What happened with SLE Kidney disease ( lupus nephritis )in the past

Report
SLE and Kidney Disease in
2014
GERALD APPEL, MD
Professor of Clinical Medicine
Columbia University –College of
Physicians and Surgeons
NY-Presbyterian Hospital
New York, New York
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)
• How does SLE involve the kidneys?
• How do you know if you have kidney involvement?
• Are there different patterns of Kidney disease with SLE?
• What happened with SLE Kidney disease ( lupus nephritis )in the past ?
• Can we treat kidney disease due to LN today?
• How successful are we?
• Will there be new ways to treat it tomorrow.
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a
nephrologist?)
• How does SLE involve the kidneys?
• How do you know if you have kidney involvement?
• Are there different patterns of Kidney disease with SLE?
• What happened with SLE Kidney disease ( lupus nephritis )in the past ?
• Can we treat kidney disease due to LN today?
• How successful are we?
• Will there be new ways to treat it tomorrow.
Where can one find a kidney?
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)
• How does SLE involve the kidneys?
• How do you know if you have kidney involvement?
• Are there different patterns of Kidney disease with SLE?
• What happened with SLE Kidney disease ( lupus nephritis )in the past ?
• Can we treat kidney disease due to LN today?
• How successful are we?
• Will there be new ways to treat it tomorrow.
ISN/RPS Classification of LN
• Class I Minimal mesangial LN
• Class II Mesangial proliferative LN
• Class III Focal LN
III (A): Active lesions: focal proliferative LN
III (A/C): Active and chronic lesions
III (C): Chronic inactive lesions with scars
• Class IV Diffuse LN
IV-S (A): Active lesions: diffuse segmental proliferative LN
IV-G (A): Active lesions: diffuse global proliferative LN
IV-S (A/C): Active and chronic lesions
IV-G (A/C): Active and chronic lesions
IV-S (C): Chronic inactive lesions with scars
IV-G (C): Chronic inactive lesions with scars
• Class V Membranous LN
• Class VI Advanced sclerotic LN
ISN = International Society of Nephrology; RPS = Renal Pathology Society
Lupus Nephritis Class I
Lupus Nephritis Class II
Lupus Nephritis Class III
Histology WHO Class IV: Diffuse Endocapillary
Proliferation With Karyorrhexis and Focal Necrosis
Focal Necrosis
Endocapillary Proliferation
Lupus Nephritis Class IV
Pre-Rx
Post-Rx
Lupus Nephritis Class IV
Lupus Nephritis Class V
End stage kidney due to chronic GN: Diffuse and global
glomerulosclerosis, tubular atrophy & interstitial fibrosis
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)
• How does SLE involve the kidneys?
• How do you know if you have kidney involvement?
• Are there different patterns of Kidney disease with SLE?
• What happened with SLE Kidney disease ( lupus nephritis )in the past ?
• Can we treat kidney disease due to LN today?
• How successful are we?
• Will there be new ways to treat it tomorrow.
Case 3: Saleswoman with rash and
arthritis
•A 29 year old saleswoman develops arthritis
multiple joints, fever
•Exam: Lymphadenopathy, and a malar rash.
•Labs:
–Urinalysis 3+ protein, 18-20 rbc’s
–Creatinine 1.2 mg/dl
–24 hr. protein 1.8 g per day
–Complement 18% (normal 50-150%)
–ANA positive, Anti-DNA antibody positive
KIDNEY BIOPSY PERFORMED
RBC cast forms a mold of tubular lumen
Diffuse proliferative lupus nephritis: Diffuse and global
mesangial and glomerular capillary wall positivity for IgG
Full house IF
staining:
IgG, IgM, IgA,
C3, C1q
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)
• How does SLE involve the kidneys?
• How do you know if you have kidney involvement?
• What happened with SLE Kidney disease ( lupus nephritis )in
the past ?
• Can we treat kidney disease due to LN today?
• How successful are we?
• Will there be new ways to treat it tomorrow.
