1

C. Michael Neuwelt, M.D. Clinical Professor of Medicine

University of California, San Francisco,

Chief of Rheumatology

Alameda County Medical Center, Oakland, CA

Director of Rheumatology, Core Curriculum

St. Mary’s Medical Center, San Francisco, CA

UPDATE 2015 AND BEYOND

Systemic Lupus Erythematosus: Diagnosis – Laboratory and Clinical Presentation

Treatment – Current Methods and Emerging Biological Treatment

2

Numerous Factors Contribute to Underlying SLE Pathogenesis and Subsequent Organ Damage1,2

Initiate Autoimmunity Immune Dysfunction

1. Tsokos GC. New Engl J Med. 2011;365:2110-2121. 2. Crow MR. Arthritis Res Ther. 2009;11:245-256.

Inflammation and Organ/Tissue Damage

Genetic Susceptibility

(Immune-Related)

Stimuli (eg, Environmental,

Hormonal, Infectious)

Musculoskeletal System

Brain

Heart

Lungs

Skin

Kidneys

Adaptive Immune System Activation

Immune Reactivity

Cytokines

Cytokines

Innate Immune System Activation

Autoantibodies

Cytokines

Autoimmune Amplification

3

Multiple Elements of the Immune Response Play a Role in Autoimmunity in SLE1-6 (cont)

Adaptive Immunity Innate Immunity

B Cells T Cells mDC pDC MO

Cytokines

Inflammation

Autoantibodies

1. Crow MR. Arthritis Res Ther. 2009;11:245-256. 2. Mok CC, et al. J Clin Pathol. 2003;56:481-490. 3. Tsokos GC. New Engl J Med. 2011;365:2110-2121. 4. Li Y, et al. Arch Immunol Ther Exp. 2010; 58:355-364. 5. Chan V S-F, et al. Autoimmun Rev. 2012; doi [Epub ahead of print ] 10.1016/j.autrev.2012.03.004. 6. Ronnblom L, et al. Nature Rev Rheum. 2010;6:339-347..

Immune Reactivity

Cytokines

• Abnormally activated T and B cells are a feature of SLE pathogenesis1,2

- Overexpression of B- and T-cell costimulatory ligands/receptors1

- Higher concentrations of B- and T-cell cytokines1,2

• Increased numbers of antibody-producing B cells, hypergammaglobulinemia, autoantibody production, and immune-complex formation2

Tissue Damage

Inflammation

mDC=myeloid dendritic cells; pDC=plasmacytoid dendritic cells; MO=macrophages

4

Autoantibodies Are a Key Feature of SLE

• Characteristic immunologic disturbance in SLE present in almost all patients at some time1-3

• Form immune complexes with nuclear, cytoplasmic, and cell-surface self antigens2,4

• Amplify immune-system activation through stimulation of innate and adaptive immune pathways and recruitment of inflammatory cells to immune complexes1,5

1. Crow MR. Arthritis Res Ther. 2009;11:245-256. 2. Mok CC, et al. J Clin Pathol. 2003;56:481-490. 3. Heinlen LD, et al. Arthritis Rheum. 2007;56:2344-2351. 4. Chan V S-F, et al. Autoimmun Rev. doi:10.1016/j.autrev.2012.03. 004. [Epub ahead of print]. 5. Tsokos GC. New Engl J Med. 2011;365:2110-2121. 6. ACR Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum. 1999;42:1785-1796.

Tissue Damage ANA=antinuclear antibodies; anti-dsDNA=anti-double-stranded deoxyribonucleic acid

Autoantibody Detected6

At Onset At Any Time

ANA 76% 94%

Anti-dsDNA 34% 71%

Autoantibodies

5

Link Between Autoantibodies and Clinical Effects

Rahman A, et al. N Engl J Med. 2008;358:929-939.

