INTAKE OF ACETAMINOPHEN SUPPRESSES ANTIVIRAL HUMORAL IMMUNE RESPONSES IN PATIENTS WITH RA FOLLOWING VACCINATION WITH ANTI SARS-CoV-2 mRNA BASED VACCINES

BackgroundAcetaminophen (APAP = paracetamol) may potentially impact vaccine-associated immune responses as the intake of APAP has been associated with a worse outcome in tumor patients receiving checkpoint inhibitors.[1]Different DMARD regimen have been shown to impair the humoral immune response to mRNA SARS-CoV-2 vaccines in patients with rheumatoid arthritis but the effect of paracetamol has not been explored thus far.ObjectivesTo analyse whether the intake of APAP may interfere with antiviral humoral immune responses following two doses of an anti-SARS-CoV-2 mRNA based vaccine in patients with rheumatoid arthritis (RA) on DMARD therapy.MethodsThe RECOVER trial (Rheumatoid Covid-19 Vaccine Immune Response) was a non-randomised, prospective observational control group trial and enrolled 77 RA patients on DMARD therapy and 21 healthy controls (HC). We performed a posthoc analysis of blood samples taken before the first vaccine dose (T0), two (T1) and three (T2) weeks after the first and second vaccine dose, and at 12 (T3) weeks. APAP intake was measured using ELISA. The antibody response (anti-S) to the receptor binding domain (RBD) within the SARS-CoV-2 S1 protein was measured with the Elecsys Anti-SARS-CoV-2-S (Roche Diagnostics GmbH) test. The neutralizing activity NT50 at week 12 was assessed using an HIV-based pseudovirus neutralization assay against Wuhan-Hu-1.ResultsBaseline characteristics of participants are detailed in Table 1. The immunogenicity analyses were based on 73 RA patients after exclusion of 4 patients with previously unnoticed SARS-CoV-2 infection (positive for anti-nucleoprotein at baseline). APAP was detected in serum samples from 34/73 (25%) RA patients and in 7/21 (33%) HC (least at one timepoint T0, T1 and/or T2). APAP intake in HC did not affect levels of anti-S at any timepoint and all HC developed potent neutralizing activity (NT50 ≥ 250) at week 12. RA patients, who tested positive for APAP at T1, showed comparable anti-S levels at T1, T2 and T3 compared to RA patients not exposed to APAP. The detection of APAP at T2 corresponded to lower anti-S levels at T2 (Figure 1 A, B). The detection of APAP at T2 was associated with a significantly lower SARS-CoV-2 neutralizing activity at week 12 compared to patients without perivaccination APAP exposure (p =0.04) (Figure 1 C).ConclusionA decrease of antiviral humoral immune responses was observed in RA patients (but not in HC) who were exposed to APAP at the time of the second mRNA vaccine dose compared to patients in whom APAP was not detected. Our data suggest that the use of paracetamol within the time period around vaccination may impair vaccine-induced immune responses in patients with an already higher risk for blunted immune responses.Reference[1]Bessede A et al. Ann Oncol 2022;33: 909-915Table 1.Baseline characteristics: RA patients and HC with/without APAP exposureRA APAP – n = 37RA APAP + n = 36p-valueHC APAP – n = 8HC APAP + n = 13p-valueAge (yrs), mean (± SD)62 (13)67 (10)0.07 (NS)45 (12)44 (14)0.90 (NS)Female sex, n (%)24 (65)19 (53)0.29 (NS)2 (25)5 (38)0.53 (NS)Vaccination type/schedulemRNA-1273, n (%)4 (11)8 (22.2)0.19 (NS)0 (0)0 (0)BNT162b2, n (%)33 (89)28 (77.8)0.19 (NS)8 (100)13 (100)RA disease characteristicsACPA ± RF, n (%)17/37 (46)19/36 (53)0.56 (NS)NANANARA disease duration (yrs ± SD)9.2 (9.8)10.2 (8.1)0.67 (NS)NANANADMARD therapycsDMARD-mono, n (%)13/37 (35)9/36 (25)0.35 (NS)NANANAbDMARD-mono/combo, n (%)16/37 (43)16/36 (44)0.92 (NS)NANANAtsDMARDs-mono/combo, n (%)8/37 (22)11/36 (31)0.38 (NS)NANANAPrednisone, n (%)15/37 (41)12/36 (33.3)0.52 (NS)NANANAMean daily dose prednisone (mg ± SD)4.6 ± 1.13.9 ± 2.30.39 (NS)NANANA* APAP = acetaminophenFigure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

COVID-19-Induced Post-Traumatic Stress Symptoms in Palliative Medicine Professionals (Sci218)

