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Systemic Lupus Erythematosus: Pathology, Diagnosis, and Treatment

Gregg J. Silverman, MD Professor of Medicine and Pathology Associate Director, Division of Rheumatology NYU School of Medicine New York, NY

Learning Objectives
As a result of participation, participants will be able to:

Appreciate advances in our understanding of the

cardiovascular complications of SLE.

Discuss recent development in understanding the use of

MMF as an immunosuppressive for SLE.

Describe the rationale and recent advances in the

development agents that target interferons in SLE.

Mortality in Systemic Lupus Erythematosus

- Prospective surveys of standardized mortality ratios from 23 centers - Overall SMR rate from all causes of 2.4 - Greatest for disease duration < 1 year (7.7 per 1000 person-year, CI 5.9-10.2) - Youngest had highest death rate (< 25 yo ) 5.3 per 1,000 person-yrs, CI 3.7-7.5) - From all cardiovascular diseases, 1.7 relative risk (1.5-1.9)

Collaboration of the Systemic Lupus International Collaborating Clinics (SLICC) and Canadian Network for Improved Outcomes in Systemic Lupus (CaNIOS) investigator groups. Death data were prospectively collected or acquired through probabilistic linkage to vital statistics registries. Expected deaths in the general population were determined by multiplying person-years at risk in the cohort by the geographically appropriate age-, sex-, and calendar-year period-matched mortality rates.
Bernatsky, et al. Arthritis Rheum. 2006;54:2550-7.

Risk of Myocardial Infarction (MI) Is More Than 50 Times Greater for Women With SLE Aged 35-44
Incidence rate of MI higher in women with SLE overall Incidence of MI in younger and premenopausal women higher vs the agematched general population
Incidence Rate of MI per 1000 Person-Years

Incidence of MI in Women by Age



Prospective analysis of the incidence of MI in 498 women with SLE. Cardiovascular incidence rates were compared to 2208 women of similar age participating in the Framingham Offspring Study, a prospective investigation of cardiovascular disease in the children of the 5209 men and women who participated in the original Framingham Heart Study. A comparison of MI rates was made over the same time period (1980-1993).
Manzi, et al. Am J Epidemiol. 1997;145:408-15.

Efforts to Identify Risk Factors for CV Events in SLE [1708]

Background: Accelerated atherosclerosis remains the major late cause of death in
SLE. Yet, "traditional" cardiovascular equations underestimate the risk.

To construct data-driven equation of CV risk in SLE, based on longitudinal cohort. To derive score, risk factors calculated based data for first 2 years of cohort participation. A formula to calculate the risk of a CVE within the next 10 yrs was derived. For 1342 pts,
(93% female) there were 109 CV events: 52 strokes, 26 MI, 18 angina/CABG, and 13 episodes of intermittent claudications.

Conclusion: Prospective studies will be needed to evaluate candidate SLE risk factors. Understanding of pathogenesis of accelerated CV disease in SLE still limited.
Petri, et al. Arthritis Rheum. 2012;62(12) S731.

Circulating Free Protein S Levels May Be Linked to CV Events and Venous Thrombosis in SLE [abs1425]
SLE increased risk for MI, stroke and thromboembolism. While autoantibodies and
accelerated ASCVD are implicated, other factors may be involved.

Protein S, a vitamin K-dependent factor implicated in coagulation cascade and ligand for
the TAM receptor tyrosine kinase family that regulates inflammatory responses and apoptotic cell clearance.

Methods: Cross-sectional surveys of 90 SLE patients, we assessed levels of free Protein

S, by commercial immunoassay, and also performed standard lab tests for APLS.

Results: Low Protein S levels correlated with a history of DVT/PE (N=12, Spearman,
P=0.0007, R= 0.41)(Sens. 0.92, Spec. 0.56).

Correlations were better than high IgG anti-cardiolipin (P=0.007, R=0.29),

IgG anti-2-GPI (P=0.03, r=0.23), and RVVT (P=0.001, R=0.34).

Patients with a hx of MI/CVA also significantly lower levels of free Protein S (N=17,
P=0.001 R=0.34) (Sens. 0.76, Spec. 0.56).

No correlations between Protein S and overall SLE disease activity levels by SELENASLEDAI, physicians global assessment, or organ damage by the SLICC index, or for nephritis. Coumadin intake did not affect Protein S levels.

Conclusion: Significantly lower levels of free Protein S were found in SLE pts with
thromboembolic disease and MI/CVA. May contribute to better testing and understanding of pathogenesis
Silverman et al. Arth Rheum. 2012;64(suppl 10):S613.