Autoantibody Associations in SLE

Antigen Specificity Prevalence (%) Main Clinical Effects

Anti-dsDNA 70-80 • Kidney disease • Skin disease

Nucleosomes 60-90 • Kidney disease • Skin disease

Ro 30-40 • Kidney disease • Skin disease • Fetal heart problems

La 15-20 • Fetal heart problems

Sm 10-30 • Kidney disease

Phospholipids 20-30 • Thrombosis • Pregnancy loss

α-Actinin 20 • Kidney disease

C1q 40-50 • Kidney disease

6

SLE Is an Autoimmune Disease That Primarily Affects Women of Childbearing Age

• SLE is a chronic, multisystem autoimmune disease1-3

‒ Diverse clinical manifestations are the result of inflammation in affected organ systems1

‒ Potentially life threatening when major organs are affected2,3

‒ Waxing and waning disease activity4

• SLE patient profile: ‒ Nine out of 10 cases occur in women2; tends to be more severe in men5

‒ Most prevalent in women 14 to 50 years of age6

‒ More common and severe among nonwhite populations5

1. Wallace DJ, Hahn B, eds. Dubois' Lupus Erythmatosus. 7th ed. Philadelphia, PA: Lippincott Williams and Wilkins;2007. 2. D’Cruz DP, et al. Lancet. 2007; 369:587‐596. 3. ACR Ad Hoc Committee Systemic Lupus Erythematosus Guidelines. Arthritis Rheum. 1999;42:1785‐1796. 4. Heinlen LD, et al. Arthritis Rheum. 2007;56:2344-2351. 5. Pons-Estel GJ, et al. Semin Arthritis Rheum. 2010;39:257‐268. 6. Cervera R, et al. Medicine. 1993;72:113‐124.

7

A Range of Organ Systems May Be Involved

ACR Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum. 1999;42:1785-1796.

Skin

Central Nervous System

Commonly Involved Organ Systems

Heart and Lungs

Kidneys

Eyes and Mucous Membranes

Gastrointestinal Musculoskeletal

Hematologic

8

Variability in Clinical Presentation Can Result in Difficulty in Diagnosis

SLE Manifestations May Be Mistaken for Other Common Conditions1

SLE Other Condition

Lupus arthritis1 Fibromyalgia with positive ANA; early rheumatoid arthritis

Lupus-associated rash3 Rosacea; polymorphous light eruptions

Malar Rash Rosacea

Reproduced with permission courtesy of the National Rosacea Society

Reproduced with permission from the American College of Rheumatology 2012

• SLE diagnosis is challenging due to its multisystem involvement and protean manifestations1

• A positive anti-nuclear antibody (ANA) test alone is insufficient to establish diagnosis1

• 47% of patients with presumptive SLE referred to an autoimmune disease center from the community ultimately had other diagnoses2

1. ACR Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum. 1999;42:1785-1796. 2. Narain S, et al. Arch Intern Med. 2004;164:2435-2441. 3. Wallace DJ. Lupus, the Essential Clinician’s Guide. New York, NY: Oxford University Press; 2008.

9

Pooled cohort analysis (University of Birmingham, AL; Johns Hopkins University, MD; University of Texas Houston Health Sciences Center, TX) of 568 adults with SLE with a disease duration of <10 years from diagnosis to enrollment. Mean ages were 38-42 years, with 86%, 92%, and 96% female in the Caucasian, African American, and Hispanic patient groups, respectively.

1. Alarcon GS, et al. 2002;11:95-101.

Dl

Pe

rce

nt

of

Pat

ien

ts

Cumulative ACR Criteria Manifestations (%) in PROFILE Cohort per Ethnic Group1

Hispanic (n=78) African American (n=216) Caucasian (n=260)

• Hispanic and black patients tend to have more renal, hematological, and serosal manifestations following diagnosis1

Clinical Manifestations Vary by Race

10 Bernatsky S, et al. Arthritis Rheum. 2006;54:2550-2557.

Rate of SLE Mortality Remains High Relative to the General Population

Collaboration of the Systemic Lupus International Collaborating Clinics (SLICC) and the Canadian Network for Improved Outcomes in Systemic Lupus (CaNIOS) investigator groups (US, Canada, England, Scotland, Iceland, Sweden, South Korea). 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. Risk of death was assessed as a standardized mortality ratio, calculated as the observed number of deaths divided by the number expected in the general population. Duration of disease at time of enrollment was <2 years for most patients, and 90% of patients were female.

