Am 9.30 manzi

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  • Similar for heart prevention
  • Similar for heart prevention
  • Define osteoporosis to illustrate importance of fractures as the primary outcome to prevent in young women, note that fracture rate was 12% in this group of 702 women Also older age at disease onset (median age 33) and duration of steroid use independent risk factors for predicting fracture risk
  • Similar for heart prevention
  • * Most of the information in the slides dealing with the international study of cancer risk in lupus also appears in the curriculum development and rough draft decks, though represented differently.
  • CC Objective: To determine if cancer incidence is increased in SLE 23 sites: 9547 patients; 76,948 patient-years; 1958-2000 Pooled cohort studies: 2762 patients, 23,696 patient-years
  • Similar for heart prevention
  • Am 9.30 manzi

    1. 1. Lupus in Women: Emerging Strategies Women’s Health Congress 2012 Washington DC March 2012 Susan Manzi, MD, MPHChair, Department of Medicine Allegheny General Professor Medicine Temple University Director, Lupus Center of Excellence Pittsburgh, PA
    2. 2. Di s cl os ures• Consultant and Scientific Advisory Board GSK/HGS
    3. 3. Topics for DiscussionWhat is lupus?Why is diagnosis so difficult..even for rheumatologists?What are the recent updates on pathogenesis?What happens to patients with lupus?Why are current treatments suboptimal?What’s on the horizon?
    4. 4. Topics for DiscussionWhat is lupus?Why is diagnosis so difficult..even for rheumatologists?What are the recent updates on pathogenesis?What happens to patients with lupus?Why are current treatments suboptimal?What’s on the horizon?
    5. 5. Gender Disparity and AutoimmunityDisease Female/Male RatioThyroid diseases Diffuse lymphocytic thyroiditis 25-50:1Primary hyperthyroidism (Graves) 4-8:1Systemic lupus erythematosus 9:1 ages of 15-45 12:1 elderly/children 2:1Rheumatoid arthritis 2-4:1Sjogren’s syndrome 9:1Idiopathic adrenal insufficiency 2-3:1
    6. 6. Misdiagnosis of SLE 263 referred for SLE - 134 (51%) SLE - 4 (1.5%) Systemic sclerosis - 7 (2.6%) Sjogrens - 1 (<1%) PM/DM - 14 (5%) Fibromyalgia - 76 (29%) Antinuclear Antibody (ANA) (+) - 27 (10%) Non-rheumatic diseaseDiagnostic accuracy 80% rheum 50% non rheum Arch Intern Med. 2004;164:2435-2441
    7. 7. Clinical PearlANA (+) ≠ LupusANA : 95% Sensitive 11% PPV
    8. 8. Misdiagnosis can go both ways. It takes an average of 4 yrs and 3 physicians for the correct diagnosis. Clinical PearlYou have to think of lupus to diagnosis lupus
    9. 9. Classification Criteria for SLE (As revised in 1997 by the American College of Rheumatology)A person is said to have SLE if four of these criteria are present at any time:Skin criteria• Butterfly rash (lupus rash over the cheeks and nose)• Discoid rash (thick rash that scars, usually on sun-exposed areas• Sun sensitivity• Oral ulcerationsSystemic criteria• Arthritis• Serositis• Proteinuria or cellular urinary casts• Seizures or psychosis with no other explanationLaboratory criteria• Hemolytic anemia, leukopenia, or thrombocytopenia• Antiphospholipid antibodies, lupus anticoagulant, anti-DNA antibodies, false positive Syphilis test, or anti-Sm antibodies• Antinuclear antibody
    10. 10. Autoantibody Determined Clinical Subsets of SLE SSA (Ro) SSB (La) RNP phospholipids Ribosomal-P dsDNA ANA (+)>95% patientsANA + > 90%, nonspecific
    11. 11. Autoantibody Determined Clinical Subsets of SLE SSA/SSB (rash and neonatal lupus, dry eyes and mouth) RNP (Raynauds) Phospholipid (clotting and miscarriage)Ribosomal-P dsDNA (kidney disease)(CNS, psychosis)
    12. 12. Diagnostic ChallengesInterpretation of criteriaManifestations not in criteriaOther diseases may mimick lupusEvolving signs and symptoms over timeNo two patients look alike
    13. 13. Disease MimickersFibromyalgia (+ ANA)Sjogren’s syndromeDermatomyositis and TTPITPPrimary antiphospholipid syndromeNeoplasms (hematologic)Drug-induced lupus
