COVID-19 Vaccination Before Initiating Rituximab Treatment Induces Strong Serological Response in Autoimmune Rheumatic Disease, Reducing Post-Pandemic Concerns About the Impact of Rituximab.

OBJECTIVE: Rituximab (RTX)-treated patients exhibit suboptimal responses to COVID-19 vaccines. However, existing research primarily involves patients already receiving RTX when vaccines were introduced, failing to account for the current landscape where patients are vaccinated before initiating RTX. Our objective was to compare the serological response to COVID-19 vaccines in patients vaccinated before or after RTX initiation. METHODS: We included 254 RTX-treated patients with autoimmune inflammatory rheumatic diseases (AIIRDs) and 113 blood donors (BDs) in a retrospective, observational cohort study. Patients were categorized based on the timing of RTX treatment relative to primary COVID-19 vaccination. Serological vaccine responses were assessed using three immunoassays, and logistic regression analysis was used to identify predictors of serological response. RESULTS: Patients vaccinated before initiating RTX treatment had significantly higher seroconversion rates of SARS-CoV-2 immunoglobulin G (87%) and neutralizing antibodies (91%) compared with those receiving RTX before and after vaccination (n = 132) (61% and 65%, respectively). In the logistic regression analysis, a positive serological response was associated with the number of vaccines administered >9 months after the last RTX treatment. Patients receiving the highest number of vaccines with >9 months after RTX showed a response comparable to that of the BDs. CONCLUSION: Vaccinating before RTX initiation yields a robust serological response in patients with AIIRDs. Furthermore, we highlight the reversibility of antibody impairment after RTX treatment cessation, provided that adequate vaccinations occur within a minimum of 9 months after RTX. Our findings offer essential insights for clinical decision-making regarding COVID-19 vaccination and RTX treatment, alleviating concerns about future RTX use.

Outcomes following SARS-CoV-2 infection in individuals with and without inflammatory rheumatic diseases: a Danish nationwide cohort study.

OBJECTIVE: In a setting with an extensive SARS-CoV-2 test strategy and availability of effective vaccines, we aimed to investigate if patients with inflammatory rheumatic diseases (IRD) face greater risk of contracting SARS-CoV-2 and have a worse prognosis of increased risk of hospitalisation, assisted ventilation and death compared with the general population. METHODS: This was a nationwide, population-based register study that compared outcomes of SARS-CoV-2 infection in Danish patients with IRD (n=66 840) with matched population controls (n=668 400). The study period was from March 2020 to January 2023. Cox regression analyses were used to calculate incidence rate ratios (IRRs) for SARS-CoV-2-related outcomes. RESULTS: We observed a difference in time to first and second positive SARS-CoV-2 test in patients with IRD compared with the general population (IRR 1.06, 95% CI 1.05 to 1.07) and (IRR 1.21, 95% CI 1.15 to 1.27). The risks of hospital contact with COVID-19 and severe COVID-19 were increased in patients with IRD compared with population controls (IRR 2.11, 95% CI 1.99 to 2.23) and (IRR 2.18, 95% CI 1.94 to 2.45). The risks of assisted ventilation (IRR 2.33, 95% CI 1.89 to 2.87) and COVID-19 leading to death were increased (IRR 1.98, 95% CI 1.69 to 2.33). Patients with IRD had more comorbidities compared with the general population. A third SARS-CoV-2 vaccination was associated with a reduced need for hospitalisation with COVID-19 and reduced the risk of death. CONCLUSION: Patients with IRD have a risk of SARS-CoV-2, which nearly corresponds to the general population but had a substantial increased risk of hospitalisation with COVID-19, severe COVID-19, requiring assisted ventilation and COVID-19 leading to death, especially in patients with comorbidities.

COVID-19 vaccination in patients with rheumatic diseases leads to a high seroconversion rate and reduced self-imposed isolation and shielding behaviour.