General Population

Rate of Death Compared to the Age-Matched General Population

19.2 X Greater Rate

8.0 X Greater Rate

1.4 X Greater Rate

SLE Patient Age (years)

3.7 X Greater Rate

≥60 40-59

25-39

16-24

11

Risk of Myocardial Infarction (MI) Is More Than 50 Times Greater for Women With SLE Aged 35-44

Manzi S, et al. Am J Epidemiol. 1997;145:408-415.

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).

• Cardiovascular disease is an ongoing issue for patients with SLE

• Compared to the general population, incidence rate of MI was higher in women with SLE overall

• Incidence of MI in younger and premenopausal women was notably higher vs the age-matched general population

Incidence of MI in Women by Age

Inci

den

ce R

ate

of

MI

p

er 1

00

0 P

erso

n-Y

ears

(n=2208)

(n=498)

12

What Is Systemic Lupus Erythematosus?

• Systemic lupus erythematosus (SLE) is a progressive autoimmune disease that results in inflammation and tissue damage

• Characterized by flares, spontaneous remission, and relapses, SLE is a chronic disease

• SLE can affect any part of the body but often results in damage to the skin, joints, heart, kidneys, lungs, and nervous system

13

The following are the ACR diagnostic criteria presented in the "SOAP BRAIN MD" mnemonic

• Serositis

• Oral ulcers

• Arthritis

• Photosensitivity

• Blood disorders

• Renal involvement

14

The following are the ACR diagnostic criteria presented in the "SOAP BRAIN MD" mnemonic

• Antinuclear antibodies

• Immunologic phenomena (eg, dsDNA; anti-Smith [Sm] antibodies)

• Neurologic disorder

• Malar rash

• Discoid rash

15

Non-Specific Manifestations of SLE

• Fever

• Weight loss

• Fatigue

• Myalgias, fibromyalgia

• Lymphadenopathy

• Raynaud’s phenomenon

16

Mucocutaneous Features of SLE

• Malar (butterfly) rash

• Discoid lupus (DLE)

• Mucosal ulcers

• Alopecia

• Subacute cutaneous lupus (SCLE)

• Cutaneous vasculitis

• Bullous lupus

• Panniculitis

ACR Ad Hoc Committee. Arthritis Rheum. 1999;42(9):1785-1796. Gill et al. Am Fam Physician. 2003;68:2179-2186. Petri et al. Best Prac Res Clin Rheumatol. 2002;16(5):847-858.

17

Malar (Butterfly) Rash

18

Discoid Lupus Rash

19

Mucosal Ulcers

20

Alopecia

21

Arthritis

22

Neuropsychiatric Manifestations of SLE

• Central nervous system

– Diffuse cerebral manifestations

– Psychiatric manifestations (depression)

– Cognitive impairment

– Seizures

– Headache

– Focal manifestations

• Peripheral nervous system

Futrell et al. Neurology. 1992;42:1649-1657.

23

Cardiac Manifestations of SLE

• Pericarditis

• Myocarditis, congestive heart failure

• Hypertension

• Coronary vasculitis

• Libman-Sacks endocarditis

• Valvular insufficiency

• SLE patients have a 7-10x increased risk of Coronary Heart disease and stroke

Esdaile et al. Arthritis Rheum. 2001;44:2331-2337.

