Steroids for prevention of long-term renal disease in Henoch-Schönlein Purpura

1. Steroids for prevention of long-term renal disease in Henoch-SchönleinPurpura 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

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 • glaucoma • peptic ulceration • 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

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 • 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 • 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”

10. (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 randomised? Yes – by computer remote from the study sites Allocation concealment satisfactory http://www.casp-uk.net/

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

12. (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/

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

14. (B) What are the results? Results 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: • Not significant • OR 0.53 (0.18 – 1.59) No (86%) Yes (14%) http://www.casp-uk.net/

15. (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: • to be inserted http://www.casp-uk.net/

16. (C) Will the results help locally? CASP analysis 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/

17. 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. (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/