Cutaneous Lupus Erythematosus

• Antimalarial therapy (quinine) used for cutaneous lupus by Payne in 1894.
• By late 1950s, synthetic antimalarials became mainstay of therapy.
• Systemic corticosteroids and other immunosuppressives introduced mid-20th century.
• Term "lupus erythemateaux" first used by Cazenave in the mid-1800s.
• Cazenave and others distinguished lupus erythematosus (LE) from lupus vulgaris (a clinical variant of cutaneous tuberculosis).
• Hutchinson, Osler, Jadassohn — recognized cutaneous LE may be associated with internal abnormalities: arthritis, nephritis, serositis, cytopenias, neurologic disease.
• 1964 — Dubois: developed concept of lupus as a spectrum of disease (isolated cutaneous lesions to life-threatening multi-organ disease).
• Gilliam: developed concept of a spectrum of cutaneous disease.
• 1979 — Gilliam, Sontheimer, Thomas: named subacute cutaneous lupus erythematosus (SCLE); description virtually identical to "ANA-negative" lupus reported by Maddison, Provost, Reichlin in 1981.
• Diagnostic milestones:
• 1948 — LE cell phenomenon discovered by Hargraves, Richmond, Morton.
• 1957 — ANA identified by Friou.
• 1963 — lupus band test described by Burnham, Neblett, Fine.
• 1981 — anti-Ro (anti-SSA) associated with neonatal lupus by Weston et al.
• 1982 — anti-Ro associated with SCLE by Sontheimer et al.

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• Both UVB and UVA implicated; UVB more efficient cause of photo-induced skin changes.
• UVR induces apoptosis → translocation of cellular/nuclear antigens; reduced clearance of apoptotic cells.
• UVR increases keratinocyte production of SSA/Ro52 and type I IFNs.
• Proinflammatory cytokines induced by UVR: TNF, IL-1, IFN-γ, HMGB1, IL-18.
• Upregulation of antimicrobial peptides; release of extracellular traps (ETs) by dying neutrophils (NETosis) — lattice of DNA, histones, cytoplasmic proteins.
• UV-irradiated keratinocytes produce chemokines: CCL5, CCL20, CCL22, CXCL8.
• Increased in cutaneous LE lesions → leukocyte recruitment.
• Requires adhesion molecules: increased ICAM-1, VCAM-1, E-selectin on endothelial cells; ICAM-1 induction on basal keratinocytes.
• IFN pathway:
• Increased IFN secretion via: apoptotic cell binding to Fcγ receptors on macrophages; viral pathogens/DNA/RNA/immune complexes binding TLRs on plasmacytoid dendritic cells; SNPs in IFN pathway genes.
• Increased CXCL9, CXCL10 (IFN-upregulated proteins) in cutaneous LE skin.
• IFN-α drives monocyte differentiation into plasmacytoid dendritic cells → amplification loop of IFN-α/β production.
• Increased plasmacytoid (CD123+) and myeloid dendritic cells within cutaneous LE lesions.
• Epidermal/dermal dendritic cells acquire keratinocyte-derived antigens, prime CD8+ T cells in skin-draining lymph nodes.
• Cutaneous LE can be induced by IFN-α therapy given for other medical conditions.
• Increased IFN signature detected in peripheral blood mononuclear cells of DLE and SCLE patients, NOT LE tumidus.
• IFN-upregulated chemokines recruit CXCR3+ CD4+/CD8+ T cells to skin plus immature plasmacytoid dendritic cells → characteristic interface infiltrate.
• Granzyme B and TIA1 (cytotoxic granule-associated proteins) found in skin of all cutaneous LE subsets, less so in SCLE (fewer CD8+ T cells).
• Disseminated scarring DLE: high circulating CCR4+ cytotoxic T cells.
• Decreased Foxp3+CD4+CD25+ T regulatory cells in skin (not blood) of cutaneous LE patients.
• In hydroxychloroquine-refractory disease: myeloid dendritic cells play a role, associated with a TNF signature.
• Fig. 41.1 pathway summary: UVR → cytokine/chemokine production, innate immune proteins, NETosis, apoptosis (DNA release) → dendritic cell activation (via TLR7/MyD88) → IFN release → chemokine production → T cell activation → lichenoid tissue reaction.

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Classification (Gilliam)

• Most commonly used classification by Dr. James Gilliam.
• Divides lesions into specific (interface dermatitis on histology) vs nonspecific (no interface dermatitis) cutaneous lesions.
• Specific lesions subdivided into: acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), chronic cutaneous LE (CCLE).
• ACLE: often transient, typified by malar erythema.
• DLE: frequently long-lived, intensely inflammatory, can cause permanent disfiguring scars.
• SCLE: photosensitive eruption, longer-lasting than ACLE but without atrophy/scarring potential.
• CCLE category (typically grouped): LE tumidus, lupus panniculitis, chilblain lupus — although these often lack interface dermatitis (especially LE tumidus).
• Some authorities propose LE tumidus be its own category: intermittent cutaneous LE.
• Nonspecific lesions: malar erythema (photodistributed, can be widespread); annular/papulosquamous/neonatal SCLE variants; vasculopathic lesions; non-scarring alopecia; bullous lesions of SLE; Rowell syndrome; other.
• Relative systemic disease risk: ACLE and SCLE = relatively higher risk; DLE (localized/widespread/hypertrophic), LE tumidus, lupus panniculitis, chilblain lupus = relatively lower risk.

Discoid Lupus Erythematosus (DLE)

• One of the most common skin manifestations of lupus.
• Most frequently on face, scalp, ears; may be widespread.
• Unusual for discoid lesions below the neck WITHOUT lesions above the neck.
• Occasionally on mucosal surfaces: lips, nasal mucosa, conjunctivae, genital mucosa.
• Some patients show photodistribution, but many have lesions on sun-protected skin — no clear sun exposure association.
• Potential for scarring; substantial proportion develop disfiguring scars.
• Active lesions intensely inflammatory, pronounced superficial + deep dermal infiltrate → lesions feel thicker/firmer on palpation.
• Adnexal involvement prominent: follicular plugging, scarring alopecia.
• Dyspigmentation common in longstanding lesions: hypopigmentation centrally, hyperpigmentation peripherally; sometimes vitiligo-like depigmentation.
• Rarely, squamous cell carcinoma develops in longstanding discoid lesions.
• Associated arthralgias possible; over time only ~10–20% eventually meet SLE classification criteria.
• Most who meet criteria do so via mucocutaneous disease and/or mild hematologic abnormalities (e.g. leukopenia) rather than serious internal disease.
• Majority who progress do so within 5 years.
• Risk may be higher with widespread (disseminated) discoid lesions (defined as lesions below the neck) and in children.
• Hypertrophic (verrucous) DLE: unusual variant with thick scaling overlying or at periphery of discoid lesion; often prominent on extensor arms; may also involve face/upper trunk; characteristic DLE lesions often present elsewhere.

Subacute Cutaneous Lupus Erythematosus (SCLE)

• Patients typically report photosensitivity; lesions occur on sun-exposed skin.
• Midface usually spared; sides of face, upper trunk, extensor upper extremities commonly involved.
• Disease may be mild: few small scaly patches after sun exposure.
• Morphology: annular (raised pink-red borders, central clearing) OR papulosquamous (chronic psoriasiform/eczematous).
• Relatively sparse, superficial infiltrate → minimally palpable.
• Dyspigmentation common (hypopigmentation/depigmentation); rarely scarring or dermal atrophy.
• Drug association: ~1/3 of SCLE patients — drug-induced onset or exacerbation.
• First drug associated: hydrochlorothiazide.
• At least 100 agents reported to induce/exacerbate SCLE.
• Swedish population-based study — most frequent (decreasing order): terbinafine, TNF inhibitors, anti-epileptics, proton pump inhibitors.
• More recently: immune checkpoint inhibitors, particularly pembrolizumab and nivolumab.
• Lesions may or may not clear after discontinuation.
• ~50% of SCLE patients fulfill SLE classification criteria — mostly via lab and mucocutaneous findings.
• Study of 85 SCLE patients: only 6 had renal, 3 had neurologic disease.
• Anti-SSA/Ro associated with Sjögren syndrome as well — overlap features possible (pulmonary/neurologic Sjögren manifestations).
• Anti-SSA/Ro autoantibodies: substantial majority have them (~70% in a large series; reported range 60–100%).

Medications Associated with Drug-Induced SCLE

• More common/higher risk (>10 cases reported as of 2023 OR relative risk ≥2.0):
• Terbinafine
• Thiazide diuretics (e.g. hydrochlorothiazide)
• TNF inhibitors (adalimumab, etanercept, golimumab, infliximab)
• Proton pump inhibitors (lansoprazole, pantoprazole, omeprazole)
• Calcium channel blockers (diltiazem, nifedipine, nitrendipine, verapamil)
• Anti-epileptics (carbamazepine, phenytoin)
• Chemotherapy (taxanes, capecitabine, gemcitabine > doxorubicin, 5-fluorouracil)
• Immune checkpoint inhibitors (nivolumab, pembrolizumab, atezolizumab)
• ACE inhibitors (enalapril, lisinopril)
• Less common (3–10 cases, relative risk <2.0):
• β-blockers, imiquimod (topical), interferon-α and -β, other immunomodulators (abatacept, leflunomide, secukinumab, ustekinumab), palbociclib, abemaciclib, ranitidine, HMG-CoA reductase inhibitors ("statins"), tamoxifen, thrombocyte inhibitors (ticlopidine), VEGF/VEGFR inhibitors (bevacizumab, pazopanib).

Acute Cutaneous Lupus Erythematosus (ACLE)

• Exemplified by bilateral malar erythema ("butterfly rash").
• Lesions transient, follow sun exposure, resolve without scarring (may leave dyspigmentation).
• Association proposed with anti-dsDNA antibodies and lupus nephritis (plausible, but some malar rash patients have neither).
• Morphology: mild erythema to intense edema; telangiectasias, erosions, dyspigmentation, epidermal atrophy (poikiloderma) help distinguish from seborrheic dermatitis/erythematotelangiectatic rosacea.
• Occasionally papular component or scaling.
• Duration: hours to several weeks.
• Face (malar area) most affected; often spares nasolabial fold; can be more widespread.
• On hands, knuckles typically spared (contrast with dermatomyositis).
• Not unusual to have oral ulcerations.
• Rowell syndrome: erythema multiforme-like lesions in lupus patients.
• Rarely, acute eruption resembling TEN or erythema multiforme major — may represent severe ACLE or SCLE variant.
• The three major types are not mutually exclusive — more than one type may occur in a given patient.

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Lupus Erythematosus Tumidus (LET)

• Firm erythematous plaques, lack scale or follicular plugging.
• Epidermis appears uninvolved; intense perivascular/periadnexal dermal infiltrate + mucin deposition.
• May be same as "urticarial plaques" described in lupus patients; NOT to be confused with urticarial vasculitis.
• Commonly on face; often also trunk.
• Morphologically similar to lymphocytic infiltrate of Jessner — may have central clearing; some believe they are the same entity/spectrum.
• Difficult to classify as LE vs independent entity due to: very low prevalence of SLE, relative lack of serologic abnormalities, very low prevalence of immunoglobulin deposition in lesions.
• Presence of LET lesions in patients with other specific cutaneous LE types supports classification as LE.
• Majority reproducible by phototesting.
• Resolves without scarring, atrophy, or dyspigmentation.

Lupus Panniculitis

• Intense fat inflammation → indurated plaques → can evolve into disfiguring, depressed areas (lipoatrophy).
• Distinctive distribution: upper arms, face, scalp, upper trunk, thighs, buttocks, breasts.
• When discoid lesions overlie panniculitis: termed lupus profundus.
• Further discussion — see Chapter 100.

Chilblain Lupus

• Also known as SLE pernio.
• Red or dusky purple papules/plaques on toes, fingers, sometimes nose, elbows, knees, lower legs.
• Brought on/exacerbated by cold, particularly moist cold climates.
• May represent concurrence of ordinary chilblains with LE; over time can develop discoid-lesion appearance (gross and microscopic).
• Familial chilblain lupus: heterozygous mutations in TREX1 or SAMHD1, onset in childhood.
• Affected individuals may have arthralgias, positive ANA, otherwise no internal disease.
• Mutations in TREX1, SAMHD1, ADAR1, IFIH1, RNASEH2A/B/C → Aicardi–Goutières syndrome (primarily autosomal recessive autoinflammatory disorder: recurrent sterile fevers, progressive developmental delay, chilblains) — see Table 45.7, Type I interferonopathies.
• These 7 genes → accumulation of nucleic acids (dsDNA, RNA:DNA duplexes).

Discoid Lupus Erythematosus/Lichen Planus Overlap Syndrome

• Lesions with features of both conditions present (see Ch. 11).

