Strategies to Stop The Disease Steroid Therapy at The First

Steroid sensitive nephrotic syndrome:
strategies for the treatment and
prevention of early relapses
Nicholas J A Webb BMedSci DM FRCP FRCPCH
Royal Manchester Children’s Hospital, UK
ESPN Meeting, Porto, September 2014
The Wellcome Trust Children’s Clinical Research Facility
is supported by the National Institute for Health Research
Overview
• Choosing the optimal steroid
regimen for early relapses
– Review of existing literature
• The potential importance of
adrenal suppression
– How best to assess this
• Avoiding relapses through the use
of daily steroids at the time of
URTI
– Previous studies
– The PREDNOS 2 study
Treatment of the presenting episode
Clinical course following first episode
• 10-20% have no further relapses
• 30% have infrequent relapses
• 50% develop frequently relapsing or steroid
dependent disease requiring alternative therapies
Relapse treatment: the ISKDC regimen
• Prednis(ol)one
– 60mg/m2 until urinary remission
(3 days zero or trace proteinuria)
– then 40mg/m2 alternate days for
28 days
Longer duration therapy? ISKDC J Pediatr 1979
• First relapse within 6m
of first presentation
54 children
ISKDC regimen
Test regimen
60mg/m2 daily
until urinary
remission
60mg/m2 daily 4w
40mg/m2
3 days out of 7
Tapering daily dose 4w
40/30/20/10mg/m2
P<0.001
No AE data collected
Longer duration therapy?
Jayantha et al. Unpublished 2002
• Relapsing SSNS
90 children
ISKDC regimen
Test regimen
60mg/m2 daily
until urinary
remission
60mg/m2 daily 4w
40mg/m2
3 days out of 7
Tapering dose 4w
50/40/30/20/10mg
AD
60mg/m2 AD 4w
Intermittent or alt day therapy?
APN Lancet 1979, Eur J Pediatr 1981
N=34
N=30
16 withdrawals during therapy – 8 toxicity
Intermittent or alt day therapy?
APN Lancet 1979, Eur J Pediatr 1981
• Alternate day therapy associated with fewer
relapses during m1-6
– Both relapse rate and relapse free interval
superior
• No difference between regimens once
prednisolone stopped m7-12
• No difference in AEs at any stage
Daily or divided dose therapy?
Ekka et al. Pediatr Nephrol 1997; 11: 597-599
• Relapse of SSNS
106 children
2mg/kg single dose
2w
2mg/kg in
3 divided doses 2w
1.5mg/kg AD 4w
1.5mg/kg AD 4w
• No difference:
– Time to remission
– Duration of first remission
– Relapses over subsequent
9m
– Cumulative prednisolone
dose over 9m
– Adverse effects
Which corticosteroid?
• ISKDC studies report the use of prednisone
– Prednisolone used routinely in UK and elsewhere
• Prednisone inactive
– Rapidly and extensively converted to active prednisolone in liver by 11-βhydroxydehydrogenase
• No head to head studies in SSNS
• Studies in adult renal transplant recipients
– No difference in bioavailability of prednisolone
– No difference in post-absorption PK
• Anecdotal reports of
– Patients unresponsive to prednisolone responding to prednisone
– Stable remission being maintained on lower dose of prednisone than
prednisolone
– ?different bioavailability in SSNS
Which corticosteroid?
• 40 SDNS randomised to 12m of deflazacort vs. prednisone for
maintenance AD and relapse treatment
• Comparable steroid exposure in both groups
– On basis that 6mg deflazacort = 5mg prednisone
Which corticosteroid?
