Foot Care in Epidermolysis Bullosa: Evidence-based Guideline

M.T. Khan; M. O'Sullivan; B. Faitli; J.E. Mellerio; R. Fawkes; M. Wood; L.D. Hubbard; A.G. Harris; L. Iacobaccio; T. Vlahovic; L. James; L. Brains; M. Fitzpatrick; K. Mayre-Chilton

Disclosures

The British Journal of Dermatology. 2020;182(3):593-604.

Research Appraisal

All published papers passing this filtering stage were then subjected to a systematic quality appraisal and risk-of-bias assessment. This appraisal was modified from the Critical Appraisal Skills Programme (http://www.casp-uk.net) and SIGN^[36] quality ratings. This allowed both quantitative and qualitative research to be appraised using one list of questions, yielding one quality rating scale to allow a comparison of studies as required (Appendix S8; see Supporting Information). The study limitations and indirectness were taken into account through the appraisal tool. The precision and statistical consistency could not be evaluated as the EB articles had no statistical values. Most studies reviewed had > 50% risk of bias, as EB is a rare condition, there are no double-blind randomized clinical studies and most people would know they have EB.

All selected papers were filtered and appraised by the two panel leads (M.T.K. and M.O'S.). In those instances where consensus could not be reached between the two panel leads, a third appraisal from the panel was allocated until this could be assured. This was conducted to reduce bias, to increase content validity checks of the literature, and most importantly to ensure the consistency of the reviews undertaken. The research quality score was obtained, with a high percentage being indicative of higher quality of the paper. Levels of bias were also measured in percentage values and all papers were graded in accordance with the SIGN method 'Level of Evidence and Grades of Recommendations' 1++ to 4 and grade A to D.^[36]

The papers were then divided into outcome topics. All papers and grey literature were allocated to these outcomes. The two panel leads and a member summarized the appraisals per outcome and rated the strength of the recommendation. Outcome summary tables were presented to highlight the population subtypes, numbers of patients, study type, percentage quality and risk of bias in accordance with SIGN. The panel checked the emerging strength of the recommendation, desired and undesired effects, costs related to benefits and the feasibility of implementation. They confirmed and discussed the recommendations elicited using the GRADE framework for the recommendation table (http://www.gradeworkinggroup.org). All recommendation summaries were circulated to the panel, and final agreement and feedback were included. The AGREE II tool^[38] was consulted to increase the quality of practice guidelines in rare diseases, and this CPG acknowledges existing guidelines by signposting with the symbol ⇒ throughout this manuscript.

The guidelines were peer reviewed by a representative cross-section of EB multidisciplinary team specialists and people living with EB. Five of eight health professionals and one person living with EB reviewed the guideline draft to assess the degree to which the recommendations presented addressed patients' concerns and identified good practice points (Table S2; see Supporting Information).

The lead and co-lead compiled a reviewer's feedback report for discussion with the guideline panel. Each point was addressed and any resulting change to the guideline was noted or, if no change was made, the reason for this was recorded. The panel conducted a final proofread of the manuscript before submission.

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Next Section

Table 1. Foot manifestations in epidermolysis bullosa (EB)
Primary types of EB	Blistering and scarring	Dystrophic nails	Hyperkeratosis, callus and corns	Pseudosyndactyly and mitten deformities
EB simplex	Yes		Yes
Dominant dystrophic EB	Yes	Yes	Yes
Recessive dystrophic EB	Yes	Yes		Yes
Junctional EB	Yes	Yes
Kindler syndrome	Yes	Yes

Table 2. Summary of key recommendations for podiatry management of foot and nail disorders in epidermolysis bullosa
Key recommendation	Grade strength of recommendation	Quality of evidence (rate average)	Key references^a
Desirable consequences clearly outweigh undesirable consequences in most settings, and for this reason we recommend offering these options
Avoidance of blistering and wounds: a podiatry education programme should be offered from birth, enabling carers, patients and staff to recognize and avoid causes of blistering and wounds, including • Footwear • Dressings • Foot biomechanics • Heat and sweating	B	2+	3–10
Management of dystrophic nails: podiatric support can include • Topical keratolytics • Trimming, reducing or removing nails	B	2+	3, 4, 8, 12–15
Management of hyperkeratosis (callus): podiatric support should include • Assessment and monitoring of weight distribution • Appropriate cushioning to prevent hyperkeratosis • Use of a validated assessment tool (Appendix S2)	B	2+	3–5, 7, 8, 10, 11
Footwear advice: information should be provided regarding suitable shoes and the appropriate use of • Insoles • Cushioning materials • Orthotics	C	3	3–5, 7–9, 21
Assessment and monitoring of mobility: podiatric care should focus on maintaining mobility, adapting to the specific needs of different subtypes and different age groups, within a multidisciplinary team	C	3	3–9, 18–28
The balance between desirable and undesirable consequences was uncertain, and for this reason we suggest consideration of this option
Assessment of pseudosyndactyly and contractures: podiatric support should include • Advice on preventative measures • Assessment of functional impairment • Referral for surgical correction • Postoperative management to prevent recurrence and promote mobility	D	3	22, 29–34

^aReference 10 contained no EB population.

