Implementation of an Accelerated Infusion Protocol (90-Minute Infusion) of Rituximab and Its Safety in Patients With Autoimmune Rheumatic Diseases at a Tertiary Veterans Affairs Center.

Background Rituximab, a chimeric monoclonal antibody targeting the CD20 protein on the surface of B cells, is used to treat several rheumatologic and oncologic diseases. The standard infusion duration of rituximab is four hours. Objective Evaluating the safety of administering the accelerated 90-minute protocol at our Veterans Affairs center to patients with rheumatologic diseases and monitoring for any infusion-related reactions. This study is unique as it examines infusion rates faster than those most described (120 minutes). Methods Patients treated with rituximab for autoimmune diseases between June 2020 and June 2022 at our center were included in the study. Our patients were over 18 years of age, met the inclusion criteria, and had received previous rituximab infusions without prior infusion-related reactions. They received the accelerated protocol of 90 minutes over their next cycles and were monitored for any reactions during their infusions. Results A total of 34 patients receiving 76 infusions were included in the analysis. Most of the patients were males (n = 27). The most prevalent indication for rituximab infusion was rheumatoid arthritis (n = 20). Out of 76 infusions, only two infusion-related reactions were recorded (2.6% incidence). The first patient had itching and a sore throat, indicating a grade 1A reaction. The second patient developed chest pain and dyspnea, which resolved with diphenhydramine and albuterol. For both, the infusion was completed after appropriate management. Conclusion The incidence of infusion-related reactions during the accelerated 90-minute rituximab infusion was remarkably low and well-tolerated by our rituximab-experienced patients. Only two infusions were complicated by a reaction, an incidence comparable to or even lower than other reported 120-minute infusion protocols. This protocol is time- and cost-efficient, allowing for more infusions per chair per day at our center.

Self-reported determinants of COVID-19 vaccine acceptance among persons with and without autoimmune disease.

OBJECTIVE: Patients with autoimmune disease (AD) are at increased risk for complications from COVID-19 infection, so, optimizing vaccine utilization in this population is of particular importance. We compared COVID-19 vaccination perspectives among persons with and without AD. METHODS: 471 patients in the MetroHealth System and Cleveland Veteran Affairs Medical Center completed a 38-item questionnaire between August 2021 and February 2022. This survey containing questions regarding COVID-19 vaccine perceptions and demographics was administered both to unvaccinated individuals and individuals who delayed vaccination for at least 2 months. Multivariable ordinary least squares regression models were created to assess factors associated with vaccination likelihood. RESULTS: The number of reasons given for (p < 0.001) and against receiving COVID-19 vaccination (p < 0.001) were highly associated with increased and decreased vaccination likelihood respectively. Factors most closely associated with obtaining vaccine were: protecting family (p = 0.045) personal safety (p < 0.001) and preventing serious infection (p < 0.001). Reasons associated with decreased vaccination likelihood were: lack of concern of COVID-19 infection (p < 0.001), vaccine safety (p < 0.001) and beliefs that the vaccine was made too quickly (p = 0.024). AD patients were more likely to cite having a chronic condition (29.1 % vs 17.1 %, p = 0.003) and physician recommendation(s) (18.4 % vs 9.1 %, p = 0.005) as reasons for vaccination and were more concerned about potential medication interaction than non-AD respondents (22.4 % vs 3.3 %, p < 0.001). CONCLUSION: The number of benefits of vaccination identified strongly related to vaccination likelihood. Affirmative provider recommendations correlated with increased vaccination likelihood in AD patients. Clinical conversations centered on the benefits of COVID-19 vaccination may help increase vaccine acceptance.

Higher Vitamin D Levels before Methotrexate Therapy Initiation Are Associated with Lower Subsequent Mortality in Patients with Rheumatoid Arthritis.

(1) Vitamin D deficiency is associated with mortality in the general population and has been observed in one rheumatoid arthritis (RA) cohort. Here, we investigate the relationship between 25-hydroxyvitamin D (25(OH)D) levels before methotrexate (MTX) therapy initiation in patients with RA and the subsequent all-cause mortality in a national Veterans Affairs (VA) cohort. (2) This is a retrospective study on RA patients time-oriented around the initial MTX prescription and 25(OH)D levels before starting MTX. We examined survival in patients with 25(OH)D levels > 50 nmol/L and ≤50 nmol/L using the Cox Proportional Hazard Model and fully adjusted for risk factors. (3) In total, 15,109 RA patients were included in the nationwide cohort. RA patients with 25(OH)D levels > 50 nmol/L before starting MTX had a 28% reduced risk of mortality when compared to those with levels ≤ 50 nmol/L (HR: 0.72, CI: 0.64-0.80, p < 0.001) after adjusting for traditional risk factors. (4) In this national RA cohort receiving standard-of-care MTX, patients with 25(OH)D levels > 50 nmol/L have a lower subsequent mortality when compared to those with 25(OH)D levels ≤ 50 nmol/L. It remains to be determined whether increasing Vitamin D levels in RA patients initially found to be Vitamin D deficient impacts their all-cause mortality.