Neonatal Lupus Erythematosus (NLE)

• SCLE-like form occurring in infants of mothers with anti-SSA/Ro autoantibodies.
• Lesions histologically identical to adult SCLE; strong anti-SSA/Ro association.
• Almost 100% of NLE babies have anti-SSA/Ro antibodies; less frequently anti-U1RNP.
• Unlike adult SCLE, predilection for face, especially periorbital region and scalp.
• Photosensitivity very common but not required (lesions can be present at birth).
• Lesions typically resolve completely; ~1/4 to 1/3 have cutaneous residua (telangiectasias, dyspigmentation, and/or atrophic scarring).
• Atrophic scarring more likely if lesions began in utero.
• Extracutaneous manifestations:
• Congenital heart block (with or without cardiomyopathy) — major finding.
• Heart block almost always present by birth; rarely develops after birth.
• Cardiomyopathy occurs concurrently in a small % with heart block; usually apparent neonatally, sometimes only after several months.
• Cardiac NLE mortality ~20%; ~2/3 of children require pacemakers.
• Hepatobiliary disease and cytopenias (especially thrombocytopenia) — may be present at birth or develop within first few months.
• Hepatobiliary disease severity ranges: liver failure in utero/neonatal period, conjugated hyperbilirubinemia in first weeks, mild aminotransferase elevation at 2–3 months.
• Also reported: hydrocephalus, microangiopathic hemolysis, disseminated intravascular coagulation.
• Systemic evaluation and counseling recommended for infants with cutaneous NLE.
• Mothers who had a baby with cutaneous NLE have increased likelihood of subsequent pregnancy complicated by NLE (including cardiac involvement) — should be cared for by perinatologist specializing in high-risk prenatal care.

Systemic Evaluation of Infant with Cutaneous NLE

• Initial and serial evaluations until 6–9 months of age:
• History, ROS, physical exam (monitor growth, head circumference*); frequency per systemic involvement degree.
• Labs: ECG +/- echocardiogram, CBC with differential and platelet count, LFTs; if normal & asymptomatic, repeat q2–3 months x2–3 (more often otherwise).
• Family counseling/care coordination: risk for NLE in subsequent pregnancies; risk for AI-CTD development in mother and possibly child.
• Preemptive treatment: consider hydroxychloroquine during subsequent pregnancies for mothers of infants with cardiac NLE.
• Long-term considerations:
• History/exam periodically per pediatrician.
• Labs: if normal/normalized and child healthy, further testing not required.
• Risk of AI-CTD as adolescent/adult.
• *Macrocephaly/hydrocephalus and chondrodysplasia punctata (stippled epiphyses) reported as possible NLE manifestations.

Bullous Lesions

• Bullous/crusted lesions may occur simply from intensity of basal cell damage in ACLE, SCLE, or possibly DLE.
• Rarely, dramatic acute eruption resembling erythema multiforme major or TEN may occur with preexisting ACLE/SCLE or de novo (also called acute syndrome of apoptotic pan-epidermolysis, ASAP).
• Blisters within ACLE/SCLE and EM-like/TEN-like cutaneous lupus fit within lupus-specific skin lesions category.
• Bullous eruption of SLE (bullous SLE): acquired blistering eruption in SLE patients.
• Vesicles and bullae; histopathology often resembles dermatitis herpetiformis — primarily neutrophilic infiltrate, microabscesses within dermal papillae.
• Some patients resemble neutrophil-rich bullous pemphigoid or epidermolysis bullosa acquisita.
• Immunoreactants often at basement membrane zone; antibodies to type VII collagen detected in several patients.
• May represent concurrence of lupus with autoimmune blistering disease (BMZ autoantibodies).
• Other autoimmune bullous diseases can also occur with lupus (case reports).

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Histopathology

• Findings depend largely on subtype.
• Overlap in histologic findings occurs among ACLE, SCLE, discoid lesions.
• Distinctive features: basal cell damage (vacuolar degeneration/hydropic change/interface dermatitis); lymphohistiocytic infiltrates admixed with CD123+ plasmacytoid dendritic cells; periadnexal inflammation, follicular plugging, scarring (primarily discoid lesions).
• ACLE: dermal changes relatively subtle; basal cell damage may be pronounced.
• SCLE: epidermal changes + superficial lymphocytic infiltrate common; in contrast to discoid lesions, SCLE has little/no hyperkeratosis, BMZ thickening, periadnexal infiltrate, follicular plugging, deep dermal infiltrate, or scarring.
• LE tumidus: prominent dermal mucin, dermal perivascular/periadnexal lymphocytic infiltrates, LACKS epidermal change.
• Lupus panniculitis: changes most prominent in subcutis; may have overlying DLE changes.
• Occasionally, cutaneous LE presents with neutrophil-rich infiltrate mimicking neutrophilic dermatosis.
• Plasmacytoid dendritic cells (producing IFNs) typically present in infiltrates.
• CD123 immunohistochemistry: marker for plasmacytoid dendritic cells; explored to distinguish cutaneous lupus from lichen planopilaris, polymorphous light eruption, cutaneous lymphoma — not specific, sensitivity/specificity not definitively established, but pattern/intensity may help.

Characteristic Histologic Findings by Subtype

(ACLE / SCLE / Discoid / LE tumidus / Lupus panniculitis*; − not defining, +/− may be present, + typically present, ++ prominent defining feature)

• Vacuolar alteration of basal layer: ++ / ++ / + / − / +/−
• Apoptotic keratinocytes: + / ++ / + / − / +/−
• Hyperkeratosis: − / −/+ / + / − / −
• Epidermal atrophy: + / ++ / +/− / − / +/−
• Pilosebaceous atrophy: − / − / + / − / −
• Follicular plugging: − / + / ++ / − / −
• BMZ thickening: +/− / + / ++ / − / −
• Lymphocytic infiltrate upper dermis: + / + / ++ / ++ / +/−
• Lymphocytic infiltrate lower dermis: − / − / ++ / ++ / +
• Lymphocytic infiltrate subcutis: − / − / +/− / +/− / ++
• Lymphocytic infiltrate, periadnexal: − / +/− / ++ / + / +/−
• Dermal mucin: + / + / + / + / +/−
• Dermal fibrosis: − / − / +/− / − / −
• *Lupus panniculitis may have overlying findings of discoid LE.

Antibody Deposits in Lesional Skin (Direct Immunofluorescence, DIF)

• DIF of lesional skin does NOT replace routine histology as method of choice, but valuable when routine histopathology equivocal.
• Most characteristic DIF finding: antibody deposition at dermal-epidermal junction and around hair follicles.
• Deposits typically granular, composed primarily of IgG and/or IgM; IgA occasionally seen. Complement deposits also expected.
• In SCLE, some investigators report granular IgG/IgM deposits primarily within the epidermis rather than DEJ — likely due to anti-SSA/Ro autoantibodies depositing directly in skin.
• DIF positive in majority of active ACLE, SCLE, DLE lesions.
• Positive DIF supports diagnosis; negative DIF does NOT exclude diagnosis.
• DIF most likely positive in well-established, active lesions.
• DIF often negative/nonspecific in LE tumidus.
• In lupus panniculitis: DIF may show immunoreactants around dermal vessels, but granular DEJ deposits not uniformly present.

Antibody Deposits Within Normal-Appearing Skin (Lupus Band Test)

• Presence of antibody deposits at DEJ in normal-appearing skin correlates reasonably well with systemic disease.
• Deposits typically granular — "lupus band"; testing = "lupus band test".
• Terminology confusing — some apply "lupus band" to lesional or non-lesional skin; recommendation to modify with "lesional" or "non-lesional".
• Weak, discontinuous deposits seen in persons without LE (healthy adults, especially chronically sun-exposed skin) — many investigators require strong and continuous deposition to call non-lesional lupus band test positive.
• True positive non-lesional lupus band test: ≥3/4 (three-quarters or more) of SLE patients if sun-exposed skin examined; ~1/2 of SLE patients if sun-protected skin examined.
• Unlikely positive in non-SLE patients, but can occasionally be positive in other autoimmune diseases.
• In most cases, clinical evaluation + serologic testing suffice, making non-lesional lupus band test superfluous; useful when presentation/labs atypical.

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• Lesional biopsy for H&E is generally the most valuable diagnostic test.
• Algorithm: Clinical exam consistent with cutaneous lupus → lesional biopsy for histology.
• Histology strongly supports diagnosis → accept diagnosis; evaluate for systemic disease.
• Histology consistent but not definitive → lesional biopsy for DIF.
• DIF characteristic of lupus → accept diagnosis or provisional diagnosis; evaluate for systemic disease.
• DIF nonspecific/negative → individualize approach.
• Histology inconsistent with lupus → individualize approach.
• Biopsy may sometimes be foregone (e.g. known SLE patient with transient facial ACLE-appearing lesions) due to high likelihood of nonspecific findings and cosmetic scar risk on face.

• Acute cutaneous lupus/malar rash: rosacea (including corticosteroid-induced); seborrheic dermatitis (especially photosensitive form); sunburn; drug-induced photosensitivity (phototoxic and photoallergic); dermatomyositis; erysipelas; pemphigus erythematosus and foliaceus; dermatitis (atopic, contact, photocontact).
• Subacute cutaneous lupus: psoriasis; dermatophytosis (including tinea incognito); photolichenoid drug eruption; polymorphous light eruption; granuloma annulare; figurate erythemas (e.g. erythema annulare centrifugum); dermatitis (atopic, contact, photocontact); pemphigus foliaceus.
• Discoid lesions: facial discoid dermatosis; tinea faciei/capitis/corporis, pityriasis (tinea) versicolor; lichen planus and lichen planopilaris; sarcoidosis; granuloma faciale; dimorphic fungal infections, lupus vulgaris; follicular mucinosis (alopecia mucinosa); when single lesion — non-melanoma skin cancer.
• Tumid lupus lesions: lymphocytic infiltrate of Jessner*; polymorphous light eruption; cutaneous lymphoid hyperplasia (pseudolymphoma of the skin); reticular erythematous mucinosis†.
• Lupus panniculitis: other panniculitides, in particular subcutaneous panniculitis-like T cell lymphoma (see Ch. 100).
• *Some believe lymphocytic infiltrate of Jessner and LE tumidus are the same/same spectrum.
• †Some believe reticular erythematous mucinosis and LE tumidus are the same/same spectrum.
• Note: mothers of boys with X-linked chronic granulomatous disease and patients with Sjögren syndrome have annular erythema similar to annular SCLE; GVHD patients can develop SCLE-like lesions.

• Clinical evaluation should consider drug-induced systemic or cutaneous lupus.
• Drug-induced SLE (DI-SLE): typically systemic illness — arthralgias, myalgias, pleuritis, fever — but lacking nephritis and CNS disease.
• Most commonly associated medications: hydralazine, procainamide, isoniazid, quinidine, methyldopa, chlorpromazine, minocycline, TNF inhibitors*.
• Cutaneous findings usually absent; may have malar or photodistributed erythema.
• Systemic findings: serositis (arthralgia, pleuritis, pericarditis); fever, weight loss, myalgia; nephritis/CNS usually absent.
• Associated autoantibodies: anti-histone†; anti-dsDNA (reported with TNF inhibitors).
• Drug-induced SCLE (DI-SCLE): most common form of drug-induced cutaneous LE; clinically/serologically indistinguishable from classic SCLE, but patients tend to be older.
• Medications: see Table 41.2.
• Cutaneous findings: SCLE.
• Systemic findings: usually none; sometimes arthralgias.
• Associated autoantibody: anti-SSA/Ro.
• *TNF inhibitors associated with both DI-SCLE and DI-SLE (and drug-induced discoid LE).
• †Anti-histone antibodies not specific for DI-SLE — also common in classic SLE and other AI-CTDs.
• Diagnosis of SLE often based on whether findings fulfill classification criteria, but criteria have limitations: developed to improve research/trial reproducibility.
• Meeting criteria does NOT necessarily imply major organ involvement; NOT meeting criteria does NOT ensure absence of SLE.

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Topical Therapy

• Topical or intralesional corticosteroids: mainstay of therapy.
• High safety; relatively rapid response.
• Systemic side effects largely avoided; cutaneous side effects are NOT avoided.
• High-potency topical corticosteroids often needed; discoid lesions are one of few instances where high-potency corticosteroids may be appropriate on the face.
• Patients instructed on risks/benefits, limiting application to affected areas, monitoring for cutaneous side effects.
• Intralesional triamcinolone: particularly for active discoid and LE tumidus lesions; typically 2.5–5 mg/ml depending on anatomic location; may repeat monthly while active.
• Topical immunomodulators (tacrolimus, pimecrolimus): reports of successful use.

Systemic Therapy — Antimalarials

• Gold standard for systemic therapy, used >half a century.
• Hydroxychloroquine sulfate: most commonly chosen, usually well tolerated.
• Chloroquine and quinacrine (mepacrine): alternatives; quinacrine not readily available in many parts of world.
• Non-responders to hydroxychloroquine: quinacrine may be added to regimen.
• Quinacrine can turn skin yellow (not invariable).
• Hydroxychloroquine dose: usually 200 mg once or twice daily. Eye toxicity unlikely if dose ≤5 mg/kg actual body weight/day.
• Chloroquine dose: usual 125–250 mg/day; eye toxicity-minimizing dose ≤2.3 mg/kg actual body weight/day.
• Quinacrine thought by most not to cause eye toxicity.
• Periodic eye exams by physician knowledgeable in antimalarial eye toxicity for patients on hydroxychloroquine or chloroquine.
• Response is slow: may take 2–3 months for efficacy to be appreciated, several more months for maximal efficacy.
• Topical/intralesional therapy should usually be combined with antimalarial therapy when starting treatment.
• Some patients do not respond to single antimalarial or combination therapy (quinacrine + hydroxychloroquine or chloroquine).