Table 3. Grades of evidence
Grade
B	A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+
C	A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 2++
D	Evidence level 3 or 4; or extrapolated evidence from studies rated as 2+
Rate
2++	High-quality systematic reviews of case–control or cohort studies; high-quality case–control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal
2+	Well-conducted case–control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal
3	Nonanalytical studies, e.g. case reports or case series
✓	Recommended best practice based on the clinical experience of the guideline development group³⁶

Descriptions are in accordance with SIGN.³⁶ Note that there was no disagreement on the quality of the appraised articles or the strength of the recommendations.

Table 4. Percentages of children with epidermolysis bullosa (EB) who reported independence and dependence for major activities for daily living ¹⁹
Walking	EBS	JEB	DDEB	RDEB
Independent	31·2	30·8	66·7	24·4
Dependent	2·1	7·7	0	13·3

EBS, EB simplex; JEB, junctional EB; DDEB, dominant dystrophic EB; RDEB, recessive dystrophic EB.

Table 5. Overview of the evidence per outcome
Outcome	Allocated papers	Participants with EB in the articles	Methodology	Average quality rate^b	Quality appraisal (range)	Benefits and limitations
Blistering and wound management	6	347^a	1 qualitative	2+	58% (52–86%)	Blisters can be reduced in size and frequency, but expertise still limited to a few centres
		EBS 171	1 quantitative
		JEB 11	1 cohort
		DDEB 31	2 case studies
		RDEB 22	1 chapter
Dystrophic nails	8	234^a	2 qualitative	2+	67% (17–90%)	Mainly toenails rather than fingernails and their use for diagnosis
		EBS 137	1 quantitative
		JEB 11	3 case studies
		DDEB 38	1 observational
		RDEB 24	1 chapter
Hyperkeratosis	5	286^a	1 qualitative	2+	58% (52–64%)	Highlights occurrence in clinic, not complexity
		EBS 137	1 quantitative
		JEB 11	2 case studies
		DDEB 33	1 chapter
		RDEB 22
Footwear	6	291^a	1 qualitative	3	56% (48–69%)	Mainly on advice, no audits
		EBS 114	1 quantitative
		JEB 11	1 cohort
		DDEB 31	2 case studies
		RDEB 22	1 chapter
Mobility	14	1067^a	3 qualitative	3	60% (48–90%)	Early stages of new approaches to assess and treat
		EBS 396	2 quantitative
		JEB 71	1 cohort
		DDEB 148	3 observational
		RDEB 105	4 case studies
			1 chapter
Pseudosyndactyly	8	3401^a	Out of 96 cases of DEB only 7 were on toe fusion	3	54% (24–95%)	Low evidence with only case reports or series of poor quality and high risk of bias
Pseudosyndactyly	8	DEB 96	1 laboratory biological and animal model	3	54% (24–95%)

EB, epidermolysis bullosa; EBS, EB simplex; JEB, junctional EB; DDEB, dominant dystrophic EB; RDEB, recessive dystrophic EB. ^aTotal number of persons with EB in all papers combined. ^bDescriptions in accordance with SIGN:36 2+, well-conducted case–control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal; 3, nonanalytical studies, e.g. case reports or case series.

Table 6. Possible future research for each outcome
Blistering and wound management • Comparative studies can be used to assess dressing types used on the feet in different EB groups
Dystrophic nails • Evaluate the benefit of a podiatrist to manage both fingernails and toenails • A review of the nail conditions affecting patients with EB is needed, and then a study to examine the treatment protocols, with topical keratolytic agents, urea-based agents and daily filing with an emollient to follow
Hyperkeratosis (callus) • Evaluate the benefits of callus debridement between manual techniques (scalpel) over keratolytic agents • Comparative studies to assess different keratolytic agents when treating hyperkeratosis in patients with EB
Footwear • Examine different podiatry materials to offer shock absorption and redistribution within footwear being worn • Studies on footwear for patients with EB and engagement with footwear and hosiery manufacturers to make friendly footwear and hosiery more accessible for a person with EB • Evaluate specific footwear funding by the service for 'suitable' patients; the outcome of this would be useful • A study would be required to show any quantifiable benefit of silver vinyl insole material
Mobility • Further assessment with larger EB groups, monitoring mobility using gait analysis platforms and fitness trackers to assess total distances achieved. • Patients can record their steps just using their mobile phones; this is not as accurate as a fitness tracker but it is less expensive, and noteveryone can wear something around their wrist • Assessing the impact that aids, suitable footwear, insoles and orthotics, and dressings have on aiding distances achieved by individuals with EB
Pseudosyndactyly • Benefit of no surgical implementation of losartan in slowing down fibrosis in patients with RDEB
Other areas • Botox injections in EBS • Pedagogical implications for the contextual positioning of EB education and training in both undergraduate and continuous professional development and postgraduate podiatric specialisms

EB, epidermolysis bullosa; EBS, EB simplex; RDEB, recessive dystrophic EB.

Box 1.
Disclaimer: Podiatrists are sometimes asked to deal with fingernails as well as toenails by their EB consultant. Podiatrists should ensure that this activity is within the scope of the podiatric practice act for their country and find out whether certification is required.