SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

Gergely Péter dr

Definition: The clinical picture of SLE is variable. The most common form of the disease: young female with non-erosive arthritis, (low grade) fever, elevated ESR, leucopenia (with or without skin and kidney involvement).

Epidemiology: Incidence: 0.7/100,000, prevalence 23-50/100,000. In Hungary the expected number of SLE cases may be between 2500 and 5000. Female dominance (male: female ratio: 1:9). Familial aggregation is known.

Prevalence of SLE

Pathomechanism of SLE

Endogeneous factors: genetichormonal

Exogeneic factors: infections, UV radiationdrugs (hydralazine, INH,quinidine, procainamide)

B cell hyperreactivity enhanced autoantibody production, in particular antinuclear antibody (ANA) production immune complex formation anddeposition tussue inflammation (skin, joints, kidney) organ lesion/regeneration

Lupus band test = IC deposition in the skin

ANA

ANA

Clinical features of SLE

Clinical picture: The well known butterfly (malar) rash is relatively uncommon, but the diagnosis is in most cases easy, if we base it on the criteria of American Rheumatism Association (ARA).

General symptoms: fever, lymphadenomegaly, weight loss are always present, their severity depends on the intensity of the disease. At first sight, such patient seem to be suffering of an infectious disease.

Joints: are frequently involved, moderate swelling and morning stiffness are the dominant features. Unlike in RA, no erosions and deformity is seen. Subluxation and Jaccoud type arthropathy are rare forms of SLE.

Jaccoud arthropathy in SLE

Skin involvement is frequent. Beside butterfly and discoid rash, chronic (IC-mediated) urticaria, livedo reticularis, skin vasculitis, biphasic Raynaud’s phenomenon, hair thickening and alopecia areata may be present.

Malar (butterfly)rash in SLE

Malar rash inSLE

Malar rash inSLE

Discoid lesion

Chronic DLEon the face

Discoid on the scalp

DLE on the scalp

SCLE

SCLE

Raynaud phenomenon

Perinugual vasculitis

Periungual vasculitis

Vasculitis on the feet

Livedo reticularis

Lupus pernio

Renal involvement is observed in 60% of patients. SLE may manifest as a monosystemic glomerulonephritis, but usually other organs are also involved. Glomerulonephritis is an IC-mediated inflammation with various histological and clinical signs: from mild proteinuria to rapidly progressive glomerulonephritis. Nephrosis syndrome is very common.According to histology, nephritis can be classified. WHO classification is shown below (in parentheses: clinical manifestations)I. normal (no alterations)II. mesangial (mild proteinuria)III. focal segmental (marked proteinuria, positive sediment)IV. diffuse (acute nephritis or nephrosis)V. membranous (nephrosis)VI. sclerosis/end stage.

Generalized edema in nephrotic syndrome

Lupus nephritis (WHO I)

Lupus nephritis (WHO II)

Lupus nephritis (WHO III)

Lupus nephritis (WHO IV)

IC deposition in the glomeruli - SLE

Hematological disorders are very common. A mild anemia (anemia of chronic disease) is always almost present in active disease, frank hemolysis is rare. Leucopenia is common, but even patients with leukocyte count <2.0 have no problems at all. Lymphopenia can be profound (0.5), granulocytopenia rarely results in infections. Thrombocytopenia is more common in patients with APS.

Central nervous system involvement is common, in particular in patients with APS. One of the most reliable method to detect CNS involvement is MRI (however, some foci, seen in MRI may be asymptomatic, therefore the correlation between MRI changes and clinical picture is weak). Psychosis due to corticosteroid treatment is much less frequent that caused by the disease itself. In cuch cases, when in doubt, a bolus corticosteroid is more likely of benefit then withdawal. There are also minor signs: headache, cognitive and emotional disturbances, e.d. depression, etc.

ACR criteria of CNS involvement:acute inflammatory demyelinizing polyradiculopathy (Guillain-

Barré syndrome)aseptic meningitisautonomous nervous system alterations (e.g. orthostatic hypotension)cerebrovascular disease (e.g. stroke)demyelinization syndromelupus headachemononeuropathymyasthenia graviscranial neuropathyplexopathyconvulsionsacute confusion stateanxietycognitive dysfunctionmood disorders

Multiple infarcerationsin SLE –APS (MRI)

Antiphospholipid syndrome (Hughes’s syndrome)A relatively recently decribed syndrome characterized by recurrent venous (or arterial) thromboses, thrombocytopenia, stroke, and in women, recurrent fetal loss. Less frequently other thromboembolic complications may also occur. The syndrome is caused by autoantibodies directed against phospholipid – glycoprotein complexes interfering with normal clotting mechanism.

Diagnostic criteria of SLE (ARA, 1982, modified in 1997)1. Malar rash (or: vespertilio, butterfly rash)2. Discoid rash3. Photosensitivity4. Oral ulcers: oral or nasopharyngeal ulceration5. Arthritis: nonerosive athritis6. Serositis: (at least one of the following)

a) pleuritisb) pericarditis

7. Renal disorder (at least one of the following):  a) persistent proteinuria (>0.5g/day or 3+)

b) cellular casts (erythrocyte, hemoglobin, granular, tubular or mixed)8. Neurological disorder (at least one of the following):a)       a) seizuresb)      b)  psychosis9. Hematologic disorder (at least one of the following):a)       a) hemolytic anemia (with reticulocytosis), orb)       b) leukopenia (<4.0 on 2 or more occasions), orc)       c) lymphopenia (<1.5 on 2 or more occasions), ord)       d) thrombocytopenia (<100 in the absence of offending drug)10. Immunologic disorder (at least one of the following):a)       a) abnormal titer anti-dsDNA antibody, orb)       b) antibody to Sm nuclear antigen, orc)       c) abnormal titer of anticardiolipin antibody1. ANA positivityIf 4 criteria are present serially or simultaneously, the diagnosis = SLE