    14. 14. Pathogenesis of SLE Tissue Damage Environmental Complement activationGenetic Gender Immune Complexes Defective Immune Regulation Autoantibodies Break in self tolerance
    15. 15. Lupus GeneticsClustering in families (autoimmunity)Concordance - monozygotic (identical twins) 25-30% - dizygotic 5%
    16. 16. ITGAMBLKBank1
    17. 17. Genes increase susceptibility to SLEIn the major histocompatibility complex (MHC) C2,C4 deficiency DR2,DR3 TNF-α polymorphismsIn non-MHC C1q deficiency (rare, but greatest risk!!) Chromosome 1 region 1q41-43 (PARP) region 1q23 (FcγRIIA, RIIIA) Polymorphisms in IL-10, IL-6 and mannose-binding protein STAT4 and IRF5
    18. 18. Genes increase susceptibility to SLEIn the major histocompatibility complex (MHC) C2,C4 deficiency DR2,DR3 TNF-α polymorphismsIn non-MHC C1q deficiency (rare, but greatest risk!!) Chromosome 1 region 1q41-43 (PARP) region 1q23 (FcγRIIA, RIIIA) Polymorphisms in IL-10, IL-6 and mannose-binding protein STAT4 and IRF5
    19. 19. Homozygous deficiency C1q 38/41 (93%) C4 14/16 (88%) C2 38/66 (58%)95% of lupus is polygenic
    20. 20. C1q plays a role in clearly apoptotic blebs
    21. 21. Pathogenesis of SLE Apoptotic cells are a source of autoantigens Lupus is characterized by a defect in apoptotic cell clearance
    22. 22. Why sun exposure may trigger lupus
    23. 23. Clinical PearlPhotoprotection is important in lupusSunblocks, photoprotective clothing
    24. 24. Survival in lupus has improved.1950 5 year survival 50%2000 10 year survival 80-90%
    25. 25. Reasons for improved survival Corticosteroids (1950) Dialysis Cyclophosphamide Anti-hypertensive Antibiotics Earlier diagnosis
    26. 26. Causes of morbidity and mortalityEarly Late lupus cardiovascular kidney osteoporosisinfection cancer
    27. 27. Natural History of SLE• Disease flares/activity (reversible) inflammation• Organ damage (irreversible) from disease or treatment scarring
    28. 28. Longterm Health Issues in Lupus Bone Cancer Cardiovascular
    29. 29. Longterm Health Issues in Lupus Bone Cancer Cardiovascular
    30. 30. Expected and Observed Number of Fractures in Women With Lupus Expected Observed 100 90 80 70 60 50 40 30 Number of fractures 20 10 0 <18 18-24 25-44 45-64 65-69 70+ Total Age (years)Ramsey-Goldman et al. Arthritis Rheum. 1999;42:882-890.
    31. 31. Osteopenia in women with SLE Caucasians (n=222) African-Americans (n=77)Lee C, Arthritis Rheum. 2007;57:585-592
    32. 32. Osteoporosis in Women with SLE Caucasians (n=222) African-Americans (n=77)Lee C, Arthritis Rheum. 2007;57:585-592
    33. 33. Adjusted risk factors for low bone mineral density (BMD) in women with SLE * Low Forearm Low Hip BMD Low Spine BMD BMD Risk Factor Adjusted Adjusted Adjusted OR (95% CI) OR (95% CI) OR (95% CI)African- 1.94 5.49 0.56 (0.93, 4.02) (2.67, 11.32) (0.18, 1.74)American raceAdjusting for age, BMI, steroid use, thyroid disease, menopausal status*Low BMD defined as either osteopenia or osteoporosis based on T-score.
    34. 34. Clinical PearlsFracture rates are greater than expected inwomen with lupusWomen with lupus have higher than expectedfrequencies of osteopenia/osteoporosisAfrican American women with lupus are notprotected from this risk (spine)
    35. 35. Longterm Health Issues in Lupus Bone Cancer Cardiovascular
    36. 36. Relative Risk for Malignancy in SLE Study SIR Point Estimate (95% CI) Peterson 1992 2.6 (1.5, 4.4) Sweeney 1995 1.4 (0.5, 3.0) Abu-Shakra 1996 1.1 (0.7, 1.6) Mellemkjaer 1997 1.3 (1.1, 1.6) Ramsey-Goldman 1998 2.0 (1.4, 2.9) Sultan 2000 1.2 (0.5, 2.1) Nived 2001 1.5 (0.8, 2.6) Bjornadel 2002 1.4 (1.3, 1.5) Cibere 2001 1.6 (1.1, 2.3) 0 1 2 3 4 5 SIRSIR, standardized incidence ratio; CI, confidence interval.Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490.
    37. 37. International Study of Cancer Risk in SLE CaNIOS and SLICC Participants Outcomes ● SIR and SMR (observed/expected rates) ● Linkage to regional tumor registriesBernatsky et al. Arthritis Rheum. 2005;52:1481-1490.
