. 155-6A). Such lesions often present

initially as dilated, hyperpigmented follicles. The scalpis involved in 60% of patients with DLE; irreversible,scarring alopecia resulting from such involvement hasbeen reported in one-third of patients (see Fig. 155-6B).The irreversible, scarring alopecia resulting from DLEdiffers from the reversible, nonscarring alopecia thatpatients with SLE often develop during periods of systemicdisease activity. This type of hair loss, so-calledlupus hair, may be telogen effluvium occurring as theresult of flaring systemic disease.Localized DLE lesions occur only on the head or neck,whereas generalized DLE lesions occur both above andbelow the neck. Generalized DLE is more commonlyassociated with underlying SLE and is often more recalcitrantto standard therapy, frequently requiring layeringof antimalarial and immunosuppressive medications.DLE lesions below the neck most commonly occur onthe 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, and attimes disabling, erosive DLE lesions. On occasion, smallDLE lesions occurring only around follicular orificesappear at the elbow and elsewhere (follicular DLE). Wehave observed that elbow/extensor arm lesions seem to

cooccur with acral finger lesions of DLE, and that patientswith this combination of findings more frequently haveactive systemic disease. DLE activity can localize to thenail unit. The nail can be impacted by other forms of CLEas well as SLE, producing nail fold erythema and telangiectasia,red lunulae, clubbing, paronychia, pitting,leukonychia striata, and onycholysis.DLE lesions can be potentiated by sunlight exposurebut to a lesser extent than ACLE and SCLE lesions.DLE, as well as other forms of LE skin disease activity,can be precipitated by any form of cutaneous trauma(i.e., the Koebner phenomenon or isomorphic effect).The relationship between classic DLE and SLE hasbeen the subject of much debate.32 The following summarypoints can be made: (1) 5% of patients presentingwith classic DLE lesions subsequently developunequivocal evidence of SLE and (2) patients withgeneralized DLE (i.e., lesions both above and belowthe neck) have somewhat higher rates of immunologicabnormalities, a higher risk for progressing to SLE,and a higher risk for developing more severe manifestationsof SLE than patients with localized DLE.Roughly one-fourth of patients with SLE developDLE lesions at some point in the course of their

disease, and such patients tend to have less severeforms of SLE. Figure 155-7 illustrates the relative risksfor systemic disease activity that are associated withthe clinical varieties of LE-specific skin disease.Aside from Classic DLE, there are several other lesscommon variants of CCLE, which are subclasssified assuch because of their overlapping histologies and tendencyto occur in a low frequency in association withunderlying SLE.

Hypertrophic DLE. Hypertrophic DLE, alsoreferred to as hyperkeratotic or verrucous DLE, is a rarevariant of CCLE in which the hyperkeratosis normallyfound in classic DLE lesions is greatly exaggerated. Theextensor aspects of the arms, the upper back, and theface are the areas most frequently affected. Overlappingfeatures of hypertrophic LE and lichen planus havebeen described under the rubric lupus planus. The entitylupus erythematosus hypertrophicus et profundus appearsto represent a rare form of hypertrophic DLE, affectingthe face with the additional features of violaceous/dull red, indurated, rolled borders and striking central,crateriform atrophy. The name for this clinical entity isambiguous because LE panniculitis is not characteristicof its histopathology. Patients with hypertrophic DLEprobably do not have a greater risk for developing SLEthan do patients with classic DLE lesions.

Mucosal DLE. Mucosal DLE occurs in approximately25% of patients with CCLE. The oral mucosa is most frequentlyaffected; however, nasal, conjunctival, and genitalmucosal surfaces can be targeted. In the mouth, thebuccal mucosal surfaces are most commonly involved,with the palate (see Fig. 155-6C), alveolar processes, andtongue being sites of less frequent involvement. Lesionsbegin as painless, erythematous patches that evolve tochronic plaques that can be confused with lichen planus.Chronic buccal mucosal plaques are sharply marginatedand have irregularly scalloped, white borderswith radiating white striae and telangiectasia. Thesurfaces of these plaques overlying the palatal mucosaoften have a honeycomb appearance. Central depression

often occurs in older lesions, and painful ulcerationcan develop. Rarely, oral mucosal DLE lesionscan degenerate into squamous cell carcinoma, similarto longstanding cutaneous DLE lesions. Any degreeof nodular asymmetry within a mucosal DLE lesionshould be evaluated for the possibility of malignantdegeneration. Chronic DLE plaques also appear on thevermilion border of the lips. At times, DLE involvementof the lips can present as a diffuse cheilitis, especially onthe more sun-exposed lower lip.DLE lesions may present on the nasal, conjunctival,and anogenital mucosa. Perforation of the nasalseptum is more often associated with SLE than DLE.Conjunctival DLE lesions affect the lower lid moreoften than the upper lid. Lesions begin as focal areasof nondescript inflammation most commonly affectingthe palpebral conjunctivae or the lid margin. Scarringbecomes evident as lesions mature, and the permanentloss of eyelashes and ectropion can develop, producingconsiderable disability.

