Get into the Research


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  • Many authors concluded that anti ds DNA Ab were largely unhelpful in detecting or predicting clinical flare. However, many of us have seen patients developing severe clinical flare, especially Lupus nephropathy following the increase of dsDNA Ab titers. WHAT IF THE QUESTION OF DsDNA could be resolved by looking at it in a new perspective?
  • Get into the Research

    1. 1. NANCY PAN, MD HOSPITAL FOR SPECIAL SURGERY NEW YORK JULY 7, 2011 Third Year Pediatric Rheumatology Fellows’ Conference
    2. 2. Background <ul><li>SLE has a relapse-remitting pattern, characterized by exacerbations and remissions </li></ul><ul><li>Difficult to define “SLE flare” using global measures of disease activity </li></ul><ul><li>Concept of flare is very complex, not one universally accepted definition </li></ul><ul><li>Lack of consensus as to whether changes in serology or therapy should be incorporated into definition </li></ul><ul><li>What if there is improvement in one organ but deterioration in another? Or worsening of chronic disease? (should this be considered new flare?) </li></ul>
    3. 3. Is dsDNA antibodies a good biomarker? <ul><li>dsDNA antibodies commonly considered specific biomarkers in diagnosis and follow up in SLE, but not all detectable anti dsDNA Ab are clinically relevant </li></ul><ul><li>dsDNA antibodies found in 40-85% of pts depending on method used to detect it </li></ul><ul><li>presence may precede the diagnosis of SLE for more than 1 yr </li></ul><ul><li>IgG Ab more pathogenic in SLE </li></ul><ul><li>IgM Ab less associated with active disease </li></ul><ul><ul><li>also seen in RA, MCTD and active hepatitis </li></ul></ul><ul><li>Anti-dsDNA Ab is used by 92% US rheumatologists to monitor disease activity (1) but: </li></ul><ul><li>SLE patients can have : </li></ul><ul><ul><li>↑ titers with no activity (2) </li></ul></ul><ul><ul><li>↑ activity with low or absent dsDNA Ab (3) </li></ul></ul><ul><ul><li>↓ titers at the time of clinical flare (4) </li></ul></ul>1. Donald, F. and M.M. Ward, Evaluative laboratory testing practices of United States rheumatologists. Arthritis Rheum, 1998. 41(4): p. 725-9. 2. Walz LeBlanc, B.A., D.D. Gladman, and M.B. Urowitz, Serologically active clinically quiescent systemic lupus erythematosus--predictors of clinical flares. J Rheumatol, 1994. 21(12): p. 2239-41. 3. Gladman, D.D., et al., Clinically active serologically quiescent systemic lupus erythematosus. J Rheumatol, 2003. 30(9): p. 1960-2. 4. Ho, A., et al., Decreases in anti-double-stranded DNA levels are associated with concurrent flares in patients with systemic lupus erythematosus. Arthritis Rheum, 2001. 44(10): p. 2342-9.
    4. 4. Yes: DsDNA Ab relationship with clinical SLE flare <ul><li>Borg et al “Measurement of increases in anti-double stranded DNA antibody levels as a predictor of disease exacerbation in systemic lupus erythematosus.” Arthritis Rheum 1990 </li></ul><ul><li>Boostma et al”Prevention of relapses in systemic lupus erythematosus.” Lancet 1995 </li></ul><ul><li>Boostma et al “Predictive value of fluctuations in IgM and IgG class anti ds DNA antibodies for relapses in systemic lupus erythematousus: a prospective long term observation” Annals of Rheum Dis 1997 </li></ul><ul><li>Sontheimer RD et al. “DNA antibody class, subclass and complement fixation in systemic lupus erythematousus with and without nephritis.” Clin Immunol Immunopathol 1978 </li></ul><ul><li>Miniter MF et al, “Rassessment of the clinical significance of native DNA antibodies in systemic lupus erythematosus” Arthritis Rheum 1979 </li></ul><ul><li>Swaak AJG et al. “Predictive value of complement profiles and anti dsDNA in systemic lupus erythematosus” Ann Rheum Dis 1986 </li></ul>
    5. 5. No relationship of dsDNA titers with SLE flare <ul><li>Esdaile, JM et al Laboratory tests as predictors of disease exacerbations in systemic lupus erythematosus Arthritis Rheum 1996 </li></ul><ul><li>Petri et al “Definition, incidence and clinical description of flare in systemic lupus erythematosus” Arthritis Rheum 1991 </li></ul><ul><li>Loes van den berg et al. Prior antidsDNA antibody status does not predict later disease manifestations in SLE. Clin Rheum 2006 </li></ul>
    6. 6. Changes in dsDNA titer altering management <ul><li>Boostma et al – reported treatment with prednisone reduced likelihood of flare without increasing the cumulative dose of corticosteroids in asymptomatic patients whose sera demonstrated rising titers of anti-dsDNA antibodies </li></ul><ul><li>Tseng et al: prospective, randomized, placebo controlled, double-blinded study – low to moderate dose steroids in patients with a 50% elevation in C3a and 25% increase in dsDNA titers </li></ul>