    38. 38. International Study of Cancer Risk in Lupus• 23 sites - 9547 patients - 76,948 patient-years - Calendar period 1958 - 2000• Pooled cohort studies - 2762 patients - 23,696 patient-yearsBernatsky et al. Arthritis Rheum. 2005;52:1481-1490
    39. 39. Total Number of Cancers Observed and Expected, with Standardized Incidence RatiosMalignancy Observed Expected SIR 95% CI Total 431 373.3 1.2 1.1, 1.3Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490
    40. 40. Hematologic Cancers, Standardized Incidence RatiosMalignancy Observed Expected SIR 95%CIAll Heme 67 24.4 2.8 2.1, 3.5NHL 42 11.5 3.6 2.6, 4.9HL 5 2.1 2.4 0.8, 5.5Leukemia 7 3.7 1.9 0.8, 3.9Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490
    41. 41. Reproductive Cancers, Standardized Incidence RatiosMalignancy Observed Expected SIR 95% CIBreast 73 96.1 0.8 0.6, 1.0Ovary 9 14.5 0.6 0.3, 1.2Cervix 14 11.1 1.3 0.7, 2.1Vagina 2 0.4 4.9 0.5, 18Vulva 2 1.3 1.6 0.2, 5.8Uterus 6 16.9 0.4 0.1, 0.8Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490
    42. 42. Other Cancers, Standardized Incidence Ratios Malignancy SIR 95% CI Lung 1.4 1.1, 1.8 Hepatobiliary 2.6 1.3, 4.8 Pancreas 0.9 0.4, 1.9 Gastric 1.1 0.5, 2.0 Colorectal 1.0 0.7, 1.4 Thyroid 1.5 0.7, 2.8 Bladder 1.2 0.7, 2.1 Prostate 0.7 0.3, 1.4 Melanoma 1.0 0.4, 1.8Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490
    43. 43. Clinical PearlsIncreased risk of cancer in SLE comparedwith general populationGreatest risk: - Hematologic (lymphoma) - Possibly lung and hepatobiliary
    44. 44. Longterm Health Issues in Lupus Bone Cancer Cardiovascular
    45. 45. Incidence rates of myocardial infarction in 498 womenwith SLE (Pittsburgh) and 2208 women from theFramingham Offspring Study: 1980-1993 Myocardial Infarction (per 1000 person- years) SLE FraminghamAge (years) Rate Rate Rate Ratio 95%CI 15-24 6.33 0.00 ∞ − 25-34 3.66 0.00 ∞ − 35-44 8.39 0.16 52.43 [21.6, 98.5] 45-54 4.82 1.95 2.47 [0.8, 6.0] 55-64 8.38 1.99 4.21 [1.7, 7.9]Manzi, et al. Am J Epidemiol, 1997
    46. 46. Prevalence of Coronary Calcification in SLE and Controls 100 90 80 70 60 50 SLEFreq % 40 Control 30 20 10 0 <40 40-49 50-59 >60 YearsSLE 20/65 (31%): Controls 6/69 (9%) NEJM 2003;349:2407Calcification score > 0
    47. 47. Prevalence of Carotid Atherosclerosis in SLE and Controls 80 70 60 50Freq % 40 SLE 30 Controls 20 10 0 <40 50-59 60-69 >70 Years NEJM 2003;349:2399SLE 37.1%: Controls 15.2%
    48. 48. Role of Traditional Risk FactorsAfter adjusting for baseline CHD risk using the Framingham risk factor estimate, patients with SLE still had a 7- to 10-fold increased risk of CHD and stroke. RR = 17 for fatal CHD Esdaile JM, Arthritis Rheum 2001
    49. 49. Cardiovascular Biomarkers and Surrogate Endpoints SymposiumProven biomarkers aPL, pro-inflammatory HDL, LDL, B/P CECs, complement activation,Proposed new biomarkers iNOS, AGEs CRP, MPO, Ox-LDL, Anti-oxLDL IL-6, IL-1, IL-18, TNFα, MMP-9, Lp-PLA2 M-CSF-1, ICAM-1, P-Selectin, VCAM-1
    50. 50. Preventive Cardiology Intervention in SLESLE Patients seen at the University of Pittsburgh Lupus Center 45 40 35 30 25 % 20 15 10 5 0 1 2 3 4 5 6 7 8 # risk factors ¥89.7% have 3 or more CV risk factors Unpublished data, Pgh
    51. 51. Clinical PearlSLE patients are at significant risk for atherosclerotic CVDThis risk cannot be fully explained by traditional risk factors aloneAwareness and practical approaches to management
    52. 52. Clinical Pearls HRT and OCPs do not increase the risk of significant disease activity in lupusCaveat: Lupus women have increased risk ofCVD and thrombosis.
    53. 53. FDA Approved Drugs for SLE Corticosteroids Hydroxychloroquine ASA Benlysta Approved March 2011
    54. 54. On the Horizon…
    55. 55. Summary• Lupus is difficult to diagnose (ANA ≠lupus)• Lupus is characterized by a break in defective clearance of apoptotic cells (photoprotection important)• Lupus patients have higher than expected bone loss,cancer risk and CVD (advanced aging)• Drought in drug development in lupus...now with promising biologic therapies in clinical trial

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