Sex ratios of autoimmune disease

F : M ratio Disease
9 : 1 Sjorgen
Hashimoto
Graves
Systemic lupus erythematosus
2-3 : 1 Myasthenia gravis
Multiple sclerosis
Rheumatoid arthritis
-1 : 1 Autoimmune hemolytic anemia
Idiopathic thrombocytopenic purpura
Type I diabetes
Vitiligo
Pemphigus
< 1 : 1 Goodpasture
Ankylosing spondylitis
Lockshin MD. Sex differences in autoimmune disease. Lupus 2006 ; 15: 753-756.
 NEW PARADIGM
OLD
PARADIGM

Screen with ANA Screen with ANA plus ENA*

ONE OR BOTH
POSITIVE NEGATIVE
POSITIVE

Interpret result in
Clarify with: Likelihood of lupus-like clinical context
DNA (More common with
#
condition low Clarify with DNA3
Homogenous ANA patterns) Further testing (More common
ENA (Often speckled ANA) probably not indicated* with Homogenous
ANA patterns)

Reeves .G.E.M, Update on the immunology, diagnosis and management of systemic lupus erythematosus.
Internal medicine journal 2004;34:338-347
 Drugs implicated in the development of DILE
Definite Probable Possible Recent case
reports
Hydralazine Sulphasalazine Antibiotics Infliximab
Procainamide Anticonvulsants Non-steroidal Etanercept
anti
inflammatory
agents
Isoniazid Anti-thyroid Antihypertensi Interleukin-2
ves
Methyldopa Statins Lithium Zafirlukast
Quinidine Terbinafine Interferons Clobazam
Minocycline Penicillamine Gold salts Tocainide
Chlorpromazine Fluoroucacil agents Lisinopril
Hydrochlorthiazide Bupropion
Vasoo S. Drug-induced lupus: anm update. Lupus 2006 ; 15 :757-761.
 Potential model for autoimmunity
development
Response to
Healthy,
Environmental
No AutoAbs
Exposure

Primordial
Autoimmne
Genetically
Response
Susceptible
Individual
Healthy
Cross
Autoimmunity Reaction (s)

Organ/ Epitope
Spreading to
Tissue Pathogenic
Damage AutoAbs

Harley JB, Harley ITW, Guthridge JM and James JA. The curiously suspicious: a role for Epstein-Barr virus in Lupus
LOOKING FOR ENVIRONMENTAL FACTORS
AT THE RIGHT TIME

MULTIPLE
ENVIRONMENTAL
EXPOSURES

Genetically DISEASE
susceptible
individual
Clinical disease
Early life infectious exposure may Threshold
programme a plastic immune system

Edwards CJ and Cooper C. Early environmental exposure and the development of lupus. Lupus 2006 ; 15 :
814-819.
 Genetic influence

Normal Benign Pathogenic Clinical

Immunity Autoimmunity Autoimmunity Illness

Environmental factors
Arbuckle MR. Development of Auto antibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med
2003;349:1526-33
 Steps in Pathogenesis of SLE
1. Genetic factors/immune
dysfunction
2. Environmental/endogenous
trigger
3. Inflammation
4. Development of
Autoimmune
5. Accelerated of Antigen
6. Tissue Damage
7. Clinical Disease
 Autoimmune pathogenesis paradigm. APC, antigen-
presenting cell; MHC, major histocompability complex
AUTOIMMUNE AUTOIMMUNITY EVOLVING
*DIATHESIS* WITHOUT DISEASE SPECTRUM OF
AUTOIMMUNE
DISEASE
Genetic Risk Factors :
Autoreactive
- MHC
Lymphocytes
- Other

Tolerance Breakdown Autoimmune Disease

Trigger
- APC stimulation Susceptible End - Lupus
Factor
- Molecular mimicry Organs - Sjrgrens
(Infective
- Cryptic antigen recognition (Skin, joint, - Scleroderma
Ischaemic
- Immune / apoptotic others) - Rheumatoid
latrogenic)
- dysregulation - Polymyositis

Autoreactive Autoreactive
Lymphocytes Lymphocytes

Modulating and Perpetuating Factors acting at multiple levels: e.g. UV radiation, hormones, drugs,
Reeves G.E.M. Update on the immunology, diagnosis and management of systemic lupus erythematosus. Internal Medicine Journal
R. Rose Noel, Mackay R. Ian. The Autoimmune Disease Fourth
edition. 2006
 Autoantibodies Precede
Disease by Years

Some AutoAb
before Dx: 80%

ANA: 3 yrs Anti-DNA: 2 yrs Anti-Sm: 1 yr

Anti-Ro/La Anti-PL Anti-RNP

Arbuckle et al NEJM 2003

 Clinics Features of SLE
Limphadenopati Fatigue
SSP 12-50% 90%
20% Panas lama
Hepatomepali/ 80-82%
Splenomegali Lost Weight
20% 60%

Sel cerna
SLE Arthritis/Arthralgia
90%
18%
Skin
Lung 50-58%
38% Kidney
Hematology 50%
Heart Vasculitis
50%
48%
 Trigger/Eksaserbation
Procainamid
Drugs: Hidralazin UV radiance
Metildopa
CPZ
(320-400 nm)

Abortion Infection
SLE

Pregnancy Surgery
 The 1997 Revised Criteria for
the Classification of SLE
(MD SOAP BRAIN)
1. Malar rash
2. Discoid rash
3. Serositis
a. Pericarditis
b. Pleuritis
4. Oral ulcer
5. Arthritis
6. Photosensitivity
 The 1997 Revised Criteria for
the Classification of SLE
7. Blood / Hematologic disorder
a. Hemolytic anemia OR
b. Leukopenia (< 4000/ ml) OR
c. Lymphopenia (<1500/ ml) OR
d. Thrombocytopenia (<100.000)

8. Renal disorder
a. Persistent Proteinuria (>0.5 gr/d)
b. Cellular cast or any tipe

9. ANA
10. Immunologic disorder
a. Anti ds DNA OR
b. Anti Sm OR
c. Antiphospholipid ab
11. Neurological disorder
 Mechanism
of Sedimentation Immune Complex
Oral Ulcers
Photosensitivity
Discoid Lupus
Discoid Lupus
Small Vessel
Vasculitis
Erythematous Rash
 Heart be involved in
SLE
Pericarditis
Myocarditis
Vasculitis
Secondary atherosclerotic coronary artery
disease & myocardial infarction
Secondary hypertensive disease
Valvular disease
Lung be involved in SLE
Pleuritis
Acute lupus pneumonitis
Chronic intestial lung disease
Pulmonary hypertension
Pulmonary embolism
 Neuropsychiatric syndromes
associated with SLE
Central nervous system Peripheral nervous system
Aseptic meningitis Guillain-Barr syndrome (acute
Cerebrovascular disease inflammatory
Demyelinating syndrome polyradiculoneuropathy)
Headache Autonomic disorder
Movement disorders (chorea) Mononeuropathy
Myelopathy (single/multiplex)
Seizures and Seizure Myasthenia gravis
disorders Cranial neuropathy
Acute confusional state Plexopathy
Anxiety disorder Polyneuropathy
Cognitive dysfunction
Mood disorders
Psychosis

