This document provides an overview and update on systemic lupus erythematosus (SLE). It discusses the definition and classification criteria for SLE, including revisions to the criteria. Genetic factors contributing to SLE susceptibility are described. Increased levels of interferon alpha are implicated in the disease pathogenesis. Clinical manifestations and leading causes of mortality in SLE patients are summarized. Current therapeutic approaches for SLE, including hydroxychloroquine, belimumab, and targeted therapies in development are outlined.

1. SLE – An Overview and Update
SAMIR EL ANSARY
ICU PROFESSOR
AIN SHAMS
CAIRO
elansarysamir@yahoo.com

2. Global Critical Care
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3. Systemic Lupus
Erythematosus (SLE)
• Definition: a chronic inflammatory systemic
autoimmune disease of unknown etiology
characterized by polyclonal B-cell activation and
abnormal autoantibodies
• Not one disease but several clinical subsets, some
mild, e.g., “skin and joint” lupus, and others more
severe, with profound thrombocytopenia, thrombosis
from APS (antiphospholipid syndrome), and severe
renal, lung, and CNS involvement

4. SLE Classification Criteria
1. Malar (butterfly) rash
2. Discoid lesions
3. Photosensitivity
4. Oral ulcers
5. Non-deforming arthritis (non-erosive for the most part)
6. Serositis: pleuropericarditis, aseptic peritonitis
7. Renal: persistent proteinuria › 0.5 g/d or ›3+ or cellular
casts
Definite SLE = 4 or more positive criteria

5. SLE Classification Criteria
1. Neurologic disorders: seizures, psychosis
2. Heme: hemolytic anemia; leukopenia,
thrombocytopenia
3. Immune: anti-DNA, or anti-Sm, or APS (ACA IgG,
IgM), or lupus anticoagulant (standard) or false +
RPR
4. Positive FANA (fluorescent antinuclear antibody)
Definite SLE = 4 or more positive criteria

6. New SLICC* Revision of the ACR
Classification Criteria - Clinical
1. Acute/subacute cutaneous lupus
2. Chronic cutaneous lupus
3. Oral/Nasal ulcers
4. Nonscarring alopecia
5. Inflammatory synovitis with physician-observed swelling
of two or more
joints OR tender joints with morning stiffness
6. Serositis
*Systemic Lupus International Collaborating Clinics (SLICC)

7. New SLICC* Revision of the ACR
Classification Criteria - Clinical
7. Renal: Urine protein/creatinine (or 24 hr urine protein)
representing at
least 500 mg of protein/24 hours or red blood cell casts
8. Neurologic: seizures, psychosis, mononeuritis multiplex,
myelitis, peripheral or cranial neuropathy, cerebritis
(acute confusional state)
9. Hemolytic anemia
10. Leukopenia (< 4000/mm3 at least once) OR
Lymphopenia (< 1000/mm3 at least once)
11. Thrombocytopenia (<100,000/mm3) at least once
*Systemic Lupus International Collaborating Clinics (SLICC)

8. SLICC Revision of the ACR
Classification Criteria – Immunologic
1. ANA (antinuclear antibody) above laboratory reference
range
2. Anti-dsDNA above laboratory reference range (except
ELISA: twice above laboratory reference range)
3. Anti-Sm (anti-Smith) antibody
4. APS abs: LAC, false-positive test for syphilis,
anticardiolipin IgG, IgM, or IgA Abs, at least twice
normal or medium-high titer, same for anti-B2
glycoprotein 1
5. Low complement: low C3, low C4, low CH50
6. Direct Coombs test in the absence of hemolytic anemia

9. Lupus - SLICC* 17 New Classification Criteria: 4
needed
• At least 1 clinical plus at least 1 immunologic
criteria (for a total of 4)
or
• Lupus nephritis by biopsy as the sole clinical
criterion plus SLE autoantibodies: (+) ANA or
(+) anti-dsDNA
*Systemic Lupus International Collaborating Clinics (SLICC)

