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Background: Anti-tumour necrosis factor drugs such as infliximab are associated with attenuated antibody responses after COVID-19 vaccination It is unknown how infliximab impacts vaccine-induced serological responses against highly transmissible Omicron variants, which possess the ability to evade host immunity and are now the dominating variants causing current waves of infection Methods: In this prospective, multicentre, observational cohort study we investigated neutralising antibody responses against SARS-CoV-2 wild-type and Omicron BA.1 and BA.4/5 variants after three doses of COVID-19 vaccination in 1288 patients with IBD without prior COVID-19 infection, who were established on either infliximab (n=871) or vedolizumab (n=417). Cox proportional hazards models were constructed to investigate the risk of breakthrough infection in relation to neutralising antibody titres Results: Following three doses of COVID-19 vaccine, neutralising titre NT50 (half-inhibitory neutralising titre) was significantly diminished in patients treated with infliximab as compared to patients treated with vedolizumab, against wild-type, BA.1 and BA.4/5 variants (Fig 1). Patients with Crohn's disease showed lower antibody NT50 compared to patients with ulcerative colitis against wild-type strain and BA.4/5 (Fig 2). Older age and thiopurine were independently associated with lower NT50 against wild-type strain and BA.4/5 (Fig 2). Non-white ethnicity was associated with higher NT50 compared to white ethnicity against wild-type strain, BA.1 and BA.4/5 (Fig 2). Breakthrough infection was significantly more frequent in patients treated with infliximab compared to patients treated with vedolizumab (Fig 3). Cox proportional hazards models of time to breakthrough infection after the third dose showed infliximab treatment to be associated with a higher hazard risk (HR) of 1.71 (95% CI [1.08 to 2.71], p=0.022) compared to vedolizumab (Fig 4). Higher neutralising antibody titres against BA.4/5 were associated with a lower hazard risk and a longer time to breakthrough infection (HR 0.87 [0.79 to 0.95] p=0.0028) (Fig 4) Conclusion(s): Following a third COVID-19 vaccine dose, patients established on infliximab treatment have significantly lower neutralising titres against SARS-CoV-2, which were especially low against Omicron variants. Increased breakthrough infection in infliximab recipients was associated with lower neutralising antibody titres against BA.4/5. These data underline the importance of continued COVID-19 vaccination programs, including second-generation bivalent vaccines, especially in patient subgroups where vaccine immunogenicity and efficacy may be reduced.
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Background: Patients with Inflammatory bowel disease (IBD) receiving anti-TNF or JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the currently dominant Omicron BA.4/5 variants. Method(s): We prospectively recruited 329 adults (68 healthy controls (HC) and 261 IBD) who had received three doses of COVID-19 vaccine at nine UK centres. The IBD population was established (>12 weeks therapy) on either thiopurine (n=60), infliximab (IFX) (n=43), thiopurine and IFX combination (n=46), ustekinumab (n=43), vedolizumab (n=46) or tofacitinib (n=23). Pseudoneutralisation assays were performed and the half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARSCoV-2 neutralising response against wild-type (WT) virus and the BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, ethnicity, vaccine type and age. Result(s): Heterologous (two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both WT SARS-CoV-2 virus and the BA.4/5 variants in HCs and IBD (fig 1). Antibody titres against BA.4/5 were significantly lower than antibodies against WT virus in both groups (Geometric Mean Ratio (GMR) [95% CI], 0.11 [0.09, 0.15], P<0.0001 in healthy participants;GMR 0.07 [0.06, 0.08], P<0.0001 in IBD patients). Multivariable models showed that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in IBD patients on IFX (GMR 0.44 [0.20, 0.97], P=0.042), IFX and thiopurine combination (GMR 0.34 [0.15, 0.77], P=0.0098) or tofacitinib (GMR 0.37 [0.15, 0.92], P=0.032), but not in patients on thiopurine monotherapy, ustekinumab or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against WT and BA.4/5 (P<0.05). Conclusion(s): A third dose of COVID-19 vaccine based on the WT spike glycoprotein boosts neutralising antibody titres in patients with IBD. However, responses are lower against the currently dominant variant BA.4/5, particularly in patients taking anti-TNF or JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed IBD patients may receive additional benefit from bivalent vaccine boosters which target Omicron variants. .