LE Profundus/LE Panniculitis. LE profundus/LE panniculitis (Kaposi-Irgang disease) is a rare formof CCLE typified by inflammatory lesions in the lowerdermis and subcutaneous tissue. Approximately 70%of patients with this type of CCLE also have typicalDLE lesions, often overlying the panniculitis lesions.Some have used the term LE profundus to designatethose patients who have both LE panniculitis and DLElesions, and LE panniculitis to refer to those havingonly subcutaneous involvement. Typical subcutaneouslesions present as firm nodules, 1–3 cm in diameter.The overlying skin often becomes attached to the subcutaneousnodules and is drawn inward to producedeep, saucerized depressions (Fig. 155-8). The head,

proximal upper arms, chest, back, breasts, buttocks,and thighs are the sites frequently affected. LE panniculitis,in the absence of overlying DLE, may producebreast nodules that can mimic carcinoma clinicallyand radiologically (lupus mastitis). Confluent facialinvolvement can simulate the appearance of lipoatrophy.Dystrophic calcification frequently occurs in olderlesions of LE profundus/LE panniculitis, and painassociated with such calcification can, at times, be thedominant clinical problem. Roughly 50% of patientswith LE profundus/panniculitis have evidence of SLE.However, the systemic features of patients with LEpanniculitis/profundus tend to be less severe, similarto those of patients with SLE who have DLE skinlesions.

Chilblain LE. Chilblain LE lesions initially develop aspurple-red patches, papules, and plaques on the toes,fingers, and face, which are precipitated by cold, dampclimates and are clinically and histologically similar toidiopathic chilblains (pernio) (see Chapter 94). As theyevolve, these lesions usually assume the appearanceof scarred atrophic plaques with associated telangiectases.They may resemble old lesions of DLE or maymimic acral lesions of small vessel vasculitis. Histologicfindings include a superficial and deep lymphocyticvascular reaction in addition to fibrin depositionin reticular, dermal-based blood vessels. Patients withchilblain LE often have typical DLE lesions on theface and head. It is possible that chilblain LE begins

as a classic acral, cold-induced lesion that then koebnerizesDLE lesions, thus explaining the spectrum ofclinico-histologic findings, which seem to vary basedon when, in the course of the lesion, the biopsy sampleis taken.Chilblain LE appears to be associated with anti-Ro/SS-A antibodies,33 and is linked to Raynaud’s phenomenonin many cases.34 Persistence of lesions beyond thecold months, a positive ANA, or presence of one of theother ACR criteria for SLE at the time of diagnosis ofchilblain lesions helps to distinguish chilblain LE fromidiopathic chilblains.35 Approximately 20% of patientspresenting with chilblain LE later develop SLE. ChilblainLE is an underrecognized entity, yet it is likelythat it is one of the most common causes of digitallesions in patients with LE. It is sometimes misdiagnosedas vasculitis and may overlap with acral DLEas mentioned above. An autosomal dominant, familialform of Chilbalin LE has recently been described, andis caused by a missense mutation in the TREX 1 (endonucleaserepair) gene.36

Lupus Erythematosus Tumidus. Lupus erythematosustumidus (LET; tumid LE) is a variant ofCCLE in which the dermal findings of DLE, namely,excessive mucin deposition and superficial perivascularand periadnexal inflammation, are found onhistologic evaluation. The characteristic epidermalhistologic changes of LE-specific skin disease are onlyminimally expressed, if at all. This results in succulent,edematous, urticaria-like plaques with little surfacechange (Fig. 155-9). Annular urticaria-like plaques canalso be seen. The paucity of epidermal change oftenproduces confusion concerning the diagnosis of LETas a form of CCLE.37,38

There have been several recent reports that supportthis subclassification and further characterize this subtypeof CCLE.39–44 Although described to occur in somepatients with SLE, most patients with LET have a negativeANA and a benign disease course. LET appearsto be the most photosensitive subtype of cutaneouslupus, and typically demonstrates a good response toantimalarials. Additionaly, LET lesions tend to resolvecompletely without either scarring or atrophy.There continues to be debate about the validity ofLET as an authentic form of LE-skin disease. Someargue that LET lesions may in fact not be a form ofCLE45 while others feel that LET deserves to be recognizedas a distinct type of CLE (intermittent cutaneousLE) equivalent in importance to acute cutaneous LE,subacute cutaneous LE, and chronic cutaneous LE.46

