improving outcomes in lupus nephritis - saraa...
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Improving Outcomes in
Lupus nephritis
David Jayne
University of Cambridge, UK
SARAA, Durban, March 2019
• Lupus nephritis – code for ‘bad lupus’
• Management guidelines
• What is trending
Outcome MEDICAID 5 years SLICC 10 years
Death 9.5% 5.9%
ESRD 22% 10.9%
SLICC: Systemic Lupus International Collaborating Clinics
EULAR/ERA-EDTA recommendations for
the management of adult and pediatric
patients with lupus nephritis
Bertsias et al, Ann Rheum Dis, 2012
When should you consider lupus nephritis ?
1. First renal biopsy
• Any sign of renal involvement
• Proteinuria > ACR 0.5, especially with hematuria
• Less commonly,
– Unexplained hematuria or leucocyturia
– Reduced GFR without explanation
Bertsias et al, Ann Rheum Dis, 2012
Renal Pathology Society/International Society of Nephrology
Classification 2003: glomerular histology
I ‘Normal’/mesangial matrix , immune deposits
II Mesangial cell proliferation
III Focal proliferative
IV Diffuse proliferative
V Membranous
VI Sclerosis
Activity/chronicity quantification not standardised
Weening et al, Kidney Int 2003
Ignores
• Tubulo-interstitium
• Blood vessels
• Thrombotic lesions
Class IV ‘Segmental’
Behara et al, Nephrol Dial Transpl 2010
Class IV ‘Global’
Behara et al, Nephrol Dial Transpl 2010
Class IV subtype (S/G) and outcome
Haring et al, J Am Soc Nephrol 2012
T/B cell
Chang et al, J Immunol 2011
3. Indications and goals of immunosuppressive therapy
Proteinuria and long term outcome
No GFR fall by 10 years(uProt by 12months)
< 0.5 90%
> 0.5 70%
Houssiau et al, Ann Rheum Dis, 2014
Proteinuria: causes and time timescale
Month
Induction Maintenance
Disease activity
Glomerular remodelling
Fibrosis
Appel G, J Am Soc Nephrol 2009; Jayne et al. Am Soc Nephrol (abstract) 2010
4. Initial treatment
Cyclophosphamide: NIH vs 500mg x 6
=
Houssiau et al, Ann Rheum Dis, 2010
Renal remission Ovarian dysfunction
• 500mg every 2 weeks x 6 vs. 750mg/m2 every 4 weeks x 6
• Fewer renal relapses, better extra-renal control
• No difference in safety
Appel GB, et al. J Am Soc Nephrol. 2009;20(5):1103-1112
24 week Partial Response & Complete Remission
Rates with Cyclophosphamide and MMF2
% o
f P
atie
nts
20
8%
*
Mycophenolate mofetil vs cyclophosphamide - ALMS
• Steroid alone ?
• 45% failure ?
• majority withdrawals
Serious adverse events and withdrawals in recent trials
0
5
10
15
20
25
30
35
40
%
withdrawal
SAE
(15%)
(25%)
Low GFR (<30ml/min) at presentation
• ALMS
– N=30
– Low CR/PR for both
– GFR better with MMF
• Meta-analysis
– No difference between MMF and CYC
– Higher relapse and later ESRD risk with MMF
Walsh & Jayne, Am J Kid Dos 2012; Rovin et al, Clin J Am Soc Nephrol 2013
Change in GFR
MMF
CYC
How much MMF ?
MMF dosing in SLE, AUC and clinical efficacy
Zahr et al, Arthritis Rheum 2012
N=40 P=0.05
Mycophenolate mofetil vs. Mycophenolate sodium
(Myfortic) for refractory disease
Jones et al, Nephron 2014
Multi-target
Date of download: 3/18/2015
From: Multitarget Therapy for Induction Treatment of Lupus Nephritis: A Randomized TrialMultitarget Therapy
for Induction Treatment of Lupus Nephritis
Ann Intern Med. 2015;162(1):18-26. doi:10.7326/M14-1030
Probability of achieving overall remission (complete remission and partial remission) in patients treated with the MT regimen or
IVCY.
MT = multitarget; IVCY = intravenous cyclophosphamide.
Figure Legend:
Copyright © American College of Physicians. All rights reserved.
What about steroids ?
MYLUPUS
n=81, eMPA, 2160mg/day
prednisolone: 1.0 vs 0.5mg/kg/day
% p
atients
Zeher et al, Lupus 2011
*
Steroid sparing
IV 1-1.5g
How is refractory disease defined ?
Haematuria
INCLUSION OF URINE SEDIMENT IN THE
RESPONSE CRITERIA OF LN TRIALS UNDERMINES
THE PROGNOSTIC VALUE OF PROTEINURIA AS
BEST PREDICTOR OF OUTCOME
Houssiau et al. EULAR (abstract) 2014
Repeat biopsy – discordance with proteinuria
Zickart et al, Lupus Sci Med 2014
What are the causes of non-response ?
• Adherence
• Severe or irreversible disease
• Ethnicity, dosing
• Intolerance/adverse events
• Lack of efficacy
Damage (scarring) is not refractory disease
Does rituximab work in lupus nephritis ?
Rituximab in Lupus Nephritis (LUNAR)
• Complete, partial or no response at 12 months
Rovin, Am Soc Nephrol 2009
11%
treatment
difference
Cambridge cohort, n=147
Cassias, Alberici & Jayne, Submitted
Probability of response relapse
64 reactions (8%)
8 admissions
Rituximab in SLE – ‘major’ infusion reactions
Juan Morales (unpublished)
Renal indications for plasma exchange ?Thrombotic
microangiopathy
Crescentic
glomerulopathy
http://www.fondazionedamico.org
4 (contd). Subsequent treatment
Bertsias et al, Ann Rheum Dis, 2012
Can you risk stratify for relapse ?
