Delayed cutaneous hypersensitivity reactions following the use of infliximab or adalimumab in patients with coronavirus disease 2019.

Recent evidence has emerged concerning delayed cutaneous hypersensitivity reactions after infliximab or adalimumab applications in patients with coronavirus disease 2019 (COVID-19). A few real-world studies compared the events, clinical features, and prognosis of infliximab- or adalimumab-related delayed cutaneous hypersensitivity reactions in COVID-19 patients. Disproportionality analysis and Bayesian analysis were utilized to determine the suspected adverse events of delayed cutaneous hypersensitivity reactions after infliximab or adalimumab use based on the Food and Drug Administration's Adverse Event Reporting Systems (FAERS) from May 2020 to December 2021. Additionally, the times to onset and fatality rates of delayed cutaneous hypersensitivity reactions following infliximab or adalimumab were compared. In total, 475 reports of delayed cutaneous hypersensitivity reactions were associated with infliximab or adalimumab. Females were affected almost twice more than males. Among the two therapies, infliximab had the highest association with delayed cutaneous hypersensitivity reactions based on the highest reporting odds ratio (2.14, 95% two-sided confidence interval [CI] = 1.2-3.81), proportional reporting ratio (1.95, χ2 = 7.03), and empirical Bayesian geometric mean (1.94, 95% one-sided CI = 1.2). Infliximab-related delayed cutaneous hypersensitivity reactions had earlier onset (0 [interquartile range (IQR): 0-0] days vs. 166.5 (IQR: 18-889.5) days, p < 0.05), while adalimumab-related delayed cutaneous hypersensitivity reactions have higher fatality rate (0.44% vs. 0.00%). Based on the FAERS database, we profiled delayed cutaneous hypersensitivity reactions related to infliximab or adalimumab application in patients with COVID-19 with more points of occurrences, clinical characteristics, and prognosis.

Infliximab in the treatment of patients with severe COVID-19 (INFLIXCOVID): protocol for a randomised, controlled, multicentre, open-label phase II clinical study.

BACKGROUND: Despite the intense global research endeavour to improve the treatment of patients with COVID-19, the current therapy remains insufficient, resulting in persisting high mortality. Severe cases are characterised by a systemic inflammatory reaction driven by the release of pro-inflammatory cytokines such as IL-6 and tumour-necrosis-factor alpha (TNF-α). TNF-α-blocking therapies have proved beneficial in patients with chronic inflammatory diseases and could therefore pose a new treatment option in COVID-19. Hitherto, no results from randomised controlled trials assessing the effectiveness and safety of infliximab-a monoclonal antibody targeting TNF-α-in the treatment of COVID-19 have been published. METHODS: In this phase-2 clinical trial, patients with COVID-19 and clinical and laboratory signs of hyperinflammation will be randomised to receive either one dose of infliximab (5 mg/kg body weight) in addition to the standard of care or the standard of care alone. The primary endpoint is the difference in 28-day mortality. Further assessments concern the safety of infliximab therapy in COVID-19 and the influence of infliximab on morbidity and the course of the disease. For the supplementary scientific programme, blood and urine samples are collected to assess concomitant molecular changes. The Ethics Committee of the Friedrich Schiller University Jena (2021-2236-AMG-ff) and the Paul-Ehrlich-Institute (4513/01) approved the study. DISCUSSION: The results of this study could influence the therapy of patients with COVID-19 and affect the course of the disease worldwide, as infliximab is globally available and approved by several international drug agencies. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov ( NCT04922827 , 11 June 2021) and at EudraCT ( 2021-002098-25 , 19 May 2021).

Incidence of COVID-19 in patients treated with infliximab compared with patients treated with rituximab.

OBJECTIVE: To determine whether patients with inflammatory autoimmune diseases treated with rituximab (RTX) have more severe forms of COVID-19 compared with patients treated with anticytokine therapies, such as Tumour Necrosis Factor (TNF) inhibitors. METHODS: We included all patients who were on either RTX or infliximab (IFX) in two Swiss cantons during the first wave of the COVID-19 pandemic. We collected self-reported symptoms compatible with COVID-19, PCR-confirmed diagnoses of COVID-19 and the evolution of COVID-19 infections. We computed the raw and propensity score-adjusted incidence of COVID-19 by treatment group. RESULTS: 190 patients were enrolled, of whom 121 (64%) were in the RTX group and 69 (36%) were in the IFX group. Twenty-one patients (11%) reported symptoms compatible with COVID-19 (RTX: 10, IFX: 11, p=0.14). Among patients with COVID-19 symptoms, four developed severe forms of the disease, with life-threatening pulmonary manifestations requiring intensive mechanical ventilation (RTX: 4 of 10, IFX: 0 of 11, Fisher's exact test p=0.04). The incidence rate of COVID-19 symptoms was 0.73 (95% CI 0.39 to 1.37) cases per 1000 patient-days on RTX vs 1.52 (95% CI 0.82 to 2.85) cases per 1000 patient-days on IFX (crude p=0.10, adjusted p=0.07). The incidence rate of severe COVID-19 was 0.28 (95% CI 0.08 to 0.7.2) cases per 1000 patient-days on RTX compared with null on IFX (95% CI 0.0 to 0.44) (p=0.13). A replication in an independent validation cohort confirmed these findings, with consistent results in the Swiss Clinical Quality Management registry. CONCLUSION: While the incidence of symptoms compatible with COVID-19 was overall similar in patients receiving RTX or IFX, the incidence of severe COVID-19 tended to be higher in the RTX group.

