BS is a complex, multisystemic disorder with unknown etiology and unique geographic distribution. There has been controversy over whether to call it a “disease” or “syndrome.” Many studies have shown that it is composed of multiple phenotypes, such as skin-mucosa, eye, gastrointestinal, vascular, and neurological involvement. The present study we focused on a unique group of BS patients whom with cytopenia. There is no large sample report on BS patients with cytopenia in the literature, and the reports are mainly case reports[17, 18].
In this retrospective study, we assessed the demographic, clinical, laboratory manifestations, and treatment of these patients from Shanghai BS database. Cytopenia was observed in 2.1% of our BS patients. From our large number sample research, BS patients with cytopenia have their own characteristics that are different from BS and MDS patients. Firstly, BS patients with cytopenia were more likely to be female and older than BS patients and much younger than MDS patients. Secondly, gastrointestinal (GI) ulceration and fever were more common, and the level of ESR and CRP significantly higher in BS patients with cytopenia. Thirdly, somatic mutations trisomy 8 were more common in BS patients with cytopenia (82.5%).
GI ulceration was observed in 77.5% of our BS patients with cytopenia. Abdominal pain and weight loss were more common while diarrhea was less common. The location in the ileocecal, small intestine and colon region were more frequently seen in intestinal BS patients with cytopenia. To investigate the role of trisomy 8 in GI ulceration, we randomly selected 20 BS patients without cytopenia and performed bone marrow karyotype analysis. Trisomy 8 (83.9%) were more common in intestinal BS with cytopenia. In summary, BS with cytopenia were more common in older women, high incidence of intestinal ulcers and trisomy 8.
Some studies have even referred to BS with cytopenia as a “Behçet-like disease”[19, 20]. Analyses of several case reports have shown an association between trisomy 8 and intestinal BS with MDS[4, 21–23]. Indeed, trisomy 8 in BS with MDS has been reported in 87% of patients, compared to 5–7% of patients with primary MDS but without BS. Trisomy 8 with BS but without MDS has also been reported[25, 26]. From our research data, we can see that 62.5% of the cytopenia BS patients whom lacking morphological criteria in the bone marrow were not considered as patients with MDS, and 85% with trisomy 8 especially isolated trisomy 8. Although our study also compared the difference analysis between patients with chromosomal abnormalities and those without chromosomal abnormalities, no statistical difference was found, and further follow-up of these patients is needed (Supplement Table 2). Another very prominent feature is that the anemia in these cytopenia patients is macrocytic anemia, unlike microcytic hypochromic anemia caused by intestinal ulcers in BS patients. In our study, no regularity was found in the timing of cytopenia and BS, and the mutation of chromosome 8 may be closely related to it. Trisomy 8 is considered a secondary or late event in the MDS transformation process[27, 28]. The precise mechanisms underlying the tumorigenesis remain unclear, although a relationship has been observed between trisomy 8 and symptoms related to BS, both in the present study and in the literature. Isolated trisomy 8 has been discussed in some studies[29, 30]. It can be a constitutional condition as a constitutional mosaicism (cT8M) in healthy people, and it was not considered a tumor marker in certain studies. Trisomy 8 is a somatic mutation. Unlike germline mutations, somatic mutations occur throughout the lifespan, and may play a causal role in non-heritable rheumatological diseases, especially conditions that start in later life. This also explains why BS patients with trisomy 8 do not have a tendency to familial aggregation and most of them occur in older age.
Management of BS patients with cytopenia can be challenging since there is no consensus- or evidence-based guidelines in the current literature. In the present cohort, our patients have been treated according to the treatment algorithm presented in Fig. 3. As the European League Against Rheumatism (EULAR) recommendations for the management of BS, most cytopenia patients especially GI involvement who received corticosteroid combined with monoclonal anti-TNF antibodies such as infliximab or adalimumab. Twenty patients did not respond to corticosteroids and anti-TNF antibodies. Two of them were then given bone marrow transplantation and one patient was then given Chinese herbal medicine. All of these three patients achieved complete remission of GI findings and cytopenia after treatment. This is consistent with some case reports[33, 34]. However, two of the patients died after switching to azacitidine. This is different from some case reports that azacitidine is effective in these patients[35, 36]. As the follow-up time increased, we found that some patients' cytopenia and intestinal ulcers recurred and became more serious. Only 9 cytopenia BS patients improved, which shows how treatment difficulties for this particular clinical phenotype.
This study has some limitations because of its retrospective design and data from one single center, including some potential selection bias and missing data. Further, we considered that BS with cytopenia to be an independent subtype and have not done further subtyping analysis with other subtypes of BS, only analyzed the intestinal BS. Because the number of BS cytopenia patients without trisomy 8 was very small, it is necessary to compare the clinical data of the with and without trisomy 8 BS patients, so as to separate the BS cytopenia patients with trisomy 8 as a new clinical syndrome.