Disruption of CCR5 signaling to treat COVID-19-associated cytokine storm: Case series of four critically ill patients treated with leronlimab.

Coronavirus disease 2019 (COVID-19) is associated with considerable morbidity and mortality. The number of confirmed cases of infection with SARS-CoV-2, the virus causing COVID-19 continues to escalate with over 70 million confirmed cases and over 1.6 million confirmed deaths. Severe-to-critical COVID-19 is associated with a dysregulated host immune response to the virus, which is thought to lead to pathogenic immune dysregulation and end-organ damage. Presently few effective treatment options are available to treat COVID-19. Leronlimab is a humanized IgG4, kappa monoclonal antibody that blocks C-C chemokine receptor type 5 (CCR5). It has been shown that in patients with severe COVID-19 treatment with leronlimab reduces elevated plasma IL-6 and chemokine ligand 5 (CCL5), and normalized CD4/CD8 ratios. We administered leronlimab to 4 critically ill COVID-19 patients in intensive care. All 4 of these patients improved clinically as measured by vasopressor support, and discontinuation of hemodialysis and mechanical ventilation. Following administration of leronlimab there was a statistically significant decrease in IL-6 observed in patient A (p=0.034) from day 0-7 and patient D (p=0.027) from day 0-14. This corresponds to restoration of the immune function as measured by CD4+/CD8+ T cell ratio. Although two of the patients went on to survive the other two subsequently died of surgical complications after an initial recovery from SARS-CoV-2 infection.

Albuminuria: when urine predicts kidney and cardiovascular disease.

Albuminuria is common. Traditionally considered a precursor to diabetic nephropathy, it has now been directly linked to adverse cardiovascular outcomes and death, independent of other risk factors. In this review, we compare the measures of albuminuria, examine the evidence linking it to renal failure, cardiovascular disease, and death, and provide recommendations for its testing and management.

Persistence and adherence to disease modifying drugs among patients with multiple sclerosis.

OBJECTIVE: This retrospective database study aimed to evaluate the adherence of multiple sclerosis (MS) patients on immunomodulatory treatments using claims data, and to identify differences between compliance and persistency measurements in the context of this disease. METHODS: Continuously enrolled MS patients treated with subcutaneous IFNbeta-1b (Betaseron * ), subcutaneous IFNbeta-1a (Rebif dagger ), intramuscular IFNbeta-1a (Avonex double dagger ), and subcutaneous glatiramer acetate (Copaxone section sign ).) were identified from the PharMetrics patient-centric database, and all information related to patient demographics and pharmacy claims for the drugs of interest were extracted. OUTCOME MEASURES: The main outcomes were treatment switches and discontinuations for patients initiated on the drugs of interest. Various compliance and persistency metrics including the proportion of days covered, treatment prevalence at 6-monthly time points after initiation, and the continuous time on drug were also examined. RESULTS: A total of 6134 MS patients were started on one of the four drugs of interest. The number of patients switching or discontinuing therapy rose over the study period. The proportion of patients switching was similar between study drugs, by the different metrics, with the highest switch rates for subcutaneous IFNbeta-1b and the lowest for subcutaneous glatiramer acetate. Discontinuation rates were highest for subcutaneous IFNbeta-1b and lowest for intramuscular IFNbeta-1a. Regression models showed that intramuscular IFNbeta-1a and subcutaneous IFNbeta-1a had similar and higher persistency compared to subcutaneous IFNbeta-1b and subcutaneous glatiramer acetate. CONCLUSIONS: Although treatment switching and discontinuation is common in MS patients, there is some noticeable variability between drugs and across measures of persistency and adherence. Also, claims data do not allow distinguishing between clinical patterns of MS, direct estimation of disease severity and observation of care that occurs outside of insurance coverage, and results need to be cautiously interpreted. The compliance to the various MS drugs was 80% or higher at all times for all four drugs. The highest rate of treatment persistency existed in the intramuscular IFNbeta-1a initiator group, while subcutaneous IFNbeta-1b was associated with a significantly lower persistence (p < 0.0001).

Healthcare resource utilization following switch or discontinuation in multiple sclerosis patients on disease modifying drugs.

OBJECTIVE: The objective of this study was to explore the cost and utilization in the period following discontinuations or switches of disease modifying drugs (DMDs) for patients with multiple sclerosis (MS). Secondary objectives included an assessment of the time to switch or discontinuation from index DMD treatment. METHODS: Cases were defined as a billed MS diagnosis in continuously enrolled patients initiated with interferon-beta1a IM, interferon-beta1b SC, glatiramer acetate, and interferon-beta1a SC found in the PharMetrics Patient-Centric Database. Information on patient demographics, diagnoses, procedures, pharmacy-dispensed drugs, and costs was extracted; reasons for discontinuation and expenses outside of the healthcare system were not available. Treatment discontinuations and switches between study drugs were defined using pharmacy prescription patterns and analyzed by descriptive and regression methods. The non-pharmacy medical costs in the 18 months following switching or discontinuation were compared to the costs in a randomly selected similar period for those patients who did not switch or discontinue these agents. RESULTS: A total of 5,772 MS patients were continuously enrolled and were treated with one or more of the four drugs of interest, and about half of these patients switched drugs or discontinued treatment for at least 90 days. Patients initiated with interferon-beta1b SC were more likely to discontinue treatment compared to interferon-beta1a IM users. Non-pharmaceutical medical costs were highest for those switching treatments followed by those discontinuing DMDs in the 18 months following a switch or discontinuation, compared to persistent users of these drugs. Interferon beta1b SC initiators had higher costs following changes or discontinuations, while glatiramer acetate and interferon-beta1a SC users had lower subsequent costs compared to interferon-beta1a IM users. LIMITATIONS: Unfortunately, the reasons for stopping the initial treatment cannot be determined from analysis of an administrative claims database. Also, the MS cases followed in this analysis are billing diagnostic events unconfirmed through a review of medical records or other data sources. The results are unstratified in terms of severity and thus while treatment patterns may vary for patients with different types of MS (e.g., progressive vs. relapsing-remitting), this cannot be examined in this analysis. CONCLUSION: Changing or discontinuing DMDs is common among MS patients and is associated with higher non-pharmaceutical medical costs that vary based on the initiating drug and other demographics characteristics.

Feasibility of using a large Clinical Data Warehouse to automate the selection of diagnostic cohorts.

Data from Clinical Data Warehouses (CDWs) can be used for retrospective studies and for benchmarking. However, automated identification of cases from large datasets containing data items in free text fields is challenging. We developed an algorithm for categorizing pediatric patients presenting with respiratory distress into Bronchiolitis, Bacterial pneumonia and Asthma using clinical variables from a CDW. A feasibility study of this approach indicates that case selection may be automated.