Autoantibodies in SLE

Antigen Nature Frequency (%)

Native DNA (double-stranded DNA) 40Denatured DNA (single-stranded DNA) 70Histon H1, H2A, H2B, H3, H4) 70*Sm RNA-protein complexes 30nuclear-RNP (U1-nRNP) 32SS-A (Ro) RNA-protein complexes 35SS-B (La) RNA-protein complexes 15Ku protein 10ribosomal-RNP phosphoproteins 10Ki/S1 protein 6

* >90% in drug-induced SLE

LE cell phenomenon

Homogenous ANA positivity on HEp-2 cells

Peripheral ANA positivity

Speckled ANA positivity

Nucleolar ANA positivity

Anti-DNA positivity (Crithidia luciliae test)

Differential diagnosis. In all cases SLE should be clearly differentiated from:1. other systemic autoimmune diseases2. infections3. malignancies, especially lymphomas.

The activity of the disease (monitoring)can be assessed by the followings:1. Clinical signs and symptoms are of utmost importance. 2. Blood count: leukopenia cannot be used, but thrombocyto-

penia and hemolysis are of importance.3. ESR may reflect disease activity, high value usually indicates acivity,

but it remains high in many cases in remission.4. Renal functions (serum creatinine) and proteinuria should be checked

regularly. High creatinine and an increase in daily proteinuria usually indicate an activation.

5. Anti-DNA level runs parallel with activity, but it may remain elevated in remission.

6. Complement activity and C3, C4 levels also indicate activity, they decrease during activity, and tend to normalize in remission.

7. CRP usually remains normal, an increase may indicate bacterial infection.

8. There are indices to measure overall disease activity, e.g. SLEDAI (SLE disease activity index).

SLEDAIScore Symptom8 acute convulsion8 psychosis8 "organic brain" syndrome8 visual disturbances (retinal vasculitis)8 cranial nerve sign (sensory, motor)8 lupus cephalalgia8 cerebrovascular laesion (excluded: atherosclerosis)8 vasculitis (ulcus, gangrena, skin vasculitis)4 myositis4 arthritis (> 2 joints)4 granular or erythrocyte casts4 hematuria (>5 red cells/field)4 new proteinuria (>0.5 g/day), or >+0.5 g/day increase4 pyuria (>5 leukocytes/field) (excluded: infection)2 new exanthema2 alopecia, new or recurrent 2 mucous membrane ulcer2 pleuritis2 pericarditis2 low complement (CH50, C3, etc.)2 high anti-DNA1 fever (>38oC) (excluded: infection)1 thrombocytopenia (<100,0)1 leucopenia (<3,0) (wxcluded: drug-induced)TOTAL SLEDAI SCORE

Therapy of SLE1) InactiveCheck-up: 3 months: blood count, urine, creatinine, blood pressure, once a year: immunology (anti-DNA

complement, anti-cardiolipin etc.2) moderately active (complaints, laboratory abnormalities,

no general signs)Organ involvement:a) skin and/or joints and/or moderate serositis

NSAID and/or (hydroxy)chloroquineRESPONSE continue chloroquine for at least 6 mo

(fundus control after 2 months, then every 6 months)NSAID as required

NO RESPONSE 30 mg prednisolone/day (24 mg methyl-prednisolone) for 1 week, then slowly (during 2 weeks)taper to 5-10 mg maintenance dose;discontinue if possible.OR: 7.5 mg methotrexate (MTX) per week (up to 15

mg/week)

b) hematology:• leucopenia: no treatment• anemia: only hemolysis should be treated if HTC<0.3• hemolysis: 30 mg or more prednisolone/day, maintenance

dose, and/or MTX added• thrombocytopenia: if >50: no treatment

if <20 prednisolone 30 mg or more/day, thenmaintenance dose

if instable: danazole, vincristinec) kidney:

normal creatinine, moderate (0.2-1 g/day) proteinuria, minimalsediment; if stable only observation, biopsy = treatmentoptions according to WHO grade.

d) ACL positivity without clinical APS: only observation

3) Active (according to both clinical, and laboratory tests)a) skin and/or arthritis and/or serositis: 30 mg

prednisolon/day (see above)NO RESPONSE: 64 mg methylprednisolone/day, maintenanceRESPONSE BUT HIGH MAINTENANCE DOSE: 100 mg Imuran or

MTX addedb) progressive nephritis, either diffuse and/or proliferativehistology: 250 mg methylprednisolone/day cca. 1 g

cumulative dose, then tapering to maintenance dose, OR6 x 1 g bolus steroid slowly tapered to maintenanceplus 600 mg cyclophosphamide (CTX) infusion once amonth for 1-2 years (or 100 mg orally for 1-2 years – not used any more!)

If CTX cannot be given or proteinuria is refractory:

4 mg/kg/day cyclosporine A for 3-6 mo, then 2 mg/kg/daymaintenance dose (corticosteroid therapy continued).Oral mycophenolate may substitute for CTX.

c) APS with thrombosis:2 mg/kg/day prednisolone + LMW heparin, then maintenence dose + warfarin,In arterial thrombosis: aspirinin severe cases: high dose IVIG

d) severe hemolysis, or CNS involvement:high dose (250 mg-1 g/day) corticosteroidalternative: IVIG, apheresis

Drug inducedexanthema

Avascular bone-necrosis

Retinopathia due to chloroquine

Neonatal lupus (caused by trasfer of SS-A antibodies)