Jennifer H. Anolik, MD, PhD
Associate Professor of Medicine, Pathology, and
Microbiology/Immunology
Division of Allergy, Immunology & Rheumatology
University of Rochester Medical Center
Oct 2014 8 th Annual Lupus Education Day
MEDICINE OF THE HIGHEST ORDER

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Basics
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Diagnosis and Biomakers
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Pathogenesis (leads to treatment)
•
New Treatments

Research in Lupus
• The more that is known about clinical outcomes and immune abnormalities associated with lupus, the better equipped we are to fight the disease!

What we ’ re doing at the U of R:
•
NIH funded networks
Autoimmunity Center of Excellence for clinical trials and basic
• mechanisms of lupus and clinical trials
Accelerating Medicines Partnership
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Clinical Cohorts: Lupus Clinical Trials Consortium
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20 centers
Collaborative Longitudinal Lupus Registry
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Clinical Trials
•
•
The AIR unit has an active program in clinical trials in SLE
Investigation of new, targeted biological interventions in SLE

Systemic Lupus Erythematosus
• Inflammatory multisystem disease
• 1.5 million cases
• Women>Men- 9:1 ratio (90% cases are women)
• African Americans>Whites
• Onset usually between ages 15 and 45 years, but can occur in childhood or later in life
• Highly variable course and prognosis, ranges from mild to life threatening
• Characterized by flares and remissions
• Associated with characteristic autoantibodies

•Lupus is the Latin word for wolf
•1 st used medically in the 10 th century
•Described clinically in the 19 th century
•Butterfly rash in 1845
•Arthritis in 1892
•Nephritis in 1895 by Osler
•Serologic tests become available in the 20 th century
•LE cell in 1948
•Lupus anticoagulant in 1952
•ANA in 1954
From Dubois

Systemic Lupus Erythematosus
Discoid or Cutaneous Lupus
Drug-Induced Lupus
Neonatal Lupus

What are the symptoms of lupus?
• Painful swollen joints
• Unexplained fever
• Extreme fatigue
• Rashes
• Sensitivity to the sun
• Mouth Sores
• Hair loss
• Pale or purple fingers or toes from cold
• Swollen glands
• Headache and/or
Depression
• Chest pain with deep breathing
• Low blood count

Other problems
• Repeated Miscarriages
• Disease in organs
– Kidney
– Heart
– Lungs
– Brain and nerves

Lupus presenting symptoms
0
Renal
Photosensitivity
Hair Loss
Clotting
Pluerisy
Facial Rash
Raynauds
Seizures
Ulcers
10 20 30 40 50 60
Painful Joints
Fevers
Swollen Joints
Extreme Fatigue
Skin Rashes
Anemia
70 80 90 100

Who gets lupus?
•World-wide prevalence : 10-100/100,000
•Estimated frequency:
•1 per 700 white women
•1 per 245 black women
•The Lupus Foundation estimates that 1.5 million Americans have some form of the disease
More people have
Lupus than
Cerebral Palsy,
Multiple Sclerosis,
Sickle Cell Anemia and Cystic Fibrosis
•16-55 years of age: 65% of cases
•< 16: 20% combined.
•> 65: 15%
•9/10 lupus patients are women

Skin criteria
1. Malar rash
2. Discoid Rash
3. Photosensitivity
4. Oral Ulcers
Systemic criteria
5. Arthritis
6. Serositis
7. Kidney
8. Neurologic
Lab criteria
9. Anti-nuclear antibody
10. Immunologic
11. Hematologic
*4 criteria simultaneously or serially for diagnosis

SLE Diagnosis: The ANA
• ANA
•
•
Seen in 99% of SLE
Not specific for SLE
•
•
Seen in many inflammatory, infectious, and neoplastic diseases
Seen in 5% to 15% of normal persons

New Diagnostics
• AVISE SLE- diagnostic test to help rule-in and rule-out RA, SLE, and other autoimmune diseasesincludes a panel of autoantibodies + cell-bound complement activation products
• A team at Stanford engineered a silicon computer chip containing thousands of subtly different protein segments derived from a single protein (known as a histone 2B), which is a common target of autoantibodies in lupus
Nature Medicine 2012
PJ Utz group

genetics hormones environment

Ultraviolet light
Stress
Medications
Infections
Hormonal Changes

New thoughts on causes and triggers
• Human Microbiome Project (HMP) an NIH initiative started in 2008 to identify the microorganisms which are found in association with both healthy and diseased humans (the human microbiome)
• Can contribute to development of a variety of autoimmune diseases including multiple sclerosis, rheumatoid arthritis, and possibly lupus