Other Variants. Other rare forms of chronic cutaneousLE have been described. These include LEhypertrophicus et profundus, lichenoid DLE, LE vermiculatus,LE telangiectaticus, linear CLE, and LEedematous (probably a historical designation for urticaria-like plaque DLE. Further information on theseclinical entities has recently been presented.47

LABORATORY TESTSeTable 155-3.1 in online edition summarizes the majorlaboratory findings associated with the varieties of LEspecificskin disease, and Table 155-5 presents the autoantibodyassociations of SLE. Because of the strongassociation between ACLE and SLE, the laboratory featuresof ACLE are those associated with SLE (high-titerANA, anti-dsDNA, anti-Sm, and hypocomplementemia).

The laboratory markers for SCLE are the presenceof anti-Ro/SS-A (70%–90%) and, less commonly,anti-La/SS-B (30%–50%) autoantibodies. ANA arepresent in 60%–80% of patients with SCLE, and rheumatoidfactor is present in approximately one-third.Other autoantibodies in patients with SCLE includefalse-positive serologic tests for syphilis (VDRL rapidplasma reagin) (7%–33%), anticardiolipin (10%–16%),

antithyroid (18%–44%), anti-Sm (10%), anti-ds-DNA(10%), and anti-U1 ribonucleoprotein (10%). Patientswith SCLE, particularly those with systemic involvement,may have a number of laboratory abnormalities,including anemia, leukopenia, thrombocytopenia,elevated erythrocyte sedimentation rate, hypergammaglobulinemia,proteinuria, hematuria, urine casts,elevated serum creatine and blood urea nitrogen, anddepressed complement levels (resulting from geneticdeficiency or increased complement consumption).ANA are present in low titer in 30%–40% of patientswith DLE; however, fewer than 5% have the higherANA levels that are characteristic of patients withovert SLE (1:320). Antibodies to single-stranded DNAare not uncommon in DLE, but antibodies to dsDNAare distinctly uncommon. Precipitating antibodies toU1RNP are sometimes found in patients whose diseasecourse is dominated by DLE lesions; however,such patients usually have only mild manifestations ofSLE or overlapping connective tissue disorders such asmixed connective tissue disease. Precipitating Ro/SS-Aand La/SS-B autoantibodies are rare in patients withDLE; low levels of anti-Ro/SS-A antibody detected byenzyme-linked immunoassay are more common. Asmall percentage of patients with DLE have low-gradeanemia, biologic false-positive serologic tests for syphilis(VDRL rapid plasma reagent), positive rheumatoidfactor tests, slight depressions in serum complementlevels, modest elevations in globulin, and modestleukopenia. It has been suggested that such findings

are risk factors for the development of SLE. ANA arepresent in 70%–75% of patients with LE profundus/panniculitis, but anti-dsDNA antibodies are rare.The laboratory findings associated with SLE, as wellas with CLE, in both adults and newborns, have beenreviewed.71,72

HISTOPATHOLOGYThe LE-specific skin disease histopathology is a distinctiveconstellation of hyperkeratosis, epidermalatrophy, vacuolar basal cell degeneration, dermalepidermaljunction basement membrane thickening,dermal edema, dermal mucin deposition, and mononuclearcell infiltration of the dermal-epidermal junctionand dermis, focused in a perivascular and periappendagealdistribution (eFig. 155-9.1 in online edition). Variabledegrees of these features are encountered in thedifferent forms of LE-specific skin disease (see Chapter6). Differences of opinion exist as to whether ACLE,SCLE, and DLE lesions can be distinguished reliably onthe basis of their histopathologic appearances alone.72–74

ACUTE CUTANEOUS LUPUSERYTHEMATOSUSThe histopathologic changes in ACLE lesions are generallyless impressive than those in SCLE and DLElesions, and are mainly those of a cell-poor interfacedermatitis. The lymphohistiocytic cellular infiltrate isrelatively sparse. Some authors have noted an increasein the number of neutrophils in the infiltrate. A milddegree of focal vacuolar alteration of basal keratinocytescan be seen, in addition to telangiectases andextravasation of erythrocytes. One may see individuallynecrotic keratinocytes, and in its most severe form,ACLE can display extensive epidermal necrosis similarto TEN. The upper dermis usually shows pronounced

mucinosis and may be very helpful in distinguishingACLE from other causes of a cell-poor interface dermatitis.It is uncommon to see basement membrane zonethickening, follicular plugging, or alteration of epidermalthickness in ACLE, although epidermal atrophy issometimes present.73,74

