ANTI-TNF THERAPY for IMMUNE MEDIATED INFLAMMATORY DISEASES MAY BE ASSOCIATED with LOWER ANTIBODY LEVELS and VIRUS NEUTRALIZATION EFFICACY FOLLOWING SARS-COV-2 MRNA VACCINATION

Background: The impact of immunosuppressants on COVID-19 vaccination response and durability in patients with immune-mediated infammatory diseases (IMID) is yet to be fully characterized. Humoral response may be attenuated in these patients especially those on B cell depleting therapy and higher doses of corticosteroids, but data regarding other immunosuppressants are scarce. Objectives: We aimed to investigate antibody and T cell responses and durability to SARS-CoV-2 mRNA vaccines (BNT162b and/or mRNA 1273) in IMID patients on immunomodulatory maintenance therapy other than B-cell depleting therapy and corticosteroids. Methods: This prospective observational cohort study examined the immuno-genicity of SARS-CoV-2 mRNA vaccines in adult patients with IMIDs (psoriatic arthritis, psoriasis, infammatory bowel disease and rheumatoid arthritis) with or without maintenance immunosuppressive therapies (anti-TNF, methotrexate/azathioprine [MTX/AZA], anti-TNF + MTX/AZA, anti IL12/23, anti-IL-17, anti-IL23) compared to healthy controls. Automated ELISA for IgGs to spike trimer, spike receptor binding domain (RBD) and the nucleocapsid (NP) and T-cell release of 9 cytokines (IFNg, IL2, IL4, IL17A, TNF) and cytotoxic molecules (sFasL, GzmA, GzmB, Perforinin) in cell culture supernatants following stimulation with spike or NP peptide arrays were conducted at 4 time points: T1=pre vaccination, T2=me-dian 26 days after dose 1, T3=median 16 days after dose 2 and T4=median 106 days after dose 2. Neutralization assays against four SARS-CoV-2 variants (wild type, delta, beta and gamma) were conducted at T3. Results: We followed 150 subjects: 26 healthy controls and 124 IMID patients: 9 untreated, 44 on anti-TNF, 16 on anti-TNF with MTX/AZA, 10 on anti-IL23, 28 on anti-IL12/23, 9 on anti-IL17, 8 on MTX/AZA (Table 1). Most patients mounted antibody and T cell responses with increases from dose 1 to dose 2 (100% sero-conversion at T3) and some decline by T4, with variability within groups. Antibody levels and neutralization efficacy was lower in anti-TNFgroups (anti-TNF, anti-TNF + MTX/AZA) compared to controls and waned by T4 (Figure 1). T cell responses were not consistently different between groups. Pooled data showed a higher antibody response to mRNA-1273 compared to BNT162b. Conclusion: Following 2 doses of mRNA vaccination there is 100% seroconver-sion in IMID patients on maintenance therapy. Antibody levels and neutralization efficacy in anti-TNF group are lower than controls, and wane substantially by 3 months after dose 2. These fndings highlight the need for third dose in patients undergoing treatment with anti-TNF therapy and continued monitoring of immunity in these patient groups, taking into consideration newer variants and additional vaccine doses.

IMMUNE RESPONSE AFTER COVID-19 VACCINATION DURING MAINTANACE THERAPY IN IMMUNE-MEDIATED INFLAMMATORY DISEASES: AN OBSERVATIONAL COHORT STUDY