Broyer et al Pediatr Nephrol 1997; 11: 418-422
• No difference in adverse
effects
–
–
–
–
–
P=0.015
Bone mineral content
Growth
Weight
Cushingoid facies
Biochemical parameters
Poor understanding of many adverse effects
Adrenal suppression
Corticosteroids
Adrenal suppression
Leisti et al. Pediatrics 1977; 60: 334-342
• 25 children with MCNS
• ACTH tests before, during and after prednisolone
treatment of relapse
• Grouped according to length of ensuing remission
(<6m, 6-12m, >12m)
• A normal response predicted a >6m remission and a
subnormal response a <6m remission
Adrenal suppression
Leisti et al. Pediatrics 1977; 60: 334-342
• 25 children with MCNS
• ACTH tests before, during and after prednisolone
treatment
relapse
’Childrenofwith
post-medication adrenocortical
• Grouped
according
to length
of ensuing
remission
suppression
should
be detected
and given
an
(<0.5y,
0.5-1.0y, cortisol
>1.0y) substitution until their
appropriate
adrenocortical
function ahas
normalised’
• A normal
response predicted
>0.5y
remission and a
subnormal response a <0.5y remission
• Post-medication responses were superior to premedication responses
Abeyagunawardena et al. Arch Dis Child 2007;
92: 585-588
• 32 children on long term AD prednisolone (+/- other therapy)
• Low dose (0.5µg) synacthen test – bloods at 0, 10, 20, 30, 40, 50, 60m
• Followed for 3y for relapses
Abeyagunawardena et al. Arch Dis Child
2007; 92: 585-588
• 32 children on long term AD prednisolone (+/- other therapy)
• Low dose (0.5µg) synacthen test – bloods at 0, 10, 20, 30, 40, 50, 60m
• Followed for 3y for relapses
How to best assess for adrenal suppression
Early morning salivary cortisol/cortisone
(EMSC)
• Adult studies report utility as a screening test
– EMSC >5.8ng/ml (16nmol/l) excludes adrenal insufficiency
and value < around 1.8ng/ml (5nmol/l) makes probability
of adrenal insufficency high
– Patel RS et al. J Laryngol Otol
– Nasal corticosteroids for allergic rhinitis
– EMSC had 100% sensitivity and 97% specificity
Early morning salivary cortisol/cortisone
• Much less well studied and potentially less useful in
children
– Cetinkaya S et al. Horm Res 2007; 67: 301
– Patients being investigated for adrenal insufficiency
– Cut-off of 0.94µg/dl for SC differentiated adrenal insufficient subjects
from normals with 80% sensitivity and 77% specificity.
– Reducing cut-off to 0.62µg/dl increased specificity to 100%; however,
reduced sensitivity to 44%.
Early morning salivary cortisol/cortisone
• Much less well studied and potentially less useful in
children
– Blair J et al. Clin Endocrinol 2014; 80: 376-383
– Inhaled corticosteroids for asthma
– 37.5% had impaired adrenal function (peak cortisol <500nmol/l) on
low dose short synacthen test
– Mean of 3 measurements of EMSC – cut-off of 8.7nmol/l gave
sensitivity of 58.6% and specificity of 60.8%
URTI and relapses
• Around 50% of relapses are preceded by an URTI
• If URTI develops, around 50% chance of a relapse
developing
• It seems logical that URTI is pivotal and attempts to
ameliorate the URTI driven process are appropriate
Pre-emptive treatment of relapses
Mattoo et al. Nephron 2000; 85: 343-345
• 36 children with SDNS (Prednisolone approx 0.5mg/kg AD)
• Not randomized but ‘prospectively divided into two groups
with comparable age and sex distribution’
• Group 1 advised to take daily prednisone for 5/7 at onset of
URTI
• No advice to group 2
• Group 1 total 40 relapses (2.2 ± 0.8 per patient)
• Group 2 total 99 relapses (5.5 ± 1.3 per patient) p=0.04
Pre-emptive treatment of relapses
Abeyagunawardena et al. Arch Dis Child 2008; 93: 226-228
• 40 (29 male) children with SDNS (Prednisolone <0.6mg/kg AD)
• At time of development of URTI randomised to 7 days of
– daily prednisolone at same dose
– placebo
• URTI defined as
–
–
–
–
–
–
Cough
Runny nose
Sore throat
Lethargy
Body aches
Fever
Pre-emptive treatment of relapses
Abeyagunawardena et al. Arch Dis Child 2008; 93: 226-228
• Cross over trial design; each child acted as their own
control
• Relapse rate 17.5% vs. 47.5% (p=0.003)
Pre-emptive treatment of relapses
Gulati et al. Clin J Am Soc Nephrol 2011; 6: 63-69
• 100 children - FRNS on AD prednisolone (32 on levamisole)
• At time of development of URTI randomised to 7 days of
– daily prednisolone at same dose
– Remained on AD prednisolone
• URTI defined as
– Fever >38, rhinorrhoea, cough, diarrhoea
• Incidence of URTI-related relapse reduced
– Relapse rate reduced by 0.7/y (95%CI 0.3-1.1: p<0.01)
Unanswered questions
• Utility of this approach in Western nations
– Different pattern of URTI – less fever, diarrhoea etc
• Utility in children receiving other therapies
– levamisole, CNIs, MMF +/- AD prednisolone?
