Interleukin-1 Inhibitors and Vaccination Including COVID-19 in Inflammatory Rheumatic Diseases: A Nonsystematic Review.

Newly emerging variants of coronavirus 2 (SARS-CoV-2) raise concerns about the spread of the disease, and with the rising case numbers, the Coronavirus disease 2019 (COVID-19) remains a challenging medical emergency towards the end of the year 2021. Swiftly developed novel vaccines aid in the prevention of the spread, and it seems that a specific cure will not be at hand soon. The prognosis of COVID-19 in patients with autoimmune/autoinflammatory rheumatic diseases (AIIRD) is more severe when compared to the otherwise healthy population, and vaccination is essential. Evidence for both the efficacy and safety of COVID-19 vaccination in AIIRD under immunosuppression is accumulating, but the effect of Interleukin-1 on vaccination in general and in AIIRD patients is rarely addressed in the current literature. In light of the current literature, it seems that the level of agreement on the timing of COVID-19 vaccination is moderate in patients using IL-1 blockers, and expert opinions may vary. Generally, it may be recommended that patients under IL-1 blockade can be vaccinated without interrupting the anti-cytokine therapy, especially in patients with ongoing high disease activity to avoid disease relapses. However, in selected cases, after balancing for disease activity and risk of relapses, vaccination may be given seven days after the drug levels have returned to baseline, especially for IL-1 blocking agents with long half-lives such as canakinumab and rilonacept. This may help to ensure an ideal vaccine response in the face of the possibility that AIIRD patients may develop a more pronounced and severe COVID-19 disease course.

Immunogenicity of SARS-CoV-2 vaccination in rituximab-treated patients: Effect of timing and immunologic parameters.

Rituximab (RTX), an important therapeutic option for patients with rheumatic diseases, has been shown to reduce immune responses to various vaccines. We asked whether following SARS-CoV-2 vaccination, response rates in RTX treated patients are reduced and whether specific patient characteristics influence the responses. We recruited patients on chronic RTX therapy undergoing anti-SARS-CoV2 vaccination and measured the post-vaccination anti-spike IgG antibody levels. The median time from pre-vaccination RTX infusion to vaccination and from vaccination to the post-vaccination RTX infusion was 20.5 weeks and 7.2 weeks respectively. Only 36.5% of patients developed measurable titers of IgG anti-SARS-CoV-2 spike antibody after vaccination. Hypogammaglobulinemia (IgG and/or IgM) but not timing of vaccination, B cell numbers, or concomitant immune suppressive medications, correlated with sero-negativity (p = 0.004). Our results underscore the fact that even after B cell reconstitution, RTX induced chronic hypogammaglobulinemia significantly impairs the ability of the immune system to respond to SARS-CoV-2 vaccination.

A prospective multicenter study assessing humoral immunogenicity and safety of the mRNA SARS-CoV-2 vaccines in Greek patients with systemic autoimmune and autoinflammatory rheumatic diseases.

OBJECTIVES: To investigate humoral responses and safety of mRNA SARS-CoV-2 vaccines in systemic autoimmune and autoinflammatory rheumatic disease (SAARD) patients subjected or not to treatment modifications during vaccination. METHODS: A nationwide, multicenter study, including 605 SAARD patients and 116 controls, prospectively evaluated serum anti-SARS-CoV-2 S1-protein IgG antibody titers, side-effects, and disease activity, one month after complete vaccination, in terms of distinct treatment modification strategies (none, partial and extended modifications). Independent risk factors associated with hampered humoral responses were identified by data-driven multivariable logistic regression analysis. RESULTS: Patients with extended treatment modifications responded to vaccines similarly to controls as well as SAARD patients without immunosuppressive therapy (97.56% vs 100%, p = 0.2468 and 97.56% vs 97.46%, p > 0.9999, respectively). In contrast, patients with partial or without therapeutic modifications responded in 87.50% and 84.50%, respectively. Furthermore, SAARD patients with extended treatment modifications developed higher anti-SARS-CoV-2 antibody levels compared to those without or with partial modifications (median:7.90 vs 7.06 vs 7.1, p = 0.0003 and p = 0.0195, respectively). Mycophenolate mofetil (MMF), rituximab (RTX) and methotrexate (MTX) negatively affected anti-SARS-CoV-2 humoral responses. In 10.5% of vaccinated patients, mild clinical deterioration was noted; however, no differences in the incidence of deterioration were observed among the distinct treatment modification SAARD subgroups. Side-effects were generally comparable between SAARD patients and controls. CONCLUSIONS: In SAARD patients, mRNA SARS-CoV-2 vaccines are effective and safe, both in terms of side-effects and disease flares. Treatment with MMF, RTX and/or MTX compromises anti-SARS-CoV-2 antibody responses, which are restored upon extended treatment modifications without affecting disease activity.