Lau Sing Chak, Atlas of Lupus Erythematosus 2007

Wallace J Daniel, Hahn Hannahs Bevra.Dubois Lupus erythematosus seventh
edition. Psychopathology of Lupus and Neuroimaging. Chapter 38. Hal : 749
 Three types of
autoantibodies associated
CNS
1. ACA
2. Antineuronal Ab
3. Antipribosome Ab
 List of manifestation of
CNS involvement in SLE1
Manifestation of diffuse:
Intractable headaches
Generalized seizures
Aseptic meningitis
Psychosis & severe depression
Coma
 List of manifestation of
CNS involvement in SLE2
Manifestation of local:
Stroke syndromes
Focal seizures
Movement disorder (chorea/transverse
myelitis)
 Clinical Monitoring1
Hematologic abnormalities (Cytopenia)
Anemia
Leukopenia
Lymphocytopenia
Thrombocytopenia

Active SLE
Secondary to drug
Sepsis associated with SLE
 Clinical Monitoring2
ESR, CRP
ANA
95% positive screening test for SLE
3 - 5% negative
5 - 25% population positive
 Clinical Monitoring3
Other Antibodies

Anti Ro (SS-A)
Anti La (SS-B)
Anti Sm
Anti RNP
ACA
ANCA
Maybe helpful in confirming
a diagnosis (not be used in
monitoring)
 Clinical Monitoring4
Anti DNA antibodies
- ~ active SLE
- Monitoring patients response to theraphy
- Associated organ disease activity renal
disease
- Complement levels: C3C4, CH50
 Global measures of disease
activity
LACC (Lupus Activity Criteria Count)
SLAM (The systemic Lupus Activity Measure) clinical
features
BILAG (The british Isles Lupus Activity Group) intent
to treat approach
SLEDAI (The systemic Lupus Disease Activity Index)
- prognostic studies severity (Toronto 1985) / clinical &
laboratory
ECLAM (European Consensus Lupus Activity
Measurement) ~ SLEDAI
 Global measures of
damage SLE

SLICC (The systemic Lupus

International Collaborative Clinics)
damage index
MANAGEMENT OF SLE
 Sun
Fatigue

Diet
Weather
General
Management

Smoking

Oral Contraception Stress and

Physical Trauma
 Therapy

Induction
Maintenance

Prednison Cyclo MM

Prednison AZT MM
Principles of therapy

1. Remission
2. Organ/ Renal
Survival
3. Patient Survival
4. Complication/
Comorbid
5. Quality of Life
(Cost)
LES MEDICATION
Anti malaria
Hydrockcycloroquin
Cloroquin

Cortikosteroide
Prednisone
Metilprednosolone

Immunosupresif
Azathioprine
MMF
Cyclophospamide

Plasmapheresis
 New Treatments for systemic lupus
erythematosus
B-cell anergy
LJP 394: abetimus
B-cell depletion
Anti-CD20: rituximab
Anti-CD22: epratuzumab

Other techniques
Immunoadsorption
AntiC5a
T cell vaccination
chain transfection
Peptide therapies: edratide targeting antiDNA
idiotypes

DCruz P David, Khamashta A Munther, Hughes RV Graham, Systemic lupus erythematosus,

Lancet 2007; 369:587-96
 Management Principles Other
Immunosupression Used in The Treatment
of SLE Patients
Avoid possible disease triggers
Prevent atherosclerosis
Prevent osteoporosis
Prevent infections
Prevent progression
Prevent clots in patient with antiphospholipid
antibodies (not on warfarin)
Treat fatigue
 Important Anti-Inflammatory and
Immunosuppresive Effects of Glucocorticoids
A. Anti-inflammatory Effects
1. Inhibition of blood vessel dilatation and
permeability
2. Inhibition of neutrophil and monocyte
migration to periphery
3. Inhibition of synthesis of inflammatory
mediators such as eicosanoids by
downregulating phospholipase A2 and COX-2
4. Downregulation of destructive enzymes
5. Alteration of cytokine balance in favor of
anti-inflammatory cytokines whereas
proinflammatory cytokines are suppressed

Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition,
Lippincot Williams & Wilkins 2007
B. Immunosuppressive effects*
1. Lymphopenia**
2. Inhibition of signal transduction events critical for T-cell
activation
3. Inhibition of IL2 synthesis and signaling
4. Downregulation of cell surface molecules important for full T-
cell activation and function
5. Inhibition of antigen-presenting cell function. Depletion of
plasmacytoid dendritic cells and production of interferon-alpha
6. Deviation of immune responses towards a Th2-type cytokine
formation
7. Induction of T-cell apoptosis

Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition, Lippincot
Williams & Wilkins 2007
 High-Dose Corticosteroid
Therapy
1. Severe lupus nephritis
2. CNS lupus with severe
manifestations
3. Autoimmune thrombocytopenia
(<30000/mm3)
4. Autoimunehemolytic anemia
5. Acute pneumonitis
 1 gr/IV 3 hari berturut-turut

Oliguria akut (RF)

Lupus serebral dengan koma
Krisis lupus (acute serious SLE)
SITES OF IMMUNOMODULATION

Journal Article
 PROTOCOL FOR USING MONTHLY
IV CYCLOPHOSPHAMIDE1

There are many different protocols that can

be used. The following is one example:
Prior to cyclophosphamide
Premedication 15-30 minutes prior to
cyclophosphamide-dexamethasone 10 mg,
lorazepam 1 mg, and ondansetron (Zofran) 8
mg or ganisetron (kytril) 1 mg in 100 cc
normal saline intravenously
Mesna (25% of cyclophosphamide dose in
milligrams) in 500 cc normal saline
 Protocol for using monthly IV
cyclophosphamide2

There are many different protocols that can be

used. The following is one example:
Cyclophosphamide infusion
Cyclophosphamide 0.75grams/m2 of body surface area in
1000 cc normal saline for initial dose. If creatinine
clearance less than 35-40 cc/min, then decrease initial dose
to 0.50 gram/m2 of BSA
Subsequent monthly doses depend on white blood cell
(WBC) counts at 10 to 14 days post cyclophosphamide
If nadir < 3000/mm3, reduce dose by 0.25gm/m2
If nadir > 4000/mm3, dose can be increased if necessary to
maximum of 1 gm/m2
 Protocol for using monthly IV
cyclophosphamide3

There are many different protocols that can be

used. The following is one example:
Post cyclophosphamide infusion:
Mesna (25% of cyclophosphamide dose in
milligrams) in 500 cc normal saline
Compazine SR 15 mg BID for 2-3 days
 Protocol for using monthly IV
cyclophosphamide4

There are many different protocols that can be

used. The following is one example:
Dose interval for cyclophosphamide
Monthly for 6 doses, then
Every 2 months for 3 doses, then
Every 3 moths for 4 doses, then
Maintenance with azathioprine or mycophenylate
mofetil
 Causes of death in lupus
patients
1. Infection
2. Lupus nephritis, renal failure, & its
complications
3. Cardiovascular disease
4. CNS lupus
 Prognosis in SLE
I. Disease manifestation

II. Disease activity

III. Specific organ damage

IV. Functional status

 Management SLE
( NANANG SUKMANA)