24

Other Mechanisms of cardiovascular events in SLE

ASSOCIATIONS OF CIRCULATING CELL-FREE MICRO RNA WITH VASCULOPATHY AND VASCULAR EVENTS IN SLE PATIENTS FURTHER INCREASE IF:

• (+) Lupus Anticoagulant

• Decreased C3

• High disease activity

American College of Rheumatology scientific session November 10, 2015. Susan Due Kay. Michele Petri, et.al. John Hopkins cohort

25

Proinflammatory HDLs in SLE – Role in Atherosclerosis

• In the inflammatory state, HDLs may lose their protective capacity and become proinflammatory (AP-HDL)

• Presence of AP HDL: – SLE: 7.9–10.1-fold increased risk of

atherosclerosis

– RA: Approx. 5-fold increased risk

• In SLE patients with evidence of atherosclerosis (CAD, stroke etc), 90% have proinflammatory HDLs

• Presence of proinflammatory HDLs likely in future to be a good measure of propensity to develop atherosclerosis independent of absolute lipid values P

ro-i

nfl

amm

ato

ry H

DL

CE-OCH MPETE, MPODE

PAF-AH

Anti-inflammatory Pro-inflammatory

HDL AP-HDL

Navab et al. Arterioscler Thromb Vasc Biol. 2001;21:1770-1776. McMahon et al. ACR, San Diego 2005, Abstract 1885.

A-I A-I

44.7

20.1

4.10

10

20

30

40

50

SLE group RA group Control

group

p<0.001 p=0.039 p=0.001

26

Pulmonary Manifestations of SLE

• Pleuritis (also pericarditis)

• Lupus pneumonitis/alveolitis

• Pulmonary hemorrhage

• Pulmonary fibrosis

• Shrinking lung syndrome

• Pulmonary embolism/in situ thrombosis

• Pulmonary hypertension

27

Pleural and Pericardial Effusions

• Pleural disease occurs in >30% of SLE patients during their course: – Often asymptomatic

– May present with chest pain, SOB

– Effusions are usually small and bilateral

– Exudative, usually with WBC <10,000

– Predominance of polys and lymphs

28

Clinical Features of Active Lupus Nephritis

• Urinary protein excretion edema

• Active urine sediment – WBCs, RBCs, protein casts, cellular casts

• Decreased glomerular filtration rate

• Hypertension

29

Progressive Decline in Renal Function

• Amount of renal damage can predict renal failure and mortality – 5%–10% of LN patients

progress to end-stage renal disease

– In one study, 25% of patients with early renal damage versus 7.3% without early damage died within 10 years of initial assessment

Alarcón et al. Rheumatol. 2004;43:202-205. Houssiau et al. Arthritis Rheumat. 2004;50(12):3934-3940. Houssiau. Lupus. 2005;14:53-58. Mikdashi et al. Rheumatol. 2004;43:1555-1560. Rahman et al. Lupus. 2001;10:93-96. Stohl et al. Rheumatol. 2004;43:1039-1044.

Red cell cast from urinary sediment of a patient with chronic glomerulonephritis

30

RACIAL AND ETHNIC DIFFERENCES

LUPUS NEPHRITIS – END STAGE MORTALITY

I. Highest – African American

II. Moderate – White

III. Lowest – Asian and Hispanic (“Hispanic Paradox”)

* ? Perhaps hispanics migrate home at end of life “Salmon Hypothesis”

* Asians – more lost to follow up at end of life

• Gomez – Puerta, et.al; Arthritis Care & Research October 2015; 67: 1453-1461

31

Gastrointestinal Manifestations of SLE

• Peritonitis

• Mesenteric vasculitis

• Vasculitis of the bowel

• Inflammatory bowel disease

• Autoimmune hepatitis

• Pancreatitis

DuBois’ Systemic Lupus Erythematosus. Lippincott and Williams. 2007.

32

Incidence of Clinical and Laboratory Manifestations of SLE (%)

DuBois’ Systemic Lupus Erythematosus. Lippincott and Williams. 2007. Cumulative % incidence of clinical and laboratory manifestations of SLE (1084 cases). *Pleural or pericardial; **adenopathy.

