The patients evaluated in the HOT-TOPIC trial were Crohn's disease patients with difficult-to-treat perianal fistulas with a median disease duration of 4 years. At Week 16 a significant improvement was found in the co-primary outcomes (PDAI and the (modified) van Assche index), with 65% of patients having an inactive perianal disease after treatment based on cut-off scores of the PDAI that were previously published. The different MRI items that were scored showed improvement in inflammatory aspects as well as fibrosis of the fistula complex in three patients. Using the fistula drainage assessment, 60% of patients had a clinical response at Week 16 and 20% were in remission. Furthermore, significant biochemical improvements were seen, paralleled by improved patient-reported outcome measures. Overall, hyperbaric oxygen treatment was well tolerated and it turned out to be feasible.
Although comparison of the results of the HOT-TOPIC trial to those of other trials concerning fistulas should be approached with caution (given the differences in trial design, study population and outcome parameters), the results for our therapy-refractory patients are highly encouraging, especially in the light of the success rates of current treatment modalities for Crohn's fistulas as presented in the introduction. In the PISA trial that was recently performed by our group, treatment outcomes among chronic seton drainage, anti-TNF therapy and surgical intervention were compared in 94 patients. Patients had a mean PDAI score between 4 and 5 at 6-month follow-up in all three groups, which is comparable to the median PDAI score found in the HOT-TOPIC trial. The PISA trial, however, involved patients with new or recently recurrent fistulas. Furthermore, the median duration of the perianal disease was shorter (1–2 years) in patients who participated in the PISA trial, and their fistulas were also less complex (median of one external opening and exclusion of patients with multiple internal openings). In contrast, the patients in the HOT-TOPIC trial were therapy-refractory and in some cases defunctioning colostomy was the only other treatment option left available. Patients will continue to be followed until Week 60 in order to assess the durability of these results.
A statistically significant drop in PDAI score was also seen in the control group, which can be mostly attributed to the four patients undergoing a surgical intervention. One patient was unexpectedly eligible for a fistulotomy, with much higher chances of success than is usual for complex fistulas in Crohn's disease patients. The other three patients had a ligation of the intersphincteric fistula tract, with two having clinical remission at Week 16 after the intervention. In the hyperbaric oxygen therapy group, however, four patients already had an unsuccessful surgical intervention and another five patients were not eligible for surgery due to multiple internal openings. This indicates that the control group is not directly comparable to the hyperbaric oxygen therapy group. Future trials can help determine the position of hyperbaric oxygen therapy with regards to surgery, as well as the efficacy compared to surgical and/or medical interventions.
Unfortunately, there is no value for the minimum clinically important difference for both the PDAI and the MRI indices, and therefore the proportion of responding patients could not be determined using these co-primary outcomes. Although the fistula drainage assessment has been used as a primary outcome in several trials, "gentle finger compression" is investigator dependent and has been shown to not always reflect healing of the underlying fistula tract. Hence, radiological imaging could give additional information on fistula healing. However, there is no reference standard for measuring radiological response. A recent trial investigated the use of mesenchymal stem cells in perianal fistulas in Crohn's disease and defined radiological remission as absence of collections larger than 2 cm, while other trials reported scores of the original van Assche index.[7,28] At the time of the design of the HOT-TOPIC trial, the modified van Assche index turned out to have higher inter-rater reliability compared to the original van Assche index. Meanwhile, another MRI index has been published (the MAGNIFI-CD), which has further improved existing items of previous indices as well as adding a new one (fistula length). External validation of this instrument is needed before it can be used as an outcome measure in clinical trials. The need for a reliable outcome measure for perianal fistulas was endorsed at the Fifth Scientific Workshop of the European Crohn's and Colitis Organization.
Assessing feasibility of hyperbaric oxygen treatment was an important objective. Feasibility of hyperbaric oxygen treatment in IBD patients has been a problem in earlier trials, and because hyperbaric oxygen treatment is demanding for patients concerns were raised that it might not be a manageable treatment option for fistula patients. Patients who refused hyperbaric oxygen treatment were asked to serve as a control group in order to assess reasons for refusal, baseline characteristics and the disease course, with only minimal effort to participate (completion of questionnaires at baseline and Week 16, no laboratory findings or MRI). Only eight of 29 patients refused to undergo hyperbaric oxygen treatment. Based on these observations, we conclude that this treatment approach is feasible for Crohn's disease patients with therapy-refractory fistulas. Due to the small number of patients who were included in the control group and allocation based on patient preference a meaningful comparison in outcomes between both groups could not be made.