Side Effects of Cyclophosphamide in the past
Event
Cy Therapy
(n = 21)
Combination Therapy
(n = 20)
n/n
n/n
Hypertension
10/20
10/20
Ischemic heart disease
1/19
4/19
Hyperlipidemia
7/20
8/19
Valvular heart disease
9/19
7/21
Avascular necrosis
6/21
6/20
Osteoporosis
4/18
3/19
Premature menopause
9/16
10/18
Major infections
7/21
9/20
Herpes zoster infection
6/21
5/20
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)
• How does SLE involve the kidneys?
• How do you know if you have kidney involvement?
• Are there different patterns of Kidney disease with SLE?
• What happened with SLE Kidney disease ( lupus nephritis )in the past ?
• Can we treat kidney disease due to LN today?
• How successful are we?
• Will there be new ways to treat it tomorrow.
Proliferative LN
ACR- KDIGO Treatment guidelines –
INDUCTION
MMF
+
glucocorticoids
(e.g. pulse methylprednisolone)
or
CYC
+
Glucocorticoids
(e.g. pulse methylprednisolone)
EURO LUPUS
Low-dose CYC
6 months
Anti-MIF & LN Ad Board, July 13, 2011
or
NIH study
Hi-dose CYC
6 months
CONFIDENTIAL
Proliferative Lupus Nephritis –
Maintenance Treatment
ACR – KDIGO Treatment guidelines
CYC
induction
NOT IMPROVED
IMPROVED
NOT IMPROVED
MMF1-2g/d
or
AZA 2 mg/kg/d
± lo dose daily GC
CYC (lo- or hidose)
+
pulse GC then
daily GC
MMF1-2g/d
or
AZA 2 mg/kg/d
± lo dose daily GC
MMF 2-3g/d x 6
months
+
pulse GC then daily
GC
6 months
IMPROVED
6 months
MMF
induction
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)
• How does SLE involve the kidneys?
• How do you know if you have kidney involvement?
• Are there different patterns of Kidney disease with SLE?
• What happened with SLE Kidney disease ( lupus nephritis )in the past ?
• Can we treat kidney disease due to LN today?
• How successful are we?
• Will there be new ways to treat it tomorrow.
ELNT - 10 year FU - ESRD
Houssiau FA et al. Ann Rheum Dis 2009,
ELNT - 10 year FU
Houssiau FA et al. Ann Rheum Dis 2009, Jan 20 (Epub ahead of print)
Response judged by
blinded Clinical Endpoint
Committee:
Decrease in proteinuria
to <3g if baseline
nephrotic (≥3g/d) ,
or by ≥50% in patients ith
subnephrotic (<3g/d)
proteinuria
and
Stabilization of serum
creatinine level (24-week
level ± 25% of baseline),
or improvement
Proportion of patients
reponding (%)
ALMS TRIAL Primary Endpoint:
Responders at Month 6
100
80
60
56.2%
53.0%
40
20
MMF
IVC
0
MMF was not superior to IVC
(p = 0.575)
Appel , Contreras, Dooley et al JASN 2009
24 hour urine protein (g/day, SD)
Serum creatinine (μmol/L, SD)
ALMS Trial - Renal Variables
160
140
120
100
IVC
MMF
80
60
40
20
0
9
8
Serum creatinine
and urine protein
levels improved
in both the MMF
and IVC groups
7
6
5
4
3
2
1
0
Baseline
4
8
12
16
Week
20
24
Endpoint
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)
• How does SLE involve the kidneys?
• How do you know if you have kidney involvement?
• Are there different patterns of Kidney disease with SLE?
• What happened with SLE Kidney disease ( lupus nephritis )in the past ?
• Can we treat kidney disease due to LN today?
• How successful are we?
• Will there be new ways to treat it tomorrow.
Rituximab:
Anti-CD20 Monoclonal Antibody
Rituximab - FDA approved for the
treatment of relapsed or refractory,
CD20-positive B-cell
NHLymphomas
• Approved for Rheumatoid Arthritis
– used in 240,000 patients > 10 yrs
• Approved for ANCA+
glomerulonephritis since 2010
• Chimeric murine/human
monoclonal antibody
Davies B, Shaw T. Presented at EULAR 2004.
Maloney DG, et al. J Clin Oncol. 1997;15(10):3266-3274.
Rituxilup Trial
• MPred + MMF + Rituximab vs MP + MMF + steroids
( ALMS regimen )
• 19 Adult + 4 Peds Centers in UK; Europe 12 Centers
in 3 networks; US Centers.
