BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Open Appendix 6 – Characteristics and safety data from the included studies How safe are topical corticosteroids compared to emollient or vehicle? Study ID Study design and Intervention and Participants Cutaneous adverse events Systemic adverse events Unspecified adverse events (Systematic study duration comparator review*) (Quality assessment) Very potent topical corticosteroids Breneman 2003 RCT Intervention: Clobetasol Severity: moderate Local application site skin Unspecified adverse events (1) propionate 0.05% lotion (twice a to severe reactions Incidence comparable between 2 weeks treatment, then day) (n=96) No clinically significant groups. (unpublished) followed up for Age: ≥ 12 years telangiectasia or skin thinning additional 2 weeks Intervention: Clobetasol Treatment-related adverse (Feldman 2005 Sample size: 229 propionate 0.05% emollient events (2) Nankervis (3)) Cochrane risk of bias tool: participants cream (twice a day) (n=100) Clobetasol lotion = 4/96 patients randomisation described, (4.2%); Clobetasol cream = 1/100 allocation concealment Comparator: Vehicle (n=33) patients (1%) unclear, intention-to- Vehicle = 6/33 patients (18.2%) treat unclear. (Difference between groups: p= 0.0006a) Kimball 2008 (4) RCT Intervention: Clobetasol Severity: not Incidence of adverse events or (trial a) propionate emulsion specified in the treatment related adverse Duration not specified in formulation foam 0.05% review events (Frangos 2008 review Clobetasol foam = 8% (5)) Comparator: Vehicle Age: not specified in Risk of bias not assessed Vehicle foam = 10% the review in any of the included (no significant differences systematic reviews. Sample size: not between groups) specified in the review Rosso 2009 (6) RCT Intervention: Fluocinonide 0.1% Severity: not Skin thinning cream (n=109) specified in the Fluocinonide: 6/109 participants (Barnes 2009 (7)) 2 weeks treatment review (5.6%) Comparator: Vehicle (n=50) Risk of bias not assessed Vehicle: 2/50 participants (4.3%) Age: not specified in in any of the included (Difference between groups: the review systematic reviews. p=0.69a) Sample size: 159 participants www.olux- Single arm study Intervention: Clobetasol Severity: ≥30% BSA HPA axis suppression e.com (online (observational) propionate emollient foam 6/37 patients (16%) Age: data) (8) (twice daily) (n=37) ≥12 years old (not specified in the review how 2 weeks treatment Sample size: 37 it was measured) (Frangos 2008 Comparator: No comparator participants (5)) Axon E, et al. BMJ Open 2021; 11:e046476. doi: 10.1136/bmjopen-2020-046476 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Open Risk of bias not assessed in any of the included systematic reviews. Kimball 2008 (4) Open label Phase II safety Intervention: Clobetasol Severity: mild to HPA axis suppression (trial b) study propionate emollient foam severe 7/30 (23.3%) had adrenal 0.05% (twice daily) (n=52) insufficiency (ACTH stimulation (Frangos 2008 2 weeks treatment Age: children (from testing, measuring serum cortisol (5); Wood Comparator: No comparator 6 years old) and Risk of bias not assessed levels). Heickman 2018 adults in any of the included 47% of children (aged 6-11) (9)) systematic reviews. Sample size: 52 0% of adolescents (aged 12- participants 17) 27% of adults ( ≥18 years) Was reported as transient and reversible. After TCS discontinuation, children with biochemical adrenal insufficiency had complete resolution at retesting. Herz 1991 (10) Single arm study Intervention: Clobetasol Severity: not Skin thinning 1 case of skin (observational) propionate (n=59) specified in the thinning reported (not clear if in a (Barnes 2015 (7)) review psoriasis or eczema patient – but (2 weeks treatment) Comparator: No comparator assume its eczema as this is the Age: not specified in Risk of bias not assessed topic of the systematic review). the review in any of the included systematic reviews. Sample size: 59 participants Potent topical corticosteroids Sugarman 2009 RCT Intervention: Fluticasone 0.05% Severity: moderate Serious adverse events (11) cream twice daily to severe The participants did not report (4 weeks treatment) (hydrocortisone 2.5% for the any in either group. (Van Zuuren Age: children 6 (Cochrane risk of bias face and body folds) (n=62) 2017 (12)) months to 18 years No further details regarding tool: low risk of selection, Comparator: Ceramide- (mean age 7.1 years) other possible