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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 MHSStacy P. Ardoin, MD, MHS Assistant Professor Clinical Medicine
Adult and Pediatric RheumatologyNationwide Children’s Hospital
Ohio State University
ObjectivesObjectivesObjectivesObjectives• Present a case of a patient with SLE
• Review long-term complications of SLE
with focus on atherosclerosiswith focus on atherosclerosis
• Discuss recent clinical trials in non-
renal SLE
• Discuss good news about an old SLE
drug (hydroxychloroquine)
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 miscarriagesg
• Medications• multivitamin, oral contraceptive
• 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 rash • polyarticular arthritis
L b• 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
2
ACR 1997 Classification CriteriaACR 1997 Classification Criteria
• Malar rash
• Discoid rash
• Photosensitivity
• Oral/nasal ulcers
• Cytopenia
• Encephalopathy– seizure or psychosis
• ANA
S l• Non-erosive
arthritis
• Pleuritis/pericarditis
• Nephritis
• Serology– anti-double stranded
DNA
– anti-Smith
– anti-phospholipid antibody
ACR 1997 Classification CriteriaACR 1997 Classification Criteria
• Malar rash
• Discoid rash
• Photosensitivity
• Oral/nasal ulcers
• Cytopenia
• Encephalopathy– seizure or psychosis
• ANA
S l• Non-erosive
arthritis
• Pleuritis/pericarditis
• Nephritis
• Serology– anti-double stranded
DNA
– anti-Smith
– anti-phospholipid antibody
4 OF 11 CRITERIA GIVES 96% SENSITIVITY/SPECIFICITY
Pathophysiology of SLEPathophysiology of SLEExposure(s)
Immune dysregulation
Susceptible host
TissueTissue damagedamage
Pathophysiology of SLEPathophysiology of SLEExposure(s)
Immune dysregulation
Susceptible hostGenes Gender/Sex Hormones
TissueTissue damagedamage
3
Pathophysiology of SLEPathophysiology of SLEExposure(s)
Immune dysregulation
UV lightDrugsInfectious agents
Susceptible hostGenes Gender/Sex Hormones
TissueTissue damagedamage
Pathophysiology of SLEPathophysiology of SLEExposure(s)
Immune dysregulation
UV lightDrugsInfectious agents
Complement activationImmune complex deposits
Susceptible host
Immune complex depositsB and T cell hyper-reactivityLoss of self toleranceAutoantibodiesCytokines
Genes Gender/Sex Hormones
TissueTissue damagedamage
Lymphocyte proliferation
MHC class II expression (HLA DR)
Immune cell maturation
Macrophage, B and T
lymphocyte
Autoantibody formation and autoreactivity
Immune Dysregulation in SLEImmune Dysregulation in SLE
maturation (e.g., CD40,
B7)
Inflammatory cytokines
Adhesion molecules
Endothelial NO synthase
lymphocyte activation
Vessel inflammation
Vasculitis and organ damage
Survival in SLESurvival in SLESurvival in SLESurvival in SLE5 year 10 year
Adult 95% 90%
Pediatric1975 83% 76%
Predictors of poor outcomeChildhood onsetLow SESHealth care accessEducationRace/ethnicity
1975
2003
83%
99%
76%
86%
Male genderDisease activityCNSRenal
4
The Bimodal Mortality Pattern of SLEThe Bimodal Mortality Pattern of SLE
Death
CV Disease
Death
Time
SLEInfection
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
Abu-Shakra M, et al. J Rheum 1995; 1265-70
• Late: > 5 years since diagnosis InfectionAtherosclerosisMalignancy
MalignancyMalignancyMalignancyMalignancy• Increased incidence in SLE
– Cervical HPV infection and cancer
– 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
5
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 0025-34 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
15202530354045
%
Role of Traditional Risk FactorsRole of Traditional Risk FactorsRole of Traditional Risk FactorsRole of Traditional Risk Factors
• High frequency of CV risk factors in SLE.