Outcomes: 1. Define the factors contributing to increased PTSD incidence due to COVID-19 among hospice and palliative medicine professionals. 2. Implement measures to screen and proactively mitigate workplace related factors associated with increased risk of PTSD in pandemic- and potentially non-pandemic-related situations. The COVID-19 pandemic has affected more than 557 million people globally. In order to assess its psychological effect on healthcare workers in hospice and palliative medicine, a survey was solicited to AAHPM members. Participation was voluntary and anonymous, with all responses kept in confidence. The survey consisted of three parts: demographics, attitudes/sentiments relating to COVID-19, and the DSM-IV-TR Post-Traumatic Stress Disorder (PTSD) Checklist-Specific (PCL-S). The PCL-S has clinical and research utility to screen for PTSD in response to a specific stressor, in this case COVID-19. A total of 323 AAHPM members participated, of which 290 (89.8%) completed the PCL-S. Utilizing the most conservative and reliable scoring method for the PCL-S, 16.6% (48/290) met diagnostic criteria for symptomatic PTSD. Demographic factors including age, relationship status, child status, years of experience, geographical location, and gender did not affect odds of PTSD symptomology, yet non-male gender was associated with higher PCL-S scores (3.2 +/- 1.5;p = 0.38). Attitudes surrounding the use and perceived efficacy of telemedicine did not impact the incidence of PTSD. Those providing critical care services (33/156;21.2%) were at greater risk of symptomatic PTSD than those not providing critical care services to COVID-19 patients (15/135;11.1%;RR = 1.9[1.08-3.35];p=0.026). Furthermore, PCL-S scores increased as a function of the number of patients where critical care (but not non-critical care) was provided (p=0.0006). Increased workload (p=0.009) and having to perform new job duties (p=0.004) as a result of COVID-19 were also associated with symptomatic PTSD. Personal stress was also a contributory factor;the risk of symptomatic PTSD was higher among respondents reporting a friend, family member, or colleague's death from COVID-19 (23.8% vs. 13.1%;RR = 1.82[1.08-3.05]). As COVID-19 continues to impact us all, understanding factors affecting the mental health of an integral part of the healthcare workforce is crucial.Copyright © 2023

Increased humoral immune response after vaccination with mRNA-1273 vs BNT162b2 in patients with inflammatory rheumatic diseases

Patients with inflammatory rheumatic diseases (IRD) have an increased risk for a worse COVID-19 outcome, and impaired immune responses following mRNA COVID-19 vaccines have been observed. In this prospective observational study, we compared the anti-S1 response following vaccination with BNT162b2 and mRNA- 1273 in a large cohort of IRD patients and assessed the effect of different immunomodulatory treatments. Patients from SCQM, the Swiss IRD cohort, who assented to an mRNA COVID-19 vaccine were recruited into the study between 3/2021-9/2021. Participants answered the study questionnaire via the mySCQM patient app and provided self-collected capillary blood samples at baseline, 4, 12, and 24 weeks post second vaccine dose. Samples were tested for IgG antibodies against the S1 domain of the SARS-CoV-2 spike protein using the EUROIMMUN ELISA. We examined differences in antibody titres depending on the vaccine and treatment received, while adjusting for age and history of SARSCoV- 2 infection, by applying mixed effects continuous outcome logistic regression models at each timepoint. Eligible samples were obtained from 564 IRD patients (mean age 53 y (s.d. 12 y), 66% female) with 36% RA, 37%, axSpA, 21% PsA, and 6% UA (undifferentiated arthritis), on no medication (no DMARD & no steroids 15%), csDMARD (9%), TNFi (48%), IL-6/17/23i (14%), JAKi (6%), rituximab (4%), abatacept (3%), and PDE4i (1%) in mono/combination therapy at baseline. 10% of patients had a past SARS-CoV-2 infection, 54% received BNT162b2, 46% mRNA-1273. Independently of the disease, treatment, and history of SARS-CoV- 2 infection, the odds of having higher anti-S1 titres at 4, 12, and 24 weeks post second vaccine dose were, respectively, 3.3, 3.9, and 3.8 times higher with mRNA-1273 compared to BNT162b2 for the average-aged patient of this population (p <0.0001). Moreover, with every year of age, the odds of higher anti-S1 levels increased by 3% to 5% following mRNA-1273 vs BNT162b2 vaccination (p <0.05), indicating an additional benefit for elderly IRD patients. Among monotherapies, rituximab, abatacept, JAKi, and TNFi had the highest odds of reduced anti-S1 responses compared to no medication. Patients on specific combination therapies showed significantly reduced antibody responses compared to respective monotherapies. Our results suggest that in IRD patients, vaccination with mRNA- 1273 vs BNT162b2 results in higher anti-S1 antibody titres, and has an additional benefit in elderly patients.

