Nocebo-Prone Behaviour in Patients with Autoimmune Rheumatic Diseases during the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic is associated with emotional distress and significant disruptions in health-care services. These are key players in the development of nocebo phenomena. We aimed to investigate nocebo-prone behaviour in patients with autoimmune rheumatic diseases (ARD) amid the COVID-19 pandemic-associated lockdown. METHODS: Consecutive patients were telephone-interviewed during the COVID-19 pandemic in Greece. Clinical and socioeconomic characteristics (eg, level of education) were recorded. For nocebo behaviour, a four-item validated questionnaire (Q-No, cut-off score>15), was used. Results were compared with pre-COVID-19 Q-No scores collected from patients followed-up in our department. RESULTS: Nocebo behaviour was detected in 51/500 (10.2%) individuals. In patients with nocebo behaviour, use of anti-hypertensives was less common (17.6% vs 31.8%, p=0.04), but a higher level of education was more common (58.8% vs 35.9%, p=0.002), compared with patients with Q-No score ≤15; the latter retained statistical significance in multivariate regression analysis (p=0.009, OR [95%CI]: 2.29, [1.23-4.25]). Total Q-No scores were higher in the COVID-19-period compared to the pre-COVID-19 era [median (range); 12 (4-20) vs 11 (4-20), p=0.02]. Among 78 patients with available Q-No questionnaires in the pre-COVID-19 era, 11 (14.1%) displayed nocebo behaviour, which increased to 16 (20.5%) amid the COVID-19 pandemic. Interim development of nocebo behaviour was also associated with higher educational level (p=0.049, OR: 3.65, 95%CI: 1.005-13.268). CONCLUSION: A considerable proportion of ARD patients manifested nocebo-prone behaviour during the COVID-19 pandemic, which was more common among those with high educational level.

Oxidative stress and endogenous DNA damage in blood mononuclear cells may predict anti-SARS-CoV-2 antibody titers after vaccination in older adults.

Immune senescence in the elderly has been associated with chronic oxidative stress and DNA damage accumulation. Herein we tested the hypothesis that increased endogenous DNA damage and oxidative stress in peripheral blood mononuclear cells of older adults associate with diminished humoral immune response to SARS-CoV-2 vaccination. Increased oxidative stress and DNA double-strand breaks (DSBs) were detected in 9 non-immunocompromised individuals aged 80-96 years compared to 11 adults aged 27-44 years, before, as well as on days 1 and 14 after the first dose, and on day 14 after the second dose of the BNT162B2-mRNA vaccine (all p < 0.05). SARS-CoV-2 vaccination induced a resolvable increase in oxidative stress and DNA damage, but individual DSB-repair efficiency was unaffected by vaccination irrespective of age, confirming vaccination safety. Individual titers of anti-Spike-Receptor Binding Domain (S-RBD)-IgG antibodies, and the neutralizing capacity of circulating anti-SARS-CoV-2 antibodies, measured on day 14 after the second dose in all participants, correlated inversely with the corresponding pre-vaccination endogenous oxidative stress and DSB levels (all p < 0.05). In particular, a strong inverse correlation of individual pre-vaccination DSB levels with both the respective anti-S-RBD-IgG antibodies titers (r = -0.867) and neutralizing capacity of circulating anti-SARS-CoV-2 antibodies (r = -0.983) among the 9 older adults was evident. These findings suggest that humoral responses to SARS-CoV-2 vaccination may be weaker when immune cells are under oxidative and/or genomic stress. Whether such measurements may serve as biomarkers of vaccine efficacy in older adults warrants further studies.

Better outcomes of COVID-19 in vaccinated compared to unvaccinated patients with systemic rheumatic diseases.

OBJECTIVE: Τo report outcomes of breakthrough COVID-19 in comparison with COVID-19 in unvaccinated patients with systemic rheumatic diseases (SRDs). METHODS: Patients with SRD with COVID-19 (vaccinated and unvaccinated) were included by their rheumatologists in a registry operated by the Greek Rheumatology Society in a voluntarily basis. Type, date and doses of SARS-CoV-2 vaccines were recorded, and demographics, type of SRD, concurrent treatment, comorbidities and COVID-19 outcomes (hospitalisation, need for oxygen supplementation and death) were compared between vaccinated and unvaccinated patients. RESULTS: Between 1 March 2020 and 31 August 2021, 195 patients with SRD with COVID-19 were included; 147 unvaccinated and 48 vaccinated with at least one dose of a SARS-CoV-2 vaccine (Pfizer n=38 or AstraZeneca n=10). Among vaccinated patients, 29 developed breakthrough COVID-19 >14 days after the second vaccine dose (fully vaccinated), while 19 between the first and <14 days after the second vaccine dose (partially vaccinated). Despite no differences in demographics, SRD type, treatment or comorbidities between unvaccinated and vaccinated patients, hospitalisation and mortality rates were higher in unvaccinated (29.3% and 4.1%, respectively) compared with partially vaccinated (21% and 0%) or fully vaccinated (10.3% and 0%) patients. CONCLUSIONS: Vaccinated patients with SRD with breakthrough COVID-19 have better outcomes compared with unvaccinated counterparts with similar disease/treatment characteristics.

