Anemia in female patients with myasthenia gravis.

Myasthenia gravis (MG) is the most common autoimmune neuromuscular disorder, and is more common in women than in men. Anemia is also more common in women. The purpose of this study was to investigate factors associated with anemia and the negative impact of anemia in female MG patients. We investigated factors related to MG and anemia in 215 female patients with MG, who were attending the MG clinic of Keio Hospital between January and December 2021. We statistically evaluated clinical factors related to anemia in patients with and without anemia. Eighty-five patients (40%) had anemia in the past, and 130 patients did not have anemia in the past. There were no significant differences in age at study, age at MG onset, body mass index, or frequency of autoantibodies between the anemia and non-anemia groups. MG severity evaluated by the MG Foundation of America classification was greater in the anemia group than in the non-anemia group. History of anemia was associated with immunosuppressive treatment, such as prednisolone and calcineurin inhibitor treatment. There was a correlation between hemoglobin levels and the MG-quality of life score. Long term immunosuppressive therapy can cause anemia in female MG patients. Anemia may negatively affect the quality of life of female MG patients.

The Cyclophilin-Dependent Calcineurin Inhibitor Voclosporin Inhibits SARS-CoV-2 Replication in Cell Culture.

Kidney transplant recipients (KTRs) are at increased risk for a more severe course of COVID-19, due to their pre-existing comorbidity and immunosuppression. Consensus protocols recommend lowering immunosuppression in KTRs with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but the optimal combination remains unclear. Calcineurin inhibitors (CNIs) are cornerstone immunosuppressants used in KTRs and some have been reported to possess antiviral activity against RNA viruses, including coronaviruses. Here, we evaluated the effect of the CNIs tacrolimus, cyclosporin A, and voclosporin (VCS), as well as other immunosuppressants, on SARS-CoV-2 replication in cell-based assays. Unexpected, loss of compound due to plastic binding and interference of excipients in pharmaceutical formulations (false-positive results) complicated the determination of EC50 values of cyclophilin-dependent CNI's in our antiviral assays. Some issues could be circumvented by using exclusively glass lab ware with pure compounds. In these experiments, VCS reduced viral progeny yields in human Calu-3 cells at low micromolar concentrations and did so more effectively than cyclosporin A, tacrolimus or other immunosuppressants. Although, we cannot recommend a particular immunosuppressive regimen in KTRs with COVID-19, our data suggest a potential benefit of cyclophilin-dependent CNIs, in particular VCS in reducing viral progeny, which warrants further clinical evaluation in SARS-CoV-2-infected KTRs.

Factors Associated With COVID-19 Vaccine Response in Transplant Recipients: A Systematic Review and Meta-analysis.

BACKGROUND: The rapid development and universal access to vaccines represent a milestone in combating the coronavirus disease 2019 (COVID-19) pandemic. However, there are major concerns about vaccine response in immunocompromised populations in particular transplant recipients. In the present study, we aim to comprehensively assess the humoral response to COVID-19 vaccination in both orthotopic organ transplant and allogeneic hematopoietic stem cell transplant recipients. METHODS: We performed a systematic review and meta-analysis of 96 studies that met inclusion criteria. RESULTS: The pooled rates of seroconversion were 49% (95% confidence interval [CI], 43%-55%) in transplant recipients and 99% (95% CI, 99%-99%) in healthy controls after the second dose of vaccine. The pooled rate was 56% (95% CI, 49%-63%) in transplant recipients after the third dose. Immunosuppressive medication is the most prominent risk factor associated with seroconversion failure, but different immunosuppressive regimens are associated with differential outcomes in this respect. Calcineurin inhibitors, steroids, or mycophenolate mofetil/mycophenolic acid are associated with an increased risk of seroconversion failure, whereas azathioprine or mammalian target of rapamycin inhibitors do not. Advanced age, short interval from receiving the vaccine to the time of transplantation, or comorbidities confers a higher risk for seroconversion failure. CONCLUSIONS: Transplant recipients compared with the general population have much lower rates of seroconversion upon receiving COVID-19 vaccines. Immunosuppressants are the most prominent factors associated with seroconversion, although different types may have differential effects.