SUBACUTE CUTANEOUS LUPUSERYTHEMATOSUSSCLE also frequently presents as an interface dermatitis,with foci of vacuolar alteration of basal keratinocytesalternating with areas of lichenoid dermatitis.Pronounced epidermal atrophy is often present. SCLEis in the differential diagnosis of atrophic lichenoid dermatitis,along with atrophic lichen planus and lichenoiddrug eruptions. Dermal changes include edema,prominent mucin deposition, and sparse mononuclearcell infiltration usually limited to areas around bloodvessels and periadnexal structures in the upper onethirdof the dermis. Lesser degrees of hyperkeratosis,follicular plugging, mononuclear cell infiltration ofadnexal structures, and dermal melanophages mighthelp distinguish SCLE lesions from DLE lesions. It hasnot been possible to differentiate papulosquamousfrom annular SCLE by histopathologic criteria alone.72

CHRONIC CUTANEOUS LUPUSERYTHEMATOSUSIn classic DLE lesions, epidermal changes includehyperkeratosis, variable atrophy, and interface changessimilar to those described for SCLE. The epidermalbasement membrane is markedly thickened. Dermalchanges include a dense mononuclear cell infiltratecomposed primarily of CD4 T lymphocytes and macrophagespredominantly in the periappendageal andperivascular areas, melanophages, and dermal mucindeposition. The infiltrate is often quite dense and typicallyextends well into the deeper reticular dermisand/or subcutis, which may help to distinguish itfrom ACLE or SCLE. In chronic scarring DLE lesions,the dense inflammatory cell infiltrate subsides and isreplaced by dermal fibroplasia. A folliculotropic variantof DLE, in which the inflammatory infiltrate is predominantlyaround hair follicles, has been described,as have lymphomatoid variants, in which there areextremely dense infiltrates that may contain atypicallymphoid cells.73

IMMUNOHISTOLOGYImmunohistology is often helpful in confirming a diagnosisof LE-specific skin disease and has been shownto boost the sensitivity and specificity of diagnosis.73

Because it is not uncommon to see negative immunofluorescencestudies in patients with acute, subacute,and chronic LE, and false-positive studies in healthyindividuals, immunohistology must be interpreted inthe context of clinical and histologic findings in a givenpatient.IgG, IgA, IgM, and complement components (C3,C4, Clq, properdin, factor B, and the membrane attackcomplex C5b-C9) deposited in a continuous granular orlinear band-like array at the dermal-epidermal junctionhave been observed in the lesional and nonlesional skinof patients with LE since the early 1960s (Fig. 155-10).However, debate about terminology in this area continuesto cloud the field. Some restrict the use of the termlupus band test to refer to the examination of nonlesional

skin biopsies for the presence of this band-like array ofimmunoreactants at the dermal-epidermal junction.Others qualify the LBT as being either “lesional” or“nonlesional.” Less confusion might exist if the termslesional LBT (lesional lupus band) and nonlesional LBT(nonlesional lupus band) were uniformly adopted.

ACUTE CUTANEOUS LUPUSERYTHEMATOSUSThe sparse data that exist suggest that 60%–100% ofACLE lesions display a lesional lupus band. However,

the realization that sun-damaged skin from otherwisehealthy individuals can display similar immunopathologyhas diluted the clinical value of this finding.

SUBACUTE CUTANEOUS LUPUSERYTHEMATOSUSInitial studies indicated that approximately 60% ofpatients with SCLE had lesional lupus bands. A “dustlikeparticle” pattern of IgG deposition focused aroundepidermal basal keratinocytes has been suggested tobe more specific for SCLE by reflecting the presence ofin vivo bound Ro/SS-A autoantibody.

CHRONIC CUTANEOUS LUPUSERYTHEMATOSUSEarly reports suggested that more than 90% of classicDLE lesions had lesional immunoreactants at thedermal-epidermal junction, often extending along thebasement membrane of the hair follicle, but subsequentstudies report somewhat lower rates. Lesions onthe head, neck, and arms are positive more frequently(80%) than those on the trunk (20%). The lesional lupusband also appears to be a function of the age of thelesion being examined, with older lesions (3 months)being positive more often than younger ones. Ultrastructurallocalization of immunoglobulin at the dermalepidermaljunction confirms that these proteins aredeposited on the upper dermal collagen fibers andalong the lamina densa of the epidermal basementmembrane zone.In LE profundus, immunoglobulin and complementdeposits are usually found in blood vessel walls of thedeep dermis and subcutis. Immunoglobulin depositsat the dermal-epidermal junction may or may not bepresent, depending on the site biopsied, the presenceor absence of accompanying SLE, and the presence orabsence of overlying changes of DLE at the dermalepidermaljunction.

