update on systemic lupus erythematosuserythematosus (sle ... - systemic lupus... · 1 update on...

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Update on Systemic Lupus Update on Systemic Lupus ErythematosusErythematosus (SLE)(SLE)

Update on Systemic Lupus Update on Systemic Lupus ErythematosusErythematosus (SLE)(SLE)

Stacy P. Ardoin, MD, MHS Assistant Professor Clinical Medicine

Adult and Pediatric RheumatologyAdult and Pediatric RheumatologyNationwide Children’s Hospital

Ohio State University

ObjectivesObjectivesObjectivesObjectives• Present a case of a patient with SLEp

• Review long-term complications of SLE

with focus on atherosclerosis

• Discuss recent clinical trials in non-

renal SLErenal SLE

• Discuss good news about an old SLE

drug (hydroxychloroquine)

2

Case: NicoleCase: NicoleCase: NicoleCase: Nicole• 31 yr old

• 8 week history of fatigue, facial rash, hair loss, joint pain

• Past Medical History• 2 first trimester miscarriages

• Medications• multivitamin, oral contraceptive

• Soc HX:• Soc HX: • single, works full time, smokes ½ pack

cigarettes daily• FHX:

• Hypertension, DM-2, no autoimmune disease

Case: NicoleCase: NicoleCase: NicoleCase: Nicole• Exam:

• HR 105, BP 147/90 • malar rashmalar rash • polyarticular arthritis

• Labs: • WBC 2,200 (absolute lymphocytes 800)• H/H 10.5/32 • ESR 45 mm/hr• Urinalysis with 100 mg/dl protein, 15 RBCs• +ANA, +double stranded DNA, +anticardiolipin IgG• Low C3 and C4

3

ACR 1997 Classification CriteriaACR 1997 Classification Criteria

• Malar rash

• Discoid rash

• Cytopenia

• Encephalopathy

• Photosensitivity

• Oral/nasal ulcers

• Non-erosive arthritis

– seizure or psychosis

• ANA

• Serology– anti-double stranded

DNA

• Pleuritis/pericarditis

• Nephritis

– anti-Smith

– anti-phospholipid antibody

ACR 1997 Classification CriteriaACR 1997 Classification Criteria

• Malar rash

• Discoid rash

• Cytopenia

• Encephalopathy

• Photosensitivity

• Oral/nasal ulcers

• Non-erosive arthritis

– seizure or psychosis

• ANA

• Serology– anti-double stranded

DNA

• Pleuritis/pericarditis

• Nephritis

– anti-Smith

– anti-phospholipid antibody

4 OF 11 CRITERIA GIVES 96% SENSITIVITY/SPECIFICITY

4

Pathophysiology of SLEPathophysiology of SLEExposure(s)

Immune dysregulation

Susceptible host

TissueTissue damagedamage



Susceptible hostGenes Gender/Sex Hormones


5


UV lightDrugsInfectious agents


Infectious agents

Susceptible hostGenes Gender/Sex Hormones



UV lightDrugsInfectious agents


Infectious agents

Complement activationImmune complex depositsB and T cell hyper-reactivityLoss of self toleranceA t tib di

Susceptible host

AutoantibodiesCytokines

Genes Gender/Sex Hormones


6

Lymphocyte proliferation

MHC class II i A t tib d

Immune Dysregulation in SLEImmune Dysregulation in SLE

expression (HLA DR)

Immune cell maturation (e.g., CD40,

B7)

Inflammatory

Macrophage, B and T

lymphocyte activation

Autoantibody formation and autoreactivity

ycytokines

Adhesion molecules

Endothelial NO synthase

Vessel inflammation

Vasculitis and organ damage

Survival in SLESurvival in SLESurvival in SLESurvival in SLE5 year 10 year

Adult 95% 90%

Predictors of poor outcome

Adult 95% 90%

Pediatric1975

2003

83%

99%

76%

86%

Predictors of poor outcomeChildhood onsetLow SESHealth care accessEducationRace/ethnicity

Male genderDisease activityCNSRenal

7

The Bimodal Mortality Pattern of SLEThe Bimodal Mortality Pattern of SLE

CV Disease

DeathSLE

Infection

Time

Urowitz M Am J Med 1976; 60: 221

Causes of Death in SLECauses of Death in SLE• Early: Within first 5 years of diagnosis

Active SLE Infection

• Late: > 5 years since diagnosis InfectionAtherosclerosis

Abu-Shakra M, et al. J Rheum 1995; 1265-70

AtherosclerosisMalignancy

8

MalignancyMalignancyMalignancyMalignancy• Increased incidence in SLE

– Cervical HPV infection and cancer

Hodgkins lymphoma– Hodgkins lymphoma

– Lung cancer

– Breast cancer

• Hydroxychloroquine protective?

