1.2.1 Lupus Erythematosus

4A40

Lupus erythematosus, discoid LE, systemic LE.

Usually affects young adults 20-40 years of age; F:M = 7-15:1, in systemic lupus erythematosus 8:1. 

Chronic inflammatory autoimmune disease with marked immunogenetic component which involves the skin and/or other organs.

Immunogenetic susceptibility (HLA associations).

Polyclonal B-cell activation with autoantibody formation: direct pathogenic antibodies (autoimmune haemolytic anaemia), circulating immune complexes (vasculitis, nephritis), antibody-mediated cytotoxicity (skin lesions).

Precipitating factors: UV, medications, oestrogens (oral contraceptives, pregnancy), possibly some viruses, trauma (Koebner phenomenon), possible stress.

In discoid lupus erythematosus persistent several mm to cm sharply bordered, sometimes confluent, and painful lesions with triad of erythema, follicular keratotic plugs, and atrophy (each of which can dominate clinical picture). In systemic LE butterfly rash. Non- specific changes include erythematous maculopapular exanthema, diffuse hair loss, Raynaud syndrome, livedo racemosa (anticardiolipin antibodies and others) as a sign of cutaneous vasculitis, can all be present.

Usually light-exposed areas, especially face, nose, ears, checks (butterfly rash), scalp.

Chronic cutaneous lupus erythematosus 
(Synonym:  chronic discoid LE (DLE)

Coin or disk-shaped erythematous plaques with follicular hyperkeratosis and a tendency to heal with scarring, usually on light-exposed areas or scalp (acquired, circumscribed scarring alopecia).

Variants:

• Hypertrophic LE (verrucosus LE)
• Disseminated DLE
• Chilblain LE (acral involvement)
• Lupus profundus/lupus panniculitis (deeper involvement) 

Subacute cutaneous LE (SCLE)

Non-scarring, polycyclic-annular or papulosquamous (psoriasiform) plaques which usually involve the upper half of the body and are clearly light-provoked. Systemic symptoms (arthritis, fever, malaise) are milder than in SLE (severe CNS or renal disease rare).

Systemic LE (SLE)

ACR (American College of Rheumatology) criteria:

1. Butterfly rash (acute cutaneous LE)
2. Discoid lesions
3. Photosensitivity
4. Oral ulcerations
5. Non-erosive arthritis
6. Serositis: pleuritis; pericarditis
7. Neurologic disease: seizures; psychosis
8. Renal disease (proteinuria >0.5g/d, cellular casts)
9. Hematologic abnormalities (hemolytic anemia, leukopenia
10. ANA
11. anti-dsDNS, anti-Sm, false positive syphilis serology >6 months (for example, with anticardiolipin antibodies) 

Most of the skin findings of DLE and SCLE can be found in SLE.

The diagnosis is based on >= 4 ACR being fulfilled. Other non-specific skin changes: Raynaud's syndrome, diffuse alopecia, vascultis/vasculopathy, maculopapular and other exanthems.

Skin involvement is usually distinguished in acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), and chronic cutaneous LE (CCLE). Skin lesions are typical evoked or exacerbated by UV light exposure.

• ACLE is characterized by the presence of erythema, localized at the nose and malar eminences, with a butterfly distribution. The erythema is often sudden in onset, accompanied by oedema and fine scale, and correlates with systemic involvement. Patients may have widespread involvement of the face as well as erythema and scaling in other sun-exposed area such as the extensor surfaces of the extremities and upper chest. Painful oral ulcerations are common. Acute cutaneous lupus and oral ulcers are the typical skin lesions of SLE.

• SCLE is characterized by non-scarring, polycyclic-papulosquamous annular lesions or psoriasiform plaques which usually involve the upper half of the body and are clearly UV-light provoked. Extracutaneous symptoms (malaise, fatigue, myalgias, arthralgias) may occur, but renal and central nervous system involvement is generally absent. Lesions affects the back, upper chest, shoulders, extensor surfaces of the arms, and dorsum of the hands; lesions are uncommon on the central face and the flexor surfaces of the arms as well as below the waist. The lesions in SCLE are more widespread but have less tendency for scarring than lesions of CCLE. Lesions often results in hypopigmentation or even dyspigmentation, but without scarring nor atrophy as sequelae. A significant portion of SCLE is drug-induced (diuretics, calcium channel blockers, terbinafine, proton pump inhibitors) sometimes with a long latency (months) between drug introduction and the emerging of skin lesions. SCLE lesions may have a chronic and relapsing course.

• Cutaneous discoid LE (CDLE) is the most common type of CCLE. It is characterized by coin or disk-shaped erythematous papules or plaques with follicular hyperkeratosis, a thick and adherent scale that occludes hair follicles, and a tendency to heal with scarring, usually on light-exposed areas (face, upper chest) or the scalp (scarring alopecia). When the scale is removed, its underside shows small lesions that correlate with the openings of hair follicles, a finding which is characteristic. Discoid lesions have a characteristic tendency for scarring and a substantial proportion of patients may develop disfiguring scarring if not properly treated. Long-standing lesions develop central atrophy, scarring and hypopigmentation in the central area with hyperpigmentation at the periphery. Lesions persist for years and tend to expand slowly. Other variants of CCLE include hypertrophic, also called verrucous LE, disseminated discoid lupus erythematosus, chilblain lupus erythematosus (acral involvement), lupus profundus/lupus panniculitis (deeper involvement). Extracutaneous symptoms and involvement is usually absent or very mild in CCLE.