NONLESIONAL LUPUS BAND TESTThere has been much debate over the past three decadesregarding the diagnostic and prognostic significance ofan immunoglobulin/complement band at the dermalepidermaljunction of nonlesional skin taken frompatients with LE.72 When totally sun-protected nonlesionalskin (e.g., buttocks) is sampled, the diagnosticspecificity for SLE appears to be very high when threeor more immunoreactants are present at the dermalepidermaljunction. Prospectively ascertained followupdata also suggest that the presence of a nonlesionalLBT correlates positively with risk for developing LEnephritis. However, the nonlesional LBT has fallen outof favor as a clinical tool largely because the informationgained has not been proven to be of significantlygreater value than the results of more readily availableserologic assays such as antibody to dsDNA.

DIFFERENTIAL DIAGNOSISThe differential diagnosis of CLE is outlined in Box155-1 and eBox 155-1.1 in online edition. In addition,reticulated erythematosus mucinosis (REM) has beensuggested by some to be a form of photosensitive cutaneousLE perhaps related to LE tumidus. REM presentsas a reticulated array of macules and/or papules on theupper chest and back.

PROGNOSIS AND CLINICALCOURSEACUTE CUTANEOUS LUPUSERYTHEMATOSUSBoth localized and generalized forms of ACLE lesionsflare and abate in parallel with underlying SLE diseaseactivity. Therefore, the prognosis for any given patientwith ACLE is dictated by the pattern of the underlyingSLE. Both 5-year (80%–95%) and 10-year (70%–90%) survivalrates for SLE have progressively improved over thepast four decades as a result of earlier diagnosis made possibleby more sensitive laboratory testing and improvedimmunosuppressive treatment regimens. Ominous prognosticsigns in SLE are hypertension, nephritis, systemicvasculitis, and central nervous system disease.

SUBACUTE CUTANEOUS LUPUSERYTHEMATOSUSBecause SCLE has been recognized as a separatedisease entity for only two decades, the long-termoutcome associated with SCLE lesions has yet to bedetermined. It is the authors’ experience that mostpatients with SCLE have intermittent recurrences

of skin disease activity over long periods of timewithout significant progression of systemic involvement(we are aware of only one death directly attributableto SLE in approximately 150 patients withSCLE). Other patients enjoy long-term if not permanentremissions of their skin disease activity. A fewpatients have experienced unremitting cutaneousdisease activity.It has also been the authors’ experience that approximately15% of the patients with SCLE develop activeSLE, including lupus nephritis. This subgroup ofpatients is marked by the presence of papulosquamousSCLE, localized ACLE, high-titer ANA, leukopenia,and/or antibodies to dsDNA. Long-term follow-upstudies of SCLE are required to determine the truerisk of severe systemic disease progression in patientspresenting with SCLE skin lesions. CCLE lesions, typicallyclassic DLE, have also arisen in patients initiallypresenting with SCLE.Evidence suggests that overlap occurs betweenSCLE and Sjögren’s syndrome. Patients with SCLEwho develop Sjögren’s syndrome are at risk for developing

the extraglandular systemic complications associatedwith Sjögren’s syndrome, including vasculitis,peripheral neuropathy, autoimmune thyroiditis, renaltubular acidosis, myositis, chronic hepatitis, primarybiliary cirrhosis, psychosis, lymphadenopathy, splenomegaly,and B-cell lymphoma.

CHRONIC CUTANEOUS LUPUSERYTHEMATOSUSMost patients with untreated classic DLE lesions sufferindolent progression to large areas of cutaneousdystrophy and scarring alopecia that can be psychosociallydevastating and occupationally disabling.However, with treatment, skin disease can be largelycontrolled. Spontaneous remission occurs occasionally,and the disease activity can recrudesce at the sites ofolder, inactive lesions. Rebound after discontinuationof treatment is typical, and slower taper of medicationsduring periods of inactivity is recommended. Squamouscell carcinoma occasionally develops in chronicsmoldering DLE lesions.Death from SLE is distinctly uncommon in patientswho present initially with localized DLE. As discussedin Section “Epidemiology,” patients presenting withlocalized DLE have only a 5% chance of subsequentlydeveloping clinically significant SLE disease activity.Generalized DLE and persistent, low-grade laboratoryabnormalities appear to be risk factors for such diseaseprogression. Unrecognized squamous-cell carcinomadeveloping within a longstanding DLE skin lesioncould be a cause of morbidity and mortality.