Identifying Novel Lupus Targets
• Hallmark of Lupus is an overactive immune system
• Recently identified that lupus patients have abnormally low levels of a switch that puts the bad-acting autoantibody-secreting B cells to sleep called PTEN
• Lupus patients with a low level of PTEN exhibit a more severe disease
Science Translational Medicine 2014

Identifying Novel Lupus Targets through genetics
• TREX1-helps the body break down unnecessary DNA molecules or fragments that may be generated during the copying of cells genetic material
• A small % of lupus patients have mutations in the TREX1 gene
• Methods to limit TREX1 stimulation of the immune response are in early stages of study
• Another example- MDA5
‘shutting off the immune response based on new molecular knowledge’
Immunity 2014

Treating inflammation or autoimmunity
•Anti-inflammatory agents
•Antimalarials
•Immunosupressive/cytotoxic agents
Other
•Prevention: management of cardiovascular risk, immunization, etc.
•Anti-thrombotic therapy
•Treating seizures
•Dialysis and kidney transplantation

The ‘ traditional treatment armamentarium ’
FDA Approved drugs
 glucocorticoids

 hydroxychloroquine low dose ASA
Benlysta
‘Off-label’ but standard of care
 azathioprine

 cyclophosphamide
NSAIDs
Immunosuppressives developed for other diseases
 mycophenolate mofetil methotrexate

 cyclosporin tacrolimus leflunomide fludarabine

Until April 2011 it had been over 50 years since a new drug was approved for lupus!
WHY?
•Lupus is hard to study:
• Clinical expression is heterogeneous
• Pathology is diverse
• Disease activity is intermittent
• Lack of agreed upon disease activity measures and endpoints
• Small patient populations- rare disease
•Development costs: Estimated $1 billion to take a drug from the research stage to FDA approval
•Lack of a clinical trial infrastructure

Clinical Trials
What are they?
• Very carefully controlled human studies of drugs that are not yet approved by the US Food and Drug Administration
(FDA) for use in a particular disease
• The FDA will approve a drug once it has been proven that the benefits outweigh the risks


We need to know what works




We need better medications for lupus
Many lupus patients have progressive damage to vital organs
Many lupus patients have ongoing symptoms that limit function
Many lupus patients suffer toxicity from medications

We need FDA approval
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We need to get insurance companies to pay for medications

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Pre-clinical studies – Non-Human
Phase I studies – 1 st time in humans <100 people
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What are the side effects and what dose should be given?
Phase II studies – 100+ people
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Does the drug work and are there other side effects?
Phase III studies – 1000+ people
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Does the drug work and is it safe long term?

SLE pathogenesis and treatment targets
Stages of autoimmunity
Loss of tolerance Innate and adaptive dysregulation
Sle1 , CD22, C1q, BANK, BAFF Sle2 (B), Sle3 (T, DC) , PTPN22
End organ targeting
Proteasome inhibitors
Autoantibodies
Immune complex
PC
Anti-B cell antibodies
BR3 sBAFF
BAFF inhibitors mBAFF mDC
IFN

FcR, ITGAM
TLR inhibitors
IFN
 blockade
TLR9 B
B7.1/2
B7.1/2
CTLA4-Ig
Abatacept
IFN

CD40
CD28 pDC
CD40L T
N
Lymphocyte signaling small molecule inhibitors
TNF blockade
IL-6 blockade

Repurposing drugs:
LRxL-STAT
(Lupus Rx List-SLE Treatment Acceleration Trials)
•New ALR-LRI collaboration
•Finding drugs and other treatment strategies that may be ripe for repurposing in lupus
•155 candidate drugs have emerged for further study in small focused science-rich clinical trials
•1 st clinical trials of the STAT initiative will kickoff in early 2015 https://www.linkedin.com/in/lrxlstat