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Background: Physical activity (PA) is an important component in the management of people with rheumatoid arthritis (RA) (1). Interventions incorporating Behaviour Change (BC) theory are needed to target physically inactive people with RA. The study Physiotherapist-led Intervention to Promote Physical Activity in Rheumatoid Arthritis (PIPPRA) was designed using the Behaviour Change Wheel (BCW) and a pilot study of feasibility undertaken (ClinicalTrials.gov Identifer: NCT03644160). Objectives: To obtain reliable estimates regarding recruitment rates;participant retention;protocol adherence and possible adverse events, and to producing estimates of the potential effect sizes of the BC intervention on changes in outcomes of physical activity;fatigue;disability and quality of life. Methods: Participants were recruited at University Hospital (UH) rheumatology clinics and randomly assigned to control group (physical activity information leafilet) or intervention group (four BC physiotherapy sessions in eight weeks). Inclusion criteria were diagnosis of RA (ACR/EULAR 2010 classifcation criteria), aged 18+ years and classifed as insufficiently physically active. Ethical approval was obtained from the UH research ethics committee. Participants were assessed at baseline (T0), 8-weeks (T1), and 24-weeks (T2). Descriptive statistics and t-tests were used to analyse the data with SPSS v22. Results: 320 participants were identifed through chart review with direct contact then with people meeting the inclusion criteria at rheumatology clinics. Of the clinic attendees n=183 (57%) were eligible to participate and n=58 (55%) of those consented to participate. The recruitment rate was 6.4 per month and refusal rate was 59%. Due to impact of COVID-19 on the study n=25 (43%) participants completed the study (n=11 (44%) in intervention and n=14 (56%) in control). Of the 25, n= 23 (92%) were female, mean age was 60 years (sd 11.5). Intervention group participants completed 100% of BC sessions 1 & 2, 88% session 3 and 81% session 4. No serious adverse events were reported. Secondary outcome measures data is Table 1. Conclusion: The PIPPRA study designed using the BCW to improve promote physical activity was feasible and safe. This pilot study provides a framework for larger intervention studies and based on these fndings a fully powered trial is recommended.
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Background: Physical activity is an important component in the management of people with rheumatoid arthritis (RA) [1]. A Physiotherapist-led Intervention to Promote Physical Activity in people with RA (PIPPRA) was undertaken using the Behaviour Change Wheel, with the aim of examining the feasibility of promoting physical activity in RA. This qualitative study involved participants and health care professionals who participated and were involved in a behaviour change pilot RCT intervention. Objectives: To determine, qualitatively, the acceptability of PIPPRA to participants with RA and health care professionals, in order to capture their reality. Methods: A qualitative study design of face-to-face semi-structured interviews was undertaken. The interview schedule explored the following areas: experience of the intervention;unintended consequences;experience and suitability of outcome measures used;views regarding the intervention;perceptions of behaviour change and physical activity. Interviews were transcribed verbatim by a professional transcriber. Thematic analysis was used as an analytical approach [2]. The research team searched for patterns, analysed and coded the data, and generated themes and sub-themes. Themes were reviewed by the research team to check if they worked in relation to the coded extracts and the entire data set. The COREQ checklist provided guidance throughout [3]. Results: Fourteen participants [13 female/1 male;mean age of 59 (SD 6.3);mean RA diagnosis of 8.6 (SD 6.8) years;moderate to severe disability (HAQ-DI: 1. 4 (SD 0.50)] and 8 healthcare staff [4 female/4 male;mean age of 41 (SD 5.6)] participated. Three main themes were generated from participants:-1) Positive experience of behaviour change intervention-'I found it very knowledgeable to help you get stronger';2) Improvement in self-management-'.motivate me maybe to go back to doing a little bit more exercise';3) Negative impact of COVID-19 on intervention-'I don't think doing it online again would be really good at all.' T w o main themes from health care professionals:-1) Positive learning experience of behaviour change delivery-'Really made me realise the importance of discussing physical activity with patients';2) Positive approach to recruitment-'Very professional team showing the importance of having a study member on site'. Conclusion: The fndings demonstrated that participants had a positive experience of being involved in a behaviour change intervention in order to improve their physical activity and found it acceptable as an intervention. However, if given the choice they would prefer the intervention delivery face to face rather than telehealth. Healthcare professionals also had a positive experience and in particular found it benefcial to their own development, in particular the importance of recommending PA to patients.