SUPPORT

CARE TREATMEN
T

MONITORING
 Use of GC During Stress
Patients on chronic GC therapy should be given
supplemental GC during the stress of surgery or
moderate severe illness
Minor Stress
25 mg of hydrocortisone (or its equivalent) should
be given daily for 1-3 days during minor sheers
Moderate/Severe Stress
50-75 mg hydrocortisone for 1-3 days
Severe Stress
100-150 mg for hydrocortisone
Usual Regimens of Systemic Glucocorticoid Therapy in SLE*
GC Regimen Representative Indications
Pulse GC (PGC): 250 mg Life or organ-threatening complications
PDNeq /d x 1-5 days. Typically 0.5- (i.e.,RPGN, myelopathy, severe acute
1 g MP/d IV x 1-3 d, monthly as confusional state, alveolar hemorrhage,
indicated. Usually with oral GC (30- vasculitis, optic neuritis)**
60 mg PDNeq/d) HDGC-refactory Disease
DPGN or severe FPGN

Very High Dose GC (VHDGC): > 100
mg PD Neq/d, IV/PO (Start with
divided doses)
High Dose GC (HDGC): >30 mg and
100 mg PDNeq/d, IV/PO
Life or organ-threatening complications (as
for PGC)**
DPGN or severe FPGN (for less than 6-8
weeks)
Thrombocytopenia/hemolytic anemia
Acute lupus pneumonitis; Lupus crisis

Moderate Dose GC (MDGC): Moderate SLE flares (i.e., myositis, severe

> 7.5 mg and 30 mg PDNeq/d, IV pleurisy, opthalmoplegia [except optic
Wallace
or PO J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus,
neuritis], Seventh Edition, Lippincot
thrombocytopenia)
Williams & Wilkins 2007
 Usual Regimens of Systemic Glucocorticoid
Therapy in SLE*

GC Regimen Representative Indications

Low Dose GC (MDGC):
7.5 mg PDNeq/d, PO
Alternate Day GC (ADGC)
Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition,
Lippincot Williams & Wilkins 2007
Arthritis, mild constitutional
symptoms (unresponsive to
analgesics/NSAID/AM).
Generalized LN
Maintenance therapy
Membranous nephritis with
nephrotic syndrome (120 mg
PDNeq)
During tapering GC dose
Maintenance therapy (i.e., 15
mg PDNeq for GN)
 Recommended Therapy for Lupus Nephritis
Disease severity Induction Therapy
Proliferative nephritis
Mild
High-dose corticosteroids (i.e.
0.5-1 mg/kg/day)
If no remission within 3 months,
treat as moderately severe
Moderate MMF (2g/day) (or AZA) with
corticoids as above. If no
remission after first 6 months,
advance to next therapy
Pulse CY alone or in combination
with pulse corticosteroids for first
6 months (total 7 pulses)
In white patients, low-dose IVCY
(6 fortnightly pulses at fixed dose
of 500 mg each) might also be
considered
Background corticosteroids 0.5
Boumpas T Dimitrios, Sidropoulus mg/kg/day
Prodromos,for 4 weeks,
Bertsias George then
Bertsias, Optimum therapeutic approaches for lupus
nephritis: what therapy and for whom?, Nature publishing group, 2005
Maintenance Therapy
Low-dose corticosteroids (i.e.
prednisolone 0.125 mg/kg/day)
Consider further gradual
tapering at the end of each year
of remission
If in remission after first 6-
12 months, MMF may be tapered
to 1.5g/day for 6-12 months
and then to 1 g/day
Consider further tapering at
the end of each year in
remission, or
AZA, or
Quarterly pulses of CY
taper
 Recommended Therapy for Lupus Nephritis

Disease Induction Therapy Maintenance

severity Therapy
Severe Monthly pulses of CY in Quarterly pulses
combination with pulse of CY for at least
corticosteroids for 6-12 1 year beyond
months remission, or
If no response, consider AZA, or
MMF (2-3 g/day) or MMF
rituximab
Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic
approaches for lupus nephritis: what therapy and for whom?, Nature publishing group, 2005
 Recommended Therapy for Lupus Nephritis
Disease severity Induction Therapy Maintenance Therapy
Membranous
nephropathy
Mild High-dose Low-dose
corticosteroids alone corticosteroids
or in combination with alone or with AZA
AZA Low-dose
Moderate-

severe Bimonthly pulse CY ( 6 corticosteroids

pulses) alone or in alone or with
combination with MP AZA, or
Ciclosporine A (3-5 AZA
mg/kg/day) alone or
with AZA
High-dose
corticosteroids with
Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic approaches for lupus
nephritis: what therapy and for whom?, Nature publishing group, 2005
MMF
 Management LUPUS
Chan et all: MMF 2 gr/ day 6 month
Taper : 1 gr / day
Ginzler : MMF 3 gr /day
Contreas : MMF 1,5 2 gr / day

(max 2 gr)
6 month 0,25 05 gr.
(Pisoni Cn, Karim Y, Cuadrado MJ. Lupus
2005, 14, s9 s11.)
 Euro Lupus Maintain Low dose Cyclo (CTX) :
6 X 500 mg pulses fortnightly
MMF or Azathioprine
PRD was started at 0,8 mg /Kg BW/day
p.o. and tapered to reach 10 mg / day at
approximately six months and then taper
then maintained
Complete remission :
- Urinary protein exertion < 0,3 gr / 24
- Normal urinary sediment
- Normal serum albumin
- Improve or stable renal function
(Cahn TM. Lupus nephritis : Induction
therapy. Lupus 2005. 14, s27-s32
 Euro Lupus Maintain Low dose Cyclo (CTX) :
6 X 500 mg pulses fortnightly
MMF or Azathioprine
PRD was started at 0,8 mg /Kg BW/day
p.o. and tapered to reach 10 mg / day at
approximately six months and then taper
then maintained
Complete remission :
- Urinary protein exertion < 0,3 gr / 24
- Normal urinary sediment
- Normal serum albumin
- Improve or stable renal function
(Cahn TM. Lupus nephritis : Induction
therapy. Lupus 2005. 14, s27-s32
 New Treatment in SLE
(cell surface molecules)
Treatment Mode of action Status
Anti CD20 (Rituximab) B cell depletion Phase II/III trial in
patients SLE is
ongoing
Anti CD22 Modulation of B cell Safe in phase I. Phase
(Epratuzumab) signaling II it is on going

Anti CD40L Blocks T-B cell cross

talk

CTLA4 Ig (abcatacept) Block co-stimulation Effective in mice

of T cells
 Suggested Monitoring and Preventive-
Therapeutic Interventions for Selected GC
Adverse Effects (AE)*3

AE Monitoring for
Muscle Psychiatric Proximal muscle weakness
Symptoms of depression,
psychosis
Eye Visual changes,
Other risk factors
(NSAIDs, co-morbidities)
 Suggested Monitoring and Preventive-
Therapeutic Interventions for Selected GC
Adverse Effects (AE)*1
AE Monitoring for
HPA-axis suppression Symptoms of adrenal
insufficiency during
significant stress ( illness,
or surgery)
Osteoporosis BMD at baseline and q12
months thereafter if
bisphosphonates are not
given .
Osteocronosis Unexplained joint /bone
pain. (Perform MRI to
detect early GION if plain
radiography not revealing)
 Suggested Monitoring and Preventive-
Therapeutic Interventions for Selected GC
Adverse Effects (AE)*2
AE Monitoring for

