Behçet´s disease (BD) is a rare autoimmune disease mostly presenting with recurrent oral and genital aphthosis, and uveitis. Other common symptoms include gastrointestinal, vascular, neurological and articular manifestations (1). The first internationally agreed criteria for BD were the International Study Group (ISG) criteria (2). They had very high specificity, but lacked satisfactory sensitivity, missing out on a sizable subset of patients. The International Criteria for Behçet’s Disease (ICBD) were created in 2006 to overcome this lack of sensitivity. This classification was revised in 2006. A score ≥ 3 is associated with sensitivity of 95% and specificity of 90.5% (3). Treatment is based on chronic immunosuppression with conventional disease-modifying or targeted biologic drugs such as corticosteroids, intravenous cyclophosphamide, cyclosporine or anti TNFα therapy (4). The most recent European League Against Rheumatism (EULAR) recommendations were updated in 2018 (5). They did not mention autologous hematopoietic stem cell transplantation (aHSCT), possibly due to limited specific data in BD.

Over the past 20 years, aHSCT has become a standard of care for early rapidly progressive Systemic Sclerosis (6–11) and has emerged as a promising treatment modality for severe Multiple Sclerosis (12–14) and Crohn’s Disease (12, 15). But patients with rarer diseases, such as BD, have undergone aHSCT based on compassionate use.

Led by the Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT), a previously published retrospective analysis of HSCT covered all vasculitis (16), in which partial and complete responses were reported for two patients with BD. Other publications on autologous stem cell transplantation for BD [without a concomitant hematologic malignancy, as it has also been reported (17, 18)] only consist of case reports (19–23). Only one failure with aHSCT in BD has been reported (22). Further data and composite analysis are required to inform the balance of benefits and risks of aHSCT in patients with severe, refractory BD. The aim of this retrospective study was therefore to bring together a larger experience in order to describe the efficacy and toxicity of aHSCT in adults with BD treated in EBMT centers.

Our study is the first retrospective cohort study conducted in patients with BD who underwent aHSCT. The results showed a high rate of efficacy in heavily pretreated patients or in patients with life-threatening complications with acceptable toxicity profile and no aHSCT-related mortality. Two patients were in CR (ie without any treatment) up to 21 years after aHSCT, raising the question of the efficacy of aHSCT as an effective cure for patients with BD refractory to multiple conventional treatments. However, one patient did not respond, one patient had a major relapse and two patients had a minor relapse reflecting some limitations of the procedure. Relapses consisted of the same clinical presentation observed at the onset of the disease. But there was no life-threatening involvement and all relapses were controlled by conventional treatments, whereas patients were refractory to those treatments before aHSCT. This is consistent with observations following aHSCT in refractory Crohn’s Disease and use of anti-TNFα therapy after aHSCT (24) and in rheumatoid arthritis and use of disease-modifying agents after aHSCT (25), where there is renewed sensitivity to drugs associated with the “immune reset” after aHSCT.

Such “immune reset” after aHSCT may explain the efficacy in BD. Although no data are available in BD, this concept is well described in other auto-immune diseases treated with aHSCT, and the mechanisms seem to be similar whatever the disease (26). The destruction of the aberrant immune system leads to restoration of a new naïve and self-tolerant immune system (27–30). Renewal of T-cell repertoire is well documented in rheumatic diseases like systemic sclerosis or systemic lupus erythematosus with the disappearance of T-cell autoimmune clones (31) and of the pre-existing serum auto-antibodies (32). A functional renewal of regulatory T cells (33) and diversification of the T-cell receptor (TCR) repertoire (30) are also associated with favorable outcomes in patients with severe resistant autoimmune and inflammatory diseases treated with aHSCT (34).

Significantly, our results are congruent with published cases showing a high rate of efficacy (16, 19–22). By selecting the patients from EBMT registry with the inclusion of consecutive patients, this study avoided publication bias, i.e. reporting only success and not failure. Furthermore, this study is the first focusing on aHSCT in BD. Other studies had no more than 2 cases as they were focused on primary vasculitis, including BD among others (16, 22), with shorter follow-up (16, 19–22, 35).

tThis study has limitations including retrospective data collection (but missing data were rare, and they pertained to secondary data) and possible under-reporting of aHSCT for BD in the EBMT registry (the 2 cases extracted from the literature illustrate this issue (20), despite the obligation of full EBMT member centers to report all cases). This bias is likely to be independent from aHSCT outcome. The literature search improved sensitivity but may have been affected by publication bias. Another bias was the heterogeneity of patients characteristics at baseline (especially in terms of organ involvements), reflecting the absence of consensus or guidelines on the indication of aHSCT in BD. The long term risk/benefit balance of aHSCT in BD should be evaluated in prospective studies, ideally randomized controlled trials of anti-TNFα therapy refractory patients against other standard of care. But it would be unlikely to be feasible due to the rare incidence of patients with this severity of BD. More pragmatically, ongoing registry-based analyses may help to define the role of aHSCT in BD and further inform transplant technique and patient selection to optimize patient outcomes.

In conclusion, based on our data, aHSCT has an acceptable safety profile and represents a feasible and relatively effective procedure in severe and conventional treatment-resistant cases of BD. It should be considered as a treatment option for patients refractory to anti-TNFα with high disease burden. Further data ideally from randomized controlled trials are warranted.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.

Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work: ALL. Drafting the work or revising it critically for important intellectual content: ALL. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: ALL. All authors contributed to the article and approved the submitted version.

No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.

JS declares previous honoraria for speaking at educational events from Sanofi, Jazz, Janssen, Actelion, Mallinckrodt and Gilead, and is a member of a trial IDMC for Kiadis Pharma (none directly related to the subject of this analysis).

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.