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Systemic Lupus ErythematosusTranslating Pathophysiology into New Therapies

Traduciendo fisiopatologia en nuevos tratamentos

Asociacion Costarricense Medicina Interna

August 7, 2015

Arthur Weinstein, MD, FACP, FRCP, MACR

Professor of Medicine, Georgetown University

Dr. Srur, Dr. Acuña, Dr. Monge

Gracias por haberme invitado

a hablar en este congreso

SLE Disclosures

Research Investigator:

Rituximab (anti-CD20) for Lupus Nephritis (Genentech)

Epratuzumab (anti-CD22) for Lupus (Immunomedics and UCB)

Lymphostat B / Belimumab [Benlysta] (anti-Blys) for SLE – phases

1, 2 and 3 and extensions (HGS/GSK) -CURRENT

Cell-bound complement activation products for SLE diagnosis

(Exagen Diagnostics)- CURRENT

Consultant /Speakers Bureau:

HGS and GSK – Benlysta for SLE - past

Consultant /Board of Directors:

Exagen Diagnostics (stock holder) - CURRENT

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SLE History Clinical/Path Features

• 1850-1900 - skin disease (Cazenave, Kaposi,

von Hebra)

• 1900 - systemic disease -”erythema

exuditavum multiforme” (Osler and others)

• 1940’s – “collagen disease”

• modern era - SLE subsets – classes of renal

disease, subacute cutaneous LE, neonatal

lupus, antiphospholipid syndrome, “borrowed“

treatments

• present – markers of diagnosis and disease

activity, large controlled clinical trials

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SLE History

Autoimmunity

• 1946 - LE cells in marrow (Hargraves)

• 1954-57 - LE cell due to antibody to nuclei (ANA) (Miescher, Friou)

• 1957 - anti-DNA in SLE (Kunkel)

• 1970’s - low complement levels (Vaughan)

• 1980’s – antiphospholipid antibodies (Hughes)

• 2000’s – genome wide association studies (GWAS)

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SLE - Systemic Autoimmune Disease

Key Features

• Multisystem organ involvement– joints, skin, kidney, brain, serositis

• Microvascular inflammation – immediate and long term consequences

• Autoantibodies – ANA, anti-DNA, antibodies to red cells, white cells, platelets, other autoantibodies (anti-phospholipid)

Frequency of SLE

manifestations

‘Lupus Spectrum Disorders’

• Skin– Subacute cutaneous lupus, bullous lupus

• CNS– Myelopathy, neuromyelitis

– “Lupoid sclerosis”

• Renal– crescentic/progressive GN (ANCA), thrombotic microangiopathy

(APL)

• Hematological– TTP

– MAS/hemophagocytic syndrome

• APLS features– strokes, gangrene, valvular heart disease (Libman-Sachs), CAPS

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Diagnosis of SLE

• ANA – universally present

• anti-DNA, anti-Smith autoantibodies –specific, lack

sensitivity

• skin, kidney tissue pathology- characteristic

• low complement (C3 and C4) – relatively specific and

reflects pathophysiology (active disease) but lack

sensitivity

• complement activation products in plasma (short-lived) or

cell-bound (CB-CAPS) - more sensitive than

hypocomplementemia

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CB-CAPS as a diagnostic tool

At activation C3/C4 break down into fragments such as C4d and C3d these bind to circulating cells (CBCAPS):

measured by flow cytometry- eg erythrocyte (EC4d) and B-cell (BC4d)

Lupus Sci Med 2014;1:e000056 doi:10.1136/lupus-2014-000056 Putterman C et al

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“Prognostic” Autoantibodies(SLICC inception cohorts)

Anti-C1q antibodies Lupus Nephritis

Anti-ribosomal P antibodies CNS lupus

Anti-phospholipid antibodies Stroke

(LAC, anticardiolipin)

1. Yin et al. Lupus. 2012 Sep;21(10):1088-97. Diagnostic value of serum anti-C1q antibodies in patients with lupus nephritis: a meta-analysis.

2. Hanly et al. Ann Rheum Dis. 2011 Oct;70(10):1726-32. Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus.

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SLE Survival

2000’s

• max in middle aged >45yrs

• 44% of all rheumatic disease deaths

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

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

≥6040-5925-3916-24

Rate of SLE Mortality Remains HighRelative to the General Population

Percentage of Patients With Permanent Organ Damage

Chambers SA, et al. Rheumatology (Oxford). 2009;48:673-675.

