Hyperbaric Oxygen Therapy for the Treatment of Perianal Fistulas in 20 Patients With Crohn's Disease

Corine A. Lansdorp; Krisztina B. Gecse; Christianne J. Buskens; Mark Löwenberg; Jaap Stoker; Willem A. Bemelman; Geert R.A.M. D'Haens; Rob A. van Hulst

Disclosures

Aliment Pharmacol Ther. 2021;53(5):587-597.

Abstract and Introduction

Abstract

Background: Positive effects of hyperbaric oxygen on perianal fistulas in Crohn's disease have been reported.

Aim: To assess efficacy, safety and feasibility of hyperbaric oxygen in Crohn's disease patients with therapy-refractory perianal fistulas.

Methods: Twenty consecutive patients were recruited at the out-patient fistula clinic of the Amsterdam UMC. Crohn's disease patients with high perianal fistula(s) failing conventional treatment for over 6 months were included. Exclusion criteria were presence of a stoma, rectovaginal fistula(s) and recent changes in treatment regimens. Patients received treatment with 40 hyperbaric oxygen sessions and outcome parameters were assessed at Week 16.

Results: Seven women and 13 men were included (median age 34 years). At Week 16, median scores of perianal disease activity index and modified van Assche index (co-primary outcome parameters) decreased from 7.5 (95% CI 6–9) to 4 (95% CI 3–6, P < 0.001), and from 9.2 (95% CI 7.3–11.2) to 7.3 (95% CI 6.9–9.7, P = 0.004) respectively. Perianal disease activity index scores ≤4 (representing inactive perianal disease) were observed in 13/20 patients (65%). Twelve patients showed a clinical response (60%) and four (20%) clinical remission, assessed with fistula drainage assessment. Median C-reactive protein and faecal calprotectin levels decreased from 4.2 mg/mL (95% CI 1.6–8) to 2.2 (95% CI 0.9–4.3, P = 0.003) and from 399 μg/g (95% CI 52–922) to 31 (95% CI 16–245, P = 0.001), respectively.

Conclusions: We found significant clinical, radiological and biochemical improvement in Crohn's disease patients with therapy-refractory perianal fistulas after treatment with hyperbaric oxygen.

Clinical trial registration: www.trialregister.nl/trial/6489.

Introduction

Perianal fistulas are common complications in Crohn's disease, with every third patient developing at least one fistulising episode during their disease course.^[1] Clinical manifestations range from painless fistula discharge to abscess formation accompanied by pelvic sepsis.^[2] Spontaneous fistula closure is rare, and most patients require medical and/or surgical intervention.

Medical treatment usually consists of anti-tumour necrosis factor therapy (anti-TNF, mostly infliximab and adalimumab) with success rates up to approximately 40%.^[3,4] Surgical treatment generally includes placement of a loose seton as a first therapeutic approach in order to prevent retention in the fistula tract and abscess formation. Subsequent surgical interventions aimed at closure include mucosal advancement flaps and ligation of the intersphincteric fistula tract, depending on the anatomy of the fistula tracts. Success percentages have been described in up to 60% of patients.^[5,6] Unfortunately, in up to 50% of patients, the fistula does recur in due time (follow-up of 48 months).^[5,6]

The use of mesenchymal stem cells is a new treatment modality in selected cases with complex fistulas; A recent study showed that closure of the internal opening with injection of stem cells around the fistula tract can achieve combined clinical and radiological (assessed by magnetic resonance imaging [MRI]) remission in 50% of patients at Week 24, compared to 34% in the placebo group.^[7]

Overall, even after multidisciplinary approach, long-term success rates remain disappointing. In a large epidemiological study, only one third of patients with complex perianal fistulas achieved clinical remission at the end of follow-up (median 10 years).^[8] Furthermore, a substantial part (63.8%) of these patients underwent a defunctioning ostomy. Along with a significant impact on quality of life and inflammatory bowel disease (IBD)-related work disability, perianal fistulas represent one of the biggest unmet needs in the treatment of Crohn's disease.^[9,10]

