Randomised, double-blind, placebo-controlled trial to determine

Steroids for prevention of long-term renal
disease in Henoch-Schönlein Purpura
SCH Journal Club
9 January 2014
Dr James Donnelly
Selected paper
Randomised, double-blind, placebo-controlled trial
to determine whether steroids reduce the incidence
and severity of nephropathy in Henoch-Schönlein
Purpura (HSP)
Dudley J, Smith G, Llewelyn-Edwards A, et al.
Arch Dis Child 2013;98:756–763
Published online 11 July 2013
Study conducted January 2001 – January 2005 (!)
What is already known on this topic:
“There has been a long debate over the role of steroids in the
prevention and management of HSP nephritis”
2 previous systematic reviews:
Weiss PF, Feinstein JA, Luan X, et al. Effects of corticosteroid on HenochSchönlein purpura: a systematic review. Pediatrics 2007;120:1079–87.
 “early corticosteroid treatment significantly reduced the odds of developing
persistent renal disease”
Chartapisak W, Opastiraku S, Willis NS, et al. Prevention and treatment of renal
disease in Henoch-Schönlein purpura: a systematic review. Arch Dis Child
 “there was no significant difference in the risk of development or persistence
of renal involvement at 1, 3, 6 and 12 months (fig 1) with prednisone compared
with placebo or no specific treatment”
PICO question
In children with Henoch-Schönlein Purpura,
does early treatment with steroids
(compared to placebo)
prevent clinically significant renal disease?
Population: Inclusion criteria
• Multicentre recruitment
– 24 secondary care centres in England & Wales
– n = 352
• Age < 18
• Definition of HSP:
– 1990 American College of Rheumatology criteria
– 2 or more of:
• age less than or equal to 20 years at disease onset
• palpable purpura
• acute abdominal pain
• biopsy showing granulocytes in the walls of small arterioles
or venules
Population: Exclusion criteria
Already receiving steroids/immunosuppressants
Already receiving ACE inhibitors
Pre-existing renal disease (excluding UTI)
Pre-existing hypertension
Evidence of immunodeficiency/systemic infection
Contraindications for steroid
◦ glaucoma
– epilepsy
– diabetes mellitus
◦ peptic ulceration
• Had the rash for more than 7 days
Intervention & Comparison
• 14 days of steroid treatment
starting from day 7 of the rash
prednisolone 2mg/kg/day for 7 days
then prednisolone 1mg/kg/day for 7 days
then stop
• Identically labelled, blinded placebo
Primary outcomes
• Proteinuria at 12 months
– urine protein : creatinine ratio >20 mg/mmol
• Need for additional treatment
– Hypertension
• on an antihypertensive agent started for hypertension
– Renal biopsy anomaly
• all showed mesangial IgA deposits and proliferation
– Renal disease
• on steroids (non-trial) for renal reasons
• on ACE inhibitors (enalapril) for proteinuria
Secondary outcome
• Symptoms of possible medication-induced toxicity by
 Polyuria 1
week 4
abdominal pain
nausea and/or vomiting
adverse events
• … but nearly all can also be
Polydipsia 1
Glycosuria 0
Irritability 2
Headache 2
Bruising/skin problems 2
Malaise 2
Infection 2
Gastrointestinal bleed 0
Behavioural change 10
Other 0
symptoms of HSP!
• “included if the clinician … deemed them probably or
definitely due to the trial medication”
(A) Are the results
of the trial valid?
CASP analysis
1. Did the trial address a clearly focused issue?
• Yes
• Designed to address “flaws” in previous trials
2. Was the assignment of patients to treatments
• Yes – by computer remote from the study sites
• Allocation concealment satisfactory
(A) Are the results
of the trial valid?
CASP analysis
3. Were all of the patients who
entered the trial properly
accounted for at its
• Yes
• Recruitment rate: 76%
• Dropout rate: 30%
• Study was powered for dropout
rate of 15%
– therefore slightly underpowered
– was this why published so late?
(A) Are the results
of the trial valid?
CASP analysis
5. Were the groups
similar at the start
of the trial?
• Yes – for 3 baseline
metrics and 6 clinical
(A) Are the results
of the trial valid?
CASP analysis
4. Were patients , health workers and study personnel
‘blind’ to treatment?
• Yes – follows from good placebo control
• Only 3 patients unblinded for investigation of adverse events
6. Aside from the experimental intervention, were the
groups treated equally?
• Yes – follows from good control and good blinding
(B) What are
the results?
7. How large was the treatment
8. How precise was the
estimate of the treatment
Proteinuria at 12/12:
◦ Not significant
◦ OR 1.46 (0.68 – 3.14)
Additional treatment:
◦ Not significant
◦ OR 0.53 (0.18 – 1.59)
Proteinuria at baseline:
No (86%)
Yes (14%)
(C) Will the results
help locally?
CASP analysis
9. Can the results be applied in your context?
 Yes
◦ UK based data, right age group, matching definition
◦ SCH guideline:
◦ to be inserted
◦ Nottingham guideline:
 steroids only for severe gut involvement; requires consultant
◦ Leeds guideline:
to be inserted
(C) Will the results
help locally?
CASP analysis
10. Were all clinically important outcomes
 For this specific study question…
 ie. does early prednisolone make a difference in terms
of prevention of renal disease
What this study adds
Enough data to change the clinical bottom line of a
systematic review
Viewed as settling the debate on a long argument
Any information on the use of steroids (or other
treatments) to treat :
◦ established HSP nephropathy
◦ extrarenal manifestations of HSP
(C) Will the results
help locally?
Clinical bottom line
11. Are the benefits worth the harms and
• No
• Steroids in early HSP do not prevent progression to
significant renal disease
• Important negative results are worth publishing, even
years later! #alltrials
– http://www.alltrials.net/