Antimalarial-Resistant Disease

• Often refractory to other therapies as well; reasonable to seek effective therapy if risk/benefit favorable.
• Options: oral retinoids, dapsone, immunosuppressive agents (mycophenolate mofetil, azathioprine, methotrexate), sulfasalazine, thalidomide or lenalidomide, systemic corticosteroids.
• Dapsone: occasionally used before advancing to immunosuppressive therapy; most often for the rare bullous eruption of SLE.
• Retinoids and thalidomide: potent teratogens — difficult choices in women of childbearing potential.
• Thalidomide: frequently causes peripheral neuropathy — some advocate low/intermittent dosing to minimize toxicity.
• Lenalidomide: second-generation thalidomide derivative — improvement in refractory cutaneous LE, possibly lower peripheral neuropathy risk.
• Belimumab and rituximab: disappointing for DLE, mixed for SCLE — suggests DLE pathogenesis may not be B-cell dependent, or rituximab depletion of regulatory B cells may be deleterious.
• Rituximab may be helpful for refractory bullous LE.
• Future/emerging agents: anifrolumab (anti-IFN-α receptor antibody); drugs depleting/inactivating plasmacytoid dendritic cells (litifilimab, daxdilimab); iberdomide (promotes degradation of Ikaros/Aiolos transcription factors regulating lymphocyte differentiation); anti-IL-33 antibody; JAK inhibitors.

Systemic LE Treatment (by Severity)

• No major organ involvement:
• Mild disease: NSAIDs.
• Moderate to severe: corticosteroids and immunosuppressives (mycophenolate mofetil, azathioprine, methotrexate, leflunomide).
• Major organ involvement:
• Mild: corticosteroids primary treatment.
• Moderate to severe: pulse cyclophosphamide or mycophenolate mofetil +/− pulse corticosteroids.

Therapy of Cutaneous Lupus Erythematosus (with Evidence Levels)

• Evidence key: (1) prospective controlled trial; (2) retrospective study or large case series; (3) small case series or individual case reports.
• Local therapy: sun protection (2); topical and intralesional corticosteroids (2); topical calcineurin inhibitors (2); topical retinoids (3); topical tofacitinib (3).
• Systemic antimalarial therapy:
• Hydroxychloroquine: 200 mg po daily–BID in adults; up to 6.5 mg/kg ideal body weight/day (1)*
• Chloroquine: 125–250 mg po daily in adults; up to 3.5–4 mg/kg ideal body weight/day (2)*
• Quinacrine: 100 mg po daily (2)
• Combination hydroxychloroquine or chloroquine + quinacrine (2)
• Systemic therapy for antimalarial-resistant cutaneous disease:
• Retinoids (e.g. acitretin, isotretinoin) (1,2)
• Thalidomide: 50–100 mg po daily for clearing, then if needed 25–50 mg po daily–twice weekly for maintenance† (2)
• Lenalidomide: 5–10 mg po daily† (2)
• Dapsone: 50–150 mg/day, primarily for bullous eruption of SLE (2)
• Methotrexate: 10–25 mg/week, orally/IM/SC (1)
• Mycophenolate mofetil: 1000–3000 mg/day (2)
• Azathioprine: 100–150 mg/day (3)
• Anifrolumab (1, systemic; 2, cutaneous)
• Litifilimab (1)
• Daxdilimab (1)
• JAK inhibitors (3)
• Sulfasalazine (2)
• Systemic corticosteroids (3)‡
• IVIg: 2 g/kg every 4–8 weeks, depending on response (2)
• Rituximab (3)
• Belimumab (3)
• Footnotes:
• *2016 American Academy of Ophthalmology recommendation: max ≤5 mg/kg real weight/day hydroxychloroquine and ≤2.3 mg/kg real weight/day chloroquine. Example: patient weighing 140 lb (63.6 kg) → dose = 300 mg daily (200 mg BID alternating with 200 mg daily, vs 1.5 tablets daily).
• †Give concurrently with antimalarials, as antimalarials may reduce thrombosis risk.
• ‡Usually reserved for severe inflammatory cutaneous disease (e.g. Rowell syndrome).
• General measures for all patients: avoid photosensitizing medications; smoking cessation.

Adjunctive Therapy

• Sun protection vital: sun exacerbates/initiates skin lesions; also important for cancer prevention (especially hypopigmented skin, chronic discoid lesions with higher skin cancer risk); essential in patients on immunosuppressive therapy; sun exposure can exacerbate systemic disease in SLE.
• Sunscreens: apply daily to exposed skin, more often with high sensitivity/intense exposure. Broad-spectrum, high-SPF preferred.
• Physical sunblock (titanium dioxide or zinc oxide) useful in some cases.
• Protective clothing often significantly more effective than sunscreens.
• Sun avoidance even more effective than protective chemicals/clothing.
• Midday sun particularly high in UVB.
• UVA harder to minimize — present throughout the day, penetrates some window glass.
• Education on sunscreen/clothing use and sun avoidance important for most patients.
• Careful attention to vitamin D and calcium intake.
• Cosmetic cover-up: most helpful intervention for some patients, particularly when disease activity subsided but dyspigmentation remains.
• Smoking cessation: larger-than-expected percentage of smokers among cutaneous lupus patients; smokers may have more extensive disease and be more treatment-refractory.

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• Systemic lupus erythematosus (SLE) — complex autoimmune disease with multiorgan involvement and immunological abnormalities.
• Greater prevalence and incidence in black, Asian and Hispanic population groups; young females disproportionately affected.
• Extracutaneous organ systems most commonly affected: joints, renal, haematological, pulmonary, central nervous system, cardiovascular.
• Skin is the SECOND most frequently affected organ in SLE — occurs in 80% of patients during the disease course.
• Skin involvement divided into specific and non-specific manifestations depending on the histological presence of interface dermatitis.
• Non-specific lupus skin disease: photosensitivity rash, non-scarring alopecia, bullous LE, neutrophilic dermatoses, vasculitis, vasculopathy.
• Specific cutaneous manifestations (all show interface dermatitis histologically): chronic, subacute and acute cutaneous LE (CLE).
• CLE can exist as an independent entity or be associated with SLE. Collectively CLE and SLE are forms of lupus erythematosus (LE).

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• Benign inflammatory disorder of the skin, most frequently involving the face and scalp, characterised by well-defined, red, scaly patches of variable size that heal with atrophy, scarring and pigmentary changes.
• May be more generalised, affecting areas away from face and scalp. Histology is characteristic.
• Haematological and serological changes in approximately half of patients — suggest an autoimmune aetiology.
• Forms one end of a spectrum of skin and internal organ disease, ending with SLE.

• Chronic cutaneous lupus erythematosus (CCLE)
• Chronic discoid lupus erythematosus

• DLE is one form of CLE; others are SCLE and ACLE (the latter seen in patients with systemic disease, usually severe internal organ disease).
• DLE is the MOST COMMON subtype of cutaneous lupus — 80% of all CLE cases.
• A fourth subtype — lupus tumidus — is described but its place in classification is unclear.
• Histological hallmark of cutaneous lupus is interface dermatitis with lymphocytic infiltration, but interface change is ABSENT in lupus tumidus.
• Same is true of Jessner lymphocytic infiltrate, thought by many to be a dermal variant of cutaneous lupus — can predate classic DLE, has similar genetic predispositions, responds to same treatments, may occur in patients already known to have DLE.
• Scarring nature of classic DLE means early diagnosis and active treatment are important to avoid irreversible long-term sequelae.

Incidence and prevalence

• Large Scandinavian study: annual incidence of cutaneous lupus 4/100 000, with 80% being DLE.
• American cohort prevalence approximately 70/100 000, with annual incidence similar to Scandinavian study.
• Overall prevalence of CLE without concurrent SLE is similar to the prevalence of SLE.

Age

• Peak age of onset fourth decade in females, slightly later in males; can occur at any age.
• In a large series: 3% of cases began earlier than 15 years, 2.5% after the age of 70 years.

Sex

• Affects twice as many females as males — a greater male predilection than in SLE.

Ethnicity

• More common in Asians, African Americans, Afro-Caribbeans and Hispanic Americans than Americans of European origin; more common in those of Asian origin in the UK.
• More severe in African Americans and Asians compared with white people.
• Black patients present with more dyspigmentation, scalp and ear involvement and scarring alopecia compared with non-black patients.

Associated diseases

• Porphyria (including porphyria cutanea tarda, variegate, acute intermittent and erythropoietic protoporphyria), pemphigus, myasthenia gravis and thymoma — all reported in association with DLE.

• Cutaneous inflammation in DLE: interferons (IFNs) — type I and type III — induce Th1-biased inflammation with predominantly lymphocytic infiltration.
• Inflammatory pattern mirrors the innate immune response to cutaneous viral infection, followed by epidermal damage, basement membrane thickening, and a scarring tissue response associated with loss of follicular stem cells.
• Predominant cell types: CD4 and CD8 T cells and natural IFN-producing plasmacytoid dendritic cells (PDCs); numbers of granzyme B-positive cells correlate with the extent of scarring.
• Compared with lichen planopilaris, DLE of the scalp shows a greater number of PDCs, and PDCs present in the dermis, perieccrine region and dermal–epidermal junction.
• IFN-α (mainly from PDCs) and IFN-γ (from keratinocytes) induce keratinocyte expression of pro-inflammatory chemokines and the apoptosis-inducing TRAIL molecule (tumour necrosis factor-related apoptosis-inducing ligand) and its receptors.
• Gene expression array of lesional DLE skin: relative enrichment of IFN-γ-associated genes and B-cell-associated genes compared with SCLE or ACLE.
• Regulatory T cells are reduced in number.
• Stimuli include ultraviolet (UV) radiation, acting through heat shock proteins, Toll-like receptors and other DAMP (danger-associated molecular pattern) molecules.
• Tissue resident memory T (Trm) cells — dysregulated subset persisting long term and through treatment; higher density in DLE and SCLE lesions than ACLE; may explain treatment failure, disease duration and progression.
• Trm survival mediated by IL-7 and IL-15 → downstream JAK/STAT signalling — potential future therapeutic target.

• Trauma (11%) — including X-rays and thermal burns
• Stress (12%)
• Ultraviolet exposure (5%) — including PUVA and laser light
• Infection (3%) — including herpes zoster and old smallpox vaccination
• Drugs — many drugs precipitate or exacerbate DLE: isoniazid, penicillamine, griseofulvin, dapsone
• Seasonal exacerbation — winter (10%) and summer (50%)
• Cold exposure (2%, but 17% of patients reported disease exacerbation due to cold)

• All clinical types of CLE show an essentially similar histological picture; subsets of CLE cannot easily be distinguished histologically.
• In more acute forms: less hyperkeratosis and dermal infiltration, but more dermal oedema, liquefaction necrosis and atrophy.
• In tumid lesions the dermal infiltrate can be very dense, sometimes almost granulomatous.
• Dermal mucin deposits occur — diffuse or localised, forming nodular lesions.
• Keratotic plugs usually found in hair follicle openings, but may also block sweat ducts or occur independently of either structure.

Histological features of cutaneous lupus erythematosus

• Lymphocytic interface dermatitis with basal layer degeneration
• Apoptotic keratinocytes
• Basement membrane thickening (greatest in DLE)
• Perivascular and periadnexal lymphohistiocytic infiltrate
• Follicular plugging
• Dermal mucinosis
• Epidermal atrophy

• Increasing reports of bacterial and viral organisms implicated in onset/exacerbation of lupus including cutaneous disease — none confirmed as yet.

• Family history found in 4% of cases; reported in identical twin sisters and in two or more family members.
• Striking relationship between polymorphic light eruption (PLE) and DLE — first in twins, then in a large cohort of patients and their relatives — suggesting a common genetic background.
• Positive HLA associations: HLA-B7, -B8, -Cw7, -DR2, -DR3, -DQw1 (not always confirmed).
• Relative risk increased with certain combinations: HLA-Cw7, -DR3 and -DQw1; and HLA-B7, -Cw7 and -DR3.
• Extended haplotype HLA01, B08, DRB1*0301 — associated with both SCLE and DLE.
• A03, B07, DRB1*15 haplotype — associated with DLE alone.
• Patients of either sex developing skin lesions between 15 and 39 years have increased incidence of HLA-B7; females over 40 years have increased HLA-B8.

• Usually presents with a rash; history of Raynaud phenomenon, chilblains or poor peripheral circulation often obtained.
• In 120 DLE patients (Chapel Allerton Hospital, Leeds): 14% Raynaud phenomenon, 22% chilblains, 26% poor peripheral circulation without a definite Raynaud story.
• Joint pains may occur. Most patients have no symptoms of systemic upset even with widespread cutaneous disease, although fatigue is not uncommon.

Presentation — Localised disease

• Most patients have disease limited to head and neck (localised DLE); a few have extensive disease affecting any skin area (disseminated DLE).
• Face and scalp most commonly affected. The circumscribed or discoid form is the most frequent type — cheeks, bridge of nose, ears, side of neck, scalp.
• Alopecia occurs in scalp lesions in approximately one-third of patients and is usually permanent. Eyebrows may be sparse with redness of eyebrow skin.
• Lesions: well-defined red or pink patches, a few millimetres to 10–15 cm.
• Adherent scale in many cases; undersurface shows horny plugs occupying dilated pilosebaceous canals = the ‘tin-tack’ sign (also seen in localised pemphigus foliaceus).
• Surface may show dirty, brownish yellow appearance, rough to touch because of follicular plugging.
• Hypertrophic/verrucous variant — hyperkeratosis overlying discoid lesions, chronicity, resistance to treatment; hyperkeratotic warty indurated plaques on face, scalp, extensor forearms, upper trunk, also palms and soles causing difficulty walking.
• Over some months, particularly if treated, lesions flatten and may clear completely without much scarring.
• If untreated: lesions expand with peripheral inflammation and hyperpigmentation, and central depressed atrophy, scarring, telangiectasia and hypopigmentation; more frequently a thin white scarred area remains.
• Localised cribriform scarring occurs, particularly on the face.
• Wide follicular pits mainly in the concha or triangular fossa of the ear — in up to one-third of cases.
• In approximately 7.5% of patients facial lesions resemble rosacea — differentiation difficult; low-titre ANA also occurs in rosacea (no clinical relevance); usually NO pustules as in true rosacea; biopsy may be required.
• Tumid lesions — tissues swollen, brawny, warm and tense; may be many centimetres, involving a whole cheek or even a whole limb.
• Annular atrophic plaques on face, neck and behind ears — centre depressed and sclerotic, resembling morphoea, lichen sclerosus or ‘annular atrophic plaques’.
• Dermoscopy of non-scalp DLE: follicular keratotic plugs, white perifollicular halo, white scale, speckled brown pigmentation, white structureless areas, arborising vessels.
• Nearly 60% of DLE patients have scalp involvement; one-third of these lead to scarring alopecia.
• Trichoscopy: follicular red dots, large yellow dots, absent follicular openings, thick arborising vessels, speckled brown or blue-grey dots and discoloration.