Cardio-vascular Lipidemia
Hypertension
Hyperglycemia Obesity

Infection Fever; PPD skin testing (+

anergy panel); severe
lymphopenia.
Maintain high index of
suspicionfor Ols
 LES Inaktif

NL
DPL
50-60% Urinalisis
Ureum/Cr/GD
APS Nepritis lupus(NL)
KEHAMILAN ACL/LA
SSA/SSB
Hipertensi C3/C4
Preleklamsi Antids DNA
24 jam Urin
Abortus Sc (+) Sc (-) protein

PARTUS

Normal Marformasi C.Heart Block Prematur IUGR

kongenital 8,8% SSA,SSB (+) 60% 30%
Pred (-) 1% SSA,SSB (-)
Sitotoksik (+)
 SLE / ITP
(Immuno Thrombocytopeni Purpura)

Prevalence : 7% - 52% (< 150.000

cells/mc)

Treatment :
Systemic GC : 1-1.5 kg PDN/ Kg/day
Clinical Response : (1-8 weeks)
Guidelines for Use Oral Contraceptives in Women
with Systemic Lupus Erythematosus
1. Inactive or stable/moderate disease
2. No history of venous or arterial thrombosis
3. IgGaPL <40, IgMaPL <40, IgAaPL <50, no circulating
lupus anticoagulant (Unknown if presence of low-to-
moderate titer of aPL in the absence of a previous
thrombosis is contraindication)
4. Nonsmoker
5. Normotensive
6. For combined pill, use lowest dose of ethinyl estradiol
(30-35 g)
7. Patient without migraine headaches
8. Can add low-dose aspirin therapy to hormone regimen
if there is concern about risk factors
Dobois Lupus Erythematosus, 1-2-3 Wallece J. Daniel, 1997
Lupus Eritematosus Sistemik (LES)

Penyakit autoimun yang melibatkan berbagai

organ dengan manifestasi klinis yang bervariasi
dari yang ringan sampai berat . Pada keadaan
awal, sering sekali sukar dikenal sebagai LES,
karena manifestasinya sering tidak terjadi
bersamaan.
Sampai saat ini penyebab LES belum diketahui
ada dugaan faktor genetik, infeksi dan
lingkungan ikut berperan pada patofisiologi LES
Wanita > laki-laki
 Sel T
Sel T yang abnormal ( jumlah dan phenotipe)
Limfopenia
Penurunan subset supressor (CD4+CD45R+, 2H4+)
Penurunan 'naive cells (CD4/8CD45RA+).
Penurunan 'memory cells (CD4/8CD29). Berkorelasi
negatif dengan pembentukan anti DNA
Penurunan aktivitas sel suppressor
Peningkatan aktivitas sel helper (CD4+, DR+)

Respon proliperasi dan signal yang abnormal

Defective anti-CD2 proliferation
Circulating anti-CD45 antibodies
 Sel B
Fungsi sel B yang abnormal
Aktifasi dari poliklonal sel B
Sel B intrinsik yang abnormal
Peningkatan respon terhadap stimulus
sitokin
Imunopatogenesis dan Penatalaksanaan

Nanang Sukmana
Subbagian Alergi - Imunologi Klinik
Bag. Ilmu Penyakit Dalam FKUI / RSCM - Jakarta
Lupus eritematosus sistemik (LES)

Penyakit autoimun yang melibatkan berbagai organ

dengan manifestasi klinis yang bervariasi dari yang
ringan sampai berat . Pada keadaan awal, sering
sekali sukar dikenal sebagai LES, karena
manifestasinya sering tidak terjadi bersamaan.
Sampai saat ini penyebab LES belum diketahui ada
dugaan faktor genetik, infeksi dan lingkungan ikut
berperan pada patofisiologi LES
Autoantibodies noted in SLE and their clinical relevance
Side Antigen Clinical features

Nucleus ds-DNA Characteristic of SLE/nephritis

ss-DNA Non-specific
U1-RNP Present in a variety of connective tissue
disease including SLE, mixed connective
tissue disease and overlap syndromes
(myositis, sclerodactyly, Raynaud's)
Sm Characteristic of SLE
Histones Present in drug-related lupus
SSB/La Presence associated with decreased
nephritis
SSA/Ro Present in a number disorders, including
SLE, Sjogrens syndrome, congenital heart
block, neonatal lupus
PCNA Presence characteristic of SLE

Cytoplasm Ribosomal P-protein Psychosis, depression

Cell membranes Red cells Coomb's positive haemolytic anemia
White celts Lymphopenia
Platelets Thrombocytopenia-
Phospholipid Thrombosis, recurrent abortions
 Sel B
Fungsi sel B yang abnormal
Aktifasi dari poliklonal sel B
Sel B intrinsik yang abnormal
Peningkatan respon terhadap stimulus
sitokin
 Gambaran klinis LES
Limphadenopati Kelelahan
SSP 12-50% 90%
20% Panas lama
Hepotomepali/ 80-82%
Splenomegali BB turun
20% 60%

Sal cerna
LES Artritis/Artralgia
90%
18%
Kulit
Paru 50-58%
38% Ginjal
Hematologi 50%
Jantung Vaskulitis
50%
48%
 Faktor
pencetus/eksaserbasi
Procainamid
Hidralazin Sinar UV
Obat : Metildopa (320-400 nm)
CPZ

Keguguran Infeksi
LES

Tindakan
Kehamilan pembedahan
 Sinar matahari
Kelelahan

Diet
Cuaca
Penatalaksanaan
Umum

Merokok
Kontrasepsi oral Stres dan
trauma fisik
 4 / 11 ARA 3 / 11
WHO LLD

LES

Kerusakan

Organ
Vaskulitis Ginjal Hematologi Jantung Paru SSP
Anemia hemolitik Efusi Metilpred
Prednison
Dosis Prednison : Dosis Prednison
60-100 mg/hari 1-1,5 mg/kgbb/hari
2 mg/kg/hari
15-40 mg/hari
(Hari-minggu) 60-80mg 100-120 mg + drainage 3-5 hari oral
(4-6 minggu / 8-12 minggu) L.pneumonitis pred
Trombositopeni Dosis Prednison 48-80 mg/hari
Prednison :1 mg/kgBB 1-1,5 mg/kg/hari
Azatiopin : 2,5 mg/kgBB
Dosis Prednison 5-7 hari
1-2 mg/kgbb/hari (4-6 minggu)
Siklophospamid : 0.5 1 gr/m2 60-80 mg/hari
(4 minggu)
 LES Inaktif

NL
DPL
50-60% Urinalisis
Ureum/Cr/GD
APS Nepritis lupus(NL)
KEHAMILAN ACL/LA
SSA/SSB
Hipertensi C3/C4
Preleklamsi Antids DNA
24 jam Urin
Abortus Sc (+) Sc (-) protein

PARTUS

Normal Marformasi C.Heart Block Prematur IUGR

kongenital 8,8% SSA,SSB (+) 60% 30%
Pred (-) 1% SSA,SSB (-)
Sitotoksik (+)
 1 gr/IV 3 hari berturut-turut

Oliguria akut (RF)

