Immunosuppression plays a crucial role in KS pathogenesis by stimulating HHV-8 proliferation and, in turn, proto-oncogene expression [
1‐
3]. In most cases, iatrogenic KS appears in kidney-transplanted patients. However, it has also been reported in chronic inflammatory conditions that require immunosuppressive therapies for a long period such as UC [
4‐
20] and CD [
21‐
24]. In this scenario, the anti-TNF-α agents, the anti-integrin agent VDZ and, recently, the anti-interleukin (IL)-12/23 ustekinumab have been added to the IBD therapeutic armamentarium, which already included steroids and the traditional immunosuppressants (i.e., azathioprine, methotrexate, and cyclosporine). All these biologics, as easily predictable, carry out a variable increased risk of opportunistic infection. Overall, 21 cases of KS in HIV-negative patients with IBD are reported. Most of them are adult males with UC refractory to medical therapy, who assumed steroids and/or traditional immunosuppressants at the time of diagnosis and did not show any cutaneous lesions (Table
1). However, in the last years, some cases of KS have been reported in patients treated with IFX and, as far as we know, the present case is the first associated to the administration of the humanized monoclonal antibody VDZ. Indeed, herein we report an HHV-8-associated colonic KS in a patient with UC treated for 8 months with VDZ. Although we cannot rule out the role of previous treatments with steroids and especially with IFX to which the patient had previously undergone in promote the reactivation of HHV-8.
Table 1Characteristics of HIV-negative patients with inflammatory bowel disease (IBD) and intestinal Kaposi’s sarcoma (KS)
| M | 49 | UC | 2 | CS/AZA/CYCL/IFX | + | – | + |
| M | 65 | UC | 15 | CS/MTX | + | + | + |
| M | 63 | UC | < 1 | CS | + | – | – |
| M | 70 | UC | 4 | CS/IFX (1 infusion) | + | – | + |
| M | 30 | UC | 2 | CS/AZA/IFX | + | – | + |
| M | 49 | UC | 5 | CS | – | + | + |
| M | 48 | UC | 25 | CS/AZA | + | – | + |
| M | 58 | UC | NA | CS | NA | – | – |
| M | 43 | UC | < 1 | CS/CYCL | + | – | + |
| M | 42 | UC | 13 | CS/AZA | – | + | – |
Thompson (1989) | M | 23 | UC | 1 | CS | NA | – | + |
| M | 62 | UC | 30 | CS/AZA | + | – | + |
| M | 68 | UC | 8 | CS | NA | – | + |
| M | 83 | UC | < 1 | CS | NA | + | + |
| M | 35 | UC | 2 | CS/AZA | NA | – | NA |
| M | 53 | UC | < 1 | CS/AZA | + | – | + |
| M | 49 | UC | NA | CS/AZA | + | – | + |
| | | CD | | CS | NA | + | + |
| F | 36 | CD | NA | CS/AZA | NA | – | – |
| F | 67 | CD | 25 | CS | NA | – | + |
| M | 21 | CD | 1 | CS/IFX | – | – | + |
VDZ selectively targets the α4-β7 integrin that binds to mucosal addressin-cell adhesion molecule-1 (MadCAM-1) to mediate T cell homing to the lamina propria of the small intestine [
25,
26]. VDZ has been approved for the treatment of moderately to severely active UC and CD in adults who failed to respond to at least one conventional drug. Differently from the other available anti-integrin agent Natalizumab (approved in the United States and Europe as monotherapy for multiple sclerosis and only available through a specific risk-minimization program), VDZ selectively acts at intestinal level in order to avoid the risk of progressive multifocal leukoencephalopathy (PME) that due to the reactivation of JC polyomavirus (JCV) [
27]. A recent systematic review on VDZ safety profile included data not only from registration studies but also from real life experiences and concluded that overall data are insufficient to draw definitive conclusions about the risk of malignancy linked to VDZ. Indeed, a reduction in immuno-surveillance, as a consequence of leucocyte trafficking inhibition, represents a theoretical concern for gastrointestinal malignancies [
26]. In the future, we will definitely assess an increasing number of IBD patients treated in sequence with different biological and immunosuppressive drugs (as in this case-report). Thus, the number of neoplasms, such as KS, linked to a state of immunosuppression that allows a reactivation of latent oncogenic viruses together with a reduced local immuno-surveillance will probably become a more frequent problem. Luckily, all cases of KS occurred in HIV-negative IBD patients, resolved with the discontinuation of immunosuppressive therapy and with colectomy or resection of the affected intestinal tract. In conclusion, this and the other cases described should alert clinicians regarding the possibility of the occurrence of colonic KS in patients with IBD (particularly UC) refractory to medical therapy and who have been treated for a long-time with several immunosuppressive and biological drugs. For the first time we described a case of VDZ-associated colonic KS. VDZ thanks to its specificity of action at the intestinal level may cause the reactivation of latent HHV-8 infection with a consequent initiation of the oncogenic processes that can lead to the onset of KS. Unfortunately, at the moment we do not have reliable tests to identify patients at increased risk of developing KS (there are few data on the usefulness of a specific PCR for the detection of HHV-8 in the blood) that should be recommended for early surgery rather than other rescue therapy. Therefore, further studies are necessary to identify early risk markers of intestinal KS. In the meantime, careful monitoring is required.