OBJECTIVES: We investigated the effect of a two-dose messenger ribonucleic acid (mRNA) vaccine on antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patient behaviour and shielding concerning fear of coronavirus disease 2019 (COVID-19) in patients with systemic lupus erythematosus or rheumatoid arthritis. METHODS: Three hundred and three patients and 44 blood donors were included. All patients received two doses of an mRNA vaccine and had total antibodies against SARS-CoV-2 measured before vaccination and 2 and 9 weeks after the second vaccination. Further, patients answered an electronic questionnaire before and after vaccination concerning behaviour, anxiety, and symptoms of depression (Patient Health Questionnaire-9). RESULTS: Significantly fewer patients (90%) had measurable antibodies against SARS-CoV-2 compared to blood donors (100%) after the second vaccination (P < .001). Treatment with rituximab was the strongest predictor of an unfavourable vaccine response, as only 27% had measurable antibodies. Nearly all patients (97%) not treated with rituximab experienced seroconversion. Prednisone and methotrexate had a negative effect on seroconversion, but no effect of age or comorbidity was observed. Patients experienced significant improvement after vaccination in 10 out of 12 questions regarding behaviour and fear of COVID-19, while no change in Patient Health Questionnaire-9 or anxiety was observed. CONCLUSION: We find a very high seroconversion rate among rheumatic patients and reduced self-imposed isolation and shielding after COVID-19 vaccination.

Time Since Rituximab Treatment Is Essential for Developing a Humoral Response to COVID-19 mRNA Vaccines in Patients With Rheumatic Diseases.

OBJECTIVE: We aimed to investigate (1) whether patients with rheumatic disease (RD) treated with rituximab (RTX) raise a serological response toward the coronavirus disease 2019 (COVID-19) mRNA vaccines, and (2) to elucidate the influence of time since the last RTX dose before vaccination on this response. METHODS: We identified and included 201 patients with RDs followed at the outpatient clinic at the Department of Rheumatology, Aarhus University Hospital, who had been treated with RTX in the period 2017-2021 and who had completed their 2-dose vaccination series with a COVID-19 mRNA vaccine. Total antibodies against the SARS-CoV-2 spike protein were measured on all patients and 44 blood donors as reference. RESULTS: We observed a time-dependent increase in antibody response as the interval from the last RTX treatment to vaccination increased. Only 17.3% of patients developed a detectable antibody response after receiving their vaccination ≤ 6 months after their previous RTX treatment. Positive antibody response increased to 66.7% in patients who had RTX 9-12 months before vaccination. All blood donors (100%) had detectable antibodies after vaccination. CONCLUSION: Patients with RDs treated with RTX have a severely impaired serological response toward COVID-19 mRNA vaccines. Our data suggest that the current recommendations of a 6-month interval between RTX treatment and vaccination should be reevaluated.

Local and systemic reactogenicity of COVID-19 vaccine BNT162b2 in patients with systemic lupus erythematosus and rheumatoid arthritis.

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were launched in December 2020. Vaccination of patients with rheumatic diseases is recommended, as they are considered at higher risk of severe COVID-19 than the general population. Patients with rheumatic disease have largely been excluded from vaccine phase 3 trials. This study explores the safety and reactogenicity of BNT162b2 among patients with rheumatic diseases. Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), median age 58.8 years, 285 subjects in total, were vaccinated twice with the BNT162b2 (Pfizer/BioNTech). Questionnaires on reactogenicity matching the original phase 3 study were answered seven days after completed vaccination. The majority of SLE and RA patients experienced either local (78.0%) or systemic reactions (80.1%). Only 1.8% experienced a grade-4 reaction. Compared to the original study, we found more frequent fatigue [Odds ratio (OR) 2.2 (1.7-2.8)], headache [OR 1.7 (1.3-2.2)], muscle pain [OR 1.8 (1.4-2.3)], and joint pain [OR 2.3 (1.7-3.0)] in patients. In contrast, the use of antipyretics was less frequent [OR 0.5 (0.3-0.6)]. Patients with SLE and RA experience reactogenicity to the Pfizer-BioNTech BNT162b2 COVID-19 vaccine. Reactogenicity was more frequent in patients, however, not more severe compared with healthy controls.