Scarring

• Common; may be atrophic, hypertrophic, cribriform or acneform.
• Pigmentary disturbances common, especially in dark-skinned people; patches of leukoderma interspersed with hyperpigmented areas — not all scarring, may be reversible post-inflammatory change.
• Once scarring has occurred, no further inflammation is seen — relapse usually starts in the reddish zone surrounding the scar.
• Calcification may occur in plaques. Ear lesions lead to considerable atrophy and scarring.

Disseminated DLE

• Characteristic DLE lesions widespread on trunk and limbs, or localised to other body sites.
• Occurs most often in women, who are usually cigarette smokers.
• May be indistinguishable from papulosquamous SCLE, but scarring occurs in most patients.
• Tends to be persistent, resistant to therapy, and associated with severe psychological upset.
• Lesions on dorsa of hands, palms or toes occurred in 6% of Chapel Allerton patients. Note white atrophic scars (atrophie blanche) proximal to the great toenail.
• Purplish plaques on the front of the knees and back of the heels.
• Non-itching, hyperkeratotic, papulonodular lesions on arms and hands resembling keratoacanthoma, hypertrophic lichen planus or nodular prurigo. Sometimes resembles psoriasis.
• Reticulate telangiectasia variant — arms, legs, back of calves, potentially widespread; probably similar to ‘lupus erythematosus telangiectoides’ (first described by Crocker).
• ‘Lupus erythematosus gyratus repens’ — migratory gyrate annular patch of red skin with histological features of LE, but lupus band test is NEGATIVE; there may be an underlying carcinoma.
• Rarely bullous lesions. Arteritic lesions resembling Degos syndrome or disseminated atrophie blanche occasionally occur; linear lesions following Blaschko lines reported.

• DLE subdivided into localised (lesions confined to face above the chin, scalp, ears) and disseminated (lesions also elsewhere).
• Haematological/serological abnormalities occur slightly more often in the disseminated form, but natural history of the two subgroups is similar — likely subsets of the same disorder.
• SCLE described as a subset intermediate between DLE and SLE.

Evidence that DLE and SLE are variants of the same disease

• Cutaneous lesions of SLE and DLE may be clinically and histologically indistinguishable.
• Certain clinical features found in both.
• Similar haematological, biochemical and immunohistochemical abnormalities in both, though incidence of abnormalities is lower in DLE.
• Patients with DLE occasionally develop overt SLE.
• Patients with SLE may develop typical DLE lesions in the chronic phase.
• Conditions such as lupus panniculitis occur in both DLE and SLE.

Observations requiring explanation (against)

1. Risk of a DLE patient developing overt SLE is small — 1.3% to about 6.5%. Higher in disseminated DLE (22%) than in DLE confined to head and neck (1.2%). Some series found no conversion despite ~30 years follow-up. A retrospective study: progression to SLE in 19% at 20 years, average time to progression 8.2 years from diagnosis of cutaneous disease.
2. Presence of laboratory abnormalities in DLE does not itself predispose to development of SLE, although they are common in disseminated DLE.
3. Immunoglobulins and complement are present in uninvolved skin of SLE patients and absent in DLE patients.
4. Most DLE patients exposed to UVR, stress, trauma etc. do NOT develop systemic disease.
5. Age and sex distribution of SLE is strikingly different from DLE.

• Proposal: genetic predisposition determines level of risk of developing one or both patterns.
• Genes associated with CLE: C1QA, CSNK2B, CTLA4, HLA-DRB3, HLA-DQA1, IL10, IRF5, ITGAM, IZKF, MICA, MICB, MSH5, RPP21, TRAF3IP2, TRIM39, TYK2.
• Conclusion: most patients with DLE and haematological/serological abnormalities are NOT cases of SLE in disguise — DLE is a separate entity from SLE with a different genetic background.

• Rash — DLE 100 / SLE 80
• Joint pains — 23 / 70
• Fever — 0 / 40
• Raynaud phenomenon — 14 / 35
• Chilblains — 22 / 22
• Poor peripheral circulation — 26 / 32
• ESR >20 mm/h — 20 / 85
• Serum globulin >3 g (%) — 29 / 76
• LE cells — 1.7 / 83
• Antinuclear factor(s) — 35 / 87
• Homogeneous — 24 / 74
• Speckled — 11 / 26
• Nucleolar — 0 / 5.4
• Precipitating autoantibodies — 4 / 42
• WR (Wassermann reaction) positive — 5 / 22
• Rheumatoid factor positive — 15 / 37
• Direct Coombs test positive — 2.5 / 15
• Leukopenia — 12.5 / 37
• Thrombocytopenia — 5 / 21

Chilblain lupus

• May occur in patients with either DLE or SLE. A subtype of chronic CLE.
• Painful or pruritic red to violaceous papules and plaques of hands and feet, primarily fingers and toes; nose and ears may be involved.
• Secondary sequelae: ulceration, fissuring, hyperkeratosis.
• Approximately 6% of cutaneous lupus patients, predominantly female, develop chilblain-like lesions; triggered by cold or damp; can be precipitated by pregnancy.
• Most patients have positive ANA, anti-Ro/SSA or anti-La/SSB. Some have cryofibrinogenaemia or cold agglutinins.
• Patients are either smokers or have markedly abnormal peripheral circulation with low resting blood flow.
• Occasionally fingers show curious atrophic spindling, sometimes with hyperextension of terminal phalanges and nail dystrophy; fingers/toes may become markedly atrophic with patchy redness and tuft resorption on X-ray.
• Fifteen per cent of patients develop SLE.
• Familial chilblain lupus — autosomal dominant, heterozygous mutations in TREX1, SAMHD1 and STING (protein stimulator of interferon) genes; manifests in early childhood. These genes encode intracellular nucleases; mutation → activation of antiviral type I interferons and autoimmunity.
• Management: maintain warm core and peripheral temperature, avoid damp. Topical: high-potency corticosteroids, tacrolimus, pimecrolimus. Systemic improvement with oral nifedipine, hydroxychloroquine, quinacrine, mycophenolate mofetil and JAK inhibitors.

Lupus erythematosus profundus (panniculitis)

• Cutaneous infiltrate primarily (but not always exclusively) in deeper portions of the corium; only microscopic epidermal changes.
• Firm, sharply defined nodules 1 to several cm beneath clinically normal skin, followed by atrophy of fat.
• Disproportionately affects middle-aged women (85%); chronic, recurring tender, red, indurated subcutaneous nodules or plaques on fatty areas.
• Lesions primarily on proximal extremities, face, back and scalp.
• Long-term sequelae: ulceration, atrophy, calcinosis, disfigurement.
• Coexistence with an overlying DLE is termed lupus profundus — occurs in more than one-third of patients.
• Clinical LE profundus occurred in 3–5% of DLE patients, but histological disease may be found in up to 30%.
• Kaposi first described subcutaneous nodules in LE in 1883; Irgang first used the term ‘lupus erythematosus profundus’ in 1940.
• Now usually accepted as a variant of LE, related more to DLE than to SLE. Approximately one-fifth of patients have concurrent SLE.
• Histology: lymphoplasmacytic lobular or mixed panniculitis with hyalinising fat necrosis and lymphoid follicles; chronic lesions may show dermal/subcutaneous calcium deposits.
• Treatment effective if started early during the active phase. Antimalarials are first line. Short course of systemic corticosteroids initially to reduce active inflammation. Intralesional steroids, dapsone, mycophenolate mofetil, ciclosporin, rituximab and IVIg reported with variable results.

Tumid lupus erythematosus (TLE)

• Rare subtype of chronic CLE. Few patients ANA-positive and weak association with SLE — some consider it a unique subtype of CLE or a separate disease from lupus altogether.
• Shares histological features with reticular erythematous mucinosis and Jessner lymphocytic infiltrate — some consider them on the same spectrum.
• Lesions: asymptomatic, annular or urticarial, red, oedematous papules and plaques with minimal or NO epidermal change; sun-exposed sites (face, neck, upper trunk); exacerbated by UV.
• Histology: well-demarcated intense periadnexal lymphocytic infiltrates, superficial and mid-dermal perivascular lymphocytic infiltrate, abundant interstitial dermal mucin deposition. May be focal/minimal vacuolar interface change, epidermal atrophy, papillary dermal oedema.
• Typically NO scarring, follicular plugging or dyspigmentation.
• Differential: DLE, SCLE, Jessner lymphocytic infiltrate, reticular erythematous mucinosis, PLE, pseudolymphoma, leukaemia/lymphoma cutis.
• Management: UV protection, antimalarials, high-potency topical steroids. Lesions resolve without scarring, atrophy or hypopigmentation.

• Annular atrophic plaque variety may resemble morphoea or lichen sclerosus.
• Jessner lymphocytic infiltration — confused with acute localised oedematous LE lesions; marked histological lymphocytic infiltration in the former; immunoglobulin deposition does NOT occur at the dermal–epidermal junction in Jessner. Some authors believe Jessner is a precursor of classic CLE.
• Benign lymphocytic infiltration of the skin may be a further form of CLE (photo testing).
• Reticular erythematous mucinosis syndrome (Ch 57) — clinical/histological features similar to DLE, also UVR-induced, but a discrete clinical entity.
• History and lesions elsewhere exclude contact eczema, seborrhoeic eczema and psoriasis.
• Lupus vulgaris — lesions occur at an early age, rarely symmetrical, may be ulcerated, show characteristic ‘apple-jelly’ nodules on diascopy.
• Necrobiosis lipoidica can give similar facial lesions.
• Rosaceous type of LE differentiated from true rosacea by absence of pustules and histology.
• Chronic DLE found in 12% of patients diagnosed with scarring alopecia of the pseudopelade type.
• Lesions on lips, tongue, scalp, buccal mucosa may be confused with lichen planus; overlap cases have lichenoid papules, verrucous lesions, anonychia, oral and vulval lesions resembling lichen planus. Patients with lichen planus do NOT have features of LE immunopathologically or by HLA typing. Verrucous lesions show immunofluorescent findings of LE.
• LE of legs/feet may resemble chilblains. Sarcoidosis plaques and eosinophilic granuloma resolved only histologically. Occasionally lesions resembling DLE caused by dermatophytes.
• Distinction from plaque-type PLE difficult — absence of antinuclear factor and of dermal–epidermal immunoglobulin deposits in PLE may help. PLE may coexist with or precede DLE by many years.
• Infants: sharply marginated reddish finely scaling plaques on cheeks and bridge of nose, sometimes sun-exacerbated; or transitory rash with telangiectases on face particularly around eyes — probably part of neonatal LE.
• LE-like facial rash with sun sensitivity occurs in Bloom syndrome (autosomal recessive).
• Congenital telangiectatic reddish skin in well-proportioned dwarfism with bird-like facies; skin changes in infancy, may be associated with ectodermal and mesodermal defects.

• CLASI — cutaneous lupus erythematosus disease area and severity index: quantifies disease activity and monitors treatment response; useful clinical and research tool.
• Activity score measures degree of redness, scale, mucous membrane lesions and non-scarring alopecia.

• Chronic and relapsing, with exacerbations in spring and summer; some patients have mild disease that settles spontaneously.
• Most disease produces scarring if untreated; disease continues episodically for many years.
• A minority burn out completely but may be left with significant, permanent damage.

• Skin biopsy to confirm diagnosis.
• ANA, extractable nuclear antigens (ENAs), anti-dsDNA antibodies, complement C3 and C4 — to assess for systemic disease.
• Routine haematology and biochemistry; urine testing for proteinuria.
• Assessment of visual acuity necessary in those needing systemic antimalarials.

• Complete medical survey at first attendance: establish DLE subtype, likely prognosis, baseline.
• Advise avoidance of overwork, mental stress and fatigue; enquire for symptoms of depression (often related to facial scarring). Scarred lesions may be camouflaged.
• Avoid excessive sun exposure and phototoxic medications; use appropriate UVA and UVB sun protection — sunscreen applied preferably every 2–3 h in bright sunlight.
• Vasodilators, particularly calcium-channel blockers such as nifedipine, helpful in Raynaud phenomenon and chilblain lesions.
• Annual assessments for SLE; regular assessments of disease severity and impact.

First line

• Topical therapy can frequently control and sometimes clear lesions without systemic treatment: 0.025% fluocinolone cream or 0.1% betamethasone 17-valerate cream alone can be effective without inducing epidermal atrophy.
• Few data supporting one topical corticosteroid over another, although more potent agents appear generally more effective; occlusion may help further.
• Intralesional corticosteroid injections helpful in resistant cases — even on lips, mouth and ears.
• Topical calcineurin inhibitors (tacrolimus) — useful alternative in localised disease.