• Malignancy screening and prevention key

Nath Arthritis Rheum 2007, Bin Lung Cancer 2007, Bernatsky Rheumatology 2007, Bernatsky J Rheum 2003, Ruiz-Irastoyoa Ann Rheum 2007.

AtherosclerosisAtherosclerosis• Increased incidence and

earlier presentation in SLE

• Bland vasculopathy (not vasculitis)

• Independent of Framingham risk factors, glucocorticoid use

• “Lupus factor” elusive– Inflammation, dyslipidemia,

autoantibodies

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Incidence of MI per 1000 person years in women with Incidence of MI per 1000 person years in women with SLE (Pittsburgh) and from the Framingham Offspring SLE (Pittsburgh) and from the Framingham Offspring Study: 1980Study: 1980--19931993

Age SLE Framingham Rate(yrs) (N=498) (N=2208) Ratio 95%CI

15-24 6.33 0.00 25-34 3.66 0.00 35-44 8.39 0.16 52.43 [21.6, 98.5]45-54 4.82 1.95 2.47 [0.8, 6.0]55-64 8.38 1.99 4.21 [1.7, 7.9]

Manzi, et al. Am J Epidemiol, 1997

4045

Role of Traditional Risk FactorsRole of Traditional Risk FactorsRole of Traditional Risk FactorsRole of Traditional Risk Factors

• High frequency of CV

05

10152025303540

1 2 3 4 5 6 7 8

%

g q yrisk factors in SLE.

• After adjusting for CHD risk using the Framingham risk factor estimate,

ti t ith SLE till # risk factorspatients with SLE still had a 7- to 10-fold increased risk of CHD and stroke.

Esdaile JM, Arthritis Rheum 2001

89.7% have > 3 CV risk factors

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AspirinLeflunomide*

Hydroxychloroquine

Timeline for SLE Drug DevelopmentTimeline for SLE Drug Development

Methotrexate*

19001900 19101910 19201920 19301930 19401940 19501950 19601960 19701970 19801980 19901990 20002000 20102010 20112011

Cyclophosphamide*

Mycophenolate mofetil*

Glucocorticoids

Rituximab*

Azathioprine*

* Not an FDA approved indicationBelimumab

Treatment of SLETreatment of SLETreatment of SLETreatment of SLE• Tailored to organ involvement

• Few controlled trials

Mild diseaseMild disease

HydroxychloroquineHydroxychloroquineNSAIDsNSAIDsLow dose corticosteroidsLow dose corticosteroidsMethotrexateMethotrexateLeflunomideLeflunomideAzathioprineAzathioprineBelim mabBelim mab

Severe disease

BelimumabBelimumabHigh dose corticosteroidsHigh dose corticosteroidsMycophenolateMycophenolate mofetilmofetilCyclophosphamideCyclophosphamide

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EXPLORER TRIALRituximab to Treat Non-Renal SLE

Study Design

EXPLORER TRIALRituximab to Treat Non-Renal SLE

Study Design

Active non-renal SLE (n=257)

Background52 wk

follow up

Mean age 40.4yNonwhite 42%

Placebo (days 1, 15, 158, 162)Prednisone taper

(n= 189)

Rituximab (days 1, 15, 168, 182)Prednisone taper

(n=88)

Background immunosuppression

follow up

Primary EndpointPrimary Endpoint: major or partial clinical : major or partial clinical response (BILAG)response (BILAG)

Secondary Endpoints: Time to disease flare

Quality of lifeMerrill JT, et al. Arthritis Rheum. 2010; 62:222-33

EXPLORER Trial: Proportion of patients with major, partial or no clinical response at 52 weeks

EXPLORER Trial: Proportion of patients with major, partial or no clinical response at 52 weeks

70

80

P = 0.9750

%)

20

30

40

50

60

Placebo

Rituximab

on

of

Pat

ien

ts (

%

0

10

No Clinical Response

Partial Clinical Response

Major Clinical Response

Major + PartialPro

po

rtio

Merrill JT, et al. Arthritis Rheum. 2010; 62:222-33.