Immune checkpoint inhibitor-induced myocarditis in cancer patients: a case report and review of reported cases.

BACKGROUND: Immune checkpoint inhibitor (ICI) induced myocarditis is a rare, severe, and often fatal adverse event. Evidence to guide appropriate immunosuppressive therapy is scarce. We present a case of ICI-induced myocarditis and a review of ICI-induced myocarditis cases to determine the most effective immunosuppressive therapeutic strategy for ICI-induced myocarditis. METHODS: A systematic search of PubMed was carried out for treatment of ICI-induced myocarditis. Reference lists from identified articles were manually reviewed for additional cases. RESULTS: A total of 87 cases with ICI-induced myocarditis were identified. The majority were melanoma (n = 39), lung cancer (n = 19), renal cell cancer (n = 10), and thymoma cancer patients (n = 4). In 38 (44%) cases, patients received high-dose steroid treatment only. A total of 49 (56%) cases were treated with immunosuppressive agents other than steroid; a total of 13 different immunosuppressive agents were used, including alemtuzumab or abatacept. The median time to onset of symptoms after initiation of ICI was 16 days (range, 1-196 days); cardiotoxic symptoms developed after 2 cycles of ICI (range, 1-13 cycles). A total of 48% of cases were fatal. In cases treated with high-dose steroids only vs. cases treated with other immunosuppressive agents, fatality was 55% and 43% respectively. In 64 out of the 87 cases, tumor control was not described. In patients treated with high-dose steroids only, two patients had stable disease as best tumor response; in patients treated with other immunosuppressive agents, one complete response, one partial response and seven stable disease were noted as best tumor response. Overall, 11 studies were at low risk of bias (12.6%), 38 at moderate risk of bias (43.7%) and 38 at high risk of bias (43.7%). CONCLUSION: Immune checkpoint inhibitor induced myocarditis is a serious and often fatal adverse event. High-dose prednisolone, alemtuzumab or abatacept are all possible treatments options for ICI-induced myocarditis, whereas infliximab increases the risk of death from cardiovascular causes, and should be avoided. Further research is needed.

Impaired Antibody Response to the BNT162b2 Messenger RNA Coronavirus Disease 2019 Vaccine in Patients With Systemic Lupus Erythematosus and Rheumatoid Arthritis.

OBJECTIVE: With a vaccine effectiveness of 95% for preventing coronavirus disease 2019 (COVID-19), Pfizer-BioNTech BNT162b2 (BNT162b2) was the first vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to be approved. However, immunosuppressive therapy was an exclusion criterion in the phase 3 trial that led to approval. Thus, extrapolation of the trial results to patients with rheumatic diseases treated with immunosuppressive drugs warrants caution. METHODS: Patients with systemic lupus erythematosus (SLE; n = 61) and rheumatoid arthritis (RA; n = 73) were included from the COPANARD (Corona Pandemic Autoimmune Rheumatic Disease) cohort, followed since the beginning of the COVID-19 pandemic. Patients received the BNT162b2 vaccine between December 2020 and April 2021. All patients had total antibodies against SARS-CoV-2 measured before vaccination and 1 week after the second vaccination (VITROS Immunodiagnostic Products). RESULTS: Of 134 patients (median age, 70 years), 77% were able to mount a detectable serological response to the vaccine. Among patients treated with rituximab, only 24% had detectable anti-SARS-CoV-2 antibodies in their serum after vaccination. The time since the last rituximab treatment did not seem to influence the vaccine response. No significant difference was observed between patients with RA or SLE when adjusting for treatment, and no correlation between antibody levels and age was detected (r = -0.12; P = 0.18). CONCLUSION: Antibody measurements against SARS-CoV-2 in patients with RA and SLE after two doses of the BNT162b2 vaccine demonstrated that 23% of patients could not mount a detectable serological response to the vaccine. B cell-depleting therapy (BCDT) is of specific concern, and our findings call for particular attention to the patients receiving BCDT.

Musculoskeletal stiffness is common in healthy adults and increases with age.