Hyperbaric oxygen therapy has been suggested as a potential adjunctive treatment for patients suffering from IBD.^[11] Hyperbaric oxygen therapy consists of breathing 100% oxygen under higher than normal atmospheric pressure: usually 202–253 kilopascal (equivalent to 2.0–2.5 atmosphere absolute). The hyper oxygenation and oxidative stress associated with hyperbaric oxygen therapy has been shown to result in anti-inflammatory effects, stem cell mobilisation and upregulation of growth factors.^[11–13] Treatment for chronic problems (eg wound healing) usually consists of daily sessions for 6 to 8 consecutive weeks. The 'Undersea and Hyperbaric Medical Society', a nonprofit organisation that plays an important role in providing scientific and medical information on hyperbaric medicine, currently lists 14 indications for hyperbaric oxygen therapy.^[14] These include late radiation tissue injuries, diabetic foot ulcers and carbon monoxide poisoning. The therapy is considered safe with few complications. Barotrauma of the ears or sinuses are among the most frequently reported side effects.^[15]

Positive outcomes with hyperbaric oxygen therapy for treating perineal Crohn's disease have been reported in small case series.^[11,16,17] However, patient characteristics and outcome parameters were not well defined in these studies, leading to a significant risk of bias. The objective of this prospective interventional study was to assess efficacy, safety and feasibility of hyperbaric oxygen therapy in Crohn's disease patients with therapy-refractory perianal fistulas.

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Abstract and Introduction
Methods
Results
Discussion
References

Table 1. Baseline characteristics of patients undergoing hyperbaric oxygen therapy
Characteristics	n = 20
Age (median age, IQR)	34 (24–49)
Gender at birth (number of patients)
Male	13 (65%)
Female	7 (35%)
Active smoking (number of patients)	4 (20%)
Luminal disease activity present (number of patients)	5 (25%)
Concomitant use of medication	17 (85%)
Anti-TNF therapy	14 (70%)
Years disease duration Crohn's disease (median, IQR)	12 (4–19)
Years disease duration perianal Crohn's disease (median, IQR)	7 (3–12)
Years disease duration current fistula (median, IQR)	4 (2–12)
Previous surgical closure (number of patients)	4 (20%)
Number internal openings (number of patients)
1	15 (75%)
2	4 (20%)
3	1 (5%)
Number of external openings (number of patients)
1	7 (35%)
2	5 (25%)
3	3 (15%)
4 or more	5 (25%)

Abbreviation: IQR, interquartile range.

Table 2. Perianal disease activity index, (modified) van Assche scores and patient-reported outcomes at baseline and Week 16 of patients treated with hyperbaric oxygen therapy
	Baseline		Week 16		Statistical significance
	Median	95% CI	Median	95% CI	P-value
Perianal disease activity index^a	7.5	6–9	4	3–6	<0.001
Modified van Assche index^b	9.2	7.3–11.2	7.3	6.9–9.7	0.004
Original van Assche index^c	13	12–15	12	10–13	0.005
VAS score^d	67.5	61–78	70	60–76	0.26
IBDQ score^e	169	141–191	183	167–199	0.001
Decision regret scale score^f	NA	NA	15	5–25	NA

Note: CI, confidence interval; VAS, visual analogue score; IBDQ, inflammatory bowel disease questionnaire; NA, not applicable.
^aThe perianal disease activity index evaluates five items: fistula production, pain and restriction of activities, limitation of sexual activities, type of perianal disease and severity of induration. Every category includes a scale ranging from 0 to 4 points, higher scores representing higher disease activity. The total score can range from 0 to 20 points.
^bThe modified van Assche index consists of five items: extension, hyperintensity on T2-weigthed images, rectal wall involvement, inflammatory mass and dominant feature of the primary tract and extensions. The total score can range from 0 to 19.5 points, with higher scores representing more severe perianal disease.
^cThe original van Assche index consists of six items: number of fistula tracts, location, extension, hyper intensity on T2-weighted images, collections and rectal wall involvement. The total score can range from 0 to 22 points, with higher scores representing more severe perianal disease.
^dThe VAS score records the respondent's self-rated health on a scale from 0 to 100, with higher scores indicating higher quality of life.
^eThe IBDQ is a 32-item questionnaire concerning four dimensions of quality of life in patients with inflammatory bowel disease (bowel function, emotional status, systemic symptoms and social functioning), with scores ranging from 32 to 224, with higher scores indicating a better quality of life.
^fThe decision regret scale consists of five statements that measure distress or remorse after a health-care decisions. The scale ranges from 0 to 100, with higher scores reflecting higher regret of the decision.