Distinguishing In-Groups and Onlookers by Language Use

Inferring group membership of social media users is of high interest in many domains. Group membership is typically inferred via network interactions with other members, or by the usage of in-group language. However, network information is incomplete when users or groups move between platforms, and in-group keywords lose significance as public discussion about a group increases. Similarly, using keywords to filter content and users can fail to distinguish between the various groups that discuss a topic-perhaps confounding research on public opinion and narrative trends. We present a classifier intended to distinguish members of groups from users discussing a group based on contextual usage of keywords. We demonstrate the classifier on a sample of community pairs from Reddit and focus on results related to the COVID-19 pandemic.

EFFECTIVENESS of A ONE-WEEK INPATIENT MULTIMODAL PAIN TREATMENT PROGRAM for PATIENTS with RHEUMATOLOGIC DISEASES and MUSCULOSKELETAL PAIN-A SINGLE CENTER OBSERVATIONAL STUDY

Background: Multimodal rheumatologic complex treatment (MRCT) is a treatment concept for patients with rheumatologic diseases requiring acute inpatient care suffering from exacerbated pain and/or functional impairment. A rheumatol-ogist directs the treatment program including multimodal assessments and treatment from three of the following: ergotherapy, physiotherapy, pain medicine and cognitive behavioural treatment. Most studies evaluated data from a two-week inpatient MRCT program.1 Available data on the effectiveness of a one-week inpatient multimodal treatment program are scarce. However, whether a shorter program might also be effective has not been studied so far. Objectives: To evaluate the effectiveness of a one-week inpatient multimodal and interprofessional treatment program on musculoskeletal pain and function of patients with rheumatologic disorders. Methods: 59 consecutive patients were entered into a program of multimodal treatment courses (MRCT) from January 2021 until December 2021. All patients completed a total of 11 hours of therapy in one week. Two patients were excluded for evaluation (one patient acquired COVID 19 during hospitalization and one patient was excluded due to missing data). Pain was assessed via visual analogue scale (VAS) and functional impairment via the 'Funktionsfragebogen Hanover (FFbH)' and the 'Health Assessment Questionnaire (HAQ)' at admission, at discharge and at 12 weeks of follow up. Paired t-test analyses for all treatment episodes were performed. Results: The mean treatment duration (days, ±SD) was 8.1 ± 0.8. Mean age (years, ±SD) of the 57 patients treated in the MRCT program was 57.2 ± 12.5, with 72% female and 28% male patients. Of all patients, 40% had an underlying infammatory disorder, 60% a non-infammatory rheumatic disease. 23% of all patients had 'back pain', 14% 'spondyloarthritis' and 11 % 'rheumatoid arthritis'. Overall, VAS (pain) mean at admission was 6.9 ± 1.0 (SD), HAQ mean 0.57 ± 0.23 (SD) and FFbH mean 81.44 ± 7.95 (SD), respectively. Signifcant improvements in VAS, HAQ and FFbH were demonstrated at discharge (day 8), with a mean improvement of VAS of-2.86 (95% CI:-3.07 to-2.64, P value: <0.0001), a mean improvement of HAQ of-0.24 (95% CI:-0.28 to-0.20, P value: <0.0001) and a mean improvement of FFbH of 5.38 (95% CI: 3.78 to 6.98, P value: <0.0001). Follow up assessment at week 12 was recorded in 22 patients (39%) with a signifcant mean improvement in VAS of-2.23 (95% CI:-2.98 to-1.48), P value < 0.0001) (Table 1 and Figure 1). Conclusion: Signifcant improvement of pain and function was demonstrated at discharge and at week 12 in patients with rheumatologic diseases and mus-culoskeletal pain completing a one-week inpatient multimodal interprofessional treatment program. A multimodal therapeutic approach may provide an effective treatment strategy superior to unimodal standard management.

