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					      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:     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
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 in
SLE
Malar rash in
SLE
Discoid lesion
Chronic DLE
on 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 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
Multiple infarcerations
in 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 rash
3.    Photosensitivity
4.    Oral ulcers: oral or nasopharyngeal ulceration
5.    Arthritis: nonerosive athritis
6.    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
11. ANA positivity
If 4 criteria are present serially or simultaneously, the diagnosis = 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
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 diseases
2. infections
3. 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).
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
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)
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
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, 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.
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
Drug induced
exanthema
Avascular bone-necrosis
Retinopathia due to chloroquine
Neonatal lupus (caused by trasfer of SS-A antibodies)

				
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posted:1/23/2011
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