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Introduction Patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy exhibit attenuated humoral immune responses to vaccination against SARS-CoV-2. The gut microbiota and its functional metabolic output, which are perturbed in IBD, play an important role in shaping host immune responses. We explored whether the gut microbiota and metabolome could explain variation in anti-SARS-CoV-2 vaccination responses in immunosuppressed IBD patients. Methods Faecal and serum samples were prospectively collected from patients with IBD established on infliximab therapy (for >12 weeks) who were undergoing vaccination against SARS-CoV-2. The Roche Elecsys Anti-SARS-CoV-2 spike (S) and nucleocapsid (N) immunoassays were used to measure antibody responses following two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccine. Seroconversion was defined by a cut-off anti-S concentration of 15 U/ml, which correlated with 20% viral neutralization;anti-S antibody concentration of < 380 U/ml was indicative of poor response to vaccination. Patients with serological evidence of prior SARS-CoV-2 infection were excluded from the analysis. Faecal calprotectin measurement, 16S rRNA gene amplicon sequencing, nuclear magnetic resonance (NMR) spectroscopy and bile acid profiling with ultra-performance liquid chromatography mass spectrometry (UPLC-MS) were performed on faecal samples. Results Forty-five infliximab-treated patients were recruited (median age 40 [range 19-67];32 Crohn's disease, 13 ulcerative colitis;28 with concomitant immunomodulator therapy;six with prior infection). 14 patients (35%) had seroconverted after one dose of vaccine and 37 (95%) seroconverted after two doses. 18 patients (46%) had a poor response after two doses of vaccine. There was no association between faecal calprotectin and vaccine response (p=0.41). No differences between satisfactory and poor vaccine responders were noted in alpha or beta diversity of the gut microbiota. The faecal metabolome of satisfactory responders was enriched in the microbial metabolite trimethylamine (q=0.03). Trends were noted linking the short chain fatty acid butyrate with satisfactory response (P=0.01) and succinate with poor response (P=0.06). No significant differences in primary or secondary bile acids were found to associate with vaccine response. The butyrate-producing genus Roseburia was positively correlated with faecal butyrate abundance (q=0.03). Conclusions Our data suggest an association between gut microbiota function and variable serological response to vaccination against SARS-CoV-2 in immunocompromised patients. Microbial metabolites including trimethylamine and butyrate may be important in mitigating anti-TNF-induced attenuation of the immune response.
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Introduction The COVID-19 pandemic resulted in a forced shift to providing remote (telephone and online) consultations following disruptions to traditional in-person care. As the pandemic wanes and IBD services recover, there is a need to rebalance provision of care and align with patient preference rather than provider convenience. Better knowledge of preferences for remote versus in-person care among people with IBD, and of the factors associated with such preferences, will guide this realignment. We report the results of a large-scale, UK-wide follow-up survey of patients who had completed the COVID-19 IBD Risk Tool during the early pandemic.1 Methods Adult patients who consented for research (n=35,329) were invited by e-mail. The survey included sociodemographics, place of residence, self-reported diagnosis, drug treatments, PRO-2 symptoms, IBD-Control Questionnaire and items relating to experience of, and future preference for, mode of IBD consultations. We investigated factors associated with: 'In-person preference' for future consultations (response option: 'Never by telephone or video' versus all other options);and 'Remote preference' (response: 'Mainly by telephone or video' versus all others) in bivariate and multivariable binary logistic regression analyses, with results expressed as adjusted odds ratios (aOR) and 95% CI. Results 7,341 respondents of which 6,015 (82%) had experienced a remote IBD consultation since the first UK lockdown. Of these, 4,396 (73%) said their first experience of a remote consultation was during the pandemic. A significant minority (9.6%) would prefer to avoid future remote consultations entirely (in-person preference) whereas a quarter (24.5%) wished to have mainly remote consultations (remote preference). The following factors were associated with in-person preference (aOR [95% CI]): Older age (>50 years;1.40 [1.19-1.63]), male gender (1.31 [1.11-1.53]), less-well controlled disease (IBD-Control-8 score <13, 2.06 [1.74-2.45]), and residents of more deprived areas (Quintile 5 [most deprived];1.72 [1.31-2.25] vs Quintile 1 [least deprived]). Conversely, we found the following associations for remote preference: Younger age (<50 years;1.24 [1.12-1.39]), Ulcerative Colitis or IBD-U (1.23 [1.10-1.37]), well-controlled disease (IBD-Control-8 score 13+, 1.55 [1.38-1.73]), not having sought emergency care during the pandemic (1.21 [1.06- 1.37]) and living in least deprived areas (Quintile 1;1.29 [1.05-1.59] vs Quintile 5). Conclusions A number of sociodemographic and clinical variables predicted future consultation preference at the time of survey. These included relatively fixed characteristics (e.g. age, gender, diagnosis, and deprivation status) and more dynamic factors (e.g. current disease control). Better understanding of factors associated with patient preference can inform efforts to realign services to provide the right mix of in-person and remote provision.