A randomised, controlled trial (RCT) seems warranted based on the results of this study. However, a traditional RCT has several downsides when it comes to internal and external validity in fistula patients that often have a distinct preference for their treatment. Given the specific nature of the hyperbaric oxygen treatment, a patient preference model or Trial within Cohorts (TwiCs) design might be more appropriate.[31,32] It might also be interesting to investigate different approaches using hyperbaric oxygen therapy, such as treatment of patients with new fistulas (instead of therapy-refractory ones) or pre- and post-operative treatment with hyperbaric oxygen therapy around definitive surgical closure.
In the HOT-TOPIC trial, seton removal was planned after 30 hyperbaric oxygen sessions, which was decided at the discretion of the treating physician. We found that clinical improvement and epithelisation of fistula tracts was already seen after 15 to 20 hyperbaric oxygen treatments, and that setons could be removed earlier than expected. Based on these observations, future trials might assess patients at a weekly interval and setons should be removed as soon as clinical symptoms such as pain and production improve, and when epithelisation of the fistula tract occurs with no signs of induration at physical examination.
Five of the 20 patients treated with hyperbaric oxygen therapy (25%) had an adverse event with signs of mild-to-moderate middle ear barotrauma on otoscopy, with three patients requiring tympanostomy tubes to complete the course of treatment. This is a relatively high number of otologic adverse events compared to other studies using hyperbaric oxygen therapy in IBD patients, as well as in patients undergoing hyperbaric oxygen therapy for other indications.[11,15] Although there were no residual complaints during follow-up and decision regret as measured in the study was low, the risk of barotrauma should be discussed with patients before treatment and adverse events should be monitored carefully in future studies.
One of the strengths of this study is that a true consecutive series of patients in a large IBD centre was included. Secondly, concomitant medication was kept stable 6 weeks before starting hyperbaric oxygen treatment and during the study period, which reduced the potential risk of measuring effects of other treatments/interventions. Despite careful consideration of the concomitant medical regimen (including evaluation of adequate trough levels of anti-TNF therapy before inclusion in the study), an increase in dose of infliximab was made by an external gastroenterologist in one patient during hyperbaric oxygen therapy. This patient, however, did not have an improvement in PDAI, MRI scores and/or the fistula drainage assessment at follow-up, and was considered a nonresponder to hyperbaric oxygen treatment. A limitation of the study is the lack of a randomised control group, which limits the ability to establish a true causal effect of hyperbaric oxygen treatment on the positive results that were found. These could have been caused by other factors such as late effects of medication, although this seems unlikely given that a high proportion of patients (17 of 20) had a stable dose of concomitant medication for at least 6 months before the start of hyperbaric oxygen therapy (ie far longer than the 6 weeks that were required for inclusion in the study). Nine of 20 patients had an examination under anaesthesia with seton placement within 6 months before the start of hyperbaric oxygen therapy, as adequate drainage was a requirement for inclusion in the study. It is possible that this procedure contributed to improvement in some outcome parameters, although to our knowledge there is no literature that suggests that examination under anaesthesia with seton placement (and no other surgical intervention) could lead to actual fistula healing. Furthermore, given the therapy-refractory nature of the patient population, all patients had multiple examinations under anaesthesia in the past without sufficient improvement. Another limitation of the study is that the assessment of MRIs was done in a nonrandom order and this might introduce bias, although the radiologist was blinded to all other findings. In a future, larger trial assessment in random order might be preferred to exclude this risk of bias. Random assessment, however, comes with logistic issues that should be taken into consideration: the index evaluates the "primary tract", and this tract can be different between baseline and follow-up (eg in case one of two tracts has healed at follow-up, and a secondary tract at baseline becomes the primary tract at follow-up). Scoring in random order might therefore lead to assessing the wrong fistula which may introduce another bias.
In conclusion, this study shows that a clinical, radiological and biochemical improvement was found after hyperbaric oxygen therapy in Crohn's disease patients with therapy-refractory fistulas, and that the treatment was feasible and tolerated well. Future controlled trials are needed to confirm these findings.
European Crohn's and Colitis Organisation
We would like to thank the Instituut voor Hyperbare Geneeskunde/the Da Vinci Clinic, Hyperbaar Geneeskundig Centrum Rijswijk and Antonius Hypercare Sneek for their cooperation and facilitation of the treatment of the study population with hyperbaric oxygen therapy.
Guarantor of the article
This research has been awarded with a Grant from the European Crohn's and Colitis Organisation and this Grant funded the research. The funder did not have any role in the study design, collection, management, analysis or interpretation of data, or writing of the report or the decision to submit the report for publication.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Aliment Pharmacol Ther. 2021;53(5):587-597. © 2021 Blackwell Publishing