Second line

• For severe, extensive or scarring disease, particularly scalp: oral prednisolone 0.5 mg/kg, rapidly tapered over 6 weeks — quickly effective, minimises scarring, allows slower-acting agents (antimalarials) to work.
• Long-term oral corticosteroids best avoided; if necessary give bone protection with vitamin D + calcium and bisphosphonates or related drugs.
• Methylprednisolone 500–1000 mg/day for 2 or 3 days IV pulse may help resistant lesions.
• First-line ongoing systemic treatment = oral antimalarials. Most start hydroxychloroquine 200 mg twice daily, reducing to 200 mg/day once a response is achieved.
• Chloroquine phosphate equally effective, usually 250 mg twice daily, but hydroxychloroquine used first because eye toxicity less likely provided dosage limit of 5 mg/kg real body weight is adhered to.
• Comparable safe daily dose for chloroquine unclear — probably around 4 mg/kg/day of chloroquine base.
• Cumulative toxicity rarely a problem with hydroxychloroquine prior to 10 years of therapy, although it can occur with chloroquine.
• Mepacrine useful and safe ophthalmologically, but often reserved for later use (yellow skin pigmentation). May be used alone or in combination of antimalarials — more effective than the equivalent amount of each drug individually.
• Monitoring: annual ophthalmological screening beginning no more than 5 years after treatment initiation.

Side effects of antimalarials

• Mild: nausea and vomiting; abdominal pain
• Severe: corneal deposits; retinopathy; pigmentation of the palate, nails and legs; bleaching of hair; exfoliative dermatitis; lichenoid rashes; myasthenia; extrapyramidal involuntary movements; neuropathy; psychiatric syndromes; myopathy

• Hydroxychloroquine — 200–400 mg; 60–75% / 20%; see Box 51.3
• Chloroquine — 200–400 mg; 60–75% / 20%; see Box 51.3
• Acitretin — 25–100 mg; 50–75% / 15–20%; dry skin, hair loss, liver or lipid abnormalities, bony ankylosis
• Auranofin — 3–9 mg; 50% / 15–20%; GI upset, haematological, renal or liver abnormality
• Dapsone — 50–150 mg; 25–50% / 10–20%; rash, haemolysis, dapsone syndrome
• Methotrexate — 5–30 mg; – / 25–50%; GI upset, hepatitis, hepatic fibrosis, pulmonary fibrosis
• Ciclosporin — 2.5–5 mg/kg; – / 30–50%; hypertension, renal function abnormalities
• Sulfasalazine — 1.5 g; – / 5–15%
• Isotretinoin — 20–80 mg; – / 15–20%
• Thalidomide — 50–150 mg; 80–90% / 40–50%; drowsiness, constipation, teratogenicity, polyneuropathy
• Clofazimine — 50–150 mg; 40–60% / 5–15%; orange-pink to brown skin discoloration
• Phenytoin — 200–300 mg; – / –
• Azathioprine — 75–200 mg; – / 20–30%; photosensitivity, skin cancer
• Cyclophosphamide — 50–200 mg; – / –
• Mycophenolate — 0.5–3 g; – / 40–50%; bone marrow suppression, hepatitis
• Mepacrine — 100–200 mg; 50–60%; hepatitis, yellow skin colour

Third line

• Not responding to topical corticosteroids, antimalarials, sunscreens: oral thalidomide, lenalidomide, methotrexate and mycophenolate are the most effective third-line agents.
• Thalidomide 100 mg/day as effective as higher doses. As initial therapy response rates 80–90%; as second-line treatment nearer 50%.
• Short courses preferable — risk of polyneuropathy and teratogenicity. Prescription tightly regulated with a pregnancy prevention programme — monthly drug amounts only, double contraception and monthly pregnancy tests for women of fertile potential.
• IVIg useful in resistant diffuse disease or panniculitis.
• Rarely IV pulses of cyclophosphamide 10 mg/kg at 3–4-weekly intervals, usually combined with IV methylprednisolone.
• Efalizumab withdrawn from the market — progressive multifocal leukoencephalopathy.
• Rituximab and belimumab helpful for skin involvement in SLE, but personal experience suggests discoid lesions do NOT respond well to B-cell antagonists.

Emerging therapies

• Belimumab — approved for SLE in 2011 in the USA; recombinant human IgG-λ monoclonal antibody inhibiting BAFF (B-cell-activating factor) → apoptosis of autoreactive B cells. A case series and small open-label study (total 12 patients with recalcitrant DLE) showed potential.
• Apremilast — phosphodiesterase 4 inhibitor; inhibits dendritic cell and leukocyte production of IFN-α and IFN-γ respectively. Open-label study of eight patients on 20 mg twice daily — four had marked reduction in DLE activity at day 85; scalp lesions completely regressed in two.
• Fumaric acid esters — immunomodulating, anti-inflammatory, antioxidative; open-label study showed improvement of longstanding therapy-refractory DLE.
• Pulsed dye laser (585–595 nm) — low to moderate evidence; improvement in symptoms, cosmetic outcomes and disease activity; caution — theoretical risk of DLE exacerbation.
• Q-switched Nd:YAG laser + intense pulsed light (IPL) — target dermal melanosomes and superficial telangiectasia respectively. Caution with IPL — can exacerbate disease and enhance dyspigmentation in darker skin types.
• Argon lasers — improve superficial vascular changes (redness, telangiectasia).
• Er:YAG laser — reported to treat scarring in inactive DLE without exacerbating disease.
• LE panniculitis with lipoatrophy: fat transfer and lipofilling are the mainstay aesthetic therapy; autologous cell-assisted lipotransfer with adipose-derived stem cells improves disfigurement, graft survival and reduces postoperative atrophy.
• Dermal fillers — hyaluronic acid, poly-L-lactic acid, polymethylmethacrylate, polyacrylamide — satisfactory correction of lipoatrophy. Common side effect: nodularity immediately post-injection (may improve over time or be mitigated by injection of normal saline).
• Anifrolumab (antibody to type I interferon receptor subunit 1), JAK inhibitors and a novel humanised IgG1 monoclonal antibody blocking blood dendritic cell antigen 2 — promising for targeted inhibition of type I interferon.
• Anifrolumab improved CLASI scores by 50% in 3 months in patients with SLE and CLE; case series show rapid, excellent response of previously drug-resistant DLE.

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• A specific ‘subset’ of cutaneous lupus first described by Sontheimer et al. in 1979.
• Patients exhibit mainly cutaneous disease and usually have a good prognosis.
• Antibodies to the Ro/SS-A antigen are closely associated with this subgroup.

• Very characteristic clinically and immunologically; usually photoaggravated; may be associated with a limited degree of systemic involvement.
• Approximately 15% fulfil the 2019 EULAR/ACR criteria for SLE at diagnosis — arthralgia/arthritis the most frequent feature.
• Fever, malaise and CNS involvement occur, but renal disease is mild and infrequent. Proteinuria, haematuria and casts may occur; only 1.1% develop lupus nephritis.

Incidence and prevalence

• Incidence of Ro/SS-A-positive SCLE in Stockholm: 0.7 per 100 000 persons per year; prevalence 6.2–14 per 100 000.
• European database study: SCLE made up 236 of 1002 registered CLE patients (23.5%).
• Nationwide cohorts in Sweden ~16% and Denmark ~20% of CLE patients diagnosed with SCLE.

Age

• Predominantly adults; increasing reports in children.

Sex

• Female predominance — 75–85% of diagnoses in females.

Associated diseases

• Sjögren syndrome, rheumatoid arthritis, vasculitis, Sweet syndrome, Crohn disease, lichen planus, psoriasis, hereditary angioedema, porphyria cutanea tarda, gluten-sensitive enteropathy, toxic epidermal necrolysis, inclusion body myositis, calcifying lupus panniculitis, Kikuchi–Fujimoto disease (necrotising lymphadenitis).
• Morphoea and dystrophic calcinosis cutis have sometimes followed the presentation of SCLE. Some develop lesions related to mucin deposition.

• Antibodies to Ro/SS-A are an almost universal finding.
• LeFeber et al. 1984 — sublethal doses of UVR induced synthesis and surface expression of Ro/SS-A antigen by cultured human keratinocytes.
• 1988 — Ro/SS-A antigen identified in both adult and neonatal epidermis in vivo.
• UVR increases Ro/SS-A antigen expression on keratinocyte surface; increased by oestrogen.
• Postulate: UVR exposure → increased synthesis and surface expression of Ro/SS-A on keratinocytes → binds antibodies → initiates disease.
• Photosensitivity and Ro/SS-A antibody titre correlate with Ro/SS-A expression in skin biopsies.
• Hypothesis limitations: does not explain why other Ro/SS-A antibody patients (e.g. Sjögren syndrome) are not photosensitive, and why Ro/SS-A titres rarely reflect disease activity clinically.

Pathogenesis of drug-induced SCLE

• Common; differs from other drug-induced skin diseases: onset often delayed after drug introduction (both first and subsequent exposures) — indicating lack of immune sensitisation; resolution slow after discontinuation.
• Commonest causes: antihypertensives (thiazides, calcium channel blockers) and terbinafine.
• Last decade: rise in proton pump inhibitors, statins, NSAIDs, immunomodulators and immune checkpoint inhibitors.
• Systematic review of therapeutic monoclonal antibody-associated SCLE: nearly half of cases induced by TNF-α inhibitors, with a stark rise in PD-1 checkpoint inhibitor-induced SCLE relative to global use.
• Mechanisms unclear — may involve photoinduction and direct epidermal cytotoxicity of reactive drug metabolites.

• Originally labelled ANA-negative lupus — probably due to test substrates lacking suitable antigens.
• Using human cell lines: homogeneous ANAs in approximately 60%; anti-Ro/SS-A antibodies in approximately 80% (higher in females).
• Next common: rheumatoid factor or anticyclic citrullinated peptide (39%) and anti-La/SSB (38%).
• Antihistone ~17% and anticardiolipin ~16%.
• Similar autoantibody prevalence in drug-induced SCLE.

• Antibiotics: doxycycline, minocycline, nitrofurantoin, amoxicillin clavulanate, ciprofloxacin, norfloxacin, rifampicin
• Anticoagulants: rivaroxaban, apixaban
• Anticonvulsants: carbamazepine, oxcarbazepine, phenytoin, lamotrigine
• Antifungals: terbinafine, griseofulvin
• Antihypertensives: thiazide diuretics, calcium-channel blockers, ACE inhibitors/ARB, beta-blockers, furosemide
• Chemotherapeutics: capecitabine, gemcitabine, carboplatin, cisplatin, docetaxel, paclitaxel, doxorubicin, systemic 5-fluorouracil, tyrosine kinase inhibitors
• Cholesterol-lowering agents: simvastatin, pravastatin, ezetimibe
• Monoclonal antibodies: TNF-α inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, PD-1/PD-L1 inhibitors, abatacept, natalizumab, denosumab
• NSAIDs: ibuprofen, diclofenac, naproxen, piroxicam, acetylsalicylic acid
• Proton pump inhibitors: lansoprazole, esomeprazole, omeprazole, pantoprazole

• Up to 65% of cases of SCLE may be drug-induced.
• Drug-induced SCLE compared with idiopathic: occurs in older patients (mean age 59 years), generally milder, but may involve the face and show bullous and erythema multiforme-like patterns; higher number of systemic symptoms such as arthralgias/arthritis and xerostomia.

• SCLE differentiated from DLE by more epidermal atrophy and less hyperkeratosis, basement-membrane thickening, follicular plugging and inflammatory infiltration.
• Colloid bodies and epidermal necrosis present in more than 50% of cases, especially with Ro/SS-A antibodies.
• Immunofluorescence: approximately 60% show granular IgG and/or complement deposition at the dermal–epidermal junction — more frequent in papulosquamous (88%) than annular (29%) lesions.
• Dust-like particles of inter- and intracellular IgG in basement layers of epidermis may be a specific feature.
• Pilosebaceous atrophy suggested as the only significant predictor of DLE versus SCLE.
• Excessive basement membrane deposition of laminin and collagen VII is seen in DLE but NOT SCLE.
• Significant numbers of cells expressing chemokine receptors CCR4 and CXCR3, ligands CXCL9, CXCL10, CXCL11; cytotoxic T cells in basal epidermis where keratinocytes show apoptotic death; strongly positive staining for TNF-α and IFN-κ.
• High serum levels of TNF-α, IFN-γ, IL-12 and IL-18.
• Drug-induced SCLE distinguished histopathologically: presence of leukocytoclastic vasculitis, reduced dermal mucin, and absence of DIF positivity for granular IgM and C3 at the basement membrane zone.

• Most common haplotype: HLA-DR3 and -B8; -DR3 most associated with the annular phenotype and Ro/SS-A antibody expression.
• More recent study: association with HLA-A1, -B8, -DR3, -DQ2, -DRw2 and C4 null haplotype.
• HLA-DR2 associated with older age of onset and papulosquamous lesions.
• Complement genes in HLA region — deficiencies in C2, C3 and C4 reported.
• SNP leading to decreased C1q antigen levels — the only genetic association outside the HLA region.
• Association with the TNF-α 308A polymorphism — may be pathogenic or a marker for the HLA-A1, B8, DRB1*0301 haplotype.

• UV exposure; also PUVA treatment of psoriasis, radiotherapy and IFN-β-1α therapy.