COVID-19: Overview of rheumatology fellows.

SARS-COV-2 infection has spread worldwide since it originated in December 2019, in Wuhan, China. The pandemic has largely demonstrated the resilience of the world's health systems and is the greatest health emergency since World War II. There is no single therapeutic approach to the treatment of COVID-19 and the associated immune disorder. The lack of randomised clinical trials (RCTs) has led different countries to tackle the disease based on case series, or from results of observational studies with off-label drugs. We as rheumatologists in general, and specifically rheumatology fellows, have been on the front line of the pandemic, modifying our activities and altering our training itinerary. We have attended patients, we have learned about the management of the disease and from our previous experience with drugs for arthritis and giant cell arteritis, we have used these drugs to treat COVID-19.

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.

Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Autoimmunity 1 Year Later: The Era of Vaccines.

Impressive efforts have been made by researchers worldwide in the development of target vaccines against the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and in improving the management of immunomodulating agents. Currently, different vaccine formulations, such as viral vector, mRNA, and protein-based, almost all directed toward the spike protein that includes the domain for receptor binding, have been approved. Although data are not conclusive, patients affected by autoimmune rheumatic diseases (ARDs) seem to have a slightly higher disease prevalence, risk of hospitalization, and death from coronavirus disease-2019 (COVID-19) than the general population. Therefore, ARD patients, under immunosuppressive agents, have been included among the priority target groups for vaccine administration. However, specific cautions are needed to optimize vaccine safety and effectiveness in these patients, such as modification in some of the ongoing immunosuppressive therapies and the preferential use of mRNA other than vector-based vaccines. Immunomodulating agents can be a therapeutic opportunity for the management of COVID-19 patients; however, their clinical impact depends on how they are handled. To place in therapy immunomodulating agents in the correct window of opportunity throughout the identification of surrogate markers of disease progression and host immune response is mandatory to optimize patient's outcome.

Adverse events of six COVID-19 vaccines in patients with autoimmune rheumatic diseases: a cross-sectional study.

Data regarding COVID-19 vaccine efficacy and adverse events (AE) in patients with autoimmune and inflammatory rheumatic diseases (AIIRD) have been published recently although these mostly include the mRNA vaccines (Pfizer-BioNTech and Moderna) and the ChAdOx1 nCoV-19/AZD1222 (Oxford-AstraZeneca). This research aimed to study the prevalence of AE presented with six different SARS-CoV-2 vaccines {ChadOX1 nCoV-19 (AZD1222), Ad5-nCoV2, Ad26.COV2.S, mRNA-1273, BNT162b2, and CoronaVac} in Mexican patients with AIIRD. We performed a cross-sectional study about vaccine history. Two hundred and twenty five consecutive patients were recruited, mean age was 50.7 years and the majority (n = 213; 94.6%) were females. One hundred and seven (47.5%) received BNT162b2 mRNA, 34 (15.1%) Ad5-nCoV, 29 (12.8%) mRNA-1273, 28 (12.4%) ChAdOX1 nCoV-19 (AZD1222), 22 (9.7%) CoronaVac and 5 (2.2%) Ad26.COV2.S. The vaccines that had the most AE proportionally to the number of patients vaccinated were Janssen (5; 100%) followed by Pfizer-BioNTEch (86; 80%) and CanSinoBIO (27; 79.4%). Localized pain was the most frequent (158; 70.2%) AE. Fatigue (78; 34.7%), headache (69; 30.6%) and muscle ache (66; 29.3%) were the most common systemic symptoms. No serious AE that required medical attention or hospitalization were reported. The current results support the safety of different COVID-19 vaccines in patients with AIIRD. This information can help fight vaccine hesitancy in this population.