One-Third of SLE Patients Accrue Permanent Organ Damage Within 5 Years of Diagnosis and

50% within 10 years

Pe

rce

nt

of

Pat

ien

ts W

ith

SD

I ≥1

5 Years(N=232)

1 Year(N=232)

10 Years(N=232)

15 Years(N=143)

20 Years(N=75)

25 Years(N=6)

0.11 0.42 0.77 1.01 1.26 2.17Mean

Damage Score

Corticosteroids use an important contributor to long

term damage accrual- up to 50% in 15 years

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Pittsburgh lupus cohortCoronary Artery Disease in SLE

• 498 women with SLE - 33 developed CAD

(f/u 13 years, ages 15-74)

• 2208 women in the Framingham study 36 developed CAD

• 6.6% (SLE) vs. 1.6 % (population)

• 35-44 age group 50X increased

• In Framingham youngest 34, in SLE group any age

Manzi S et al. Am J Epidemiol 1997

SLE PATHOGENESIS – ?UNIFYING HYPOTHESIS

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HEREDITY & GENES

10% chance of SLE in family of patient with lupus

2% concordance dizygotic twins, 25% monozygotic

PROTEINS

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Genetic Associations in SLE (GWAS studies)

Crow M. N Engl J Med 2008;358:956-961

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GENES CAN BE TURNED ON & OFF

Upregulation of

interferon I genes in

SLE

“interferon signature

of active SLE”

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Immunological ResponseLymphocytes in SLE

Immune Dysregulation

Macrophage/

APC

B CELL

Cytokines –

Interleukins (IL-6,

BLys,…)

Auto

Antibodies

Th CELL

Ts CELL

+

++

-

++

++

Self or

exogenous

antigens

Tregs , Th17cells

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Tissue Damage in SLE is Antibody Mediated

• the target antigens are double-stranded (ds)-

DNA, nucleohistones

• circulating (or in situ) immune complexes form,

lodge in vascular and nonvascular basement

membranes (kidney glomeruli, skin dermo-

epidermal junction, synovial membrane) -

complement activation (low C3 and C4 levels,

complement split products on cells)

• can get antibody-mediated cytotoxicity - RBC,

leukocyte, platelet

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Drugs Approved and Drugs Used to Treat SLE

BENLYSTA

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SLE Common Treatments

• Prednisone oral – low (<0.5mg/kg/day) to moderate to high dose (>1mg/kg/day) [IV pulse – acute, severe]

• hydroxychloroquine (Plaquenil) – rash, fatigue, joint, muscle pains, thrombovascular- can be used in pregnancy – prevents flares

• methotrexate, leflunomide (Arava) – arthritis

• azathioprine (Imuran) – maintenance

• mycophenolate (CellCept) - skin, renal –induction/maintenance

• cyclophosphamide (Cytoxan) I.V. – remission induction - renal, brain inflammation, vasculitis

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Tweaking Treatments

• HCQ “the lupus vitamin”- prevents flares, prevents/slows organ damage, decreases thrombosis, may improve survival

• Use corticosteroids in high doses for acute flares, limit long term use – use other immunosuppressive agents

• Mycophenolate mofetil (CellCept) for lupus nephritis – induction and maintenance

• Tacrolimus for lupus/lupus nephritis

• Euro-Lupus nephritis regimen for IV cyclophosphamide – 500mg q 2 weeks x 6

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?Cyclophosphamide for Remission MaintenanceSequential Therapies for Proliferative Lupus Nephritis

N Engl J Med 2004;350:971-80

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Targeted Therapeutic Approaches in Systemic Lupus Erythematosus

Modified from Rahman A, Isenberg D. N Engl J Med 2008;358:929-939

anti-interferon

sifalimumab

anti-IL-6

tocilizumab

epratuzumab

Th17

TTregs

rituximabbelimumab

abatacept

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Targeted Treatments – B-cell

Rituximab – B cell lysis

Belimumab – B cell apoptosis

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Rituximab Anti-CD20 Monoclonal Antibody

• Rituximab

– Induces B-cell death via several mechanisms

• Chimeric murine/human monoclonal antibody

• Long serum half-life:

– At a dose of 375 mg/m2

– Single dose t1/2 = 76 hours

– Multidose t1/2 = 206 hours

• Total 2 Gm by IV infusion 500mg weekly x 4 or 1Gm x2 14 days apart

RTX

Berinstein NL, et al. Ann Oncol 1998;9:995-1001; Maloney DG, et al. J Clin Oncol 1997;15:3266–74;

Maloney DG, et al. Blood. 1997;90:2188–95.