BACKGROUND Little is known about the impact of immunosuppressants on COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMID). Although humoral response may be attenuated in patients using immunomodulators (IMM) and TNFinhibitors (anti-TNF), data regarding cellular response are scarce and conflicting. This study was aimed to identify immune response to COVID-19 vaccination in IMID patients. METHODS A prospective observational multicentre cohort study was conducted to examine the immunogenicity of mRNA vaccines to SARS-CoV-2 in adult IMID patients using immunosuppressive therapy (anti-TNF, IMM, anti-TNF+IMM, anti-IL12/23, anti-IL-17, anti-IL-23) or no therapy as compared to healthy controls (HC). Patient details and vaccination history were recorded. Blood samples were drawn at 3 time points: before, 3-4 weeks after first and 2 weeks after second vaccination. Humoral immune response to S and RBD proteins were assessed by ELISA. Neutralization was tested against 4 variants of SARS-CoV-2 by surrogate neutralization ELISA. Cellular immune responses were determined based on analysis of 9 secreted cytokines and cytotoxic molecules after stimulation of PBMC with S peptide pools. Response to N protein was used to assess SARS-CoV-2 exposure. RESULTS A total of 159 subjects (133 IMID patients and 26 HC) were included in this study (median age 42 years [IQR 30-53], 52% male). Of 133 IMID patients, 87 had inflammatory bowel disease, 23 psoriatic arthritis, 18 psoriasis, 11 ankylosing spondylarthritis and 4 rheumatoid arthritis. Of these, 44 used anti-TNF, 9 IMM, 18 anti-TNF+IMM, 33 anti-IL-12/23, 9 anti-IL-17, 10 anti-IL-23 therapy and 10 no therapy. All subjects received 2 doses of mRNA vaccines (2x Pfizer, 2x Moderna or mixed) between December 2020 and September 2021. The vast majority of subjects had minimal binding antibody and T cell responses to N, indicating they were COVID-19 naïve. After dose 1, anti-TNF group had lower IL-2 vs untreated IMID (p<0.01), and the anti-IL-23 group had lower IFN-g vs HC (p<0.01), though there was wide variation in responses within groups. Following dose 2, median responses between groups were mostly similar, but antibody responses were significantly lower in patients on anti-TNF as compared to HC in subjects that received two doses of Pfizer (p=0.01). Pooled data for all subjects combined show a higher response to Moderna over Pfizer in ELISA, neutralization and T cell readouts, and a lower response for those over 60 years of age after dose 2. Longer follow-up is in process to monitor the durability of these responses over time and after third dose. CONCLUSION Immune responses after 2 doses of mRNA vaccines in immunocompromised IMID patients largely reach the level of that of HC albeit antibody responses in the anti-TNF group are weaker and with wide variability between subjects within some groups

Health-related quality of life, optimism and self-efficacy among people with CF beginning triple combination therapy

Background: With FDA approval in October 2019 of elexacaftor/ tezacaftor/ivacaftor, a CFTR modulator triple combination therapy (TCT), approximately 85% of the CF population was eligible to initiate this treatment. Clinical trial data indicates numerous improvements in physical health and health-related quality of life (HRQoL). Real-world studies of treatment initiation recommend including mental health as an outcome meaure, not reported in clinical trials. Objective: To describe the QoL and mental health outcomes of people with CF (pwCF) initiating TCT in a real-world setting. Methods: This longitudinal study enrolled pwCF 14 years and older who are followed at a large, combined pediatric and adult CF center. Data will be obtained at the following timepoints: within 6 months of initiating TCT (baseline), and then at 3, 6, and 12 months after baseline. Study self-report measures evaluate: HRQoL (CFQ-R), optimism, perceived social stigma of illness, self-efficacy, medication-related beliefs, and body image. Four open-ended questions were included to elicit qualitative data on experiences starting TCT. Data from the baseline survey are reported here. Results: Sixty-five adults and adolescents with CF completed the full set of surveys at baseline. Mean participant age was 30.2 years (SD= 14.0). Among this group, 57% identified as female, 42% as male, and 2% as nonbinary. With respect to education, 20.8% completed high school or less, 23.6% completed some college, and 45.9% completed college or above. As compared to a large 2010 US sample (Quittner, et al), participants reported higher Physical functioning (t=3.0;p<0.01), lower Emotional functioning (t=-6.7;p<0.001), and lower Social functioning (t=-2.1;p<0.05) on the CFQ-R measure of HRQoL. In terms of mental health, participants reported a mean score of 15.6 (SD= 5.7) on the LOT-R Optimism scale, falling in the Moderate optimism range. Participants had a mean score of 32.4 (SD= 4.3) on the General Self-Efficacy Scale measure, representing a t-score of 56 (73rd percentile). Open-ended questions revealed that patients' expectations regarding initiating TCT ranged from skepticism, to cautious optimism, to high expectations for life-changing results. Common hopes for TCT included reduction in treatment burden and increased quality of life, while collective fears included ineffectiveness and negative side effects. Many patients identified a change in future planning in response to starting TCT, namely increased hope and ambition. Conclusion: On average, pwCF in our sample who were starting TCT reported feeling moderate optimism and self-efficacy. They reported better physical functioning, but worse emotional and social functioning, than a 2010 sample. Whether these differences in HRQoL are due to TCT, COVID-19, or other factors requires further study. Open-ended questions elicited a mixture of positive and negative feelings related to starting TCT. Future analyses for this study include evaluation of key outcomes from the 3-month follow-up timepoint, including data on the mental health impact of COVID-19. Future directions include longitudinal analyses of the impact of TCT on HRQoL and mental health.