treatment related attrition and other dominant barrier repair adverse events were reported. biases. Unclear risk of Sample size: 121 formulation (EpiCeram) twice reporting and participants daily (emollient) (n=59) performance bias, High risk of detection bias. (12)) (Cochrane risk of bias tool: unclear risk of selection bias, high risk from no blinding. (3)) Axon E, et al. BMJ Open 2021; 11:e046476. doi: 10.1136/bmjopen-2020-046476 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Open Griffiths 2002 (13) RCT Intervention: Hydrocortisone Severity: not No difference in cutaneous Unspecified adverse events 17-butyrate cream (0.1%) specified adverse events which were Hydrocortisone group: 20/49 (Nankervis 2017 (up to 14 days treatment) maximum application of 2g (four possibly or probably related to (40.8%) participants reported 41 (3)) Age: adults ≥18 (Cochrane risk of bias fingertip units) per day (n=49) treatment in either group (p = adverse events in total. years old tool: low risk of selection 0.13) Emollient: 29/52 (55.8%) Comparator: Cipamfylline cream bias from sequence Sample size: 103 participants reported 63 adverse (1.5 mg of cipamfylline per gram The adverse events were mostly generation, unclear risk participants events in total. of cream) used up to a application site reactions, of selection bias from (Difference between groups: p= maximum of 2 g (four fingertip including itching, stinging or allocation concealment, 0.14 a) units) of cream per day burning, and drug reactions. low risk from blinding. (3)) (emollient) (n=54) Eichenfield 2006 RCT Intervention: Fluticasone Severity: moderate Withdrawal due to adverse (14) propionate four times daily to severe events (4 weeks treatment) (n=221) Topical corticosteroids: 4 (Nankervis 2017 Age: children from 3 Risk of bias not assessed participants in total from this (3)) Comparator: Vehicle four times months old to 16 study and from Hebert 2007 daily (n=217) years old The number of participants Sample size: 438 reporting at least 1 adverse children event Fluticasone: 77/221 (34.8%) participants Vehicle: 82/217 (37.8%) participants (Difference between groups: p=0.52a) Wu 2013 (15) RCT Intervention: Mometasone Severity: all None of the safety tests (e.g. full No clinical adverse events were furoate 0.1% cream, twice a day severities blood count, kidney and liver reported. (Nankervis 2017 (10 days treatment) (n=20) function test, and (3), Fishbein Age: children from 1 (Cochrane risk of bias electrocardiogram) showed any 2019 (16)) Comparator: placebo of distilled month to 1 year old tool: low risk of selection significant differences compared water in 1% dimethyl sulfoxide bias from sequence Sample size: 60 with baseline for all three mixed with the identical cream generation. Unclear risk participants treatment groups. base as used for the 15(R/S)- of selection bias from methyl-lipoxin A4 (n=20) allocation concealment, unclear risk from blinding Comparator: 15(R/S)-methyl- and other biases: Two lipoxin A4 0.1% cream (n=20) out of 60 participants were excluded from the analyses as they used concomitant medication (3)) Axon E, et al. BMJ Open 2021; 11:e046476. doi: 10.1136/bmjopen-2020-046476 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Open Pellanda 2005 RCT Intervention: Triamcinolone Severity: mild to Skin changes (17) acetonide moderate One report by a participant using (Duration not specified in placebo (no further details) (Nankervis 2017 the review) Comparator: Vehicle Age: not specified in (3)) the review Risk of bias not assessed Sample size: not specified in the review Lebwohl 1996 RCT Intervention: Fluticasone Severity: not The review authors only reported (18) propionate ointment 0.005% specified in the that “Drug related adverse (29 days treatment) review effects were rare” (Hoare 2000 (19)) Comparator: Vehicle (Moher 1995 quality Age: not specified in checklist: method and the review concealment of randomisation unclear, Sample size: 203 double blinded, large participants number of withdrawals and dropouts, no ITT analysis (19)) Lebwohl 1999 RCT Intervention: Fluticasone Severity: not The review authors only reported (20) propionate ointment 0.005% specified in the that “Drug related adverse (29 days treatment) review effects were rare” (Hoare 2000 (19)) Comparator: Vehicle (Moher 1995 quality Age: not specified in checklist: method and the review concealment of randomisation unclear, Sample size: 169 double blinded, large participants