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 Feb 25. doi: /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 %.
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 pyoderma gangrenosum, 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: Limitations:
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. Conclusions What 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.

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