• After adjusting for CHD i k i th
05
1015
1 2 3 4 5 6 7 8
# risk factors
risk using the Framingham risk factor estimate, patients 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
19001900 19101910 19201920 19301930 19401940 19501950 19601960 19701970 19801980 19901990 20002000 20102010 20112011
AspirinLeflunomide*
Hydroxychloroquine
Cyclophosphamide*
Timeline for SLE Drug DevelopmentTimeline for SLE Drug Development
Methotrexate*
19001900 19101910 19201920 19301930 19401940 19501950 19601960 19701970 19801980 19901990 20002000 20102010 20112011
Glucocorticoids
Rituximab*
Azathioprine*
* Not an FDA approved indication
Mycophenolate mofetil*
Belimumab
Treatment of SLETreatment of SLETreatment of SLETreatment of SLE• Tailored to organ involvement
• Few controlled trials
Mild diseaseMild disease
HydroxychloroquineHydroxychloroquineNSAIDsNSAIDsLow dose corticosteroidsLow dose corticosteroidsM th t tM th t t
Severe disease
MethotrexateMethotrexateLeflunomideLeflunomideAzathioprineAzathioprineBelimumabBelimumabHigh dose corticosteroidsHigh dose corticosteroidsMycophenolateMycophenolate mofetilmofetilCyclophosphamideCyclophosphamide
6
EXPLORER TRIALRituximab to Treat Non-Renal SLE
Study Design
EXPLORER TRIALRituximab to Treat Non-Renal SLE
Study Design
Active non-renal SLE (n=257)
Placebo (days 1 15 158 162)Rituximab (days 1 15 168 182)
Background immunosuppression
52 wk follow up
Mean age 40.4yNonwhite 42%
Primary EndpointPrimary Endpoint: major or partial clinical : major or partial clinical response (BILAG)response (BILAG)
Placebo (days 1, 15, 158, 162)Prednisone taper
(n= 189)
Rituximab (days 1, 15, 168, 182)Prednisone taper
(n=88)
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
50
60
70
80
P = 0.9750
tie
nts
(%
)
0
10
20
30
40
No Clinical Response
Partial Clinical Response
Major Clinical Response
Major + Partial
Placebo
Rituximab
Pro
po
rtio
n o
f P
a
Merrill JT, et al. Arthritis Rheum. 2010; 62:222-33.
Belimumab to Treat Active Non-Renal SLE: Study Design
Belimumab to Treat Active Non-Renal SLE: Study Design
Active non-renal SLE (n-867)
PlaceboBelimumab 1 mg/kg
Background immunosuppression
52 wk follow upMean age 35 yNonwhite 75%
Belimumab 10 mg/kg
Primary Endpoint: Improvement in SLE Primary Endpoint: Improvement in SLE Responder Index (SRI)Responder Index (SRI)
Placebo(n=288)
Belimumab 1 mg/kg(n=289)
Secondary Endpoints: Physician Global Assessment
Belimumab 10 mg/kg(n=290)
Navarra S et al. Lancet 2011; 377: 721-731
h Im
pro
ved
er I
nd
ex (
SR
I)
Efficacy of Efficacy of BelimumabBelimumab to Treat Active Nonto Treat Active Non--Renal SLE Renal SLE at 52 Weeks at 52 Weeks
Odds ratio for response to belimumab 10 mg/kg vs placebo1.83 (1.30 to 2.59), p = 0.0006
Pro
po
rtio
n w
ith
SL
E R
esp
on
de
Navarra S et al. Lancet 2011; 377: 721-731
7
Lupus Atherosclerosis Prevention (LAPS) Study Design
Lupus Atherosclerosis Prevention (LAPS) Study Design
Adult SLE(n = 200)
Standard therapy
2 year follow upMean age: 44 yrsMean SLEDAI: 2Nonwhite: 39%
Primary Endpoint: CT coronary calcium Primary Endpoint: CT coronary calcium scorescore
PlaceboAtorvastatin 40 mg/day
Secondary Endpoints: CIMT
Disease activity (SLEDAI)
Inflammatory Mediators (hs-CRP))
MeasureMean
baselineMean 2 years
Mean change
P Value
Difference in change, statin
minus placebo (95% CI)
P Value
Loge (coronary artery calcium score + 1)
LAPS Study: LAPS Study: Change in Coronary Calcium Score and CIMTChange in Coronary Calcium Score and CIMT
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)
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
Atherosclerosis Prevention in Pediatric Lupus Erythematosus
Study Design
Atherosclerosis Prevention in Pediatric Lupus Erythematosus
Study Design
Pediatric SLE (>10 and <21)(n = 221)
Standard therapy
APPLE
3 year follow up
Mean age 15.7 yNonwhite 65%SLEDAI 4.7LDL 86HSCRP 3.6
Primary Endpoint: IMT progressionPrimary Endpoint: IMT progression
hydroxychloroquine, ASA, folate, AHA TLC diet + placebo
hydroxychloroquine, ASA, folate, AHA TLC diet + atorvastatin
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-Max Common
Mean-Mean
Mean-Max
Mean-Mean Common
Atorvastatin slower Placebo slower
APPLE
Mean-Mean Near Wall
Mean-Max Near Wall
Mean-Mean Far Wall
Mean-Max Far Wall
Mean-Mean Bifurcation
Mean-Max Bifurcation
Mean-Mean Internal
Mean-Max Internal
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
8
HydroxychloroquineHydroxychloroquine• Antimalarial; limited toxicity
• Beneficial in SLE
– Prevents flares
– Improves lipid profiles
– Improves pregnancy outcomesp p g y
– 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 protein • LDL 144, HDL 38