In addition to these lupus-specific manifestations, there are non-lupus-specific cutaneous manifestations. These include alopecia (diffuse, ‘lupus hair’), periungual telangiectasias, Raynaud’s phenomenon, palmar erythema, small vessel vasculitis presenting with urticarial lesions (urticarial vasculitis), hemorrhagic papules (palpable purpura) and skin necrosis. Cutaneous signs of antiphospholipid syndrome are livedo racemosa, acrocyanosis, skin necrosis, ulcerations, and stellate atrophic white lesions (livedoid vasculopathy).

Extracutaneous and systemic symptoms and involvement in SLE include malaise, asthenia, mild fever, oral ulcers, arthralgia/non-erosive arthritis serositis (pleuritis, pericarditis), neurologic disease with seizures and psychosis, renal disease, characterized by proteinuria > 0.5g/d, nephritis, and hematologic abnormalities with hemolytic anemia, leukopenia, lymphopenia, and thrombocytopenia. Most patients with SLE have intermittent polyarthritis, characterized by soft tissue swelling and tenderness in joints and tendons of hand, wrists and knees. Joint deformity of hands and feet occurs in only 10% of cases. Erosions develop in almost 50% of cases. Myositis can occur, but myalgias without myositis are more common. Nephritis is the most frequent renal manifestation, and the most serious in SLE and a major cause of mortality in these patients. In person suspected to have SLE, it is very important the urinalysis, because of nephritis could be initially asymptomatic. The next passage is to manage a renal biopsy. Patients with dangerous proliferative forms of glomerular damage usually have microscopic haematuria and proteinuria; one half develop nephrotic syndrome, and most develop hypertension. Renal biopsy is required for the diagnosis of nephritis. The central nervous system and peripheral nervous system manifestations of SLE are an important cause of morbidity and mortality. The most common manifestations are: difficulties with memory and reasoning, and also headaches, seizures, psychosis; some patients develop myelopathy. Also, vascular occlusion occurs in patients with SLE, and consist in ischemic attacks, strokes, myocardial infarction. These patients usually have SLE with antiphospholipid antibodies, which are associated to hypercoagulability and thrombotic events. Atherosclerosis is more common in patients with chronic SLE. Pleuritis is the most common pulmonary manifestation of SLE. Pulmonary infiltrates are a manifestation of active SLE. Pericarditis is the most frequent cardiac manifestation of SLE, followed by myocarditis and fibrinous endocarditis of Libman-Sacks. Anemia (normochromic normocytic) is the most frequent hematologic manifestation; leukopenia is also common and is characterized by lymphopenia.

CCLE: ANA in 25-60% (often low titers); anti-dsDNA negative; complement factors C3, C4 normal.

SCLE: With active disease erythrocyte sedimentation rate elevated , anti-SSA (Ro) 70-90%, anti-dsDNA <33%, rheumatoid factor (RF) 20%, leukopenia (lymphopenia).

SLE: Normo-hypochromic anemia, leukopenia, thrombocytopenia, C-reactive protein and sedimentation rate elevated, anti-native-DNA (40-90%), anti-U1-RNP (40-60%), anti-SSA (Ro) (40-60%), anti-histone (70%), RF 30%, anti-cardiolipin antibodies (false positive syphilis serology).

CCLE: Epidermal atrophy, hyperkeratosis (primarily follicular), vacuolar degeneration of basal keratinocytes, thickened basement membrane zone (PAS stain), edema, dense lymphocytic perivascular and periadnexal infiltrate at all levels, and, including subcutaneous fat in lupus profundus.

In SCLE and SLE milder and less characteristic histologic changes, but lymphomononuclear infiltrate surrounding the capillaries and some vacuolisation at the BMZ. Incontinence of melanin pigment.

Direct immunofluorescence examination: identification of granular band of C3- and IgG along the epidermal-dermal junction in lesional skin; in SLE also in sun-exposed normal skin (lupus band test).

Pure cutaneous disease usually chronic with hypopigmentation and scarring, especially when discoid. Systemic disease takes highly variable course, ranging from mild disease to acute, life-threatening disease, especially with renal, cardiac or central nervous system involvement.

Depends on systemic involvement (CNS lupus, lupus nephritis).
Rarely squamous cell carcinoma (lupus carcinoma) develops in old DLE scars.

Clinical features (using ACR criteria);

Immune serology (autoantibody profile);

Histology;

Direct immunofluorescence.

DLE: psoriasis, tinea, other photodermatoses.

SCLE:  psoriasis, tinea, pityriasis rosea, syphilis, other photodermatoses.

SLE: Depending on pattern of systemic involvement, other multisystem diseases, such as rheumatoid arthritis, dermatomyositis or mixed connective tissue diseases.

CCLE and SCLE: antimalarials (hydroxychloroquine, chloroquine), can be combined with low-dose corticosteroids, light protection; in SCLE: thalidomide off-label.

SLE: multidisciplinary management adjusted to organ involvement (antimalarials, systemic immunosuppression with corticosteroids and immunosuppressive agents such as azathioprine, cyclophosphamide, biologicals: belimumab and ustekinumab).

Self-help groups.