Large-Scale Postmarketing Surveillance of Biological Drugs for Immune-Mediated Inflammatory Diseases Through an Italian Distributed Multi-Database Healthcare Network: The VALORE Project.

BACKGROUND: Biological drugs have improved the management of immune-mediated inflammatory diseases (IMIDs) despite being associated with important safety issues such as immunogenicity, infections, and malignancies in real-world settings. OBJECTIVE: The aim of this study was to explore the potential of a large Italian multi-database distributed network for use in the postmarketing surveillance of biological drugs, including biosimilars, in patients with IMID. METHODS: A retrospective cohort study was conducted using 13 Italian regional claims databases during 2010-2019. A tailor-made R-based tool developed for distributed analysis of claims data using a study-specific common data model was customized for this study. We measured the yearly prevalence of biological drug users and the frequency of switches between originator and biosimilars for infliximab, etanercept, and adalimumab separately and stratified them by calendar year and region. We then calculated the cumulative number of users and person-years (PYs) of exposure to individual biological drugs approved for IMIDs. For a number of safety outcomes (e.g., severe acute respiratory syndrome coronavirus 2 [SARS-COV-2] infection), we conducted a sample power calculation to estimate the PYs of exposure required to investigate their association with individual biological drugs approved for IMIDs, considering different strengths of association. RESULTS: From a total underlying population of almost 50 million inhabitants from 13 Italian regions, we identified 143,602 (0.3%) biological drug users, with a cumulative exposure of 507,745 PYs during the entire follow-up. The mean age ± standard deviation of biological drug users was 49.3 ± 16.3, with a female-to-male ratio of 1.2. The age-adjusted yearly prevalence of biological drug users increased threefold from 0.7 per 1000 in 2010 to 2.1 per 1000 in 2019. Overall, we identified 40,996 users of biosimilars of tumor necrosis factor (TNF)-α inhibitors (i.e., etanercept, adalimumab, and infliximab) in the years 2015-2019. Of these, 46% (N = 18,845) switched at any time between originator and biosimilars or vice versa. To investigate a moderate association (incidence rate ratio 2) between biological drugs approved for IMIDs and safety events of interest, such as optic neuritis (lowest background incidence rate 10.4/100,000 PYs) or severe infection (highest background incidence rate 4312/100,000 PYs), a total of 43,311 PYs and 104 PYs of exposure to individual biological drugs, respectively, would be required. As such, using this network, of 15 individual biological drugs approved for IMIDs, the association with those adverse events could be investigated for four (27%) and 14 (93%), respectively. CONCLUSION: The VALORE project multi-database network has access to data on more than 140,000 biological drug users (and > 0.5 million PYs) from 13 Italian regions during the years 2010-2019, which will be further expanded with the inclusion of data from other regions and more recent calendar years. Overall, the cumulated amount of person-time of exposure to biological drugs approved for IMIDs provides enough statistical power to investigate weak/moderate associations of almost all individual compounds and the most relevant safety outcomes. Moreover, this network may offer the opportunity to investigate the interchangeability of originator and biosimilars of several TNFα inhibitors in different therapeutic areas in real-world settings.

Switching infliximab in psoriatic patients during COVID-19 pandemics: A real-life retrospective study comparing intra-versus interclass switching strategies.

During this pandemic, dermatological infusion centers were partially unavailable, suspended or even reconverted to guest COVID-19 patients, consequently infliximab (IFX) infusions became challenging for their both logistic arrangement and also for patients' COVID-19 phobia. This 48 weeks follow-up retrospective observational study included 37 PsO patients that underwent IFX SB2 during pandemic in two primary dermatological referral centers. In 23 (62.1%) we had to switch from IFX to other biologics, not motivated by adverse reactions, contraindication or even loss of response but only to pandemic related conditions. Nine patients underwent interclass switching and 15 underwent intraclass switching; interestingly 2 patients that underwent adalimumab SB-5 switched back to IFX. Interclass switching was privileged in elder patients and smokers. All patients at week 48 achieved PASI 100. Intra- and interclass switchings are both safe and effective strategies in psoriatic patients with COVID-19 phobia and/or difficulties to undergo infliximab infusions.

