1 / 51

The ABC’s of SLE

The ABC’s of SLE. Katja F Daoud Providence Arthritis Center December 15, 2010. Today’s Topics. Define and describe the disease and it’s clinical spectrum Diagnosing the disease Address specific issues that arise in the management of lupus patients Review long term prognosis

cyndi
Télécharger la présentation

The ABC’s of SLE

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. The ABC’s of SLE Katja F Daoud Providence Arthritis Center December 15, 2010

  2. Today’s Topics • Define and describe the disease and it’s clinical spectrum • Diagnosing the disease • Address specific issues that arise in the management of lupus patients • Review long term prognosis • Snapshot of what is coming in treatment

  3. What is lupus? • Chronic inflammatory disease with underlying autoimmune process • Potential to affect most organ systems • Characterized by acute/chronic flares and periods of remission • Presentation variable; ranges from rash and arthralgia to life-threatening organ disease • Bimodal mortality pattern: early death from active disease and infection, later death from atherosclerotic disease

  4. Who gets lupus? • Females with 10:1 ratio • Has been reported in most countries • Incidence, prevalence, presentation and mortality all effected by gender, race and age • 5.7 in 100,000 for caucasian women aged 20-39 • 19.2 in 100,000 for african-american women • Countries with higher GDP and HDI (access to health care, physician availability, education level, treatment compliance) have better survival rates • Compared to other MS diagnoses: • 100x less common than RA • 250x less common than Fibromyalgia • 1000x less common than OA

  5. Epidemiology of SLE • Lupus registries since 1990’s • German Collaborative Arthritis Database 5% with lupus • 5 yr survival rates 96.6% • 10 yr survival 83-90% • Eurolupus project 1000 pts • 10 yr survival 92% (25% dz, 25% infection, 25% thrombosis) • 30% with nephritis • Japan SLE registry with over 50,000 pts • Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) Canada, UK, USA, South Korea • Lupus in Minorities: Nature vs nurture (LUMINA) started 1994 to study 3 different ethnic groups: Hispanic, African American and white • Differences in rates of lupus nephritis • GrupoLatinoamericano de Estudio del Lupus (GLADEL) 1214 pts Vasudevan et al, Rheum Disclin N Am 36 (2010)

  6. Genetic Factors • Polygenic disease- many genes identified by whole genome scans of affected families • multiple susceptiblity loci have been identified • Genes assoc with immune response/inflammation, DNA repair, inflam cells adherence to endothelium, tissue response to injury • Concordance rate for monozygotic twins 25%, dizygotic twins 2% • Environmental component in triggering disease • Viruses… EBV

  7. Pathogenesis

  8. Pathogenesis • B cells – • Immune dysregulation • Cytokines, present antigen, regulate T cell function • pathogenic autoantibodies lead to tissue damage • Immune complex formation • Complement activation • Direct effect on cells • T Cells –regulatory and effecter functions

  9. Case Presentation - CL • 19 yochinese female in US 4 yrs. 12/2006 • Fever to 104, ST 10 days then polyarthralgia, 4 # wt loss for one month, occaspleuritic CP • No prior medical issues, negative ROS • Exam polyarticular symmetric arthritis PIP/MCP, wrist, shoulder, knee, ankle, MTP • Initial Labs: • 3.6, 31.9, 202 lymph 1.1; nlcmp; rapid strep/blood cx/parvo/hepb/cneg; ANA 1:5120, RF neg, ESR 100; UA 4+ blood (menses) • Further labs: • C3 31, C4 <8, dsDNA 1836, repeat UA no blood, 2+ protein with 0.8 gm on spot

  10. Case CL • Does this pt have lupus? • If so, is there evidence of organ involvement? • Initial Treatment?: • What is the data for hydroxychloroquine and potential side effects? • Counseling: • What advice should be given regarding pregnancy and pregnancy prevention?

  11. Malar Rash 50% of patients Spares nasolabial fold DDx: Rosacea, seborrheic dermatitis

  12. Discoid Lupus Only 5% with pure DLE progress to SLE Central hypopigmentation, atrophy, scaling & follicular plugging, scar

  13. Photosensitivity MMo. Morison WL, NEJM March 2004; 350 (11), 1111-1117

  14. Photosensitivity Polymorphic Light Eruption -most common probably accounts for 90% of cases -Erythematous papules can have vesicles, may coalesce to form plaques -pruritis present

  15. Subacute cutaneous lupus -Punch biopsy can distinguish from PMLE -assoc anti SSA antibodies

  16. Lab Studies: What is an ANA? • Autoantibodies that react with antigens in cell nucleus including DNA, RNA, nuclear proteins, protein nucleic acid complexes • Detected currently by immunofluorescence or ELISA • Hep 2 cells (derived from human epithelial tumor cell lines) incubated with pt sera • Fluoresceinated antibody added which binds pt Ab if present