Early clinical experience with nirmatrelvir/ritonavir for the treatment of COVID-19 in solid organ transplant recipients.

Nirmatrelvir/ritonavir (NR) use has not yet been described in solid organ transplant recipients (SOTRs) with mild COVID-19. The objective was to evaluate outcomes among SOTR and describe the drug-drug interaction of NR. This is an IRB-approved, retrospective study of all adult SOTR on a calcineurin inhibitor (CNI) or mammalian target of rapamycin inhibitor who were prescribed NR between December 28, 2021 and January 6, 2022. A total of 25 adult SOTR were included (n = 21 tacrolimus, n = 4 cyclosporine, n = 3 everolimus, n = 1 sirolimus). All patients were instructed to follow the following standardized protocol during treatment with 5 days of NR: hold tacrolimus or mTOR inhibitor or reduce cyclosporine dose to 20% of baseline daily dose. Four patients (16%) were hospitalized by day 30; one for infectious diarrhea and three for symptoms related to COVID-19. No patients died within 30 days of receipt of NR. Median tacrolimus level pre- and post-NR were 7.4 ng/ml (IQR, 6.6-8.6) and 5.2 (IQR, 3.6-8.7), respectively. Four patients experienced a supratherapeutic tacrolimus concentration after restarting tacrolimus post-NR. Our results show the clinically significant interaction between NR and immunosuppressive agents can be reasonably managed with a standardized dosing protocol. Prescribers should carefully re-introduce CNI after the NR course is complete.

Calcineurin inhibitors and related medicines: a cohort study examining England's primary care prescription changes during the COVID-19 pandemic (January 2019 to March 2021).

PURPOSE: To examine the impact of the COVID-19 pandemic on calcineurin inhibitors and related prescriptions for community patients in England. METHODS: Data from all primary-care patients who had calcineurin inhibitors prescriptions, dispensed in the community in England were included. Descriptive statistics and interrupted time series analysis over 27 months (15 months before and 12 months after 1st lockdown) was evaluated. RESULTS: Descriptive statistics show that mean values have declined since the pandemic's onset. Over the 27 months: mean Tacrolimus 865,045 doses, standard deviation (SD) 76,147 doses, with 95% CI 834,923, 895,168, (min 567,508, max 1,010,900), ciclosporin 315,496 doses, SD 40,094, 95% CI 299,635, 331,356 (min 191,281, max 382,253) and sirolimus 21,384 doses, SD 2,610, 95% CI 20,352, 22,417 (min 13,022, max 26,156). Analysis of variance between the pre- and post- periods show significant variations in quantities of tacrolimus F 7.432, p = 0.012, ciclosporin F 33.147, p < 0.001 and sirolimus F 18.596, p < 0.001 (1df), mirrored in price analysis. The Interrupted Time Series (ARIMA Modelling) shows declining trends. After the pandemic's onset, a statistically significant downward trend in quantity for tacrolimus p = 0.008 is observed, with an estimated monthly decline of 14,524 doses, ciclosporin p = 0.185, with an estimated decline of 2,161 doses and sirolimus p = 0.002 with an estimated decline of 485 doses, along with declining prices. CONCLUSION: A decrease in prescription medicines use raises concerns for the care of (renal) transplant patients. Patients are encouraged to discuss their planned care with their doctor, secure supplies and remain adherent to their medication.

COVID-19 survivors with calcineurin-inhibitors-treated rheumatoid arthritis.

We report two cases recovered from coronavirus disease 2019 with rheumatoid arthritis which had been in remission or low disease activity by taking calcineurin inhibitor (CNI). Both cases had moderate to severe pneumonia treated with intravenous dexamethasone or in the severe case remdesivir in addition to it. These cases suggest that the use of CNI may have affected the improvement of severe pneumonia.