INTRODUCTION/OBJECTIVE: Musculoskeletal stiffness is a common feature in rheumatologic inflammatory diseases but little is known about background joint stiffness in the healthy population. The aim of this survey was to determine the variation in musculoskeletal stiffness with age in a cohort of healthy adults using a patient reported outcome instrument designed to assess stiffness in rheumatoid arthritis. METHODS: Healthy subjects ≥18 years old were enrolled at two sites. Those with a diagnosis of rheumatological disease were excluded. Each subject completed a 21-item questionnaire designed to evaluate the severity of musculoskeletal stiffness, its physical impact and psychosocial impact, and to provide an overall stiffness score, expressed as a percentage. Scores were analyzed by age group. RESULTS: Two hundred eighty-two subjects were included with a mean age of 42 years (±17, range 18-85). More than 50% of subjects reported stiffness in each age group but with a low median overall stiffness score of 5.4% (IQR 0, 12.6). Scores were markedly higher in those aged ≥60 years, median 10.0% (IQR 2.6, 21.9), and only in this age group did the majority of subjects report a physical or psychosocial impact of stiffness. Scores in males and females were similar. CONCLUSION: The prevalence of musculoskeletal stiffness in healthy subjects of all ages is not negligible, and the high frequency of stiffness and greater severity in the upper age cohort suggest that the background joint stiffness amongst older subjects should be considered when interpreting stiffness in rheumatologic patients.

[Lack of clinical evidence for the use of hydroxychloroquine to treat SARS-CoV-2 infection].

The severity of COVID-19 disease has led to an urgent need for the discovery of new treatments. Thus, global stocks of hydroxychloroquine (HCQ) have been put under pressure with a study of 26 patients treated with HCQ during their infection with SARS-CoV-2. Despite the study's lack of quality, several countries' medicines agencies subsequently issued guidelines for the use of HCQ for COVID-19. This review aims to elucidate potential mechanisms, which make HCQ treatment interesting in the fight against SARS-CoV-2 infection, as well as the current evidence for clinical use of HCQ to treat COVID-19.

Helicobacter pylori infection is associated with reduced prevalence of colonic diverticular disease.

BACKGROUND: Colonic diverticular disease is a common disorder with increasing incidence in Western societies. The intestinal microbiome may be among etiological factors. Helicobacter pylori may protect against some intestinal diseases, and incidence of H. pylori is decreasing in Western societies. Thus, we aimed to determine whether H. pylori is associated to decreased prevalence of registered colonic diverticular disease. MATERIALS AND METHODS: In a historical cohort study, patients were enrolled from primary health care centers after urea breath test for H. pylori and then followed for a median of 6 years. The patient's diagnostic codes and country of birth were acquired from nationwide Danish administrative registries. We used logistic regression to compare prevalence and Cox regression to compare incidence of diverticular disease between H. pylori-positive and H. pylori-negative patients, adjusting for confounding variables. RESULTS: Patients infected with H. pylori had lower prevalence of colonic diverticular disease (0.87% vs 1.14%, OR=0.62, 95% CI: 0.50-0.78). This phenomenon was observed whether we studied all registered diagnoses or only cases registered as primary diagnoses at discharge. After urea breath test, we observed no statistical difference in incidence rates of diverticular disease. CONCLUSION: H. pylori is associated with reduced prevalence of colonic diverticular disease. The inverse association was absent after the urea breath test. Thus, we speculate that H. pylori may provide protection from colonic diverticular disease. Alternatively, H. pylori is a marker for other factors affecting disease development.

21 Days head-down bed rest induces weakening of cell-mediated immunity - Some spaceflight findings confirmed in a ground-based analog.