  17. Laboratory Studies: ANA • What should you order? • ANA screen: selected antigens and Hep 2 • Cost $65 • Reflexive Panel: screen plus ssDNA, dsDNA, RNP, Smith, SSA and SSB • Cost $700 ($115 for each individual test) • Quantitative Panel: all above run regardless of screen • Cost $700 ( if panel done)

  18. Laboratory studies: ANA • Highly sensitive for lupus; negative makes lupus unlikely • Low specificity… • Only send in pts with high suspicion of disease • If low pretest probability of disease, likely to get more false positives than true positives • ANA commonly seen in other diseases including • Other CTD’s, autoimmune disease (AI hepatitis, PBC, primary pulmonary hypertension, Graves disease, Hashimoto thyroiditis • Chronic infection (hepatitis C) • Medications (hydralazine, minocycline, Isoniazid, procainamide) • Healthy individuals • Elderly (10-37%) usually low titer

  19. Laboratory Studies: ANA • Not useful in predicting disease activity • In general, the titer is meaningful: • The higher the number the more meaningful it is • 125 healthy individual with + ANA, • 1:40 in 32% • 1:80 in 13% • 1:320 in 3%

  20. ANA - Specifics • Specific Antinuclear Antibodies: • ssDNA - nonspecific, clinically not useful • dsDNA - highly suggestive of lupus • associated with more severe disease including renal • Levels may correlate with disease activity • If positive but not active 80% will develop active dz within 5 yrs • Smith (small nuclear ribonucleoprotein, snRNP)– highly specific, insensitive for SLE • RNP – SLE, MCTD • SSA (Ro) – 50% of pts with SLE • Associated with photosensitivity, SCLE, ILD, neonatal lupus, fetal congential heart block (< 1% risk) • Histone – drug induced lupus • Scl 70 – diffuse systemic sclerosis • Centromere – limited systemic sclerosis

  21. Indications for prednisone • Proliferative glomerulonephritis • Diffuse CNS syndromes • Pneumonitis; myocarditis • Refractory serositis • Severe & refractory polyarthritis • Severe thrombocytopenia; hemolytic anemia • Vasculitis • Pregnancy with active disease

  22. Antimalarials for lupus Ruiz-Irastorza, et al Ann Rheum Dis 2010; 69: 20-28

  23. Antimalarial Drugs Ruiz-Irastorza, et al Ann Rheum Dis 2010; 69: 20-28

  24. Ruiz-Irastorza, et al Ann Rheum Dis 2010; 69: 20-28

  25. Antimalarial Drugs: Adverse Effects • Usually gastrointestinal or cutaneous • Retinal toxicity in meta-analysis: use >10 years • 16/647 on chloroquine (2.5%) • 2/2043 on HCQ (0.1%) • Wolfe and Marmor 2010: • 4,000 RA and SLE pt on HCQ • 6.5% discontinued drug due to eye problems, 1.8% reported retinal • Definite or probable documented in 0.65%, risk increases with duration of use > 7yrs Wolfe et al, Arth Care and Res June 2010; 62(6) 775-784

  26. Pregnancy and SLE • Fertility normal • Increase risk of fetal morbidity & mortality • Fetal complications • 25% pregnancy loss • 45% pre-term delivery • Neonatal lupus (associated with anti-Ro) • Decreased risk of flare if lupus inactive at conception • High risk OB should be involved early

  27. Pregnancy prevention Contraception: Culwell et al literature review addressing risk of OCP’s: 2 RCT NEJM 2005 • Excluded pt with severe disease and CI to OCP • Petri excluded mod- high levels of ACL or LA • Followed pts one year • Sachez-Guerrero et al: • Single blind, non-placebo controlled, randomized • 162 women • 54 combined oral contraceptive, 54 progesterone only, 54 IUD • No difference in disease activity or adverse events • Thrombotic events 4 ocp(all + APLA), 2 progesterone only • Petri et al: • Multicenter, double blind, placebo-controlled • 183 women combined ocpvs placebo • No difference in mild, mod or severe flare rate or adverse events • 5 thrombotic events 3 in placebo arm (APLA unknown) Culwell et al, August 2009; 114(2 part 1); 341-353

  28. Sanchez-Guerrero J et al, NEJM Dec 2005; 353(24): 2539-2549

  29. Contraception - Conclusions • Limited data regarding thrombotic outcomes in SLE with OCP use, but trend towards association -associated with APLA • May be associated with a reduction in musculoskeletal damage including muscle and bone • OCP: benefits > risk • Reasonable choice for pt with inactive or stable, moderate lupus at low risk for thrombosis

  30. Case # 1 - CL • 16 mos later develops 2.5 gms of proteinuria, hematuria in the setting of normal renal function. Biopsy shows WHO class IV GN • Induction treatment for Lupus nephritis- where are we now? • Long term prognosis/complications?