SARILUMAB in PATIENTS with RELAPSING POLYMYALGIA RHEUMATICA: A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED TRIAL (SAPHYR)

Background: Interleukin-6 (IL-6) is elevated in patients with active polymyalgia rheumatica (PMR) and is associated with disease activity, relapse and severity. Clinical trials with IL-6 receptor (IL-6R) inhibitors in PMR showed higher remission rates and reduced glucocorticoid (GC) use vs GC alone.1-4 Objectives: The SAPHYR study (NCT03600818) assessed the efficacy and safety of sarilumab (SAR), a fully human anti IL-6Rα monoclonal antibody, with a 14 week (wk) GC taper in patients with steroid resistant active PMR who fared on ≥7.5 mg/day prednisone or equivalent. Methods: Patients were randomized (1:1) to 52 wks of treatment with SAR 200 mg every 2 wks (Q2W) + 14 wk GC tapered regimen (SAR arm) OR placebo Q2W + 52 wk GC tapered regimen (comparator arm). The primary endpoint was the proportion of patients achieving sustained remission at wk 52, defned as disease remission by wk 12, absence of disease fare, CRP normalization from wks 12 to 52 and adherence to the per protocol GC taper from wks 12 to 52. Results: The study was terminated early due to protracted recruitment timelines during the COVID-19 pandemic, resulting in 118 of the intended 280 patients recruited between Oct 2018 and Jul 2020, and 117 were treated (SAR n=59, comparator n=58). The demographics were balanced;patients were primarily female, Caucasian, and a median age of ~70 years (Table 1). Overall, 78 patients completed the treatment (SAR n=42;comparator n=36). Primary reasons for treatment discontinuation were adverse events (AEs;SAR n=7, comparator n=4) and lack of efficacy (SAR n=4, comparator n=9). Sustained remission rate was signifcantly higher in the SAR arm vs the comparator arm (28.3% vs 10.3%;P=0.0193). Results of a sensitivity analysis excluding CRP from the sustained remission defnition was consistent with the primary analysis (31.7% vs 13.8%;P=0.0280). All sustained remission components favored SAR (Figure 1). Patients in the SAR arm were 44% less likely to have a fare after achieving clinical remission vs the comparator arm (16.7% vs 29.3%;HR 0.56;95% CI 0.35-0.90;P=0.0158). The comparator arm required more additional GCs vs the SAR arm, mainly due to PMR fare (median difference in actual and expected cumulative dose 199.5 mg vs 0.0 mg;P=0.0189). The cumulative GC toxicity index scores numerically favored SAR but the difference was not statistically signifcant. PMR activity scores improved in the SAR arm vs the comparator arm (LS mean-15.57 vs-10.27, nominal P=0.0002). Patient reported outcomes (eg, physical and mental health component scores, disability index, etc) favored SAR (Figure 1). Incidence of treatment-emergent AEs (TEAEs) was numerically higher in the SAR arm vs the comparator arm (94.9% vs 84.5%) and included neutropenia (15.3%) and arthralgia (15.3%) in the SAR arm, and insomnia (15.5%) in the comparator arm. Conversely, the frequency of serious AEs was higher in the comparator arm vs the SAR arm (20.7% vs 13.6%). No deaths were reported. Conclusion: SAR + 14 wk GC taper demonstrated signifcant efficacy vs the comparator arm in steroid refractory PMR patients, including clinically meaningful improvement in quality of life. Safety was consistent with the known safety profile of SAR.

LONGTERM IMMUNOGENICITY and TOLERABILITY of A 3RD DOSE of AN MRNA ANTI-SARS-COV-2 VACCINE in RA PATIENTS with AN INADEQUATE RESPONSE to A PREVIOUS STANDARD TWO DOSE REGIMEN