OUTCOMES MEASURESThe recent development of a validated instrument tomeasure activity of CLE, the Cutaneous Lupus ErythematosusArea and Severity Index (CLASI), has made itpossible to objectively follow patients’ disease courseand response to therapy. The instrument has separatescores for damage (scarring) and activity which isimportant, because one would not expect a “burnedout”scarred area to normalize with drugs that weremeant to abate LE activity.76 It has been validated as auseful tool to measure clinical response.77

TREATMENTThe initial management of patients with any form ofCLE should include an evaluation to rule out underlyingSLE disease activity at the time of diagnosis. Allpatients with CLE should receive instruction aboutprotection from sunlight and artificial sources of UVRand should be advised to avoid the use of potentiallyphotosensitizing drugs such as hydrochlorothiazide,tetracycline, griseofulvin, and piroxicam. With regardto specific medical therapy, local measures should bemaximized and systemic agents used if significantlocal disease activity persists or systemic activity issuperimposed.ACLE lesions usually respond to the systemic immunosuppressivemeasures required to treat the underlyingSLE disease activity that so frequently accompaniesthis form of CLE (e.g., systemic glucocorticoids, azathioprine,and cyclophosphamide). Increasing evidencesuggests that aminoquinoline antimalarial agents suchas hydroxychloroquine can have a steroid-sparingeffect 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 thelesions of SCLE and CCLE are often found in patientswho have little or no evidence of underlying systemicdisease activity, unlike the lesions of ACLE, nonimmunosuppressivetreatment modalities are preferred forSCLE and CCLE (Table 155-6). For the most part, SCLEand CCLE lesions respond equally to such agents.

LOCAL THERAPYSUN PROTECTION. Advise patients to avoid directsun exposure, wear tightly woven clothing and broadbrimmedhats, and regularly use broad-spectrum,water-resistant sunscreens [SPF ≥30 with an efficientUVA blocking agent such as a photostabilized formof avobenzone (Parsol 1789), micronized titaniumdioxide, micronized zinc oxide, or Mexoryl SX]. UVblockingfilms should be applied to home and automobilewindows, and acrylic diffusion shields shouldbe placed over fluorescent lighting. Corrective camouflagecosmetics such as Dermablend® and Covermark®

offer the dual benefit of being highly effective physicalsunscreens as well as aesthetically pleasing cosmeticmasking agents. An in-depth discussion of practicaland theoretical photoprotection and local therapy forautoimmune connective tissue skin disease has beendiscussed in detail (see Chapter 223).78

LOCAL GLUCOCORTICOIDS. Although someprefer intermediate-strength preparations, such as triamcinoloneacetonide 0.1%, for sensitive areas suchas the face, superpotent topical class I agents, such asclobetasol propionate 0.05% or betamethasone dipropionate0.05%, produce the greatest benefit in CLE.Twice-daily application of the superpotent preparationsto lesional skin for 2 weeks followed by a 2-weekrest period can minimize the risk of local complicationssuch as steroid atrophy and telangiectasia. Alternatively,a topical calcineurin inhibitor can be used dailyduring the 2-week rest period from topical corticosteroids.Ointments are more effective than creams formore hyperkeratotic lesions such as hypertrophic DLE.Occlusive therapy with glucocorticoid-impregnatedtape (e.g., flurandrenolide) or glucocorticoids withplastic food wrap (e.g., Saran or Glad Press-N-Seal)can potentiate the beneficial effects of topical glucocorticoidsbut also carries a higher risk of local side effects.Class I or class II topical glucocorticoid solutions andgels are best for treating the scalp. Unfortunately, eventhe most aggressive regimen of topical glucocorticoidsby itself does not provide adequate improvement formost patients with SCLE and CCLE.

TOPICAL CALCINEURIN INHIBITORS. Pimecrolimus1% cream and tacrolimus 0.1% ointment havedemonstrated efficacy in the treatment of ACLE, DLE,and SCLE.79–81 A double blind, placebo controlled pilotstudy showed that pimecrolimus 1% cream had equalefficacy with betamethasone valerate 0.1% cream intreating facial DLE,82 and a different study demonstrated

the efficacy of topical tacrolimus 0.3% compound in clobetasolpropionate 0.05% for recalcitrant CLE.83

INTRALESIONAL GLUCOCORTICOIDS. Intralesionalglucocorticoids (e.g., triamcinolone acetonidesuspension, 2.5–5.0 mg/mL for the face with higherconcentrations allowable in less sensitive sites) aremore useful in the management of DLE than SCLE.