Lupus serebral dengan koma
Krisis lupus (acute serious SLE)
 D. I. F - Renal

IgA Good Pasteur Cresent GN SLE

S. V. V
IgG (-) IgG Linear (+) (-) (+)
IgA (+) (-) (-) (+)
mesangial
IgM (-) (-) (-) (+)
C3 (+) (+) (-) (+)
mesangial granular
C1q (-) (-) (-) (+)
Fbrin (-) (+) (+) (-)
mesangial cresent fullhouse
Wallace J Daniel, Hahn Hannahs Bevra.Dubois Lupus erythematosus seventh
edition. Psychopathology of Lupus and Neuroimaging. Chapter 38. Hal : 749
 Important Anti-Inflammatory and
Immunosuppresive Effects of Glucocorticoids
A. Anti-inflammatory Effects
1. Inhibition of blood vessel dilatation and
permeability
2. Inhibition of neutrophil and monocyte
migration to periphery
3. Inhibition of synthesis of inflammatory
mediators such as eicosanoids by
downregulating phospholipase A2 and COX-2
4. Downregulation of destructive enzymes
5. Alteration of cytokine balance in favor of
anti-inflammatory cytokines whereas
proinflammatory cytokines are suppressed

Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition,
Lippincot Williams & Wilkins 2007
B. Immunosuppressive effects*
1. Lymphopenia**
2. Inhibition of signal transduction events critical for
T-cell activation
3. Inhibition of IL2 synthesis and signaling
4. Downregulation of cell surface molecules important
for full T-cell activation and function
5. Inhibition of antigen-presenting cell function.
Depletion of plasmacytoid dendritic cells and
production of interferon-alpha
6. Deviation of immune responses towards a Th2-type
cytokine formation
7. Induction of T-cell apoptosis

Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition, Lippincot
Usual Regimens of Systemic Glucocorticoid Therapy in SLE*
GC Regimen
Pulse GC (PGC): 250 mg
PDNeq /d x 1-5 days. Typically 0.5-
1 g MP/d IV x 1-3 d, monthly as
indicated. Usually with oral GC (30-
60 mg PDNeq/d)
Very High Dose GC (VHDGC): > 100
mg PD Neq/d, IV/PO (Start with
divided doses)
High Dose GC (HDGC): >30 mg and
100 mg PDNeq/d, IV/PO
Moderate Dose GC (MDGC):
> 7.5 mg and 30 mg PDNeq/d, IV
Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition, Lippincot
or PO
Representative Indications
Life or organ-threatening complications
(i.e.,RPGN, myelopathy, severe acute
confusional state, alveolar hemorrhage,
vasculitis, optic neuritis)**
HDGC-refactory Disease
DPGN or severe FPGN
Life or organ-threatening complications (as
for PGC)**
DPGN or severe FPGN (for less than 6-8
weeks)
Thrombocytopenia/hemolytic anemia
Acute lupus pneumonitis; Lupus crisis
Moderate SLE flares (i.e., myositis, severe
pleurisy, opthalmoplegia [except optic
neuritis], thrombocytopenia)
With PGC, or CY/AZA for severe disease
 Use of GC During Stress
Patients on chronic GC therapy should be given
supplemental GC during the stress of surgery or
moderate severe illness
Minor Stress
25 mg of hydrocortisone (or its equivalent) should
be given daily for 1-3 days during minor sheers
Moderate/Severe Stress
50-75 mg hydrocortisone for 1-3 days
Severe Stress
100-150 mg for hydrocortisone
 SLE / ITP
(Immuno Thrombocytopeni Purpura)

Prevalence : 7% - 52% (< 150.000

cells/mc)

Treatment :
Systemic GC : 1-1.5 kg PDN/ Kg/day
Clinical Response : (1-8 weeks)
 Recommended Therapy for Lupus Nephritis
Disease severity Induction Therapy
Proliferative nephritis
Mild
High-dose corticosteroids (i.e.
0.5-1 mg/kg/day)
If no remission within 3 months,
treat as moderately severe
Moderate MMF (2g/day) (or AZA) with
corticoids as above. If no
remission after first 6 months,
advance to next therapy
Pulse CY alone or in combination
with pulse corticosteroids for first
6 months (total 7 pulses)
In white patients, low-dose IVCY
(6 fortnightly pulses at fixed dose
of 500 mg each) might also be
considered
Background corticosteroids 0.5
Boumpas T Dimitrios, Sidropoulus mg/kg/day
Prodromos,for 4 weeks,
Bertsias George then
Bertsias, Optimum therapeutic approaches for lupus
nephritis: what therapy and for whom?, Nature publishing group, 2005
Maintenance Therapy
Low-dose corticosteroids (i.e.
prednisolone 0.125 mg/kg/day)
Consider further gradual
tapering at the end of each year
of remission
If in remission after first 6-
12 months, MMF may be tapered
to 1.5g/day for 6-12 months
and then to 1 g/day
Consider further tapering at
the end of each year in
remission, or
AZA, or
Quarterly pulses of CY
taper
 Recommended Therapy for Lupus Nephritis

Disease Induction Therapy Maintenance

severity Therapy
Severe Monthly pulses of CY in Quarterly pulses of
combination with pulse CY for at least 1
corticosteroids for 6-12 year beyond
months remission, or
If no response, consider AZA, or
MMF (2-3 g/day) or MMF
rituximab
Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic
approaches for lupus nephritis: what therapy and for whom?, Nature publishing group, 2005
 Recommended Therapy for Lupus Nephritis
Disease severity Induction Therapy Maintenance Therapy
Membranous
nephropathy
Mild High-dose Low-dose

corticosteroids alone or corticosteroids alone

in combination with AZA or with AZA
Moderate- Bimonthly pulse CY ( 6 Low-dose
severe pulses) alone or in corticosteroids alone
combination with MP or with AZA, or
Ciclosporine A (3-5 AZA
mg/kg/day) alone or with
AZA
High-dose
Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic approaches for lupus
corticosteroids
nephritis: what therapy and for whom?, with
Nature publishing group, 2005 MMF
 Management LUPUS
Chan et all: MMF 2 gr/ day 6 month
Taper : 1 gr / day
Ginzler : MMF 3 gr /day
Contreas : MMF 1,5 2 gr / day (max 2 gr)
6 month 0,25 05 gr.
(Pisoni Cn, Karim Y, Cuadrado MJ. Lupus
2005, 14, s9 s11.)
 Euro Lupus Maintain Low dose Cyclo (CTX) :
6 X 500 mg pulses fortnightly
MMF or Azathiprine

PRD was started at 0,8 mg /Kg BW/day p.o. and tapered to reach 10 mg /
day at approximately six months and then taper then maintined
Complete remission :
- Urinary protein exretion < 0,3 gr / 24 hours
- Normal urinary sediment
- Normal serum albumin
- Improve or stable renal function
(Cahn TM. Lupus nephritis : Induction therapy. Lupus 2005.
14, s27-s32
 Outcome measure in the induction and
maintenance treatment of lupus nephritis
Induction treatment
Remission and response
Decrease in proteinuria to < 1g/day(or < 0.8 g/day in
cases of lupus nephritis that were diagnosed in the past
6 months) with normal serum albumin concentrations;
inactive urine sediment ; improved or stable renal
function