Positive ANA 97 Arthritis and Arthralgia 80 Skin Changes 71 Myalgia 60 Low Complement 51 Fever 48 High Anti DNA 46 Leukopenia 46 Pleuritis 44 Proteinuria 42 Anemia 42 Anticardiolipin Antibody 35 CNS 32 High gamma globulin 32 Effusion* **

12 10

33

Heredity and SLE

• 1 in 40 if she has a daughter

• 1 in 250 if she has a son

Hellman and Stone. Systemic Lupus Erythematosus. In Current medical Diagnosis and Treatment 2007. McGraw Hill.

A children’s risk of developing SLE if their mother has the disease is:

34

Proactive and Preventive Strategies in SLE

• Proactive

– Patient education programs

– Eliminate patient nonadherence

– Specialist access

– Exercise, PT, OT, ergonomic work stations

– Cognitive therapy (lupus fog), biofeedback (Raynaud’s)

• Preventive

– Aggressive vigilance for hypertension, hyperglycemia, hyperlipidemia, obesity, smoking cessation

– Yearly bone densitometry and use of bisphosphonates

– Annual EKG, chest X-ray, duplex scanning, stress tests, 2-D echo for pulmonary pressures in high-risk patients

– Prompt evaluation of all fevers

– Antiphospholipid antibody screening and prophylaxis

Wallace. Curr Opinion Rheumatol. 2002;14:212-219.

35

Management of Non-Organ Threatening Lupus

• Physical measures – Sun avoidance, use of

sunscreens

– Temperature

– Physical therapy (use of heat)

– Occupational therapy

• Medication

• Counseling

• Surgery

– Vocational rehabilitation

– Exercise

– Diet and vitamins

– Management of fatigue

36

Anti-Malarials in the Treatment of Lupus

First use of quinine for cutaneous disease (Payne, 1894)

Plasmochin helps 22/28 with cutaneous lupus (Mastenstein, 1928)

“Excellent” results in 1920 with quinine bisulfate (Davidson, 1938)

Chloroquine patent (1934)

Hydroxychloroquine synthesized (mid-1940s)

3 million US and allied soldiers had used atabrine between 1943-1946; efficacy is documented in lupus from these observations (Page et al,

Lancet. 1951;21:755-758)

37

1948: A Turning Point in Lupus Treatment

• Before 1948 lupus treatments also included Aspirin, bismuth, arsenic, vitamins E and B12, and liver extract

• In 1948, LE cells were discovered by Hargraves (Mayo Clinic)

• Steroids were first used in rheumatic diseases

• Nitrogen mustard was first used for glomerulonephritis

• Marian Ropes reported that half with lupus die in 2 years, and the others survive, dividing the disease into organ vs non-organ threatening manifestations

38

Advances in Lupus Management (1948–2000)

2000

Nonsteroidals

1951: phenyl- butazone

1965: Indo- methacin

1974: Ibuprofen

Antimalarials 1940: Quinacrine

1951: Chloro- quine

1947: Nitrogen mustard, methotrexate

1965: cyclophosphamide, azathioprine

Corticosteroids

Early 1950s: Prednisolone, prednisone

1948: Cortisone

Immune suppressives

1955:Hydroxy- chloroquine

1998, 1999: Biologics approved for use in RA

39

Current Standard Therapy: Mild-to-Moderate Disease

Mild-to-Moderate Disease

– Arthritis

– Fever

– Pleurisy

– Pericarditis

– Cutaneous

Therapy

– Photoprotection

– NSAIDs

– Corticosteroids

– Methotrexate

– Leflunomide

– Thalidomide

– Antimalarials

– Topicals

– Physical therapy

40

Current Standard Therapy

Moderate-to-Severe Disease

– Nephritis

– Vasculitis

– Pneumonitis

– CNS

– Hematologic

Treatment

– Corticosteroids

– Cyclophosphamide

– Azathioprine

– Mycophenolate Mofetil

– Cyclosporine

– IV Ig

– Plasmapheresis?

