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

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 (!)

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”

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?

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

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

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

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

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 http://www.casp-uk.net/

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? http://www.casp-uk.net/

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 http://www.casp-uk.net/

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 http://www.casp-uk.net/

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%) http://www.casp-uk.net/

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 https://www.nuh.nhs.uk/healthcare-professionals/clinical-guidelines/ Leeds guideline: http://www.casp-uk.net/

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 http://www.casp-uk.net/

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

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 http://www.alltrials.net/ http://www.casp-uk.net/