Partial remission or partial response

Significant change in proteinuria (i.e. if nephrotic at
haseline 50% decrease in proteinuria to <3 g/day; if
non-nephrotic at baseline but not meeting the remission
and response criteria decrease to 1g/day) and
improved or stable renal function

Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic approaches for lupus
nephritis: what therapy and for whom?, Nature publishing group, 2005
 Outcome measure in the induction and
maintenance treatment of lupus
nephritis

Treatment failure
Persistent proteinuria of 3g/day or any degree of
proteinuria with serum albumin <3g/day or progressive
renal impairment (i.e. a reproducible 33% or > 0.3
mg/dl increase from baseline serum creatinine, whichever
is greater) after the first 6-12 months of treatment

Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic

approaches for lupus nephritis: what therapy and for whom?, Nature publishing group, 2005
 Outcome measure in the induction and
maintenance treatment of lupus nephritis

Maintenance (in patients having achieved remission or a response)

Relapse or flare

Proteinuric: > 2g increase in 24 h proteinuria or > 0.5 g/day

but with serum albumin <3.5 g/day (if only partial response
with proteinuria still at the nephrotic range, > 50% increase in
24 h proteinuria)

Nephritic: mild (active urine sediment with dysmorphic red

blood cells and cellular casts0, moderate (active urine sediment
with proteinuria of 1 g/day) or severe ( active urine
sediment with a reproducible 30% increase in serum creatinine
levels over a period of 6 months)

Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic approaches for lupus
nephritis: what therapy and for whom?, Nature publishing group, 2005
Beberapa jenis obat untuk berbagai kondisi pada Lupus1
Class Generic name Uses
Non-steroidal anti- Ibuprofen Relief of Inflammatory
inflammatory drugs pains in muscles, joints,
serosae etc
Naproxen
Indomethacin
Celecoxib COX-2 inhibitors (2 less
Gr toxicity)
Rofecoxib
Antimalarias Hydroxychloroquine Autoimmune-related
fatigue, arthropathy
and rash; limited
evidence of efficacy for
sicca, thrombophilia and
pain
Reeves. G.E.M. Update on the immunology, diagnosis and management of systemic lupus
erythematosus. Internal Medicine Journal 2004;34:338-347.
Beberapa jenis obat untuk berbagai kondisi pada Lupus2
Class Generic name Uses
Corticosteroids Prednisone Serositis, cytopenias,
major organ Involvement;
low-dose transient use for
refractory
musculocutaneous features
Potent Azathioprine All potent
Immunomodulators Methotrexate immunomodulators have the
Cyclosporine following uses: Severe
Cyclophosphamide organ involvement or
Leflunomide cytopenia, steroid-sparing
Mycophenolate role where disease
relapses with attempted
steroid weaning, and
introduced relatively early
in moderate-severe
rheumatoid arthritis to
Reeves. G.E.M. Update on the immunology, diagnosis andlimit jointof damage
management systemic lupus
erythematosus. Internal Medicine Journal 2004;34:338-347.
 New Treatments for systemic lupus
erythematosus
B-cell anergy
LJP 394: abetimus
B-cell depletion
Anti-CD20: rituximab
Anti-CD22: epratuzumab

Other techniques
Immunoadsorption
AntiC5a
T cell vaccination
chain transfection
Peptide therapies: edratide targeting antiDNA
idiotypes

DCruz P David, Khamashta A Munther, Hughes RV Graham, Systemic lupus erythematosus,

Lancet 2007; 369:587-96
 Suggested Monitoring and Preventive-
Therapeutic Interventions for Selected GC
Adverse Effects (AE)*3

AE Monitoring for
Muscle Psychiatric Proximal muscle weakness
Symptoms of depression,
psychosis
Eye PUD Visual changes,
Other PUD risk factors
(NSAIDs, co-morbidities)
 Suggested Monitoring and Preventive-
Therapeutic Interventions for Selected GC
Adverse Effects (AE)*1
AE Monitoring for
HPA-axis suppression Symptoms of adrenal
insufficiency during
significant stress ( illness,
or surgery)
Osteoporosis BMD at baseline and q12
months thereafter if
bisphosphonates are not
given .
Osteocronosis Unexplained joint /bone
pain. (Perform MRI to
detect early GION if plain
radiography not revealing)
 Suggested Monitoring and Preventive-
Therapeutic Interventions for Selected GC
Adverse Effects (AE)*2
AE Monitoring for

Cardio-vascular Lipidemia
Hypertension
Hyperglycemia Obesity

Infection Fever; PPD skin testing (+

anergy panel); severe
lymphopenia.
Maintain high index of
suspicionfor Ols
Management SLE
Usulan dr Nanang sukmana

SUPPORT

CARE TREATMEN
T

MONITORIN
G
Thank You
Algorithm for the treatment of poliferattive
(class III or IV ) nephritis
 Vasculitis

Severe : 1 gr / day for 3 days

Mild / Moderate : 10-40 mg /day
(add) : AZA 50 150 mg / day
Mechanisms and Examples of Anti-Inflammatory and
Immunosuppressive Actions of GC2

B. Post- transcriptional effects through inihibition of p38

MAPK. Probably mediated through induction of MKP1
and inhibition of p38 MAPK
Decreased mRNA stability of cytokines, COX-2, iNOS.
C. Rapid nongenomic effects through cytoplasmic GRE.
Activation of enthothelial NOS (eNOS) and generation
of NO through GR-mediated activation of
phosphatidylinositol 3-kinase (PI-3K) and protein kinase
Akt.
Rapid phosphorylation of Anx1 and blockade of
activation of cytoplasmic PLA2 by growth factor
receptors.
Rapid nongenomic effects membrane GR.
Mechanisms and Examples of Anti-Inflammatory and
Immunosuppressive Actions of GC3

E. Rapid nonspecific effects through

physicochemical interaction with cell
membranes. These are thought to occur at
pulse IV doses of GC. Disruption of calcium
and sodium cycling with low intracellular
calcium levels, as well as mitochondrial proton
leak, probably contribute to rapid GC-
mediated immunosuppression.
 Mechanisms and Examples of Anti-
Inflammatory and Immunosuppressive
Actions of GC1
A. Transrepression through protein-protein
cross talk: activated glucocorticoid
receptor (GR) monomers interact and
inhibit proinflammatory transcription
factors.

