DOP64 Endoscopically injected allogeneic mesenchymal stromal cells alter the mucosal immune cell compartment in patients with ulcerative proctitis

Background Local mesenchymal stromal cell (MSC)-therapy is approved for the treatment of Crohn’s disease-associated perianal fistulas. However, little is known about the working mechanism of local MSC-therapy. For the first time we evaluated engraftment and immunoregulatory effects of local MSC-therapy in patients with refractory proctitis. To do so, we analyzed biopsies and serum from patients with ulcerative proctitis before and after treatment with endoscopically injected MSCs in a phase IIa clinical trial (EudraCT number 2017-003524-75). Methods Thirteen therapy-refractory ulcerative proctitis patients were endoscopically injected bone marrow-derived allogeneic MSCs from healthy donors. Clinical efficacy was evaluated by the endoscopic and full Mayo score. Engraftment of the MSCs was investigated using fluorescence in-situ hybridization (FISH) of sex chromosomes on post-treatment biopsies. The presence of anti-HLA-antibodies against the MSC-donor was determined in the serum. Changes in immune cell subsets were evaluated using cytometry-by-time-of-flight (CyTOF) analysis. Results Thirteen patients with an endoscopic Mayo score of 2 (n=3) or 3 (n=10) of the rectum were treated with local MSC-therapy. Although complete remission was not achieved, full Mayo score was improved at week 6 (median 8 [IQR 6–10]) compared to baseline (median 11 [IQR 9.5–12]) (p=0.001). Preliminary data using FISH on the Y-chromosome, indicated the presence of MSCs in the rectum biopsies of female patients treated with male donor derived-MSCs at week 6. At baseline, HLA-antibodies were present in four patients. Six weeks after local injection of the MSCs, two out of thirteen patients developed new class I and II HLA-antibodies against the MSCs. Interestingly, in two patients pre-existing HLA-antibodies showed increased/boosted levels after local MSC-therapy, while one additionally developed new HLA-antibodies. CyTOF analysis of inflamed rectal biopsies 6 weeks after MSC treatment revealed significantly increased frequencies of several myeloid subsets (i.e. CD11b+CD14+CCR7+/-CD127+CD25+HLADR+ and CD14+HLA-DR-CD123-CCR7+) and a subset of CD4+ memory T cells with a more exhausted/regulated phenotype (PD-1+TIGIT+CD69+CD38+CD69). Conclusion Local MSC-therapy in patients with refractory proctitis changed the rectal immune profile characterised by a significant increase in a subset of effector memory CD4+ cells and several myeloid subsets, which might be associated with immune modulation. These results provide the basis for future studies on the mechanism of action of MSCs on rectal mucosa. New anti-HLA class antibodies developed in 2/13 patients after local administration. Whether these latter results have consequences for MSC-donor selection deserves further study.

P135 Proximal Extension of lower rectal Ulcerative Proctitis

Background Previous studies have shown proximal extension (PE) rate of ulcerative proctitis (UP) is approximately 50%. This rate teach us the importance of treating UP adequately. Basically, we have to treat them with topical 5-ASA. But in clinical practice, we sometimes experience the case whose inflammation remain endoscopically, even though the symptoms have been relieved. Should we strengthen our treatment at this situation, especially inflammation at lower rectum? We aimed to know PE rate of lower rectal UP and optimize the treatment. Methods We retrospectively investigated the medical charts of patients with UP from 2010 to 2020 at Kenseikai Nara Coloproctology Center. We excluded the patients with UP shrinking from left-sided or pancolitis as a result of the treatment. The cases with missing value were excluded too. Variables of interest included gender, onset age, disease location, initial mayo endoscopic subscore (MES) and treatment, and the time to PE. To compare the cohorts we used Fisher’s exact test and Mann-Whitney test. Proximal extension free survival (PEFS) was calculated using the Kaplan-Meier method. Results Sixty-five patients were recruited. Mean age was 42 years old, the ratio of males to females was 1.17. The number of lower rectal UP patients at first examination was 24. We observed MES 1 inflammation for 30 patients, and MES 2 for 35. Median follow-up duration was 73.5 months. PE occurred in 34 patients: 28 patients had left-sided colitis and 6 had pancolitis. Fifty-four patients were medicated and other 11 patients were just observed. Among the patients medicated, 23 patients were took only topical drugs, 18 were took only oral drugs and other 13 were took both. We couldn’t find any relationships between initial medication and PE rate. The multivariate analysis revealed that having peri-appendiceal red patch and lower rectal UP were reduce the risk of PE. MES was not related to PE (table 1). PEFS at 1 year, 2 year are 81%, 81% for lower rectal UP (Rb group), and 66%, 61% for the patients having the disease beyond middle Houston’s valve (Not-Rb group), though we couldn’t find significant difference (Fig.1). Among 34 patients having PE, we used biologics for only five patients and got their inflammation under control. Conclusion Patients with lower rectal UP is less likely to extent their disease location. There’s no difference between the route of treatment and PE rate, but it’s important to carefully check PE within first one year.

Mesalazine-induced Hypersensitivity Pneumonitis

A 57-year-old woman with Crohn's disease (ulcerative proctitis) treated with mesalazine (5-ASA) developed worsening respiratory distress and cough. The lack of response to antibiotics and the results of bronchoalveolar lavage led to the diagnosis of mesalazine-related hypersensitivity pneumonitis, an infrequent entity. Symptoms improved after discontinuation of mesalazine and the administration of corticosteroid therapy. The authors discuss the diagnosis and management of this rare condition.