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Belimumab to Treat Active Non-Renal SLE: Study Design

Belimumab to Treat Active Non-Renal SLE: Study Design

Active non-renal SLE (n-867)

Background52 wk follow up

Mean age 35 yNonwhite 75%

Primary Endpoint: Improvement in SLEPrimary Endpoint: Improvement in SLE

Placebo(n=288)

Belimumab 1 mg/kg(n=289)

Background immunosuppression

Belimumab 10 mg/kg(n=290)

Primary Endpoint: Improvement in SLE Primary Endpoint: Improvement in SLE Responder Index (SRI)Responder Index (SRI)

Secondary Endpoints: Physician Global Assessment

Navarra S et al. Lancet 2011; 377: 721-731

ved

(SR

I)

Efficacy of Efficacy of BelimumabBelimumab to Treat Active Nonto Treat Active Non--Renal SLE Renal SLE at 52 Weeks at 52 Weeks

tio

n w

ith

Imp

rov

esp

on

der

In

dex

(

Odds ratio for response to belimumab 10 mg/kg vs placebo1.83 (1.30 to 2.59), p = 0.0006

Pro

po

rtS

LE

Re

Navarra S et al. Lancet 2011; 377: 721-731

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Lupus Atherosclerosis Prevention (LAPS) Study Design

Lupus Atherosclerosis Prevention (LAPS) Study Design

Adult SLE(n = 200) 2 year follow up

Mean age: 44 yrsMean SLEDAI: 2

Primary Endpoint: CT coronary calciumPrimary Endpoint: CT coronary calcium

PlaceboAtorvastatin 40 mg/day

Standard therapy

y pNonwhite: 39%

Primary Endpoint: CT coronary calcium Primary Endpoint: CT coronary calcium scorescore

Secondary Endpoints: CIMT

Disease activity (SLEDAI)

Inflammatory Mediators (hs-CRP))

MeasureMean

baselineMean 2 Mean

hP

V l

Difference in change, statin

i l b (95%P

V l

LAPS Study: LAPS Study: Change in Coronary Calcium Score and CIMTChange in Coronary Calcium Score and CIMT

baseline years change Value minus placebo (95% CI)

Value

Loge (coronary artery calcium score + 1)

Atorvastatin1.16 1.24 0.08 0.52

−0.08 (−0.39 to 0.23) 0.62

Placebo 1.19 1.35 0.15 0.16

Carotid intima media thickness (mm)Carotid intima media thickness (mm)

Atorvastatin 0.59 0.66 0.07 <0.0001−0.02 (−0.05 to 0.01) 0.24

Placebo 0.57 0.66 0.09 <0.0001

Petri et al Ann Rheum Dis 2011

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Atherosclerosis Prevention in Pediatric Lupus Erythematosus

Study Design

Atherosclerosis Prevention in Pediatric Lupus Erythematosus

Study Design

Pediatric SLE (>10 and <21)(n = 221)

APPLE

3 year follow up

Mean age 15.7 yNonwhite 65%SLEDAI 4.7 ( )

hydroxychloroquine, ASA, folate, AHA TLC diet + placebo

hydroxychloroquine, ASA, folate, AHA TLC diet + atorvastatin

Standard therapyLDL 86HSCRP 3.6

Primary Endpoint: IMT progressionPrimary Endpoint: IMT progression

Secondary Endpoints: Disease Severity (SLEDAI, SLICC)

Quality of Life (PedsQL)Inflammatory Mediators (hs-CRP))

APPLE Results: CIMT EndpointsAPPLE Results: CIMT EndpointsAPPLE Results: CIMT EndpointsAPPLE Results: CIMT Endpoints

Mean-Mean Common

Atorvastatin slower Placebo slower

APPLE

Mean Mean Bifurcation

Mean-Max Bifurcation

Mean-Mean Internal

Mean-Max Internal

Mean-Max Common

Mean-Mean

Mean-Max

Mean-Mean Near Wall

Mean-Max Near Wall

Mean-Mean Far Wall

Mean-Max Far Wall

Mean-Mean Bifurcation

Difference of CIMT Progression (mm/year) with 95% CI-0.0125 -0.0100 -0.0075 -0.0050 -0.0025 0.0000 0.0025 0.0050