GR GC
X
NF B
NF B site
 Hemolycte Anemia
60 mg prednisone daily
( add ) AZA (50-150 mg daily)
Leucopenia
Rarely requires any treatment
Thrombocytopenia
> 50.000 usually donate require
treatment
Life threatening thrombocytopenia

IV : MPD : 1 gr / day for 3 days

 CNS
Seizure
Always role out brain lesion or stroke as the cause
Use antiseizure medication and corticosteoid as needed
Psychosis
Investigate toxic and metabolic causes
Organic brain syndrome
Investigate : toxic, metabolic and infectious
MPD 1 gr / day for 3 days
Stroke
To rule out embolic thrombotic and artero relative causes
APS anti coagulant
 Kyrialco A, Kirou and D-T Boumpas have previously
classified the various dose GC regimen in:

Pulse GC : 15-30 kg MP/kg/day

or 1 gr MP/m2 body surface area
i v x 1- 3 days.
Very high-dose GC : > 1-2 mg PDN/kg/day
High dose GC : 0,6 1 mg PDN/kg/day
Medium dose GC : 0,125-0,5 mg PDN/kg/d
Low dose : < 0,125 g PDN/kg/day
GC : Glucocorticord
PDN : Prednisone
MP : Methyl prednisolon
Autoantibodies in SLE
Autoantibody Frequency Clinical Associations
ANA 95-99% if active disease 90% If in Any or all of the broad
remission spectrum of clinical
Usually high titer manifestations
Homogeneous or speckled pattern
Sensitive but not specific
May appear yrs before disease overt (NEJM
2003; 349:1526)
Anti - ds - DNA 70 %; very specific for SLE Titers parallel Lupus nephritis
disease activity, especially renal disease Vasculitis
Anti - Sm 30%; very specific for SLE Lupus nephritis
Anti Ro 15-35% Sjgrens/SLE overlap
Anti - La Anti Ro in - ANA Neonatal lupus
Photosensitivity
Subacute cutaneous lupus
Anti-U1-RNP 40% MCTD;Raynauds
Tend not to have nephritis
Anti-histone Drug-induced lupus (DLE), SLE Mild arthritis and serositis
Sabatine, S Marc : Pocket Medicine Second Edition ; 2004
 Clinical Utility of Measuring Anti-DNA
High titers of anti-dsDNA
Have approximately 90% specificity for SLE
Often indicate clinically active disease and increased risk for nephritis
Low titers of anti-dsDNA
Can be detecting anti-ssDNA
Can be found in
Drug-induced lupus
Rheumatoid arthritis
Sjorgen syndrome
Other CTD
Chronic infections
Chronic liver disease
Aging
CTD, Connective tissue disease.
Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition, Lippincot Williams & Wilkins 2007
Usual Regimens of Systemic Glucocorticoid Therapy in SLE*
GC Regimen Representative Indications
Low Dose GC (LDGC): 7.5 mg Arthritis, mild constitutional symptoms
PDNeq/d, PO (unresponsive to analgesics/NSAID/AM).
Generalized LN
Maintenance Therapy

Alternate Day GC (ADGC) Membranous nephritis with nephrotic sydrome

(120 mg PDNeq)
During tapering GC dose
Maintenance therapy (i.e., 15 mg PDNeq for GN)
AZA, azathioprine; CY, cyclophospamide, LN, lymphadenopathy; MP, methylprednisolone; ON, osteonecrosis, OP,
osteoporosis; PDNeq, prednisone equivalent; RPGN, rapidly progressive glomerulonephritis: FPGN, Focal
proliferativeglomerulonephritis; AM, Antimalarial.
All PDNeq doses assume a 60 Kg patient; adjustments should be done for different weights
**Cyclophosphamide therapy, usually I.V. (IVCY), is often needed as well
In combination with IVCY
Lupus crisis refers to the acutely and severely ill patient with high fever, extreme prostration, and other symptoms of active
SLE (i.e., pleurisy, arthritis, vasculitic rash), who requires large doses of GC for disease control. Infection has of course been
excluded as the cause of the symptoms.

Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition, Lippincot Williams & Wilkins 2007
 Primary Causes of Death and Their Contributing Factors in SLE
Primary Cause N (%)

I. Active SLE 20 (16)

II. Infections 40 (32)
III. Other morbidity related: 38 (31)
Acute vascular events 19 (15.4)
Myocardial infarction 13 (10.5)
CVA 5 (4)
Rupture of abdominal aneurysm 1 (0.8)
Sudden death 10 (8)
CHF 2 (1.6)
Pulmonary embolism 2 (1.6)
Renal failure 2 (1.6)
Pulmonary fibrosis 2 (1.6)
Others 1 (0.8)
IV. Unrelated to SLE 13 (10.5)
V. Malignancy 8 (6.5)
Suicide/accident 3 (2.4)
Chronic obstructive lung disease 2 (1.6)
Apalastic anemia
V. Unknown 13 (10.5)
Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition, Lippincot Williams & Wilkins 2007
 Prevalence and Association with Anti-Sm and Anti-
nRNP in Systemic Lupus Erythematosus
and Related Disorders
Specificity Clinical Association Prevalence
Anti-U5 SLE (with anti-nRNP) Very Rare
MCTD (with anti-nRNP) Very Rare
Anti-U7 Scleroderma Very Rare
Anti-U11 Scleroderma Very Rare
Anti-U1 RNA SLE (with anti-nRNP) 15%
MCTD (with anti-nRNP) 30%
Scleroderma (pulmonary 5%-10%
fibrosis)

Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition, Lippincot Williams & Wilkins 2007
 Definitions for mild, moderately severe, and
severe lupus nephritis

Proliferative nephrtitis (Class II or IV)

Mild Disease
Focal proliferative nephritis (Class III) without adverese
histologic features such as CRESCENTS, fibrinoid necrosis or
high chronicity (i.e. chronicity index .3), or adverse clinical
features (normal renal function, proteinuria <3 g/day)

Moderately severe disease

Mild disease as defined above with partial or no response after
the initial induction therappy, or delayed remission (. 6 months),
or

Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic approaches for lupus
nephritis: what therapy and for whom?, Nature publishing group, 2005
Mechanisms and Examples of Anti-Inflammatory
and Immunosuppressive Actions of GC
B. Transactivation of anti-inflammatory genes through binding of
activated GR dimers to glucocorticoid responsive elements
(GRE) on the corresponding gene promoter or enhancer
regions.
Annexin-1 (Anx1 or lipocortin-1; a phospholipase A2 inhibitor), I
B (inhibitor of NF B ), IL1 receptor antagonist (IL1Ra; inhibitor
of IL1-), MAPK phosphatase-1 (MKP1), secretory leucocyte
inhibitory protein (SLPI), neutral endopeptidase, IL10, etc.

GC GR GR GC
GRE GRE
 Mechanisms and Examples of Anti-
Inflammatory and Immunosuppressive Actions
of GC
Mainly NF - B is affected, but also AP1, NFAT, and so on
with end result the transcriptional inhibition of :

1. Cytokines: IL1- , IL2, IL4, IL5, IL12, TNF, GMSC, etc.

2. Chemokines: IL8, MCP-1, MIP1- , eotaxin, etc.
3. Proinflammatory enzymes: iNOS, COX2,
collagenase.
4. Adhesion molecules: ICAM1, E-selectin, etc.
 A practical guide to interpretation of the ANA test

Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition, Lippincot Williams & Wilkins 2007
Principal Immune Serologies and Their Value in SLE
Autoantibody % in SLE % in Normals
Antinuclear 98 5-10
Anti-DNA 50 <1
Anti-Sm 25 <1
Anti RNP 25 <1
Antiphospholipid 33 5
Anti-Ro/SSA 20 <1
Anti-La/SSB 15 <1
Antineuronal 20 <1
Antiribosomal P 20 <1
Low serum complement 50 5
MCTD, mixed connective tissue disease

Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition, Lippincot Williams & Wilkins 2007
 Definitions for mild, moderately severe, and
severe lupus nephritis

Proliferative nephritis with high chronicity alone or

in combination with high activity (i.e.chronicity
index >4 or chronicity index >3 and activity index
>10), or

Rapidly progressive glomerulonephritis (doubling

of serum creatinine within 2-3 months)
Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic approaches for lupus
nephritis: what therapy and for whom?, Nature publishing group, 2005
 Definitions for mild, moderately severe, and
severe lupus nephritis