10. The Use of ANA for Screening
• Anti-nuclear antibody (ANA) is considered a
screening method for diagnosis of autoimmune
disorders
• Immunofluorescence ANA assay (IF) remains the gold
standard for detection of ANA {position statement)
• Many laboratories perform immunoassays (such as
the multiplexed immunobead assay), for the
detection of ANA as it is less labor-intensive

11. • To compare ANA detection by multiplex
immunobead assay with the gold standard
immunofluorescence (IF)
• Patient samples tested for both assays:
• Multiplex immunobead assay (MIA) were
considered positive based on the
manufacturer’s instructions
• Immunofluorescence (IF) was considered
positive at a titer ≥ 1:160

12. Methods
• Data collected prospectively on rheumatology patients
tested for ANA by multiplex immunobead assay MIA
• Performance characteristics of the immuno-assay were
determined using the IF results as the “gold standard”

13. Conclusions
• Patients tested negative by the MIA (bioplex) included
patients with definite ANA-associated autoimmune diseases
• These data suggest that screening with an immunoassay
would result in misclassification and potential delay or
missed diagnoses of certain systemic autoimmune diseases -
Multiplex immunobead assay unreliable
• Immunofluorescence (IF) should remain the preferred assay
for ANA testing in patients with suspicion of autoimmune
disorders until platforms with sensitivities comparable to IF
or better are developed. IF the preferred method – Endorsed
by the American College of Rheumatology (ACR)

14. The Genetics of SLE

15. SLE – Genetic Susceptibility
MHC Related
• HLA-DR1, 2, 3, 4
• Alleles of HLA-DRB1, IRF5,
and STAT4
• C2 - C4 deficiency
• TNF- polymorphisms
Not MHC Related
• C1q deficiency (rare but highest risk)
• Chromosome 1 region 1q41-43 (PARP),
region 1q23 (FcγRIIA, FcγRIIIA)
• IL-10, IL-6 and MBL polymorphisms
• Chromosome 8.p23.1: reduced
expression of BLK and increased
expression of C8orf13 (B cell tyrosine
kinase), chromosome 16p11.22: integrin
 genes IGAM-ITGAX
• B cell gene BANK1
• X chromosome-linked gene IRAK1
MHC = Major Histocompatibility Complex

16. The Genetics of Lupus – A Complex Disease
Immune complex
processing: C1q, C2-4, CRP,
ITGAM, FcGR2A, etc
TLR/type I, IFN pathway:
STAT 1, IRAK1,
TREX1, etc
Immune signal
transduction: HLA-DR, IRF5,
STAT4, BANK1, PTPN22, BLK,
TNFSF4, etc
TLR = Toll-like receptor
IFN = interferon

17. Increased Interferon Alpha
(IFNα) in Lupus
The signature cytokine for the disease?

18. Is It Lupus or IFN- Side Effects?
IFN  side effects
 Cytopenias
 Anemia
 Arthralgias/myalgias
 Skin rash
 Alopecia
 (+) autoantibodies
 Fever, malaise/flu-like
syndrome
 Seizures, pneumonitis,
etc
Lupus clinical features
Basically the same
constellation of
signs/symptoms plus
(+) autoantibodies
One and the same?

19. SLE
How Does Tissue Injury
Occur?

20. SLE
Several Pathogenetic Mechanisms
• Immune complex-mediated damage: glomerulonephritis
• Direct autoantibody-induced damage: thrombocytopenia
and hemolytic anemia
• APS-induced thrombosis and pregnancy morbidity
• BLyS (BAFF)-APRIL (B lymphocyte stimulators) over-
expression:  IFN, TNF, IL-1, IL-6, IL-17, etc
• Complement-mediated inflammation: CNS lupus (C3a),
hypoxemia, and also anti-phospholipid mediated fetal loss
• Either failure of or abnormal response to normal apoptosis

22. Lupus – Complement Levels
Patients who are always
hypocomplementemic regardless of
clinical disease activity may have an
underlying complement deficiency!