Schanberg et al, Arthritis Rheum 2010

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HydroxychloroquineHydroxychloroquine• Antimalarial; limited toxicity

• Beneficial in SLE

Prevents flares– Prevents flares

– Improves lipid profiles

– Improves pregnancy outcomes

– Reduces clotting risk

– Associated with decreases in mortality, renal morbidity, malignancy

• Mechanism

– Mediates Toll-like receptor 7, 9 signaling?Tsakonas Lupus 1998, Alarcon Ann Rheum Dis 2007, Costedoat-Chalumeau Arthritis Rheum2006, Lafyatis Arthritis Rheum 2006, Clowse Arthritis Rheum 2006, Rahman J Rheum 1999, Kasitanon Lupus 2006.

Back to our CaseBack to our Case: Nicole: NicoleBack to our CaseBack to our Case: Nicole: Nicole

• Additional evaluation:• 24 hour urine protein with 2 grams protein24 hour urine protein with 2 grams protein • LDL 144, HDL 38

• Plan: • Prednisone• Hydroxychloroquine• Address CV risk: dyslipidemia BP tobacco• Address CV risk: dyslipidemia, BP, tobacco

use• Referral to nephrology to evaluate for lupus

nephritis

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New Developments in the New Developments in the Treatment of Lupus NephritisTreatment of Lupus Nephritis

New Developments in the New Developments in the Treatment of Lupus NephritisTreatment of Lupus Nephritis

Brad H. Rovin, MD, FACP, FASNProfessor of Medicine and Pathology

Vice Chairman of Research for Internal MedicineVice Chairman of Research for Internal MedicineDirector, Division of Nephrology

The Ohio State University College of Medicine

• LOW‐DOSE CYCLOPHOSPHAMIDE IS EFFECTIVE INDUCTION THERAPY IN SOME POPULATIONS

MAJORMAJOR NEW FINDINGS IN THE NEW FINDINGS IN THE THERAPY OF PROLIFERATIVE LNTHERAPY OF PROLIFERATIVE LN

INDUCTION THERAPY IN SOME POPULATIONS

• MMF AND IV CYCLOPSHOSPHAMIDE ARE EQUALLY EFFECTIVE AS INDUCTION THERAPY

• RITUXIMAB DOES NOT IMPROVE INDUCTION THERAPY

• MMF MAY BE THE IMMUNOSUPPRESSIVE OF CHOICE FOR MAINTENANCE THERAPY

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LowLow--Dose (EuroDose (Euro--Lupus) CyclophosphamideLupus) Cyclophosphamide

• Low Dose CYC: 500 mg every 2 weeks for 6 doses/Cumulative Dose 3g

Houssiau, et al., Arth Rheum, 2002

• High Dose CYC: 0.5‐1g/m2 monthly for 6 months, followed by 2 quarterly pulses/Cumulative Dose >8g

• Done mainly in Caucasians with mild‐moderate disease• The current Immune Tolerance Network CTLA4 Trial is using Euro‐

Lupus in African American, Asian, Hispanic, and Caucasian

Prevention of Kidney Failure in the LongPrevention of Kidney Failure in the Long--TermTerm

Austin, et al, NEJM, 1986 Gourley, et al, Ann Int Med, 1996

• These seminal studies, despite criticism of low numbers at follow‐up showed that the addition of CYC to steroids improved the long‐term outcome of kidneys in LN

• The benefit of CYC was not seen for about 3‐5 years• All new therapies/regimens should provide similar evidence to be generally

accepted as equivalent to CYC for long‐term kidney survival

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LowLow--DoseDose CyclophosphamideCyclophosphamide--LongLong--Term ResultsTerm Results

Failure:• Absence of primary response at 6 months

High Dose Low Dose

Randomized 46 44

Lost to Follow‐Up 3 3

months• Occurrence of steroid‐resistant flare• Doubling of SCr

Houssiau, et al., Arth Rheum, 2002; Ann Rheum Dis, 2010

Mean Follow‐Up 119 111

Mean Age 40 42

Deaths 2 5

Doubling SCr 5 6

ESRD 4 2

10 Year Follow‐Up

MAJOR NEW FINDINGS IN THE MAJOR NEW FINDINGS IN THE THERAPY OF PROLIFERATIVE LNTHERAPY OF PROLIFERATIVE LN

• LOW‐DOSE CYCLOPHOSPHAMIDE IS EFFECTIVE INDUCTION THERAPY IN SOME POPULATIONSINDUCTION THERAPY IN SOME POPULATIONS


• RITUXIMAB DOES NOT IMPROVE INDUCTIONRITUXIMAB DOES NOT IMPROVE INDUCTION THERAPY


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MMF MMF vsvs CyclophosphamideCyclophosphamide