41

Reasons for Improved Prognosis Other than Lupus Medicines

• Availability of dialysis and transplantation

• Development of joint replacement surgeries

• Available of platelet and red cell transfusions and growth factors

• Introduction of improved antihypertensives, antihyperlipidemic, and antibiotic therapies

• Utilization of bone mineralization treatments

42

Modern Asian City – (Translation Antibodies) “Bench to Bedside”

Loneliness – Insomnia - = SLE (51 Years of Waiting)!!!

43

Systemic Lupus

Erythematosus:

After 50 Years No Longer

“Lost in Translation”

44

Drug Target

Design

Phas

e Status Global

Nephritis

AI FP

Abetimus (putative

toleragen)

AutoAb III Active

Lymphostat B (anti-BLyS)

B cells III Active

Rituximab (anti-CD20)

B cells II Active

Anti-CD40 Ligand Abs T cells II Inactive

Abatacept (CTLA4Ig) T-B

cells

II Active

MMF

Lymph III Active

Ablation; transplantation WBC I Active

Epratuzumab (anti-CD22) Lymph II Active

Anti-IL6 R Cy R I Active

B-Cell Therapies Under Investigation for SLE

45

Rituximab for Patients With Moderate-to-Severe SLE or LN

Study Patients Regimen

Albert et al. A&R.

2004;50:S446.

N = 11 8

completed

375 mg/m2 x 4

100 mg methylprednisolone prior

Leandro et al. A&R.

2002;46:2673. N = 6

500 mg/m2 x 2

750 mg x 2 CTX + oral steroids

Looney et al. A&R..

2004;50:S2580.

Anolik et al. A&R.

2004;50:S3580.

N = 19

8 completed

100 mg/m2 x 1 (n = 6), 375 mg/m2 x 1 (n = 6), 375 mg/m2

x 4 (n = 4)

40 mg x 2 prednisone prior

Neuwelt et al. EULAR05.

Vienna.

N = 22

CNS lupus

375mg/m2 x 4, 54% monotherapy , 32% combined with

CTX, 14% concomitant CTX/PP

Sfikakis PP, et al. A&R.

2005;52:501-13.

N = 10

Active

proliferative

nephritis

375 mg/m2 x 4

0.5 mg/kg/day prednisone for 10 weeks, then tapered

Smith and Jayne. J Am Soc

Nephrol. 2003;14:380A. N = 6

375 mg/m2 x 4

500 mg CTX prior infusion

Van Vollenhoven. A&R.

2004;50:S414.

CTX

refractory,

nephritis

375 mg/m2 x 4

500 mg x 2 CTX

250 mg methylprednisolone prior

Evaluation of Rituximab in 7 Small-Scale, Open-Label, Uncontrolled Trials

46

Efficacy and Safety of Rituximab in Patients with Moderately to Severely Active Systemic Lupus Erythematosus (SLE): Results from the Randomized, Double-blind Phase II/III Study EXPLORER

• Joan T Merrill1, C Michael Neuwelt2, Daniel J Wallace3,

Joseph C Shanahan4, Kevin M Latinis5, James C Oates6, Tammy O Utset7, Caroline Gordon8, David A Isenberg9, Hsin-Ju Hsieh10, David Zhang10, Paul G Brunetta10

• 1Oklahoma Medical Research, Oklahoma City, OK; 2Alameda Medical Center, Oakland, CA; 3Cedars-Sinai/UCLA, LA, CA; 4Duke University, Durham, NC; 5University Kansas Medical Center Kansas City, KS; 6Medical University South Carolina, Charleston, SC; 7University of Chicago, Chicago, IL; 8University Birmingham, Birmingham, United Kingdom; 9University College, London, United Kingdom; 10Genentech Inc, South San Francisco, CA

47

84.4

66.2

6.3

20

9.413.8 15.7

33.8

0

10

20

30

40

50

60

70

80

90

Pro

po

rtio

n o

f P

ati

ents

(%

)

No Clinical Response Partial Clinical

Response

Major Clinical

Response

Major* Partial

Placebo

Rituximab

Pre-specified Exploratory Analysis: Clinical Response by Ethnicity

African-Americans/Hispanics

____________Responders____________

African-American/Hispanic subgroup showed significant response in

the rituximab-treated group compared with the placebo group.