Background: Lower seroconversion rates have been reported in patients with rheumatic diseases receiving immunomodulatory therapies following a standard mRNA-based vaccine regimen. Data with regard to immunogenicity and safety of a 3rd vaccine dose in this patient population is limited1. Objectives: We aim to study immunogenicity, vaccine associated side effects and the occurrence of fares in RA patients unresponsive to a standard vaccine regimen eligible for a 3rd vaccine dose. Methods: RA patients who had a low or absent anti-S1 response after 12 (Cohort A) or 24 weeks (Cohort B) following a standard vaccination regimen received a 3rd vaccine dose. Temporary discontinuation of DMARD therapy was recommended. Serum samples were collected before, 2, 12, and 24 weeks after the 3rd vaccine dose. Quantitative measurement of anti-S was performed using the Roche Elecsys Anti-SARS-CoV-2 spike subunit assay. Neutralizing activity (NT50) against Wuhan WT and aasβ-, y-, and ô-variants was assessed by using a HIV-based pseudovirus system. Results: Baseline characteristics are shown in Table 1. 45/47 patients temporarily discontinued DMARD therapy: Mtx and JAKi were paused one 1 week before/restarted 2 weeks after the 3rd vaccine dose, bDMARDs were paused 2 weeks before/restarted 2 weeks after the 3rd dose. Local pain and/or systemic vaccine associated side effects following the 3rd vaccine dose were reported in 12/17 (71%) in Cohort A, and 10/29 (35%) patients in Cohort B (p = 0.018). Flares were defned as loss of low disease activity (LDA), subsequent to the 3rd vaccine dose and occurred in 17/47 (36%) patients (p = 0.0332) with comparable frequencies in both cohorts (41% Cohort A, 33% Cohort B (NS)). Low or absent anti-S titers were confrmed before the third vaccination (Cohort A: median 19.5 U/ml, IQR 0.47-57;cohort B: median 65.9 U/ml, IQR 22-154) (p = 0.0018). Two weeks after the 3rd dose, a rapid and signifcant increase in anti-S were observed in 12/17 (82%) and 25/28 (89%) patients (Cohort A: median 2500 U/ml, IQR 798-2500;Cohort B: median 2500 U/ml, IQR 2500-2500) (NS). High levels of anti-S were maintained in the majority of patients 55% (11/20) until week 12 in both cohorts (Figure 1). NT50 against Wuhan-WT and other variants was assessed in 21 patients 2 weeks after the 3rd vaccine dose revealing a low or absent NT50 against delta in 38% of patients despite a median anti-S response of 2500 U/ml (IQR 798-2500). 14/21 patients had peak anti-S titres of 2500 U/ml, of those 12/14 developed a strong NT50 response against the delta variant. Conclusion: Our data demonstrate that a 3rd vaccine dose, maybe complimented by temporary discontinuation of DMARD therapy, may lead to a rapid increase in anti-S antibodies when using a homologous vaccine and profound neutralizing activity in the majority of RA patients previously unresponsive to a standard two dose regimen. This seems to be independent of the interval to the previous standard vaccine regimen. As fares occurred in 36% of all patients, the necessity and length of DMARD discontinuation should be explored in more detail to balance between sustained control of disease activity and optimized vaccine induced immune responses.

TYPE of MRNA COVID-19 VACCINE and TREATMENT INFLUENCE ANTIBODY KINETICS in PATIENTS with INFLAMMATORY RHEUMATIC DISEASES

Background: Patients on immunomodulatory treatments mount an attenuated immune response following mRNA COVID-19 vaccination, yet longterm studies of vaccine-induced anti-SARS-CoV-2 antibody (Ab) kinetics are missing. Objectives: In this prospective observational study, we mapped the humoral antibody response to mRNA COVID-19 vaccines up to 24 weeks post full vaccination in patients with infammatory rheumatic diseases (IRDs). We aimed to assess differences due to treatment, age, past SARS-CoV-2 infection, and vaccine (BNT162b2 vs. mRNA-1273). Methods: Adult patients from the SCQM cohort who assented to an mRNA COVID-19 vaccine were recruited between 3/21-9/21. Participants answered questionnaires via an app and received kits for the self-collection of capillary blood samples at baseline, 4, 12, and 24 weeks post full vaccination. Samples were tested for IgG Ab against the S1 domain of the SARS-CoV-2 spike protein (anti-S1-IgG) using the EUROIMMUN ELISA. To examine differences in Ab titres arising from the defned parameters, while accounting for inter-assay variability, mixed effects continuous outcome logistic regression models were applied at each timepoint. Results: Samples were obtained from 570 patients: 67% female, mean age 53 y (SD 12 y) with 37% RA, 36% axSpA, 21% PsA, and 6% UA (undifferentiated arthritis), on no medication (no DMARDs & no glucocorticoids;15%), csD-MARDs (10%), TNFi (48%), IL-1/6/17/23i (14%), JAKi (6%), rituximab (RTX;4%), or abatacept (ABA;2%) in mono/combination therapy at the frst vaccination. 10% of patients had a past SARS-CoV-2 infection, 54% received BNT162b2, 46% mRNA-1273. For any Ab threshold, the odds of having a higher Ab titre at 4, 12, and 24 weeks post full vaccination were 3.3-4 times higher with mRNA-1273 compared to BNT162b2 (Table 1, Figure 1). TNFi, JAKi, RTX, and ABA as monotherapy resulted in signifcantly lower Ab levels compared to no medication at almost all timepoints. In combination therapy, TNFi, IL-1/6/17/23i, RTX, and csDMARDs led to consistently lower Ab titres at all timepoints compared to respective monotherapy. Conclusion: Compared to no medication, some immunomodulatory therapies resulted in markedly lower Ab levels at all timepoints. In IRD patients, a past SARS-CoV-2 infection resulted in strikingly increased immunogenicity, as did mRNA-1273 compared to BNT162b2.

