1. SCH Journal Club 9 January 2014 Dr James Donnelly
Steroids for prevention of long-term renal disease in Henoch-Schönlein Purpura
SCH Journal Club
9 January 2014
Dr James Donnelly

2. 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 (!)

3. Background 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 Henoch- Schönlein 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 2009;94:132–7.
“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”

4. PICO question Population In children with Henoch-Schönlein Purpura,
Intervention
does early treatment with steroids
Comparison
(compared to placebo)
Outcome
prevent clinically significant renal disease?

5. 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

6. 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 therapy
epilepsy
diabetes mellitus
Had the rash for more than 7 days
glaucoma
peptic ulceration

7. 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
vs.
Identically labelled, blinded placebo

8. Primary outcomes Proteinuria at 12 months
urine protein : creatinine ratio >20 mg/mmol OR
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

9. Secondary outcome symptoms of HSP!
Symptoms of possible medication-induced toxicity by week 4
hypertension
abdominal pain
nausea and/or vomiting
adverse events
… but nearly all can also be
symptoms of HSP!
“included if the clinician … deemed them probably or definitely due to the trial medication”
Polyuria 1
Polydipsia 1
Glycosuria 0
Irritability 2
Headache 2
Bruising/skin problems 2
Malaise 2
Infection 2
Gastrointestinal bleed 0
Behavioural change 10
Other 0

10. CASP analysis (A) Are the results of the trial valid?
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 randomised?
Yes – by computer remote from the study sites
Allocation concealment satisfactory

11. CASP analysis (A) Are the results of the trial valid?
76%
70%
3. Were all of the patients who entered the trial properly accounted for at its conclusion?
Yes
Recruitment rate: 76%
Dropout rate: 30%
Study was powered for dropout rate of 15%
therefore slightly underpowered
was this why published so late?

12. CASP analysis 5. Were the groups similar at the start of the trial?
(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 characteristics

13. CASP analysis (A) Are the results of the trial valid?
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

14. Results (B) What are the results? Proteinuria at 12/12:
Proteinuria at baseline:
7. How large was the treatment effect?
8. How precise was the estimate of the treatment effect?
Proteinuria at 12/12:
Not significant
OR 1.46 (0.68 – 3.14)
Additional treatment:
OR 0.53 (0.18 – 1.59)
No (86%)
Yes (14%)

15. CASP analysis 9. Can the results be applied in your context? Yes
(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 approval
Leeds guideline:

16. CASP analysis (C) Will the results help locally?
10. Were all clinically important outcomes considered?
For this specific study question…
ie. does early prednisolone make a difference in terms of prevention of renal disease

17. What this study does not add
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
What this study does not add

18. Clinical bottom line 11. Are the benefits worth the harms and costs?
(C) Will the results help locally?
Clinical bottom line
11. Are the benefits worth the harms and costs? No
Steroids in early HSP do not prevent progression to significant renal disease
Important negative results are worth publishing, even years later! #alltrials