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Does Rituximab work in SLE?Systematic review 188 patients

Clinical response/

treated patients % of response

Cardiopulmonary 12/12 100

Haematological 50/53 94

Renal 94/103 91

Articular 92/101 91

CNS 26/29 89

Mucosal/cutaneous 79/88 89

Alveolar haemorrhage 2/2 100

Haemolytic anaemia 24/25 96

Thrombocytopenia 15/16 93

Cutaneous vasculitis 17/19 89

Ramos-Casals M: Lupus 2009

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Does Rituximab work in SLE?Serology (Explorer trial)

257 pts active SLE

Background therapy – MTX, MMF,

AZA

Steroid taper

Rituximab infusions- baseline and

6 months

No differences in

clinical end points

Merrill JT et al : Arthritis Rheum 2010

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B- Lymphocyte Stimulator (BLyS) Is Elevated in Patients With Autoimmune

Disease; correlates with disease activity

0

10

20

30

40

50

Normal(n = 38)

SLE

Sera(n = 40)

P <0.0001

RAsf(n = 57)

P <0.0001

RA(n = 44)

P <0.001

SLE

Plasma(n = 110)

P <0.0001

Zhang J et al. J Immunology. 2001;166:6-10; Petri M et al. Arthritis Rheum 2008

Belimumab: A Potential New Approach to SLE Treatment 32

LymphoStat-B (Belimumab)

• Fully human monoclonal

antibody targets soluble BlyS

• Inhibition of BLyS can result in

autoreactive B-cell apoptosis

Inhibition of Survival by Belimumab

Autoimmune Disease

Autoreactive B-cell survival

Autoreactive B-cell apoptosis

Belimumab: A Potential New Approach to SLE Treatment

SRI Response Rate in Autoantibody-Positive Belimumab-Treated Patients Over 7 years Ginzler et al J Rheumatol 2014

*

All Belimumab-Treated

Patientsa

Responder

Rate

, %

Years of Belimumab Treatment

Double Blind, n=321

Seropositive Patients

Responder

Rate

, %

Study Week

Placebo

Belimumab 1, 4, 10 mg/kg

46%*

29%

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n = 252 205 187 171 158 142

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Decrease Flare Rate Over 7 Years

Change in Autoantibody Levels Over 7 years

aPatients switched from placebo to belimumab are included from 1st belimumab exposure; bmedian percent change of

zero.

Years of Treatment

b bb b

Extension-Continuation (all belimumab-treated patients)a

Placebo Belimumab

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Incidence Rates of AEs, Infections, Malignancies, and Mortality

aRate = (100X no. of patients starting given AE in given interval)/(total patient-years in given interval); bpatients originally

randomized to placebo are included from 1st belimumab exposure.

‘Malignancies’ excludes non-melanoma skin cancer and includes unspecified lung malignancies;

7 deaths

Ginzler EM et al: Disease control and safety of belimumab plus standard therapy over 7 years

in patients with systemic lupus erythematosus. J Rheumatol 2014

CASE: SLE with rash, joints, fatigue

• 24 year recently married woman has a 2 year history of mild

to moderate SLE – skin rashes, joint pains, fatigue –

controlled with plaquenil 400mg and 7.5 mg prednisone daily.

She now has a 3 month history of increasing fatigue, episodic

low grade fevers, more joint pains hands, wrists and knees

and hair coming out with combing. She works as an

accountant and has been able to continue working.

• On examination she has a malar blush, thinning of hair at the

temples, joint swelling and tenderness bilateral wrists and

MCP joints 2 & 3.

• Labs show mild anemia, WBC 2500 with lymphopenia. Urine

protein 500mg, no blood. Serum creatinine 1.0 mg/dl. ANA

1:320 homogeneous. Anti – DNA 200 units (normal<20).

Other antibodies neg. C3- 60, C4- 5.

CASE: SLE with rash, joints, fatigue

• Does she have mild, moderate or severe SLE flare?

• How would you treat this flare –pulse steroid, moderate dose oral steroid, high dose oral steroids, other ?

• What would you use for long term control? – methotrexate, prednisone 10mg/day, CellCept, tacrolimus,

• ? rituximab, belimumab

• What is her SLEDAI score?

•17 (>12- mod to severe)

Recurrent active SLE and low grade active SLE is common and undertreated

•Quantitate Disease Activity

•Test for Prognostic Markers

_______________________________

•Treat to Target studies ---Low disease Activity

•Comparative Effectiveness Studies

•Early vs Late use of Immunosuppressives

GRACIAS