    7. 7. Clinical Question <ul><li>Is there a clinically relevant way to interpret changes in dsDNA titer? </li></ul><ul><li>Use of the currently utilized assays for dsDNA detection </li></ul><ul><li>What is the role of a rapid and dramatic rise in dsDNA titer in a clinically quiescent patient with SLE? </li></ul><ul><ul><li>Does it herald a clinically significant SLE flare? </li></ul></ul>
    8. 8. Methods <ul><li>Utilized the SLE Registry at HSS </li></ul><ul><li>Prospectively collected data on a cohort of SLE patients </li></ul><ul><ul><li>Including laboratory parameters checked at each visit (including dsDNA titer) </li></ul></ul><ul><ul><li>SLEDAI, BILAG, SLICC </li></ul></ul><ul><li>All patients will fulfill the 1982 ACR revised criteria for SLE </li></ul><ul><li>All patients who are enrolled in the HSS SLE registry cohort from 1994 to 2010 and have at least two anti-dsDNA tests recorded ( Crithidia) </li></ul>
    9. 9. Definitions <ul><li>DNA Flare is defined as a rapid and substantial increase of anti-double stranded DNA (anti-dsDNA) titers (from 0 to 3+/4+, or from 1+ to 4+) within a period of less than 12 months. Those SLE patients whose disease course is characterized by one or more DNA Flares were considered the Cases. </li></ul><ul><li>Disease Control patients were patients whose disease course is not characterized by DNA Flares . Two Controls were matched to each Case. More specifically, controls will be identified as the first two patients to be enrolled in the registry after the corresponding case and who match to the case for age, sex, and race. </li></ul>
    10. 10. Objectives <ul><li>Assess in patients with SLE the association between : </li></ul><ul><ul><ul><li>“ DNA flare” and a subsequent Severe Clinical flare </li></ul></ul></ul><ul><ul><ul><li>“ DNA flare” and a subsequent Renal flare </li></ul></ul></ul><ul><ul><ul><li>“ DNA flare” and a subsequent Mild-Moderate Clinical flare </li></ul></ul></ul><ul><li>Characterize the type of clinical flares by: </li></ul><ul><ul><ul><li>Severity </li></ul></ul></ul><ul><ul><ul><li>Organ involvement </li></ul></ul></ul><ul><ul><ul><li>Time to development in regard to each “ DNA flare” </li></ul></ul></ul>
    11. 11. Definitions <ul><li>Day 0 is defined as: </li></ul><ul><ul><li>1. the date of DNA Flare (for Cases), and </li></ul></ul><ul><ul><li>2. for Controls as their closest next date in the registry to the date of DNA Flare of their corresponding Case   </li></ul></ul><ul><li>- Clinical Flares are defined using the definition of a flare according to the </li></ul><ul><ul><li>Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) SLE Disease Activity Index (SLEDAI) [SS] [1] and </li></ul></ul><ul><ul><li>the 2004 British Isles Lupus Assessment Group (2004-BILAG) [2] </li></ul></ul><ul><ul><li>SELENA Flare Index </li></ul></ul>
    12. 12. Definitions <ul><li>Severe Clinical Flares are defined as those flares that satisfy either the SS severe flare criteria </li></ul><ul><li>Mild-Moderate Clinical Flares will be defined as those that either satisfy the SS Mild/Moderate flare criteria and/or the 2004 BILAG B criteria </li></ul><ul><li>Renal Flare is defined as any 2004-BILAG A or B flare in that subcategory </li></ul><ul><li>Follow-up period to detect outcome: Clinical flares will only be considered within 6 months after Day 0 </li></ul>
    13. 13. Outcomes <ul><li>Primary outcome: </li></ul><ul><ul><li>Odds Ratio (OR) of a patient with DNA Flare to develop a Severe Clinical Flare within 6 months of follow-up compared to a control patient as defined above. </li></ul></ul><ul><li>Secondary outcomes: </li></ul><ul><ul><li>OR of a patient with DNA Flare to develop a Renal Flare compared to a control patient. Follow-up time: 6 months after Day 0. </li></ul></ul><ul><ul><li>OR of a patient with DNA Flare to develop a Mild/Moderate Clinical Flare compared to a control patient. Follow-up time: 6 months after Day 0. </li></ul></ul><ul><ul><li>OR of patient with DNA flare to develop a Mild/Moderate/Severe flare by SFI (modified SELENA Flare Index) </li></ul></ul>
    14. 15. SLE Patients (registry) n=1026 Patients who had their ds-DNA checked at least once n=489 Patients with at least one positive ds-DNA n=285 Patients with at least one negative dsDNA n=140 Exclusion: -Pts with <3 tests n=2 -variation over>1 year n=6 -Pts with no DNA flare, n=14 Patients with dsDNA>2+ n=37 n=15 Patients with dsDNA>3+ n= 94 Exclusion: Patients with at least one negative dsDNA n=71 n=23 Patients with dsDNA 1 to 4 n=4 Patients with dsDNA flare n=16 Patients with dsDNA 0 to 4 n=7 Patients with dsDNA 0 to 3 n=5 Exclusion: -Pts with no DNA=1: n=19 -Pts with <3 tests n=1 -Pts with no DNA flare n=2 n=1
    15. 16. <ul><li>difference in commercial test kits </li></ul><ul><ul><li>Farr radioimmunoassay (better at detecting high avidity antibodies thought to be more closely related to SLE activity </li></ul></ul><ul><ul><li>crithidia and ELISA detect both high and low avidity antibodies) </li></ul></ul><ul><ul><li>Crithidia considered most specific of the 3 assays (only dsDNA not ss DNA) </li></ul></ul>