History

• History of previous sun-induced skin problems, often classic polymorphic light eruption.
• Raynaud phenomenon may precede the rash; mild arthralgia may occur; frank arthritis unusual before onset of rash.

Presentation

• Presents either as a non-scarring papulosquamous eruption (two-thirds) or annular polycyclic lesions (one-third).
• Lesions usually above the waist — neck, trunk, outer aspects of arms; reported along the lines of Blaschko.
• Borders may show vesiculation and crusting, occasionally bullae — may be associated with coexistent porphyria cutanea tarda.
• Follicular plugging and hyperkeratosis are NOT prominent; lesions resolve leaving grey-white hypopigmentation and telangiectases; pigmentary changes usually resolve completely.
• Diffuse non-scarring alopecia and photosensitivity in approximately half of patients.
• Other features: mouth ulceration (especially of the palate), reticular livedo, periungual telangiectasia.
• Reported presentations: pityriasiform lesions, erythroderma, poikilodermatous lesions.
• Dermoscopy: patchy distributions of scarce white-yellow scales, pink and white structureless areas, and a mixed vascular pattern (dotted, linear branching, linear curved vessels) — the mixed pattern helps differentiate SCLE from nummular dermatitis and psoriasis, which show dotted vessels exclusively.

Clinical variants

• Chilblain pattern and vasculitis (particularly with concomitant Sjögren syndrome).
• Annular lesions may resemble Rowell syndrome or the gyrate erythema secondary to occult malignancy.

• Dermatomyositis
• Lupus erythematosus, acute or discoid
• Erythema annulare centrifugum
• Erythema gyratum repens
• Erythema multiforme
• Granuloma annulare
• Lichen planus
• Psoriasis
• Tinea corporis

• Urticarial vasculitis, chronic interstitial pneumonitis, hypokalaemic tetraparesis reported.
• Occasional cancer associations: breast carcinoma, meningioma, colon cancer, gastric adenocarcinoma, pancreatic adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, non-Hodgkin lymphoma, Hodgkin disease, lung cancer, prostate cancer, melanoma, squamous carcinoma of the head and neck.
• Occasional patients develop overt SLE with severe internal organ disease.

• Variable exacerbating and remitting course, possibly related to sun exposure.
• Over a 3-year period, 17–25% of SCLE patients developed SLE.
• Worsening CLASI scores over time may be a risk factor for progression to SLE.
• Median time to SLE diagnosis was 1.65 years.

• Screen for internal organ involvement. Initial evaluation: thorough history and physical examination including EULAR/ACR clinical criteria.
• Initial bloods: complete blood count with differential, liver enzymes, creatinine and blood urea nitrogen, urinalysis, ANA, ENA, dsDNA, complement levels, ESR or CRP.
• Active disease → follow monthly; stable disease → biannual.

• Based on extrapolation from DLE treatment studies and case reports. Avoid UV exposure, particularly in spring in northern latitudes — patients flare rapidly with the first significant UV exposure of the year.

First line

• Sunscreens; moderate- to high-potency topical or intralesional corticosteroids; topical macrolides — pimecrolimus and tacrolimus.

Second line

• Antimalarials — hydroxychloroquine or chloroquine (sulphate or phosphate); hydroxychloroquine safer ophthalmologically and requires less monitoring.
• Long-term use of more than 7 years or a large cumulative dose may still be problematic.
• Hydroxychloroquine ≤5 mg/kg of real body weight per day. Dose adjustment/discontinuation in significant renal disease, retinal or macular disease, or concurrent tamoxifen use.
• Mepacrine (quinacrine) — no ocular side effects but yellow skin discoloration.
• Combination of hydroxychloroquine or chloroquine with mepacrine may be more effective than either alone; less effective in smokers.

Third line (in order of benefit–risk and evidence)

• Oral corticosteroids or methylprednisolone → acitretin → isotretinoin → dapsone → oral and subcutaneous methotrexate → azathioprine → mycophenolate mofetil → cereblon inhibitors thalidomide or lenalidomide → IVIg → rituximab → JAK inhibitors.
• Phototherapy with UVA has also paradoxically been reported to be useful.

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• A well-recognised subtype of LE — an acquired syndrome caused by the transplacental passage of maternal antibodies to SSA or SSB, or both.
• Most frequent clinical manifestations: cutaneous lesions and congenital heart block (CHB).

• Congenital heart block first reported in 1928 in the children of a mother with Sjögren syndrome.
• McCuiston and Schoch were the first to suggest NLE may be related to transplacental transfer of ‘a transmittable aetiological agent’ — reinforced by the fact that NLE skin lesions resolve as maternal antibodies are cleared from the infant’s serum.

Incidence and prevalence

• CHB occurs in 1–2% of children born to Ro antibody-positive mothers.
• Neonatal lupus rash occurs in 8–10% of offspring of these mothers.
• Risk of CHB in a subsequent pregnancy is 10-fold (20%) if a previous child had NLE.

Age

• Neonates may present up to the age of 12–16 weeks postpartum.

Sex

• Affects the sexes equally.

Associated diseases

• Occurs in offspring of women with positive Ro/SSA antibodies and occasionally La/SSB antibodies, transmitted across the placenta.
• Less frequently anti-U1-RNP antibodies cause classic NLE lesions but NOT CHB.
• These autoantibodies are present in 90% of Sjögren syndrome, 20–30% of SLE, 3% of rheumatoid arthritis, and in SCLE, mixed connective tissue disease or undifferentiated autoimmune syndrome.
• In 25–60% of cases mothers may not have clinical evidence of autoimmune disease; half of these asymptomatic mothers will develop an autoimmune disease after 3 years.
• Up to 1.5% of healthy pregnant women may have the antibodies.
• Hypothyroidism — women with both hypothyroidism and anti-Ro/SSA were nine times more likely to give birth to children with CHB than women with only anti-Ro/SSA.

• Ro/SSA antibody present in 82–100% of infants and 92–100% of mothers.
• The 52 kDa protein version is more frequently found in CHB; the 60 kDa more frequently associated with cutaneous disease (though disputed).
• The aa200-239 (p200) locus on the 52 kDa Ro/SS-A protein may be a more specific predictor of CHB (not confirmed).
• La/SS-B antibodies less frequent — 50% of NLE infants and 60% of mothers, usually with Ro/SS-A antibodies. 50 kDa La/SS-B antibodies associated with cutaneous disease; anti-idiotype antibodies to La/SS-B may be protective.
• U1-RNP antibodies detected as the only antibody in a limited number of patients with cutaneous NLE, but not with CHB.
• Lee et al. showed purified Ro antibody bound to human skin grafted onto nude mice in a pattern similar to typical LE lesions; Ro/SS-A antigen is also present in neonatal skin.

Two hypotheses for conduction abnormalities

1. Fetal autoantigens Ro/SSA and La/SSB translocate to the surface of cardiomyocytes during apoptosis → complexes with maternal antibodies → opsonised and phagocytosed by macrophages → release of pro-inflammatory cytokines (TNF-α and TGF-β) → atrioventricular node dysfunction and conduction abnormalities.
2. Molecular mimicry — autoantibodies cross-react with cardiac L-type calcium channels, disrupt calcium homeostasis and potential propagation → arrhythmias.

• Other proposed indirect mechanisms: (i) 52 kDa Ro/SS-A antigen homology with the 5-hydroxytryptamine-4 serotoninergic receptor; (ii) antibodies to a completely separate 57 kDa protein; (iii) the TNF-α 308A allele (high TNF-α production), HLA-DRQB102, HLA-DRB103 and TGF-β polymorphisms; (iv) maternal microchimerism.
• Cytokine profile: two siblings with NLE both had elevated IL-6, IL-8, IFN-γ and monocyte chemoattractant protein 1, but IL-12, IL-13 and IL-17 were elevated only in the newborn with skin lesions.

• Following antibody binding: sequence of opsonisation, apoptosis and fibrosis proposed in both skin and cardiac conducting system.
• Skin histopathology is that of classic lupus histology.

• Maternal anti-Ro/SSA antibodies are major risk factors, but only 12–20% of subsequent pregnancies lead to CHB despite persisting maternal autoantibodies.
• Mothers with HLA-DR3 and HLA-B8 haplotypes, when associated with DQA1 and DQB1, may have offspring more likely to have NLE and atrioventricular heart blocks.
• Infants with cutaneous disease may carry all three alleles — DRB103, DQB102 and TNF-α-308A promoter polymorphism — twice as frequently as unaffected children.
• Swedish Congenital Heart Block study: fetal HLA-DRB104 and HLA-Cw05 confer susceptibility to CHB in response to Ro/SSA exposure; DRB113 and Cw06 confer protection.
• Case series identified HLA-B15, HLA-C02, HLA-DQ5 and HLA-DR10 in a mother and both her children with NLE.

• UV exposure of the neonate may be relevant — UV may increase antigen expression on keratinocyte surfaces → increased interaction with autoantibodies → exacerbation of skin lesions.
• However, NLE skin lesions may be present at birth or involve UV-protected sites — UV exposure may not be necessary for cutaneous disease.

Cutaneous features

• Approximately half of NLE infants manifest skin lesions — may be present at birth or occur in the first few weeks of life.
• Most common finding: red, slightly scaly eruption on the face and periorbital skin — the ‘raccoon sign’ / ‘owl eye’ / ‘eye mask’; then scalp, trunk, extremities, neck and intertriginous areas in decreasing order of frequency.
• Resemblance to SCLE on pathology.
• Eruption exacerbated by UV; reports of the rash being precipitated by phototherapy for neonatal jaundice — although the rash is sometimes present at birth.
• Other manifestations: vitiligo-like eruption in a black infant, morphoea-like lesions, atypical targetoid-like lesions, cutis marmorata telangiectatica congenita-like lesions, transient bullae and papules on the feet.

Cardiac features

• NLE typically associated with a structurally normal heart.
• CHB occurs in approximately 60% of white infants with NLE; may be less common in Japanese patients.
• Moderate to high levels of maternal anti-Ro/SSA antibody titres appear to be a risk factor for CHB.
• Associated features: pericardial effusions, pleural effusions, ascites, intrauterine growth retardation and hydrops fetalis.
• Up to 50% of infants with CHB require pacing in the neonatal period; others require a pacemaker later.
• Dilated cardiomyopathy occurred in up to 23% with CHB in one Finnish cohort — significant mortality in the first year of life.
• CHB usually develops between the 18th and 24th gestational weeks. Fetal bradycardia with a ventricular rate of 40–60 beats per minute can be detected prenatally.
• CHB usually complete or third-degree, but first- and second-degree blocks may occur and resolve completely during the first few months after birth, or develop into irreversible CHB.
• Less frequently: Wolff–Parkinson–White syndrome, sinoatrial node dysfunction, prolongation of the QT interval, transient sinus bradycardia.
• Dilated cardiomyopathy usually detected in utero but may develop after birth.
• Structural cardiac abnormalities rare but reported: patent foramen ovale, ventricular or atrial septal defect, pulmonary stenosis, persistent patent ductus arteriosus, fusion of the chordae tendinae.

Haematological features

• Approximately 10–20% develop haematological symptoms: anaemia (less frequently haemolytic or aplastic), thrombocytopenia and neutropenia.
• Cytopenias develop from immunological suppression of the fetal bone marrow by maternal autoantibodies and, to a lesser extent, peripheral destruction of blood components.
• Other reported: thrombosis and disseminated intravascular coagulation, microangiopathic haemolytic anaemia, immune thrombocytopenia.

Hepatic features

• Most common hepato-biliary manifestations affect 10–25% of NLE infants: asymptomatic elevation of aminotransferases, γ-glutamyl transferase, hepatomegaly and splenomegaly.
• Cholestasis and cholestatic hepatitis described; hepato-biliary disease found in 19 of 219 patients with NLE — in three this was the only finding.
• Hepato-biliary and haematological manifestations can be isolated or accompany cutaneous/cardiac abnormalities.

Neurological features

• CNS abnormalities uncommon; symptomatic neurological expression even rarer.
• Macrocephaly ± hydrocephalus higher in infants with NLE than the general population, although most cases are asymptomatic.
• Other structural abnormalities: subependymal pseudocysts, subependymal haemorrhage, cerebral haemorrhage, ventriculomegaly, lenticulostriate vasculopathy, vasculitis, calcification of the basal ganglia.
• Symptomatic CNS manifestations are more commonly associated with cutaneous disease than with CHB: myelopathy, changes in consciousness, focal seizure, spastic paraparesis, neuropsychiatric disorders.

• Easily recognised in neonates of at-risk mothers.
• With no known risk, skin rash may be confused with congenital infections or inherited immune disorders such as Bloom, Cockayne or Rothmund–Thomson syndromes.
• By morphology: annular erythema of childhood, annular urticaria, tinea faciei/capitis/corporis, seborrhoeic dermatitis, atopic dermatitis, Langerhans cell histiocytosis, congenital rubella, congenital syphilis.

• Case reports associating NLE with pneumonitis, haemochromatosis, aseptic meningitis, transient myasthenia gravis and chondrodysplasia punctata.

• Rash improves over the first few months and has usually resolved without scarring by 12 months of age.
• Occasional patients exhibit residual telangiectasiae, dyspigmentation, atrophy or atrophic scarring.
• Heart block (in roughly 2% of children born to anti-Ro-positive mothers) is PERMANENT and requires a permanent pacemaker in roughly 50%.
• Infant: less than 5% go on to develop autoimmune diseases (juvenile idiopathic arthritis, psoriasis, Hashimoto thyroiditis, nephritic syndrome, iritis, type 1 diabetes) — follow-up advised.
• Mother: many develop signs and symptoms of autoimmune disease, especially Sjögren syndrome, SLE and undifferentiated connective tissue disease — follow-up advised.