• Cost-effectiveness
• Adverse-effect risk?
– Particularly effect on behaviour
PREDNOS 2
• 300 children with relapsing SSNS (≥2 relapses in past
12m)
• On any long-term immunosuppressive regimen
• Randomised to prednisolone or placebo arm at study
entry
• When URTI develops, parents commence child on 6
days of daily prednisolone (15mg/m2) or placebo
• Repeated with each URTI that develops over 12
month follow-up period
PREDNOS 2: Primary study objective
• To determine whether a six day course of oral
prednisolone given at the time of URTI reduces the
incidence of first URTI-related relapse
PREDNOS 2
• URTI defined as the presence of at least 2 of
the following for at least 24 hours:
–
–
–
–
–
–
sore throat
ear pain/discharge
runny nose
cough (dry/barking)
hoarse voice
fever >37OC (measured using tympanometric
electronic thermometer)
PREDNOS 2
• Primary end-point – development of URTI-related
relapse
• Secondary end points – relapse rate, culmulative
prednisolone dose, adverse events (particularly
behavioural), escalation / de-escalation of
background immunosuppressive therapy
• Quality of Life Assessment
• Formal Health Economic Analysis (Frew, Birmingham)
Mechanistic studies
• A single 10ml sample of blood collected for DNA/RNA
extraction
– GWAS to look for possible genetic loci associated with steroid
sensitive nephrotic syndrome
• Kleta / Bockenhauer
UCL
– Gene expression studies
• Koziell / Saleem
Kings / Bristol
PREDNOS 2 recruitment
• Total 117 subjects
• 102 centres in UK currently
participating
• Slightly behind initial
recruitment target, though
steady state of recruitment
Conclusions
• Relative paucity of research into early relapsing
disease
–
–
–
–
AD therapy more effective than intermittent therapy
Daily therapy more effective than intermittent therapy
Single daily dosing as effective as split multiple dosing
Deflazacort may be more effective than prednisone
• Monitoring of adrenal suppression may be helpful to
identify those at greatest risk of relapse
– Need for a simple test of adrenal function
• Daily prednisolone at the time of URTI may be of
benefit
– PREDNOS 2 study results awaited
Thank you
[email protected]
www.bctu.bham.ac.uk/prednos
[email protected]
Reserve slides
IMP study
•
•
•
•
Aim to identify imaging changes that can
be correlated with behavioural change
and be used as putative imaging
biomarkers
Children seen at time of relapse,
following 2-3 weeks of high dose
prednisolone and then once
prednisolone is discontinued
Achenbach CBC, blood and urine
sampling
Advanced multiparametric imaging
–
–
–
–
–
High res T1 and FLAIR of whole brain
Resting state fMRI
Diffusion tensor assessment
Multi-voxol proton MRS
3D arterial spin labelling
Prednisolone adverse effects: APN trial
Kidney Int. 2005; 68: 2304-2309
2
p<0.0001 p<0.0001
34 patients
In adult life
vBMD SDS
1
0
-1
-2
-3
-4
-5
Z score T score
Total
Z score
T score
Trabecular
Kidney Int. 2005; 68: 2304-2309
1.5
Height Z score
1.0
0.5
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
p=0.007
60 children with SSNS: mean 23g
prednisolone lifetime exposure
195 controls
No difference in bone mineral content of
spine
Steroids are toxic agents
Cosmetic effects
may ↓ adherence
Choonara et al Arch Dis Child 1989; 64: 610-621
• 9: relapsing SSNS
• 8: newly presenting SSNS
30mg/m2 daily until
urinary remission
Increased to
60mg/m2 daily if no
response by 2w
Once remission: dose
reduced over next 46w
Adrenal suppression
• 1977 Leisti was first to report that children who
develop severe HPA suppression were more likely to
relapse early
• Also demonstrated that supplementation with a
small dose of glucocorticoid could prevent some of
the relapses
• Suggested that HPA suppression could be an
important risk factor triggering relapse, possibly due
to inadequate glucocorticoid response to infections
and stress