1. 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 Female dominance (male: female ratio: 1:9). Familial aggregation is known.

2. Prevalence of SLE

3. Pathomechanism of SLE
Endogeneous factors: genetic
hormonal
Exogeneic factors: infections,
UV radiation
drugs (hydralazine, INH,
quinidine, procainamide)
B cell hyperreactivity  enhanced autoantibody production, in particular antinuclear antibody (ANA) production  immune complex formation and
deposition  tussue inflammation (skin, joints, kidney)
 organ lesion/regeneration

4. Lupus band test = IC deposition in the skin

5. ANA
ANA

6. ANA
ANA

7. 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.

8. Joints
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.

9. Hand

10. Jaccoud arthropathy in SLE

11. Skin involvement is frequent
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.

12. Malar (butterfly) rash in SLE

13. Malar rash in SLE
Malar rash in
SLE

14. Malar rash in SLE
Malar rash in
SLE

15. Discoid lesion
Discoid lesion

16. Chronic DLE on the face
Chronic DLE
on the face

17. Discoid on the scalp
Discoid on the scalp

18. DLE on the scalp
DLE on the scalp

19. SCLE
SCLE

20. SCLE
SCLE

21. Raynaud phenomenon
Raynaud phenomenon

22. Perinugual vasculitis

23. Perinugual vasculitis
Periungual vasculitis

24. Vasculitis on the feet
Vasculitis on the feet

25. Livedo reticularis
Livedo reticularis

26. Lupus pernio
Lupus pernio

27. Renal involvement is observed in 60% of patients
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.

28. Generalized edema in nephrotic syndrome

29. Lupus nephritis (WHO I)

30. Lupus nephritis (WHO II)

31. Lupus nephritis (WHO III)

32. Lupus nephritis (WHO IV)

33. IC deposition in the glomeruli - SLE

34. Hematological disorders are very common
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.

35. ACR criteria of CNS involvement
acute inflammatory demyelinizing polyradiculopathy (Guillain- Barré syndrome)
aseptic meningitis
autonomous nervous system alterations (e.g. orthostatic hypotension)
cerebrovascular disease (e.g. stroke)
demyelinization syndrome
lupus headache
mononeuropathy
myasthenia gravis
cranial neuropathy
plexopathy
convulsions
acute confusion state
anxiety
cognitive dysfunction
mood disorders

36. Multiple infarcerations in SLE –APS (MRI)

37. 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.

38. Diagnostic criteria of SLE (ARA, 1982, modified in 1997)
Malar rash (or: vespertilio, butterfly rash)
Discoid rash
Photosensitivity
Oral ulcers: oral or nasopharyngeal ulceration
Arthritis: nonerosive athritis
Serositis: (at least one of the following)
a) pleuritis
b) 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) seizures
b)      b)  psychosis
9. Hematologic disorder (at least one of the following):
a)       a) hemolytic anemia (with reticulocytosis), or
b)       b) leukopenia (<4.0 on 2 or more occasions), or
c)       c) lymphopenia (<1.5 on 2 or more occasions), or
d)       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, or
b)       b) antibody to Sm nuclear antigen, or
c)       c) abnormal titer of anticardiolipin antibody
ANA positivity
If 4 criteria are present serially or simultaneously, the diagnosis = SLE

39. Autoantibodies in SLE Autoantibodies in SLE
Antigen Nature Frequency (%)
Native DNA (double-stranded DNA) 40
Denatured DNA (single-stranded DNA) 70
Histon H1, H2A, H2B, H3, H4) 70*
Sm RNA-protein complexes 30
nuclear-RNP (U1-nRNP) 32
SS-A (Ro) RNA-protein complexes 35
SS-B (La) RNA-protein complexes 15
Ku protein 10
ribosomal-RNP phosphoproteins 10
Ki/S1 protein 6
* >90% in drug-induced SLE

40. LE cell phenomenon
LE cell phenomenon

41. Homogenous ANA positivity on HEp-2 cells

42. Peripheral ANA positivity

43. Speckled ANA positivity

44. Nucleolar ANA positivity

45. Anti-DNA positivity (Crithidia luciliae test)

46. Differential diagnosis
In all cases SLE should be clearly differentiated from:
1. other systemic autoimmune diseases
2. infections
3. malignancies, especially lymphomas.

47. 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).

48. SLEDAI SLEDAI Score Symptom 8 acute convulsion 8 psychosis
8 "organic brain" syndrome
8 visual disturbances (retinal vasculitis)
8 cranial nerve sign (sensory, motor)
8 lupus cephalalgia
8 cerebrovascular laesion (excluded: atherosclerosis)
8 vasculitis (ulcus, gangrena, skin vasculitis)
4 myositis
4 arthritis (> 2 joints)
4 granular or erythrocyte casts
4 hematuria (>5 red cells/field)
4 new proteinuria (>0.5 g/day), or >+0.5 g/day increase
4 pyuria (>5 leukocytes/field) (excluded: infection)
2 new exanthema
2 alopecia, new or recurrent
2 mucous membrane ulcer
2 pleuritis
2 pericarditis
2 low complement (CH50, C3, etc.)
2 high anti-DNA
1 fever (>38oC) (excluded: infection)
1 thrombocytopenia (<100,0)
1 leucopenia (<3,0) (wxcluded: drug-induced)
TOTAL SLEDAI SCORE

49. Therapy of SLE Therapy of SLE 1) Inactive
Therapy of SLE
Therapy of SLE
1) Inactive
Check-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)chloroquine
RESPONSE 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)

50. hematology 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, then maintenance dose
if instable: danazole, vincristine c) kidney:
normal creatinine, moderate (0.2-1 g/day) proteinuria, minimal sediment; if stable only observation, biopsy = treatment options according to WHO grade.
d) ACL positivity without clinical APS: only observation

51. 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, maintenance
RESPONSE BUT HIGH MAINTENANCE DOSE: 100 mg Imuran or
MTX added
b) progressive nephritis, either diffuse and/or proliferative
histology: 250 mg methylprednisolone/day cca. 1 g
cumulative dose, then tapering to maintenance dose, OR 6 x 1 g bolus steroid slowly tapered to maintenance
plus 600 mg cyclophosphamide (CTX) infusion once a
month 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/day
maintenance dose (corticosteroid therapy continued).
Oral mycophenolate may substitute for CTX.

52. APS with thrombosis c) APS with thrombosis:
2 mg/kg/day prednisolone + LMW heparin, then
maintenence dose + warfarin,
In arterial thrombosis: aspirin
in severe cases: high dose IVIG
d) severe hemolysis, or CNS involvement:
high dose (250 mg-1 g/day) corticosteroid
alternative: IVIG, apheresis

53. Drug induced exanthema

54. Avascular bone-necrosis

55. Retinopathia due to chloroquine

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