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Introduction: Patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy exhibit attenuated humoral immune responses to vaccination against SARS-CoV-2. The gut microbiota and its functional metabolic output, which are perturbed in IBD, play an important role in shaping host immune responses. We explored whether the gut microbiota and metabolome could explain variation in anti-SARS-CoV-2 vaccination responses in immunosuppressed IBD patients. Methods: Faecal and serum samples were prospectively collected from patients with IBD established on infliximab therapy (for >12 weeks) who were undergoing vaccination against SARS-CoV-2. The Roche Elecsys Anti-SARS-CoV-2 spike (S) and nucleocapsid (N) immunoassays were used to measure antibody responses following two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccine. Seroconversion was defined by a cut-off anti-S concentration of 15 U/ml, which correlated with 20% viral neutralization;anti-S antibody concentration of < 380 U/ml was indicative of poor response to vaccination. Patients with serological evidence of prior SARS-CoV-2 infection were excluded from the analysis. Faecal calprotectin measurement, 16S rRNA gene amplicon sequencing, nuclear magnetic resonance (NMR) spectroscopy and bile acid profiling with ultra-performance liquid chromatography mass spectrometry (UPLC-MS) were performed on faecal samples. Results: Forty-five infliximab-treated patients were recruited (median age 40 [range 19-67];32 Crohn's disease, 13 ulcerative colitis;28 with concomitant immunomodulator therapy;six with prior infection). 14 patients (35%) had seroconverted after one dose of vaccine and 37 (95%) seroconverted after two doses. 18 patients (46%) had a poor response after two doses of vaccine. There was no association between faecal calprotectin and vaccine response (p=0.41). No differences between satisfactory and poor vaccine responders were noted in alpha or beta diversity of the gut microbiota. The faecal metabolome of satisfactory responders was enriched in the microbial metabolite trimethylamine (q=0.03). Trends were noted linking the short chain fatty acid butyrate with satisfactory response (P=0.01) and succinate with poor response (P=0.06). No significant differences in primary or secondary bile acids were found to associate with vaccine response. The butyrate-producing genus Roseburia was positively correlated with faecal butyrate abundance (q=0.03). Conclusion: Our data suggest an association between gut microbiota function and variable serological response to vaccination against SARS-CoV-2 in immunocompromised patients. Microbial metabolites including trimethylamine and butyrate may be important in mitigating anti-TNF-induced attenuation of the immune response.
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Background : Robust COVID-19 vaccine-induced antibody (Ab) responses are important for protective anti-viral immunity. Data are urgently needed to determine whether vaccineinduced immunity is impacted by commonly used immunosuppressive drug regimens in IBD. Methods: We prospectively recruited 447 adults (90 healthy controls and 357 IBD) at nine UK centres. The IBD study population was established (>12 weeks therapy) on either thiopurine monotherapy (n=78), infliximab (IFX) monotherapy (n=61), thiopurine & IFX combination therapy (n=70), ustekinumab (uste) monotherapy (n=56), vedolizumab (vedo) monotherapy (n=62) or tofacitinib (tofa) monotherapy (n=30). Participants had two doses of either ChAdOx1 nCoV-19, BNT162b2 or mRNA1273 vaccines. The primary outcome was anti-SARS-CoV-2 spike (S1 RBD) Ab concentrations, measured using the Elecsys anti- SARS-CoV-2 spike (S) Ab assay, 53-92 days after second vaccine dose, in participants without prior infection, adjusted by age & vaccine type. Secondary outcomes included proportions failing to generate protective Ab responses (defined cut-off anti-S concentration 15 U/ml, which correlated with 20% viral neutralization). Results: Geometric mean S Ab concentrations (figure 1) were lower in patients treated with IFX (153U/ml;p<0.0001), IFX and thiopurine combination (109U/mL;p<0.0001), tofa (430U/ml;p<0.0001) and uste (561U/ml;p=0.013) compared to controls (1596U/ml). No differences in S Ab concentrations were found between controls and thiopurine monotherapy-treated patients (1020U/ml;p=0.62), nor between controls and vedo-treated patients (944U/ml;p=0.69). In multivariable modelling (figure 2), lower S Ab concentrations were independently associated with IFX (FC 0.10 [95% CI 0.07-0.14], p<0.0001), tofa (0.36 [95% CI 