Black, H

ispan

icc, Mixed

•370 Class III/IV LN patients‐ALMS Trial

•Randomized to IV CYC pulses for 6 months or MMF 3 gm/d target dose for 6 months

Appel, et al., JASN, 2009 Isenberg, et al., Rheumatology, 2010

MMF Concerns and CaveatsMMF Concerns and Caveats•Despite ALMS results, and fact that ALMS was NOT designed as a non‐inferiority trial, it has increasingly become standard of care

•Although MMF is perceived as safer than CYC, ALMS showed a similar incidence of adverse events for MMF and CYC, including serious infections and death; while not statistically significant, there were almost twice as many withdrawals for side‐effects from the MMF arm

Adverse Events

MMF IVC

Chan, et al., JASN, 2005

•Long‐term outcomes are key for a true comparison with CYC

Deaths 9 (4.9%) 5 (2.8%)

W/drawals 24 (13%) 13 (7.2%)

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LongLong--Term Outcome After MMF TreatmentTerm Outcome After MMF Treatment

80

100u

re (%

)MMF AZA

20

40

60

80

Pat

ien

ts w

ith

Tx

fail

u

16%21%

36%

11%

28%32%

Data from the ALMS Maintenance Trial‐Ninth International Congress on SLE, Vancouver, 2010

0

Overall Induction MMF Induction IVC

P

LongLong--Term Outcome: MMF Term Outcome: MMF vsvs Oral CTXOral CTX

ProteinuriaNo Flare

Comparing induction with MMF to CYC, after median of 64 months there were no differences in renal function; however MMF group trended to have more relapses, prolonged proteinuria >1gm/d, and more subjects with SCr > 2 mg/dl, all risk factors for CKD.

Chan, et. al. JASN 2005

21

Choosing Initial TherapyChoosing Initial Therapy

•Consider a full-dose CYC protocol for patients with severe, proliferative LN; severity is defined as rapidly progressive loss of kidney function, usually accompanied by widespread crescents and glomerular capillary necrosis

•WHY: IV CYC protocols have been used in prospective trials in patients with severe LN whereas MMF and Euro-lupus have mainly been used to treat mild-moderate LN

•Consider Euro-lupus, low-dose CYC protocol for Caucasian patients with mild-moderate LN

•WHY: Euro-lupus has not been tested in a BlackWHY: Euro lupus has not been tested in a Black population, a group that traditionally has more severe LN than Caucasians

•Consider MMF in those patients who have received CYC in the past and are near or above a life-time cumulative dose of 36 grams

Biomarkers of Renal Response Biomarkers of Renal Response A PostA Post--Hoc Analysis of ALMSHoc Analysis of ALMS

ODDS OF A RENAL RESPONSE AT 24 WEEKS BASED ON PARAMETER IMPROVEMENT AT 8 WEEKS‐MULTIVARIATE

MODEL

PARAMETER ODDS RATIO 95% CI

↓ proteinuria by ≥25% 2.9 1.6‐5.1

Normalization of C3/C4* 2.7 1.4‐5.0

Dall’Era et al., Arth Care Res, 2011

*only applicable if patients had baseline low C3 and C4

Do we need to think about changing therapy sooner during induction?

22

Therapeutic Drug Monitoring for MMFTherapeutic Drug Monitoring for MMFImproving OutcomesImproving Outcomes

Lertdumrongluk et al., Kidney Int, 2010

• Responders have a higher mycophenolic acid area under the curve (12 hour) than non‐responders

• Response rate increases with increasing mycophenolic acid area under the curve

• This is not practical for most patients with LN undergoing MMF therapy

Therapeutic Drug Monitoring for MMFTherapeutic Drug Monitoring for MMFImproving OutcomesImproving Outcomes

• Need to have a practical way to determine therapeutic MMF dosing

• The trough and one hour peak MPA were significantly correlated with the MPA‐AUC and also response

• For trough MPA r=0.90• For 1 hour Peak MPA r=0.92• One may be able to use trough and

peak to optimize MMF dosing• Our recommendation:

Lertdumrongluk et al., Kidney Int, 2010

Dose MMF so that: Trough level is 3 mg/l 1 hour peak level is > 22 mg/l

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MAJOR NEW FINDINGS IN THE MAJOR NEW FINDINGS IN THE THERAPY OF PROLIFERATIVE LNTHERAPY OF PROLIFERATIVE LN





What About Rituximab?