Intralesional glucocorticoids themselves can producecutaneous and subcutaneous atrophy (deep injectionsinto the subcutaneous tissue enhances this risk).A 30-gauge needle is preferred because it producesonly mild discomfort on penetration, especially wheninjected perpendicularly to the skin. The active bordersof lesions should be thoroughly infiltrated. Intralesionaltherapy is indicated for particularly hyperkeratoticlesions or lesions that are unresponsive to topicalglucocorticoids, but most patients with CLE have toomany lesions to be managed exclusively by intralesionalglucocorticoid injections.

SYSTEMIC THERAPYANTIMALARIALS. One or a combination of the aminoquinolineantimalarials can be effective for approximately75% of patients with CLE who have failed tobenefit adequately from the local measures describedin Section “Local Therapy.”84 The risks of retinal toxicityshould be discussed with the patient, and a pretreatmentophthalmologic examination should be performed.However, the risk of antimalarial retinopathy is extremelyrare, particularly in the first 10 years of therapy, if recommendeddaily dose maximum levels of these agentsare not exceeded (hydroxychloroquine, 6.5 mg/kg/daybased on ideal body weight; chloroquine, 3 mg/kg/day).Patients should have follow-up ophthalmologic evaluationsevery 6–12 months while on therapy.Hydroxychloroquine sulfate (Plaquenil), 6–6.5 mg/kg, should be given daily, either once daily or in twodivided doses to prevent GI side effects. Patientsshould be informed about 2–3 month delayed onsetof therapeutic benefit. If no response is seen after 8–12weeks, quinacrine hydrochloride, 100 mg/day (currentlyavailable in the United States only throughcompounding pharmacies), can be added to thehydroxychloroquine without enhancing the risk of retinopathy(quinacrine does not cause retinopathy). If,after 4–6 weeks, adequate clinical control has not beenachieved, consideration should be given to replacingthe hydroxychloroquine with chloroquine diphosphate(Aralen), 3 mg/kg to prevent retinopathy. Doses mayneed to be adjusted for patients with decreased renalor hepatic function. In Europe, chloroquine is generallyfelt to be more efficacious than hydroxychloroquine intreating CLE, perhaps due to the earlier therapeutic

time period required to reach steady state blood levelswith chloroquine as compared to hydroxychloroquine.Hydroxychloroquine and chloroquine should not beused simultaneously because of enhanced risk for retinaltoxicity. There is some evidence that chloroquinemay be more retinotoxic than hydroxychloroquine.Multiple side effects other than retinal toxicity areassociated with the use of antimalarials. Quinacrine isassociated with a higher incidence of side effects, suchas headache, gastrointestinal intolerance, hematologictoxicity, pruritus, lichenoid drug eruptions, and mucosalor cutaneous pigmentary deposition, than is eitherhydroxychloroquine or chloroquine. Quinacrine commonlyproduces a yellow discoloration of the entireskin and sclera in fair-skinned individuals, which iscompletely reversible when the drug is discontinued.Quinacrine can produce significant hemolysisin patients with glucose-6-phosphate dehydrogenasedeficiency (this adverse effect has also been reportedto occur rarely with hydroxychloroquine and chloroquine).Each of the aminoquinoline antimalarials canproduce bone marrow suppression, including aplasticanemia, although this effect is exceedingly rare withthe current dosage regimens. Toxic psychosis, grandmal seizures, neuromyopathy, and cardiac arrhythmiasoccurred with the use of high doses of these drugs inthe past; these reactions are uncommon with the lowerdaily dose regimens used today.Before therapy with hydroxychloroquine and chloroquineis begun, complete blood cell counts, as wellas liver and renal function tests, should be performed;these tests should be repeated 4–6 weeks after therapyhas been initiated, and every 4–6 months thereafter. Ascreen for hematologic toxicity when quinacrine is usedis recommended more often. Patients with overt or subclinical

porphyria cutanea tarda are at particularly highrisk for developing acute hepatotoxicity, which oftensimulates an acute surgical abdomen, when treatedwith therapeutic doses of antimalarials for CLE. It isalso recommended to check urine levels of -humanchorionic gonadotropin initially in women with childbearingpotential, although recent evidence indicatesthat the risk to pregnant women of currently recommendeddose regimens of antimalarials is minimal.