Predictive value of MPA levels for lupus flare
Djabarouti et al, Arthritis Res & Therapy 2010
Houssiau et al, Arthritis Rheum 2015
5. Adjunctive treatment
• Better blood pressure control
• Lower proteinuria
• Lower SLEDAI
• Less steroid
SLE no nephritis Lupus nephritis
Myocardial infarction 2.2 18.3*
Stroke 2.1 4.1
Cardiac death 1.6 7.8*
Hazard ratios vs. background population, * = p<0.05
Hydroxychloroquine
Canadian hydroxychloroquine group, New Engl J Med 1991 Siso et al, Lupus 2008
Effect of withdrawal on SLE flare Reduction of ESRD
6. Monitoring and prognosis
• Urine
• Serology
• Co-morbidity
Mosca M et al, Ann Rheum Dis 2010
Newer therapies
Failure and trials in lupus nephritisAgent TRIAL Target Outcome
Rituximab
Rituximab +
Belimumab
LUNAR
CALIBRATE
CD20
CD20/BAFF
Negative
Negative
Ocrelizumab BELONG CD20 Safety concerns
Atacicept BLyS/APRIL Safety concerns
Abatacept IM-10175
ACCESS
ALLURE
CTLA4/CD28 Negative
Negative
Negative
Anti-CD40L CD40/40L Safety concerns
Anti-TWEAK ATLAS TWEAK Negative
Anti-IL6 IL6 Negative
Laquinimod Anti-
inflammatory
Positive
(failed business case)
Autologous
stem cell
transplant
‘Immune
resetting’
Failed
Ixazomib Proteasome
inhibition
Failed
Presentation number:
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Abatacept or Placebo on a Background of MMF and Corticosteroids in Subjects with Active Class III or IV Lupus Nephritis
D Jayne,1 MA Dooley,2 D Wofsy,3 T Takeuchi,4 A Malvar,5 A Doria,6 J Romero-Díaz,7
TM Chan,8 A Elegbe,9 GB Appel,10 R Furie,11 MA Maldonado9
1University of Cambridge, Cambridge, UK; 2University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 3University of California San Francisco, San Francisco, CA, USA; 4Keio University, Tokyo, Japan; 5Hospital Fernández,
Buenos Aires, Argentina; 6University of Padua, Padua, Italy; 7Instituto Nacional de Ciencias Médicas y Nutrición,
Mexico City, Mexico; 8University of Hong Kong, Hong Kong; 9Bristol-Myers Squibb, Princeton, NJ, USA; 10Columbia
University Medical Center, New York, NY, USA; 11Northwell Health, New York, NY, USA
IM101291
ERA-EDTA 55th Annual Congress
24–27 May 2018 ● Copenhagen, Denmark
53
Primary Endpoint at Year 1
Abatacept IV
n=202
Placebo IV
n=203
Subjects, n (%) 71 (35.1) 68 (33.5)
95% CI (28.565, 41.732)(27.005,
39.990)
Adjusted odds ratio of
CRR (abatacept vs
placebo) (95% CI)
1.08
(0.7077, 1.6421)N/A
p value 0.7264 N/A
Proportion of subjects in
CRR
Time to Complete response
38%
48%
0 30 60 90 120 150 180210 240270 330300 360 390 420
Time since randomization (days)
50
Cu
mu
lati
ve
pro
po
rtio
n
of
su
bje
cts
(%
)
45
40
35
30
25
20
15
10
5
0
Number of subjects at riskAbatacept IV
Placebo IV202 193 189 180 169158 135 120 112105 96 95 88 5
203 198 190 185174 161 144134 128121 115115 113 1
0
0
Abatacept IV (n=202)
Placebo IV (n=203)
Voclosporin - a new CNI ?
Rovin B et al, Kidney International 2018
Ongoing trials in lupus nephritis
Agent Target Name Phase
Belimumab BLyS BLISS-LN Phase III
Voclosporin Calcineurin AURORA Phase III
BI 655064 CD40 Phase II
Anifrolumab Alpha IFNr TULIP-LN Phase II
Obinutuzumab CD20 NOBILITY Phase II
BMS-986165 Tyk2 Phase II
Prognostic factors in lupus nephritis
Demography Genetics Histology Serology Presentation Disease course
Black, hispanic,
south east asian
race
ITGAM
TNFSF
Class III/IV (v) Anti-
phospholipid
Lower GFR Long disease
course
Male sex ACE
APOL-1
MYBH
Chronicity
Repeat biopsy
High anti-
dsDNA, low
Complement
Higher
proteinuria
Delay in
commencing
therapy
Lower socio-
economic status
Tubulitis Anti-C1q cytopaenia Failure to reduce
proteinuria
Vascular
lesions, TMA
Relapse
B/T infiltrates or
follicles
All patients African American patients
Conclusions
• Healthcare delivery is more important than the drugs
– Delayed diagnosis, poor access, socio-economic factors, poor adherence
• Incremental improvements in drug management
– It is the response that matters, not the drug
• Treatment adverse events and the disease remain dangerous
– Steroid exposure is reducing
– Ovarian failure now rare
• Drug development is slow
– Complexities of the disease and its assessment not appreciated
Who should manage lupus nephritis ?