1. State of Lupus Treatment:
New Therapeutics
Richard Furie, MD
Chief, Division of Rheumatology
Professor of Medicine
Hofstra North Shore-LIJ School of Medicine
New York
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7. Like Snowflakes
No Two Cases Are Alike
• Case 1: 22 y/o Caucasian female with fatigue,
photosensitive malar rash, arthralgias, adenopathy,
ANA 1/320 (Sp), SS-A Ab; better with NSAIDs and
hydroxychloroquine
• Case 2: 22 y/o African American female with fatigue,
alopecia, scarring rash in the scalp and ears,
hypertension, arthritis, nephritis, ANA 1/1280 (H),
high DNA Ab, low C’, anemia, and thrombocytopenia;
refractory to high doses of steroids and MMF; dialysis
in the near future
8. Goals of Therapy:
Back to Basics
• Do Good
• Control disease activity
• Prevent damage from disease
• Prevent flares
• Do No Harm
• Prevent damage from treatment
• Do not treat damage with agents intended for
active disease
9. Principles of Treatment Design
• Identify disease manifestations
• Distinguish activity from chronicity
– Does rash represent active disease or
scar?
– Does proteinuria represent active
nephritis or previous damage?
• Prioritize active disease manifestations
10. Principles of Treatment Design
• Disease activity is a continuum
• Use the least toxic medicine and lowest
dose to treat the most concerning disease
manifestation (and hope the less
concerning manifestations come under
control)
• Treatment rules would not be an issue if it
were not for the toxicities of our most potent
agents
12. Specificity and Safety of
Therapeutic Interventions
Normal Tissues
Pathologic Process (lupus)
Immunosuppressives Desired
Steroids Therapy
13. Corticosteroids: Toxicities
Hypertension Hirsuitism
Cushingoid appearance Osteoporosis
Osteonecrosis Fluid retention
Glucose intolerance Skin fragility
Increased infection risk Cataracts
• Side effects are related to dose and duration
• Use the lowest dose that does the job
15. Cyclophosphamide: Toxicities
1. Cytopenias
2. Infection
3. Hemorrhagic cystitis
4. Sterility (risk related to dose and age)
5. Cancer (bladder cancer; leukemia)
16. A Case: Rank the
Disease Manifestations
• Swollen and painful finger joints (arthritis):
• Pain in right hip (osteonecrosis)
• Hematuria/proteinuria/high DNA Ab/low C’
(nephritis)
• Hair loss (alopecia)
• Platelet count low (thrombocytopenia)
• Fatigue
17. A Case: Rank the Disease
Manifestations (Patient)
1. Swollen and painful finger joints (arthritis)
2. Hair loss (alopecia)
3. Fatigue
4. Pain in right hip (osteonecrosis)
5. Platelet count low (thrombocytopenia)
6. Hematuria/proteinuria/high DNA Ab/low C’
18. A Case: Rank the Disease
Manifestations (Physician)
1. Platelet count low (thrombocytopenia)
2. Hematuria/proteinuria/high DNA Ab/low C’
3. Swollen and painful finger joints (arthritis)
4. Hair loss (alopecia)
5. Fatigue
6. Pain in right hip (osteonecrosis)
20. What Does One Follow?:
1. Symptoms (pain, fatigue)
2. Signs (joint swelling, rash)
3. Laboratory values (cell counts, kidney
function, DNA Ab, C’)
4. SLEDAI or BILAG (in studies)
Much of this is art and not science
21. What if Conventional
Therapy Fails?:
1. “Pulse” steroids
2. Bone marrow transplantation
3. Other chemotherapy/IS (calcineurin inhibitors)
4. TNF inhibitors
5. Biologics: belimumab
6. Off-label biologics: rituximab, abatacept
7. Experimental medicine
22. Probability of Survival Survival in SLE
100
80 Cytotoxic Agents
60 Glucocorticoids
40
Pre-Glucocorticoids
20
0
0 1 5 10
Years After Diagnosis
23. Driving Forces Behind
SLE Drug Development
• Need for more efficacious therapies
– Lupus nephritis
– Severe extra-renal lupus
– Flare prevention
– Remission induction
• Safer therapies
– Replace steroids & cyclophosphamide
24. SLE Clinical Trial Challenges
• Heterogeneity of manifestations
– Complicates entry criteria, trial design,
and endpoints
• Confounding by background meds
• Trial endpoints
25. Innate
DNA
FcR
Sun
Adaptive TLR 9
IL 6
pDendritic Cell
mDC IL 12 CXCL10
IFNγ
IL 10 IFNα
CD28 - CD80/86
TCR - MHC
T Cell B Cell APRIL
CD40L - CD40 C’ PMN
ICOS - ICOS-L BLyS/BAFF
Ab Plasma
Cell
DNA Macrophage
IC
26. B Cell-Directed Therapies:
Extracellular Targets
Ab CD 20
Ab
CD 80
CTLA4 Ig
BLyS R
CD 86 BLyS
B TACI
Ab CD 19 TACI
MHC II APRIL
Ag BCMA
Ab CD40
LFA-3
ICOS L CD 22 Ab
Ab
27. Biologic Rationale for Targeting BLyS
• Crucial to B cells
– Maturation
– Differentiation
– Survival (anti-apoptotic [overrides Bcl-2])
• Murine models
– Transgenic mice develop SLE-like disease
– TACI-Ig ameliorates murine lupus activity
• Human SLE
– Elevated levels (predictive of flare)
28. Novel Response Endpoint
(SLE Responder Index: SRI)
• Index generated from belimumab phase II
• Responder index composed of:
– > 4 point improvement in SS score
– No BILAG worsening (new A or 2 B flares)
– No worsening in PGA (< 0.3 point increase)
Furie RA et al. Arthritis Care and Research. 2009;61:1143-51
29. BLISS Phase III Summary
• Primary endpoint was met in both phase 3 studies
– Significant improvement in SRI at wk 52
BLISS-52 BLISS-76
p = 0.013
• Belimumab plus current routine therapy was generally well
tolerated, with a safety profile comparable to that of
a
placebo plus current routine therapya Nov 9, 2010, Poster 1172.
Wallace et al. Presented at the American College of Rheumatology Annual Meeting,
30. Belimumab
– Who should be treated?
– What manifestations respond best?
– When is a response expected?
– When should failure be declared?
– If successful, how long should it be used?
– How clinically significant is the SRI?
31. Lessons Learned:
SLE Clinical Trials
The recent past
– Developing drugs in SLE is humbling
– Surprising failures: rituximab
– Successful failures: MMF
– Sucesses: belimumab
– An endpoint that worked
32. Lessons Learned:
SLE Clinical Trials
The future
– Unprecedented trials activity now
– Challenges
• Not enough patients to fill studies
• Trial design challenges remain
33. Move over ACR 20 (and DAS),
make room for SLEDAI and BILAG
Thank you