Rheumatoid arthritis and older age are associated with lower humoral and cellular immune response to primary series COVID-19 mRNA vaccine.

OBJECTIVE: People with autoimmune disease have worse COVID-19 infection-related outcomes, lower antibody responses to COVID-19 vaccine, and higher rates of breakthrough infection. Immunosuppressive medications used to treat rheumatoid arthritis (RA) are associated with lower COVID-19 vaccine responses, though independent contributions of comorbidities, T-cell immunity, and age are less clear. We sought to test the hypothesis that RA, immunosuppressive medications used to treat RA, and older age, contribute to reduced B and T cell response to COVID-19 vaccine. METHODS: We evaluated serum samples, taken the day of 1st vaccine dose, the day of 2nd dose, 2-6 weeks after 2nd dose, 7-12 weeks after 2nd dose, 13-24 weeks after 2nd dose, and 2-6 weeks after the 3rd dose, for anti-spike IgG and neutralizing antibody levels to Wuhan and Omicron BA.1 and peripheral blood mononuclear cells (PBMC) for spike-specific IFN-γ and IL-2 production by ELISPOT assay in 46 RA and 101 non-autoimmune control participants before and after the primary series COVID-19 mRNA vaccination. RESULTS: RA participants had lower spike-specific IgG and Wuhan-strain neutralizing antibody levels 2-6 weeks compared to controls after the second dose of primary vaccine series. Neutralizing antibody levels against Omicron BA.1 were low in both groups. IFN-γ production correlated with Wuhan neutralizing antibody levels, while older age negatively correlated with spike-specific IL-2, IFN-γ and IgG. Lower antibody levels were associated with older age, RA status, and medication usage, while lower T cell responses were associated primarily with older age. CONCLUSIONS: These data indicate lower COVID-19 mRNA vaccine-induced antibody levels in persons with RA compared to individuals without RA, likely partially attributable to immune suppressive medications. At the same time, older age is associated with lower antibody and cellular immune response to COVID-19 vaccines.

COVID-19 vaccination experience in patients with rheumatoid arthritis treated at a single VA medical center.

Background: Following the introduction of the COVID-19 vaccines, there has been uncertainty as to whether receiving the COVID-19 vaccine will result in overactivation of the immune system and subsequently lead to an autoimmune disease flare.The purpose of this study was to assess whether rheumatoid arthritis (RA) patients who received the mRNA COVID-19 vaccine are at increased risk for disease flare. Methods: We conducted a single-center retrospective and prospective study at the Louis Stokes Cleveland VA Medical Center between 12/2021 and 2/2022. We included 100 patients with rheumatoid arthritis (RA) who were actively on immunosuppressive therapy and received three doses of the Pfizer-BioNTech vaccine. A survey questionnaire was used to collect data about their RA and if they developed symptoms post vaccination. Our primary end point was to determine incidence of flare of RA after COVID-19 vaccine. Secondary end points were to estimate the side effect profile from the vaccine, and to check if patients developed a COVID-19 infection after they received the vaccine. Results: None of the patients reported symptoms of RA flare within two months of receiving the 3 doses of the vaccine. Most common vaccine side effects were soreness over the injection site (n = 14), headache (n = 11), fatigue(n = 7) and myalgias(n = 4). 5 patients developed a COVID-19 infection prior to receiving the vaccine, 8 after being vaccinated, 3 of the 8 within 5 months from the second dose and 5 out of the 8 within 3 months from the third vaccine dose. Conclusion: RA patients receiving the COVID-19 Pfizer mRNA vaccine do not appear to commonly develop major symptoms, flares or side effects following the vaccine. Further research with larger numbers of patients with rheumatoid arthritis as well as those with other autoimmune disease is needed to better understand the safety and effectiveness of COVID-19 vaccine.

Financial Incentives Are Associated with Lower Likelihood of COVID-19 Vaccination in Northeast Ohio.