• Skin biopsy usually required to confirm the diagnosis; exclusion of infection or rare inherited syndromes may be necessary.
• Antibody testing required in BOTH the child and mother.
• Complete blood count with differential and liver enzymes — especially with signs of anaemia and/or hepatic dysfunction.
• Electrocardiogram and echocardiogram recommended after birth.
• Mothers with known anti-Ro/SSA and/or anti-La/SSB antibodies should have fetal echocardiography screening initiated during pregnancy.

Cutaneous lesions

• Skin disease often mild and usually requires no treatment.
• Sun avoidance; low-potency topical steroids may be of benefit; antimalarials may be necessary for persistent skin disease.
• Persistent telangiectasia reported to respond to tunable dye laser.

Cardiac problems

• Mortality rate in neonates with CHB is approximately 20%.
• Higher risk of mortality with: diagnosis of CHB at <20 weeks’ gestational age, hydrops fetalis, low ventricular rate (<50 beats per minute), impaired left ventricular function, cardiomegaly, endocardial fibroelastosis, atrioventricular valve regurgitation, low aortic flow velocity.
• Up to 50% require pacing in the newborn period.
• Despite initial reports, recent large cohort studies do NOT support the use of fluorinated steroids for prevention of cardiac abnormalities.
• Maternal hydroxychloroquine decreases the risk of developing primary CHB, recurrent CHB (prior sibling with CHB) and skin disease; safe in pregnant or breastfeeding mothers with SLE. Proposed: hydroxychloroquine 400 mg daily taken between the 6th and 10th gestational weeks.
• IVIg for both prevention and treatment of CHB remains of unproven value.
• Plasmapheresis three times weekly with systemic steroids during gestation may have helped protect an at-risk pregnancy.

Haematological and hepatic problems

• Most resolve spontaneously; symptomatic anaemia and thrombocytopenia may require blood and platelet transfusion.

Pregnancy

• Counsel the Ro/SS-A or La/SS-B antibody-positive mother and her obstetrician.
• Risk of NLE in a Ro/SS-A-positive mother without connective tissue disease or previous NLE is probably low — about 2%.
• For women who have already had a baby with NLE, estimated risk of another affected child is probably about 25%.
• Prenatal screening for anti-Ro/SSA and anti-La/SSB in individuals more likely to have these antibodies based on pre-existing connective tissue disease.
• Monitoring of fetal cardiac function is standard practice — safe, non-invasive assessment of heart structure, extranodal disease and conduction abnormalities.
• Treatment of FIRST-degree heart block with fluorinated steroids is controversial — medication side effects, spontaneous reversion to normal sinus rhythm without treatment, and lack of evidence that untreated first-degree block progresses.
• Fluorinated steroids may be beneficial for SECOND-degree heart blocks identified in utero — may decrease inflammation and/or prevent progression to CHB, which is not reversible.
• Weekly screening with pulsed-Doppler fetal echocardiography from a 16-week gestational age, frequency decreased after 26 weeks in the absence of abnormalities — less than 20% of CHB cases are detected later in pregnancy.
• Observation is reasonable during the first month of life — 2% of reported cases of CHB are diagnosed postnatally.
• Ro/SS-A and La/SS-B antibodies in human breast milk had NO pathological consequences.

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• Lupus Erythematosus (LE): Heterogeneous autoimmune disorders linked by autoimmunity to self-nucleic acids and associated ribonucleoproteins/nucleosomes
• Clinical spectrum ranges from skin-only disease (e.g., discoid LE) to life-threatening multiorgan systemic LE (SLE)
• Epidemiology: Marked female predominance (9:1 female-to-male ratio overall)
• Key pathogenic driver: Upregulation of Class I Interferon-α (IFN-α) signaling

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Characterized histopathologically by interface dermatitis (vacuolar degeneration of basal layer):

• Acute Cutaneous LE (ACLE):
• Localized ACLE: Malar rash ("butterfly rash")
• Generalized ACLE: Maculopapular / exanthematous lupus rash, photosensitive dermatitis, TEN-like LE
• Subacute Cutaneous LE (SCLE):
• Annular / polycyclic SCLE
• Papulosquamous / psoriasiform SCLE
• Chronic Cutaneous LE (CCLE):
• Classic Discoid LE (DLE) — Localized (above neck) vs Generalized (above and below neck)
• Hypertrophic / verrucous DLE
• Lupus profundus / Lupus panniculitis
• Mucosal DLE (Oral, Conjunctival, Nasal, Genital)
• Lupus tumidus (LET / urticarial plaque of LE)
• Chilblain LE (chilblain lupus)
• Lichenoid DLE (LE / lichen planus overlap)

Lesions lacking characteristic LE interface histopathology; often reflect active systemic inflammation or vasculopathy:

• Vascular lesions: Leukocytoclastic vasculitis (palpable purpura, urticarial vasculitis), Livedo reticularis, Periungual telangiectasias, Raynaud phenomenon, Degos-like vasculopathy, Erythromelalgia
• Nonscarring alopecia: "Lupus hair" (frayed frontotemporal hair), telogen effluvium, alopecia areata
• Other: Papulonodular mucinosis, Calcinosis cutis, Bullous LE (anti-type VII collagen), Urticaria, Rheumatoid nodules, Sclerodactyly, Leg ulcers

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• Strongest association with active, systemic, flaring SLE (>90% have underlying SLE)
• Localized ACLE: Symmetric confluent erythema and edema over malar eminences and nasal bridge (butterfly rash); spares nasolabial folds
• Generalized ACLE: Morbilliform/exanthematous maculopapular eruption on sun-exposed skin (V-neck, arms, dorsum of hands); spares knuckles (contrast: dermatomyositis involves knuckles [Gottron papules])
• TEN-like ACLE: Severe vesiculobullous form with full-thickness epidermal necrosis due to widespread keratinocyte apoptosis
• Nonscarring (unless secondarily infected); leaves postinflammatory hyperpigmentation

• Highly photosensitive, nonscarring, symmetric eruption in sun-exposed areas (shoulder, upper back, V-neck, extensor arms)
• Serology: Strongly associated with Anti-Ro/SS-A antibodies (70%–90%) and HLA-DR3
• Two morphological variants:
• Annular / Polycyclic: Ring-like erythematous plaques with central clearing/hypopigmentation
• Papulosquamous / Psoriasiform: Red scaly papules and plaques resembling psoriasis
• Heals without scarring, but leaves long-lasting vitiligo-like leukoderma and telangiectasia
• Systemic involvement: ~50% meet ACR criteria for SLE, but severe systemic manifestations (nephritis, CNS) occur in only 10%–15%
• Drug-Induced SCLE: Triggered by drugs (Thiazides, Calcium channel blockers, ACE inhibitors, Terbinafine, PPIs, Anti-TNF agents, Griseofulvin, NSAIDs)

1. Classic Discoid LE (DLE)

• Most common form of CCLE; female-to-male ratio 3:1 (lower than SLE 9:1)
• Coin-shaped, sharply demarcated erythematous plaques with adherent carpet-tack scale, follicular plugging, central atrophic scarring, and peripheral hyperpigmentation
• Localized DLE (head/neck only) vs Generalized DLE (above and below neck; higher risk for SLE)
• Scalp involvement (60%) → irreversible scarring alopecia (cicatricial)
• Risk of progression to SLE: ~5% for localized DLE; higher for generalized DLE

2. Hypertrophic / Verrucous DLE

• Marked verrucous hyperkeratosis overlying DLE plaques on extensor arms, face, and back; mimics SCC or keratoacanthoma

3. Mucosal DLE

• Affects ~25% of DLE patients; oral mucosa (buccal, palate) most common; painful central ulceration with white radiating striae; malignant degeneration into SCC can occur rarely

4. Lupus Profundus / Lupus Panniculitis (Kaposi-Irgang Disease)

• Inflammatory indurated subcutaneous nodules (1–3 cm) under deep dermis/fat
• Overlying skin drawn inward → saucerized deep depressions; common on face, arms, breasts (lupus mastitis), buttocks
• Overlying DLE present in ~70%; dystrophic calcification common

5. Chilblain LE (Chilblain Lupus)

• Cold-precipitated purplish-red papules/plaques on toes, fingers, nose, ears; associated with anti-Ro/SS-A and Raynaud phenomenon; familial form caused by TREX1 gene mutation

6. Lupus Erythematosus Tumidus (LET)

• Urticaria-like, succulent, edematous erythematous plaques with NO epidermal change (no scale, no scarring, no atrophy)
• Extremely photosensitive; negative ANA in most; excellent response to antimalarials; resolves without scarring

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• Interface Dermatitis: Vacuolar degeneration of basal keratinocytes + necrotic (apoptotic) keratinocytes (cytoid / Civatte bodies)
• Epidermal atrophy with alternating hyperkeratosis and follicular keratotic plugging
• Thickening of basement membrane zone (PAS-positive)
• Dermal mucin deposition (abundant in superficial and reticular dermis)
• Perivascular and periappendageal dense lymphocytic infiltrate (CD4+ T cells, macrophages)

• Lesional LBT: Granular band of immunoglobulins (IgG, IgM, IgA) and complement (C3, C1q) at dermal-epidermal junction in lesional skin
• Positive in >90% of DLE, 60% of SCLE, 60–100% of ACLE
• Nonlesional LBT: Positive band in sun-protected normal skin (e.g., buttock) strongly correlates with active SLE and high risk for lupus nephritis

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• ACLE (Malar): Acne rosacea, seborrheic dermatitis, dermatomyositis (involves nasolabial folds), polymorphic light eruption (PMLE), photoallergic contact dermatitis
• SCLE (Annular/Psoriasiform): Psoriasis, erythema annulare centrifugum (EAC), tinea corporis, granuloma annulare, subacute lichenoid drug eruption
• DLE (Discoid): Actinic keratosis, Squamous cell carcinoma (SCC), sarcoidosis, lichen planus, hypertrophic lichen planus, polymorphous light eruption

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• Strict avoidance of direct sun exposure; broad-spectrum sunscreen (SPF ≥30 with UVA blockers avobenzone/zinc oxide/titanium dioxide)
• Window tinting films; avoidance of photosensitizing medications (thiazides, tetracyclines)
• Smoking Cessation: Crucial — smoking interferes with antimalarial efficacy and worsens CLE

• Topical Corticosteroids: Class I superpotent steroids (clobetasol propionate 0.05%) applied bid for 2 weeks on / 2 weeks off to avoid atrophy
• Topical Calcineurin Inhibitors: Tacrolimus 0.1% ointment or Pimecrolimus 1% cream (ideal during steroid-rest periods or for facial lesions)
• Intralesional Corticosteroids: Triamcinolone acetonide 2.5–5 mg/mL injected into hyperkeratotic DLE margins

• Hydroxychloroquine (Plaquenil): Mainstay systemic therapy
• Dose: ≤6.5 mg/kg/day based on ideal body weight
• Onset: Requires 8–12 weeks for full therapeutic benefit
• Ocular safety: Annual baseline and periodic ophthalmologic screening for retinal toxicity (rare in first 10 years)
• Quinacrine: 100 mg/day added to hydroxychloroquine for synergistic effect in refractory cases (does NOT cause retinopathy; causes yellow skin discoloration)
• Chloroquine: 3.0–3.5 mg/kg/day (alternative if hydroxychloroquine fails; slightly higher retinal toxicity risk)

• Thalidomide: 50–200 mg/day; highly effective (85%–100% response in refractory CLE); strictly regulated due to teratogenicity and risk of peripheral sensory neuropathy (25%–75%)
• Systemic Immunosuppressives: Methotrexate (7.5–25 mg/week), Mycophenolate Mofetil (2–3 g/day), Azathioprine (1.5–2.5 mg/kg/day)
• Other Agents: Dapsone (50–200 mg/day; especially for bullous LE or vasculitic CLE), Acitretin, Belimumab (anti-BAFF mAb), Rituximab

• Drug-induced SLE (DIL): rarely has skin lesions; occurs in older patients; men = women. Mild symptoms: fever, myalgias/arthralgias, serositis.
• Positive ANA (homogeneous pattern) and antihistone antibodies, but NEGATIVE anti-dsDNA and normal complement.
• Culprits: procainamide, hydralazine, quinidine, captopril, isoniazid, minocycline, carbamazepine, propylthiouracil, sulfasalazine, statins. Hydralazine can induce lupus AND vasculitis (occasional overlap).
• TNF inhibitors (esp. etanercept): SLE-like syndrome WITH prominent skin lesions; ANA+ AND anti-dsDNA+; >half hypocomplementemic.
• Methimazole implicated in bullous SLE. Flares/new lupus rarely after COVID-19 infection and SARS-CoV-2 vaccination. Checkpoint inhibitor-induced lupus discussed above.
• Drug-induced SCLE: ~20% of all SCLE cases believed drug-induced. Occurs in older patients, more systemic symptoms than idiopathic; concomitant LCV in some.
• Onset days to many years after starting.
• Traditionally most common: hydrochlorothiazide, diltiazem (and other CCBs), terbinafine — but proton pump inhibitors (widely available OTC) and TNF inhibitors (and growing biologic list) rapidly rising to top.
• Others: ACE inhibitors, statins, anticonvulsants, NSAIDs, paclitaxel, doxycycline; even lupus-treating agents (hydroxychloroquine, leflunomide) can induce it.
• ANA+ AND anti-SSA+; antihistone antibodies less common than DIL.
• Lesions: annular polycyclic in V of upper back, or psoriasiform papulosquamous thin plaques, may be photodistributed. Treatment: sun avoidance, topical/systemic corticosteroids; withdrawal → resolution over weeks-months; positive serologies may decrease.
• HLA-B8 or DR3 haplotype more likely.
• Dermatomyositis: less commonly drug-associated; reported with penicillamine, TNF inhibitors, checkpoint inhibitors, other targeted oncologic agents. Hydroxyurea can mimic dermatomyositis clinically. Herbal supplement spirulina recently associated with new onset/flares.

