SLE Pathophysiology and Management

systemic lupus by prof dr SAMIR ALANSARY

1. SLE – An Overview and Update SAMIR EL ANSARY ICU PROFESSOR AIN SHAMS CAIRO [email protected]

2. 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

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

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

5. 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 Serositis *Systemic Lupus International Collaborating Clinics (SLICC)

6. 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)

7. 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

8. 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)

9. 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

10. 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

11. 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 ”

12. 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)

13. The Genetics of SLE

14. 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 ( Fc γ RIIA, Fc γ RIIIA) 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

15. 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

16. Increased Interferon Alpha (IFN α ) in Lupus The signature cytokine for the disease?

17. 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?

18. SLE How Does Tissue Injury Occur?

19. 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

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

21. 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

22. 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

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

24. SLE Therapeutic Approaches

25. 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)?*

26. 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

27. 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

28. 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 .

29. Elevated biomarkers in persistently aPL -positive patients; IL6 VEGF IP10 sCD40L INF α2 IL1 β TNF α 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 )

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

31. 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

32. 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).

33. 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 (IFN γ ) blockers: for renal lupus. Ongoing trials

34. GOOD LUCK SAMIR EL ANSARY ICU PROFESSOR AIN SHAMS CAIRO [email protected]