Rituximab + MMF (n=72)Treatment Period

As suggested by the outcomes with CYC or MMF as initial therapy for proliferative LN, there is plenty of room for improvement in CR and PR rates!

Screening

Follow‐up PeriodPlacebo + MMF (n=72)

Prednisone taper

W kWeeks 1 and 2

(Days 1 and 15)

Week 16 Weeks

24 and 26

(Days 168 and 182)

Week 52

Week

78

= Study drug infusion.

= Corticosteroids: 2 doses of 1000 mg IV methlyprednisolone given on day 1 and day 2, 3, or 4. This was followed by oral prednisone initiated at 0.75 mg/kg/day and then tapered to10 mg/day by day 112

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Primary Endpoint: Renal Response at Week 52Primary Endpoint: Renal Response at Week 52

54.160ts

Placebo Rituximab

30.6

15.3

26.4 30.6

43.0

10

20

30

40

50

oportion of Patient

P=0.55*P=0.55*

0

10

Complete Renal Response (CRR)

Partial RenalResponse (PRR)

No Response (NR)

Pro

* Wilcoxon Rank‐sum test Mean MMF dose: Placebo: 2.4±0.62 g;Rituximab: 2.7±0.41 g

22/72 19/72 11/72 22/72 39/72 31/72

PrePre--Specified Analysis: Proportion of Specified Analysis: Proportion of SubjectsSubjectsAchieving Response by RaceAchieving Response by Race

70 080% Placebo Rituximab

45.0 47.8 50.0

70.0

55.0 52.6

20%

30%

40%

50%60%

70%

ponse Proportion

9/20 14/20 11/23 16/29 13/26 10/190%

10%20%

Black (n=40) Hispanic (n=52) Caucasian (n=45)

Res

25

MAJOR NEW FINDINGS IN THE THERAPY OF PROLIFERATIVE LN





ALMS Maintenance TrialTime to Treatment

Failure, n=227

MAINTAIN Nephritis TrialMAINTAIN Nephritis TrialTime to FlareTime to Flare

Appel, ASN Denver 2010H i l A Rh Di 2010

Appel, ASN Denver 2010Houssiau et al., Ann Rheum Dis, 2010

• Open versus blinded (ALMS)• Different ethnic background• ALMS larger study• Composite endpoint in ALMS (ESRD, Flare, Double SCr, Rescue Meds)• Only patients with a response (including to MMF...) were entered in ALMS• In MAINTAIN patients were randomized for maintenance at baseline and given

maintenance after Euro‐Lupus no matter the response

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ApoptosisDeficient clearance1

Nucleosomes

Y Y

Y

Y Y YY

Y

Y

Y

YAnti-dsDNA

2

Nucleosome-IC depositionin glomerular capillaries

Complement activationFcR activationTLR activation

3

Y

Auto-reactiveB Cell

Auto-reactivePlasma Cell Y Y

Y Y

Production of pro-inflammatory cytokinese.g. C3a/C5a, MCP-1, IL-17, IL-18

Cell infiltration and activationMonocytes, Lymphocytes, pDCs

Increased production of cytokinesIFN‐a

Anti-C5(Eculizumab)

Anti-TLR

Anti-IFN-α

Anti-CD20(Rituximab, Ocrelizumab)

Anti-CD22(Epratuzumab)

Endothelial CellGBM

Podocyte

MΦMΦ

ROSProteases

ROSProteases

IL-6

Anti-IL-6(Tocilizumab)

CTLA4-Ig(Abatacept)

Y

Y

YY

Y

Y

YYYYY

Y YY

Accelerated autoimmune responselocal, Th1-skewed

Increased IC accumulation andcomplement and FcR activation

Renal tissue damage

BLyS

APRIL

Anti-BLyS(Belimumab)

TACI-Ig(Atacicept)

4MAC

Auto-reactive

T Cell

Lupuzor

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