Network meta-analysis of infliximab biosimilars for the treatment of rheumatoid arthritis.

PURPOSE: This article assesses the relative efficacy and safety of infliximab biosimilars in treatment of patients with rheumatoid arthritis (RA). METHODS: A frequentist, random-effects network meta-analysis was performed to evaluate evidence from randomized controlled trials that examined the use of infliximab biosimilars for treatment of patients with RA. PubMed/MEDLINE and other sources were searched for reports evaluating rates of response to treatment with the reference product (infliximab) vs an infliximab biosimilar. The primary efficacy outcome of interest was the rate of attainment of ACR20 (ie, 20% improvement in American College of Rheumatology core measures). The primary safety outcome was the rate of treatment-related serious adverse events (SAEs). Data were extracted by the primary author, and an assessment for risks of methodological bias was performed for each evaluated study. RESULTS: Five studies that enrolled a total of 2,499 patients were included. Overall comparisons using odds ratios and 95% confidence intervals (CIs) did not indicate statistically significant differences in response to treatment with biosimilar agents relative to each other or the infliximab reference product. ORs for ACR20 response for biosimilars vs infliximab were as follows: 1.475 (95% CI, 0.940-2.315) for infliximab-axxq, 1.259 (95% CI, 0.854-1.855) for infliximab-dyyb, 0.865 (95% CI, 0.5511.358) for infliximab-qbtx, and 0.832 (95% CI, 0.506-1.367) for infliximab-abda. Similar findings were observed in reported SAE rates among patients treated with the various biosimilars. CONCLUSION: ACR20 response appears to be comparable and nonsignificantly different between infliximab biosimilars. In the absence of any meaningful differences in safety or efficacy, biosimilar cost may be the deciding factor in choosing a treatment or agent for formulary inclusion.

Safety of Biological Therapy in Children With Inflammatory Bowel Disease.

OBJECTIVES: Retrospective, observational, single-center, cohort study investigating the safety profile of biological therapy in children with inflammatory bowel disease (IBD). METHODS: Retrospective, observational, cohort study of pediatric patients with IBD, receiving infliximab, adalimumab, vedolizumab, or ustekinumab for at least 2 months. Data related to the immediate and delayed adverse events (AEs) were collected, focusing on the reaction type and severity, the time of onset, the outcome and the temporary or definitive therapy discontinuation secondary to the AE. Number of suspected and confirmed coronavirus disease-209 (COVID-19) cases and their outcomes, as well as flu vaccination coverage were collected. RESULTS: One hundred eighty-five children were included (101 [55%] CD, 82 [44%] UC, and 2 [1%] IBDU): 149 received infliximab (IFX) (81%), 88 (48%) adalimumab (ADA), 18 (21%) vedolizumab, and 4 (2%) ustekinumab. The overall AE rates were 49%, 67% of whom likely medication-related. Eleven (6%) patients experienced more than 1 AE, 18 patients (10%) presented an immediate reaction, and 82 (45%) a delayed AE. Among the 90 patients experiencing at least 1 AE, 97% had mild-to-moderate AEs. Only 4 SAEs were reported (4%). Treatment discontinuation because of AE occurred in 25 patients (14%). Four COVID-19 cases were reported, all with a mild course. CONCLUSIONS: Our findings confirm a good safety profile of biologics. Infusion reactions to IFX administration remain one of the main issues, significantly linked to its immunogenicity and consequently with an impact on its efficacy and durability.

COVID-19 patients with psoriasis and psoriatic arthritis on biologic immunosuppressant therapy vs apremilast in North Spain.

Immunosuppressive and immunomodulatory treatments are critical for the management of inflammatory and autoimmune conditions such as psoriasis or psoriatic arthritis. Similar to those illnesses, the lung injury and acute respiratory distress shown in coronavirus disease 2019 (COVID-19) patients are the result of a disruption in the balance of pro- and anti-inflammatory cytokines. This hyperinflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), associated with the severity of the coronavirus disease, is called the cytokine storm. There is a growing concern regarding how patients on immunosuppressant biologic therapies might be at higher risk of being infected and whether they need to discontinue their treatment preemptively. Clinical data on COVID-19-infected patients with psoriasis or psoriatic arthritis are still scarce. Here, we presented seven cases of these type of patients. The patient infected with COVID-19 on apremilast and the one on apremilast with infected spouse showed the best safety profile and mildest symptoms. One of the secukinumab patients also presented a relatively good outcome. Infliximab patients and the one with serious comorbidities showed the worst outcome. Even though more clinical data are yet needed to draw strong conclusions, apremilast could be a safer alternative for dermatology and rheumatology patients in case of clinically important active infection.