• Non-inferiority Trial of 252 LN patients
• Primary endpoint complete remission at 1 yr.
• Secondary Endpoints – Time to CR, Partial
remissions, PR with histologic response, serious
infections, SAEs, SRI score etc.
IMNL-SCT-019799
Belimumab – FDA Approved for SLE
Placebo
1 mg/kg belimumab
* p<0.05
+ + +
*
*
+
+
p<0.05
+
*
+
*
+
*
+
*
+
*
40
% SRI Responders
SRI Responders (%)
60
10 mg/kg belimumab
20
0
p<0.05
50
*
40
30
20
10
0
0 4 8
0
4
8
12
16
20
24
28
16
32
24
32
40
48 52
Week 44
36Visit 40
60
68
48
76
52
Visit Week
Navarra, et al. Lancet. 2011;377(9767):721-31
Furie, et al. Arthritis Rheum. 2011;63(12):3918-30
SRI, SLE Responder Index
Abatacept ( CTLA4Ig Co-Stimulatory Blocker )
Study in 300 LN PTS
Abatacept 30/10
30 mg/kg x4, then 10 mg/kg Q 28 days
Randomization
1:1:1
Abatacept 10/10
10 mg/kg days 1,15, 29, then Q 28 days
Placebo
Days 1 and 15
(1st and 2nd dose)
Dose every 28 days
Day 337
Final dose
Background Rx: MMF up to 3 g/day plus corticosteroids
Primary Outcome Measure: Time to complete response
Courtesy of D Wofsy
Treatment of LN with Abatacept and Low-Dose Pulse
Cyclophosphamide: The
ACCESS Trial
Brad H. Rovin
on behalf of the ACCESS Trial Group
• EuroLupus Low dose Cyclophosphamide and
prednisone starting at 60 mg (tapering to 10 mg
by week 12 )
• Azathioprine 2 mg/kg/day PO maintenance
• Abatacept 500 mg or 1000 mg at 0, 2, 4, then Q4
wk until week 24 vs Placebo
Proteasome Inhibitors
N
N
O
N
H O
OH
H
N B OH
Bortezomib
Carfilzomib
( Velcade™)
(Kyprolis)
Manufacturer
Takeda
Onyx/Amgen
Status
Approved
Approved
Indications
Myeloma & Mantle Cell
Lymphoma
Myeloma & Solid Tumors
Class
Boronic Acid
Ketoepoxide
Active Sites
Targeted
b5/LMP7/LMP2
b5/LMP7
Bortezomib for NZB/W F1: Kidney Disease
Neubert Nat. Med. 2008
An Open Label Randomized Phase IV Study of the Safety
and Efficacy of ACTHAR GEL in Patients with Membranous
(Class V) Lupus Nephritis
Principal Investigator: Brad H. Rovin MD, Ohio State University
Primary Objectives:
• To determine the safety and tolerability of Acthar Gel in patients with Class V lupus
nephritis
• To determine the efficacy of Acthar Gel in patients with Class V lupus nephritis as
CRR+PRR
Administration of Acthar
SCRN 0
1
2
3
4
5
Follow-Up
6
9
12
Study Month

ARM 1. Acthar Gel 80 IU administered subcutaneously 2 times
per week, 12 patients

ARM 2. Acthar Gel 80 IU administered subcutaneously 3 times
per week, 13 patients
Treatment of Severe LN in the Future
• Treatment will still be divided into an induction and
maintenance phase.
• Induction therapy will consist of Cyclophosphamide
(usually IV ) or MMF or Newer regimens e.g. older drugs
combined with CNI’s, ACTH, proteosome inhibitors, or
corticosteroid free Rituximab regimens.
• Maintenance therapy will consist of MMF or AZA or
rituximab or other newer agents .
• Use of combinations of immunosuppressives will increase.
• One Regimen Will Not Fit All
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)
• How does SLE involve the kidneys?
• How do you know if you have kidney involvement?
• Are there different patterns of Kidney disease with SLE?
• What happened with SLE Kidney disease ( lupus nephritis )in the past ?
• Can we treat kidney disease due to LN today?
• How successful are we?
• Will there be new ways to treat it tomorrow.

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