Membranous nephropathy (Class V)

Mild disease
Proteinuria <3g/day with normal renal function

Moderate disease
Nephrotic range proteinuria with normal renal function

Severe disease
Nephrotic range proteinuria in combination with impaired
renal function (at least 30% increase in serum creatinine)

Boumpas T Dimitrios, Sidropoulus Prodromos, Bertsias George Bertsias, Optimum therapeutic approaches for lupus
nephritis: what therapy and for whom?, Nature publishing group, 2005
 Relative Biologic Potency and
Pharmacokinetics of selected Glucocorticoids
(GC)
Genomic Mineralc Biologic Half
Half-Life
GC Anti- orticoid Life
(Minutes)
inflammatory Activity (Hours)
Cortisol 20 1 60 8-12
Cortisone 25 0.8 60 8-12
Prednisone 5 0.8 180 12-36
Prednisolone 5 0.8 180 12-36
Methylprednisolone 4 0.5 180 12-36
Triamcinolone 4 0 180 12-36
Dexamethasone 0.75 0 220 36-72
 Steps in Pathogenesis of SLE
1. Genetic factors/immune dysfunction
2. Environmental/endogenous trigger
3. Inflammation
4. Development of Autoimmune
5. Accelerated of Antigen
6. Tissue Damage
7. Clinical Disease
Potential involvement of the innate immune system in atherogenesis.
Different molecules belonging to the innate system can be involved
in the process of atherogenesis. Petraxines, patterns-recognation
receptors, and different cytokine have been shown to induce some
pro-atherogenic phenomenon.

Matsuura E, Kobayashi K, Inoue K, Lopez LR, Y Shoenfeld. Oxidized LDL/ 2-glycoprotein

Gilliam classification of LE-associated skin lesions

LE-nonspecific skin disease Alopecia

Cutaneous vascular disease Lupus hair
Vasculitis Telogen effluvium
Leukocytoclastic Alopecia areata
Palpable purpura
Sclerodactyly
Urticarial vasculitis
Rheumatoid nodules
Periarteritis nodosa-like
Calcinosis cutis
Vasculopathy
LE-nonspecific bullous lesions
Degos disease-like Epidermolysis bullosa
Atrophy blanche-like acquisita
Periungual telangiectasia Dermatitis herpetiformis-
Livedo reticularis like bullos LE
Thrombophlebitis Pemphigus erythematosus
Raynauds phenmenon Bullous pemphigoid
Erythromelalgia/erythermalgia Poryphyria cutanea tarda

Lau Sing Chak, Atlas of Lupus Erythematosus 2007

Gilliam classification of LE-associated skin
lesions

Urticaria
Papulonodular mucinosis
Anetoderma/cutis laxa
Acanthosis nigricans
Erythema multiforme
Leg ulcers
Lichen Planus

Lau Sing Chak, Atlas of Lupus Erythematosus 2007

The 1997 Revised Criteria for Classification
of Systemic Lupus Erythematosus

Lau Sing Chak, Atlas of Lupus Erythematosus 2007

Gilliam classification of LE-associated skin lesions

LE-nonspecific skin disease Alopecia

Cutaneous vascular disease Lupus hair
Vasculitis Telogen effluvium
Leukocytoclastic Alopecia areata
Palpable purpura
Sclerodactyly
Urticarial vasculitis
Rheumatoid nodules
Periarteritis nodosa-like
Calcinosis cutis
Vasculopathy
LE-nonspecific bullous lesions
Degos disease-like Epidermolysis bullosa
Atrophy blanche-like acquisita
Periungual telangiectasia Dermatitis herpetiformis-
Livedo reticularis like bullos LE
Thrombophlebitis Pemphigus erythematosus
Raynauds phenmenon Bullous pemphigoid
Erythromelalgia/erythermalgia Poryphyria cutanea tarda

Lau Sing Chak, Atlas of Lupus Erythematosus 2007

The 1997 Revised Criteria for Classification
of Systemic Lupus Erythematosus

Lau Sing Chak, Atlas of Lupus Erythematosus 2007

 The 1997 Revised Criteria for
Classification of Systemic Lupus
Erythematosus

Lau Sing Chak, Atlas of Lupus Erythematosus 2007

International Society of Nephrology/Renal
Pathology Society (ISN/RPS) 2003
classification of lupus nephritis

Lau Sing Chak, Atlas of Lupus Erythematosus 2007

International Society of Nephrology/Renal
Pathology Society (ISN/RPS) 2003
classification of lupus nephritis

Lau Sing Chak, Atlas of Lupus Erythematosus 2007

International Society of Nephrology/Renal
Pathology Society (ISN/RPS) 2003
classification of lupus nephritis

Lau Sing Chak, Atlas of Lupus Erythematosus 2007

 Prevalence and Association with Anti-Sm and Anti-
nRNP in Systemic Lupus Erythematosus and Related
Disorders

Specificity Clinical Association Prevalence

Anti-Sm SLE 10%-30%
Anti-nRNP Mixed connective tissue 100%
(U1) disease 30%-40%
SLE 60% (SLE) <20%
Raynaulds phenomenon (others)
Myositis 10%
Scleroderma 10%
Sjorgen syndrome Rare
Anti-U2 snRNP MCTD, SLE, Rare
Anti-U4/U6 scleroderma/myositis Very Rare
snRNP Sjorgen syndrome Very Rare
Scleroderma
Wallace J Daniel & Hahn Hannahs Bevra : Dubois lupus Erythematosus, Seventh Edition, Lippincot
Williams & Wilkins 2007
 Definitions for mild, moderately
severe, and severe lupus nephritis1

Focal proliferative nephritis with adverse

histologic features or reproducible
increase of at least 30% in serum
creatinine levels or

Diffuse proliferative nephritis (Class IV)

without adverse histological features
 Definitions for mild, moderately
severe, and severe lupus nephritis2

Severe Disease
Moderately severe as defined above but not
remitting after 6-12 months of therapy, or

Proliferative disease (focal or diffuse) with

impaired renal function and fibrinoid necrosis or
crecents in >25% of glomeruli, or

Mixed membranous and proliferative nephritis, or

 Active and chronic glomerular lesions
Active lesions
Endocapilary hypercellularity with or without leukocyte
infiltration and with substantial luminal reduction
Karyorrhexis
Fibrinoid necrosis
Rupture of glomerular basement membrane
Crescents, cellular or fibrocellular
Subendothelial deposits identifiable by light microscopy (wire-
loops)
Intraluminal immune aggregates (hyaline thrombi)

Chronic lesions
Glomerular sclerosis (segmental, global)
Fibrous adhesions
Fibrous crescents
Lau Sing Chak, Atlas of Lupus Erythematosus 2007
 New Treatments for systemic lupus
erythematosus
Anticytokine therapies
AntiTNF
Anti-interleukin-1-receptor:anakinra
Anti-interleukin 10
Anti-interleukin 6 receptor
Anti-interferon alpha
Anti B-lympocyte stimulator (Blys)

Costimulation inhibition
AntiCD154
CTA4lg: abatacept

DCruz P David, Khamashta A Munther, Hughes RV Graham, Systemic lupus erythematosus,

Lancet 2007; 369:587-96