IMMUNE CORRELATES and CLINICAL COURSE of PATIENTS with RHEUMATOID ARTHRITIS FOLLOWING VACCINATION with ANTI SARS-COV-2 MRNA BASED VACCINES: RESULTS from A PROSPECTIVE, OBSERVATIONAL and CONTROLLED STUDY

Background: Vaccines are highly effective in preventing COVID-19 associated hospitalization and deaths. Strong and persistent immune responses are critical to provide protection for patients with immunomodulatory therapies. Objectives: To assess humoral and cellular immune responses following 2 doses of an anti-SARS-CoV-2 mRNA based vaccine in rheumatoid arthritis (RA). Immune responses in patients treated with csDMARDs, bDMARDs (with the exception of rituximab) and JAK inhibitors were compared to healthy controls (HC) over 24 weeks. In addition, disease activity by CDAI and vaccine-induced side effects were prospectively monitored. Methods: The RECOVER trial (Rheumatoid Covid-19 Vaccine Immune Response) is a non-randomised, prospective observational control group trial and enrolled 77 RA patients on DMARD therapy and 21 HC. Clinical assessment and blood sampling was performed at baseline, 3 weeks after the 1st and 2 weeks after the 2nd vaccine dose and at week 12 and 24 after the 1st. Antibody response to the receptor binding domain (RBD) within the SARS-CoV-2 S1 protein was measured with the Elecsys Anti-SARS-CoV-2-S (Roche Diagnostics GmbH) test. The seroprofling assay ABCORA, which has been suggested as a surrogate for neutralization,1 was used to determine IgG, IgA and IgM responses to RBD, S1, S2 and N. The neutralizing activity NT50 at week 12 was assessed against Wuhan-Hu-1 pseudoviruses (HIV-based). IFN-y ELISpots were applied to detect spike-reactive T cell responses after in vitro stimulation with a spike peptide mix. Results: Baseline characteristics of participants are detailed in Table 1. Vaccination was well tolerated with no differences between RA patients and HC. At baseline, the majority of RA patients were in remission/LDA (57/77, 74%), this proportion decreased to 51% (39/77) after the second vaccine dose (p = 0.005). Treatment adjustments were required in 11/77 patients. The immunogenicity analyses were based on 73 RA patients after exclusion of 4 patients with previously unnoticed SARS-CoV-2 infection (positive for anti-nucleoprotein). In contrast to HC, anti-S titers were lower at all timepoints with signifcantly reduced titers observed in patients on abatacept and JAK inhibitors (Figure 1). Potent neutralizing activity (NT50 ≥ 250)) was detected in all HC at week 12, in contrast to 62% RA patients. NT50 correlated to the results based on the ABCORA assay. Peak anti-S titers (2 weeks after 2nd vaccine) were predictive of NT50 ≥ 250 at week 12 (p < 0.0001). In contrast to marked differences in the humoral immune responses, spike-protein specifc IFN-α secreting T cells were largely unaltered by different DMARD regimen. Conclusion: RA patients, in comparison with HC, revealed a slower kinetic and lower magnitude of humoral immune responses depending on the treatment regimen while T cell responses were largely maintained. Peak anti-S responses two weeks after the second vaccine were able to predict the development of potent neutralizing activity and should therefore be considered to individually tailor vaccination strategies.

Safety, Pharmacokinetics, and Activity of High Dose Ivermectin and Chloroquine against the Liver Stage of Plasmodium cynomolgi Infection in Rhesus Macaques

Previously, ivermectin (1 to 10 mg/kg of body weight) was shown to inhibit the liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (50% inhibitory concentration [IC50], 10.42 micro M) and hypnozoites (IC50, 29.24 micro M) in primary macaque hepatocytes when administered as a high dose prophylactically but not when administered in radical cure mode. The safety, pharmacokinetics, and efficacy of oral ivermectin (0.3, 0.6, and 1.2 mg/kg) with and without chloroquine (10 mg/kg) administered for 7 consecutive days were evaluated for prophylaxis or radical cure of P. cynomolgi liver stages in rhesus macaques. No inhibition or delay to blood-stage P. cynomolgi parasitemia was observed at any ivermectin dose (0.3, 0.6, and 1.2 mg/kg). Ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) in combination were well-tolerated with no adverse events and no significant pharmacokinetic drug-drug interactions observed. Repeated daily ivermectin administration for 7 days did not inhibit ivermectin bioavailability. It was recently demonstrated that both ivermectin and chloroquine inhibit replication of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in Plasmodium vivax control and as adjunctive therapies against COVID-19 infections.

