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Global Critical Carehttps://www.facebook.com/groups/1451610115129555/#!/groups/145161011512
9555/ Wellcome in our new group ..... Dr.SAMIR EL ANSARY
Systemic LupusErythematosus (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
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
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
New SLICC* Revision of the ACRClassification Criteria - Clinical
1. Acute/subacute cutaneous lupus2. Chronic cutaneous lupus3. Oral/Nasal ulcers4. Nonscarring alopecia5. 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)
New SLICC* Revision of the ACRClassification 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 casts8. Neurologic: seizures, psychosis, mononeuritis multiplex,
myelitis, peripheral or cranial neuropathy, cerebritis(acute confusional state)
9. Hemolytic anemia10. 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)
SLICC Revision of the ACRClassification 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) antibody4. 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 CH506. Direct Coombs test in the absence of hemolytic anemia
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)
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
• To compare ANA detection by multipleximmunobead assay with the gold standardimmunofluorescence (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
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”
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)
The Genetics of SLE
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
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
Increased Interferon Alpha (IFNα) in Lupus
The signature cytokine for the disease?
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?
SLEHow Does Tissue Injury
Occur?
SLESeveral 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
Lupus – Complement Levels
Patients who are always hypocomplementemic regardless of clinical disease activity may have an underlying complement deficiency!
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
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
Leading Causes of Death in SLE
Active lupus
Infection
Cardiovascular
disease
SLE
Therapeutic Approaches
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 (antiphospholipidsyndrome)?*
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
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
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 .
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)
NSAIDS and Steroids
INCREASES CARDIOVASCULAR DAMAGE AND SHOULD BE AVOIDED
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
The FutureBiomarkers 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).
The FutureBiomarkers 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
Global Critical Carehttps://www.facebook.com/groups/1451610115129555/#!/groups/145161011512
9555/ Wellcome in our new group ..... Dr.SAMIR EL ANSARY