Serologic Response to Coronavirus Disease 2019 (COVID-19) Vaccination in Patients With Immune-Mediated Inflammatory Diseases: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Patients with immune-mediated inflammatory diseases (IMIDs) have an increased risk of coronavirus disease 2019 (COVID-19), primarily attributed to the use of immunosuppressive drugs such as glucocorticoids, which may attenuate the response to vaccines. This meta-analysis assessed the serologic response to COVID-19 vaccination in patients with IMIDs. METHODS: Electronic databases were searched on August 1, 2021, for observational studies. Data extracted included reference population, medications, vaccination, and proportion of patients achieving a serologic response. RESULTS: The analysis included 25 observational studies (5360 patients). Most of the studies used messenger RNA (mRNA) vaccines (BNT162b2, mRNA-1273), with a small number of studies including other types of vaccines (AZD1222, CoronaVac, BBV152, Ad26.COV2.S). Serologic response after 1 dose (6 studies) and 2 doses (17 studies) of mRNA vaccine were 73.2% (95% confidence interval [CI], 65.7%-79.5%) and 83.4% (95% CI, 76.8%-88.4%), respectively. On meta-regression, anti-CD20 therapy was associated with lower response rates (P < .001) and anti-tumor necrosis factor therapy also showed a trend toward lower response rates (P = .058). Patients with IMIDs were less likely to achieve a serologic response compared with controls after 2 doses of mRNA vaccine (6 studies; odds ratio, 0.086; 95% CI, 0.036-0.206; P < .001). There were not enough studies to assess response to the adenoviral or inactivated vaccines. CONCLUSIONS: Our meta-analysis demonstrated that patients with IMIDs have a reduced response to mRNA COVID-19 vaccines. These results suggest that IMID patients receiving mRNA vaccines should complete the vaccine series without delay and support the strategy of providing a third dose of the vaccine.

Disease activity and humoral response in patients with inflammatory rheumatic diseases after two doses of the Pfizer mRNA vaccine against SARS-CoV-2.

BACKGROUND: The registration trials of messenger RNA (mRNA) vaccines against SARS-CoV-2 did not address patients with inflammatory rheumatic diseases (IRD). OBJECTIVE: To assess the humoral response after two doses of mRNA vaccine against SARS-CoV-2, in patients with IRD treated with immunomodulating drugs and the impact on IRD activity. METHODS: Consecutive patients treated at the rheumatology institute, who received their first SARS-CoV-2 (Pfizer) vaccine, were recruited to the study, at their routine visit. They were reassessed 4-6 weeks after receiving the second dose of vaccine, and blood samples were obtained for serology. IRD activity assessment and the vaccine side effects were documented during both visits. IgG antibodies (Abs) against SARS-CoV-2 were detected using the SARS-CoV-2 IgG II Quant (Abbott) assay. RESULTS: Two hundred and sixty-four patients with stable disease, (mean(SD) age 57.6 (13.18) years, disease duration 11.06 (7.42) years), were recruited. The immunomodulatory therapy was not modified before or after the vaccination. After the second vaccination, 227 patients (86%) mounted IgG Ab against SARS-CoV-2 (mean (SD) 5830.8 (8937) AU/mL) and 37 patients (14%) did not, 22/37 were treated with B cell-depleting agents. The reported side effects of the vaccine were minor. The rheumatic disease remained stable in all patients. CONCLUSIONS: The vast majority of patients with IRD developed a significant humoral response following the administration of the second dose of the Pfizer mRNA vaccine against SARS-CoV-2 virus. Only minor side effects were reported and no apparent impact on IRD activity was noted.

A bond between rheumatic diseases and cancer in the elderly: The interleukin-6 pathway.

