KANG Yin-nan, JIE You-cheng, LIU Shan-shan, WANG Jun-ke, LI Chu-yi, YU Xiao-hui?, ZHANG Jiu-cong?

1. The Second District of the Department of Gastroenterology, No. 940 Hospital, Joint Logistics Support Force of the Chinese People's Liberation Army,Lanzhou 730050, China

2. The First Clinical Medical College of Gansu University of Traditional Chinese Medicine, Lanzhou 730000, China

Keywords:SARS?CoV?2 Ulcerative colitis Biologics Immunosuppressants SARS?CoV?2 vaccine Therapy Progress

ABSTRACT Novel coronavirus (SARS?CoV?2, SARS?CoV?2 for short) infection can cause a series of gastrointestinal damage. Related studies have reported that SARS?CoV?2 infection can lead to the occurrence and progression of ulcerative colitis , which may be related to the cytokine storm caused by SARS?CoV?2 infection. Recently, we have also paid attention to whether infection with SARS?CoV?2 will aggravate the condition of UC patients receiving biological immunotherapy and whether vaccination with SARS?CoV?2 is safe and effective for these patients. At present, the interaction mechanism between SARS?CoV?2, SARS?CoV?2 vaccine and ulcerative colitis is not fully understood, and more research is needed to further clarify the relationship.

1. Introduction

Currently, the novel coronavirus disease (COVID?19) caused by SARS?CoV?2 infection has caused a huge impact on countries around the world . In addition to the lung damage caused by SARS?CoV?2 infection, COVID?19 combined with U C is also worthy of attention. At present, the treatment of ulcerative colitis (UC) aims to control the abnormal immune inflammatory response of the intestinal mucosa through glucocorticoids, immunosuppressants,biological agents, etc. At the same time, it may cause a significant increase in the risk of patients being infected with SARS?CoV?2[4]. In addition, with the widespread vaccination of SARS?CoV?2 vaccine, SARS?CoV?2 vaccine will play a key role in the prevention of this pandemic[5]. As UC patients receive long?term immunotherapy, this may have implications for SARS?CoV?2 vaccination.

UC is a chronic, idiopathic intestinal inflammatory disease of which the etiology is not yet fully understood. Its pathogenesis is thought to be caused by the abnormal immune response of the genetically susceptible host to the intestinal mucosa and intestinal flora. At present, the treatment drugs for UC mainly include immunosuppressants, tumor necrosis factor (Tumor necrosis factor, TNF) antagonists, non?TNF? targeted drugs and targeted small?molecule drugs[6]. However, studies have shown that SARS?CoV?2 infection in UC patients treated with immunosuppressants,biological agents, etc. may be a more severe form of infection[7].A large number of studies have also pointed out that patients with underlying comorbidities are at greater risk of infection with SARS?CoV?2, including UC patients receiving immunotherapy[8-9].Therefore, this article briefly reviews the research progress of SARS?CoV?2 infection and UC patients receiving immunotherapy and the safety and efficacy of SARS?CoV?2 vaccine in these patients.

2. SARS-CoV-2 infection and UC

Due to the global pandemic of SARS?CoV?2, lung damage caused by SARS?CoV?2 infection has become a general consensus[10].Angiotensin converting enzyme 2 (ACE2), as a receptor for SARS?COV?2 to invade host cells, has been found to be highly expressed in human alveolar type II epithelial cells and gastrointestinal mucosal epithelial cells[11]. Similarly, transmembrane serine protease(TMPRSS2), a molecule that interacts with ACE2, can assist SARS?CoV?2 to enter host cells by initiating the SARS?COV?2 spike protein[12], and in gastrointestinal mucosal epithelium It is also highly expressed in cells[13]. It is still unclear whether the abnormal mucosal inflammatory response of the gastrointestinal tract caused by SARS?CoV?2 infection affects the expression of ACE2 or TMPRSS2 and promotes virus entry into host cells, but there is high co?expression of ACE2 and TMPRSS2 in UC patients, Burgue?o et al[14] found that the simultaneous up?regulation of ACE2 and TMPRSS2 may facilitate viral entry into host cells , and Burke et al. [15] also found that SARS?CoV?2?induced overexpression of ACE2 promoted the progression of colonic inflammation in UC patients. However, Pal R et al[16] proposed that decreased intestinal ACE2 expression in UC patients is associated with poor prognosis in COVID?19 .

Recently Singh et al[17] found that in addition to being detected in the lungs, SARS?CoV?2 was also detected in other organs including the kidneys, gastrointestinal tract, and nervous system, suggesting that SARS?CoV?2 ?2 May invade the human body through other extrapulmonary routes . Several studies reported positive SARS?CoV?2 viral RNA in stool samples from patients with COVID?19, and colonoscopy found extensive damage to the colon in these patients, which may be related to the abnormal intestinal mucosal inflammatory response caused by SARS?CoV?2 infection[8-13]. Roy et al[18] analyzed 20,000 IBD patients and found that UC patients infected with SARS?CoV?2 may be a more severe form of infection.

