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 ?