Improving mental health screening at a large cystic fibrosis center

Background: People with cystic fibrosis (CF) are 2-3 times more likely to experience depression, anxiety, or both. Untreated depression and anxiety can affect both physical and emotional health. Left untreated, people with CF are less likely to manage their treatment plans effectively, have worse lung function, have a lower BMI, and experience more hospitalizations. At Boston Children's Hospital/Brigham and Women's Hospital combined pediatric and adult CF center, we have 598 patients total (274 in the pediatric program and 324 in the adult program). 79% of our patients are over 12 and eligible for depression and anxiety screening. Our pediatric care team consists of 15 MDs/NPs and 2 social workers. Our adult care team consists of 7 MDs/NPs and 1 social worker. There is 1 psychologist that sees both pediatric and adult patients. Objectives: (1) To streamline mental health screening process, (2) improve mental health screening rates for our CF pediatric and adult populations, and (3) identify patients who need further mental health services. Methods: To ensure we address mental health, we developed a new process for distributing the PHQ-9 assessment tool for depression and GAD-7 assessment tool for anxiety. We implemented a screening note template into our electronic medical record for better documentation of completed screens and began including mental health screens as a part of the weekly pre-visit planning amongst clinicians, nurses, and social workers. We refined the process to allow for our clinic administrators to hand out the assessments to patients at check-in and nursing assisted in collecting the screens and responding appropriately depending on the score. Results: Our average mental health screening rate in 2018 was 46% for the pediatric program and 71% for the adult program. After implementing our new process in 2019, our screening rates increased to 71% for the pediatric program and 83% for the adult program. With increased rates of screening, we did not observe a significant difference in the percentage of patients screening at-risk. A majority of patients scored in the minimal-mild range on both the PHQ-9 and GAD-7. On the PHQ-9, 8% scored in the moderate range (vs 7% in 2018) and 2% scored in the severe range (vs 2% in 2018). On the GAD-7, 10% scored in the moderate range (vs 9% in 2018) and 3% scored in the severe range (vs 6% in 2018). On question #9, 98% indicated “not at all” (vs 96% in 2018). Conclusion: Our mental health screening process has become an embedded part of our CF clinic flow. Our process has led to sustained increases in mental health screening rates. Future work will focus on follow-up on mental health treatment referrals. In addition, with the rapid shift to telehealth due to COVID, we are adapting our process to account for telehealth visits.

The role of miR-193B-5P in virus induced ARDS

Introduction: The avian influenza virus (IAV) commonly cause acute respiratory distress syndrome (ARDS), shock and death. Unlike the current coronavirus outbreak, IAV does not grab the same level of public attention, although its clinical implications remain dire. As of 2019, a recorded 10,000 patients have died and 180,000 were hospitalized according to CDC. ARDS leads to a surge in the use of mechanical ventilators for life support. Host-derived cellular microRNAs (miRs) play a critical role in ARDS dependent lung injury, alveolar-capillary membrane integrity, and host responses to viral infections. We hypothesize that increased miR193b-5p upon IAV infection, downregulates occludin expression, and is associated with increased inflammation and injury in experimental models of pneumonia. Methods: Wild type mice (C57Bl/6J, 10 -14 weeks) were randomized to infection with H1N1 virus (A/PR/8/34) treated a miR193b-5p inhibitor (INH) versus placebo delivered on day 4 post-infection. On day 8, lung injury was assessed using histology, bronchoalveolar lavage fluid cell counts and differential, membrane permeability, and viral load. In vitro, Beas2b cells were infected with H1N1 and treated with or without miR- 193b-5p inhibitor (INH) or mimic, and occludin was knocked down. Transcript expression levels were determined by qRT-PCR. Beas2b cells were treated with IFNb and qRT-PCR and digital droplet PCR was used to assess targets. Results: Intranasal infection of IAV increased pulmonary inflammation, lung edema, increased levels of miR193b-5p (20- fold) and decreased expression of occludin (>50%) that peak at day 5 days post-infection. Reporter construct demonstrates miR-193b-5p binds specifically to the 3'UTR of occludin. Inhibition of miR193b- 5p mitigates H1N1-induced lung injury, edema formation, viral load, and anti-viral Interferon b (IFNb) and Interferon Regulated Genes expression. In vitro, silencing of occludin results in increased viral load and dysregulation of the host antiviral response. miR193b-5p is IFNb responsive confirmed by qRT-PCR and ddPCR. Conclusions: We demonstrate the role of miR193b-5p in barrier function, viral infection and host anti-viral responses in a murine model of H1N1. IFNb, a natural host antiviral response, promotes miR193b upregulation. The upregulation of miR-193b-5p downregulates occludin. And the inhibition of miR-193b-5p results in decreased lung injury, inflammation, and viral load.