Effectiveness of Systemic Treatments for Pyoderma Gangrenosum: A Systematic Review

1. Effectiveness of Systemic Treatments for Pyoderma Gangrenosum: A Systematic Review of Observational Studies & Clinical Trials ACR Partridge1, JW Bai1, CF Rosen2,3, SR Walsh2,4, WP Gulliver4, P Fleming2 1MD Program, Faculty of Medicine, University of Toronto, Toronto, Canada; 2Division of Dermatology, University of Toronto, Toronto, Canada; 3Division of Dermatology, University Health Network, Toronto, Canada; 4Department of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Canada Br J Dermatol. 2018 Feb 25. doi: 10.1111/bjd.16485

2. Arun Partridge: Lead author

3. Introduction What’s already known? • Pyoderma gangrenosum is a neutrophilic dermatosis associated with substantial mortality and morbidity, that can be managed with multiple systemic agents. • There is no consensus on most effective therapy. • There is a lack of large randomized trials and synthesis studies on treatment effectiveness and adverse effects, and no published systemic reviews on systemic treatments for PG.

4. Objective • To systematically review and summarize the evidence on the effectiveness and safety of systemic treatments used to treat adult patients with PG.

5. Methods (1) • Based on PRISMA guidelines, the authors systematically searched Cochrane Central, Cochrane DSR, EMBASE, MEDLINE, PubMed, Web of Science, and several grey literature databases; up to July 2016. • The authors used unique search strings for each database using keywords and subject headings for “pyoderma gangrenosum” and >24 known systemic therapies. • Two reviewers independently screened titles and abstracts of all identified citations, and subsequently reviewed all remaining full-text articles; kappa statistics were calculated to determine inter-rater reliability.

6. Methods (2) • Articles were included if they: (i) used ≥1 systemic therapy to treat PG; (ii) studied adult participants (>18 years old); (iii) used experimental or observational study design; and (iv) reported empirical outcomes for each treatment regimen. • Articles were excluded if: (i) inclusion criteria were not met, (ii) they presented non-primary data, (iii) they were case series of less than 5 patients.

7. Methods (3) • Primary outcomes: rates of complete healing and clinical improvement. • Secondary outcomes: time-to-healing, adverse effects, pain level, quality of life, treatment failures and time to recurrence. The authors conducted a risk of bias using validated tools including the Newcastle-Ottawa Scale (NOS), adapted NOS, and Cochrane Risk of Bias Assessment Tool.

8. Results (1) • 3,326 citations identified, of which 375 articles underwent full-text review, and 41 studies met inclusion criteria. • There were 704 participants amongst 26 retrospective cohort studies, 3 prospective cohort studies, 7 case series, 1 case-control study, 2 open-label trials, and 2 RCTs. • Systemic corticosteroids were the most studied (n=32 studies), followed by ciclosporin (n=21), biologics (n=16), and oral dapsone (n=11).

9. Results (2) 2 RCT’s • STOP-GAP n=121: similar efficacy with prednisolone and ciclosporin, 15-20% complete healing at 6-weeks and 47% at 6-months. • n=30: infliximab superior to placebo at 2-weeks (46% vs. 6% response), with 21% complete healing rate at 6-weeks. Two uncontrolled trials showed 60% and 37.5% healing in four months with canakinumab and infliximab, respectively.

10. Results (3) Observational studies and case series • n=37 • Evidence to support the use of corticosteroids, ciclosporin and biologics but significant bias and confounding.

11. Results (4) • Nine studies focused on treating PG in participants with concurrent IBD or peristomal lesions. • These were observational and generally of low-to-moderate quality and presented moderate-to-high risk of bias with broad heterogeneity in participants, interventions, and outcomes. • Infliximab demonstrated healing rates between 33-100%. • Adalimumab, azathioprine, and ciclosporin were shown to be effective. • Corticosteroids performed poorly unless started early and at high doses.

12. Discussion (1) Principal findings: • The systematic review examined 704 adult PG patients treated with systemic therapies from 37 observational and 4 interventional studies. • Systemic corticosteroids, ciclosporin, infliximab, and canakinumab had the strongest evidence in treating pyodermagangrenosum, although overall there are few high-quality studies.

13. Discussion (2) • Many inflammatory components involved in pathophysiology of PG are targeted by systemic therapies, as shown in existing literature; it is possible that the most effective regimens may involve tailored combinations of topical and systemic agents. • In general, there is a lack of high-quality, well-powered trials on systemic treatments for PG, and broad heterogeneity in their designs.

14. Discussion (3) Strengths: • The study is the only systematic review on the effectiveness of systemic treatments for PG. • The authors used a systematic and comprehensive search strategy with robust study design to review the available literature in the field. Limitations: • It was not possible to include only high-quality data. • Meta-analysis was precluded due to heterogeneity of available studies in the field. • Most study participants were inpatients, increasing risk of selection bias and reducing external validity. • There is inconsistent reporting of treatment complications and PG recurrence, precluding measurement of these adverse effects.

15. ConclusionsWhat does this study add? • The review supports the use of corticosteroids, ciclosporin, and TNFα inhibitors, though there remains a high rate of non-response and recurrence. • Current literature is limited to small and lower-quality studies with substantial heterogeneity. • Future research should include high-quality RCTs with clear outcome reporting, examine newer biologic agents, and explore the role of multi-modal treatments. • The authors suggest more consistent outcome reporting which would enable direct treatment comparisons and meta-analyses.

16. Call for correspondence • Why not join the debate on this article through our correspondence section? • Rapid responses should not exceed 350 words, four references and one figure • Further details can be found here