COVID-19 vaccine safety and nocebo-prone associated hesitancy in patients with systemic rheumatic diseases: a cross-sectional study.

OBJECTIVE: To describe the rate and type of adverse effects (AEs) and the frequency of disease flares after COVID-19 vaccination and to assess the reasons for vaccination hesitancy (non-vaccination) in SRD patients. METHODS: Telephone interviews were conducted of SRD patients consecutively enrolled (15/06/2021-1/7/2021). Participants were asked about the type of AEs and disease flare after vaccination. Reasons for vaccination hesitancy were recorded. Univariate and mutivariable analyses examined associations of demographic, clinical and other features, with occurrence of AEs, disease flare and non-vaccination. For the latter, association with negative vaccination behaviour (not influenza vaccinated for the last 2 years) and nocebo-prone behaviour (denoting AEs attributed to negative expectations [Q-No questionnaire]) was also tested. RESULTS: 561 out of 580 contacted patients were included in the study. 441/561 (78.6%) patients were vaccinated [90% (Pfizer, Moderna), 10% (Astra-Zeneca)]. AEs were reported by 148/441 (33.6%), with rates being comparable between the three vaccines. AEs were more common in females and those with chronic obstructive pulmonary disease [OR, 95% CI; females: 2.23 (1.30-3.83); COPD: 3.31 (1.24-8.83)]. Disease flare was reported in 9/441 (2%) patients. For those unvaccinated, fear that the vaccine would be harmful (53.3%), could cause disease flare (24.2%) and/or could cause thrombosis (21.7%) were the main reasons to do so. Multivariable analysis identified as independent variables for non-vaccination: nocebo-prone behaviour (OR; 95% CI, 3.88; 1.76-8.55), negative vaccination behaviour (6.56; 3.21-13.42) and previous COVID-19 infection (2.83; 1.13-7.05). Higher educational status was protective (0.49; 0.26-0.92). CONCLUSION: No new safety signals for COVID-19 vaccination were observed. Vaccination campaign should target SRD patients with nocebo-prone and negative influenza vaccination behaviour.

Effective DNA damage response after acute but not chronic immune challenge: SARS-CoV-2 vaccine versus Systemic Lupus Erythematosus.

Whether and how an acute immune challenge may affect DNA Damage Response (DDR) is unknown. By studying vaccinations against Influenza and SARS-CoV-2 (mRNA-based) we found acute increases of type-I interferon-inducible gene expression, oxidative stress and DNA damage accumulation in blood mononuclear cells of 9 healthy controls, coupled with effective anti-SARS-CoV-2 neutralizing antibody production in all. Increased DNA damage after SARS-CoV-2 vaccine, partly due to increased oxidative stress, was transient, whereas the inherent DNA repair capacity was found intact. In contrast, in 26 patients with Systemic Lupus Erythematosus, who served as controls in the context of chronic immune activation, we validated increased DNA damage accumulation, increased type-I interferon-inducible gene expression and induction of oxidative stress, however aberrant DDR was associated with deficiencies in nucleotide excision repair pathways. These results indicate that acute immune challenge can indeed activate DDR pathways, whereas, contrary to chronic immune challenge, successful repair of DNA lesions occurs.

Increased influenza vaccination rates in patients with autoimmune rheumatic diseases during the Covid-19 pandemic: a cross-sectional study.

To assess non-compliance and potential changes in seasonal flu vaccination coverage before and during the Covid-19 pandemic in patients with autoimmune rheumatic diseases (ARDs). Consecutive patients with ARDs followed-up in 2 tertiary hospitals were telephone-interviewed (December 12-30, 2020) regarding seasonal flu vaccination during the 2019/20 and 2020/21 time periods. Self-reported disease flares that occurred after flu vaccination, as well as reasons for non-vaccination were recorded. One thousand fifteen patients were included. The rate of flu vaccination increased from 76% before to 83% during the COVID-19 pandemic (p = 0.0001). The rate of self-reported disease flares was < 1% among vaccinated patients. Reasons for not vaccination in both periods, respectively, included: 'was not recommended by their rheumatologists' (35.0vs.12.2%, p < 0.0001), 'did not feel that they would have any benefit' (36.9 vs. 32.6%), felt unsafe to do so (27.5 vs. 30.2%), or other reasons (18.9 vs. 23.8%). By multivariate analysis, age [OR = 1.03 (95% CI 1.02-1.04)] vs. [1.04 (95% CI 1.02-1.05)] and treatment with biologics [OR = 1.66 (95% CI 1.22-2.24) vs. [1.68 (95% CI 1.19-2.38)] were independent factors associated with vaccination in both periods. These findings, although are temporally encouraging, emphasize the need for continuous campaigns aiming at increasing patients' and physicians' awareness about the benefits of vaccination.