Anti-S1 antibodies after vaccination with anti SARS-CoV-2 mRNA vaccines in patients with rheumatoid arthritis differ in magnitude and kinetics from healthy controls: Results from a prospective, observational controlled study

Background: Vaccination against anti SARS-CoV-2 is recommended in patients with rheumatic diseases, but limited data are available in patients on immunosuppressive therapy. The objective of this study is to analyse magnitude and kinetics of mRNA vaccine induced anti-S1 titers in patients with rheumatoid arthritis (RA) on DMARD therapy and healthy controls (HC). Methods: 77 RA patients and 21 HC were eligible for vaccination according to federal guidelines and were enrolled in the prospective RECOVER trial (Rheumatoid Covid-19 Vaccine Immune Response) between 10th January and March 15th 2021. Vaccination itself was not part of the study. The anti-SARS-CoV-2 vaccines mRNA-1273 and BNT162b2 were applied according to the manufacturers' recommendations. All patients continued their DMARD therapy. Serum samples were obtained before the first vaccine, 3 weeks after the first, 2 weeks after the second vaccine and after 12 weeks. Quantitative antibody testing was performed using the Roche Elecsys® Anti-SARS-CoV-2 S1 assay that measures antibodies to the S1 protein (range 0.4-2500 U/l) and nucleoprotein to exclude subclinical SARS-CoV-2 infection. A threshold level of anti-S1 that correlates to neutralization has been proposed at 133 U/l.1. More recently, even lower cut-off levels (>15 U/l) have been suggested. 2 Results: At present, 43/77 patients reached the 12 week timepoint after the first vaccine dose. 4/77 patients with antibodies to nucleoprotein at baseline were excluded from the analysis. Median titers of anti-S1 antibodies were significantly lower in RA patients at all time points. 3 weeks after the first vaccine dose, 9/21 HC but only 1/73 RA patients developed anti-S1 titers exceeding 133 U/l (p = 0.0001) or 15 U/l (19/21 HC versus 11/73 RA patients). Two weeks after the second vaccine, the proportion of RA patients with anti-S1 titers exceeding 133 u/l was still significantly lower than in HC (75.3% versus 100%, p = 0.01). Of note, RA patients on abatacept (n = 9) or JAK inhibitors (n = 19) achieved both threshold levels significantly less frequently compared to patients on csDMARDs and/or anti-cytokine directed biologics. Conclusions: The development of anti-S1 titers after vaccination with mRNA vaccines against SARS-CoV-2 in patients with RA is overall slower and results in lower antibody titers in comparison to healthy controls.

Forty-eight week efficacy and safety of pegcetacoplan in adult patients with paroxysmal nocturnal hemoglobinuria and suboptimal response to prior eculizumab treatment

Background: Pegcetacoplan (PEG), a PEGylated peptide targeting proximal complement protein C3, can control both intravascular and extravascular hemolysis. In the PEGASUS trial (NCT03500549), a phase 3, randomized, open-label, active-comparator controlled study, PEG was shown to be superior to eculizumab (ECU) after 16 weeks in improving hemoglobin levels (Hb) and clinical outcomes in patients with paroxysmal nocturnal hemoglobinuria (PNH) (Hillmen P et al, EHA 2020). Aims: We report on the efficacy and safety of PEG through 48 weeks of treatment. Methods: This study is a continuation of the PEGASUS trial. Eighty patients ≥18 years with PNH, and Hb levels <10.5 g/dL despite stable ECU treatment for ≥3 months, were enrolled. Patients completed a 4-week run-in period with both ECU and PEG before 1:1 randomization to PEG (n=41;1080 mg subcutaneously twice weekly) or ECU monotherapy (n=39;continued dosing regimen). The primary endpoint was the change from baseline (CFB) in Hb levels to Week 16. After the randomized control period (RCP), patients could continue to an open-label period (OLP), which included a 4-week run-in period for ECU patients (ECU-to-PEG), followed by PEG monotherapy (same dosage as in RCP) for all patients for a 48-week total study period. Key secondary endpoints included blood transfusion avoidance, CFB in absolute reticulocyte count (ARC), CFB in lactate dehydrogenase (LDH), CFB in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, and adverse events (AEs). Results: Three patients discontinued PEG during the 16-Week RCP due to hemolysis;the remaining 77 patients entered the OLP. PEG demonstrated superiority to ECU with a mean Hb level improvement of 2.7 g/dL at Week 16, which was sustained throughout the OLP in all patients receiving PEG monotherapy. ECU-to-PEG patients demonstrated Hb improvement with mean Hb levels of 11.6 g/dL at Week 48 (CFB: 2.9 g/dL), while PEG-to-PEG patients maintained high Hb levels through the OLP with a mean Hb level of 11.3 g/dL at Week 48 (CFB: 2.6 g/dL) (Figure A). Seventy-three percent of PEG-to-PEG patients remained transfusion free for the 48-week study, and 72% of the ECU-to-PEG patients were transfusion free during the OLP through Week 48. Improvements in ARC (PEG-to- PEG: 80.0×109 cells/L;ECU-to-PEG: 94.0×109 cells/L), LDH (PEG-to-PEG: 222.7U/L;ECU-to-PEG: 224.1 U/L), and FACIT-fatigue score (PEG-to- PEG: 40.6;ECU-to-PEG: 42.5) were also observed at Week 48 (Figure B). The most common AEs by physician-reported preferred term throughout the study for all patients who received PEG were injection site reactions (36%), hemolysis (24%), and diarrhea (21%). Of all study patients, 30% experienced serious AEs with 6% possibly related to PEG. No cases of meningitis were reported. One death was reported due to COVID-19, unrelated to study treatment. Six patients discontinued due to hemolytic events: 5 classified by the treating physician as "hemolysis" and 1 as "hemolytic anemia." Overall, 12 patients (15%) discontinued PEG: 3 in RCP, 8 in OLP due to TEAEs (6 in ECU-to-PEG, 2 in PEG-to-PEG), and one during follow-up;one patient withdrew due to physician decision. Summary/Conclusion: Adult patients with PNH with suboptimal response on prior ECU treatment received PEG in this continuation of the PEGASUS trial and experienced durable treatment effect in all efficacy parameters at Week 48. The safety profile of PEG was consistent with previously reported data. The results suggest that PEG represents a new effective therapeutic option for patients with PNH.