3. Effects of SARS-CoV-2 on UC patients treated with biologics

The treatment of UC requires the use of immunosuppressive drugs,biological agents, and other drugs to control the intestinal abnormal immune inflammatory response[19]. However, it is unclear whether UC patients receiving biologics have an increased risk of infection with SARS ?CoV?2 and other pathogenic microorganisms[20].The Wallis[21] study found that about 40% of UC patients had an increased risk of Mycobacterium tuberculosis (MTB) infection after receiving TNF antagonist therapy. A meta?analysis by Cao[22]found that the incidence of MTB was significantly increased in CD patients following anti?TNF?α drug treatment .Anti?TNF drugs can induce Mycobacterium avium subsp. Paratuberculosis (MAP)to survive in macrophages[23]. MAP is an obligate intracellular pathogen associated with many autoimmune diseases, including RA and IBD[24]. These data explain why some patients with IBD do not respond well to anti?TNF therapy.

On the other hand, circulating ACE2 can compete with SARS?CoV?2 for binding to neutralize the virus and protect host cells. The reduction of ACE2 in the plasma of COVID?19 patients leads to a decrease in its ability to prevent the binding of SARS?CoV?2 to host cells[25] . Keewan et al[26] found that UC patients receiving anti?TNF therapy had significantly lower levels of ACE2 compared with healthy controls. This has also raised concerns about the safety of TNF antagonists. Meanwhile, anti?TNF?α therapy is associated with an increased risk of intracellular infections, including MAP and SARS?CoV?2 infection, by inducing Notch?1 signaling[25,26]. In addition, anti?TNF antibodies can affect the expression of ACE2 and at the same time promote the entry of SARS?CoV?2 into host cells through the shedding mechanism of Notch signaling[27].

Although biologics are associated with an increased risk of SARS?CoV?2 infection, they can suppress T cell hyperactivation and the cytokine storm that occurs during COVID?19[28]. The International Organization for the Study of Inflammatory Bowel Disease (IOIBD)recommends that UC patients can continue to receive anti?TNF therapy in the event of a SARS?CoV?2 pandemic, and only if they are infected with SARS?CoV?2?2 Temporarily discontinued[29].Tripathi[30] found that the use of 5?aminosalicylic acids(5?Aminosalicylic acids, 5?ASA) compounds was closely associated with adverse outcomes such as increased hospitalization and death in UC patients. In contras , the use of biological agents can reduce these adverse consequences. Burke et al.[31] showed that biologics were associated with good prognosis in patients infected with SARS?CoV?2 by reducing cytokine storm . In their study, of the 53 UC patients treated with anti?TNF, only 9 % required hospitalization and less than 1% died. Therefore, it is safe and effective to continue the use of biologics for UC patients who are in remission or in stable disease.

4. Effects of SARS-CoV-2 on immunosuppressivetreated UC patients

Immunosuppressants can significantly improve intestinal inflammation and play an important role in the treatment of UC[32] . How to treat patients safely and effectively with COVID?19 combined with UC is an urgent problem to be solved[33] , and there is still a lack of relevant guidelines and consensus on the treatment of COVID?19 combined with UC[34] . Recently, a study from the International SECURE?IBD Registry reported that the use of mesalazine was associated with poor outcomes in patients with COVID?19 and UC. Azathioprine monotherapy was associated with an increased risk of severe COVID?19 compared with TNF antagonist monotherapy, and 5?ASA was associated with a slightly increased risk of severe COVID?19[35] . Singh et al.[36] found higher rates of hospitalization and relative risk of severe COVID?19 in UC patients using 5?ASA or mesalazine. Bonfanti[37] found that infection with SARS?CoV?2 may affect the effect of immunosuppressive agents in UC patients and increase the risk of SARS?CoV?2 infection.

Norsa et al[38] tested circulating anti?SARS?CoV?2 in 90 of 103 UC patients receiving immunosuppressive agents . The investigation of IgG and/or IgM found that 19 of the patients were positive for IgG and/or IgM, indicating that most patients experienced an asymptomatic infection process. Berte[39] used ELISA to detect anti?SARS?CoV?2?specific IgG and IgA in 354 UC patients from 3 different centers and treated them with double antibodies , compared with a control population of healthy subjects, UC patients were not significantly different , and they further found that only anosmia and advanced age were independent predictors of IgG seropositivity by multivariate analysis (RR 54.5, 95% confidence interval 2.1-1434.9,P= 0.016). Data from a study in Italy showed that active disease,advanced age, and other systemic comorbidities were the main risk factors for poor prognosis in COVID?19 patients with UC, while the use of immunosuppressants was not[40]. A prospective observational study in Israel also pointed out that immunosuppressants may have a protective effect on UC patients, even against severe COVID?19.Similarly, the 52 patients in the study who received anti?TNF therapy also experienced only mild COVID?19[41].