BACKGROUND: Declining COVID-19 vaccination rates have led to implementation of monetary incentives to increase vaccine uptake. The Ohio Vax-a-Million lottery and subsequent $100 incentives were created to encourage individuals to become vaccinated. The purpose of this survey was to determine the efficacy of these monetary incentives on vaccination rates. METHODS: A 38-item questionnaire was given to outpatients at MetroHealth and Cleveland Veteran Affairs Hospitals between August 2021 and February 2022 who either waited 2 or more months to receive the COVID-19 vaccination or have not yet been vaccinated. The survey contained questions regarding demographics and perceptions of COVID-19 monetary incentives on vaccination likelihood. RESULTS: Of the 471 participants surveyed, 0.95% reported that the Ohio Vax-a-Million lottery increased their vaccination likelihood, while 29.7% reported that it decreased their likelihood. 6.8% of respondents reported the $100 incentive increased their vaccination likelihood while 17.4% reported it decreased their vaccination chances. 20.6% of participants stated news of the Delta (δ) variant increased their vaccination likelihood. CONCLUSION: Our study results suggest that monetary incentives were not associated with increased COVID-19 vaccination rates. Instead, more participants believed that these incentives decreased their vaccination likelihood. Expansion of the survey across a wider sociodemographic range can provide further evidence of the efficacy of these programs before reimplementation.

Red Cell Distribution Width and Absolute Lymphocyte Count Associate With Biomarkers of Inflammation and Subsequent Mortality in Rheumatoid Arthritis.

OBJECTIVE: Morbidity and mortality in rheumatoid arthritis (RA) is partly mitigated by maintaining immune and hematologic homeostasis. Identification of those at risk is challenging. Red cell distribution width (RDW) and absolute lymphocyte count (ALC) associate with cardiovascular disease (CVD) and mortality in the general population, and with disease activity in RA. How these variables relate to inflammation and mortality in RA was investigated. METHODS: In a retrospective single Veterans Affairs (VA) Rheumatology Clinic cohort of 327 patients with RA treated with methotrexate (MTX)+/- a tumor necrosis factor (TNF) inhibitor (TNFi), we evaluated RDW and ALC before and during therapy and in relation to subsequent mortality. Findings were validated in a national VA cohort (n = 13,914). In a subset of patients and controls, we evaluated inflammatory markers. RESULTS: In the local cohort, high RDW and low ALC prior to MTX treatment was associated with subsequent mortality over 10 years (both P < 0.001). The highest mortality was observed in those with both high RDW and low ALC. This remained after adjusting for age and comorbidities and was validated in the national RA cohort. In the immunology cohort, soluble and cellular inflammatory markers were higher in patients with RA than in controls. ALC correlated with age, plasma TNF receptor II, natural killer HLA-DR mean fluorescence intensity, and CD4CM/CD8CM HLA-DR/CD38%, whereas RDW associated with age and ALC. MTX initiation was followed by an increase in RDW and a decrease in ALC. TNFi therapy added to MTX resulted in an increase in ALC. CONCLUSION: RDW and ALC before disease-modifying antirheumatic drug therapy are associated with biomarkers of monocyte/macrophage inflammation and subsequent mortality. The mechanistic linkage between TNF signaling and lymphopenia found here warrants further investigation.

A Case Series on the COVID-19 Vaccines and Possible Immune-Related Adverse Events: A New Challenge for the Rheumatologists.

The COVID-19 pandemic has been a prime health issue since December 2019. Consequently, there has been an urgent need to prevent severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection and its associated morbidity and mortality. The currently available vaccines are designed to prevent infection. Their efficacy and safety have been demonstrated in clinical trials. Yet, given the short duration of the trials and the urgency to start vaccination, adverse events have been reported worldwide in real-life data format. Immune-mediated disease flares or new-onset inflammatory diseases following vaccine administration have recently been reported worldwide. Here, we present three cases of inflammatory arthritis (IA) caused by the BNT162b2 COVID vaccination, including two new-onset cases and one case of a flare of existing disease. The first case is new-onset IA, the second case is new-onset rheumatoid arthritis, and the third case is a flare of existing rheumatoid arthritis. Given the timeline of when our patients developed either a flare of their existing rheumatoid arthritis or new-onset IA or polymyalgia rheumatica (PMR) (a few days after receiving the COVID-19 vaccine), in addition to the currently available evidence of documented similar cases post administration of mRNA vaccines, as well as the link between their mechanism of action and the pathogenesis of those diseases, we can speculate a causal relationship between the vaccine and the triggering of these disease entities. In the future, it is important to consider that autoimmune diseases might be triggered or flared by the administration of vaccines, which appears to be associated with the COVID vaccine as well. Further evaluation of its incidence will provide additional clarity, though the rarity of this occurrence in the setting of more than half of the US population becoming vaccinated indicates that the benefit of the vaccine in terms of protection from COVID morbidity and mortality far outweighs this risk.

Transient elastography score is elevated during rheumatoid factor-positive chronic hepatitis C virus infection and rheumatoid factor decline is highly variable over the course of direct-acting antiviral therapy.