• Plan:Plan: • Prednisone• Hydroxychloroquine• Address CV risk: dyslipidemia, BP, tobacco
use• Referral to nephrology to evaluate for lupus
nephritis
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
B d H R i MD FACP FASNBrad H. Rovin, MD, FACP, FASNProfessor of Medicine and Pathology
Vice 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
• MMF AND IV CYCLOPSHOSPHAMIDE ARE EQUALLY EFFECTIVE AS INDUCTION THERAPY
MAJORMAJOR NEW FINDINGS IN THE NEW FINDINGS IN THE THERAPY OF PROLIFERATIVE LNTHERAPY OF PROLIFERATIVE LN
EFFECTIVE AS INDUCTION THERAPY
• RITUXIMAB DOES NOT IMPROVE INDUCTION THERAPY
• MMF MAY BE THE IMMUNOSUPPRESSIVE OF CHOICE FOR MAINTENANCE THERAPY
9
LowLow--Dose (EuroDose (Euro--Lupus) CyclophosphamideLupus) Cyclophosphamide
Houssiau, et al., Arth Rheum, 2002
• Low Dose CYC: 500 mg every 2 weeks for 6 doses/Cumulative Dose 3g
• 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
LowLow--DoseDose CyclophosphamideCyclophosphamide--LongLong--Term ResultsTerm Results
Failure:• Absence of primary response at 6 months
• Occurrence of steroid‐resistant flare• Doubling of SCr
Houssiau, et al., Arth Rheum, 2002; Ann Rheum Dis, 2010
High Dose Low Dose
Randomized 46 44
Lost to Follow‐Up 3 3
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 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
10
Blac
MMF MMF vsvs CyclophosphamideCyclophosphamide
ck, Hisp
anic, M
ixed
•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
Chan, et al., JASN, 2005
•Long‐term outcomes are key for a true comparison with CYC
Adverse Events
MMF IVC
Deaths 9 (4.9%) 5 (2.8%)
W/drawals 24 (13%) 13 (7.2%)
LongLong--Term Outcome After MMF TreatmentTerm Outcome After MMF Treatment
60
80
100
ith
Tx
fail
ure
(%)
MMF AZA
Data from the ALMS Maintenance Trial‐Ninth International Congress on SLE, Vancouver, 2010
0
20
40
Overall Induction MMF Induction IVC
Pat
ien
ts w
i
16%21%
36%
11%
28%32%
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
11
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 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
Dall’Era et al., Arth Care Res, 2011
↓ proteinuria by ≥25% 2.9 1.6‐5.1
Normalization of C3/C4* 2.7 1.4‐5.0
*only applicable if patients had baseline low C3 and C4
Do we need to think about changing therapy sooner during induction?
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
Lertdumrongluk et al., Kidney Int, 2010
For 1 hour Peak MPA r 0.92• One may be able to use trough and
peak to optimize MMF dosing• Our recommendation:
Dose MMF so that: Trough level is 3 mg/l 1 hour peak level is > 22 mg/l
12
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 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
What About Rituximab?
Screening
Rituximab + MMF (n=72)
Prednisone taper
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!
Follow‐up PeriodPlacebo + MMF (n=72)
Weeks 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
Primary Endpoint: Renal Response at Week 52Primary Endpoint: Renal Response at Week 52
30.6
54.1
26 430.6
43.0
30
40
50
60
of Patients
Placebo Rituximab
P=0.55*P=0.55*
15.3
26.4
0
10
20
30
Complete Renal Response (CRR)
Partial RenalResponse (PRR)
No Response (NR)
Proportion
* 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
45.0 47.8 50.0
70.0
55.0 52.650%
60%
70%
80%
oportion
Placebo Rituximab
9/20 14/20 11/23 16/29 13/26 10/19
45.0
0%
10%20%
30%
40%
Black (n=40) Hispanic (n=52) Caucasian (n=45)
Response Pro
13
MAJOR NEW FINDINGS IN THE THERAPY OF PROLIFERATIVE LN
• LOW‐DOSE CYCLOPHOSPHAMIDE IS EFFECTIVE 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
ALMS Maintenance TrialTime to Treatment
Failure, n=227
MAINTAIN Nephritis TrialMAINTAIN Nephritis TrialTime to FlareTime to Flare
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
ApoptosisDeficient clearance1
Nucleosomes
Y Y
Y
Y Y
Auto-reactivePlasma Cell
YY
Y
Y
Y
Y
YAnti-dsDNA
2
Nucleosome-IC depositionin glomerular capillaries
Complement activationFcR activationTLR activation
Production of pro-inflammatory cytokinese.g. C3a/C5a, MCP-1, IL-17, IL-18
3
Anti-TLR
Anti-CD20(Rituximab, Ocrelizumab)
Endothelial CellGBM
PodocyteAnti-IL-6(Tocilizumab)
CTLA4 Ig
Y
Y
Auto-reactiveB Cell
Y
Y
Y
Y
YY YYY
Y Y
Y
Cell infiltration and activationMonocytes, Lymphocytes, pDCs
Increased production of cytokinesIFN‐a
Accelerated autoimmune responselocal, Th1-skewed
Increased IC accumulation andcomplement and FcR activation
Renal tissue damage
Anti-C5(Eculizumab)
Anti-IFN-α
Anti-CD22(Epratuzumab)
BLyS
APRIL
Anti-BLyS(Belimumab)
TACI-Ig(Atacicept)
4
MΦMΦ
ROSProteases
ROSProteases
MAC
IL-6
Auto-reactive
T Cell
CTLA4-Ig(Abatacept)
Lupuzor