*p value refers to the test on 3-category endpoints (MCR/PCR/NCR).

P=0.0408

48

Systemic Lupus Erythematosus Pathogenesis

Targets for

• B Cells (B)

• T Cells (T)

• Interferon α (IFN)

• Inducible Costimulator (ICOS)

• Unique Toleragens

Translational Antibodies

49

Belimumab (Benlysta®) March 3, 2011!

U.S. Food and Drug Approval – Why:

• Innovative outcome measures

• 50 year need

• Steroid sparing effect

• Toxic medications we currently use

• Belimumab – acceptable safety profile

50

What Does BLyS (BAFF) Do to B Cells?

Macrophage

Macrophage

Normal

person

Lupus

patient

BLyS

B cell

B cell

51

• Arthritis

• Serositis

• Hematologic

• Steroid dependent

• Fever

• Fatigue

• Skin Rash

Subset of patients for use:

52

Comparison of Lupus Trials

Navarra S, et al. ACR 2009: LGB1; Merril JT, Neuwelt CM, Wallace DJ, et al. Arthritis Rheum. 2010;62:222; Wallace DJ, et al. EULAR 2010. Abstract/SAT0212; Wallace DJ, et al. 9th IC on SLE. Abstract PO2.E.4.

Negative

Study

1Duke University Medical Center, Durham, USA; 2Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, USA; 3Division of Rheumatology, North Shore-Long Island Jewish Health System, New York, USA; 4Division of Rheumatology,

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, USA; 5MedPharm Consulting, Inc., Cambridge, USA; 6Department of Rheumatology and Rehabilitation, Poznan University of Medical Sciences, Poznan, Poland; 7Division of

Rheumatology, Alameda County Health System, Oakland, USA

Ef f i c a c y a n d S a fe t y o f E p ra t u z u m a b i n Pa t i e nt s w i t h M o d e ra te to S e v e r e

Sy s te m i c L u p u s E r y t h e m a to s u s : Re s u l t s f r o m Tw o P h a s e 3 , R a n d o m i ze d ,

P l a c e b o - C o nt r o l l e d Tr i a l s

• M.E.B. Clowse,1 D.J. Wallace,2 R. Furie,3 M. Petri,4 M. Pike,5 P. Leszczyński,6

C. M. Neuwelt,7 Et. al

54

Epratuzumab

■ Epratuzumab is a humanized monoclonal antibody that targets CD22 on B cells

■ This modulates B cell signalling, without substantial reductions in the number of peripheral B cells

■ In Phase 2b trials, epratuzumab treatment led to improvements in disease activity in patients with moderate to severe systemic lupus erythematosus (SLE)1

Epratuzumab Structure

IgG1Fc

Fab

(CD22 Binding)

55

New Biologicals in pipeline with different mechanisms of action

I. Anifrolumab – blocks receptor to interferon.

II. XMAB5871-04 – Fc Fraction of immunoglobulins.

III. Lupuzor – blocks T cell CD4 T cells

IV. Many others …

56

Epigenetics

Epigenetics – caused by external or environmental factors that switch genes on and off.

Epigenetics in SLE – DNA in African Americans make their T

cells more pro-inflammatory and more active compared to other

populations .

American College of Rheumatology November 9, 2015

57

Conclusions

Neither EMBODY™ 1 nor EMBODY™ 2 met the primary endpoint of BICLA response rate at Week 48.