NONIMMUNOSUPPRESSIVE OPTIONS FORANTIMALARIAL-REFRACTORY DISEASE.Some patients with refractory CLE (SCLE more thanDLE) respond to diaminodiphenylsulfone (dapsone).85

An initial dose of 25 mg by mouth twice daily can beincreased up to 200–400 mg/day, if necessary. Significantdose-related hemolysis and/or methemoglobinemiacan result from the use of dapsone, especially inindividuals deficient in glucose-6-phosphate dehydrogenaseactivity, and, therefore, complete blood countsand liver function tests should be performed regularly.Isotretinoin, 0.5–2.0 mg/kg/day, and acitretin, 10–50mg/day, have also been used in this setting, but theirefficacy is limited by their side effects (teratogenicity,mucocutaneous dryness, and hyperlipidemia).In addition, breakthrough of CLE activity has been aproblem with the long-term use of retinoids.Thalidomide (see Chapter 235) (50–200 mg/day) isstrikingly effective for CLE that is refractory to othermedications. Numerous studies have cited responserates between 85% and 100%, with many patients experiencingcomplete remission.86 However, strict prescribingregulations put in place in the United Statesin 1998 because of severe teratogenicity, make thalidomidechallenging to dispense to women of childbearingpotential. Sensory neuropathy is another toxicityassociated with thalidomide, and 25%–75% of patientswith CLE develop peripheral neuropathy while takingthe drug. Most cases are reversible when therapyis stopped. Neuropathy seems to correlate with totaltreatment times so that short courses are preferred.Relapses after the drug is stopped are common. Excesssomnolence as well as constipation and other minorside effects sometimes limit its use, although theseeffects usually abate with lower daily doses.87 Thromboembolismis a serious adverse event that may occurin patients with a preexisting hypercoagulable state(e.g., presence of antiphospholipid antibodies). Oncologistswho use thalidomide for multiple myeloma frequentlyinitiate concomitant anticoagulation therapyto prevent this side effect. Lenalidomide (Revlamid,Celgene) is a thalidomide analog that is more efficaciousbut has similar rates of teratogenicity, peripheralneuropathy, thromboembolism, and also has the additionalpotential side effect of profound leukopenia.88

Other drugs reported to be of value in the treatmentof refractory CLE are gold and clofazimine; however,the benefit varies from case to case and both of theseagents are associated with the risk of significant sideeffects. Vitamin E, phenytoin, sulfasalazine, danazol,DHEA, and phototherapy (UVAI phototherapy, photopheresis)have also been reported in uncontrolled trialsto be of value in CLE.

SYSTEMIC GLUCOCORTICOIDS. Every effortshould be made to avoid the use of systemic glucocorticoidsin patients with LE limited to the skin. However,

in occasional patients who have especially severe andsymptomatic skin disease, intravenous pulse methylprednisolonehas been used. In less acute cases, moderatedaily doses of oral glucocorticoids (prednisone,20–40 mg/day, given as a single morning dose) can beused as supplemental therapy during the loading phaseof therapy with an antimalarial agent. The dose shouldbe reduced at the earliest possible time because of thecomplications of long-term glucocorticoid therapy,especially avascular (aseptic) bone necrosis, a side effectto which patients with LE are particularly susceptible.Because steroid-induced bone loss occurs most rapidlyin the first 6 months of use, all patients who do nothave contraindications should begin agents to preventosteoporosis with the initiation of steroid therapy. Anexcellent review describing current recommendationsfor prevention of bone loss and other side effects of systemicglucocorticoids has been published.89 When thedisease activity is controlled, the daily dosage shouldbe reduced by 5- to 10-mg decrements until activityflares again or until a daily dosage of 20 mg/day isachieved. The daily dose should then be lowered by2.5-mg decrements (some physicians prefer to use 1-mg

dose decrements below 10 mg/day). Alternate-dayglucocorticoid therapy has not been successful in suppressingdisease activity in most patients with CLE orSLE. Prednisolone rather than prednisone should beused in patients who have significant underlying liverdisease, because prednisone requires hydroxylation inthe liver to become biologically active. Any amount ofprednisone given as a single oral dose in the morninghas less adrenal-suppressing activity than the sameamount given in divided doses throughout the day.However, any given amount of this drug, taken individed doses, has a greater LE-suppressing activitythan does the same amount of drug given as a singlemorning dose.

PREVENTIONPredicting and preventing the initial clinical manifestationof LE, whether it is skin disease or systemic, isnot feasible at this time. However, as many LE patientsexhibit worsening of their skin disease activity withUV light exposure, physical protection from sunlightand artificial sources of UV light as well as the regularuse of broad-spectrum sunscreens having a SPF of 30or greater should be encouraged.