Targeting chronic COVID-19 lung injury; Tofacitinib can be used against tissue-resident memory T cells.

Post-Covid pulmonary fibrosis is evident following severe COVID-19. There is an urgent need to identify the cellular and pathophysiological characteristics of chronic lung squeals of Covid-19 for the development of future preventive and/or therapeutic interventions. Tissue-resident memory T (TRM) cells can mediate local immune protection against infections and cancer. Less beneficially, lung TRM cells cause chronic airway inflammation and fibrosis by stimulating pathologic inflammation. The effects of Janus kinase (JAK), an inducer pathway of cytokine storm, inhibition on acute Covid-19 cases have been previously evaluated. Here, we propose that Tofacitinib by targeting the CD8+ TRM cells could be a potential candidate for the treatment of chronic lung diseases induced by acute SARS-CoV-2 infection.

A guide to immunotherapy for COVID-19.

Immune dysregulation is an important component of the pathophysiology of COVID-19. A large body of literature has reported the effect of immune-based therapies in patients with COVID-19, with some remarkable successes such as the use of steroids or anti-cytokine therapies. However, challenges in clinical decision-making arise from the complexity of the disease phenotypes and patient heterogeneity, as well as the variable quality of evidence from immunotherapy studies. This Review aims to support clinical decision-making by providing an overview of the evidence generated by major clinical trials of host-directed therapy. We discuss patient stratification and propose an algorithm to guide the use of immunotherapy strategies in the clinic. This will not only help guide treatment decisions, but may also help to design future trials that investigate immunotherapy in other severe infections.

Case Report: Home-based Management of Severe COVID-19 with Low-dose Tofacitinib.

Human lives and nations' economies have been adversely affected worldwide by the COVID-19 pandemic. The hyperinflammatory state associated with the disease may be related to mortality. Systemic glucocorticoid is the first-line therapy for cytokine storm. Various immunomodulatory drugs such as tocilizumab and baricitinib have been used in those not responding to glucocorticoid monotherapy. Amid the peak crisis of COVID-19 in India, there was an extreme paucity of medications, oxygen, and hospital beds. We describe three patients with COVID-19 who received low-dose tofacitinib (an oral Janus kinase inhibitor) in addition to moderate-dose glucocorticoid. These patients were treated at their homes, as the hospitals were short of beds. Rapid reduction in hypoxemia along with gradual resolution of other signs of the disease were observed. The results are reassuring regarding the feasibility of managing of severe COVID-19 outside the hospital setting when healthcare resources are overwhelmed by pandemic-related caseload.

Treatment efficacy and safety of tofacitinib versus methotrexate in Takayasu arteritis: a prospective observational study.

OBJECTIVE: To compare the treatment efficacy and safety of tofacitinib (TOF) versus methotrexate (MTX) in Takayasu arteritis (TAK). METHODS: Fifty-three patients with active disease from an ongoing prospective TAK cohort in China were included in this study. Twenty-seven patients were treated with glucocorticoids (GCs) and TOF, and 26 patients were treated with GCs with MTX. The observation period was 12 months. Complete remission (CR), inflammatory parameter changes, GCs tapering and safety were assessed at the 6th, 9th and 12th month. Vascular lesions were evaluated at the 6th and 12th month, and relapse was analysed during 12 months. RESULTS: The CR rate was higher in the TOF group than in the MTX group (6 months: 85.19% vs 61.54%, p=0.07; 12 months: 88.46% vs 56.52%, p=0.02). During 12 months' treatment, patients in the TOF group achieved a relatively lower relapse rate (11.54% vs 34.78%, p=0.052) and a longer median relapse-free duration (11.65±0.98 vs 10.48±2.31 months, p=0.03). Average GCs dose at the 3rd, 6th and 12th month was lower in the TOF group than that in the MTX group (p<0.05). A difference was not observed in disease improvement or disease progression on imaging between the two groups (p>0.05). Prevalence of side effects was low in both groups (3.70% vs 15.38%, p=0.19). CONCLUSION: TOF was superior to MTX for CR induction, a tendency to prevent relapse and tapering of the GCs dose in TAK treatment. A good safety profile for TOF was also documented in patients with TAK.

Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial.

BACKGROUND: Patients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate safety and efficacy of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls. METHODS: 539 study subjects (449 patients and 90 controls) were included. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/CAR T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection. FINDINGS: Adverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72.2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43.4%) and CLL (63.3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively. INTERPRETATION: The results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. Rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups to improve immunity. FUNDING: Knut and Alice Wallenberg Foundation, the Swedish Research Council, Nordstjernan AB, Region Stockholm, Karolinska Institutet, and organizations for PID/CLL-patients in Sweden.

2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19.

OBJECTIVES: To update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19. METHODS: According to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting. RESULTS: We updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapy CONCLUSIONS: Growing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19.

Atogepant for the Preventive Treatment of Migraine.

BACKGROUND: Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist that is being investigated for the preventive treatment of migraine. METHODS: In a phase 3, double-blind trial, we randomly assigned adults with 4 to 14 migraine days per month in a 1:1:1:1 ratio to receive a once-daily dose of oral atogepant (10 mg, 30 mg, or 60 mg) or placebo for 12 weeks. The primary end point was the change from baseline in the mean number of migraine days per month across the 12 weeks. Secondary end points included headache days per month, a reduction from baseline of at least 50% in the 3-month average of migraine days per month, quality of life, and scores on the Activity Impairment in Migraine-Diary (AIM-D). RESULTS: A total of 2270 participants were screened, 910 were enrolled, and 873 were included in the efficacy analysis; 214 were assigned to the 10-mg atogepant group, 223 to the 30-mg atogepant group, 222 to the 60-mg atogepant group, and 214 to the placebo group. The mean number of migraine days per month at baseline ranged from 7.5 to 7.9 in the four groups. The changes from baseline across 12 weeks were -3.7 days with 10-mg atogepant, -3.9 days with 30-mg atogepant, -4.2 days with 60-mg atogepant, and -2.5 days with placebo. The mean differences from placebo in the change from baseline were -1.2 days with 10-mg atogepant (95% confidence interval [CI], -1.8 to -0.6), -1.4 days with 30-mg atogepant (95% CI, -1.9 to -0.8), and -1.7 days with 60-mg atogepant (95% CI, -2.3 to -1.2) (P<0.001 for all comparisons with placebo). Results for the secondary end points favored atogepant over placebo with the exceptions of the AIM-D Performance of Daily Activities score and the AIM-D Physical Impairment score for the 10-mg dose. The most common adverse events were constipation (6.9 to 7.7% across atogepant doses) and nausea (4.4 to 6.1% across atogepant doses). Serious adverse events included one case each of asthma and optic neuritis in the 10-mg atogepant group. CONCLUSIONS: Oral atogepant once daily was effective in reducing the number of migraine days and headache days over a period of 12 weeks. Adverse events included constipation and nausea. Longer and larger trials are needed to determine the effect and safety of atogepant for migraine prevention. (Funded by Allergan; ADVANCE ClinicalTrials.gov number, NCT03777059.).

Keeping a balance in chronic lymphocytic leukemia (CLL) patients taking ibrutinib: ibrutinib-associated adverse events and their management based on drug interactions.

INTRODUCTION: Ibrutinib is a highly effective drug for patients with chronic lymphocytic leukemia (CLL), and is well tolerated even by older patients and those unfit to receive conventional immuno-chemotherapy. AREAS COVERED: The occurrence of adverse events was revealed as a major cause of ibrutinib failure in the real-world. Ibrutinib-induced lymphocytosis carries the risk of an untimely interruption of therapy because it may be misinterpreted as disease progression. In addition, drug interactions can worsen ibrutinib-associated toxicities by increasing the plasma concentration of ibrutinib. In this review, we present a case of major hemorrhage and atrial fibrillation (AF) during ibrutinib use and summarize the adverse events associated with ibrutinib. Furthermore, the practical management of ibrutinib-associated toxicities was covered with reference to a drug interaction mechanism. EXPERT OPINION: Clinicians should examine the prescribed drugs prior to ibrutinib initiation and carefully monitor toxicities while taking ibrutinib. A reduced dose of ibrutinib with the concurrent use of CYP3A inhibitors such as antifungal agents could be an attractive strategy to reduce toxicities and may confer financial benefits. Reducing unexpected toxicities is as significant as achieving treatment response in the era of life-long therapy with ibrutinib in patients with CLL.