Authors and Disclosures

Corine A. Lansdorp¹, Krisztina B. Gecse², Christianne J. Buskens³, Mark Löwenberg², Jaap Stoker⁴, Willem A. Bemelman³, Geert R.A.M. D'Haens² and Rob A. van Hulst¹

¹Department of Anesthesiology/Hyperbaric Medicine, Amsterdam UMC, location AMC, Amsterdam, The Netherlands
²Department of Gastroenterology and Hepatology, Amsterdam UMC, location AMC, Amsterdam, The Netherlands
³Department of Surgery, Amsterdam UMC, location AMC, Amsterdam, The Netherlands
⁴Department of Radiology and Nuclear Medicine, Amsterdam UMC, location AMC, Amsterdam, The Netherlands

Correspondence
Corine A. Lansdorp, Amsterdam UMC, location AMC, Department of Anesthesiology/Hyperbaric Medicine, location H1-158, PO Box 22700, 1100 DE Amsterdam, The Netherlands. Email: n.lansdorp@amsterdamumc.nl

Author contributions
CAL, KBG, CJB, ML, JS, WAB, GDH and RAH contributed to the study conception, design and data collection. CAL, KBG, CJB, ML, WAB and GDH were involved in participant recruitment. CAL, KBG, CJB, GDH and RAH were involved in the analysis of the results. CAL drafted the manuscript and all other authors contributed to the manuscript with important intellectual content.

Declaration of personal interests
CAL has no conflicts of interest to declare. KBG has received consultancy fees and/or speaker's honoraria from AbbVie, Celltrion, Ferring, Immunic Therapeutics, Janssen, Pfizer, Roche, Sandoz, Samsung Bioepis, Takeda and Tillotts. CJB has received speakers' honoraria from Takeda and Tillotts. She has an unrestricted grant from Boehringer Ingelheim, and is part of the advisory board of Johnson & Johnson energy devices. ML has served as speaker and/or principal investigator for: Abbvie, Celgene, Covidien, Dr Falk, Ferring Pharmaceuticals, Gilead, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, Protagonist therapeutics, Receptos, Robarts Clinical Trials, Takeda, Tillotts and Tramedico. He has received research grants from AbbVie, Merck Sharp & Dohme, Dr Falk, Achmea healthcare and ZonMW. JS has a research agreement with Takeda on a nonrelated topic. WAB has served as speaker for Takeda, Johnson and Johnson and Braun. He has received research grants from Braun and Vifor. GDH has served as advisor for Abbvie, Ablynx, Active Biotech AB, Agomab Therapeutics, Allergan, Alphabiomics, Amakem, Amgen, AM Pharma, Applied Molecular Therapeutics; Arena Pharmaceuticals, AstraZeneca, Avaxia, Biogen, Bristol Meiers Squibb/Celgene, Boehringer Ingelheim, Celltrion, Cosmo, DSM Pharma; Echo Pharmaceuticals, Eli Lilly, Engene, Exeliom Biosciences; Ferring, DrFALK Pharma, Galapagos, Genentech/Roche, Gilead, Glaxo Smith Kline, Gossamerbio, Pfizer, Immunic, Johnson and Johnson, Kintai Therapeutics, Lycera, Medimetrics, Takeda, Medtronic, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Nextbiotics, Novonordisk, Otsuka, Photopill, ProciseDx, Prodigest, Prometheus laboratories/Nestle, Progenity, Protagonist, RedHill; Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Seres/Nestec/Nestle, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant and Vifor; received speaker fees from Abbvie, Biogen, Ferring, Galapagos/Gilead, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts and Vifor. RAH has no conflicts of interest to declare.