0.19-0.69], p=0.002) and uste (0.56 [95% CI 0.31-1.00], p=0.049), but not with thiopurine (0.77 [95% CI 0.54-1.11], p=0.17) or vedo (1.01 [95% CI 0.61-1.68], p=0.96). mRNA vaccines (3.67 [95% CI 2.72-4.96], p<0.0001) and older age (0.82 [95% CI 0.73-0.91], p=0.0003) were independently associated with higher & lower S Ab concentrations respectively. Protective Ab responses were generated by all thiopurine monotherapy, vedo, tofa and healthy control participants, but not by 11% of patients on IFX monotherapy, 13% on thiopurine & IFX combination therapy and 4% on uste. Conclusions : COVID-19 vaccine-induced Ab responses are significantly reduced in patients treated with IFX, or tofa, and to a lesser extent with uste. No significant reduction was seen in vedo or thiopurine monotherapy-treated patients. Our data suggest that 3rd primary or booster vaccine doses for IBD patients might be tailored to an individual's immunosuppressive treatment. (Figure Presented) (Figure Presented)
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Background: The COVID-19 pandemic continues to pose complex problems across Europe and the world, with rising numbers of infections and the ongoing need for drastic public health interventions. This is difficult for patients with immune-mediated disorders like Inflammatory Bowel Disease (IBD), where immunosuppressive medications may affect susceptibility to serious infection. It was particularly challenging for physicians and patients during the first wave of the pandemic, when it was unclear whether anti-inflammatory flare treatment should be adapted to reduce infection risk, whilst trying to ensure symptomatic control and avoid admission to overwhelmed hospitals. Despite the development of various IBD / COVID-19 databases, the treatment adaptations and outcomes of patients experiencing IBD flares during the COVID-19 pandemic remain undefined. We aimed to compare IBD management and outcomes between pandemic and prepandemic cohorts. Methods: An observational cohort study was performed, comprising patients who contacted IBD teams for a symptom flare between March - June, 2020 in, 60 National Health Service trusts in the United Kingdom. Data were compared to a pre-pandemic cohort after propensity- matching for age and disease severity. Statistical analyses were performed using R (version, 4.1.0, Vienna, Austria). Results: In total, 3728 patients in the pandemic (n=1864) and pre-pandemic (n=1864) cohorts were included. The principal findings were reduced systemic corticosteroid prescription during the pandemic in both Crohn's disease (prednisolone: pandemic, 199/752, 26.5% vs, 263/708, 37.1%;p<0.001) and ulcerative colitis (UC) (prednisolone: pandemic, 372/1112, 33.5% vs, 470/1156, 40.7%, p<0.001), with increases in poorly bioavailable oral corticosteroids in Crohn's (pandemic, 117/752, 15.6% vs, 48/708, 6.8%;p<0.001) and UC (pandemic, 131/1112, 11.8% vs, 60/1156, 5.2%;p<0.001). Ustekinumab (Crohn's and UC) and vedolizumab (UC) treatment also significantly increased during the pandemic. Three-month steroid-free remission was similar in both Crohn's (pandemic, 175/616, 28.4% vs, 195/608, 32.1%;p=0.17) and UC (pandemic, 312/858, 36.4% vs, 404/1006, 40.2%;p=0.095). The, 65 patients experiencing a flare and COVID-19 were more likely to have moderate-to-severely active disease at three months compared to those with a flare alone. Conclusion: Despite several treatment adaptations during the pandemic, steroid-free outcomes were comparable to pre-pandemic levels, though patients with a flare and COVID-19 experienced worse outcomes. These findings have implications for IBD management during future waves or pandemics.
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Background: Antibody responses following SARS-CoV-2 infection or a single-dose of SARS-CoV-2 vaccine are impaired in patients with inflammatory bowel disease treated with anti-TNF compared to those treated with vedolizumab, a gut-selective anti-integrin α4β7 monoclonal antibody. Here we sought to determine if patients treated with infliximab have attenuated serological and T cell responses and an increased risk of breakthrough COVID-19 infection following primary SARS-CoV-2 vaccination. Methods: Anti-spike (S) receptor binding domain (RBD) antibody concentration in 2306 infliximab-treated patients were compared to a cohort of 1045 vedolizumab-treated patients. Our primary outcome was anti-S RBD antibodies 2 to 10 weeks after a second dose of the BNT162b2 or ChAdOx1 nCoV-19 vaccines. Secondary outcomes were anti-spike T cell responses, durability of vaccine responses and risk of breakthrough