  31. Lupus Nephritis • Mycophenalatemofetil similar efficacy to IV cyclophosphamide for induction • No difference in infection, but less infertility • ALMS study failed to show superiority of MMF over cyclophosphamide: • Subgroup analysis racial and ethnic difference in response to treatment

  32. Forest plot of the primary outcome: complete and partial remission. Mak A et al. Rheumatology 2009;48:944-952

  33. Forest plots of the secondary outcomes (adverse events). Mak A et al. Rheumatology 2009;48:944-952

  34. Percentage of patients achieving the primary efficacy endpoint, by race and treatment group (A), where Black is a subset of the Other racial group; and percentage of patients achieving the primary efficacy endpoint, by region and treatment group (B) (intent-to-treat populations). Isenberg D et al. Rheumatology 2010;49:128-140

  35. Mortality • Approximate 5, 10, 15 yr survival 96%, 93%, 76% • Pt diagnosed at age 20 has 1 in 6 chance of dying by age 35 • Factors associated with mortality • Genetic background/ethnicity • Socioeconomic status • Male gender, late onset lupus • Disease activity and damage accrual

  36. Specific Causes of Mortality • Active disease • Infection • Assoc with standardized mortality ratio of 5 • One of most common causes of death in 1st 5 yrs • Malignancy • Slightly increased risk of cancer overall • Increased risk of cervical dysplasia • Atherosclerosis Ippolito A and Petri M, Clin Exp Rheum August 2008; 26(S51): S72-79

  37. Prognosis and Causes of Death in SLE • Prospective study of 207 consecutive pts • 17/207 pts died • 35% active disease, mean age 31 yrs • 64.7% from complications of dz or treatment • Risk factors male gender, positive LA, severe disease • Survival curves diverge after 10-15 yr in pts with mild vs severe disease

  38. Survival after diagnosis Doria A et al, Am J of Medicine June 2006; 119: 700-706

  39. Survival based on disease severity Doria A et al, Am J of Medicine June 2006; 119: 700-706

  40. atherosclerosis • Manzi et al 1997 – retrospective cohort 1980-1993 women compared to framingham offspring • 37/498 had CV event (7.4%) • 54 deceased mean age of 49 yrs • 33 MI/ 10 angina; 60% cath or autopsy and 82% had atherosclerosis • Concluded that SLE 52x more likely to have MI b/t ages of 35-44 controlling for all other risk factors Manzi et al, Am J Epid 1997; 145 (5)

  41. atherosclerosis • Atherogenic effect of inflammation • Endothelial dysfunction • Induces secondary dyslipidemia • Active coagulation cascade • SLE • Proinflammatory • Pro-oxidative Van Leuven et al, Rheumatology 2008; 47: 3-7

  42. atherosclerosis

  43. Atherosclerosis and risk factors: LASER study • UK population 13 centers: BILAG and special interest grp • Retrospective chart review 53 cases of CV event and 96 controls matched only by disease duration • 23 MI (43%) and 30 angina (56%) • Mean age of 1st event 53 (range 33-73), 12 occurred under age of 45 • 52 survived initial event; 12 (23%) died over next 8 yrs • Older 53 vs 42 and more likely to be male 11(20%) vs 3 (7%) • All classic risk factors more common (htn, lipids, tobacco, F Hx and BMI) Haque S et al, J of Rheum 2010; 37:2

  44. SLICC registry for atherosclerosis • 26 centers in 11 countries including N America, Europe, Asia, 1249 pts between 2000-2008 • 89.5% women, 50% white, 15% each hispanic/asian/africanamerican, disease duration 5.5 mos • Atherosclerotic vascular events • More likely to be men 11% of cohort, 41% of events • Age at diagnosis • HTN, obesity, smokers, Fhx Urowitz MB et al, Arth Care and Res June 2010; 62: 6

  45. What is new? • Benlysta, Lupus Treatment, Endorsed by F.D.A.
Benlysta would be the first approved drug to treat lupus in • Human Genome Sciences shares dropped from $115 to 50 cents in a decade, but now some analysts expect its new drug, Benlysta, to become a huge seller. ... • Lupus Drug Benefits Questioned by F.D.A.
If Benlysta is approved, its annual global sales are forecast at $2.2 billion ... Human Genome will split Benlysta profits with a partner, 
GlaxoSmithKline PLC. • The agency had concerns about suicide and other possible risks from the drug, Benlysta, but analysts said they still expected approval. November 13, 2010

  46. Targeted Therapeutic Approaches for treatment Rahman et al. NEJM February 358; 9

  47. Treatments on the horizon

More Related