Voclosporin: First Approval.

Voclosporin (Lupkynis™) is an oral calcineurin inhibitor immunosuppressant that is being developed by Aurinia Pharmaceuticals. In January 2021, based on positive results from the pivotal phases II and III trials, oral voclosporin received its first approval in the USA for use in combination with a background immunosuppressive therapy regimen for adults with active lupus nephritis. Voclosporin is also being explored for the novel coronavirus disease 2019 (COVID-19) in kidney transplant recipients. This article summarizes the milestones in the development of voclosporin leading to this first approval for lupus nephritis.

Effect of Calcineurin Inhibitors and Mammalian Target of Rapamycin Inhibitors on the Course of COVID-19 in Kidney Transplant Recipients.

Coronavirus disease 19 (COVID-19) has been an ongoing pandemic since December 2019. Unfortunately, kidney transplant recipients are a high-risk group during the disease course, and scientific data are still limited in this patient group. Beyond the dosage of immunosuppressive drugs, pharmacological immunosuppression may also alter the infection response in the COVID-19 course. The effects of immunosuppressive agents on the development and process of infection should not be decided only by determining how potent they are and how much they suppress the immune system; it is also thought that the direct effect of the virus, increased oxidative stress, and cytokine storm play a role in the pathogenesis of COVID-19 disease. There are data about immunosuppressive drugs like calcineurin inhibitors (CNI) or mammalian target of rapamycin inhibitors (mTORi) therapy related to their beneficial effects during any infection course. Limited data suggest that the use of CNI or mTORi may have beneficial effects on the process. In this hypothetical review, the probable impacts of CNI and mTORi on the pathogenesis of the COVID-19 were investigated.

Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients.

BACKGROUND & AIMS: The incidence and outcomes of coronavirus disease 2019 (COVID-19) in immunocompromised patients are a matter of debate. METHODS: We performed a prospective nationwide study including a consecutive cohort of liver transplant patients with COVID-19 recruited during the Spanish outbreak from 28 February to 7 April, 2020. The primary outcome was severe COVID-19, defined as the need for mechanical ventilation, intensive care, and/or death. Age- and gender-standardised incidence and mortality ratios (SIR and SMR) were calculated using data from the Ministry of Health and the Spanish liver transplant registry. Independent predictors of severe COVID-19 among hospitalised patients were analysed using multivariate Cox regression. RESULTS: A total of 111 liver transplant patients were diagnosed with COVID-19 (SIR = 191.2 [95% CI 190.3-192.2]). The epidemiological curve and geographic distribution overlapped widely between the liver transplant and general populations. After a median follow-up of 23 days, 96 patients (86.5%) were admitted to hospital and 22 patients (19.8%) required respiratory support. A total of 12 patients were admitted to the ICU (10.8%). The mortality rate was 18%, which was lower than in the matched general population (SMR = 95.5 [95% CI 94.2-96.8]). Overall, 35 patients (31.5%) met criteria of severe COVID-19. Baseline immunosuppression containing mycophenolate was an independent predictor of severe COVID-19 (relative risk = 3.94; 95% CI 1.59-9.74; p = 0.003), particularly at doses higher than 1,000 mg/day (p = 0.003). This deleterious effect was not observed with calcineurin inhibitors or everolimus and complete immunosuppression withdrawal showed no benefit. CONCLUSIONS: Being chronically immunosuppressed, liver transplant patients have an increased risk of acquiring COVID-19 but their mortality rates are lower than the matched general population. Upon hospital admission, mycophenolate dose reduction or withdrawal could help in preventing severe COVID-19. However, complete immunosuppression withdrawal should be discouraged. LAY SUMMARY: In liver transplant patients, chronic immunosuppression increases the risk of acquiring COVID-19 but it could reduce disease severity. Complete immunosuppression withdrawal may not be justified. However, mycophenolate withdrawal or temporary conversion to calcineurin inhibitors or everolimus until disease resolution could be beneficial in hospitalised patients.