Preliminary findings from the feasibility trial of families moving forward connect mobile health intervention for caregivers of children with FASD

Objectives: Although fetal alcohol spectrum disorders (FASD) affect approximately 2-5% of the US population, most families are unable to access FASD-informed interventions. FMF Connect is a comprehensive mobile Health (mHealth) intervention derived from the scientifically-validated Families Moving Forward (FMF) Program, developed at Seattle Children's Research Institute/University of Washington. FMF Connect has five main components: 1) Learning Modules;2) Family Forum;3) Library;4) Notebook;and 5) Dashboard. Methods: A 3-month feasibility trial of the FMF Connect app was conducted with caregivers of children (ages 3-12) with FASD. Data presented are from 63 iOS users enrolled in the trial (conducted February-September 2020);an Android trial is underway. Participants reported on satisfaction using the app, and the impact of COVID-19. Usage metrics were also calculated. Qualitative interviews were completed with a subsample to elicit user experience from both technological and content perspectives. Interviews were coded thematically. Results: Of 63 eligible users, 52 completed baseline surveys, and 41 downloaded the FMF Connect app. Of those caregivers, 29 (71%) completed at least one Learning Module and 6 (14%) completed all 12 modules. 64% of participants indicated the COVID-19 pandemic negatively impacted their ability to use the app. Participants reported high satisfaction with the app, including on Engagement, Information, and Total App Quality scales. 14 caregivers completed interviews. Participants generally had positive experiences with the app and offered constructive feedback to improve user experience. Specifically, caregivers described the content and exercises within the Learning Modules and Library as useful and motivating. However, some caregivers felt the Learning Modules were too long and suggested consolidation. Many struggled with the step-by-step progression and said they would have preferred open access to content. Although Family Forum use was lower than expected, participants valued the idea of connecting with other caregivers who understand. Caregivers suggested adding more notifications and state-specific forums. Caregivers described the Tip of the Day feature as very useful, with a positive emotional impact. The Notebook and Dashboard received limited discussion. Conclusions: Results indicate caregivers were generally satisfied with the FMF Connect app. Iterative feedback from key stakeholders and early development trials are strengths of this project. Content refinement based on feedback is underway.

The intimacies of screens, homes and learning hierarchies

This article is a result of the way in which the design of a first-year anthropology course attempted to undo stern structural hierarchies between students and teachers. Instead, the participants regarded one another as fellow anthropologists undertaking ethnographic research on the university context. This article examines the intimate relations that came available to participants when the course moved from in-person to Zoom format. Participants moved into homes to document the unfurling COVID-19 crisis, (back) into intimate familial relations. But this was not the only intimacy with which participants had to grapple anthropologically. The lecture materials, too, connected themselves to things and experiences in immediacy as they arrived into homes through laptop screens. The screens themselves offered up new insights into the lives of others – something newly minted anthropologists had to account for as they completed the course. © The Author(s).