Mycophenolate mofetil (CellCept®) Use for
Kidney Inflammation in Lupus
• Generally well tolerated
• “ Turns down ” the immune system
• FDA-approved for use in patients receiving organ transplants
• May have fewer side effects than older medications

Accelerating Medicines Partnership (AMP)
Initiative
• New venture between the NIH, 10 biopharmaceutical companies and non-profit organizations to transform the current model for developing new diagnostics and treatments by jointly identifying and validating promising biological targets of disease
• The ultimate goal is to increase the number of new diagnostics and therapies for patients and reduce the time and cost of developing them
• Lupus and Rheumatoid Arthritis: Define shared and disease specific biological pathways
• $41 million dollars; 11 sites recently awarded including UR!

www.clinicaltrials.gov

• Targeting B cells with anti-CD20
– Initial studies
– Rituximab in general lupus (Genentech; phase II/III): completed; Rituximab in proliferative lupus nephritis (LN)
(Genentech; phase II/III): completed
– ?Induction therapy
• Cytokine blockade: BAFF blockade- LN, black patients, pediatric, long-term safety, SQ
• Other B cell targeted therapies:
• Anti-CD22: phase III underway
• Other anti-CD20s-largely halted
• Anti-CD19
• Proteasome inhibitors

• Blocks a B cell survival factor, inducing B cell death
• 1 ST DRUG APPROVED FOR LUPUS IN
• 1 ST BIOLOGIC APPROVED FOR LUPUS http://www.youtube.com/watch?v=i24UTvOKK-8

• Two large trials of anti-CD20 (rituximab) in SLE failed to meet their primary outcomes
• Advances in the field on how to successfully do lupus clinical trials
• Rituximab is still thought to be effective in lupus and indicated for a subset of refractory patients
• Innovative ways to combine rituximab with benlysta

• Targeting autoreactive plasma cells
• Most current therapies do not effectively decrease autoantibodies
• Amgen acquires Onyx: Kyprolis=carlfizomib for myeloma
Ichikawa…Anolik; Arthritis and Rheum 2012

Targeting cytokines of pathogenic importance
• Targeting Interferon α
• Targeting IL6

TLR
Current Opinion in Rheumatology 2003 Pascual

•Sun exposure
•Drug reactions, e.g. sulfa drugs
•Infections
Some of our current drugs are now believed to target IFN pathways: e.g. anti-malarials

•Multiple studies on monoclonal antibodies against IFN alpha in various stages of development
•Recent press release that sifalimumab
(Medi-545) met primary endpoint of reduction in global disease activity score in moderate/severe SLE

• TLRs are key receptors of the innate immune system that can induce strong inflammatory responsesimportant in production of IFN
• Small molecules inhibitors of Toll-like Receptors (TLRs)
7, 8, and/or 9 are under development

• Mitogen-activated protein kinases (MAPK), tyrosine kinases (TK), Janus kinases (JAK) and nuclear factor κB
(NFκB)
• Interesting therapeutic targets
• Experience in RA (tofacitinib=JAK3 inhibitor)
3
2
**
1
**
0
0 1 2 3 4 5 6 7 8
Weeks of treatment
X 10 3
80
60
40
20
0
Untreated
Low
High SINEs
Anolik et al.

Things to Remember Tomorrow
• SLE is a heterogeneous autoimmune disease
• SLE can be mild and is almost always treatable
• Although lupus can affect almost any part of the body, most people experience symptoms in only a few organs.
• Treatment must be directed at the whole person not just the disease.

Concluding points
• We are learning how to “ borrow ” drugs used to treat other diseases
• Some drugs may provide clues about how lupus develops
• Despite barriers, novel mechanism-based therapies are in development for SLE
• Therapy will attempt to target specific pathways in the body
• Eventual treatments may involve combination therapies, i.e.,
“ cocktails ” of targeted and semi-targeted therapies
• Patients receive an “ individualized ” treatment

Learn More
• www.lupusresearch.org/research/research_update.html
• LupusTrials.org
• www.clinicaltrials.gov
• The National Institute of Arthritis and Musculoskeletal and Skin Diseases
(NIAMS) and the Office on Women’s Heath have developed a strategic plan for reducing health disparities. Lupus is included as an area of research focus. Further information on disparities in lupus and educational material at:
• http://thelupusinitiative.org
• www.couldihavelupus.gov