Pharmacotherapeutic considerations in solid organ transplant patients with COVID-19.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide. While there are presently a few case reports/series on COVID-19 amongst solid organ transplant (SOT) patients, there is no official guideline for the management of SOT patients. AREAS COVERED: The authors discuss the pharmacotherapeutic management of SOT patients during the COVID-19 outbreak and provide their expert perspectives. EXPERT OPINION: Prophylactic reduction of immunosuppression because of fear of COVID-19 is not suggested in SOT patients. With maintenance immunosuppressive regimens, corticosteroids can be continued during COVID-19. Continuing other immunosuppressive drugs with lowest effective dose/blood concentration is suggested for patients with mild to moderate COVID-19. Discontinuation of antimetabolites and perhaps inhibitors of mammalian target of rapamycin (mTOR) is suggested in moderate to severe COVID-19. Calcineurin inhibitors (CNIs) may be continued or substituted for mTOR inhibitors with lowest therapeutic concentrations in moderate to severe COVID-19. If continued in patients with COVID-19, therapeutic drug monitoring of CNIs/mTOR inhibitors and appropriate dose reduction is recommended in co-administration with protease inhibitors, hydroxychloroquine/chloroquine, or interleukin (IL)-1/IL-6 receptor antagonists. Complete blood count monitoring is recommended in patients who continue taking antimetabolites or mTOR inhibitors. Dose modification/avoidance should be considered for chloroquine, atazanavir, oseltamivir, ribavirin, anakinra, and Janus associated kinase inhibitors in patients with organ function impairment.

Liver transplant immunosuppression during the covid-19 pandemic. / Inmunosupresión en el trasplante hepático en la era covid-19.

SARS-CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS-CoV-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on SARS-CoV-2 infection, and suggests guidelines for the management of immunosuppression.

Calcineurin inhibitors revisited: A new paradigm for COVID-19?

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can cause mild, moderate or severe disease (COVID-19). In severe disease, there is hyperinflammation causing severe symptoms. Severe COVID-19 is an immunological phenomenon, rather than a direct viral damage disease. Therapies for COVID-19 are all investigational therapies. In case of severe disease, treatment with a calcineurin inhibitor could be promising. In this article we explain the mechanisms of calcineurin inhibitor treatment for COVID-19, based on experiences seen in solid organ transplant recipients who suffered from COVID-19.

Harnessing CAR T-cell Insights to Develop Treatments for Hyperinflammatory Responses in Patients with COVID-19.

Cytokine release and macrophage activation contribute to immunopathology after SARS-CoV-2 infection. We discuss approaches to decrease the morbidity and mortality in patients with COVID-19 by repurposing existing drugs previously developed for cancer therapy.

Two distinct cases with COVID-19 in kidney transplant recipients.

The fatality of novel coronavirus disease 2019 (COVID-19) is precipitously increased in patients with underlying comorbidities or elderly people. Kidney transplant (KT) recipients are one of the vulnerable populations for infection. COVID-19 infection in KT recipients might be a complicated and awkward situation, but there has been a lack of reports concerning this group. Herein, we demonstrated two distinct cases with different clinical progress. The first case was a 36-year-old man who underwent KT 3 years ago. He was diagnosed with COVID-19 expressing relevant symptoms. Following administration of lopinavir/ritonavir and hydroxychloroquine with reduced immunosuppressant, he recovered from COVID-19. However, the unexpected fluctuations in tacrolimus trough levels needed to be managed because of drug-to-drug interaction. The second case was developed in a 56-year-old man without any symptoms. He received a second KT from an ABO-incompatible donor 8 years ago. He was diagnosed with COVID-19 by screening due to exposure history. During the hospitalization period, the chest infiltrative lesion showed a wax and wane, but he successfully recovered by administration of hydroxychloroquine with azithromycin. These apparently different cases suggest that assertive screening and management could improve the clinical course. In addition, antiviral agents should be used cautiously, especially in patients on calcineurin inhibitors.