23. Mortality in Lupus - Bimodal Peaks
Early:
• Increased disease activity
• Infections due to immunosuppression
Late:
• Deaths the result of permanent damage: treatment side
effects, atherosclerosis with CAD and heart attacks,
strokes, pulmonary, end-stage renal disease (ESRD), etc

24. Coronary Heart Disease in Lupus
Premature or Accelerated Atherosclerosis
 The prevalence ranges from 6 to 15%
 The incidence of a MI is 5 times higher in lupus than
in the general population
 The risk of adverse cardiovascular outcomes is  by
a factor of 7 to 17 in patients with lupus
 Young women (between ages 35 and 44) are
significantly more likely (52-fold increased risk) to
experience an MI if they have lupus
 Reasons: multifactorial and not explained just by the
traditional CAD risk factors

25. Leading Causes of Death in SLE
 Active lupus
 Infection
 Cardiovascular
disease

26. SLE
Therapeutic
Approaches

27. Treatment of Lupus
• Vitamin D (an immunomodulator!)
• Hydroxychloroquine (HCQ) (Plaquenil®)
• Corticosteroids – Minimize to the extent possible
• Immunosuppressive agents (MTX, azathioprine,
mycophenolate mofetil, etc)
• Targeted biologic therapies: belimumab (Benlysta®),
rituximab (Rituxan®)
• Statins? especially for APS (antiphospholipid
syndrome)?*

28. Every patient with lupus should be on vitamin D
and hydroxychloroquine (HCQ)!
• A 20-ng/ml increase in the 25 (OH) D level was
associated with a 21% decrease in the odds of
having a high disease activity score
• There was no evidence of additional benefit of
25 (OH) D beyond a level of 40 ng/ml

29. Hydroxychloroquine (HCQ)
• It prevents thrombotic events in lupus patients.
• HCQ is an anti-platelet agent, inhibiting aPL-
induced GPIIb/IIIa expression; it does not prolong
bleeding time
• It prevents lupus flare-ups and progression of
disease, including lupus nephritis . It prevents
diabetes in patients with RA receiving it

30. Hydroxychloroquine (HCQ)
• It lowers glycemia and lipids (although
modestly)
• It downregulates inflammation at different
levels: prostaglandins, DNA Abs, T cell
activation, inhibits intracellular TLR
activation , inhibits IFN-a, IL-1 and IL-6
production .

31. Elevated biomarkers in persistently
aPL-positive patients;
– IL6
– VEGF
– IP10
– sCD40L
– INFα2
– IL1β
– TNFα
– sTF
– sICAM-1
Fluvastatin 40 mg daily for 3
months reduced the levels of the
following biomarkers in
persistently aPL-positive patients
– IL1β
– VEGF
– TNFα
– IP10
– sCD40L
– sTF
Fluvastatin effects
Fluvastatin significantly and reversibly reduced the levels of
biomarkers (IL1β, VEGF, TNFα, IP10, sCD40L and sTF)

32. NSAIDS and Steroids
INCREASES CARDIOVASCULAR
DAMAGE AND SHOULD BE AVOIDED

33. New FDA-Approved Agent – Belimumab
(Benlysta®)
• Anti-BLYS humanized monoclonal antibody.
• Problematic indications: not for thrombocytopenia,
CNS, or renal lupus
• Helpful but modest efficacy
• It helps reduce steroids, prevent flares, and
maintain disease remission

34. The Future
Biomarkers and Targeted Therapies
• Develop better biomarkers for flares and
predictors of response
• Corticosteroid-free regimens
• Other B cell blockers, e.g., ocrelizumab,
epratuzumab, TACI-Ig (atacicept, an anti-
BLyS/April agent).

35. The Future
Biomarkers and Targeted Therapies
Ongoing trials :
• Interferon alpha (IFN) blockers, e.g.,
sifalimumab. Good promising data. Ongoing trials
• Anti-C5: humanized monoclonal Ab, especially
for APS, ongoing trials.
• Interferon gamma (IFNγ) blockers: for renal
lupus. Ongoing trials

36. Global Critical Care
https://www.facebook.com/groups/1451610115129555/#!/groups/145161011512
9555/
Wellcome in our new group ..... Dr.SAMIR EL ANSARY

37. GOOD LUCK
SAMIR EL ANSARY
ICU PROFESSOR
AIN SHAMS
CAIRO
elansarysamir@yahoo.com