infections following two doses of vaccine. Results: Anti-S RBD antibody concentrations were lower in patients treated with infliximab than in those treated with vedolizumab, following a second dose of BNT162b2 (567.3 U/mL [6.1] vs 4601.1 U/ mL [5.3], p <0.0001) and ChAdOx1 nCoV-19 (183.9 U/mL [5.0] vs 789.4 U/mL [3.5], p <0.0001) vaccines (Fig. 1). Vaccination with the BNT162b2 vaccine compared to the ChAdOx1 nCoV-19 was independently associated with a 3.7-fold [95% CI 3.30 - 4.13] higher anti-S RBD antibody concentration (p < 0.0001) (Fig. 2). There were no significant differences in the magnitude of anti-spike T cell responses observed in infliximab- compared with vedolizumabtreated patients after one or two doses of either vaccine. Antibody half-life was shorter in infliximab- than vedolizumabtreated patients following two-doses of BNT162b2 (4.0 weeks [95% CI 3.8 - 4.1] vs 7.2 weeks [95% CI 6.8 - 7.6]) and ChAdOx1 nCoV- 19 (5.3 weeks [95% CI 5.1 - 5.5] vs 9.3 weeks [95% CI 8.5 - 10.2], p value < 0.0001). Breakthrough SARS-CoV-2 infections were more frequent (5.8% (202/3467) vs 3.9% (66/1691), p = 0.0032) and the time to breakthrough shorter in patients treated with infliximab than vedolizumab (p = 0.0023) (Fig. 3). Higher anti-S RBD antibody concentrations following a second dose of SARS-CoV-2 vaccine protected against breakthrough SARS-CoV-2 infection: overall, for every 10-fold rise in anti-S RBD antibody level we observed a 0.8-fold reduction in odds of breakthrough infection ([95% CI 0.70 - 0.99], p = 0.035). Conclusion: Infliximab was associated with attenuated, less durable vaccine induced anti-S RBD antibody responses and a 50% increase in breakthrough SARS-CoV-2 infection. Further follow-up is required to assess whether third primary doses can mitigate the effects of infliximab on anti-S RBD antibody responses.
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Background: Robust COVID-19 vaccine-induced antibody (Ab) responses are important for protective anti-viral immunity. Data are urgently needed to determine whether vaccine-induced immunity is impacted by commonly used immunosuppressive drug regimens in IBD. Methods: We prospectively recruited 447 adults (90 healthy controls and 357 IBD) at nine UK centres. The IBD study population was established (>12 weeks therapy) on either thiopurine monotherapy (n=78), infliximab (IFX) monotherapy (n=61), thiopurine & IFX combination therapy (n=70), ustekinumab (uste) monotherapy (n=56), vedolizumab (vedo) monotherapy (n=62) or tofacitinib (tofa) monotherapy (n=30). Participants had two doses of either ChAdOx1 nCoV-19, BNT162b2 or mRNA1273 vaccines. The primary outcome was anti-SARS-CoV-2 spike (S1 RBD) Ab concentrations, measured using the Elecsys anti- SARS-CoV-2 spike (S) Ab assay, 53-92 days after second vaccine dose, in participants without prior infection, adjusted by age & vaccine type. Secondary outcomes included proportions failing to generate protective Ab responses (defined cut-off anti-S concentration 15 U/mL, which correlated with 20% viral neutralization). Results: Geometric mean S Ab concentrations (figure 1) were lower in patients treated with IFX (153U/mL;p<0.0001), IFX and thiopurine combination (109U/mL;p<0.0001), tofa (430U/mL;p<0.0001) and uste (561U/mL;p=0.013) compared to controls (1596U/ml). No differences in S Ab concentrations were found between controls and thiopurine monotherapy- treated patients (1020U/mL;p=0.62), nor between controls and vedo-treated patients (944 U/mL;p=0.69). In multivariable modelling (figure 2), lower S Ab concentrations were independently associated with IFX (FC 0.10 [95% CI 0.07-0.14], p<0.0001), tofa (0.36 [95% CI 0.19-0.69], p=0.002) and uste (0.56 [95% CI 0.31-1.00], p=0.049), but not with thiopurine (0.77 [95% CI 0.54-1.11], p=0.17) or vedo (1.01 [95% CI 0.61-1.68], p=0.96). mRNA vaccines (3.67 [95% CI 2.72- 4.96], p<0.0001) and older age (0.82 [95% CI 0.73-0.91], p=0.0003) were independently associated with higher & lower S Ab concentrations respectively. Protective Ab responses were generated by all thiopurine monotherapy, vedo, tofa and healthy control participants, but not by 11% of patients on IFX monotherapy, 13% on thiopurine & IFX combination therapy and 4% on uste. Conclusion: COVID-19 vaccine-induced Ab responses are significantly reduced in patients treated with IFX, or tofa, and to a lesser extent with uste. No significant reduction was seen in vedo or thiopurine monotherapy-treated patients. Our data suggest that 3rd primary or booster vaccine doses for IBD patients might be tailored to an individual's immunosuppressive treatment.