In conclusion, the favorable results observed in UC patients receiving immunosuppressants support the potential protective effect of immunosuppressants against COVID?19, but further studies are needed to confirm.

5. The effect of SARS-CoV-2 vaccine on the efficacy and safety of UC patients receiving biological immunotherapy

SARS?CoV?2 has raised major concerns about the infection of UC patients with SARS?CoV?2 during the pandemic[42]. Vaccination against SARS?CoV?2 is considered to be the best way to contain the new coronavirus epidemic[43]. Currently, a variety of vaccines have been approved for human use, and registration studies on their safety and efficacy have shown that in healthy subjects, the SARS?CoV?2 vaccine is effective in preventing SARS?CoV?2 infection and severe complications. It is safe and effective in terms of disease[44], but there is no research data for UC patients with COVID?19 complicated by UC or receiving immunotherapy. Likewise, to date no prospective studies have reported the efficacy of SARS?CoV?2 vaccines in such patients, and only a few expert guidelines exist or published studies of SARS?CoV?2 vaccines in UC patients early in the pandemic[45-47]. Therefore, little is known about the safety, efficacy, and side effects of SARS?CoV?2 vaccine in UC patients, especially those receiving concurrent biological immunotherapy.

Borman[48] found that UC patients had attenuated immune responses to SARS?CoV?2 infection after receiving immunosuppressive/anti?TNF drugs, and SARS?CoV?2 vaccination may have adverse outcomes. Crouwel[49] also found that compared with vedolizumab, patients treated with infliximab had attenuated humoral immune responses, lower serum antibody concentrations,and lower seroconversion rates after the first vaccination with BNT162b2 or ChAdOx1. However, the immune response of UC patients depends on the type of vaccine and treatmen[50], and Hadi et al[5] indicated that non?live vaccines are safe for UC patients regardless of their treatment, although some patients receiving immunotherapy Patients may have a reduced response to the SARS?CoV?2 vaccine, but such patients are not advised to delay or stop vaccination, but to reduce the dose of immunosuppressive/ anti?TNF drugs . If the patient's condition persists or is active, SARS?CoV?2 vaccination may need to be delayed. Liu[51] indicated that UC patients can be vaccinated while receiving stable therapy with the lowest possible level of immunosuppression. Similarly, experts such as Siegel et al[52] suggested that UC patients should be vaccinated with SARS?CoV?2 as soon as possible regardless of treatment,except for live attenuated vaccines or replication?competent viral vector vaccines[53]. More recently, Weaver et al[54] indicated that vaccination against SARS?CoV?2 infected patients is safe and generally safe and effective for UC patients and can be strongly recommended. Botwin[55] conducted a longitudinal survey analysis of 246 IBD patients who received two vaccinations of BNT162b2 or mRNA?1273 vaccine, and adverse events (AEs) usually occurred on the 8th day after each dose. sky. After the first and second vaccination, the incidence of AEs was not significantly different from healthy subjects, and the incidence of AEs was higher in UC patients than in Crohn 's disease[56].

These studies suggest that in UC patients, SARS?CoV?2 mRNA vaccine is safe to receive biological immunotherapy early after vaccination. Therefore, although UC patients receiving biological immunotherapy are at risk of reduced immune response. However,these patients are still expected to gain protective immunity from vaccination[57].

6. Summary

present, SARS?CoV?2 is still spreading widely and mutating multiple times around the world, causing a serious impact on the global medical and health system. At the same time, it has had a huge impact on the course and treatment of various inflammatory diseases, including ulcerative colitis. Therefore, we urgently need to understand the impact of SARS?CoV?2 on the treatment of ulcerative colitis, especially in patients receiving biological immunotherapy.

It has been reported that UC patients who have received long?term biological immunotherapy may be more susceptible to SARS?CoV?2 infection than healthy people, but there is a need for prevention of SARS?CoV?2 infection in these patients and treatment of such patients infected with SARS?CoV?2. There are many difficulties.For example: how to balance UC patients receiving biological immunotherapy without increasing their risk of SARS?CoV?2 infection; how to adjust immunity while ensuring that patients do not suffer from severe immunosuppression while maintaining drug efficacy Dosage of inhibitors/biologics; how to address the reduced response to SARS?CoV?2 vaccine in such patients and the need for booster vaccinations. The solution of these problems requires us to further explore and study the relationship between SARS?CoV?2 and these special patients.

Conflict of Interest Statement

All authors declare no conflict of interest.

Author Contribution

Yin?Nan Kang: writing and revising the paper; You?Cheng Xie and Jun?Ke Wang: responsible for reviewing and revising the paper;Shan?Shan Liu and Chu?Yi Li: responsible for data sorting; Xiao?Hui Yu and Jiu?Cong Zhang: responsible for thesis design and topic selection, and responsible for data sorting and analysis.