Patients treated with epratuzumab + standard of care therapies did not show improvements in disease activity, corticosteroid use or health-related quality of life compared to those receiving placebo + standard of care therapies.

The safety profile of epratuzumab was consistent with previous studies, with no new safety signals identified.

58

EPRATUZUMAB: SUSTAINED SAFETY PROFILE AND EFFECT ON CORTICOSTEROID USE ON LONG-TERM TREATMENT IN PATIENTS WITH MODERATE-TO-SEVERE SYSTEMIC LUPUS ERYTHEMATOSUS: RESULTS FROM AN OPEN-LABEL LONG-TERM EXTENSION STUDY (SL0008)

• D. J. Wallace 1,*, J. Ordi-Ros 2, M. Neuwelt 3, K. Kalunian 4, B. Kilgallen 5, S. Bongardt 6 ,M. Petri 7, M. Pike 8, S. Jeka 9, C. Gordon 10, V. Strand 11

1Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, United

States, 2Hospital Vall d'Hebron, Barcelona, Spain, 3East Bay Rheumatology Medical Group,

San Leandro, 4UCSD School of Medicine, La Jolla, 5UCB Pharma, Raleigh, United States,

6UCB Pharma, Brussels, Belgium, 7School of Medicine, Johns Hopkins University, Baltimore,

8Harvard Medical School, Harvard, United States, 9University Hospital No. 2, Bydgoszcz,

Poland, 10University of Birmingham, Birmingham, United Kingdom, 11Stanford University School of Medicine, Palo Alto, United States

59

Individualized Cocktails of the Present and Near Future for Systemic Lupus Erythematosus

I. Experience suggests that in order to deplete B cells in all patients, one must use the of Cyclophosphamide, Rituximab, and Corticosteroids1

II. Increased production of BLyS after B cell depletion may counteract the clinical benefit. may be a rational combination to test2

1. Tim Y.-T. Lu, Edwards JCW, Isenberg DA, et al. A Retrospective Seven-Year Analysis of the

Use of B cell Depletion Therapy in Systemic Lupus Erythematosus at University College

London Hospital: The First Fifty Patients. Arthritis Care and Research. April 2009. 61:482-487

2. Tsokas GC. Mechanisms of Disease, Systemic Lupus Erythematosus. New England Journal

of Medicine. Dec 2012. 365:2110-21

60

TREAT-TO-TARGET:

THE NEW GOAL IN LUPUS

(T2T)

International task force 2014.

Published online 2015

61

The Principles (T2T)

Recognize the patient’s autonomy, with decision – making shared between the patient and clinicians.

Treatment should encompass survival, preservation of organ function, and encouraging the optimal quality of life.

Recognition of the protean nature of SLE with its effects on multiple organ systems, requiring an interdisciplinary approach.

Regular monitoring & treatment adjustments are needed to balance disease control and potential treatment toxicities.

62

The Recommendations (T2T)

Prevention of disease flares, and particularly severe flares of nephritis, neuropsychiatric symptoms, and SLE overall.

There are interventions that can prevent at least some flares with a reasonable balance to risks/side effects.

Prevention of damage also was addressed and accorded considerable importance because of the associations between organ damage and poor prognosis.

Patients who are clinically asymptomatic should be monitored closely but are at risk for overtreatment if serology alone guides treatment.

63

The Recommendations (T2T)

Promptly evaluate renal function for all patients because of evidence in the literature suggesting that each 1-month delay in diagnosis and initiating immunosuppression increases the risk of relapse (RR1.03).

Lupus nephritis consists of both induction and maintenance, and, in general, the maintenance phase should include at least 3yrs of treatment.

Using the lowest dose of steroids that can control the disease and recommending that most patients be on an anti-malaria if not contraindicated.

Treatment of comorbidities, such as antihypertensives and lipid-lowering agents.

64

Bill Murray and Scarlett Johannson & SLE

are no longer Lost In Translation!!