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Background: Surveillance Epidemiology of Coronavirus Under Research Exclusion for Inflammatory Bowel Disease (SECURE-IBD) is an international database that monitors COVID-19 outcomes in IBD patients. We examined the influence of IBD disease activity on COVID-19 severity, while accounting for confounders and exploring the modifying effect of age. Methods: This was a retrospective analysis of all cases reported to SECURE-IBD with complete Physician Global Assessment (PGA) of IBD activity and age data (N=3028). PGA was categorized as remission/mild (reference) vs moderate vs severe. Outcomes used as surrogates of severe SARS-CoV2 infection were hospitalization and a composite of ICU/ ventilation/death. We compared cohort characteristics across PGA categories using the Chisquare and Kruskal-Wallis test. Using logistic regression, we determined the unadjusted association between disease activity and COVID-19 outcomes, overall and by age decade. Multivariable logistic regression models included PGA, age, sex, IBD type, comorbidities (0, 1, ≥2) and systemic corticosteroids (CS) a priori and additional confounders if they changed the estimate by ≥10% (we tested BMI, race, and medications). Risk estimates were expressed as crude and adjusted odds ratios (OR) with 95% CI. We also built models stratified by age (≤50 vs >50 years). Results: Race, IBD type, BMI and current medications (CS, anti-TNF, thiopurine monotherapy, aminosalicylates, ustekinumab and tofacitinib) differed across PGA categories (p<0.05). COVID-19 was more severe in patients with more active IBD: hospitalization rates 19% (remission/mild), 26% (moderate) and 45% (severe);ICU/ventilation/death rates 5% (remission/ mild), 6% (moderate) and 12% (severe) (p<0.05 for both outcomes). In unadjusted analyses, higher PGA was associated with an increased risk of hospitalization (moderate: OR 1.52, 95% CI 1.21-1.92;severe: OR 3.57, 95% CI 2.56-4.98) and ICU/ventilation/death (moderate: OR 1.40, 95% CI 0.94-2.10;severe: OR 2.72, 95% CI 1.63-4.55). Figure 1 illustrates the OR for hospitalization and ICU/ventilation/death for severe PGA vs remission/ mild by decade;effect sizes are greatest in patients ≤50 years. In multivariable analyses, PGA remained significantly associated with hospitalization, but not ICU/ventilation/death (effect lost after adjusting for CS) (Table 1). However, in analyses stratified by age, PGA remained significantly associated with both hospitalization and ICU/ventilation/death, even after adjusting for medications, in patients ≤50 but not >50 years (Table 1).Conclusions: The association between IBD activity and severe COVID-19 varied with age. The association was stronger in younger patients and, after adjusting for the confounding effect of medications, particularly CS, disease activity was significantly associated with severe outcomes only in younger (≤50 years) patients.(Figure Presented)Odds Ratios for A) hospitalization and B) ICU/ventilation/death for severe PGA vs remission/mild by decade (Table Presented)Adjusted Odds Ratios for Hospitalization and ICU/ventilation/death by Disease Activity, Overall and Stratified by Age
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Background During the first wave of the coronavirus (COVID-19) pandemic, restrictive public health measures including prolonged shielding, were recommended by the United Kingdom government for many patients with immune-mediated inflammatory disorders treated with immunosuppressive and biologic drugs. Low-volume intracapillary blood sampling can be undertaken by patients at home and returned by post and may ensure access to therapeutic drug monitoring (TDM) for all patients irrespective of shielding status. Methods We undertook a cross-sectional blood sampling methods comparison study to assess the clinical validity and acceptability to patients of low volume intracapillary testing for serum TDM enzyme-linked immunosorbent assays (ELISA) compared to conventional venepuncture. Sample types were compared using linear regression and fit-for-purpose equivalence was defined using total allowable error (TEa) rates derived using interassay coefficient of variations from routine clinical practice. Acceptability was assessed using a purpose-designed questionnaire. Results The median (IQR) volume of serum obtained using intracapillary sampling was 195μL (130 - 210). We showed drug level equivalence (slope [95% CI]: TEa vs observed mean % difference) between intracapillary sampling and conventional venepuncture for adalimumab (1.02 [0.90 - 1.14]: 11.7% vs 2.1%) (Figure 1), infliximab (1.08 [0.98 - 1.18]: 18.3% vs 1.2%), vedolizumab (0.91 [0.85 - 0.96]: 17.6% vs 4.1%), and ustekinumab (0.92 [0.90 - 0.94]: 19.4% vs 3.3%). Anti-drug antibody equivalence was observed for antiadalimumab (0.96 [0.95 - 0.98]: 24.5% vs 2.1%) and anti-infliximab (0.89 [0.81 - 0.97]: 17.3% vs 1.3%) antibody levels. Most patients reported that intracapillary testing was easy, convenient, and that they preferred it to conventional venepuncture (Figure 2). Conclusions Low-volume intracapillary blood sampling was equivalent to conventional venepuncture for the measurement of biologic drug and anti-drug antibodies. Patients preferred intra-capillary testing to conventional venepuncture. Irrespective of future COVID-19 surges, patient-led intracapillary blood sampling is likely to become a key adjunct to telemedicine in patients with immune-mediated inflammatory diseases.(Figure Presented) Adalimumab drug Linear regression and Bland Altman plot Left: Linear regression analysis of venous vs capillary adalimumab drug level results (mg/L), Slope 1.02 [0.90 - 1.14]. Right: Bland Altman plot of mean of venous and capillary adalimumab drug measurement against percentage difference between TEa vs observed mean % difference.(Figure Presented) Figure 2: Questionnaire acceptability response data Patient acceptability questionnaire response results by 5-point Likert scale. (A) Itemised proportional responses, grouped by domain. (B) Cumulative agreement per respondent;+1/+2 points for agree/strongly agree, 0 for neither agree nor disagree, -1/-2 for disagree/strongly disagree. Lowest decile reflecting participants with lowest acceptability scores indicated.