BACKGROUND: Elevated rheumatoid factor (RF) levels and systemic immune activation are highly prevalent during chronic hepatitis C virus (HCV) infection. Direct-acting antiviral (DAA) therapy has been associated with normalization of various soluble immune activation parameters. Whether the RF levels relate to soluble immune activation markers during chronic HCV infection, and over what time frame RF levels normalize during and after DAA treatment is unknown and was investigated here. METHODS: In a longitudinal study, plasma and serum was obtained from HCV infected RF positive (RF+) and RF negative (RF-) participants. The levels of RF, HCV RNA and soluble markers of inflammation were determined before (week 0), during (weeks 4, 8 and 12) and after (week 24) treatment with HCV DAA therapy. In a subset of RF+ participants, the analysis was extended to over 70 weeks after therapy initiation. Hepatic and other clinical parameters were determined at baseline (week 0) in all participants. RESULTS: Before therapy, transient elastography (TE) score was greater in RF+ compared to RF- HCV infected participants, while the systemic levels of soluble inflammatory markers were comparable. Following DAA therapy initiation, HCV RNA levels became undetectable within 4 weeks in both the RF+ and RF- groups. RF levels declined in the first 6 months in most RF+ persons but most commonly remained positive. The levels of some soluble inflammatory markers declined, mainly within 4 weeks of DAA therapy start, in both the RF+ and RF- groups. The baseline (week 0) TE score correlated with RF levels before, during and after DAA therapy, while plasma IL-18 levels correlated with RF level after DAA therapy. CONCLUSION: During chronic HCV infection, TE score is elevated in RF+ HCV infected individuals and factors other than HCV viremia (including liver stiffness or fibrosis and select markers of inflammation) likely contribute to persistence of RF after treatment of HCV with DAA.

Red Cell Distribution Width Is Positively Correlated with Atherosclerotic Cardiovascular Disease 10-Year Risk Score, Age, and CRP in Spondyloarthritis with Axial or Peripheral Disease.

BACKGROUND: Red blood cell distribution width (RDW) is a routine hematologic parameter that is a predictor of cardiovascular disease (CVD) events and is independent of combined traditional risk factor scoring systems. The RDW has also been associated with rheumatic disease activity. Whether RDW is associated with traditional CVD risk factors or Atherosclerotic Cardiovascular Disease (ASCVD) 10-year CVD risk score in patients with seronegative spondyloarthritis with axial or peripheral disease has not been previously determined. METHODS: We performed a retrospective, chart review study evaluating the relationship between RDW, albumin, hemoglobin, C-reactive protein (CRP), absolute lymphocyte count (ALC), and ASCVD scoring parameters [age, hypertension status, diabetes mellitus (DM) status, lipid profile, and smoking status] in a cohort of spondyloarthritis patients, taking into consideration their HLA-B27 status, race, and treatment status. RESULTS: RDW was found to positively correlate with ASCVD 10-year score and age, and ASCVD score did not change over time after patients were treated for spondyloarthritis. Albumin was found to negatively correlate with ASCVD 10-year risk score. Both RDW and albumin correlated with CRP. ALC failed to correlate with ASCVD 10-year score but did show a tendency to be associated with CVD, CVD events, and cardiac conduction abnormalities. CONCLUSIONS: These data indicate that further study is warranted to evaluate RDW, albumin level, and ALC as potential predictors of CVD in the spondyloarthritis patient population.

Achieving Sustained Viral Remission in Patients with Chronic HCV Infection and Cryoglobulinemic Vasculitis Does Not Always Correlate with Normalization of the Serologic Markers.

OBJECTIVE: We aim to describe the persistence of symptoms associated with HCV-associated cryoglobulinemic vasculitis following achievement of (SVR) with IFN- free direct acting antiviral (DAA) therapy. In particular, we describe the persistence of C4 hypocomplementemia and positive Rheumatoid Factor (RF). METHODS: We analyzed a case series of four patients enrolled from the Cleveland VA and known to have chronic HCV infection complicated by mixed cryoglobulinemia. The study included patients treated with interferon (IFN) based treatment and IFN free direct acting antiviral (DAA) therapy. RESULTS: Of the four patients, patients 1 and 2 experienced decline of RF without resolution following DAA therapy. Patient 1 continues to have evidence of disease following treatment. Patient 3 did not have resolution of RF during IFN-based treatment and experienced stabilization of kidney function while on treatment. Patient 4, previously a non-responder to IFN based treatment, experienced significant decline in RF titers along with resolution of cryoglobulin-associated rash with DAA therapy. C4 remained low following treatment in patients 1 and 3. Of the four patients, only patient 1 had prolonged persistence of cryoglobulinemia, measured at 3%, 17 months following achievement of SVR. CONCLUSIONS: We highlight the complexity of the viral-mediated immunologic mechanism that causes cryoglobulinemic vasculitis. Our cases also emphasize the need to consider cryoglobulinemic vasculitis as part of the differential diagnosis even with treated HCV infection. Recognizing these findings are important in our understanding of the pathophysiology of the disease and management in the era of IFN-free DAA therapy.