Mycophenolate Mofetil (MMF): MOA May Implicate B Cells Background: MMF can provide benefits in lupus nephritis (1), yet
associated with high frequency of side effects as co-treatment with Atacicept, a decoy receptor for BAFF and APRIL (i.e., B cell survival factors) (2).

Open label trial of 107 subjects with SLE; MMF n=30; AZA n=30;
controls took no immunosuppressives n=38) (3).

Blood B cell levels higher in MMF treated subjects, with higher

frequencies of early B cell precursors (transitional B cells) but lower frequencies of plasmablasts (i.e., normalized)

No differences in T cells between groups (3) MMF inhibited in vitro B cell proliferation (3) Patients taking AZA flared more frequently than those on MMF (3) As SLE is associated with enhanced B cell activation and proliferation, MMF benefits may involve inhibiting B cell activation and plasma cell formation.
1. 2. 3. Appeel. J Am Soc Nephrol. 2009 20(5):1103-12 Ginzler, et al. .Arthritis Res Ther. 2012;14(1):R33. Eikenberg, et al. Arthritis Res Ther. 2012;14(3):R110.

Type I Interferons and SLE

Many patients with systemic autoimmune diseases have signs of a
continuous production of type I interferon (IFN) and increased expression of IFN--regulated genes.

On-going IFN- synthesis may involve activation of plasmacytoid

dendritic cells (pDCs) by immune complexes (ICs) of IgG autoantibodies combined with DNA or RNA-containing autoantigens.

Variants of genes involved in IFN- synthesis and response have

been linked to an increased risk to develop systemic lupus erythematosus (SLE) and other autoimmune diseases.

Among these autoimmunity risk genes are IFN regulatory factor 5

(IRF5) involved in TLR signaling, and signal transducer and activator of transcription 4 (STAT4) that interacts with the type I IFN receptor.

Can targeting IFN-alpha provide clinical benefits?

Ronnblom. Ups J Med Soc. 2012;116(4):227.

Development of New Biologics: Anti-interferon Antibodies

AGS-009 MEDI 546/Sifalimumab AMG 811 MEDI 545 (Sifalumumab) Rontalizumab
good safety data2

IFN-alpha IFN-alpha IFN-gamma IFN-alpha IFN-alpha

Phase I Phase II Phase I Phase II Phase II

had modest clinical effects and high rates of infusion reactions1

1. Merrill, et al. Ann Rheum Dis. 2011;70:1905-13. 2. McBride, et al. Arth Rheum. 2012: doi: 10.1002/art.34632

Pharmacokinetics of Rontalizumab: Anti Alpha-IFN

PK across all dose levels exhibited bi-phasic distribution PK levels proportional to dose, following both single IV & SC administration Bioavailability was ~ 40% after SC administration Clearance (CL)and terminal half life (T1/2) were 2.8ml/day/kg and 18 days respectively Rontalizumab has PK properties similar to other humanized IgG1 Abs specific for soluble ligands

McBride, et al. Arth Rheum. 2012: doi: 10.1002/art.34632

Efficacy and Safety of Rontalizumab (Anti-Interferon Alpha) in SLE Subjects with Restricted Immunosuppressant Use: Results of A Randomized, Double-Blind, PlaceboControlled Phase 2 Study. [ACR abs 2622]

159 SLE pts in a double blinded Phase II RCT, immunosuppressives

stopped at randomization and steroids also tapered to 10 mg/day by wk 8

Mean SELENA SLEDAI of 9.8, most pts with musculoskeletal and


Failed primary endpoint: Overall response rates no different in treatment

and pbo (by BILAG and SLE Response Index)

Overall Rontalizimab decreased flares vs. pbo (HR (0.61 (0.46-0.81.


Pts divided by IFN signature metric (ISM) for 76% ISM high vs ISM low Better responses in ISM low compared to pbo, especially with IV treatment

Interpretation: SLE disease suppressed only in those with low IFN activity.
Is this agent not potent enough? Or were the tested doses too low?
Kalunian et al. ACR abs 2622 Arth Rheum (2012) 64 (10) Suppl page S1111

Concluding Remarks
SLE continues to affect many individuals with high burden of

CV disease as well as PE/DVT pose significant clinical

challenges. Interim progress in the clinical assessment of patients could lead to better therapeutic decision making.

Interim reports have provided new insights into MOA and efficacy
of MMF, which may aid decision making in clinical practice, especially when used as a background agent for targeted biologics.

Early IFN-a blockade trials may show evidence of limited

efficacy. Future trials may need to integrate higher doses or more powerful agents.

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