ABSTRACT
Introduction The first wave of the COVID-19 pandemic saw a sharp rise in UK cases during March 2020. We analysed UK IBD Registry data to investigate changes in contacts and prescribing in the immediate post-COVID period to gain insights into the impact of the pandemic on IBD care. Methods We aggregated quarterly data (Jan-Mar 2019 to Apr- Jun 2020), extracting counts of clinical events (outpatient contacts and biologics reviews), contact types (face-to-face, 'F2F';or telephone/virtual, 'non-F2F'), new diagnoses and drug starts (oral steroids, further categorised as prednisolone and non- prednisolone;thiopurines;biologics). Rates are expressed as counts per 1,000 clinical events. Results Comparing Apr-Jun 2020 (post-COVID) to Apr-Jun 2019 (pre-COVID): Total clinical event fell (9975 to 8208;- 18%), with a sharp drop in F2F OPD (3436 to 1203;-65%) accompanied by a compensatory rise in non-F2F (1777 to 3161;+78%). Rate of new diagnoses fell (49 to 13 per 1,000 events;-74%). Prescription rates reduced sharply for thiopurines (26 to 5;-81%), with lesser reductions for biologics (89 to 55;-38%) and oral prednisolone (25 vs 20;-20%) but with a rise for non-prednisolone steroids (5 vs 8;+60%). No change in relative proportion of different biologic classes. Conclusions Records of patient contacts were reduced in the immediate post-COVID period with a rapid shift from F2F to non-F2F. The drop in new patient records may reflect delayed pathways. Prescribing trends suggest a selective reduction in thiopurine and some shift from systemic to more topically-acting steroids. Longer term trends will be presented.
ABSTRACT
Background : Low platelets and fibrinogen levels at term are associated with pre-ecplampsia and abruption of placenta whilst congenital hypofibrogenemia in pregnancy is extremely rare, all have potential significant haemorrhagic consequences. We present a case of antepartum haemorrhage (APH), hypofibrinogenemia and thrombocytopenia on a background of a COVID-19 diagnosis. Aims : A 26 y, G3 P0 +2 miscarriages presented at 36 weeks with APH of 500 ml and positive PCR for Covid-19. She had an epidural sited for labour analgesia, her subsequent blood tests revealed thrombocytopenia (87) and a hypofibrogenemia of 0.5 g/dl despite normal platelets 12 weeks prior. She had an uneventful emergency caesarean necessitated by foetal compromise in labour (working diagnosis of placental abruption), 2 units of cryoprecipitate was transfused, blood loss was 600 ml and no abruption found. We monitored her for neurological recovery from the epidural block and delayed removal of epidural catheter until her post-partum fibrinogen was 1.5 g/dl and platelets 112 after discussion with haematology. She and her baby were discharged uneventfully on day two. Methods : The cause for this patient's severe hypofibrogenemia and associated thrombocytopenia was unclear at the time. Results : A normal platelet count earlier in her pregnancy suggests an acute or pregnancy related process. Pre-eclampsia and placental abruption were ruled out at c-section. Conclusions : Coagulopathy associated with Coivd-19 remains a real possibility as our knowledge continues to evolve and expand, this has large implications for obstetric anaesthetic practice given that the status quo is to default to neuroaxial blockade to avoid intubation, the presenting APH is likely secondary to the COVID driven coagulopathy despite mild symptoms. In addition to measurement of platelets, routine measurement of PT, APTTR and fibrinogen levels should be routinely considered in all pregnant women with Covid-19 per the ISTH guidance to help in differential diagnosis, guide admission to hospital/intensive care and need for obstetric intervention.