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HYPERBARIC OXYGEN THERAPY DOWNSTAGES REFRACTORY PERIANAL FISTULIZING CROHN’S DISEASE AND ALLOWS FOR SURGICAL CLOSURE
Lieven Mulders^*1, Kim Beek¹, Marte Becker¹, Pim J. Koelink¹, Marloes Zwart¹, Jarmila D.W. van der Bilt², Malaika Vlug¹, Jeroen Tielbeek³, Svend Rietdijk⁴, Jeroen M. Jansen⁴, Milan Ridderikhof¹, Wouter J. De Jonge¹, Willem A. Bemelman¹, Jaap Stoker¹, Geert D’Haens¹, Rob van Hulst¹, Manon E. Wildenberg¹, Christianne J. Buskens¹, Krisztina Gecse^1
1Amsterdam UMC Locatie AMC, Amsterdam, Noord-Holland, Netherlands; ²Flevoziekenhuis, Almere, Flevoland, Netherlands; ³Spaarne Gasthuis, Haarlem, Noord-Holland, Netherlands; ⁴OLVG, Amsterdam, Noord-Holland, Netherlands

Background
Hyperbaric Oxygen Therapy (HBOT) has previously shown benefit in treatment-refractory perianal fistulizing Crohn’s disease (PFCD). In this prospective study, we aimed to assess the feasibility, efficacy, and safety of HBOT followed by surgical closure in refractory fistulas, while also investigating translational changes associated with HBOT.

Methods
Patients with active PFCD refractory to >6 months of optimized medical therapy were included. During first EUA, fistula tracts were sanitized and double vessel-loops were placed. HBOT was started in preparation of a second EUA half-way, after 20 sessions of HBOT, to attempt to close the internal fistula openings with either a cross-linked suture or advancement flap. HBOT was continued until a total of 40 sessions were completed, each session lasted 110 minutes with 5-minute air breaks, on 100% oxygen at 2.4 atmosphere. All patients continued stable dose of medical treatment during the study. Response was assessed clinically, by pelvic MRI and by patient-reported QoL. RNAseq data of surgical biopsies of the internal fistula opening were explored between patients after completion of HBOT and matched non-HBOT patients.

Results
Sixteen patients were included and all of them completed 40 sessions of HBOT (see Table 1). During the second EUA, 13 (81%) patients had an epithelialized internal opening and all patients could undergo a technically successful surgical procedure. From 9 weeks follow-up, 43% achieved clinical remission (no drainage upon pressure), increasing to 70% after 52 weeks (Figure 1). MRI remission (MAGNIFI-CD ?6) was achieved by 42% (W26) and 57% (W52), and MRI healing (MAGNIFI-CD = 0) was achieved by 8% (W26) and 40% (W52). Quality of Life (CAFQOL) improved significantly from week 26, with a mean improvement of 10.7 (SE 3.9) by W26 and 22.7 (SE 6.0) by W52. (S)AEs included one patient with a potential oxygen toxicity seizure without long term effects, and one patient reported claustrophobia, no new AEs were reported.
Surgical biopsies obtained after HBOT displayed increased expression of cornification markers including CRNN, KRT4, KRT13 and SPRR2B compared to matched patients without HBOT on stable medical treatment who mainly showed general immune activiation. Pathway analysis confirmed biological activity of ‘keratinization’ and ‘dermal development’ in post-HBOT samples. This is similar to those observed previously in cryptoglandular fistulas.

Conclusion
HBOT resulted in downstaging of active PFCD and increased expression of pathways associated with keratinization and dermal development in and around the internal fistula opening, as is seen in cryptoglandular-like fistulas. This was associated with successful surgical closure after 4 weeks of HBOT. The combined treatment approach resulted in sustained clinical and MRI remission in patients with refractory disease.


Table 1. Baseline and disease characteristics

Figure 1. A. Clinical and B. MRI outcomes of HBOT followed by surgical closure at weeks 9, 26 and 52 of follow-up.

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