SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

1. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) 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.

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 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 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 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 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 Generalized edema in nephrotic syndrome

29. Lupus nephritis (WHO I) Lupus nephritis (WHO I)

30. Lupus nephritis (WHO II) Lupus nephritis (WHO II)

31. Lupus nephritis (WHO III) Lupus nephritis (WHO III)

32. Lupus nephritis (WHO IV) Lupus nephritis (WHO IV)

33. IC deposition in the glomeruli - SLE 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 ACR criteria of CNS involvement: acuteinflammatory demyelinizing polyradiculopathy (Guillain-Barré syndrome) aseptic meningitis autonomousnervous system alterations (e.g. orthostatic hypotension) cerebrovascular disease (e.g. stroke) demyelinization syndrome lupus headache mononeuropathy myasthenia gravis cranial neuropathy plexopathy convulsions acute confusionstate anxiety cognitive dysfunction mood disorders

36. Multiple infarcerationsin SLE –APS (MRI) Multiple infarcerations in SLE –APS (MRI)

37. Antiphospholipid syndrome (Hughes’s syndrome) 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) • 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 NatureFrequency (%) 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 Homogenous ANA positivity on HEp-2 cells

42. Peripheral ANA positivity Peripheral ANA positivity

43. Speckled ANA positivity Speckled ANA positivity

44. Nucleolar ANA positivity Nucleolar ANA positivity

45. Anti-DNA positivity (Crithidia luciliae test) Anti-DNA positivity (Crithidia luciliae test)

46. Differential diagnosis 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 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 andhemolysis are of importance. 3. ESR may reflect disease activity, high valueusually 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 ScoreSymptom 8 acute convulsion 8 psychosis 8 "organic brain" syndrome 8 visual disturbances (retinal vasculitis) 8 cranial nervesign (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 >+0.5g/dayincrease 4 pyuria (>5 leukocytes/field) (excluded: infection) 2 new exanthema 2 alopecia, newor recurrent 2 mucous membrane ulcer 2 pleuritis 2 pericarditis 2 lowcomplement (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 • Check-up: 3 months: blood count, urine, creatinine, • blood pressure, once a year: immunology (anti-DNAcomplement, anti-cardiolipin etc. • 2) moderately active (complaints, laboratory abnormalities, no general signs) • Organ involvement: • a) skinand/orjointsand/ormoderate 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 mgmethyl- • 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, vincristinec) kidney: • normalcreatinine, 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