Structure-Based Virtual Screening Reveals Ibrutinib and Zanubrutinib as Potential Repurposed Drugs against COVID-19.

Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2). Recent clinical trials reported that the use of Bruton's tyrosine kinase (BTK) inhibitors to treat COVID-19 patients could reduce dyspnea and hypoxia, thromboinflammation, hypercoagulability and improve oxygenation. However, the mechanism of action remains unclear. Thus, this study employs structure-based virtual screening (SBVS) to repurpose BTK inhibitors acalabrutinib, dasatinib, evobrutinib, fostamatinib, ibrutinib, inositol 1,3,4,5-tetrakisphosphate, spebrutinib, XL418 and zanubrutinib against SARS-CoV-2. Molecular docking is conducted with BTK inhibitors against structural and nonstructural proteins of SARS-CoV-2 and host targets (ACE2, TMPRSS2 and BTK). Molecular mechanics-generalized Born surface area (MM/GBSA) calculations and molecular dynamics (MD) simulations are then carried out on the selected complexes with high binding energy. Ibrutinib and zanubrutinib are found to be the most potent of the drugs screened based on the results of computational studies. Results further show that ibrutinib and zanubrutinib could exploit different mechanisms at the viral entry and replication stage and could be repurposed as potential inhibitors of SARS-CoV-2 pathogenesis.

Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia.

BACKGROUND: The efficacy and safety of tofacitinib, a Janus kinase inhibitor, in patients who are hospitalized with coronavirus disease 2019 (Covid-19) pneumonia are unclear. METHODS: We randomly assigned, in a 1:1 ratio, hospitalized adults with Covid-19 pneumonia to receive either tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until hospital discharge. The primary outcome was the occurrence of death or respiratory failure through day 28 as assessed with the use of an eight-level ordinal scale (with scores ranging from 1 to 8 and higher scores indicating a worse condition). All-cause mortality and safety were also assessed. RESULTS: A total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumulative incidence of death or respiratory failure through day 28 was 18.1% in the tofacitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P = 0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the placebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the tofacitinib group and in 17 (12.0%) in the placebo group. CONCLUSIONS: Among patients hospitalized with Covid-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo. (Funded by Pfizer; STOP-COVID ClinicalTrials.gov number, NCT04469114.).

Development and validation of a rapid high-performance thin-layer chromatographic method for quantification of gallic acid, cinnamic acid, piperine, eugenol, and glycyrrhizin in Divya-Swasari-Vati, an ayurvedic medicine for respiratory ailments.

Divya-Swasari-Vati is a calcium containing polyherbal ayurvedic medicine prescribed for the lung-related ailments observed in the current pandemic of Severe Acute Respiratory Syndrome Coronavirus 2 infections. The formulation is a unique quintessential blend of nine herbs cited in Ayurvedic texts for chronic cough and lung infection. Analytical standardization of herbal medicines is the pressing need of the hour to ascertain the quality compliance. This persuaded us to develop a simple, rapid, and selective high-performance thin-layer chromatographic method for Divya-Swasari-Vati quality standardization. The developed method was validated for the quantification of marker components, gallic acid, cinnamic acid, piperine, eugenol and glycyrrhizin, against reference standards in five different batches of Divya-Swasari-Vati. The analytes were identified by visualization at 254 nm, and by matching their retention factor with authentic standards. The developed method was validated as per the guidelines recommended by the International Council for Harmonization for parameters like, linearity, limit of detection, limit of quantification, accuracy, and precision. Therefore, the developed novel high-performance thin-layer chromatographic process could be employed for rapid standardization of Divya-Swasari-Vati and other related herbal formulation, which would aid in quality manufacturing and product development.