Interleukin (IL)-6 is a soluble factor secreted by T lymphocytes, involved in antibody generation by B lymphocytes. The IL-6 pathway has risen as a pivotal pathway implicated in immune regulation and dysregulation in various rheumatic diseases. Nonetheless, elevated IL-6 levels can also play a role in cancer. Targeting the IL-6 pathway has led to innovative therapeutic approaches for rheumatic diseases and for COVID-19, particularly in the elderly. Indeed, tocilizumab, an agent targeting IL-6, has recently amassed significant attention as a promising univocal agent for different conditions. In this viewpoint, we sought to recall and describe the common pathway among osteoarthritis, rheumatoid arthritis, and cancer, suggesting that anti-IL-6 may be considered a jack-of-all-trades against inflammaging in the elderly.

Disease Flare and Reactogenicity in Patients With Rheumatic and Musculoskeletal Diseases Following Two-Dose SARS-CoV-2 Messenger RNA Vaccination.

OBJECTIVE: To evaluate disease flare and postvaccination reactions (reactogenicity) in patients with rheumatic and musculoskeletal diseases (RMDs) following 2-dose SARS-CoV-2 messenger RNA (mRNA) vaccination. METHODS: RMD patients (n = 1,377) who received 2-dose SARS-CoV-2 mRNA vaccination between December 16, 2020 and April 15, 2021 completed questionnaires detailing local and systemic reactions experienced within 7 days of each vaccine dose (dose 1 and dose 2), and 1 month after dose 2, detailing any flares of RMD. Associations between demographic/clinical characteristics and flares requiring treatment were evaluated using modified Poisson regression. RESULTS: Among the patients, 11% reported flares requiring treatment; there were no reports of severe flares. Flares were associated with prior SARS-CoV-2 infection (incidence rate ratio [IRR] 2.09, P = 0.02), flares in the 6 months preceding vaccination (IRR 2.36, P < 0.001), and the use of combination immunomodulatory therapy (IRR 1.95, P < 0.001). The most frequently reported local and systemic reactions included injection site pain (87% after dose 1, 86% after dose 2) and fatigue (60% after dose 1, 80% after dose 2). Reactogenicity increased after dose 2, particularly for systemic reactions. No allergic reactions or SARS-CoV-2 diagnoses were reported. CONCLUSION: Flares of underlying RMD following SARS-CoV-2 vaccination were uncommon. There were no reports of severe flares. Local and systemic reactions typically did not interfere with daily activity. These early safety data can help address vaccine hesitancy in RMD patients.

COVID-19 vaccine hesitancy in patients with systemic autoimmune rheumatic disease: an interview-based survey.

Patients with a systemic autoimmune rheumatic disease (AIRD) are vulnerable to SARS Cov-2 infection. Vaccination against this infection can prevent the patients from developing severe disease. But vaccine hesitancy in this group can emerge as a hurdle. So there is a need to understand the perception regarding vaccination in AIRD patients. The study is an interview-based survey done in AIRD patients and a control group from the general population. The questionnaire included the subject's demographic details, duration, diagnosis, the activity of AIRD, and questions regarding the perception of the vaccination. The survey included 280 patients with AIRD and 102 control subjects. 54% (152/280) of the patients and 67% (68/102) of the controls were willing to get vaccinated (p = 0.03). Patients > 45-years of age were more willing to vaccinate than those with age ≤ 45-years (61.9% vs. 44.8%; p = 0.001). Patients with lower education had more vaccine hesitancy than those with graduation and above (38% vs. 69%; p < 0.001). The common reason for vaccine hesitancy was not-yet-decided, fear related to vaccine side-effects, and disease worsening. 29% (82/280) patients were already vaccinated, out of which 35% (35/82) had mild events (fever/myalgia/headache). AIRD patients had fewer side effects than controls, and disease flare was seen in only one patient. Thus, educating AIRD patients regarding the pros and cons of vaccination, particularly concerning immunological disease, can help us overcome vaccine hesitancy. The message should clearly penetrate that there is a negligible risk of AIRD-flares with the COVID-19 immunization and the side effects are mild and manageable.