• May manifest as systemic disease or purely cutaneous forms.
• Cutaneous manifestations classified as acute, subacute, and chronic.
• Study of 191 patients: 68% one type, 29% two types, 3% three types.
• Progression cutaneous → systemic: ~5% at 5 years, 10% at 10 years, 15% at 15 years.

I. CHRONIC CUTANEOUS LE

• A. Discoid LE: 1. Localized 2. Disseminated
• B. Verrucous (hypertrophic) LE — usually acral, often lichenoid
• C. LE–lichen planus overlap
• D. Chilblain LE
• E. Tumid lupus
• F. Lupus panniculitis (LE profundus): 1. No other involvement 2. With overlying discoid LE 3. With systemic LE

II. SUBACUTE CUTANEOUS LE

• A. Papulosquamous B. Annular
• C. Syndromes with similar morphology: 1. Neonatal LE 2. Complement deficiency syndromes 3. Drug induced

III. ACUTE CUTANEOUS LE: localized or generalized erythema or bullae, generally associated with SLE.

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• Young adults; women:men 2:1. Dull-red macules/indurated plaques with adherent scale → atrophy, scarring, pigment changes.
• Darker-skinned: both hyperpigmentation AND depigmentation. Lighter-skinned: gray or minimal pigment change.
• Hyperkeratosis extends into patulous follicles → "carpet tack" spines on undersurface of scale.

Localized DLE

• Usually above the neck, sun-exposed sites: scalp, nose bridge, malar areas, lower lip, ears (concha/external canal frequently involved). Disk-shaped erythema with follicular plugging → atrophy, scarring, pigment change.
• Periorbital edema/erythema in some. Scalp: erythematous patches/plaques → white, often depressed, hairless patches. Perifollicular erythema and easily extractable anagen hairs = active disease signs.
• Lips: gray or red, hyperkeratotic, may erode, surrounded by narrow red inflammatory zone.
• 24% of DLE patients had mucosal involvement (mouth, nose, eye, vulva). Rarely aggressive SCC arises in long-standing DLE.
• CLE patients may develop systemic disease with delay (8-10 years); progression from pure DLE to SLE INFREQUENT, but SLE patients frequently have discoid lesions (these patients generally have systemic involvement early, not evolving from CLE). Fever/arthralgia common when discoid + SLE.

Generalized DLE

• Less common than localized. Thorax/upper extremities plus head/neck typically. Scalp can become quite bald with hyper/depigmentation. Diffuse scarring of face/upper extremities.
• Elevated ESR, ANAs, ssDNA antibodies, leukopenia MORE common than localized DLE — more likely to meet SLE criteria.

Childhood DLE

• Low photosensitivity frequency, higher SLE association — one study: 15% concurrent SLE, 26% of remaining eventually met SLE criteria. Should prompt SLE screening/surveillance.

Histology

• Effacement of rete ridge pattern or irregular acanthosis. Compact hyperkeratosis WITHOUT parakeratosis, prominent follicular plugging.
• Hydropic degeneration of basal layer (epidermis + follicular epithelium) → pigmentary incontinence. Patchy perivascular/periadnexal lymphoid infiltrate (superficial + deep dermis), characteristically surrounding vessels, follicles, and eccrine coil.
• Increased mucin often present (not reliable to distinguish from mimickers). BMZ thickening may be prominent.
• Stage-dependent: acute = patchy inflammation + vacuolar interface; months-old = hyperkeratosis + BMZ thickening + mucin; chronic inactive = atrophy, postinflammatory pigment, scarring, sparse/absent infiltrate, pilosebaceous units destroyed (except "orphaned" arrector muscles).
• DIF positive in >75% of active lesions (several months+) — strong continuous granular Ig+complement at DEJ.

Differential Diagnosis

• Seborrheic dermatitis (no atrophy/alopecia/dilated follicles, greasy yellow scale, no follicular plugs), rosacea (no atrophy, pustules present), lupus vulgaris (apple-jelly nodules on diascopy), sarcoidosis, drug eruptions, actinic keratosis, Bowen disease, LP, tertiary syphilis, facial discoid dermatosis, PMLE (no scarring, edematous plaques, DIF negative/nonspecific).
• Sunlight-sensitizing agents (sulfonamides) may mimic LE via phototoxic vacuolar interface dermatitis.

• Nonpruritic papulonodular lesions, arms/hands — resembles keratoacanthoma or hypertrophic LP. Lips/scalp may resemble LP/LPP.
• Dermoscopy may help distinguish from SCC; biopsy often needed. BMZ thickening, dermal mucin, eccrine coil involvement, subcutaneous nodular lymphoid infiltrates = LE features NOT in LP.
• Plasmacytoid dendritic cell pattern/number may help distinguish SCC from hypertrophic LE.

• True overlap: large, atrophic, hypopigmented, red/pink patches/plaques; pigment abnormalities prominent over time; fine telangiectasia/scaling.
• Extensor extremities and midline back typically affected. Prominent palmoplantar involvement = most troublesome feature. Nail dystrophy/anonychia; scarring alopecia; oral involvement in some.
• Histology has LP and/or LE features; DIF may help but overlap possible. Response to treatment poor — potent topical corticosteroids, dapsone, thalidomide, isotretinoin may help; some need MMF/azathioprine. Antimalarials can occasionally produce lichenoid drug eruption.
• Pigmented macular variant: rare, lichenoid-to-gray pigmentation in sun-exposed areas; interface reaction on biopsy, may be seropositive, systemic disease rare — unclear if lupus subtype or separate lichenoid entity. Responds to topical steroids, sun protection, hydroquinone.

• Chronic, unremitting — fingertips, ear rims, calves, heels, especially women. Usually preceded by facial DLE. Systemic involvement sometimes seen; may mimic sarcoidosis.
• Check cryoglobulins and APLA. Familial chilblain lupus linked to TREX-1 mutations — part of the interferonopathy genetic disease group.

• Rare, distinctive. Edematous erythematous plaques, usually trunk.
• Histology: patchy superficial+deep perivascular/periadnexal lymphoid infiltrate, frequently affecting eccrine coil; striking dermal mucin deposition.
• Generally responds readily to antimalarials. Shares many features with reticular erythematous mucinosis — some consider them closely related.

• Erythematous palpable nodules/plaques with atrophy/contour change. Firm, sharply defined, nontender. Usually ≥2 sites: proximal extremities, face, back. Overlying skin usually normal, but overlying discoid/tumid lesions possible.
• Progress to deep depressions ("dells") from panniculus loss. Chronic, most often women ages 20-45. Many have DLE elsewhere.
• Histology: lymphoid nodules in subcutaneous septa, fat lobule necrosis, fibrinoid/hyaline lipocyte degeneration. Lipomembranous change ("frost on windowpane" — more typical of stasis panniculitis) may occur focally.
• Overlying epidermis may show basal liquefaction/follicular plugging or be normal. Dermal lymphoid nodules or vertical lymphoid columns in fibrous tract remnants. Dermal mucin prominent; collagen hyalinization (like morphea) possible. Continuous granular Ig/C3 at DEJ. Abundant fibrin in panniculus when active.
• Most important differential: SPTCL (subcutaneous panniculitis-like T-cell lymphoma). Clues: lipocytes rimmed by atypical lymphocytes with nuclear molding, constitutional symptoms. Erythrophagocytosis focally possible; T-cell clonality demonstrable.
• CAUTION: T-cell clonality, erythrophagocytosis, CD8 predominance, loss of CD5/CD7 CAN occur in LE panniculitis that responds to antimalarials/corticosteroids and does NOT progress to lymphoma — some cases may be virtually indistinguishable, or represent abortive lymphoid dyscrasia. Monitor for progression.

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• 1979, Sontheimer, Thomas, Gilliam described this distinct subset. Most often White women ages 15-40. ~10-15% of the LE population.
• Scaly, evolve as polycyclic annular or psoriasiform plaques; rare widespread erythrodermic SCLE or SJS/TEN-resembling cases.
• Red to pink with faint violet tones; thin, easily detached scale; telangiectasia/dyspigmentation possible. Follicles NOT involved; lesions transient/migratory; NO scarring.
• Sites: sun-exposed face/neck, V of chest/back, sun-exposed arms. Photosensitivity in ~half. Concomitant DLE in 20%.
• ~3/4 have arthralgia or arthritis; 20% leukopenia; 80% positive ANA (usually particulate pattern). 20-50% meet SLE criteria.
• >70% have anti-Ro/SSA antibodies; most HLA-DR3 positive. La/SSB may be present; many have Sjögren overlap.
• Generally mild course — renal/CNS/vascular complications unusual. Association with autoimmune thyroid disease. Most respond to sun protection + antimalarials.

• Traditionally: hydrochlorothiazide (wide use); proton pump inhibitors increasingly recognized (OTC availability). Also: hydralazine, terbinafine, ACE inhibitors, CCBs, IFNs, anticonvulsants, griseofulvin, glyburide, piroxicam, penicillamine, spironolactone, statins, voriconazole.
• Chemo agents: fluorouracil, capecitabine, gemcitabine, docetaxel, paclitaxel, doxorubicin; emerging: nivolumab/other checkpoint inhibitors, masitinib. CDK4/6 inhibitors induce both SCLE and DLE.
• TNF inhibitors and other biologics increasingly recognized — important because psoriasiform SCLE can be mistaken for TNF-induced psoriasis (photosensitivity is a clue to SCLE). Topical terbinafine and imiquimod also reported.

• Vacuolar interface dermatitis universal in active lesions. Mild hyperkeratosis/parakeratosis possible. DLE chronic changes (follicular plugging, BMZ thickening, heavy lymphoid aggregates) usually LACKING. Variable dermal mucin.
• DIF positive in lesional skin in only ~1/3. Dustlike particulate IgG deposition in epidermal nuclei of Ro-positive patients — helpful diagnostic finding.

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• Most infants girls, born to mothers carrying Ro/SSA antibody (not lupus-specific — occurs in Sjögren too).
• No skin lesions at birth — develop during first weeks of life. Annular erythematous macules/plaques (head, extremities); periocular involvement ("raccoon eyes") prominent.
• Fade over time, become atrophic. Telangiectasia or dermal mucinosis in acral papular pattern may predominate in some. Telangiectatic macules/angiomatous papules in sun-protected sites (diaper area) may be independent/persistent.
• Skin lesions usually resolve by 6 months, usually without significant scarring (atrophy/telangiectatic mats may persist; dyspigmentation/telangiectasias may remain months-years).
• Half of mothers asymptomatic at delivery, but many later develop arthralgia, Sjögren, or mild systemic findings.
• Half of patients have associated ISOLATED CONGENITAL HEART BLOCK (usually third degree, permanent). Thrombocytopenia/hepatic disease may occur as frequently as cardiac disease in patients with skin involvement.
• Close monitoring for at least first 3 months; by 9 months most cases resolve, only 10% have persistent antibodies then.
• Strong Ro/SSA association — almost all mothers/infants positive. Some mothers also La/SSB+; some with only U1RNP antibodies described (haven't developed heart block). HLA-DR3 linkage in mother.
• Risk of second child with neonatal LE ~25%. Japanese infants: may express anti-dsDNA, 8% progress to SLE. Unselected women with anti-Ro: only 1-2% have infant with neonatal LE.

Subtypes of Cutaneous Lupus

• Clinical: Non-scarring, highly photosensitive annular/polycyclic or psoriasiform scaly plaques on shoulders, upper chest, back, and extensor arms.
• Serology: Strongly linked to Anti-Ro/SSA antibodies (>70%).
• Drug-Induced SCLE: Triggered by Hydrochlorothiazide, Terbinafine, Diltiazem, Proton Pump Inhibitors (PPIs), TNF-α inhibitors.

• Clinical: Chronic scarring localized (head/neck) or generalized plaques with erythema, adherent scale, Follicular Plugging ("Carpet-Tack Sign"), central atrophy, hypopigmentation, and hyperpigmented border.
• Alopecia: Causes permanent Cicatrize/Scarring Alopecia on scalp.
• Systemic Risk: Only 5% of patients with localized DLE progress to SLE.
• Pharmacotherapy:
• Topical / Intralesional Corticosteroids.
• Hydroxychloroquine (Plaquenil): First-line systemic agent (200–400 mg daily; max dose ≤ 5.0 mg/kg actual body weight).
• Ocular Safety: Baseline and annual ophthalmology screening required for irreversible Retinal Toxicity (Bull\'s-eye Maculopathy).

• Pathophysiology: Transplacental passage of maternal Anti-Ro/SSA or Anti-La/SSB IgG autoantibodies.
• Clinical Features:
• Cutaneous: Transient, self-limiting periorbital erythema ("Raccoon-Eyes" / "Owl-Eyes") and annular plaques appearing at 6 weeks of life (resolves as maternal antibodies clear by 6 months).
• Cardiac: PERMANENT IRREVERSIBLE CONGENITAL COMPLETE HEART BLOCK (3rd-Degree AV Block) requiring pacemaker implantation.