NANCY PAN, MDHOSPITAL FOR SPECIAL SURGERY

NEW YORKJULY 7, 2011

Third Year Pediatric Rheumatology Fellows’

Conference

Background

SLE has a relapse-remitting pattern, characterized by exacerbations and remissions

Difficult to define “SLE flare” using global measures of disease activity

Concept of flare is very complex, not one universally accepted definition

Lack of consensus as to whether changes in serology or therapy should be incorporated into definition

What if there is improvement in one organ but deterioration in another? Or worsening of chronic disease? (should this be considered new flare?)

Is dsDNA antibodies a good biomarker?

dsDNA antibodies commonly considered specific biomarkers in diagnosis and follow up in SLE, but not all detectable anti dsDNA Ab are clinically relevant

dsDNA antibodies found in 40-85% of pts depending on method used to detect it

presence may precede the diagnosis of SLE for more than 1 yr IgG Ab more pathogenic in SLE IgM Ab less associated with active disease

also seen in RA, MCTD and active hepatitis Anti-dsDNA Ab is used by 92% US rheumatologists to monitor disease

activity (1) but: SLE patients can have:

↑ titers with no activity (2) ↑ activity with low or absent dsDNA Ab (3) ↓ titers at the time of clinical flare (4)

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.

Yes: DsDNA Ab relationship with clinical SLE flare

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

Boostma et al”Prevention of relapses in systemic lupus erythematosus.” Lancet 1995

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

Sontheimer RD et al. “DNA antibody class, subclass and complement fixation in systemic lupus erythematousus with and without nephritis.” Clin Immunol Immunopathol 1978

Miniter MF et al, “Rassessment of the clinical significance of native DNA antibodies in systemic lupus erythematosus” Arthritis Rheum 1979

Swaak AJG et al. “Predictive value of complement profiles and anti dsDNA in systemic lupus erythematosus” Ann Rheum Dis 1986

No relationship of dsDNA titers with SLE flare

Esdaile, JM et al Laboratory tests as predictors of disease exacerbations in systemic lupus erythematosus Arthritis Rheum 1996

Petri et al “Definition, incidence and clinical description of flare in systemic lupus erythematosus” Arthritis Rheum 1991

Loes van den berg et al. Prior antidsDNA antibody status does not predict later disease manifestations in SLE. Clin Rheum 2006

Changes in dsDNA titer altering management

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

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

Clinical Question

Is there a clinically relevant way to interpret changes in dsDNA titer?

Use of the currently utilized assays for dsDNA detection

What is the role of a rapid and dramatic rise in dsDNA titer in a clinically quiescent patient with SLE? Does it herald a clinically significant SLE flare?

Methods

Utilized the SLE Registry at HSSProspectively collected data on a cohort of

SLE patients Including laboratory parameters checked at each visit

(including dsDNA titer) SLEDAI, BILAG, SLICC

All patients will fulfill the 1982 ACR revised criteria for SLE

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)

Definitions

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.

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.

Objectives

1. Assess in patients with SLE the association between :

1. “DNA flare” and a subsequent Severe Clinical flare2. “DNA flare” and a subsequent Renal flare3. “DNA flare” and a subsequent Mild-Moderate

Clinical flare

2. Characterize the type of clinical flares by:1. Severity2. Organ involvement3. Time to development in regard to each “DNA flare”

Definitions

Day 0 is defined as: 1. the date of DNA Flare (for Cases), and 2. for Controls as their closest next date in the

registry to the date of DNA Flare of their corresponding Case 

-Clinical Flares are defined using the definition of a flare according to the

Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) SLE Disease Activity Index (SLEDAI) [SS] [1] and

the 2004 British Isles Lupus Assessment Group (2004-BILAG) [2]

SELENA Flare Index

Definitions

Severe Clinical Flares are defined as those flares that satisfy either the SS severe flare criteria

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

Renal Flare is defined as any 2004-BILAG A or B flare in that subcategory

Follow-up period to detect outcome: Clinical flares will only be considered within 6 months after Day 0

Outcomes

Primary outcome: 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.

Secondary outcomes: 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.

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.

OR of patient with DNA flare to develop a Mild/Moderate/Severe flare by SFI (modified SELENA Flare Index)

SLE Patients(registry)n=1026

Patients who had their ds-DNA checked at least once

n=489

Patients with at least one positive

ds-DNAn=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 dsDNAn=71 n=23

Patients with dsDNA 1 to 4n=4

Patients with dsDNA flaren=16

Patients with dsDNA 0 to 4n=7

Patients with dsDNA 0 to 3n=5

Exclusion:-Pts with no DNA=1: n=19-Pts with <3 tests n=1-Pts with no DNA flare n=2

n=1

difference in commercial test kits Farr radioimmunoassay (better at detecting high

avidity antibodies thought to be more closely related to SLE activity

crithidia and ELISA detect both high and low avidity antibodies)

Crithidia considered most specific of the 3 assays (only dsDNA not ss DNA)