Several studies indicate a weakening of cell-mediated immunity (CMI) and reactivation of latent herpes viruses during spaceflight. We tested the hypothesis that head-down bed rest (HDBR), a ground-based analog of spaceflight, mimics the impact of microgravity on human immunity. Seven healthy young males underwent two periods of 3 weeks HDBR in the test facility of the German Aerospace Center. As a nutritional countermeasure aimed against bone demineralisation, 90 mmol potassium bicarbonate (KHCO(3)) was administered daily in a crossover design. Blood samples were drawn on five occasions. Whole blood was stimulated with antigen i.e. Candida albicans, purified protein derivative (PPD) tuberculin, tetanus toxoid and Cytomegalovirus (CMV) (CMV-QuantiFERON). Flow cytometric analysis included CD4(+)CD25(+)CD127(-)FOXP3(+) regulatory T cells (Tregs), γδ T cells, B cells, NK cells and dendritic cells. In one of the two bed rest periods, we observed a significant decrease in production of interleukin-2 (IL-2), interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) following phytohemagglutinin (PHA) stimulation, with a rapid normalization being observed after HDBR. The cytokine levels showed a V-shaped pattern that led to a relativeTh2-shift in cytokine balance. Only three individuals responded to the specific T cell antigens without showing signs of an altered response during HDBR, nor did we observe reactivation of CMV or Epstein-Barr virus (EBV). Of unknown significance, dietary supplementation with KHCO(3) counteracted the decrease in IL-2 levels during HDBR, while there was no impact on other immunological parameters. We conclude that discrete alterations in CMI may be induced by HDBR in selected individuals.

1,25-dihydroxyvitamin D3 and dexamethasone increase interleukin-10 production in CD4+ T cells from patients with Crohn's disease.

BACKGROUND AND AIM: In Crohn's disease (CD), epidemiological data and animal studies suggest that vitamin D (vitD) has protective immune-modulating properties. 1,25-dihydroxyvitamin D3 and dexamethasone (DEX) induce interleukin (IL)-10 productions in healthy controls (HC) T cells. We studied if 1,25-dihydroxyvitamin D3 with and without DEX could induce IL-10 production, downregulate pro-inflammatory Interferon (IFN)-gamma and Tumor Necrosis Factor (TNF)-alpha production, and influence cell kinetics in peripheral CD4+ T cells from CD patients. METHODS: CD4+ T cells were separated from peripheral blood from CD patients and HC. Cells were activated by anti-CD3 and anti-CD28 in the presence of 1,25-dihydroxyvitamin D3 and/or DEX. Cytokine levels, proliferation, and apoptosis were measured following 7 days of culture. RESULTS: In T cells from CD patients, 1,25-dihydroxyvitamin D3 and DEX increased IL-10 production from a median of 0.08 ng/ml to 0.2 ng/ml (p<0.01) and downregulated IFN-gamma production from 8.3 ng/ml to 3.1 ng/ml (p<0.01). The induced IL-10 increase in cultures from HC (0.2 ng/ml to 1.0 ng/ml, p<0.01) was significantly higher than in CD patients (p<0.05). In CD cultures, the IL-4 production increased from 0.3 ng/ml to 0.5 ng/ml (p<0.01) and IL-6 production from 2.5 ng/ml to 6.1 ng/ml (p<0.05). Similar changes in cytokine levels were observed with 1,25-dihydroxyvitamin D3 independently of DEX. In addition, 1,25-dihydroxyvitamin D3 and DEX decreased proliferation and reduced viability of T cells. CONCLUSION: We found that 1,25-dihydroxyvitamin D3 with and without DEX stimulation increased IL-10 and reduced IFN-gamma production. These findings suggest that vitD may play a therapeutic role in CD.

[Vitamin D insufficiency--possible etiologic factor of autoimmune diseases]. / D-vitamin-insufficiens--en mulig aetiologisk faktor ved autoimmune sygdomme.

The primary source of vitamin D in humans is sun exposure to the skin. The incidence of certain autoimmune diseases correlates positively with latitude. As vitamin D production increases with sun exposure, vitamin D insufficiency is hypothesised to influence the development of autoimmune diseases. In experimental animal and cellular studies in vitro 1.25-(OH)2-vitamin D reduces inflammation. This article discusses the role of vitamin D in inflammatory bowel disease, type 1 diabetes mellitus, multiple sclerosis, and rheumatoid arthritis.